WO2017028797A1 - 取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体及其药用组合物和应用 - Google Patents

取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体及其药用组合物和应用 Download PDF

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WO2017028797A1
WO2017028797A1 PCT/CN2016/095813 CN2016095813W WO2017028797A1 WO 2017028797 A1 WO2017028797 A1 WO 2017028797A1 CN 2016095813 W CN2016095813 W CN 2016095813W WO 2017028797 A1 WO2017028797 A1 WO 2017028797A1
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oxy
phenyl
substituted
carboxamide
dihydroquinoline
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PCT/CN2016/095813
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English (en)
French (fr)
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丁克
耿美玉
谈理
丁健
张章
艾菁
任小梅
高冬林
涂正超
陆小云
张冬梅
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暨南大学
中国科学院上海药物研究所
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Application filed by 暨南大学, 中国科学院上海药物研究所 filed Critical 暨南大学
Priority to JP2018509619A priority Critical patent/JP6530857B2/ja
Priority to AU2016309833A priority patent/AU2016309833B2/en
Priority to KR1020187007648A priority patent/KR102237707B1/ko
Priority to ES16836661T priority patent/ES2873515T3/es
Priority to EP16836661.5A priority patent/EP3339294B1/en
Priority to CN201680058335.6A priority patent/CN108473434B/zh
Priority to US15/752,896 priority patent/US10683278B2/en
Priority to DK16836661.5T priority patent/DK3339294T3/da
Publication of WO2017028797A1 publication Critical patent/WO2017028797A1/zh
Priority to IL257481A priority patent/IL257481B/en

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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
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Definitions

  • the invention belongs to the technical field of chemical medicine, and particularly relates to a substituted quinolone derivative or a pharmaceutically acceptable salt thereof or a stereoisomer or a prodrug molecule thereof and a pharmaceutical composition thereof, and an application thereof in preparing a medicament for controlling tumors, in particular
  • the derivatives, salts, stereoisomers, prodrug molecules and pharmaceutical compositions thereof of the present invention can be used as protein kinase inhibitors, effectively inhibit the activity of AXL protein kinase and inhibit proliferation, migration and invasion of various tumor cells.
  • AXL is a class of receptor tyrosine kinases belonging to the TAM receptor tyrosine kinase family, which also includes two other members: Mer and Tyro3. TAM was first discovered in tumor cells, and its overexpression and ectopic expression are closely related to immune regulation, tumor proliferation, growth and migration. AXL was isolated from chronic myeloid leukemia patients and chronic myeloproliferative diseases in 1988. AXL is widely expressed in tissues such as the brain, immune cells, platelets, endothelial cells, skeletal muscle, heart, liver and kidney.
  • the vitamin K-dependent protein kinase Gas6 (growth arrest-specific 6) is the most widely studied AXL ligand, and other ligands of the TAM family include Protein S, Tubby, Tulp-1, and Galectin-3.
  • the TAMs family has a similar protein structure, consisting mainly of three parts: the extracellular domain, the transmembrane domain, and the intracellular domain.
  • the extracellular domain includes two N-terminal immunoglobulin-like regions Ig, and two fibronectin III repeats (FNIII). .
  • Gas6 binds to the extracellular domain of AXL to induce AXL dimerization, triggering trans-autophosphorylation in the intracellular domain, thereby activating intracellular signaling pathways and regulating a range of physiological activities.
  • AXL can also be activated in a ligand-independent manner. AXL is involved in the adhesion and immunoregulation of normal cells. It has been found that overexpression of AXL is present in a variety of tumor cells.
  • the signaling pathway regulated by Gas6/AXL is closely related to the occurrence and development of various tumors, such as chronic myeloid leukemia.
  • AXL is an effective target for targeted tumor therapy.
  • Bosutinib (SKI606, PF5208763, Bosulif; Pfizer, 2012), Cabozantinib (XL184, Cometriq; Exelixis, 2012), Sunitinib (SU11248, Sutent; Pfizer, 2006) and other marketed drugs, although having AXL activity, are multi-target drugs.
  • BGB324 (R428; Rigel Pharmaceuticals, BergenBio) is currently the most specific AXL small molecule inhibitor, and is in the first phase of clinical research. In December 2014, the FDA granted BGB324 the title of AML orphan drug. Currently, no small molecule inhibitors against AXL kinase have been marketed.
  • Another object of the present invention is to provide a pharmaceutical composition based on the above substituted quinolone derivative or a pharmaceutically acceptable salt or stereoisomer thereof.
  • Still another object of the present invention is to provide the use of the above substituted quinolone derivative or a pharmaceutically acceptable salt or stereoisomer thereof.
  • a further object of the present invention is to provide the use of the above pharmaceutical compositions.
  • X is selected from: CH or N;
  • R 1 is selected from: hydrogen or halogen
  • R 2 is selected from: R 9 is optionally selected from the group consisting of hydrogen, C 1 -C 5 alkyl or C 3 -C 6 cycloalkyl;
  • B is selected from: an aryl group, a heteroaryl group, a monocyclic or polycyclic alkyl group;
  • R 3 is optionally selected from the group consisting of hydrogen, halogen, trifluoromethyl or C 1 -C 3 alkyl;
  • R 4 is optionally selected from the group consisting of hydrogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, substituted or unsubstituted phenyl;
  • R 5 is optionally selected from the group consisting of: hydrogen, -(CH 2 ) r -COOR 22 , -(CH 2 ) r -NR 23 R 24 , -L-heteroaryl or
  • R 5 , r, s 1 , s 2 , s 3 are each independently selected from 0, 1, 2 or 3;
  • V is selected from: CH or N;
  • U is selected from: O, S, CR 23 R 24 or NR 23 ;
  • R 22 is optionally selected from the group consisting of: hydrogen or C 1 -C 4 alkyl
  • L is selected from: C 1 -C 3 alkyl, -NR 25 -, -NR 25 CO-, -CONR 25 -, -O-, -CO-, -SO- or -SO 2 -;
  • R 25 is selected from : C 1 - C 3 alkyl;
  • R 6 is optionally selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 1 -C 5 alkane Oxy, trifluoromethyl or trifluoromethoxy;
  • R 7 is optionally selected from the group consisting of hydrogen, C 1 -C 5 alkyl or C 3 -C 6 cycloalkyl;
  • R 8 is hydrogen
  • R 7 , R 8 and C, D ring constitute a 5- to 7-membered fatty naphthenic ring with or without a hetero atom
  • n 0 to 2; W is selected from CH 2 or O; and R 10 is selected from H or CH 3 .
  • the 5- to 6-membered substituted heterocyclic ring is preferably one of the following structures:
  • X is CH 2 or N
  • R 11 is optionally selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy or isopropoxy;
  • R 19 and R 20 are the same or differently selected from: hydrogen, halogen, C 1 -C 6 alkyl; or R 19 and R 20 constitute a saturated or unsaturated 5- to 8-membered heterocyclic group;
  • R 12 and R 13 constitute a substituted or unsubstituted C 5 -C 18 aliphatic cycloalkyl group having 1 to 4 hetero atoms.
  • the R 4 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclo Pentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropoxy or
  • R 21 is selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 5 alkyl.
  • the R 5 is selected from the group consisting of hydrogen,
  • said R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl , propenyl, isopropenyl, butenyl, pentenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, methoxy, Ethoxy, propoxy, isopropoxy, trifluoromethyl or trifluoromethoxy.
  • R 7 is preferably selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the ternary ring is preferably one of the following structures:
  • the substituted quinolone derivative of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof preferably has the structure shown below:
  • n 0 to 2
  • W is CH 2 or O
  • X is selected from: CH or N;
  • R 1 is selected from: hydrogen or halogen
  • R 2 is selected from: R 9 is optionally selected from the group consisting of hydrogen, C 1 -C 5 alkyl or C 3 -C 6 cycloalkyl;
  • R 3 is optionally selected from the group consisting of hydrogen, halogen, trifluoromethyl or C 1 -C 3 alkyl;
  • R 4 is optionally selected from the group consisting of hydrogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 3 alkoxy, substituted or unsubstituted phenyl;
  • R 5 is optionally selected from the group consisting of: hydrogen, -(CH 2 ) r -COOR 22 , -(CH 2 ) r -NR 23 R 24 , -L-heteroaryl or
  • R 5 , r, s 1 , s 2 , s 3 are each independently selected from 0, 1, 2 or 3;
  • V is selected from: CH or N;
  • U is selected from: O, S, CR 23 R 24 or NR 23 ;
  • R 22 is optionally selected from the group consisting of: hydrogen or C 1 -C 4 alkyl
  • L is selected from: C 1 -C 3 alkyl, -NR 25 -, -NR 25 CO-, -CONR 25 -, -O-, -CO-, -SO- or -SO 2 -;
  • R 25 is selected from : C 1 - C 3 alkyl;
  • R 6 is optionally selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl, C 2 -C 6 alkenyl, C 3 -C 6 cycloalkyl, C 4 -C 6 cycloalkenyl, C 1 -C 5 alkane Oxy, trifluoromethyl or trifluoromethoxy;
  • R 7 is optionally selected from the group consisting of hydrogen, C 1 -C 5 alkyl or C 3 -C 6 cycloalkyl;
  • R 7 and C and D rings form a ternary ring
  • R 10 is selected from H or CH 3 .
  • the ternary ring is preferably one of the following structures:
  • R 5 and R 6 are the same as before.
  • the substituted quinolone derivative or a pharmaceutically acceptable salt or stereoisomer thereof according to the present invention has one of the structures represented by the formulae (II) to (IX), preferably:
  • R 4 is optionally selected from the group consisting of hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, Methoxy, ethoxy, propoxy, isopropoxy,
  • R 21 is selected from the group consisting of hydrogen, halogen, C 1 -C 5 alkyl, C 3 -C 6 cycloalkyl or C 1 -C 5 alkyl;
  • R 5 is selected from: hydrogen
  • R 6 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, propenyl, isopropene Base, butenyl, pentenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, methoxy, ethoxy, propoxy Base, isopropoxy, trifluoromethyl or trifluoromethoxy.
  • the substituted quinolone derivative of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof preferably has a structure of the formula III, V, VII, IX, that is, the E and A ring components are substituted by 5 to 6 members.
  • the heterocyclic ring is preferably the following structure:
  • R 11 is optionally selected from the group consisting of hydrogen, halogen, methyl, ethyl, propyl, isopropyl, cyclopropyl, methoxy, ethoxy, propoxy or isopropoxy;
  • R 19 and R 20 are the same or differently selected from: hydrogen, halogen, C 1 -C 6 alkyl; or R 19 and R 20 constitute a saturated or unsaturated 5- to 8-membered heterocyclic group;
  • R 12 and R 13 constitute a substituted or unsubstituted C 5 -C 18 aliphatic cycloalkyl group having 1 to 4 hetero atoms.
  • the substituted quinolone derivative of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof is preferably one of the following compounds:
  • the present invention also provides a pharmaceutical composition for treating a tumor based on the above substituted quinolone derivative of the present invention or a pharmaceutically acceptable salt or stereoisomer thereof, the pharmaceutical composition comprising the above substitution A quinolone derivative, a pharmaceutically acceptable salt thereof, a stereoisomer or a prodrug molecule thereof, and a pharmaceutically acceptable carrier.
  • the substituted quinolone derivative of the present invention or a pharmaceutically acceptable salt thereof, a prodrug molecule, or a pharmaceutical composition thereof can be used for the preparation of a medicament for controlling tumors.
  • a medicament for controlling tumors In particular, it is used for the preparation of hematological tumors such as leukemia, gastrointestinal stromal tumors, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer,
  • a drug for transitional proliferative diseases such as liver cancer, skin cancer, epithelial cell carcinoma, and nasopharyngeal cancer.
  • the substituted quinolone derivative of the present invention or a pharmaceutically acceptable salt thereof, a prodrug molecule or a pharmaceutical composition thereof can effectively inhibit the action of protein kinases such as AXL, and can inhibit proliferation, migration and invasion of various tumor cells, and can be used.
  • protein kinases such as AXL
  • the compounds and pharmaceutically acceptable salts thereof of the present application are useful in the manufacture of a medicament for the treatment of hyperproliferative diseases such as tumors in humans and other mammals.
  • Figure 1 is a graph showing the effect of quinolone derivatives on AXL kinase phosphorylation in MDA-MB-231 cells.
  • Figure 2 is a graph showing the effect of quinolone derivatives on AXL kinase phosphorylation in A549 cells.
  • Figure 3 is a graph showing the effect of quinolone derivatives on cell morphology and protein expression during TMT- ⁇ 1-induced MMT in MDA-MB-231 cells.
  • Figure 4 is a graph showing the effect of quinolone derivatives on cell morphology and protein expression during TMT- ⁇ 1-induced MMT in MDA-MB-231 cells.
  • Figure 5 is a graph showing the effect of quinolone derivatives on migration and invasion of MDA-MB-231 cells.
  • Figure 6 is a graph showing the effect of quinolone derivatives on migration and invasion of MDA-MB-231 cells.
  • Figure 7 is a diagram showing the effect of quinolone derivative 4T1 transplanted tumor in vivo.
  • any variable e.g. R 1, R, etc.
  • any variable e.g. R 1, R, etc.
  • combinations of substituents and variables are allowed as long as such combinations stabilize the compound.
  • a line drawn from a substituent into the ring system means that the bond referred to can be attached to any ring atom that can be substituted. If the ring system is polycyclic, it means that the bond is only attached to any suitable carbon atom adjacent to the ring. It will be understood that one of ordinary skill in the art can select the substituents and substitution patterns of the compounds of the invention to provide chemical stability. Compounds which are readily synthesized from readily available starting materials by the techniques of the art and the methods set forth below. If the substituent itself is substituted by more than one group, it is understood that these groups may be on the same carbon atom or on different carbon atoms as long as the structure is stabilized.
  • alkyl as used herein is meant to include branched and straight chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms.
  • the definition of "C 1 -C 5 " in "C 1 -C 5 alkyl” includes a group having 1, 2, 3, 4 or 5 carbon atoms arranged in a straight chain or a branched chain.
  • “C 1 -C 5 alkyl” specifically includes methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, pentyl.
  • cycloalkyl refers to a monocyclic saturated aliphatic hydrocarbon group having the specified number of carbon atoms.
  • cycloalkyl includes cyclopropyl, methyl-cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • heteroaryl denotes a stable monocyclic ring of up to 5 atoms in the ring or up to 5 atoms of a bicyclic carbocyclic ring in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 selected from Heteroatoms of O, N and S.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, imidazolyl, pyrazolyl, furyl, thienyl, oxazolyl, isoxazolyl, pyrazinyl, pyridyl, pyrimidinyl, pyrrolyl.
  • Heteroaryl is also understood to include any N-oxide derivative of a nitrogen-containing heteroaryl group for the definition of the following heteroaryl.
  • the heteroaryl substituent is bicyclic and contains a ring which is non-aromatic or contains no heteroatoms, it is understood that each is attached via an aromatic ring or via a heteroatom-containing ring.
  • heterocycle refers to a 5- to 6-membered aromatic or non-aromatic heterocyclic ring containing from 1 to 4 heteroatoms selected from O, N and S, and includes a bicyclic group. group.
  • heterocyclyl thus includes the heteroaryl groups mentioned above, as well as the dihydrogenated and tetrahydrogenated analogs thereof.
  • heterocyclyl examples include, but are not limited to, imidazolyl, thiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, oxetanyl, pyranyl, pyrazinyl , pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinoxalinyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl, oxazolyl.
  • the attachment of a heterocyclic substituent can be achieved by a carbon atom or by a hetero atom.
  • halo or halogen as used herein is meant to include chloro, fluoro, bromo and iodo.
  • alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl substituents may be unsubstituted or substituted.
  • (C 1 -C 6 )alkyl may be selected from one, two or three selected from OH, halogen, nitro, cyano, alkoxy, dialkylamino or heterocyclic groups such as morpholinyl, piperidine Substituents such as pyridine are substituted.
  • the present invention includes free forms of the compounds of Formulas I-IX, as well as pharmaceutically acceptable salts and stereoisomers thereof.
  • Some specific exemplary compounds herein are protonated salts of amine compounds.
  • the term "free form” refers to an amine compound in a non-salt form.
  • the pharmaceutically acceptable salts included include not only exemplary salts of the particular compounds described herein, but also all typical pharmaceutically acceptable salts of the free forms of the compounds of formula I.
  • the free form of the particular salt of the compound can be isolated using techniques known in the art.
  • the free form can be regenerated by treating the salt with a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • a suitable dilute aqueous base such as a dilute aqueous solution of NaOH, a dilute aqueous solution of potassium carbonate, dilute aqueous ammonia, and a dilute aqueous solution of sodium bicarbonate.
  • the free form differs somewhat from its respective salt form in solubility in certain physical properties, such as in polar solvents, but for purposes of the invention such acid and base salts are otherwise pharmaceutically equivalent to their respective free forms.
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of the present invention containing a basic moiety or an acidic moiety by conventional chemical methods.
  • the salt of the basic compound is prepared by ion exchange chromatography or by reaction of the free base with a stoichiometric or excess amount of the desired salt or mixture of the inorganic or organic acid in a suitable solvent or combination of solvents.
  • a salt of an acidic compound is formed by reaction with a suitable inorganic or organic base.
  • pharmaceutically acceptable salts of the compounds of the invention include the conventional non-toxic salts of the compounds of the invention which are formed by the reaction of a basic compound of the invention with an inorganic or organic acid.
  • conventional non-toxic salts include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and the like, and also include organic acids such as acetic acid, propionic acid, succinic acid, glycolic acid, and hard.
  • Fatty acid lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, pamoic acid, maleic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, p-aminobenzenesulfonic acid, 2-acetyl A salt prepared from oxy-benzoic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, ethanedisulfonic acid, oxalic acid, isethionic acid, trifluoroacetic acid or the like.
  • a suitable "pharmaceutically acceptable salt” refers to a salt prepared by pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
  • Salts derived from inorganic bases include aluminum salts, ammonium salts. Salt, calcium salt, copper salt, iron salt, ferrous salt, lithium salt, magnesium salt, manganese salt, manganese salt, potassium salt, sodium salt, zinc salt and the like. Ammonium salts, calcium salts, magnesium salts, potassium salts and sodium salts are particularly preferred.
  • a salt derived from a pharmaceutically acceptable organic non-toxic base comprising a salt of a primary, secondary and tertiary amine, the substituted amine comprising a naturally occurring substituted amine, a cyclic amine and a basic ion exchange resin such as a fine Amino acid, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, aminoethanol, ethanolamine, B Diamine, N-ethylmorpholine, N-ethylpiperidine, glucosamine, glucosamine, histidine, hydroxycobalamin, isopropylamine, lysine, methylglucamine, morpholine, piperazine , piperidine, guanidine, polyamine resin, procaine, guanidine, theobromine, triethylamine, trimethylamine, tripropylamine, t
  • the acidic moiety such as a carboxyl group
  • a cationic moiety such as tetravalent
  • the compounds of the invention are potential internal salts or zwitterions.
  • the compounds of the invention can be prepared using the reactions as shown in the scheme below. Accordingly, the following illustrative schemes are for illustrative purposes and are not limited to the listed compounds or any particular substituents. The number of substituents shown in the scheme does not necessarily have to correspond to the number used in the claims, and for the sake of clarity, it is shown that the mono-substituent is attached to a compound which allows multiple substituents under the definition of formula (I) above.
  • the compound of formula (I) as shown in Scheme A can be synthesized from 4-chloropyrrolopyrimidine as a starting material by an 8-step reaction.
  • the present application provides a method of treating a hyperproliferative disease or condition, such as a tumor in a human or other mammal, using a compound of formula (I) and a pharmaceutically acceptable salt thereof.
  • the compounds designed herein and pharmaceutically acceptable salts thereof can be used in the preparation of a therapeutic or control gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma , drugs for hyperproliferative diseases such as lung squamous cell carcinoma, pancreatic cancer, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, prostate cancer, nasopharyngeal cancer, and leukemia.
  • the compounds designed herein and pharmaceutically acceptable salts thereof can be used with estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators currently in use or at the stage of development.
  • Drugs and apoptosis inducers that interfere with cell cycle checkpoints, cytotoxic drugs, tyrosine protein inhibitors, EGFR inhibitors, VEGFR inhibitors, serine/threonine protein inhibitors, Bcr-Abl inhibitors, c -Kit inhibitor, Met inhibitor, Raf inhibitor, MEK inhibitor, MMP inhibitor, topoisomerase inhibitor, histidine deacetylase inhibitor, proteasome inhibitor, CDK inhibitor, Bcl-2 Family protein inhibitors, MDM2 family protein inhibitors, IAP
  • the compound having the structure of the formula (I) and a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof according to the present application can be used for the preparation of a medicament for the prevention and treatment of the following diseases and other diseases not listed below:
  • Respiratory cancers in humans or other mammals including but not limited to small cell & non-small cell lung cancer, as well as bronchial adenomas and pleural pulmonary blastomas.
  • Brain cancer in humans or other mammals including but not limited to brain stem and sub-glial glioma, cerebellum and cerebral astrocytoma, ependymoma, and neuroectoderm and pineal tumor.
  • tumors of male and female reproductive organs of humans or other mammals include, but are not limited to, prostate and testicular cancer; tumors of female reproductive organs include, but are not limited to, endometrial cancer, cervical cancer, ovarian cancer , vaginal cancer and vulvar cancer as well as intrauterine tumors.
  • Tumors of the digestive tract of human or other mammals including but not limited to anal cancer, colon cancer, colonic straight cancer, esophageal cancer, gastric cancer, pancreatic cancer, rectal cancer, small intestine cancer or salivary gland cancer.
  • Tumors of the urethra of a human or other mammal including but not limited to bladder cancer, penile cancer, renal cancer, renal pelvic cancer, ureteral cancer or urethral cancer.
  • Eye cancer in humans or other mammals including but not limited to intraocular melanoma and retinoblastoma.
  • Liver cancer of a human or other mammal including but not limited to hepatoma (stem cell carcinoma with or without fibril changes), cholangiocarcinoma (intrahepatic cholangiocarcinoma), and mixed hepatocellular cholangiocarcinoma.
  • Skin cancer of human or other mammals including, but not limited to, squamous cell carcinoma, Kaposi's sarcoma, malignant melanoma, Merck's cell skin cancer, and non-melanoma cell carcinoma.
  • Head and neck cancer in humans or other mammals including, but not limited to, larynx, hypopharynx, nasopharynx, oropharyngeal cancer, and lip and oral cancer.
  • Lymphoma of human or other mammals including but not limited to AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Hodgson's disease, and central nervous system lymphoma.
  • Sarcomas of human or other mammals including but not limited to soft tissue sarcoma, osteosarcoma, malignant fibrous histiocytoma, sarcoma and rhabdomyosarcoma.
  • Leukemia in humans or other mammals including but not limited to acute myeloid leukemia, acute forest cell leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • the compounds of the invention may be administered to a mammal, preferably a human, alone or in a pharmaceutical composition, in combination with a pharmaceutically acceptable receptor, adjuvant or diluent, according to standard pharmaceutical techniques.
  • the compound can be administered orally or subcutaneously, intramuscularly, intraperitoneally, intravenously, rectally and topically, ocularly, pulmonaryly, nasally, or parenterally.
  • the use of a compound of formula (I) for the preparation of a medicament for treating or controlling a patient, such as cancer is administered at a dose ranging from 0.1 to 500 mg/day/kg body weight.
  • a suitable mode of administration is daily single dose administration or multiple administrations twice, three times, four times a day, or by sustained release techniques.
  • preferred dosages range from 0.1 to 1500 mg/day/kg body weight, preferably from 0.5 to 100 mg/day/kg body weight.
  • the daily dose is 1 to 500 mg.
  • the daily dose for adult patients can be as low as 0.1 mg/day.
  • Metabolites of the compounds and pharmaceutically acceptable salts thereof, and prodrugs which can be converted in vivo to the structures of the compounds and pharmaceutically acceptable salts thereof, are also included in the claims of the present application. in.
  • the compounds of formula (I) may be combined with other agents known to treat or ameliorate similar conditions.
  • the mode of administration & dosage of the original drug remains unchanged, while the compound of formula (I) is administered simultaneously or subsequently.
  • the compound of the formula (I) is administered simultaneously with one or more other drugs, it is preferred to use a pharmaceutical composition containing both one or several known drugs and a compound of the formula (I).
  • Combination of drugs also includes the administration of a compound of formula (I) with one or more other known drugs over an overlapping period of time.
  • the dose of the compound of formula (I) or a known drug may be lower than when they are administered alone.
  • Drugs or active ingredients which may be combined with a compound of formula (I) include, but are not limited to:
  • the pharmaceutical or active ingredient that can be administered in combination with a compound of formula (I) includes, but is not limited to, leucine, alendronate, interferon, atraxine, allopurinol, Sodium decylate, palonosetron hydrochloride, hexamethylene melamine, aminoglutamine, amifostine, amrubicin, amsacrine, anastrozole, dolasetron, aranesp, arglabin, Arsenic trioxide, anoxin, 5-azacytidine, azathioprine, BCG or tici BCG, betahidine, betamethasone acetate, betamethasone sodium phosphate, bexarotene, bleomycin sulfate, bromine Gan, bortezomib, busulfan, calcitonin, alemzumab injection, capecitabine, carboplatin, constance, cefesone, simmein, daunorubicin, chlor
  • Step a2 Preparation of 1,6-dimethyl-1H-benzo[d][1,3]oxazine-2,4-dione (Compound 2)
  • Step a3 Preparation of methyl 1,2,6-trimethyl-4-oxy-1,4-dihydroquinoline-3-carboxylate (Compound 3)
  • Step a4 Preparation of 1,2,6-trimethyl-4-oxy-1,4-dihydroquinoline-3-carboxylic acid (Compound 4)
  • Step b1 Preparation of 4-(2-fluoro-4-nitrophenoxy)-7H-pyrrole [2,3,-d]pyrimidine (Compound 5)
  • Step b2 Preparation of 4-(2-fluoro-4-nitrophenoxy)-5-iodo-7H-pyrrole[2,3-d]pyrimidine (Compound 6)
  • Step b3 4-(2-Fluoro-4-nitrophenoxy)-5-iodo-7((2-trimethylsilyl)ethoxy)methyl)-7H-pyrrole [2,3- Preparation of d]pyrimidine (Compound 7)
  • Step b4 4-(2-Fluoro-4-nitrophenoxy)-5-phenyl-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole [2 , 3-d] pyrimidine (compound 8) preparation
  • Step b5 3-Fluoro-4-(5-phenyl--7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3-d]pyrimidine-4 Preparation of -substituted)oxy)aniline (Compound 9)
  • Step b6 N-(3-Fluoro-4-((5-phenyl-7-((2-trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3-d]pyrimidine Preparation of -4-substituted)oxy)phenyl) 1,2,6-trimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 10)
  • Step b7 N-(3-Fluoro-4-((7-(hydroxymethyl))-5-phenyl)-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl) Preparation of 1,2,6-trimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 11)
  • Step b8 N-(3-Fluoro-4-((phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)1,2,6-trimethyl-4 Of oxy-1,4-dihydroquinoline-3-carboxamide (Compound 12, TL50115)
  • Example 12 6-Chloro-N-(3-fluoro-4-((3-phenyl-1H-pyrrole[2,3-b]pyridine-4-substituted)oxy)phenyl)-1,2 -Preparation of dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL50128)
  • Example 13 6-Bromo-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-1,2 -Preparation of dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL50133)
  • Example 15 N-(3-Fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-6-methoxy-1, Preparation of 2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL4800005)
  • Example 17 1-ethyl-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-2, Preparation of 6-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL4800067)
  • Example 18 N-(3-Fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-2,6-dimethyl -4-oxy-1-propyl-1,4- Preparation of dihydroquinoline-3-carboxamide (designated TL4800104)
  • Example 19 1-butyl-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-2, Preparation of 6-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL4800080)
  • Example 20 2-ethyl-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-1, Preparation of 6-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL4800139)
  • Example 22 9-Fluoro-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-3-methyl -10-(4-methylpiperazine-1-substituted)-7-oxy-3,7-dihydro-[1,4]oxazo[2,3,4-ij]quinoline-6 Preparation of Formamide (named TL4800088)
  • Example 23 1-Cyclopropyl-6-fluoro-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)benzene Preparation of -4-oxy-7-(piperazin-1-substituted)-1,4-dihydroquinoline-3-carboxamide (designated TL4800095)
  • Example 24 9-Fluoro-N-(3-fluoro-4-((5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-8- (4-Hydroxypiperidin-1-yl)-5-methyl-1-oxo-1,5,6,7-tetrahydropyrido[3,2,1-ij]quinoline-2-carboxamide Preparation (named GDL5000076)
  • Example 25 6-Ethyl-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-1, Preparation of 2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL4800075)
  • Step c1 2-(1-((4-ethylphenyl)amino)ethylidene)malonate (Compound 13)
  • Step c2 Ethyl 6-ethyl-2-methyl-4-oxy-1,4-dihydroquinoline-3-carboxylate (Compound 14)
  • Step c3 Ethyl 6-ethyl-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxylate (Compound 15)
  • Step c4 6-Ethyl-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxylic acid (Compound 16)
  • Step c5 6-Ethyl-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-1,2 -Dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 17, TL 4800075)
  • Example 33 6-Ethyl-N-(3-fluoro-4-((3-phenyl-1H-pyrrole[2,3-d]pyridine-4-substituted)oxy)phenyl)-1, Preparation of 2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL4800172)
  • Example 34 6-Ethyl-N-(3-fluoro-4-((5-(4-methoxyphenyl)-7H-pyrrole[2,3-d]pyrimidine-4-substituted)oxy) Preparation of phenyl)-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated GDL5000037)
  • Step d1 2-(((4-ethylphenyl)amino)methylene)malonate diethyl ester (Compound 18)
  • Step d2 ethyl 6-ethyl-4-oxy-1,4-dihydroquinoline-3-carboxylate (Compound 19)
  • Step d3 6-ethyl-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-1-yl Benzyloxy-1,4-dihydroquinoline-3-carboxamide (Compound 20, TL4800178)
  • Example 36 N-(3-Fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-9-methyl-1- Preparation of oxy-1,5,6,7-tetrahydropyridine [3,2,1-ij]quinoline-2-carboxamide (designated TL4800160)
  • Methyl 6-bromo-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxylate (1.5 g, 4.85 mmol), 2-propene boronic acid (1.22 g, 7.28 mmol) Pd(PPh 3 ) 4 (280 mg, 0.24 mmol), K 2 CO 3 (1.34 g, 9.7 mmol) was dissolved in 30 mL of dioxane and 5 mL of water and allowed to react at 90 ° C overnight under argon.
  • Step e2 N-(3-Fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-1,2-dimethyl- 4-oxy-6-(propyl-1-alkenyl-2-substituted)-1,4-dihydroquinoline-3-carboxamide (Compound 22, TL50167)
  • Example 41 6-(Cyclopentyl-1-alkenyl-1-substituted)-N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidine-4) Preparation of -substituted)oxy)phenyl)-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL50160)
  • Step f1 ethyl 6-isopropyl-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxylate (Compound 23)
  • Step f2 N-(3-fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-6-isopropyl-1, 2-Dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 24, TL50172)
  • Example 46 3-(3-Fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)carbamoyl-1,2- Preparation of methyl dimethyl-4-oxy-1,4-dihydroquinoline-6-carboxylate (designated TL4800019)
  • Step g1 3-(3-Fluoro-4-((5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)carbamoyl-1,2-di Methyl methyl-4-oxo-1,4-dihydroquinoline-6-carboxylate (Compound 25, TL4800019)
  • Step h1 N-(3-Fluoro-4-((7-methyl-5-phenyl-7H-pyrrole[2,3-d]pyrimidin-4-substituted)oxy)phenyl)-1,2 ,6-Trimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 26, TL50134)
  • Example 48 N-(4-((6,7-Dimethoxyquinazolin-4-substituted)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl Preparation of -4-oxy-1,4-dihydroquinoline-3-carboxamide (designated TL4800191)
  • Methyl 2-amino-4,5-dimethoxybenzoate (Compound 27) (7 g, 33 mmol) was dissolved in 100 mL of DMF and 50 mL of methanol, and to the mixture was added to formamide (10.5 mL, 264 mmol) and sodium methoxide ( 10.69 g, 198 mmol), refluxed overnight.
  • Step j3 4-chloro-6,7-dimethoxyquinazoline (compound 29)
  • Step j4 4-(2-Fluoro-4-nitrophenoxy)-6,7-dimethoxyquinazoline (Compound 30)
  • Step j5 N-(4-((6,7-dimethoxyquinazolin-4-substituted)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl- 4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 31, TL4800191)
  • Example 49 N-(4-((6,7-Dimethoxyquinazolin-4-substituted)oxy)-3-fluorophenyl)-6-fluoro-1-methyl-7- ( 4-((5-methyl-2-oxo-1,3- Dioxol-4-yl)methyl)piperazin-1-yl)-4-oxo-1,4-dihydro-[1,3]thiazetetane[3,2 -a]Preparation of quinoline-3-carboxamide (designated GDL5000082)
  • Example 50 N-(4-((6,7-Dimethoxyquinazolin-4-substituted)oxy)-3-fluorophenyl)-9-fluoro-8-(4-hydroxypiperidine
  • 1-substituted)-5-methyl-1-oxy-1,5,6,7-tetrahydropyrrole [3,2,2-ij]quinoline-2-carboxamide designated TL4830031
  • Example 53 N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-6,8-difluoro-1-(2- Preparation of fluoroethyl)-7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated TL4830040)
  • Example 54 N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-6-fluoro-1-(4-fluorophenyl) Preparation of 4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (designated TL4830042)
  • Example 55 5-Amino-1-cyclopropyl-N-(4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-7- Preparation of (3,5-dimethylpiperazin-1-yl)-6,8-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated TL4830044)
  • Example 56 1-Cyclopropyl-N-(4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-7-(4-B Preparation of piperazine-1-yl)-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated as GDL5000093)
  • Example 57 7-(3-Aminopyrrolidin-1-yl)-1-(2,4-difluorophenyl)-N-(4-((6,7-dimethoxyquinazoline)- Preparation of 4-yl)oxy)-3-fluorophenyl)-6-fluoro-4-oxo-1,4-dihydro-1,8-naphthyridin-3-carboxamide (designated as GDL5000101)
  • Example 58 N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-1-ethyl-6-fluoro-4-oxo Preparation of 7-(piperazin-1-yl)-1,4-dihydro-1,8-naphthyridin-3-carboxamide (designated GDL5000102)
  • Example 59 1-Cyclopropyl-N-(4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-6-yl-4- Preparation of oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxamide (designated GDL5000110)
  • Example 60 N-(4-((2-Chloropyridine-4-substituted)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy-1 Of 4-dihydroquinoline-3-carboxamide (designated TL4800199)
  • Step J1 4-((2-Chloropyridine-4-substituted)oxy-3-fluoroaniline (Compound 32)
  • Step J2 N-(4-((2-chloropyridin-4-substituted)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy-1, 4-Dihydroquinoline-3-carboxamide (Compound 33, TL4800199)
  • Step k1 4-(4-Amino-2-fluorophenoxy)-N-benzylpyridin-2-amino (Compound 34)
  • Step k2 N-(4-((2-benzylpyridin-4-substituted)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy-1 ,4-dihydroquinoline-3-carboxamide (Compound 35, TL4800200)
  • Example 62 6-Ethyl-N-((3-fluoro-4-((-phenylfluoro[2,3-b]pyridin-4-yl)oxy)phenyl)-1,2-di Preparation of methyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated GDL5000039)
  • Step l4 3-Fluoro-4-((5-phenylfuro[2,3-d]pyrimidin-4-substituted)oxy)aniline (Compound 39)
  • Step l5 6-ethyl-N-((3-fluoro-4-((-phenylfluoro[2,3-b]pyridine-4-substituted)oxy)phenyl)-1,2-dimethyl Benzyloxy-1,4-dihydroquinoline-3-carboxamide (Compound 40, GDL 5000039)
  • Example 63 N-(4-((2-carbamoylpyridin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy -1,4-Dihydroquinoline-3-carboxamide (designated GDL5000045)
  • Step m1 4-((4-Amino-2-fluorophenoxy)pyridamide (Compound 41)
  • 4-amino-2-fluorophenol (2.43 g, 19 mmol, 1.5 eq) was dissolved in 25 mL of DMSO, and t-BuOK (2.3 g, 21 mmol, 1.6 eq) was added at room temperature for 15 min.
  • Pyridine-2-carboxamide (2 g, 13 mmol, 1.0 eq) was heated to 80 ° C for 1 h. Cool to room temperature, add 25 mL of 1 M NaOH solution, 25 mL of water, stir for 5 h, filter, wash with water, and dry to give 2.7 g (85%).
  • Step m2 N-(4-((2-carbamoylpyridin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy- 1,4-Dihydroquinoline-3-carboxamide (Compound 42, GDL 5000045)
  • Example 64 N-(4-((2-Aminopyridin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy-1 Of 4-dihydroquinoline-3-carboxamide (designated GDL5000050)
  • Step n1 N-(4-((2-aminopyridin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy-1, 4-Dihydroquinoline-3-carboxamide (Compound 43, GDL 5000050)
  • N-(4-((2-Aminopyridin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4-oxy-1,4-di dihydroquinoline-3-carboxamide (106mg, 0.22mmol, 1.0eq) was dissolved in DMF 2mL, H 2 O (11mg , 0.60mmol, 2.6eq), pyridine (70mg ,, 0.88mmol, 3.9eq) was added [ Bis(trifluoroacetoxy)iodo]benzene (135 mg, 0.31 mmol, 1.4 eq) was stirred at room temperature for 4 h, then 50 mL of water was stirred for 30 min, filtered, and the residue was purified by column chromatography.
  • Example 65 6-Ethyl-N-(3-fluoro-4-(5-(1-methyl-1H-pyrazole-4-substituted)-7H-pyrrole[2,3-d]pyrimidine- Preparation of 4-substituted)oxy)phenyl)-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (designated GDL5000038)
  • Step o2 4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole[2,3-d]pyrimidine (Compound 45)
  • Step o3 4-chloro-5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrole [ 2,3-d]pyrimidine (compound 46)
  • Step o4 3-fluoro-4-((5-(1-methyl-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-) 7H-pyrrole[2,3-d]pyrimidin-4-yl)oxy)phenylamine (Compound 47)
  • Step o5 6-Ethyl-N-(3-fluoro-4-(5-(1-methyl-1H-pyrazole-4-substituted)-7H-pyrrole[2,3-d]pyrimidine-4 -substituted)oxy)phenyl)-1,2-dimethyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 48, GDL 5000038)
  • Step p1 Methyl 2,6-diethyl-1-methyl-4-oxy-1,4-dihydroquinoline-3-carboxylate (Compound 49)
  • Step p2 2,6-Diethyl-N-(3-fluoro-4-((5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-substituted)oxy)phenyl) -1-methyl-4-oxy-1,4-dihydroquinoline-3-carboxamide (Compound 50, TL4830005)
  • Example 68 N-(4-((2-carbamoyl-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl- Preparation of 4-oxy-1,4-dihydroquinoline-3-carboxamide (designated GDL5000056)
  • n-BuLi (2.4 M, 19.5 mL, 31 mol, 1.15 eq) was slowly added dropwise to 2,2,6,6-tetramethylpiperidine (4.4 g, 31 mmol, 1.15 eq) of diethyl ether at -78 °C.
  • a solution of 50 mL after 2 h of reaction, a solution of 3,4-dichloropyridine (4 g, 27 mol, 1.0 eq) in diethyl ether (5 mL) was added dropwise to the reaction solution, and the reaction was continued at -78 ° C for 2 h.
  • Step q2 4-((4-Amino-2-fluorophenoxy)-3-chloropyridine amide (Compound 52)
  • 4-amino-2-fluorophenol (0.93 g, 7.3 mmol, 1.4 eq) was dissolved in 10 mL of DMF, and t-BuOK (0.88 g, 7.8 mmol, 1.6 eq) was added for 30 min at room temperature, and stirred under stirring for 3 min.
  • 4-Dichloro-2-pyridinecarboxamide (1 g, 5.2 mmol, 1.0 eq), heated to 50 ° C for 3 h. Cooled to room temperature, saturated NaHCO 3 solution, extracted with ethyl acetate, the product by column chromatography to give 440mg (30%).
  • Step q3 N-(4-((2-carbamoyl-3-chloropyridin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl-4 -oxy-1,4-dihydroquinoline-3-carboxamide (Compound 53, GDL 5000056)
  • Example 70 N-(3-Fluoro-4-((5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-2,6-dimethyl Preparation of keto-4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide (designated GDL5000083)
  • Oxalyl chloride (2.6 mL, 30.5 mmol, 5.2 eq) was slowly added dropwise to a solution of 2-chloro-5-methyl-benzoic acid (1 g, 5.9 mmol, 1.0 eq) in CH 2 Cl 2 (15 mL) Add one drop of DMF, stir at room temperature overnight, and spin dry.
  • Step r3 Methyl 2,6-dimethyl-4-oxy-1-phenyl-1,4-dihydroquinoline-3-carboxylate (Compound 56)
  • Step r4 2,6-Dimethyl-4-oxy-1-phenyl-1,4-dihydroquinoline-3-carboxylic acid (Compound 57)
  • Step r5 N-(3-Fluoro-4-((5-phenyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy)phenyl)-2,6-dimethyl 4-oxo-1-phenyl-1,4-dihydroquinoline-3-carboxamide (Compound 58, GDL 5000083)
  • Step s1 Preparation of 4-((7-(decyloxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluoroaniline (Compound 59)
  • Step s2 Preparation of 4-(4-amino-2-fluorophenoxy)-6-methoxyquinazolin-7-ol (Compound 60)
  • Step s3 Preparation of 3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-yl)oxy)phenylamine (Compound 61)
  • Step s4 6-ethyl-N-(3-fluoro-4-((6-methoxy-7-(3-morpholinopropoxy)quinazolin-4-substituted)oxy)phenyl Preparation of-1,2-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 62, GDL5000123)
  • Example 72 N-(4-((7-(2-(Dimethylamino)ethoxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluorophenyl)- Preparation of 6-ethyl-1,2-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated GDL5000128)
  • Example 74 6-Ethyl-N-(3-fluoro-4-((6-methoxy-7-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-yl) Preparation of oxy)phenyl)-1,2-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated TL4830058)
  • Example 75 6-Ethyl-N-(3-fluoro-4-((6-methoxy-7-(3-methoxypropoxy)quinazolin-4-yl)oxy)phenyl) Preparation of-1,2-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated TL4830073)
  • Example 76 N-(4-((7-(2-(Dimethylamino)propoxy)-6-methoxyquinazolin-4-yl)oxy)-3-fluorophenyl)- Preparation of 6-ethyl-1,2-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated TL4830076)
  • Example 77 N-(4-((6,7-Dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl Preparation of -7-(4-methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (designated TL4830071)
  • Step t3 2-(1-((3-Bromo-4-ethylphenyl)amino)ethylidene malonate diethyl ester (Compound 65)
  • Step t4 ethyl 7-bromo-6-ethyl-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (Compound 66)
  • Step t5 ethyl 7-bromo-6-ethyl-1,2-dimethyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (Compound 67)
  • Ethyl 7-bromo-6-ethyl-2-methyl-4-oxo-1,4-dihydroquinoline-3-carboxylate (Compound 66, 5.6 g, 17 mmol), K 2 CO 3 , ( 7 g, 51 mmol) was dissolved in 75 mL of DMF and then added with EtOAc (l. The mixture was cooled to room temperature, quenched with water, and a solid was precipitated and washed with water. The solid was extracted with DCM multiple times, and the organic phase was combined and dried to give a white solid 4.5 g (75%).
  • Step t6 6-ethyl-1,2-dimethyl-7-(-4-methylpiperazine-1 substituted)-4-oxo-1,4-1,4-hydroquinoline-3-carboxylic acid Ethyl ester (compound 68)
  • Step t7 6-ethyl-1,2-dimethyl-7-(-4-methylpiperazine-1 substituted)-4-oxo-1,4-1,4-dihydroquinoline-3-carboxylic acid (Compound 69)
  • Step t8 N-(4-((6,7-dimethoxyquinazolin-4-yl)oxy)-3-fluorophenyl)-6-ethyl-1,2-dimethyl- 7-(4-Methylpiperazin-1-yl)-4-oxo-1,4-dihydroquinoline-3-carboxamide (Compound 70, TL4830071)
  • Example 78 IC 50 test of quinolone derivatives against AXL and FLT3 kinase
  • kinase Assay The Z'-LYTE TM technology (fluorescence detection, an enzyme conjugated form, phosphorylated and non-phosphorylated polypeptide susceptibility to proteolytic cleavage difference based), fluorescence resonance energy transfer (FRET) principle, using the Z'-LYTE TM FRET peptide substrate, the second reactive compound to detect kinase activity.
  • FRET fluorescence resonance energy transfer
  • AXL kinase invitrogen, PV4803 was diluted stepwise, then FRET peptide, ATP, and different concentrations of compounds were added. After 1 h of reaction, site specificity was added.
  • the protease recognizes and cleaves the non-phosphorylated FRET peptide, reacts for 1 h, and uses the excitation wavelength of 400 nm to detect absorption at 445 nm and 520 nm. It was concluded that the inhibition rate was positively correlated with the drug concentration, and the relationship between kinase activity and concentration was calculated, and the IC 50 value was calculated. The results are shown in Table 1.
  • TL50025 0.569 TL4800117 0.075 TL4830042 0.038 TL50046 >10 TL4830014 0.105 TL4830044 0.503 TL50053 1.889 TL4830016 1.122 GDL5000093 0.277 TL50054 >10 GDL5000091 0.042 GDL5000101 0.081 TL50080 >10 TL4800147 0.157 GDL5000102 0.064 TL50081 >10 TL4800172 0.0298 GDL5000110 0.020 TL50086 >10 GDL5000037 0.016 TL4800199 >10 TL50087 >10 TL4800178 0.056 TL4800200 >10 TL50090 2.629 TL4800160 0.129 GDL5000039 0.192 TL50121 0.153 TL4830032 0.0265 GDL5000045 4.377 TL50128 0.211 TL4800167 0.152 GDL5000050 0.888 TL50133 3.118 TL50167 0.324 GDL5000038 0.034
  • Example 79 Test for inhibition of FLT3 kinase by quinolone derivatives
  • the compound was centrifuged at 12,000 g for 5 min, and DMSO was added to prepare a 10 -2 M stock solution. After vortexing, the mixture was sonicated for 10 min, and stored at -40 ° C. Compounds were diluted from the stock solution with DMSO to 100 times the concentration tested (DMSO concentration in the system was 1%).
  • the enzyme reaction substrate Poly(Glu, Tyr) 4:1 was diluted with potassium-free PBS (10 mM sodium phosphate buffer, 150 mM NaCl, pH 7.2-7.4) to 20 ⁇ g/mL, 125 ⁇ L/well coated with the enzyme label. The plate was reacted at 37 ° C for 12-16 hours. Discard the liquid in the well. The plate was washed, and the plate was washed three times with T-PBS (0.1% Tween-20 in potassium-free PBS, 200 ⁇ L/well) for 5 minutes each time. The plate was dried in an oven at 37 ° C for 1-2 hours.
  • reaction buffer 50 mM HEPES pH 7.4, 50 mM MgCl 2 , 0.5 mM MnCl 2 , 0.2 mM Na 3 VO 4 , 1 mM DTT
  • 50 ⁇ L of FLT-3 kinase domain recombinant protein diluted in reaction buffer was added to initiate the reaction, and two wells without ATP control wells were required for each experiment.
  • the reaction was carried out for 1 hour at 37 ° C on a shaker (100 rpm). The liquid in the well was discarded and the plate was washed three times with T-PBS.
  • Horseradish peroxidase-labeled goat anti-mouse secondary antibody dilution (antibody diluted 1:2000 with BSA 5 mg/ml T-PBS) was added, 100 ⁇ L/well, and shaken at 37 ° C for 0.5 hour. The liquid in the well was discarded and the plate was washed three times with T-PBS.
  • the inhibition rate of the FLT-3 enzyme activity of the batch compound is shown in Table 2, and most of the compounds have a strong inhibitory effect on the FLT-3 enzyme activity;
  • the positive compound inhibits the activity of FLT-3 enzyme activity and is similar to that reported in the literature.
  • Example 80 Inhibition of proliferation of Molm-13 and MV4-11 cells by quinolone derivatives
  • the compound was centrifuged at 12,000 g for 5 min, and DMSO was added to prepare a 10 -2 M stock solution. After vortexing, the mixture was sonicated for 10 min, and stored at -40 ° C. During the test, the compound was diluted from the stock solution with physiological saline to 10 times the concentration tested (the concentration of DMSO in the system did not exceed 0.5%).
  • the inhibitory effect of the compound on proliferation of MV4-11 cells was detected by CCK-8 Cell Counting Kit (Dojindo).
  • the specific steps are as follows: MV4-11 cells in logarithmic growth phase were inoculated into 96-well culture plates at a suitable density, 90 ⁇ L per well, and cultured overnight, different concentrations of compounds were added for 72 hr, and the solvent control group was set (negative control). ). After the compound was treated for 72h, the effect of the compound on cell proliferation was detected by CCK-8 cell counting kit (Dojindo). Add 10 ⁇ L of CCK-8 reagent to each well and place in a 37 ° C incubator for 2-4 hours. The full-wavelength microplate reader SpectraMax 190 reads at a wavelength of 450 nm.
  • the inhibition rate (%) of the compound on tumor cell growth was calculated by the following formula:
  • Inhibition rate (%) (OD control well-OD administration well) / OD control well ⁇ 100%
  • IC 50 values were obtained by four-parameter regression using software attached to the microplate reader.
  • Example 81 Effect of quinolone derivatives on phosphorylation of AXL kinase in MDA-MB-231 and 4T1 cells
  • Western Blot immunoblotting
  • sample preparation electrophoretic separation
  • membrane transfer of proteins immunohybridization
  • color development protein detection
  • MDA-MB-231 cells were inoculated into a 6-well plate at a suitable density, cultured for 24 hours, and the cell confluence reached about 80%, respectively, the corresponding concentration of the drug-containing medium was added, and cultured for 2-24 hours;
  • the cell lysate is sonicated for 10-15 seconds, and the DNA is cleaved to reduce the viscosity of the sample;
  • Electrophoretic separation 8% to 12% SDS-PAGE polyacrylamide gel was applied, 15-20 ⁇ L was applied, 90v electrophoresis was applied, and 120v electrophoresis was applied.
  • Transfer film Place the transfer tank in an ice bath and put in a sandwich to ensure that the glue faces the negative electrode and PVDF faces the positive electrode. Add 1x transfer buffer, constant pressure, according to the molecular weight of the protein to be detected, 110V transfer film 0.5-2h.
  • the primary antibody (antibody AXL, phosphor-AXL, AKT, phosphor-AKT, GAPDH, etc.) was diluted 1:200 to 1:1000.
  • the PVDF membrane was incubated with the antibody in a wet box at 4 ° C overnight to allow the antibody to bind well to the protein of interest.
  • TL4800075 and TL4800191 can significantly inhibit the phosphorylation of MDA-MB-231 cells AXL and its downstream signaling protein AKT.
  • Example 82 Effect of quinolone derivatives on TGF- ⁇ 1-induced EMT transformation of MDA-MB-231 cells, as well as invasion and migration
  • MDA-MB-231 cells were seeded on glass slides previously placed on 6-well plates, and then treated with different concentrations of test compound (0.04, 0.2, 1.5 ⁇ M) with or without TGF- ⁇ 1 (10 ng/ml). hour. It was fixed with a 4% formaldehyde solution for 15 minutes, 0.5% Triton X-100 for 10 minutes at room temperature, and blocked with 3% sheep serum albumin in PBS for one hour, then with anti-E-cadherin and N-cadherin antibodies. (1:1000; Abcam, ab10983) was incubated for 1.5 hours at room temperature.
  • MDA-MB-231 breast cancer cells were seeded on a 6-well culture plate at a number of 5 ⁇ 10 5 cells per well. When cultured to 100% of the medium, the medium was removed, and a 200- ⁇ L pipette tip was used. A uniform width of scratches is drawn in the middle of the layer cells. The cells were washed three times with phosphate buffer (PBS) to remove cell debris, and then 2% FBS with or without TGF- ⁇ 1 (10 ng/mL) and different concentrations of the analytes were cultured in RPMI-1640 for 24 hours.
  • PBS phosphate buffer
  • the cells were resuspended by centrifugation, resuspended in serum-free medium, diluted to 5 ⁇ 10 4 to 5 ⁇ 10 5 /mL, and different concentrations of AXL inhibitor solution were prepared by using cell suspension.
  • 800 ⁇ L of medium containing 10% FBS was added to the lower chamber.
  • Example 83 Quinolone derivatives inhibit migration of xenografts in vivo
  • mice were selected for subcutaneous inoculation of 4T1 cells (0.5 ⁇ 10 6 /mouse). 24 days after the inoculation, the mice were randomly divided into a treatment group and a control group (10 per group). Each group of mice was orally administered for 21 days, and the therapeutic group was given a dose of 30 mg/kg and 90 mg/kg of compound 2-1 infusion per day. Mouse body weight and tumor volume were measured every two days. After the mice reached the end point of administration, the liver tissues of the mice were excised and collected, fixed with 10% formalin, embedded in paraffin, sectioned, and liver sections were stained with eosin. The micrometastases in at least 3 fields of view were examined microscopically and the number of liver micrometastases was calculated.
  • Example 84 In vivo pharmacokinetic experiment of quinolone derivatives
  • Rat pharmacokinetics and bioavailability test SD rats were administered orally (25 mg/kg) and intravenously (2.5-5 mg/kg). Blood samples were collected at appropriate time points after administration. Heparin anticoagulation was performed at 8000 rpm for 6 minutes. The supernatant was stored at -20 ° C for HPLC-MS analysis. The blood samples were precipitated with acetonitrile at 12000 rpm*10 min and the supernatant was used for HPCL-MS analysis. The data were fitted with parameters using DAS2.0, and the parameters of the atrioventricular model and the non-compartment model were obtained. The oral bioavailability of the compound was calculated from the AUC data.

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Abstract

提供了式（I）所示的取代喹诺酮类衍生物或其药学上可接受的盐、前药分子及其药用组合物和在制备防治肿瘤药物中的应用。所述喹诺酮类衍生物、盐、前药分子及其药用组合物可作为蛋白激酶抑制剂，有效抑制AXL蛋白激酶的活性并且能抑制多种肿瘤细胞的增殖、迁移和侵袭；可用于制备抗肿瘤药物，特别是制备治疗人类及其它哺乳动物的肿瘤等过度增殖性疾病的药物中。

Description

取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体及其药用组合物和应用 技术领域
本发明属于化学医药技术领域，特别涉及取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体或前药分子及其药用组合物和在制备防治肿瘤药物中的应用，特别是本发明衍生物、盐、立体异构体、前药分子及其药用组合物可作为蛋白激酶抑制剂，有效抑制AXL蛋白激酶的活性并且能抑制多种肿瘤细胞的增殖、迁移和侵袭。
背景技术
AXL是一类受体酪氨酸激酶，属于TAM受体酪氨酸激酶家族，该家族还包括其他两个成员：Mer和Tyro3。TAM最早发现于肿瘤细胞，其过表达和异位表达与免疫调节，肿瘤增殖、生长和迁移等密切相关。AXL于1988年从慢性髓性白血病病人和慢性骨髓增殖性疾病中分离。AXL广泛表达于大脑、免疫细胞、血小板、内皮细胞、骨骼肌、心脏、肝和肾等组织。维生素K依赖蛋白激酶Gas6(growth arrest-specific 6)是目前发现的研究最为广泛的一个AXL配体，TAM家族的其他配体还包括Protein S，Tubby，Tulp-1，Galectin-3。TAMs家族具有相似的蛋白结构，主要由胞外域、跨膜区和胞内域三部分组成，胞外域包括两个N-端免疫球样区Ig，和二个纤连蛋白Ⅲ重复片段(FNⅢ)。Gas6与AXL胞外域结合以后诱导AXL二聚化，引发胞内域发生反式自磷酸化，从而激活胞内信号通路，调节一系列生理活动。如通过Src/MAPK/ERK通路，调节细胞的生长和增殖；通过PI3K/AKT通路刺激抗凋亡蛋白的表达；通过PI3K/p38/MAPK通路调节细胞迁移和增殖。AXL除了Gas6依赖的激活外，还可以通过配体非依赖的方式被激活。AXL参与正常细胞的粘附和免疫调节作用，研究发现AXL的过表达存在于多种肿瘤细胞中，Gas6/AXL调节的信号通路与多种肿瘤的发生和发展密切相关，如慢性髓细胞性白血病、乳腺癌、前列腺癌、非小细胞肺癌、胰腺癌、黑色素瘤、神经胶质瘤和肾细胞癌。已证实抑制AXL的表达可以降低胰腺癌细胞的增殖和生长，抑制乳腺癌细胞的侵袭和迁移。在非小细胞肺癌中，基因沉默AXL可以抑制肿瘤的生长。同时，AXL的高表达也与肿瘤的复发和其他抗癌药物的耐受相关，如伊马替尼(Gliver)、厄洛替尼(Tarceva)、拉帕替尼(Tyverb)。这些证据表明AXL是一个有效的肿瘤靶向治疗靶点。
Bosutinib(SKI606，PF5208763，Bosulif；Pfizer，2012)，Cabozantinib(XL184，Cometriq；Exelixis，2012)，Sunitinib(SU11248，Sutent；Pfizer，2006)等上市药物虽然具有AXL活性，但它们是多靶点药物，不具有特异性。BGB324(R428；Rigel Pharmaceuticals，BergenBio)是目前已知的特异性最高的AXL小分子抑制剂，正处于临床一期研究，2014年12月，FDA授予BGB324治疗AML孤儿药称号。目前，还没有针对AXL激酶的小分子抑制剂上市。
发明内容
为了克服上述现有技术的缺点与不足，本发明的首要目的在于提供取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体。
本发明另一目的在于提供一种基于上述取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体的药用组合物。
本发明再一目的在于提供上述取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体的应用。
本发明再一目的在于提供上述药用组合物的应用。
本发明的目的通过下述方案实现：
取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，具有式(Ⅰ)所示结构：
Figure PCTCN2016095813-appb-000001
其中，X任选自：CH或N；
R1任选自：氢或卤素；
R2任选自：
Figure PCTCN2016095813-appb-000002
R9任选自：氢、C1～C5烷基或C3～C6环烷基；
或者R1、R2与A环组成含1～3个N的取代或未取代并5～6元杂环
Figure PCTCN2016095813-appb-000003
m＝2～3，X任选自CH或N，Y任选自C、N或O；
B任选自：芳基、杂芳基、单环或多环烷基；
R3任选自：氢、卤素、三氟甲基或C1～C3烷基；
R4任选自：氢、C1～C5烷基、C3～C6环烷基、C1～C3烷氧基、取代或未取代苯基；
R5任选自：氢、-(CH2)r-COOR22、-(CH2)r-NR23R24、-L-杂芳基或
Figure PCTCN2016095813-appb-000004
R5中，r、s1、s2、s3各自独立的选自0、1、2或3；
V任选自：CH或N；
U任选自：O、S、CR23R24或NR23；
R22任选自：氢或C1～C4烷基；
R23、R24任选自：H、C1～C3烷基、C3～C6环烷基、-NH(C1～C3烷基)、-N(C1～C3烷基)(C1～C3烷基)或-C(＝O)(C1～C3烷基)；
L任选自：C1～C3烷基、-NR25-、-NR25CO-、-CONR25-、-O-、-CO-、-SO-或-SO2-；R25选自：C1～C3烷基；
R6任选自：氢、卤素、C1～C5烷基、C2～C6烯基、C3～C6环烷基、C4～C6环烯基、C1～C5烷氧基、三氟甲基或三氟甲氧基；
R7任选自：氢、C1～C5烷基或C3～C6环烷基；
R8为氢；
或者R7、R8与C、D环组成含有或不含有杂原子的5～7元脂肪环烷
Figure PCTCN2016095813-appb-000005
其中，n＝0～2；W任选自CH2或O；R10任选自H或CH3。
本发明的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体：
优选地，当所述R1、R2与A环组成并5～6元取代杂环，所述的并5～6元取代杂环优选为如下结构中的一种：
Figure PCTCN2016095813-appb-000006
其中，X为CH2或N；
R11任选自：氢、卤素、甲基、乙基、丙基、异丙基、环丙基、甲氧基、乙氧基、丙氧基或异丙氧基；
R12、R13相同或不同地任选自：氢、卤素、-(CR15R16)OR14、-O(CR15R16)OR14、-(CR17＝CR18)pR14、-O(CR17＝CR18)pR14、
Figure PCTCN2016095813-appb-000007
其中，o、p、q＝0～6，R14、R15、R16、R17、R18相同或不同地任选自：-H、-F、-Cl、-Br、-I、-CF3、-OCF3、-OH、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH(CH3)2、-COOC(CH3)3、-(C＝O)-NR19R20、-SOm-NR19R20、-CHR19R20、-OR19或-NR19R20；m＝1～2；
R19、R20相同或不同地任选自：氢、卤素、C1～C6烷基；或者，R19与R20组成饱和或不饱和的5～8元杂环基团；
或者，R12、R13组成含1～4个杂原子的取代或未取代C5～C18脂肪环烷基。
优选地，所述R4选自以下结构：氢、甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、异丙氧基或
Figure PCTCN2016095813-appb-000008
其中，R21任选自：氢、卤素、C1～C5烷基、C3～C6环烷基或C1～C5烷基。
优选地，所述R5选自以下结构：氢、
Figure PCTCN2016095813-appb-000009
Figure PCTCN2016095813-appb-000010
Figure PCTCN2016095813-appb-000011
优选地，所述R6选自以下结构：氢，氟，氯，溴，甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，异戊基，丙烯基，异丙烯基，丁烯基，戊烯基，环丙基，环丁基，环戊基，环己基，环丁烯基，环戊烯基，环己烯基，甲氧基，乙氧基，丙氧基，异丙氧基，三氟甲基或三氟甲氧基。
当所述R8为H时，R7优选自以下结构：氢，甲基，乙基，丙基，异丙基，丁基，环丙基，环丁基，环戊基或环己基。
当所述R7、R8与C、D环组成三元并环，所述三元并环优选为以下结构之一：
Figure PCTCN2016095813-appb-000012
本发明所述取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，优选具有如下所示结构：
Figure PCTCN2016095813-appb-000013
Figure PCTCN2016095813-appb-000014
其中，n＝0～2，W为CH2或O；
X任选自：CH或N；
R1任选自：氢或卤素；
R2任选自：
Figure PCTCN2016095813-appb-000015
R9任选自：氢、C1～C5烷基或C3～C6环烷基；
R3任选自：氢、卤素、三氟甲基或C1～C3烷基；
R4任选自：氢、C1～C5烷基、C 3～C6环烷基、C1～C3烷氧基、取代或未取代苯基；
R5任选自：氢、-(CH2)r-COOR22、-(CH2)r-NR23R24、-L-杂芳基或
Figure PCTCN2016095813-appb-000016
R5中，r、s1、s2、s3各自独立的选自0、1、2或3；
V任选自：CH或N；
U任选自：O、S、CR23R24或NR23；
R22任选自：氢或C1～C4烷基；
R23、R24任选自：H、C1～C3烷基、C3～C6环烷基、-NH(C1～C3烷基)、-N(C1～C3烷基)(C1～C3烷基)或-C(＝O)(C1～C3烷基)；
L任选自：C1～C3烷基、-NR25-、-NR25CO-、-CONR25-、-O-、-CO-、-SO-或-SO2-；R25选自：C1～C3烷基；
R6任选自：氢、卤素、C1～C5烷基、C2～C6烯基、C3～C6环烷基、C4～C6环烯基、C1～C5烷氧基、三氟甲基或三氟甲氧基；
R7任选自：氢、C1～C5烷基或C3～C6环烷基；
或者R7与C、D环组成三元并环
Figure PCTCN2016095813-appb-000017
R10任选自H或CH3。
所述的三元并环优选为以下结构之一：
Figure PCTCN2016095813-appb-000018
R5，R6的定义与前面相同。
本发明所述取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，具有式(Ⅱ)～(Ⅸ)所示结构其中一种，优选地：
R4任选自：氢，甲基，乙基，丙基，异丙基，丁基，异丁基，戊基，异戊基，环丙基，环丁基，环戊基，环己基，甲氧基，乙氧基，丙氧基，异丙氧基，
Figure PCTCN2016095813-appb-000019
其中，R21任选自：氢，卤素，C1～C5烷基，C3～C6环烷基或C1～C5烷基；
R5任选自：氢，
Figure PCTCN2016095813-appb-000020
Figure PCTCN2016095813-appb-000021
Figure PCTCN2016095813-appb-000022
R6任选自：氢，氟，氯，溴，甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，异戊基，丙烯基，异丙烯基，丁烯基，戊烯基，环丙基，环丁基，环戊基，环己基，环丁烯基，环戊烯基，环己烯基，甲氧基，乙氧基，丙氧基，异丙氧基，三氟甲基或三氟甲氧基。
本发明所述取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，优选具有式Ⅲ，Ⅴ，Ⅶ，Ⅸ的结构，即所述E与A环组成并5～6元取代杂环，优选为以下结构：
Figure PCTCN2016095813-appb-000023
其中，X为CH或N；
R11任选自：氢，卤素，甲基，乙基，丙基，异丙基，环丙基，甲氧基，乙氧基，丙氧基或异丙氧基；
R12、R13相同或不同地任选自：氢，卤素，-(CR15R16)OR14、-O(CR15R16)OR14、-(CR17＝CR18)pR14、-O(CR17＝CR18)pR14、
Figure PCTCN2016095813-appb-000024
其中，o、p、q＝0～6；R14、R15、R16、R17、R18相同或不同地任选自：-H、-F、-Cl、-Br、-I、-CF3、 -OCF3、-OH、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH(CH3)2、-COOC(CH3)3、-(C＝O)-NR19R20、-SOm-NR19R20、-CHR19R20、-OR19或-NR19R20；
R19、R20相同或不同地任选自：氢、卤素、C1～C6烷基；或者，R19与R20组成饱和或不饱和的5～8元杂环基团；
或者，R12、R13组成含1～4个杂原子的取代或未取代C5～C18脂肪环烷基。
本发明所述取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，优选为以下化合物中的一种：
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-氯-N-(3-氟-4-((3-苯基-1H-吡唑[3,4-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((7H-吡咯[2,3-d]嘧啶-4-取代)氧基)-3氟苯基)-6-氯-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
7-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
5-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-7-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺
6-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((1H-吡咯[2,3-b]吡啶-4-取代)氧基)-3氟苯基)-6-氯-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-三氟甲基-1,4-二氢喹啉-3-甲酰胺
6-氯-N-(3-氟-4-((3-苯基-1H-吡咯[2,3-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-溴-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢苯并[g]喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-6甲氧基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
1-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1-丙基-1,4-二氢喹啉-3-甲酰胺
1-丁基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
2-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-2-苯基-1,4-二氢喹啉-3-甲酰胺
9-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-3-甲基-10-(4-甲基哌嗪-1-取代)-7-氧 基-3,7-二氢-[1,4]氧氮卓[2,3,4-ij]喹啉-6-甲酰胺
1-环丙基-6-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-4-氧基-7-(哌嗪-1-取代)-1,4-二氢喹啉-3-甲酰胺
9-氟-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-8-(4-羟基哌啶-1-基)-5-甲基-1-氧代-1,5,6,7-四氢吡啶并[3,2,1-ij]喹啉-2-甲酰胺
6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-叔丁基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-丙基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-三氟甲氧基-1,4-二氢喹啉-3-甲酰胺
6-乙基-1,2-二甲基-4-氧基-N-(4((5-苯基-7H-吡咯[2,3,d]嘧啶-4-取代)氧基)-1,4-二氢喹啉-3-甲酰胺
6-乙基-12-二甲基-N-(3-甲基-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(2-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((7H-吡咯[2,3-d]嘧啶-4-取代)氧基)-3-三氟苯基)-6-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟-4-((3-苯基-1H-吡咯[2,3-d]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟-4-((5-(4-甲氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-9-甲基-1-氧基-1,5,6,7-四氢吡啶[3,2,1-ij]喹啉-2-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-9-甲基-1-氧代-6,7-二氢-1H,5H-吡啶并[3,2,1-ij]喹啉-2-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-(丙基-1-烯基-2-取代)-1,4-二氢喹啉-3-甲酰胺
6-环丙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-(环戊基-1-烯基-1-取代)-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-苯基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-(1-哌啶-4-取代)-1H-吡唑-4-取代)-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-6-异丙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-环戊基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
3-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)氨甲酰基-1,2-二甲基-4-氧基-1,4-二氢喹啉 -6-羧酸甲酯
N-(3-氟-4-((7-甲基-5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-6-氟-1-甲基-7-(4-((5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基)哌嗪-1-基)-4-氧代-1,4-二氢-[1,3]硫氮杂环丁烷并[3,2-a]喹啉-3-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-9-氟-8-(4-羟基哌啶-1-取代)-5-甲基-1-氧基-1,5,6,7-四氢吡咯[3,2,2-ij]喹啉-2-甲酰胺
(S)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-9-氟-3-甲基-10-(4-甲基哌嗪-1-基)-7-氧代-2,3-二氢-7H-[1,4]恶嗪[2,3,4-ij]喹啉-6-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-9-氟-3-甲基-10-(4-甲基哌嗪-1-基)-7-氧代-2,3-二氢-7H-[1,3,4]恶二嗪[6,5,4-ij]喹啉-6-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6,8-二氟-1-(2-氟乙基)-7-(4-甲基哌嗪-1-基)-4-氧代-1,4-二氢喹啉-3-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-氟-1-(4-氟苯基)-4-氧代-7-(哌嗪-1-基)-1,4-二氢喹啉-3-甲酰胺
5-氨基-1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-7-(3,5-二甲基哌嗪-1-基)-6,8-二氟-4-氧代-1,4-二氢喹啉-3-甲酰胺
1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-7-(4-乙基哌嗪-1-基)-6-氟-4-氧代-1,4-二氢喹啉-3-甲酰胺
7-(3-氨基吡咯烷-1-基)-1-(2,4-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-氟-4-氧代-1,4-二氢-1,8-萘啶-3-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-1-乙基-6-氟-4-氧代-7-(哌嗪-1-基)-1,4-二氢-1,8-萘啶-3-甲酰胺
1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-基-4-氧代-7-(哌嗪-1-基)-1,4-二氢喹啉-3-甲酰胺
N-(4-((2-氯吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((2-苄基吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-((3-氟-4-((-苯基氟[2,3-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((2-氨基甲酰基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟基-4-(5-(1-甲基-1H-吡唑-4-取代)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
2,6-二乙基-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-2,6-二乙基-1-甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
N-(4-((2-氨基甲酰基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2,6-二甲基-4-氧代-1-苯基-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-吗啉代丙氧基)喹唑啉-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
N-(4-((7-(2-(二甲氨基)乙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-(4-甲基哌嗪1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟-4-((6-甲氧基-7-(2-(吡咯烷-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-甲氧丙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
N-(4-((7-(2-(二甲氨基)丙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-7-(4-甲基哌嗪-1-基)-4-氧代-1,4-二氢喹啉-3-甲酰胺
本发明还提供了一种基于上述本发明所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体的治疗肿瘤的药用组合物，所述药用组合物包括上述取代喹诺酮类衍生物、其药学上可接受的盐、立体异构体或其前药分子，及药学上可接受的载体。
本发明的取代喹诺酮类衍生物或其药学上可接受的盐、前药分子、药用组合物可用于制备防治肿瘤药物中。特别是用于制备治疗白血病等血液性肿瘤、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、鼻咽癌等过渡增殖性疾病的药物中。
本发明的取代喹诺酮类衍生物或其药学上可接受的盐、前药分子、药用组合物可以有效抑制AXL等蛋白激酶的作用，并可抑制多种肿瘤细胞的增殖、迁移和侵袭，可用于制备抗肿瘤药物。如本领域技术人员所理解的，本申请所涉及的化合物及其药学可接受的盐可用于制备治疗人类及其它哺乳动物的肿瘤等过度增殖性疾病的药物中。
附图说明
图1为喹诺酮类衍生物对MDA-MB-231细胞AXL激酶磷酸化的影响图。
图2为喹诺酮类衍生物对A549细胞AXL激酶磷酸化的影响图。
图3为喹诺酮类衍生物对TGF-β1诱导MDA-MB-231细胞EMT过程中细胞形态及蛋白表达的影响图。
图4为喹诺酮类衍生物对TGF-β1诱导MDA-MB-231细胞EMT过程中细胞形态及蛋白表达的影响图。
图5为喹诺酮类衍生物对MDA-MB-231细胞迁移和侵袭的影响图
图6为喹诺酮类衍生物对MDA-MB-231细胞迁移和侵袭的影响图
图7为喹诺酮类衍生物4T1移植瘤体内转移的影响图
具体实施方式
下面结合实施例和附图对本发明作进一步详细的描述，但本发明的实施方式不限于此。
本发明所述化学物中，当任何变量(例如R1、R等)在任何组分中出现超过一次，则其每次出现的定义独立于其它每次出现的定义。同样，允许取代基及变量的组合，只要这种组合使化合物稳定。自取代基划入环系统的线表示所指的键可连接到任何能取代的环原子上。如果环系统为多环，其意味着这种键仅连接到邻近环的任何适当的碳原子上.要理解本领域普通技术人员可选择本发明化合物的取代基及取代型式而提供化学上稳定的并可通过本领域技术和下列提出的方法自可容易获得的原料容易的合成的化合物。如果取代基自身被超过一个基团取代，应理解这些基团可在相同碳原子上或不同碳原子上，只要使结构稳定。
本文所用术语“烷基”意指包括具有特定碳原子数目的支链的和直链的饱和脂肪烃基。例如，“C1-C5烷基”中“C1-C5”的定义包括以直链或支链排列的具有1、2、3、4或5个碳原子的基团。例如，“C1-C5烷基”具体包括甲基、乙基、正丙基、异丙基、正丁基、叔丁基、异丁基、戊基。术语“环烷基”指具 有特定碳原子数目的单环饱和脂肪烃基。例如“环烷基”包括环丙基、甲基-环丙基、环丁基、环戊基、环己基等。
本文所用术语“杂芳基”代表环中多达5个原子的稳定的单环或每个环中多达5个原子双环碳环，其中至少一个环为芳香环且含有1～4个选自O、N和S的杂原子。本定义范围内的杂芳基包括但不限于：咪唑基、吡唑基、呋喃基、噻吩基、噁唑基、异噁唑基、吡嗪基、吡啶基、嘧啶基、吡咯基。对于下列杂芳基的定义，“杂芳基”也理解为包括任何含有氮的杂芳基的N-氧化物衍生物。在杂芳基取代基是双环的且含有一个环为非芳香性或不含有杂原子的例子中，应理解各自经芳香环或经含杂原子环连接。
本文中所用术语“杂环”或“杂环基”是指含有1～4个选自O、N和S的杂原子的5元～6元芳香性或非芳香性杂环，且包括双环基团。“杂环基”因此包括上面提及的杂芳基，也包括其二氢化及四氢化类似物。“杂环基”进一步的实例包括但不限于：咪唑基、噻唑基、异噁唑基、噁二唑基、噁唑基、氧杂环丁烷基(oxetanyl)、吡喃基、吡嗪基、吡唑基、哒嗪基、吡啶基、嘧啶基、吡咯基、喹噁啉基、四唑基、噻二唑基、噻唑基、噻吩基、唑基。杂环取代基的连接可通过碳原子或通过杂原子实现。
正如本领域技术人员所理解的，本文中所用“卤素”(“halo”)或“卤素”意指包括氯、氟、溴和碘。
除非另有定义，烷基、环烷基、芳基、杂芳基和杂环基取代基可为未被取代的或取代的。例如，(C1～C6)烷基可被一个、两个或三个选自OH、卤素、硝基、氰基、烷氧基、二烷基氨基或杂环基例如吗啉基、哌啶基等的取代基取代。
本发明包括式Ⅰ～Ⅸ化合物的游离形式，也包括其药学上可接受的盐及立体异构体。本文中一些特定的示例性化合物为胺类化合物的质子化的盐。术语“游离形式”指以非盐形式的胺类化合物。包括在内的药学上可接受盐不仅包括本文所述特定化合物的示例性盐，也包括所有式Ⅰ化合物游离形式的典型的药学上可接受的盐。可使用本领域已知技术分离所述化合物特定盐的游离形式。例如，可通过用适当的碱稀水溶液例如NaOH稀水溶液、碳酸钾稀水溶液、稀氨水及碳酸氢钠稀水溶液处理该盐使游离形式再生。游离形式在某些物理性质例如在极性溶剂中溶解度上与其各自盐形式多少有些区别，但是为发明的目的这种酸盐及碱盐在其它药学方面与其各自游离形式相当。
可通过常规化学方法自含有碱性部分或酸性部分的本发明化合物合成本发明的药学上可接受的盐。通常，通过离子交换色谱或通过游离碱和化学计算量或过量的所需盐形式的无机或有机酸在适当溶剂或多种溶剂的组合中反应制备碱性化合物的盐。类似的，通过和适当的无机或有机碱反应形成酸性化合物的盐。
因此，本发明化合物的药学上可接受的盐包括通过碱性本发明化合物和无机或有机酸反应形成的本发明化合物的常规无毒盐。例如，常规的无毒盐包括得自无机酸例如盐酸、氢溴酸、硫酸、氨基磺酸、磷酸、硝酸等的盐，也包括自有机酸例如乙酸、丙酸、琥珀酸、乙醇酸、硬脂酸、乳酸、苹果酸、酒石酸、柠檬酸、抗坏血酸、扑酸、马来酸、羟基马来酸、苯乙酸、谷氨酸、苯甲酸、水杨酸、对氨基苯磺酸、2-乙酰氧基一苯甲酸、富马酸、甲苯磺酸、甲磺酸、乙烷二磺酸、草酸、羟乙基磺酸、三氟乙酸等制备的盐。
如果本发明化合物为酸性的，则适当的“药学上可接受的盐”指通过药学上可接受的无毒碱包括无机碱及有机碱制备的盐.得自无机碱的盐包括铝盐、铵盐、钙盐、铜盐、铁盐、亚铁盐、锂盐、镁盐、锰盐、亚锰盐、钾盐、钠盐、锌盐等。特别优选铵盐、钙盐、镁盐、钾盐和钠盐。得自药学上可接受的有机无毒碱的盐，所述碱包括伯胺、仲胺和叔胺的盐，取代的胺包括天然存在的取代胺、环状胺及碱性离子交换树脂例如精氨酸、甜菜碱、咖啡因、胆碱、N,N'-二苄基乙二胺、二乙胺、2-二乙基氨基乙醇、2-二甲基氨基乙醇、氨基乙醇、乙醇胺、乙二胺、N-乙基吗啉、N-乙基哌啶、葡萄糖胺、氨基葡萄糖、组氨酸、羟钴胺、异丙基胺、赖氨酸、甲基葡萄糖胺、吗啉、哌嗪,哌啶、呱咤、多胺树脂、普鲁卡因、嘌呤、可可碱、三乙胺、三甲胺、三丙胺、氨基丁三醇等。
Berg等，“Pharmaceutical Salts,”J.Pharm.Sci.1977:66:1-19.更详细描述了上文所述药学上可接受的盐及其它典型的药学上可接受的盐的制备。
由于在生理条件下化合物中脱质子化的酸性部分例如羧基可为阴离子的，而这种带有的电荷然后可被内部带有阳离子的质子化了的或烷基化的碱性部分例如四价氮原子平衡抵消，所以应注意本发明化合物是潜在的内盐或两性离子。
除在文献中已知的或在实验程序中例证的标准方法外，可采用如下列方案中显示的反应制备本发明化合物。因此，下列说明性方案是为说明的目的而不是局限于所列化合物或任何特定的取代基。方案中显示的取代基数目并不必需符合权利要求中所用的数目，且为清楚起见，显示单取代基连接到在上文中式(I)的定义下允许有多取代基的化合物上。
方案
如方案A中所示式(I)中化合物可以由4-氯吡咯并嘧啶为起始原料通过8步反应合成。
方案A：
Figure PCTCN2016095813-appb-000025
在一个实施方案中，本申请提供了一种利用具有式(I)的化合物及其药学可接受的盐治疗人或其它哺乳动物肿瘤等过度增殖性疾病或症状。
在一个实施方案中，本申请所设计的化合物及其药学可接受的盐可以用于制备治疗或控制胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、前列腺癌、鼻咽癌、白血病等过度增殖性疾病的药物中。
在一个实施方案中，本申请所设计的化合物及其药学可接受的盐可以与目前应用的或正处开发阶段的雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂，c-Kit抑制剂，Met抑制剂，Raf抑制剂,MEK抑制剂,MMP抑制剂,拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂，Bcl-2家族蛋白抑制剂，MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53激活剂、VEGF抗体、EGF抗体等药物联合用药增加其临床效果。
本申请所涉及的、具有式(I)结构的化合物及其药学可接受的盐或其药用组合物可用于制备防治下列疾病以及下面没有列出的其它疾病的药物：
(1)人或其它哺乳动物的乳腺癌，包括但不局限于侵袭性导管癌、侵袭性小叶癌、原位管癌和原位小叶癌。
(2)人或其它哺乳动物的呼吸道癌，包括但不局限于小细胞&非小细胞肺癌以及支气管腺瘤和胸膜肺母细胞瘤。
(3)人或其它哺乳动物的脑癌，包括但不局限于脑干和眼下神经胶质瘤、小脑和大脑星形细胞瘤、室管膜细胞瘤以及神经外胚层和松果瘤体。
(4)人或其它哺乳动物的雄、雌性生殖器官的肿瘤，雄性生殖器官的肿瘤包括但不限于前列腺和睾丸癌；雌性生殖器官的肿瘤包括但不限于子宫内膜癌、宫颈癌、卵巢癌、阴道癌和外阴癌以及子宫内瘤。
(5)人或其它哺乳动物的消化道的肿瘤，包括但不限于肛门癌、结肠癌、结肠直道癌、食道癌、胃癌、胰腺癌直肠癌、小肠癌或唾腺癌。
(6)人或其它哺乳动物的尿道的肿瘤，包括但不限于膀胱癌、阴茎癌、肾癌、肾盂癌、输尿管癌或尿道癌。
(7)人或其它哺乳动物的眼癌，包括但不限于眼内黑素瘤和视网膜细胞瘤。
(8)人或其它哺乳动物的肝癌，包括但不限于肝细胞瘤(具有或不具有纤维板变化的干细胞癌)、胆管癌(肝内胆管癌)以及混合的肝细胞性胆管癌。
(9)人或其它哺乳动物的皮肤癌，包括但不限于扁平细胞癌、卡波济氏肉瘤、恶性黑素瘤、默克氏细胞皮肤癌以及非黑素瘤细胞癌。
(10)人或其它哺乳动物的头颈癌，包括但不限于喉、下咽、鼻咽、口咽癌以及唇和口腔癌。
(11)人或其它哺乳动物的淋巴瘤，包括但不限于AIDS相关淋巴瘤、非何杰金淋巴瘤、皮肤T细胞淋巴瘤、何杰森病和中枢神经系统淋巴瘤。
(12)人或其它哺乳动物的肉瘤，包括但不限于软组织肉瘤、骨肉瘤、恶性纤维性组织细胞瘤、林把肉瘤和横纹肌肉瘤。
(13)人或其它哺乳动物的白血病，包括但不限于急性髓样白血病、急性林细胞白血病、慢性淋细胞白血病、慢性骨髓性白血病以及多毛细胞白血病。
服用方式与剂量范围
根据标准药学技术，本发明化合物可单独或在药用组合物中与药学上可接受的受体、辅料或稀释剂组合给予哺乳动物，优选人。可口服或皮下、肌注、腹膜内、静脉、直肠及局部、眼睛、肺部、鼻腔、胃肠外给予化合物。
在一个实施方案中，利用式(I)化合物制备药物治疗或控制癌症等患者时，服用剂量范围为在口服0.1～500毫克/天/公斤体重。适当的给药方式为每日单剂量给药或每日二次、三次、四次等多次给药或利用缓释技术给药。对于多种大型哺乳动物，其优选的剂量范围为0.1～1500毫克/天/公斤体重，优选于0.5～100毫克/天/公斤体重。对于平均体重为70公斤的病人，其每日剂量为1～500毫克。对于一些特别高活性化合物，成年病人每日剂量可低达0.1毫克/天。
药物代谢物及前药
本申请所涉及的化合物及其药学可接受的盐的代谢产物，以及可以在体内转变为本申请所涉及的化合物及其药学可接受的盐的结构的前药，也包含在本申请的权利要求中。
联合用药
式(I)化合物可以与已知的治疗或改进相似病状的其它药物联用。联合给药时，原来药物的给药方式&剂量保持不变，而同时或随后服用式(I)化合物。当式(I)化合物与其它一种或几种药物同时服用时，优选使用同时含有一种或几种已知药物和式(I)化合物的药用组合物。药物联用也包括在重叠的时间段服用式(I)化合物与其它一种或几种已知药物。当式(I)化合物与其它一种或几种药物进行药物联用时，式(I)化合物或已知药物的剂量可能比它们单独用药时的剂量较低。
可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限为：
雌激素受体调节剂、雄激素受体调节剂、视网膜样受体调节剂、细胞毒素/细胞抑制剂、抗增殖剂、蛋白转移酶抑制剂、HMG-CoA还原酶抑制剂、HIV蛋白激酶抑制剂、逆转录酶抑制剂、血管生成抑制剂、细胞增殖及生存信号抑制剂、干扰细胞周期关卡的药物和细胞凋亡诱导剂，细胞毒类药物、酪氨酸蛋白抑制剂、EGFR抑制剂、VEGFR抑制剂、丝氨酸/苏氨酸蛋白抑制剂、Bcr-Abl抑制剂、c-Kit抑制剂、Met抑制剂、Raf抑制剂、MEK抑制剂、MMP抑制剂、拓扑异构酶抑制剂、组氨酸去乙酰化酶抑制剂、蛋白酶体抑制剂、CDK抑制剂、Bcl-2家族蛋白抑制剂、MDM2家族蛋白抑制剂、IAP家族蛋白抑制剂、STAT家族蛋白抑制剂、PI3K抑制剂、AKT抑制剂、整联蛋白阻滞剂、干扰素-α、白介素-12、COX-2抑制剂、p53、p53激活剂、VEGF抗体、EGF抗体等。
在一个实施方案中，可以与式(I)化合物进行药物联用的药物或活性成分包括但不局限为：阿地白介素、阿仑膦酸、干扰素、阿曲诺英、别嘌醇、别嘌醇钠、帕洛诺司琼盐酸盐、六甲蜜胺、氨基格鲁米特、氨磷汀、氨柔比星、安丫啶、阿纳托唑、多拉司琼、aranesp、arglabin、三氧化二砷、阿诺新、5-氮胞苷、硫唑嘌呤、卡介苗或tice卡介苗、贝他定、醋酸倍他米松、倍他米松磷酸钠制剂、贝沙罗汀、硫酸博来霉素、溴尿甘、bortezomib、白消安、降钙素、阿来佐单抗注射剂、卡培他滨、卡铂、康士得、cefesone、西莫白介素、柔红霉素、苯丁酸氮芥、顺铂、克拉屈滨、克拉屈滨、氯屈磷酸、环磷酰胺、阿糖胞昔、达卡巴嗪、放线菌素D、柔红霉素脂质体、地塞米松、磷酸地塞米松、戊酸雌二醇、地尼白介素2、狄波美、地洛瑞林、地拉佐生、己烯雌酚、大扶康、多西他奇、去氧氟尿苷、阿霉素、屈大麻酚、钦-166-壳聚糖复合物、eligard、拉布立酶、盐酸表柔比星、阿瑞吡坦、表阿霉素、阿法依伯汀、红细胞生成素、依铂、左旋咪唑片、雌二醇制剂、17-β-雌二醇、雌莫司汀磷酸钠、炔雌醇、氨磷汀、羟磷酸、凡毕复、依托泊甙、法倔唑、他莫昔芬制剂、非格司亭、非那司提、非雷司替、氟尿苷、氟康唑、氟达拉滨、5-氟脱氧尿嘧啶核苷一磷酸盐、5-氟尿嘧啶、氟甲睾酮、氟他胺、福麦斯坦、1-β-D-阿糖呋喃糖胞噻啶-5’-硬脂酰磷酸酯、福莫司汀、氟维司群、丙种球蛋白、吉西他滨、吉妥单抗、甲磺酸伊马替尼、卡氮芥糯米纸胶囊剂、戈舍瑞林、盐酸格拉尼西隆、组氨瑞林、和美新、氢化可的松、赤型-羟 基壬基腺嘌呤、羟基脲、替坦异贝莫单抗、伊达比星、异环磷酰胺、干扰素α、干扰素-α2、干扰素α-2A、干扰素α-2B、干扰素α-nl、干扰素α-n3、干扰素β、干扰素γ-la、白细胞介素-2、内含子A、易瑞沙、依立替康、凯特瑞、硫酸香菇多糖、来曲唑、甲酰四氢叶酸、亮丙瑞林、亮丙瑞林醋酸盐、左旋四咪唑、左旋亚叶酸钙盐、左甲状腺素钠、左甲状腺素钠制剂、洛莫司汀、氯尼达明、屈大麻酚、氮芥、甲钴胺、甲羟孕酮醋酸酯、醋酸甲地孕酮、美法仑、酯化雌激素、6-琉基嘌呤、美司钠、氨甲蝶呤、氨基乙酰丙酸甲酯、米替福新、美满霉素、丝裂霉素C、米托坦、米托葱醌、曲洛司坦、柠檬酸阿霉素脂质体、奈达铂、聚乙二醇化非格司亭、奥普瑞白介素、neupogen、尼鲁米特、三苯氧胺、NSC-631570、重组人白细胞介素1-β、奥曲肽、盐酸奥丹西隆、去氢氢化可的松口服溶液剂、奥沙利铂、紫杉醇、泼尼松磷酸钠制剂、培门冬酶、派罗欣、喷司他丁、溶链菌制剂、盐酸匹鲁卡品、毗柔比星、普卡霉素、卟吩姆钠、泼尼莫司汀、司替泼尼松龙、泼尼松、倍美力、丙卡巴脐、重组人类红细胞生成素、雷替曲塞、利比、依替膦酸铼-186、美罗华、力度伸-A、罗莫肽、盐酸毛果芸香碱片剂、奥曲肽、沙莫司亭、司莫司汀、西佐喃、索布佐生、唬钠甲强龙、帕福斯酸、干细胞治疗、链佐星、氯化锶-89、左旋甲状腺素钠、他莫昔芬、坦舒洛辛、他索那明、tastolactone、泰索帝、替西硫津、替莫唑胺、替尼泊苷、丙酸睾酮、甲睾酮、硫鸟嘌呤、噻替哌、促甲状腺激素、替鲁膦酸、拓扑替康、托瑞米芬、托西莫单抗、曲妥珠单抗、曲奥舒凡、维A酸、甲氨喋呤片剂、三甲基密胺、三甲曲沙、乙酸曲普瑞林、双羟萘酸曲普瑞林、优福定、尿苷、戊柔比星、维司力农、长春碱、长春新碱、长春酰胺、长春瑞滨、维鲁利秦、右旋丙亚胺、净司他丁斯酯、枢复宁、紫杉醇蛋白质稳定制剂、acolbifene、干扰素r-lb、affinitak、氨基喋呤、阿佐昔芬、asoprisnil、阿他美坦、阿曲生坦、BAY 43-9006、阿瓦斯丁、CCI-779、CDC-501、西乐葆、西妥昔单抗、克立那托、环丙孕酮醋酸酯、地西他滨、DN-101、阿霉素-MTC、dSLIM、度他雄胺、edotecarin、依氟鸟氨酸、依喜替康、芬维A胺、组胺二盐酸盐、组氨瑞林水凝胶植入物、钬-166DOTMP、伊班膦酸、干扰素γ、内含子-PEG、ixabepilone、匙孔形血蓝蛋白、L-651582、兰乐肽、拉索昔芬、libra、lonafamib、米泼昔芬、米诺屈酸酯、MS-209、脂质体MTP-PE、MX-6、那法瑞林、奈莫柔比星、新伐司他、诺拉曲特、奥利默森、onco-TCS、osidem、紫杉醇聚谷氨酸酯、帛米酸钠、PN-401、QS-21、夸西洋、R-1549、雷洛昔芬、豹蛙酶、13-顺维A酸、沙铂、西奥骨化醇、T-138067、tarceva、二十二碳六烯酸紫杉醇、胸腺素αl、嘎唑呋林、tipifarnib、替拉扎明、TLK-286、托瑞米芬、反式MID-lo7R、伐司朴达、伐普肽、vatalanib、维替泊芬、长春氟宁、Z-100和唑来麟酸或它们的组合。
下列实施例中所用试剂均可购买得到。
实施例1：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50115)的制备
a.
Figure PCTCN2016095813-appb-000026
b.
Figure PCTCN2016095813-appb-000027
步骤a1：6-甲基-1H-苯并[d][1,3]恶嗪-2,4-二酮(化合物1)的制备
2-氨基-5-甲基苯甲酸(3.6g，23.8mmol)，吡啶(3.83mL，47.6mmol)溶于50mL乙腈，在冰浴下缓慢加入三光气(2.37g，8mmol)，加热至55℃搅拌2小时。降至室温，加入饱和碳酸钠溶液淬灭反应，有固体析出，过滤，固体用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干得固体3.93g(93.6％)。1HNMR(400MHz,d6-DMSO),δ11.63(s,1H),7.72(s,1H),7.56(dd,J＝4.0,8.0Hz,1H),7.06(d,J＝8.0Hz,1H),2.33(s,3H)。MS(ESI),m/z:178[M+H]+。
步骤a2：1,6-二甲基-1H-苯并[d][1,3]恶嗪-2,4-二酮(化合物2)的制备
6-甲基-1H-苯并[d][1,3]恶嗪2,4-二酮(化合物1)(3g，16.9mmol)，DIEA(5.6mL，33.8mmol)溶于50mL DMF，缓慢滴加MeI(2.1mL，33.8mmol)，40℃反应过夜。冷至室温，加水淬灭，用二氯甲烷多次萃取，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体2.82g(87.6％)。1HNMR(400MHz,d6-DMSO),δ7.8(s,1H),7.68(dd,J＝4.0,8.0Hz,1H),7.34(d,J＝8.0Hz,1H),3.44(s,3H),2.36(s,3H)。MS(ESI),m/z:192[M+H]+。
步骤a3：1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-羧酸甲酯(化合物3)的制备
乙酰乙酸甲酯(1.94mL，18mmol)溶于50mL DMF中，冰浴下缓慢加入NaH(60％)(720mg，18mmol)，室温下反应30min，搅拌下加入1,6-二甲基-1H-苯并[d][1,3]恶嗪2,4-二酮(化合物2)(2.86g，15mmol)，120℃反应过夜。冷至室温，加水淬灭，用二氯甲烷多次萃取，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体3g(81.7％)。1HNMR(400MHz,d6-DMSO),δ7.95(s,1H),7.74(d,J＝8.0Hz,1H),7.58(dd,J＝4.0,8.0Hz,1H),3.77(s,3H),3.75(s,3H),2.44(s,3H),2.42(s,3H)。MS(ESI),m/z:246[M+H]+。
步骤a4：1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-羧酸(化合物4)的制备
1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-羧酸甲酯(化合物3)(3g，12.2mmol)，NaOH(1.95g，48.8mmol)溶于40mL THF和20mL水中，回流反应过夜。冷至室温，旋干大部分有机溶剂，加入冰水，用稀HCl 调节pH至7～8，有固体析出，过滤，抽干得白色固体2.6g(92.8％)。1HNMR(400MHz,d6-DMSO),δ8.16(s,1H),7.99(d,J＝8.0Hz,1H),7.58(d,J＝8.0Hz,1H),3.96(s,3H),3.11(s,3H),2.49(s,3H)。MS(ESI),m/z:232[M+H]+。
步骤b1：4-(2-氟-4-硝基苯氧基)-7H-吡咯[2,3,-d]嘧啶(化合物5)的制备
4-氯吡咯并嘧啶(7.68g，50mmol)，2-氟-4-硝基苯酚(11g，70mmol)，DIEA(11.57mL，70mmol)溶于80mL N-甲基吡咯烷酮中，在微波反应器中于200℃反应1小时。冷至室温，加水有黄色固体析出，过滤，水洗两次，用二氯甲烷反复萃取多次，合并有机相，用饱和食盐水洗涤一遍，有机相用无水Na2SO4干燥，然后过滤旋干得黄棕色固体11.65g(85％)。1HNMR(400MHz,d6-DMSO),δ12.42(s,1H),8.38(dd,J＝2.8,10.4Hz,1H),8.33(s,1H),8.22(t,J＝1.2Hz,1H),8.20(t,J＝1.2Hz,1H),7.81-7.77(m,1H),7.58(t,J＝2.8Hz,1H),6.68(dd,J＝1.6,3.6Hz,1H)。MS(ESI),m/z:275[M+H]+。
步骤b2：4-(2-氟-4-硝基苯氧基)-5-碘-7H-吡咯[2,3-d]嘧啶(化合物6)的制备
4-(2-氟-4-硝基苯氧基)-7H-吡咯[2,3,-d]嘧啶(化合物5)(11g，40mmol)，KOH(6.72g，120mmol)溶于200mL DMF中，在冰浴下加入碘(15.22g，60mmol)，0℃下搅拌4小时。在反应液中加入冰水，析出黄色固体，过滤，固体用水洗两次，用二氯甲烷反复萃取多次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干得黄色固体14g(87.5％)。1HNMR(400MHz,d6-DMSO),δ12.74(s,1H),8.38(dd,J＝2.4,10.0Hz,1H),8.34(s,1H),8.21(dd,J＝1.2,8.8Hz,1H),7.80(m,2H)。MS(ESI),m/z:400[M+H]+。
步骤b3：4-(2-氟-4-硝基苯氧基)-5-碘-7((2-三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(化合物7)的制备
4-(2-氟-4-硝基苯氧基)-5-碘-7H-吡咯[2,3-d]嘧啶(化合物6)(12g，30mmol)溶于200mL DMF中，在冰浴中加入NaH(1.32g，33mmol)，混合物冰浴下搅拌15min，向反应液中滴加2-(三甲基硅烷基)乙氧甲基氯(5.84mL，33mmol)，室温搅拌过夜。加冰水淬灭，二氯甲烷萃取3次，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得白色固体13.2g(83％)。1H NMR(400MHz,d6-DMSO)δ8.43(s,1H),8.39(dd,J＝2.8,10.4Hz,1H),8.22(m,1H),8.00(s,1H),7.82(t,J＝8.4Hz,1H),5.61(s,2H),3.54(t,J＝8.0Hz,2H),0.84(t,J＝8.0Hz,2H),-0.08(s,9H).MS(ESI),m/z 531[M+H]+.
步骤b4：4-(2-氟-4-硝基苯氧基)-5-苯基-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(化合物8)的制备
4-(2-氟-4-硝基苯氧基)-5-苯基-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(化合物7)(12g，22.7mmol)，苯硼酸(3.32g，27.24mmol)，四三苯基膦钯(1.31g，1.14mmol)，碳酸钠(7.22g，68.1mmol)溶于200mL甲苯中，Ar保护下于90℃反应过夜。冷至室温，过滤，滤液用二氯甲烷萃取多次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得黄色固体8.3g(76.4％)。1HNMR(400MHz,d6-DMSO),δ8.45(s,1H),8.37(dd,J＝2.8,10.0Hz,1H),8.21(m,1H),8.01(s,1H),7.86-7.83(m,1H),7.76(m,2H),7.43(m,1H),7.31(m,1H),5.70(s,2H),3.61(t,J＝8.0Hz,2H),0.86(t,J＝8.0Hz,2H),-0.08(s,9H)。MS(ESI),m/z:481.17[M+H]+。
步骤b5：3-氟-4-(5-苯基--7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯胺(化合物9)的制备
4-(2-氟-4-硝基苯氧基)-5-苯基-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(化合物8)(8g，16.6mmol)，六水合二氯化镍(394mg，1.66mmol)溶于90mL THF和30mL甲醇中，在冰浴下缓慢加入硼氢化钠(3.77g，99.6mmol)，室温洗搅拌2小时。加水淬灭，过滤，旋干有机溶剂后用二氯甲烷萃取，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得黄色固体5.32g(71.2％)。1HNMR(400MHz,d6-DMSO),δ8.39(s,1H),7.89(s,1H),7.74(m,2H),7.41(t,J＝7.6Hz,2H),7.29(t,J＝7.6Hz,1H),7.01(t,J＝8.8Hz,1H),6.47(dd,J＝2.4,12.8Hz,1H),6.39(dd,J＝2.0,8.8Hz,1H),5.66(s,2H),3.59(t,J＝8.0Hz,2H),0.85(t,J＝8.0Hz,2H),-0.08(s,9H)。MS(ESI),m/z:451[M+H]+。
步骤b6：N-(3-氟-4-((5-苯基-7-((2-三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物10)的制备
3-氟-4-(5-苯基--7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯胺(化合物9)(450mg，1mmol)，1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-羧酸(化合物4)(277mg，1.2mmol)，HATU(570mg，1.5mmol)，DIEA(0.5mL，3mmol)溶于30mL DMF，室温搅拌过夜。反应液中加入冰水，有固体析出，过滤，固体用二氯甲烷萃取两次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得白色固体478mg(72％)。1HNMR(400MHz,d6-DMSO),δ11.01(s,1H),8.43(s,1H),8.07(s,1H),7.95(s,2H),7.94-7.90(dd,J＝2.0,8.8Hz,2H),7.82-7.77(m,3H),7.63(dd,J＝2.0,8.8Hz,1H),7.48-7.40(m,4H),7.34(m,1H),5.70(s,2H),3.84(s,3H),3.62(t,J＝8.0Hz,2H),2.74(s,3H),2.46(s,3H),0.88(t,J＝8.0Hz,2H),-0.06(s,9H)。MS(ESI),m/z:664[M+H]+。
步骤b7：N-(3-氟-4-((7-(羟甲基)-5-苯基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物11)的制备
N-(3-氟-4-((5-苯基-7-((2-三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物10)(400mg，0.6mmol)溶于30mL二氯甲烷中，滴加3mL三氟醋酸，室温搅拌过夜。旋干大部分溶剂，加水有固体析出，过滤，用二氯甲烷和甲醇洗，得白色固体300mg(88.75％)。1HNMR(400MHz,d6-DMSO),δ11.00(s,1H),8.41(s,1H),8.07(s,1H),7.89(d,J＝12.0Hz,2H),7.85(s,1H),7.81-7.76(m,1H),7.63(d,J＝8Hz,1H),7.47-7.39(m,4H),7.31(t,J＝8.0Hz,1H),5.68(s,2H),3.83(s,3H),2.64(s,3H),2.46(s,3H)。MS(ESI),m/z:564[M+H]+。
步骤b8：N-(3-氟-4-((苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物12，TL50115)的制备
N-(3-氟-4-((7-(羟甲基)-5-苯基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物11)(250mg，0.44mmol)溶于10mL THF和8mL水中，加入NaOH(71mg，1.76mmol)，室温搅拌过夜。旋干大部分溶剂，旋出的固体分别用水洗、甲醇洗，过滤得白色固体220mg(94％)。1H NMR(500MHz,d6-DMSO)δ12.52(s,1H),11.00(s,1H),8.33(s,1H),8.05(s,1H),7.91(d,J＝13.0Hz,1H),7.79-7.75(m,4H),7.61(d,J＝8.5Hz,1H),7.46(d,J＝8.5Hz,1H),7.41(m,3H),7.27(t,J＝7.0Hz,1H),3.81(s,3H),2.63(s,3H),2.45(s,3H).13C NMR(125MHz,d6-DMSO)δ174.0,166,161.7,154.6,154.1(d,J＝247.5Hz,1C),152.9,150.6,139.5,138.4(d,J＝9.0Hz,1C),135.1(d,J＝12.8Hz,1C),134.5,134.4,133.8,128.8,128.6,126.7,126.2,125.5,124.8,124.1,118.6,117.3,116.1,116.0(d,J＝1.9Hz,1C),108.1(d,J＝23.1Hz,1C),102.4,35.6,20.8,19.4.HRMS(ESI)Calcd for[M+H]+＝534.1936,found:[M+H]+＝534.1934.HPLC analysis:MeOH-H2O(75:25),4.92min,95.33％。
实施例2：6-氯-N-(3-氟-4-((3-苯基-1H-吡唑[3,4-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50025)的制备
Figure PCTCN2016095813-appb-000028
合成方法如实施例1。
HRMS(ESI)Calcd for[M+H]+＝554.1390,found:[M+H]+＝554.1386.
实施例3：N-(4-((7H-吡咯[2,3-d]嘧啶-4-取代)氧基)-3氟苯基)-6-氯-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50046)的制备
Figure PCTCN2016095813-appb-000029
合成方法如实施例1。
MS(ESI)m/z479[M+H]+.HPLC analysis:MeOH-H2O(85:15),3.78min,98.23％.
实施例4：6-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50053)的制备
Figure PCTCN2016095813-appb-000030
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ12.53(s,1H),10.80(s,1H),8.33(s,1H),8.15(d,J＝2.5Hz,1H),7.93-7.89(m,2H),7.81(dd,J＝2.5,9.0Hz,1H),7.77(m,3H),7.46(dd,J＝1.5,9.0Hz,1H),7.43-7.39(m,3H),7.27(t,J＝7.5Hz,1H),3.83(s,3H),2.62(s,3H).
13C NMR(125MHz,d6-DMSO)δ172.7,165.6,161.7,154.6,154.1(d,J＝242.9Hz,1C),152.7,150.7,150.5,140.1,138.4(d,J＝9.8Hz,1C),135.2(d,J＝13.0Hz,1C),134.6,132.9,129.2,128.9,128.7,127.4,126.8,125.0,124.8,124.2,120.4,120.2,116.0(d,J＝2.5Hz,1C),108.0(d,J＝23.2Hz,1C),102.3,35.9,19.5.
HRMS(ESI)for C30H21ClFN5O3[M+H]+,calcd:554.1390,found:554.1386.HPLC analysis:MeOH-H2O(75:25),5.18min,95.02％
实施例5：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50054)的制备
Figure PCTCN2016095813-appb-000031
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.91(s,1H),8.32(s,1H),8.25(dd,J＝1.0,8.0Hz,1H),7.91-7.87(m,2H),7.80(dd,J＝1.5,7.0Hz,1H),7.76(d,J＝7.5Hz,2H),7.74(s,1H),7.48-7.44(m,2H),7.42-7.38(m,3H),7.26(t,J＝7.0Hz,1H),3.83(s,3H),2.62(s,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.0,161.7,154.8,154.1(d,J＝242.6Hz,1C),152.6,150.6,141.4,138.5(d,J＝9.5Hz,1C),135.1(d,J＝12.8Hz,1C),134.7,133.2,128.9,128.7,126.7,126.3,126.1, 124.9,124.5,124.3,119.7,117.5,116.0(d,J＝5.6Hz,1C),108.0(d,J＝23.4Hz,1C),102.3,35.6,30.9,19.6.
HRMS(ESI)for C30H22FN5O3[M+H]+,calcd:520.1779,found:520.1778.
HPLC analysis:MeOH-H2O(80:20),7.00min,99.44％purity.
实施例6：7-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50080)的制备
Figure PCTCN2016095813-appb-000032
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ12.53(s,1H),10.80(s,1H),8.33(s,1H),8.15(d,J＝2.5Hz,1H),7.93-7.89(m,2H),7.81(dd,J＝2.5,9.0Hz,1H),7.77(m,3H),7.46(dd,J＝1.5,9.0Hz,1H),7.43-7.39(m,3H),7.27(t,J＝7.5Hz,1H),3.83(s,3H),2.62(s,3H).
13C NMR(125MHz,d6-DMSO)δ172.7,165.6,161.7,154.6,154.1(d,J＝242.9Hz,1C),152.7,150.7,150.5,140.1,138.4(d,J＝9.8Hz,1C),135.2(d,J＝13.0Hz,1C),134.6,132.9,129.2,128.9,128.7,127.4,126.8,125.0,124.8,124.2,120.4,120.2,116.0(d,J＝2.5Hz,1C),108.0(d,J＝23.2Hz,1C),102.3,35.9,19.5.
HRMS(ESI)for C30H21ClFN5O3[M+H]+,calcd:554.1390,found:554.1386.
HPLC analysis:MeOH-H2O(75:25),5.18min,95.02％purity.
实施例7：5-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50081)的制备
Figure PCTCN2016095813-appb-000033
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.61(s,1H),8.31(s,1H),7.88(d,J＝12.5Hz,1H),7.82(d,J＝9.0Hz,1H),7.78-7.75(m,3H),7.69-7.66(t,J＝8.0Hz,1H),7.46-7.39(m,5H),7.25(t,J＝7.5Hz,1H),3.78(s,3H),2.54(s,3H).
13C NMR(125MHz,d6-DMSO)δ173.3,165.8,161.7,155.1,154.1(d,J＝242.5Hz,1C),150.4,150.2,144.1,138.4(d,J＝10.4Hz,1C),135.2(d,J＝12.5Hz,1C),134.8,133.2,132.5,128.8,128.7,127.1,126.6,125.0,122.7,122.5,116.9,115.9,107.9(d,J＝23.1Hz,1C),102.4,36.5,19.3.
HRMS(ESI)for C30H21ClFN5O3[M+H]+,calcd:554.1390,found:554.1389.
HPLC analysis:MeOH-H2O(85:15),4.30min,97.76％purity.
Melting point:269.4-271.1℃
实施例8：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-7-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺(命名为TL50086)的制备
Figure PCTCN2016095813-appb-000034
合成方法如实施例1。
MS(ESI)m/z 588[M+H]+.
实施例9：6-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50087)的制备
Figure PCTCN2016095813-appb-000035
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.85(s,1H),8.32(s,1H),7.99(dd,J＝4.0,9.5Hz,1H),7.89(m,2H),7.76(m,3H),7.73-7.69(m,1H),7.45(m,1H),7.40(m,3H),7.26(m,1H),3.86(s,3H),2.63(s,3H).
13C NMR(125MHz,d6-DMSO)δ173.0,165.8,161.7,160.0,158.1,154.9,154.1(d,J＝243.0Hz,1C),152.5,150.5,138.4(d,J＝9.9Hz,1C),138.2,135.2(d,J＝12.8Hz,1C),134.7,128.9,128.7,127.8,127.7,126.7,125.0,124.8,121.5,121.3,120.8,120.7,119.5,115.9(d,J＝5.8Hz,1C),110.3,110.1,108.0(d,J＝23.1Hz,1C),102.3,36.1,19.5.
HRMS(ESI)for C30H21F2N5O3[M+H]+,calcd:538.1685,found:538.1680.
HPLC analysis:MeOH-H2O(85:15),4.56min,98.56％purity..
实施例10：N-(4-((1H-吡咯[2,3-b]吡啶-4-取代)氧基)-3氟苯基)-6-氯-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50090)的制备
Figure PCTCN2016095813-appb-000036
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ11.77(s,1H),10.81(s,1H),8.15(d,J＝2.5Hz,1H),8.07(d,J＝5.0Hz,1H),7.98-7.93(m,2H),7.82(dd,J＝2.5,9.5Hz,1H),7.50(dd,J＝1.0,8.5Hz,1H),7.40-7.36(m,2H),6.39(d,J＝5.0Hz,1H),6.27(dd,J＝2.0,3.5Hz,1H),3.84(s,3H),2.62(s,3H).
13C NMR(125MHz,d6-DMSO)δ172.6,165.7,157.7,154.1(d,J＝243.63Hz,1C),138.4(d,J＝9.63Hz, 1C),136.8(d,J＝12.25Hz,1C),132.9,129.2,127.4,125.3,124.8,124.3,120.5,120.3,116.3(d,J＝2.63Hz,1C),109.8,108.3(d,J＝23.13Hz,1C),101.1,97.3,35.9,19.6.
MS(ESI)m/z 478[M+H]+.
HPLC analysis:MeOH-H2O(85:15),3.78min,99.41％.
实施例11：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-三氟甲基-1,4-二氢喹啉-3-甲酰胺(命名为TL50121)的制备
Figure PCTCN2016095813-appb-000037
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ12.54(s,1H),10.74(s,1H),8.50(s,1H),8.33(s,1H),8.11(s,2H),7.89(d,J＝12.5Hz,1H),7.77(m,3H),7.43(m,4H),7.28(s,1H),3.89(s,3H),2.64(s,3H).13C NMR(125MHz,d6-DMSO)δ173.0,165.3,161.6,154.5,154.0(d,J＝243.8Hz,1C),153.0,150.5,143.4,138.2(d,J＝9.9Hz,1C),135.1(d,J＝13.0Hz,1C),134.4,128.8,128.6,126.6,125.7,124.9,124.3(q,J＝33.2Hz,1C),123.3(q,J＝4.4Hz,1C),122.3(q,J＝260.1Hz,1C),115.8(d,J＝5.0Hz,1C),107.9(d,J＝23.7Hz,1C),107.8,102.1,35.8,19.5.HRMS(ESI)for C31H21F4N5O3[M+H]+,calcd:588.1653,found:588.1644.HPLC analysis:MeOH-H2O(75:25),11.65min,95.52％purity.
实施例12：6-氯-N-(3-氟-4-((3-苯基-1H-吡咯[2,3-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50128)的制备
Figure PCTCN2016095813-appb-000038
合成方法如实施例1。
MS(ESI)m/z 553[M+H]+。
实施例13：6-溴-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50133)的制备
Figure PCTCN2016095813-appb-000039
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ12.52(s,1H),10.79(s,1H),8.33(s,1H),8.30(d,J＝1.5Hz,1H),7.94-7.86(m,3H),7.77(t,J＝7.5Hz,3H),7.45(d,J＝9.0Hz,1H),7.40(t,J＝8.0Hz,3H),7.28-7.26(t,J＝7.5Hz,1H),3.83(s,3H),2.61(s,3H).
13C NMR(125MHz,d6-DMSO)δ172.5,165.6,161.7,154.7,154.1(d,J＝242.8Hz,1C),152.6,150.7,140.4,138.4(d,J＝10.0Hz,1C),135.6,135.2(d,J＝13.0Hz,1C),134.6,128.9,128.7,128.1,127.8,126.8,126.7,125.0,124.3,120.5,120.4,117.2,116.0,115.9(d,J＝2.5Hz,1C),108.0(d,J＝23.4Hz,1C),102.3,35.9,19.6.
HRMS(ESI)for C30H21BrFN5O3[M+H]+,calcd:598.0885,found:598.0877.
HPLC analysis:MeOH-H2O(75:25),5.41min,95.02％purity.
实施例14：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢苯并[g]喹啉-3-甲酰胺(命名为TL50198)的制备
Figure PCTCN2016095813-appb-000040
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.91(s,1H),8.91(s,1H),8.40(s,1H),8.34(s,1H),8.2(d,J＝8.0Hz,1H),8.12(d,J＝8.0Hz,1H),7.93(d,J＝12.0Hz,1H),7.79-7.76(m,3H),7.68-7.65(t,J＝7.5Hz,1H),7.55(d,J＝7.5Hz,1H),7.48(d,J＝8.5Hz,1H),7.43-7.40(m,3H),7.27(t,J＝7.5Hz,1H),3.92(s,3H),2.69(s,3H).
13C NMR(125MHz,d6-DMSO)δ174.9,166.1,161.8,154.6,154.2,154.1(d,J＝242.3Hz,1C),150.7,138.6(d,J＝8.5Hz,1C),135.4,135.0(d,J＝12.6Hz,1C),134.6,129.5,129.4,128.9,128.8,128.7,128.2,126.8,126.7,126.3,125.3,125.0,124.3,117.6,116.0,115.9(d,J＝2.8Hz,1C),114.5,107.9(d,J＝22.6Hz,1C),102.3,35.8,19.9.
HRMS(ESI)for C34H24FN5O3[M+H]+,calcd:570.1936,found:570.1931.
HPLC analysis:MeOH-H2O(85:15),6.37min,95.08％purity.
实施例15：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-6甲氧基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800005)的制备
Figure PCTCN2016095813-appb-000041
合成方法如实施例1。
1H NMR(400MHz,d6-DMSO)δ11.10(s,1H),8.30(s,1H),7.92(dd,J＝2.0,12.8Hz,1H),7.85(d,J＝9.6Hz,1H),7.75-7.78(m,3H),7.67(d,J＝3.2Hz,1H),7.46(dd,J＝1.6,8.8Hz,1H),7.42-7.38(m,4H),7.25(m,1H),3.87(s,3H),3.83(s,3H),2.65(s,3H).
13C NMR(125MHz,d6-DMSO)δ173.3,166.1,161.6,156.3,154.2(d,J＝242.3Hz,1C),151.9,150.2, 138.4(d,J＝9.4Hz,1C),135.9,135.1(d,J＝13.6Hz,1C),134.8,128.7,128.6,127.5,126.4,125.4,124.9,122.6,119.4,118.2,115.9,115.7,107.9(d,J＝22.6Hz,1C),105.9,102.3,55.9,35.8,19.4.
HRMS(ESI)for C31H24FN5O4[M+H]+,calcd:550.1885,found:550.1881.
HPLC analysis:MeOH-H2O(85:15),4.69min,95.04％purity.
实施例16：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800025)的制备
Figure PCTCN2016095813-appb-000042
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ12.96(s,1H),12.52(s,1H),8.34(s,1H),8.03(s,1H),7.97(dd,J1＝2.0,14.0Hz,1H),7.78(dd,J1＝1.0,8.0Hz,2H),7.75(s,1H),7.59-7.54(m,2H),7.43-7.38(m,4H),7.27(t,J＝7.5Hz,1H),2.83(s,3H),2.44(s 3H).
13C NMR(125MHz,d6-DMSO)δ176.6,165.2,161.8,156.2,154.6,154.2(d,J＝242.4Hz,1C),150.7,138.4(d,J＝9.4Hz,1C),136.9,134.8(d,J＝12.4Hz,1C),134.6,128.9,128.7,126.8,125.1,125.0,124.2,118.8,116.2(d,J＝2.6Hz,1C),116.0,110.7,108.3(d,J＝23.3Hz,1C),102.3,22.0,21.3.
HRMS(ESI)for C30H22FN5O3[M+H]+,calcd:520.1779,found:520.1784.
HPLC analysis:MeOH-H2O(85:15),8.86min,98.25％purity.
实施例17：1-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800067)的制备
Figure PCTCN2016095813-appb-000043
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.87(s,1H),8.32(s,1H),8.07(s,1H),7.92(d,J＝2.0Hz,1H),7.89-7.76(m,4H),7.62(dd,J＝1.0,8.5Hz,1H),7.45(m,1H),7.40(m,3H),7.26(m,1H),4.38(q,J＝6.5Hz,2H),2.62(s,3H),2.45(s,3H),1.35(t,J＝6.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ173.7,166.2,161.7,154.9,154.1(d,J＝242.5Hz,1C),150.8,150.5,138.5(d,J＝9.6Hz,1C),138.3,135.1(d,J＝12.6Hz,1C),134.7,134.6,133.7,128.9,128.7,126.7,126.5,125.7,125.0,124.8,119.9,117.3,115.9(d,J＝3.8Hz,1C),107.9(d,J＝23.0Hz,1C),102.3,42.3,20.9,18.6,14.1.
HRMS(ESI)for C32H26FN5O3[M+H]+,calcd:548.2092,found:548.2085.
HPLC analysis:MeOH-H2O(85:15),5.32min,98.31％purity.
实施例18：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1-丙基-1,4- 二氢喹啉-3-甲酰胺(命名为TL4800104)的制备
Figure PCTCN2016095813-appb-000044
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.85(s,1H),8.29(s,1H),8.06(s,1H),7.91(d,J＝2.0Hz,1H),7.89-7.75(m,4H),7.61(dd,J＝2.0,9.0Hz,1H),7.45(m,1H),7.44-7.38(m,3H),7.25(m,1H),4.25(t,J＝7.5Hz,2H),2.61(s,3H),2.45(s,3H),1.77-1.73(m,2H),1.02(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ173.6,166.2,161.7,155.3,154.1(d,J＝242.4Hz,1C),150.8,150.3,138.5(d,J＝14.3Hz,1C),135.1(d,J＝12.6Hz,1C),134.9,134.5,133.7,128.8,128.7,126.5,126.5,125.6,125.3,125.0,120.0,117.5,115.9(d,J＝2.5Hz,1C),115.8,107.9(d,J＝22.9Hz,1C),102.3,48.5,22.0,20.9,18.7,11.1.
HRMS(ESI)for C33H28FN5O3[M+H]+,calcd:562.2249,found:562.2245.
HPLC analysis:MeOH-H2O(85:15),6.12min,98.11％purity..
实施例19：1-丁基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800080)的制备
Figure PCTCN2016095813-appb-000045
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.87(s,1H),8.28(s,1H),8.06(s,1H),7.92(dd,J1＝2.0Hz,J2＝13.0Hz,1H),7.78-7.74(m,4H),7.61(dd,J＝1.5,8.5Hz,1H),7.45(dd,J＝1.0,9.0Hz,1H),7.41-7.38(m,3H),7.24(t,J＝7.5Hz,1H),4.31-4.27(t,J＝8.0Hz,2H),2.61(s,3H),2.45(s,3H),1.69(m,2H),1.50-1.45(q,J＝7.5Hz,2H),0.97(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ173.6,166.2,161.6,155.8,154.2(d,J＝242.6Hz,1C),150.7,150.0,138.5,138.4(d,J＝10.0Hz,1C),135.3(d,J＝12.9Hz,1C),135.1,134.5,133.6,128.7,128.6,126.5,126.3,126.1,125.6,125.0,120.0,117.4,115.8(d,J＝2.3Hz,1C),115.5,107.9(d,J＝23.1Hz,1C),102.4,46.9,30.7,26.0,20.9,19.7,18.7,14.1.
HRMS(ESI)for C34H30FN5O3[M+H]+,calcd:576.2405,found:576.2407.
HPLC analysis:MeOH-H2O(85:15),7.46min,98.19％purity..
实施例20：2-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800139)的制备
Figure PCTCN2016095813-appb-000046
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.84(s,1H),8.29(s,1H),8.05(s,1H),7.90(dd,J＝2.5,13.0Hz,1H),7.79-7.76(m,3H),7.74(s,1H),7.62(dd,J＝2.0,9.0Hz,1H),7.45(dd,J＝2.0,9.0Hz,1H),7.41-7.37(m,3H),7.24(t,J＝7.0Hz,1H),3.84(s,3H),2.96(d,J＝7.0Hz,2H),2.46(s,3H),1.30(t,J＝7.0Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.2,161.6,155.7,155.5,154.2(d,J＝242.0Hz,1C),150.1,139.8,138.4(d,J＝9.9Hz,1C),135.2(d,J＝13.6Hz,1C),135.0,134.4,133.8,128.8,128.7,126.4,126.3,125.9,125.3,125.0,119.6,117.7,115.9(d,J＝2.5Hz,1C),115.6,107.9(d,J＝22.5Hz,1C),102.4,35.3,25.2,20.9,13.7.
HRMS(ESI)for C32H26FN5O3[M+H]+,calcd:548.2092,found:548.2080.
HPLC analysis:MeOH-H2O(85:15),5.08min,95.14％purity.
实施例21：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-2-苯基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800144)的制备
Figure PCTCN2016095813-appb-000047
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ10.60(s,1H),8.27(s,1H),8.14(s,1H),7.78(d,J＝9.0Hz,1H),7.74(d,J＝8.5Hz,3H),7.71-7.69(dd,J＝2.0,9.0Hz,1H),7.55-7.50(m,6H),7.39-7.36(m,2H),7.30-7.27(m,1H),7.23(t,J＝7.5Hz,1H),7.19(dd,J1＝1.5,8.5Hz,1H),3.50(s,3H),2.51(s,3H).
13C NMR(125MHz,d6-DMSO)δ173.8,164.7,161.5,155.6,154.0(d,J＝242.4Hz,1C),152.6,150.1,139.5,138.1(d,J＝9.8Hz,1C),135.0(d,J＝12.8Hz,1C),134.7,134.2,134.1,130.0,129.1,128.9,128.7,128.6,126.7,126.4,125.3,124.8,120.8,118.0,115.6(d,J＝2.5Hz,1C),115.5,107.6(d,J＝22.9Hz,1C),102.3,37.6,21.0.
HRMS(ESI)for C36H26FN5O3[M+H]+,calcd:596.2092,found:596.2096.
HPLC analysis:MeOH-H2O(85:15),5.14min,98.3％purity.
实施例22：9-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-3-甲基-10-(4-甲基哌嗪-1-取代)-7-氧基-3,7-二氢-[1,4]氧氮卓[2,3,4-ij]喹啉-6-甲酰胺(命名为TL4800088)的制备
Figure PCTCN2016095813-appb-000048
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ12.56(s,1H),8.93(s,1H),8.31(s,1H),7.98(d,J＝12.0Hz,1H),7.78-7.75(m,3H),7.57(d,J＝12.5Hz,1H),7.42-7.38(m,4H),7.25(t,J＝7.5Hz,1H),4.90(d,J＝6.5Hz,1H),4.56(d,J＝10.5Hz,1H),4.37(d,J＝10.0Hz,1H),3.27(s,4H),2.43(s,4H),2.22(s,3H),1.45(d,J＝6.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.9,163.3,161.6,155.8(d,J＝243.9Hz,1C),155.2,154.2(d,J＝242.9Hz,1C),150.4,146.0,140.7(d,J＝7.1Hz,1C),137.6(d,J＝10.0Hz,1C),135.3(d,J＝12.8Hz,1C),134.8,131.8(d,J＝14.1Hz,1C),128.8,128.7,126.6,125.2,124.8,121.9(d,J＝8.9Hz,1C),116.3,115.8,109.8,108.5(d,J＝22.9Hz,1C),104.0(d,J＝23.8Hz,1C),102.3,68.6,55.8,54.8,50.6,50.6,46.5,18.3.
HRMS(ESI)for C36H31F2N7O4[M+H]+,calcd:664.2478,found:664.2467.
HPLC analysis:MeOH-H2O(85:15),16.90min,96.01％purity.
实施例23：1-环丙基-6-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-4-氧基-7-(哌嗪-1-取代)-1,4-二氢喹啉-3-甲酰胺(命名为TL4800095)的制备
Figure PCTCN2016095813-appb-000049
合成方法如实施例1。
MS(ESI)m/z 634[M+H]+.
实施例24：9-氟-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-8-(4-羟基哌啶-1-基)-5-甲基-1-氧代-1,5,6,7-四氢吡啶并[3,2,1-ij]喹啉-2-甲酰胺(命名为GDL5000076)的制备
Figure PCTCN2016095813-appb-000050
合成方法如实施例1。
1H NMR(500MHz,d6-DMSO)δ12.61(s,1H),8.95(s,1H),8.30(s,1H),7.98(d,J＝12.5Hz,1H),7.88(d,J＝12.5Hz,1H),7.78-7.74(m,3H),7.43-7.38(m,4H),7.24(t,J＝7.0Hz,1H),4.86(s,1H),3.68(s,1H),3.20(m,4H),2.92(m,3H),2.13-2.06(m,2H),1.85(m,2H),1.62(d,J＝8.5Hz,2H),1.52(s,1H),1.43(d,J＝ 6.0Hz,3H).
13C NMR(125MHz,d6-DMSO)δ175.1,163.3,161.5,157.5(d,J＝247.9Hz,1C),155.5,154.3(d,J＝243.0Hz,1C),150.2,147.4,142.4,137.6(d,J＝9.9Hz,1C),135.4(d,J＝12.9Hz,1C),135.0,133.6,128.8,128.7,126.4,125.8,125.2,124.2,116.3,115.7,109.8(d,J＝22.8Hz,1C),109.6,108.5(d,J＝22.9Hz,1C),102.4,57.1,25.6,20.1,19.0.
HRMS(ESI)for C37H32F2N6O4[M+H]+,calcd:663.2526,found:663.2520.
HPLC analysis:MeOH-H2O(85:15),11.93min,99.22％purity.
实施例25：6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800075)的制备
c.
Figure PCTCN2016095813-appb-000051
步骤c1：2-(1-((4-乙基苯基)氨基)亚乙基)丙二酸二乙酯(化合物13)
对乙基苯胺(2.42g，20mmol)，乙酰基丙二酸二乙酯(2.02g，10mmol)溶于50mL正戊烷，加入催化量对甲基苯磺酸(20mg)，回流反应过夜。降至室温，加少量饱和NaHCO3，用EA萃取两次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体2.68g(87.8％)。1HNMR(400MHz,d6-DMSO),δ10.98(s,1H),7.23(d,J＝8.0Hz,2H),7.14(d,J＝8.0Hz,2H),4.10(m,4H),2.63-2.58(q,J＝8.0Hz,2H),2.00(s,3H),1.21-1.16(m,9H).MS(ESI),m/z:306[M+H]+.
步骤c2：6-乙基-2-甲基-4-氧基-1,4-二氢喹啉-3-羧酸乙酯(化合物14)
2-(1-((4-乙基苯基)氨基)亚乙基)丙二酸二乙酯(化合物13)(2.5g，8.2mmol)溶于25mL二苯醚，搅拌下加热至200℃反应2小时。降至室温，有固体析出，过滤，用PE洗，抽干得白色固体2g(94.3％)。1HNMR(400MHz,d6-DMSO),δ11.78(s,1H),7.86(s,1H),7.53(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),4.23(q,J＝8.0Hz,2H),2.73-2.68(q,J＝8.0Hz,2H),2.37(s,3H),1.26(t,J＝8.0Hz,3H),1.21(t,J＝8.0Hz,3H).MS(ESI),m/z:260[M+H]+.
步骤c3：6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-羧酸乙酯(化合物15)
6-乙基-2-甲基-4-氧基-1,4-二氢喹啉-3羧酸乙酯(化合物14)(2g，7.7mmol)，K2CO3,(3.18g，23.1mmol)溶于50mL DMF，搅拌下加入MeI(0.72mL，11.55mmol)，50℃反应过夜。降至室温，加水淬灭，有固体析出，用水洗多次，固体用DCM多次萃取，合并有机相旋干，柱层析得白色固体1.52g(72.4％)。1HNMR(400MHz,CDCl3),δ8.23(s,1H),7.46(d,J＝8.0Hz,1H),7.37(d,J＝8.0Hz,1H),4.40(q,J＝8.0Hz,2H),3.719(s,3H),2.76-2.71(q,J＝8.0Hz,2H),2.48(s,3H),1.38(t,J＝8.0Hz,3H),1.26(t,J＝8.0Hz,3H).MS (ESI),m/z:274[M+H]+.
步骤c4：6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-羧酸(化合物16)
6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-羧酸乙酯(化合物15)(1.5g，5.5mmol)，NaOH(880mg，22mmol)溶于30mL乙醇和15mL水中，回流反应过夜。降至室温，旋干大部分有机溶剂，加水，在冰浴下用稀HCl调节PH至7-8，有固体析出，过滤，抽干得白色固体1.25g(93.3％)。1HNMR(400MHz,d6-DMSO),δ8.11(s,1H),7.88(d,J＝8.0Hz,1H),7.69(d,J＝8.0Hz,1H),3.87(s,3H),2.87(s,3H),2.80-2.74(q,J＝8.0Hz,2H),2.48(s,3H),1.24(t,J＝8.0Hz,3H).MS(ESI),m/z:246[M+H]+.
步骤c5：6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物17，TL4800075)
中间体16到17合成路线如实施例1b。
1H NMR(500MHz,d6-DMSO)δ11.02(s,1H),8.33(s,1H),8.09(s,1H),7.93(d,J＝1.5Hz,1H),7.91-7.76(m,4H),7.65(m,1H),7.46(d,J＝9.5Hz,1H),7.41(m,3H),7.26(m,1H),3.82(s,3H),2.75(q,J＝7.5Hz,2H),2.65(s,3H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.1,161.7,154.8,154.1(d,J＝242.6Hz,1C),152.4,150.5,139.9,139.6,138.5(d,J＝9.8Hz,1C),135.0(d,J＝13.1Hz,1C),133.3,128.8,128.6,126.6,126.2,124.9,124.6,124.1,119.0,117.5,115.9,107.9(d,J＝23.8Hz,1C),102.3,35.6,27.9,19.4,15.9.
HRMS(ESI)for C32H26FN5O3[M+H]+,calcd:548.2092,found:548.2089.
HPLC analysis:MeOH-H2O(85:15),5.61min,97.34％purity.
实施例26：6-叔丁基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800062)的制备
Figure PCTCN2016095813-appb-000052
合成方法如实施例25。
1H NMR(500MHz,d6-DMSO)δ11.03(s,1H),8.32(s,1H),8.25(d,J＝2.0Hz,1H),7.92-7.87(m,2H),7.83(m,1H),7.78(d,J＝7.5Hz,2H),7.75(s,1H),7.45(dd,J＝2.0,8.5Hz,1H),7.42-7.38(m,3H),7.26(t,J＝7.5Hz,1H),3.84(s,3H),2.66(s,3H),1.36(s,9H).
13C NMR(125MHz,d6-DMSO)δ174.2,166.1,161.7,154.8,154.1(d,J＝242.6Hz,1C),152.7,150.6146.8,139.4,138.5(d,J＝9.8Hz,1C),135.0(d,J＝13.0Hz,1C),134.7,131.1,128.9,128.7,126.7,125.8,125.0,124.6,121.5,118.9,117.5,115.9,108.0(d,J＝23.4Hz,1C),102.3,35.6,34.8,31.5,19.5.
HRMS(ESI)for C34H30FN5O3[M+H]+,calcd:576.2405,found:576.2411.
HPLC analysis:MeOH-H2O(85:15),7.12min,97.03％purity.
实施例27：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-丙基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800116)的制备
Figure PCTCN2016095813-appb-000053
合成方法如实施例25。
1H NMR(500MHz,d6-DMSO)δ11.00(s,1H),8.30(s,1H),8.06(d,J＝2.0Hz,1H),7.91(dd,J＝2.0,12.5Hz,1H),7.81-7.77(m,3H),7.74(s,1H),7.64(dd,J＝2.0,9.0Hz,1H),7.45(dd,J＝1.5,9.0Hz,1H),7.41-7.38(m,3H),7.25(m,1H),3.83(s,3H),2.71(t,J＝7.2Hz,2H),2.64(s,3H),1.69-1.61(q,J＝7.1Hz,2H),0.89(t,J＝7.0Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.1,161.6,155.4,154.2(d,J＝242.8Hz,1C),152.4,150.3,139.7,138.5(d,J＝9.8Hz,1C),138.3,135.2(d,J＝12.8Hz,1C),134.9,133.8,128.8,128.7,126.5,126.2,125.5,125.0,119.1,117.5,115.9(d,J＝2.6Hz,1C),115.7,108.0(d,J＝23.1Hz,1C),102.4,36.9,35.7,24.4,19.5,13.9.
HRMS(ESI)for C33H28FN5O3[M+H]+,calcd:562.2249,found:562.2249.
HPLC analysis:MeOH-H2O(85:15),6.60min,95.83％purity.
实施例28：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-三氟甲氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800117)的制备
Figure PCTCN2016095813-appb-000054
合成方法如实施例25。
1H NMR(500MHz,d6-DMSO)δ12.53(s,1H),10.76(s,1H),8.33(s,1H),8.09(m,2H),7.89(d,J＝12.5Hz,1H),7.82-7.76(m,4H),7.46-7.40(m,4H),7.27(m,1H),3.87(s,3H),2.63(s,3H).
13C NMR(125MHz,d6-DMSO)δ172.9,165.6,161.7,154.6,154.1(d,J＝242.8Hz,1C),152.8,150.7,144.9,140.1,138.4(d,J＝9.8Hz,1C),135.2(d,J＝12.5Hz,1C),134.6,128.9,128.7,126.8,126.2,125.0,124.3,121.7,120.7,120.3,119.6,116.8,116.0,115.9,108.0(d,J＝23.4Hz,1C),102.3,36.0,19.6.
HRMS(ESI)for C31H21F4N5O4[M+H]+,calcd:604.1602,found:604.1597.
HPLC analysis:MeOH-H2O(85:15),5.31min,97.59％purity..
实施例29：6-乙基-1,2-二甲基-4-氧基-N-(4((5-苯基-7H-吡咯[2,3,d]嘧啶-4-取代)氧基)-1,4-二氢喹啉-3-甲酰胺(命名为TL4830014)的制备
Figure PCTCN2016095813-appb-000055
合成方法如实施例25。
1H NMR(500MHz,d6-DMSO)δ10.81(s,1H),8.29(s,1H),8.09(s,1H),7.81(d,J＝9.0Hz,1H),7.78-7.75(m,4H),7.70(s,1H),7.65(dd,J＝1.5,8.5Hz,1H),7.38(m,2H),7.26-7.21(m,3H),3.83(s,3H),2.79-2.74(q,J＝7.5Hz,2H),2.64(s,3H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.9,174.0,165.8,162.5,152.2,150.4,148.5,139.9,139.7,137.0,135.1,133.3,128.9,128.6,126.4,126.3,124.2,122.6,120.9,119.5,117.5,115.8,103.0,35.6,27.9,19.5,16.0.
HRMS(ESI)for C32H27N5O3[M+H]+,calcd:530.2187,found:530.2182.
HPLC analysis:MeOH-H2O(85:15),5.25min,97.83％purity.
实施例30：6-乙基-12-二甲基-N-(3-甲基-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4830016)的制备
Figure PCTCN2016095813-appb-000056
合成方法如实施例25。
1H NMR(500MHz,d6-DMSO)δ10.79(s,1H),8.28(s,1H),8.09(s,1H),7.80(m,3H),7.71-7.65(m,3H),7.53(d,J＝7.5Hz,1H),7.40(t,J＝7.5Hz,2H),7.26(t,J＝7.5Hz,1H),7.11(d,J＝8.5Hz,1H),3.83(s,3H),2.76(q,J＝7.5Hz,2H),2.65(s,3H),2.09(s,3H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,165.7,162.2,154.7,152.3,150.7,147.0,139.9,139.7,137.2,134.8,133.3,130.7,128.9,128.6,126.6,126.3,124.2,123.0,122.2,119.3,118.6,117.5,116.1,102.6,35.6,27.9,19.5,16.9,15.9.
HRMS(ESI)for C33H29N5O3[M+H]+,calcd:544.2343,found:544.2348.
HPLC analysis:MeOH-H2O(85:15),5.74min,96.04％purity.
实施例31：6-乙基-N-(2-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000091)的制备
Figure PCTCN2016095813-appb-000057
合成方法如实施例25。
1H NMR(400MHz,d6-DMSO)δ12.13(s,1H),8.29(s,1H),8.24(t,J＝8.8Hz,1H),8.17(s,1H),7.88(d,J＝8.8Hz,1H),7.76(d,J＝7.6Hz,2H),7.71-7.69(m,2H),7.40-7.34(m,3H),7.22(t,J＝8.0Hz,1H),7.10(d,J＝7.2Hz,1H),3.90(s,3H),2.91(s,3H),2.79(q,J＝7.6Hz,2H),1.26(t,J＝7.6Hz,3H).
13C NMR(125MHz,d6-DMSO)δ175.6,165.9,162.4,157.4,156.2,153.9(d,J＝244.0Hz,1C),150.5,149.3(d,J＝10.5Hz,1C),141.1,139.7,135.6,134.1,129.3,129.0,126.7,126.5,126.4,125.0(d,J＝11.1Hz,1C),124.8,124.1,118.7,118.2,116.0,115.2,110.9(d,J＝22.3Hz,1C),103.5,36.6,28.4,20.3,16.3.
HRMS(ESI)for C32H26FN5O3[M+H]+,calcd:548.2092,found:548.2098.
HPLC analysis:MeOH-H2O(85:15),7.37min,95.08％purity.
Melting point:241.1-243.7℃.
实施例32：N-(4-((7H-吡咯[2,3-d]嘧啶-4-取代)氧基)-3-三氟苯基)-6-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800147)的制备
Figure PCTCN2016095813-appb-000058
合成方法如实施例25。
1H NMR(500MHz,d6-DMSO)δ12.28(s,1H),10.98(s,1H),8.30(d,J＝2.0Hz,1H),7.92(dd,J＝2.0,12.5Hz,1H),7.81(d,J＝9.0Hz,1H),7.66(dd,J＝2.0,9.0Hz,1H),7.51(m,1H),7.87(dd,J＝2.0,9.0Hz,1H),7.39(m,1H),6.59(m,1H),3.83(s,3H),2.79-2.75(q,J＝7.5Hz,2H),2.64(s,3H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.2,161.5,154.2(d,J＝242.9Hz,1C),154.1,152.3,150.5,140.0,138.6(d,J＝9.9Hz,1C),135.1(d,J＝12.9Hz,1C),133.4,126.3,126.0,124.9,124.2,119.2,117.6,115.9(d,J＝2.6Hz,1C),108.0(d,J＝23.2Hz,1C),104.5,98.3,35.7,27.9,19.5,16.0.
HRMS(ESI)for C26H22FN5O3[M+H]+,calcd:472.1779,found:472.1776.
HPLC analysis:MeOH-H2O(85:15),3.99min,96.56％purity.
实施例33：6-乙基-N-(3-氟-4-((3-苯基-1H-吡咯[2,3-d]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800172)的制备
Figure PCTCN2016095813-appb-000059
合成方法如实施例25。
1H NMR(500MHz,d6-DMSO)δ12.03(s,1H),11.02(s,1H),8.08(m,2H),7.98-7.95(d,J＝13.0Hz,2H),7.81(d,J＝8.5Hz,1H),7.70(d,J＝7.5Hz,2H),7.66(d,J＝8.5Hz,1H),7.60(s,1H),7.47(d,J＝9.0Hz,1H),7.54(m,3H),7.21(t,J＝7Hz,1H),6.31(d,J＝5.0Hz,1H),3.83(s,3H),2.79-2.74(q,J＝7.5Hz,2H),2.64(s,3H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.2,158.8,153.9(d,J＝243.8Hz,1C),152.4,152.0,145.1,140.0,139.7,138.5(d,J＝9.4Hz,1C),136.1(d,J＝11.9Hz,1C),135.8,133.4,129.1,128.4,126.3,126.2,124.2,119.1,117.6,116.4(d,J＝2.6Hz,1C),115.6,108.5(d,J＝22.0Hz,1C),107.6,101.1,35.7,27.9,19.5,16.0.
HRMS(ESI)for C33H27FN4O3[M+H]+,calcd:547.214,found:547.2145.
HPLC analysis:MeOH-H2O(85:15),6.31min,95.08％purity.
实施例34：6-乙基-N-(3-氟-4-((5-(4-甲氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000037)的制备
Figure PCTCN2016095813-appb-000060
合成方法如实施例25。
1H NMR(400MHz,d6-DMSO)δ10.99(s,1H),8.28(s,1H),8.09(s,1H),7.90(dd,J＝2.0,15.0Hz,1H),7.81(d,J＝8.0Hz,1H),7.70-7.64(m,4H),7.46-7.36(m,2H),6.97(d,J＝8Hz,2H),3.84(s,3H),3.78(s,3H),2.76(q,J＝7.5Hz,2H),2.65(s,3H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.4,166.6,162.1,158.9,155.6(d,J＝244.0Hz,1C),155.4,152.8,150.71,140.4,140.1,138.9(d,J＝9.8Hz,1C),135.6(d,J＝13.2Hz.1C),133.8,130.4,127.6,126.7,125.41,124.6,119.5,118.0,116.4(d,J＝1.3Hz,1C),116.0,114.7,108.4(J＝23.3Hz,1C),102.8,56.0,36.1,28.4,19.9,16.4.
HRMS(ESI)for C33H28FN5O4[M+H]+,calcd:578.2198,found:578.2190.
HPLC analysis:MeOH-H2O(85:15),5.22min,96.31％.
实施例35：6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(TL4800178)的制备
d.
Figure PCTCN2016095813-appb-000061
步骤d1：2-(((4-乙基苯基)氨基)亚甲基)丙二酸二乙酯(化合物18)
对乙基苯胺(3.21g，30mmol)，乙氧基甲叉丙二酸二乙酯(3.24g，15mmol)，催化量对甲基苯磺酸溶于正戊烷，回流反应过夜。冷至室温，加少量饱和NaHCO3，用EA萃取两次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体3.98g(96％)。1HNMR(400MHz,CDCl3),δ10.98(d,J＝12.0Hz,1H),8.50(d,J＝12.0Hz,1H),7.18(d,J＝8.0Hz,2H),7.05(d,J＝8.0Hz,2H),4.32-4.28(q,J＝4.0Hz,2H),4.26-4.21(q,J＝4.0Hz,2H),2.65-2.60(q,J＝4.0Hz,3H),1.37(t,J＝4.0Hz,3H),1.32(t,J＝4.0Hz,3H),1.21(t,J＝4.0Hz,3H).MS(ESI),m/z:292[M+H]+.
步骤d2：6-乙基-4-氧基-1,4-二氢喹啉-3-羧酸乙酯(化合物19)
2-(((4-乙基苯基)氨基)亚甲基)丙二酸二乙酯(化合物18)(3.5g，12mmol)溶于多聚磷酸，加热至100℃，反应过夜。冷至室温，加水搅拌有固体析出，过滤，固体用PE洗三次，溶于EA，旋干，柱层析得固体2.65g(90％)。
步骤d3：6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物20，TL4800178)
其他合成步骤如实施例25中化合物15～17的合成方法。
1H NMR(500MHz,d6-DMSO)δ12.70(s,1H),8.99(s,1H),8.29(s,1H),8.24(s,1H),7.98(d,J＝12.0Hz,1H),7.81-7.75(m,5H),7.43-7.40(m,4H),7.24(s,1H),4.07(s,3H),2.81(d,J＝6.5Hz,2H),1.27(t,J＝6.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ176.1,163.5,161.5,150.1,149.4,142.0,138.8,135.0,134.1,128.8,128.7,127.2,126.4,125.2,124.5,118.3,116.2,115.6,110.2,108.5,102.4,41.9,28.2,15.9.
HRMS(ESI)Calcd for[M+H]+＝534.1936,found:[M+H]+＝534.1932.
HPLC analysis:MeOH-H2O(85:15),11.54min,97.15％.
实施例36：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-9-甲基-1-氧基-1,5,6,7-四氢吡啶[3,2,1-ij]喹啉-2-甲酰胺(命名为TL4800160)的制备
Figure PCTCN2016095813-appb-000062
合成方法如实施例35。
1H NMR(500MHz,d6-DMSO)δ12.75(s,1H),8.86(s,1H),8.28(s,1H),8.01(s,1H),8.00-7.97(m,1H),7.77(d,J＝7.5Hz,2H),7.74(s,1H),7.49(s,1H),7.44-7.38(m,4H),7.24(t,J＝7.5Hz,1H),4.42(t,J＝5.0Hz,2H),3.03(t,J＝6.0Hz,2H),2.45(s,3H),2.14(t,J＝5.0Hz,2H).
13C NMR(125MHz,d6-DMSO)δ176.0,163.6,161.5,155.8,154.3(d,J＝243.0Hz,1C),150.0,147.4,137.7(d,J＝9.9Hz,1C),135.3(d,J＝12.9Hz,1C),135.2,135.1,135.1,134.2,129.0,128.7,128.67,127.2,126.3,125.2,123.6,116.2,115.6,109.8,108.4(d,J＝23.1Hz,1C),102.4,52.9,26.5,21.2,21.2.
HRMS(ESI)for C32H24FN5O3[M+H]+,calcd:546.1936,found:546.1932.
HPLC analysis:MeOH-H2O(85:15),12.28min,97.3％purity.
实施例37:N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-9-甲基-1-氧代-6,7-二氢-1H,5H-吡啶并[3,2,1-ij]喹啉-2-甲酰胺(TL4830032)的制备
Figure PCTCN2016095813-appb-000063
合成方法如实施例35。
1H NMR(500MHz,CDCl3)δ12.64(s,1H),8.73(s,1H),8.63(d,J＝1.5Hz,1H),8.17(s,1H),8.01(d,J＝12.5Hz,1H),7.59(s,1H),7.47(d,J＝2.1Hz,1H),7.36(s,1H),7.33(s,1H),7.28(m,1H),4.29(s,2H),4.08(s,3H),4.07(s,3H),3.08(s,2H),2.49(s,3H),2.28(s,2H).
13C NMR(125MHz,CDCl3)δ176.7,164.9,163.5,156.0,154.3(d,J＝246.0Hz,1C),152.9,150.3,149.5,146.1,137.9(d,J＝9.9Hz,1C),135.5,135.3(d,J＝13.1Hz,1C),134.8,133.9,127.5,127.1,124.5,123.8,116.1(d,J＝3.0Hz,1C),110.8,110.3,109.2(d,J＝23.1Hz,1C),106.9,101.1,56.4,53.2,26.7,21.4,21.16.
HRMS(ESI)for C30H25FN4O5[M+H]+,calcd:658.2472,found:658.2753.
HPLC analysis:MeOH-H2O(85:15),10.41min,97.42％purity。
实施例38：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800167)的制备
Figure PCTCN2016095813-appb-000064
合成方法如实施例35。
1H NMR(500MHz,d6-DMSO)δ12.67(s,1H),8.97(s,1H),8.30(s,1H),8.20(s,1H),7.99-7.97(d,J＝12.5Hz,1H),7.80-7.74(m,5H),7.42-7.38(m,4H),7.25(m,1H),4.06(s,3H),2.49(s,3H).
13C NMR(125MHz,d6-DMSO)δ176.0,163.5,161.6,155.3,154.3(d,J＝242.5Hz,1C),150.3,149.4,138.6,137.7(d,J＝9.6Hz,1C),135.8,135.3(d,J＝12.9Hz,1C),135.1,134.9,128.8,128.7,127.1,126.5,125.8,125.2,118.2,116.3(d,J＝2.9Hz,1C),115.8,110.2,108.5(d,J＝23.3Hz,1C),102.4,41.9,21.1.
HRMS(ESI)for C31H24FN5O3[M+H]+,calcd:534.1936,found:534.19324.
HPLC analysis:MeOH-H2O(85:15),3.78min,97.54％purity.
实施例39：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-(丙基-1-烯基-2-取代)-1,4-二氢喹啉-3-甲酰胺(命名为T50167)的制备
e.
Figure PCTCN2016095813-appb-000065
步骤e1：1,2-二甲基-4-氧基-6-(丙基-1-烯基-2-取代)-1,4-二氢喹啉-3-羧酸甲酯(化合物21)
6-溴-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-羧酸甲酯(1.5g，4.85mmol)，2-丙烯硼酸(1.22g，7.28mmol)，Pd(PPh3)4(280mg，0.24mmol)，K2CO3(1.34g，9.7mmol)溶于30mL二氧六环和5mL水中，在氩气保护下，90℃反应过夜。冷至室温，过滤，旋干大部分有机溶剂，用EA萃取两次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体1.23g(93.8％)。1HNMR(500MHz,d6-DMSO),δ8.18(s,1H),8.96(d,J＝10.0Hz,1H),7.80(d,J＝10.0Hz,1H),5.58(m,1H),5.21(s,1H),3.78(s,3H),3.77(s,3H),2.45(s,3H),2.17(s,3H).MS(ESI),m/z:272[M+H]+.
步骤e2：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-(丙基-1-烯基-2-取代)-1,4-二氢喹啉-3-甲酰胺(化合物22，TL50167)
其他合成步骤如实施例25。
1H NMR(500MHz,d6-DMSO)δ10.93(s,1H),8.29(m,2H),8.01(d,J＝9.0Hz,1H),7.92-7.86(m,2H),7.78-7.74(m,3H),7.45(d,J＝9.0Hz,1H),7.41-7.38(t,J＝8.0Hz,3H),7.25(t,J＝7.5Hz,1H),5.61(s,1H),5.23(s,1H),3.85(s,3H),2.64(s,3H),2.20(s,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.0,161.8,154.6,154.1(d,J＝242.3Hz,1C),152.5,150.7,141.6,140.7,138.5(d,J＝9.6Hz,1C),135.9,135.1(d,J＝12.8Hz,1C),134.6,130.2,128.9,128.7,126.8,126.0, 125.0,124.3,122.1,119.7,117.7,116.0,113.9,108.0(d,J＝21.9Hz,1C),102.3,35.7,21.8,19.5.
HRMS(ESI)for C33H26FN5O3[M+H]+,calcd:560.2092,found:560.2081.
HPLC analysis:MeOH-H2O(90:10),8.13min,97.79％purity..
实施例40：6-环丙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50148)的制备
Figure PCTCN2016095813-appb-000066
合成方法如实施例39。
1H NMR(500MHz,d6-DMSO)δ11.02(s,1H),8.29(s,1H),7.95(d,J＝2.0Hz,1H),7.90(dd,J＝2.0,12.5Hz,1H),7.79-7.77(m,3H),7.73(s,1H),7.51(dd,J＝2.0,8.5Hz,1H),7.45(dd,J＝2.0,9.5Hz,1H),7.41-7.37(m,3H),7.24(t,J＝7.0Hz,1H),3.82(s,3H),2.64(s,3H),2.14-2.09(m,1H),1.04(m,2H),0.76(m,2H).
13C NMR(125MHz,d6-DMSO)δ173.8,166.1,161.6,154.2(d,J＝242.8Hz,1C),152.4,150.1,140.1,139.4,138.4(d,J＝9.9Hz,1C),135.2(d,J＝13.1Hz,1C),135.0,130.9,128.8,128.7,126.4,126.3,125.0,121.8,119.0,117.6,115.9,115.6,108.0(d,J＝23.4Hz,1C),102.4,35.7,19.5,15.0,10.2.
HRMS(ESI)for C33H26FN5O3[M+H]+,calcd:560.2092,found:560.2081.
HPLC analysis:MeOH-H2O(75:25),5.63min,95.14％purity.
实施例41：6-(环戊基-1-烯基-1-取代)-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50160)的制备
Figure PCTCN2016095813-appb-000067
合成方法如实施例39。
1H NMR(500MHz,d6-DMSO)δ12.52(s,1H),10.98(s,1H),8.33(s,1H),8.16(s,1H),7.99(d,J＝8.0Hz,1H),7.91(d,J＝12.0Hz,1H),7.83(d,J＝9.0Hz,1H),7.77(m,3H),7.46(d,J＝9.0Hz,1H),7.41(m,3H),7.27(t,J＝7.0Hz,1H),6.87(s,1H),6.44(s,1H),3.84(s,3H),2.75(m,2H),2.64(s,3H),2.53(m,2H),2.01(m,2H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.0,161.8,154.6,154.1(d,J＝243.0Hz,1C),152.4,151.9,150.7,141.2,140.3,139.6,138.5(d,J＝10.0Hz,1C),135.1(d,J＝12.6Hz,1C),134.6,132.1,130.7,128.9,128.7,127.5,127.8,126.8,126.2,125.4,124.9,124.2,122.0,119.5,117.7,116.0(d,J＝2.1Hz,1C),108.0(d,J＝23.3Hz,1C),102.3,67.5,35.7,34.8,33.6,33.2,30.9,25.6,23.3,21.5,19.5.
HRMS(ESI)for C35H28FN5O3[M+H]+,calcd:586.2249,found:586.2243.
HPLC analysis:MeOH-H2O(85:15),11.32min,97.72％purity.
实施例42：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-苯基-1,4-二氢喹啉-3-甲酰胺(命名为TL50163)的制备
Figure PCTCN2016095813-appb-000068
合成方法如实施例39。
1H NMR(500MHz,d6-DMSO)δ10.94(s,1H),8.51(d,J＝2.0Hz,1H),8.31(s,1H),8.13(dd,J＝2.5,9.0Hz,1H),7.99(d,J＝9.0Hz,1H),7.91(dd,J＝2.0,13.0Hz,1H),7.78(m,4H),7.75(s,1H),7.52(t,J＝7.5Hz,2H),7.47(dd,J1＝2.0,9.0Hz,1H),7.43-7.39(m,4H),7.26(t,J＝7.5Hz,1H),3.88(s,3H),2.65(s,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.0,161.7,155.2,154.2(d,J＝242.9Hz,1C),152.5,150.4,140.8,139.2,138.4(d,J＝9.8Hz,1C),135.9,135.2(d,J＝12.9Hz,1C),134.8,131.5,129.7,128.8,128.7,128.3,127.1,126.6,125.0,123.3,119.9,118.4,116.0(d,J＝2.9Hz,1C),115.8,108.0(d,J＝23.0Hz,1C),102.4,35.8,19.5.
HRMS(ESI)for C36H26FN5O3[M+H]+,calcd:596.2092,found:596.2089.
HPLC analysis:MeOH-H2O(85:15),6.78min,95.15％purity.
实施例43：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-(1-哌啶-4-取代)-1H-吡唑-4-取代)-1,4-二氢喹啉-3-甲酰胺(命名为TL50180)的制备
Figure PCTCN2016095813-appb-000069
合成方法如实施例39。
MS(ESI)m/z 669[M+H]+.
实施例44：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-6-异丙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50172)的制备
f.
Figure PCTCN2016095813-appb-000070
步骤f1：6-异丙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-羧酸乙酯(化合物23)
1,2-二甲基-4-氧基-6-(丙基-1-烯基-2-取代)-1,4-二氢喹啉-3-羧酸甲酯(化合物21)(542mg，2mmol)溶于MeOH，加入55mg Pd/C催化剂，氢气压保护下，室温反应8小时。过滤，滤液旋干，柱层析得固 体440mg(80.59％)。1HNMR(400MHz,d6-DMSO),δ7.99(s,1H),7.77(d,J＝8.0Hz,1H),7.67(d,J＝8.0Hz,1H),3.77(s,3H),3.76(s,3H),3.08-3.01(m,1H),2.44(s,3H),1.26(s,3H),1.24(s,3H).MS(ESI),m/z:274[M+H]+.
步骤f2：N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-6-异丙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物24，TL50172)
其他合成步骤如实施例25。
1H NMR(500MHz,d6-DMSO)δ11.02(s,1H),8.31(s,1H),8.12(s,1H),7.90(d,J＝12.5Hz,1H),7.84-7.72(m,5H),7.46-7.27(m,4H),7.27(d,J＝6.5Hz,1H),3.84(s,3H),3.07(m,1H),2.66(s,3H),1.27(m,6H).
13C NMR(125MHz,d6-DMSO)δ174.1,166.1,161.7,154.2(d,J＝246.0Hz,1C),152.5,150.4,144.5,139.8,138.5(d,J＝9.1Hz,1C),135.1(d,J＝12.6Hz,1C),134.8,132.1,128.8,128.7,126.6,126.2,125.1,125.0,122.6,119.0,117.6,115.9,115.8,108.0(d,J＝23.3Hz,1C),102.4,35.7,33.2,24.2,19.5.
HRMS(ESI)for C33H28FN5O3[M+H]+,calcd:562.2249,found:562.2253.
HPLC analysis:MeOH-H2O(85:15),6.28min,98.65％purity.
实施例45：6-环戊基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50161)的制备
Figure PCTCN2016095813-appb-000071
合成方法如实施例44。
1H NMR(500MHz,d6-DMSO)δ11.03(s,1H),8.33(d,J＝2.0Hz,1H),8.12(d,J＝1.5Hz,1H),7.91(dd,J＝2.0,12.5Hz,1H),7.82-7.75(m,4H),7.69(dd,J＝2.0,9.0Hz,1H),7.45(dd,J＝1.5,9.0Hz,1H),7.42-7.38(m,3H),7.27(m,1H),3.83(s,3H),3.15(m,1H),2.65(s,3H),2.10-2.06(m,2H),1.82-1.78(m,2H),1.71-1.68(m,2H),1.62-1.56(m,2H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.1,161.7,154.7,154.1(d,J＝242.5Hz,1C),152.6,150.6,142.2,139.7,138.5(d,J＝9.9Hz,1C),135.0(d,J＝12.8Hz,1C),134.6,132.6,128.9,128.8,128.7,126.7,126.1,125.4 124.9,124.4,123.3,118.9,117.5,116.0,115.9(d,J＝2.8Hz,1C),108.0(d,J＝23.0Hz,1C),102.3,45.0,35.7,34.6,30.9,25.5,19.5.
HRMS(ESI)for C35H30FN5O3[M+H]+,calcd:588.2405,found:588.2394.
HPLC analysis:MeOH-H2O(85:15),8.40min,96.84％purity.
实施例46：3-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)氨甲酰基-1,2-二甲基-4-氧基-1,4-二氢喹啉-6-羧酸甲酯(命名为TL4800019)的制备
g.
Figure PCTCN2016095813-appb-000072
步骤g1：3-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)氨甲酰基-1,2-二甲基-4-氧基-1,4-二氢喹啉-6-羧酸甲酯(化合物25，TL4800019)
6-溴-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(200mg，0.33mmol)，PdCl2(dppf)，三乙胺溶于甲醇和催化量DMF，在CO压力下，95℃反应过夜。冷至室温，过滤，旋干大部分有机溶剂，DCM萃取两次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体120mg(63.16％)。
1H NMR(500MHz,d6-DMSO)δ12.52(s,1H),10.76(s,1H),8.82(d,J＝2.0Hz,1H),8.33(s,1H),8.25(dd,J＝2.0,9.0Hz,1H),8.00(d,J＝9.0Hz,1H),7.91-7.88(dd,J＝2.0,12.5Hz,1H),7.77(m,3H),7.46(dd,J＝1.0,9.0Hz,1H),7.41(m,3H),7.28(t,J＝7.0Hz,1H),3.92(s,3H),3.86(s,3H),2.62(s,3H).
13C NMR(125MHz,d6-DMSO)δ173.7,166.0,165.5,161.7,154.6,154.1(d,J＝242.8Hz,1C),152.8,150.7,144.2,138.3(d,J＝10.0Hz,1C),135.2(d,J＝12.8Hz,1C),134.7,132.7,128.9,128.7,128.1,126.8,125.8,125.0,124.9,124.3,121.4,118.3,116.0,115.9(d,J＝2.5Hz,1C),108.0(d,J＝23.0Hz,1C),102.3,52.8,35.9,19.6.
HRMS(ESI)for C32H24FN5O5[M+H]+,calcd:578.1834,found:578.1833.
HPLC analysis:MeOH-H2O(85:15),4.26min,96.31％purity.
实施例47：N-(3-氟-4-((7-甲基-5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL50134)的制备
h.
Figure PCTCN2016095813-appb-000073
步骤h1：N-(3-氟-4-((7-甲基-5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物26，TL50134)
N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(100mg，0.18mmol)，碳酸铯(122mg，0.36mmol)溶于20mL DMF，加入MeI(22μL，0.36mmol)，40℃反应过夜。冷至室温，加水淬灭，DCM萃取两次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体80mg(81.63％)。
1H NMR(500MHz,d6-DMSO)δ11.00(s,1H),8.38(s,1H),8.06(s,1H),7.90(dd,J＝2.0,13.0Hz,1H),7.82-7.75(m,4H),7.62(dd,J＝2.0,8.5Hz,1H),7.47-7.38(m,4H),7.28(t,J＝7.5Hz,1H),3.89(s,3H),3.82(s,3H),2.63(s,3H),2.45(s,3H).
13C NMR(125MHz,d6-DMSO)δ173.9,166.1,161.8,154.1(d,J＝242.8Hz,1C),153.1,152.3,150.6,139.5,138.6(d,J＝10.5Hz,1C),135.0(d,J＝12.6Hz,1C),134.4,134.2,133.8,128.8,128.8,128.3,126.9,126.2,125.5,124.9,119.2,117.4,115.9(d,J＝2.4Hz,1C),115.3,108.0(d,J＝23.0Hz,1C),102.4,35.6,31.8,20.9,19.5.
HRMS(ESI)Calcd for[M+H]+＝548.2092,found:[M+H]+＝548.2087.
HPLC analysis:MeOH-H2O(85:15),5.86min,97.75％.
实施例48：N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800191)的制备
i.
Figure PCTCN2016095813-appb-000074
步骤j1：2-氨基-4,5-二甲氧基苯甲酸甲酯(化合物27)
4,5-二甲氧基-2-硝基苯甲酸甲酯(10g，41mmol)，1g Pd/C溶于200mL乙醇，在氢气压力下室温反应过夜。过滤，有机相旋干，柱层析得固体7.3g(84.88％)。1HNMR(500MHz,d6-DMSO),δ7.33(s,1H),7.31(s,1H),5.62(s,2H),3.90(s,3H),3.89(s,3H),3.87(s,3H).MS(ESI),m/z:212[M+H]+.
步骤j2：6,7-二甲氧基喹唑啉-4(1H)-酮(化合物28)
2-氨基-4,5-二甲氧基苯甲酸甲酯(化合物27)(7g，33mmol)溶于100mL DMF和50mL甲醇，向混合液中加入甲酰胺(10.5mL，264mmol)和甲醇钠(10.69g，198mmol)，回流反应过夜。冷至室温，加水淬灭反应，用稀盐酸中和反应液，过滤，用水和乙醚洗，抽干得固体6.08g(89.44％)。1HNMR(500MHz,d6-DMSO),δ12.05(s,1H),7.98(s,1H),7.44(s,1H),7.13(s,1H),3.90(s,3H),3.87(s,3H).MS(ESI),m/z:207[M+H]+.
步骤j3：4-氯-6,7-二甲氧基喹唑啉(化合物29)
6,7-二甲氧基喹唑啉-4(1H)-酮(化合物28)(6g，29mmol)溶于100mL二氯亚砜和10mL DMF，回流反应过夜。冷至室温，旋干大部分溶剂，将旋干的溶液缓慢倒入冰水中，有固体析出，过滤，用水和乙醚洗，抽干得固体5.34g(82.15％)。1HNMR(500MHz,d6-DMSO),δ8.88(s,1H),7.46(s,1H),7.40(s,1H),4.02(s,3H),4.00(s,3H).MS(ESI),m/z:226[M+H]+.
步骤j4：4-(2-氟-4-硝基苯氧基)-6,7-二甲氧基喹唑啉(化合物30)
4-氯-6,7-二甲氧基喹唑啉(化合物29)(5g，22.3mmol)，2-氟-4-硝基苯酚(4.2g，26.7mmol)溶于100mL氯苯，于130℃反应过夜。冷至室温，过滤，固体在NaOH溶液中搅拌1小时，再过滤得固体5.22g(67.8％)。1HNMR(500MHz,d6-DMSO),δ8.59(s,1H),8.42(dd,J＝5.0,10.0Hz,1H),8.25(dd,J＝5.0,10.0Hz,1H),7.85(t,J＝10.0Hz,1H),7.60(s,1H),7.50(s,1H),4.01(s,3H),4.00(s,3H).MS(ESI),m/z:346[M+H]+.
步骤j5：N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物31，TL4800191)
其他合成步骤如实施例25。
1H NMR(500MHz,CDCl3)δ12.69(s,1H),8.64(s,1H),8.34(s,1H),7.99(dd,J＝2.0,12.5Hz,1H),7.60(m,2H),7.53(d,J＝8.5Hz,1H),7.45(d,J＝8.5Hz,1H),7.36(s,1H),7.29-7.26(m,1H),4.09(s,3H),4.07(s,3H),3.91(s,3H),3.08(s,3H),2.84-2.80(q,J＝7.5Hz,2H),1.35-1.32(t,J＝7.5Hz,3H).
13C NMR(125MHz,CDCl3)δ176.6,165.0,164.9,158.2,156.0,154.3(d,J＝245.6Hz,1C),152.9,150.3,149.4,141.5,138.7,138.3(d,J＝9.6Hz,1C),135.12(d,J＝12.9Hz,1C),133.6,126.4,125.4,125.3,123.7,123.7,116.2(d,J＝2.8Hz,1C),115.8,113.6,110.3,109.4(d,J＝22.9Hz,1C),106.8,101.1,56.4,35.7,28.3,20.4,15.3.
HRMS(ESI)Calcd for[M+H]+＝543.2038,found:[M+H]+＝543.2035.
HPLC analysis:MeOH-H2O(85:15),5.03min,99.75％.
实施例49：N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-6-氟-1-甲基-7-(4-((5-甲基-2-氧代-1,3- 二氧杂环戊烯-4-基)甲基)哌嗪-1-基)-4-氧代-1,4-二氢-[1,3]硫氮杂环丁烷并[3,2-a]喹啉-3-甲酰胺(命名为GDL5000082)的制备
Figure PCTCN2016095813-appb-000075
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)δ12.08(s,1H),8.56(s,1H),7.93(d,J＝13.0Hz,1H),7.80(d,J＝13.5Hz,1H),7.56(s,1H),7.46-7.40(m,3H),6.86(d,J＝7.0Hz,1H),6.33(q,J＝6.0Hz,1H),4.00(s,3H),3.98(s,3H),3.46(s,2H),3.27(s,4H),2.63(s,4H),2.13-2.10(m,6H).
13C NMR(125MHz,d6-DMSO)δ173.8,164.5,163.8,163.6,156.4,154.1(d,J＝243.5Hz,1C),152.9,152.6,152.2(d,J＝243.9Hz,1C),150.8,149.4,144.9(d,J＝10.4Hz,1C),138.9,137.7(d,J＝9.6Hz,1C),135.8,135.1(d,J＝12.8Hz,1C),134.9,125.0,119.8(d,J＝6.5Hz,1C),116.1,112.9(d,J＝23.3Hz,1C),109.6,108.3(d,J＝23.0Hz,1C),107.3,104.3,102.8,101.0,72.2,56.7,56.5,52.0,49.9,49.6,21.0,9.2.
HRMS(ESI)for C37H32F2N6O8S[M+H]+,calcd:759.2042,found:759.2046.
HPLC analysis:MeOH-H2O(85:15),9.48min,95.23％purity.
实施例50：N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-9-氟-8-(4-羟基哌啶-1-取代)-5-甲基-1-氧基-1,5,6,7-四氢吡咯[3,2,2-ij]喹啉-2-甲酰胺(命名为TL4830031)的制备
Figure PCTCN2016095813-appb-000076
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)δ12.66(s,1H),8.95(s,1H),8.57(s,1H),8.02(d,J＝12.0Hz,1H),7.89(d,J＝12.5Hz,1H),7.58(s,1H),7.48(s,2H),7.41(s,1H),4.87(s,1H),4.75(s,1H),3.99(s,6H),3.68(s,1H),3.20(m,3H),2.93(m,2H),2.14-2.06(m,2H),1.86(m,2H),1.63-1.51(m,2H),1.43(d,J＝5.0Hz,3H).
13C NMR(125MHz,d6-DMSO)δ175.04,164.47,163.30,157.47(d,J＝249.3Hz,1C),156.41,154.04(d,J＝244.9Hz,1C),152.51,150.74,149.41,147.12,142.33(d,J＝13.7Hz,1C),138.01(d,J＝9.4Hz,1C),135.06(d,J＝12.9Hz,1C),133.57,126.65,124.92,124.16,116.22,109.79,109.60,109.56,108.37(d,J＝23.2Hz,1C),107.21,101.03,57.09,56.60,56.46,49.08,35.86,35.50,25.58,20.05,18.94.
HRMS(ESI)for C35H33F2N5O6[M+H]+,calcd:658.2472,found:658.2753.
HPLC analysis:MeOH-H2O(85:15),10.63min,99.51％purity。
实施例51：(S)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-9-氟-3-甲基-10-(4-甲基哌嗪-1-基)-7-氧代-2,3-二氢-7H-[1,4]恶嗪[2,3,4-ij]喹啉-6-甲酰胺(命名为GDL5000111)的制备
Figure PCTCN2016095813-appb-000077
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)δ12.59(s,1H),8.95(s,1H),8.57(s,1H),8.01(m,1H),7.58(m,2H),7.46(m,2H),7.40(s,1H),4.92(m,1H),4.57(d,J＝10.5Hz,1H),4.38(d,J＝9.5Hz,1H),4.00(s,3H),3.99(s,3H),3.33(m,4H),2.63(s,4H),2.37(s,3H),1.47(d,J＝7.0Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.8,164.5,163.3,156.4,155.8(d,J＝244.0Hz,1C),154.09(d,J＝243.5Hz,1C),152.6,150.8,149.5,146.0,140.8(d,J＝7.1Hz,1C),138.0(d,J＝10.1Hz,1C),135.1(d,J＝12.9Hz,1C),131.4(d,J＝14.8Hz,1C),125.1,124.8,122.1(d,J＝8.6Hz,1C),116.4,109.8,109.6,108.5(d,J＝21.1Hz,1C),107.3,104.0(d,J＝23.3Hz,1C),101.0,68.6,56.7,56.5,55.4,54.9,50.0,45.8,18.4.
HRMS(ESI)for C34H32F2N6O6[M+H]+,calcd:659.2424,found:659.2425.
HPLC analysis:MeOH-H2O(85:15),15.81min,98.54％purity.
实施例52：N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-9-氟-3-甲基-10-(4-甲基哌嗪-1-基)-7-氧代-2,3-二氢-7H-[1,3,4]恶二嗪[6,5,4-ij]喹啉-6-甲酰胺(命名为TL4830039)的制备
Figure PCTCN2016095813-appb-000078
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)12.47(s,1H),8.73(s,1H),8.56(s,1H),7.99(m,1H),7.57(t,J＝6.0Hz,2H),7.45(m,2H),7.41(s,1H),5.32(s,2H),4.00(s,3H),3.99(s,3H),3.33(m,4H),3.03(s,3H),2.45(s,4H),2.24(s,3H).
13C NMR(125MHz,d6-DMSO)δ174.5,164.5,162.8,156.4,155.7(d,J＝244.5Hz,1C),154.08(d,J＝243.5Hz,1C),152.6,150.8,149.5,144.7,138.7(d,J＝7.4Hz,1C),137.9(d,J＝10.0Hz,1C),135.2(d,J＝12.8Hz,1C),131.5(d,J＝14.1Hz,1C),125.1,123.9,121.5(d,J＝8.1Hz,1C),116.4,109.6,109.5,108.5(d,J＝22.8Hz,1C),107.3,104.5(d,J＝23.4Hz,1C),101.0,82.6,56.7,56.5,55.7,50.5,46.5,43.2.
HRMS(ESI)for C33H31F2N7O6[M+H]+,calcd:660.2377,found:660.2373.
HPLC analysis:MeOH-H2O(85:15),15.48min,99.89％purity.
实施例53：N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6,8-二氟-1-(2-氟乙基)-7-(4-甲基哌嗪-1-基)-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为TL4830040)的制备
Figure PCTCN2016095813-appb-000079
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)δ12.35(s,1H),8.84(s,1H),8.57(s,1H),8.00(d,J＝12.5Hz,1H),7.88(d,J＝12.0Hz,1H),7.57(s,1H),7.48(s,2H),7.41(s,1H),4.95(s,2H),4.88(m,2H),4.00(s,3H),3.99(s,3H),3.33(s,4H),2.45(s,4H),2.23(s,3H).
13C NMR(125MHz,CDCl3)δ174.6,164.8,162.4,156.0,155.0(d,J＝249.0Hz,1C),154.3(d,J＝246.3Hz,1C),152.9,150.9,150.3,149.5,145.9(dd,J＝6.4,244.4Hz,1C),137.5(d,J＝9.5Hz,1C),135.5(d,J＝13.0Hz,1C),133.8(t,J＝13.8Hz,1C),126.6(d,J＝5.2Hz,1C),123.9,122.9(d,J＝7.9Hz,1C),116.1(d,J＝2.8Hz,1C),111.0,110.3,109.3(d,J＝23.1Hz,1C),108.8(d,J＝22.9Hz,1C),106.9,101.1,81.3(dd,J＝5.4,172.3Hz,1C),58.3(dd,J＝14.9,20.4Hz,1C),56.4,56.4,55.5,50.9(t,J＝4.0Hz,2C),46.3.
HRMS(ESI)for C33H30F4N6O5[M+H]+,calcd:667.2287,found:667.2290.
HPLC analysis:MeOH-H2O(85:15),14.66min,99.56％purity.
实施例54：N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-氟-1-(4-氟苯基)-4-氧代-7-(哌嗪-1-基)-1,4-二氢喹啉-3-甲酰胺(命名为TL4830042)的制备
Figure PCTCN2016095813-appb-000080
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)δ12.51(s,1H),8.61(s,1H),8.54(s,1H),7.96(m,1H),7.92(d,J＝13.0Hz,1H),7.81(m,2H),7.55(m,3H),7.45(m,2H),7.39(s,1H),3.98(s,3H),3.97(s,3H),2.91(s,4H),2.77(s,4H).
13C NMR(125MHz,d6-DMSO)δ180.0,169.3,167.7,167.7(d,J＝246.1Hz,1C),161.2,158.8(d,J＝243.5Hz,1C),158.0(d,J＝247.0Hz,1C),157.3(d,J＝24.4Hz,1C),155.5,154.2,152.9(d,J＝23.1Hz,1C),150.4(d,J＝10.4Hz,1C),143.8,142.6(d,J＝9.8Hz,1C),141.9,140.0(d,J＝12.9Hz,1C),135.1,129.8,125.1(d,J＝7.3Hz,1C),122.6(d,J＝23.4Hz,1C),121.2,116.6,115.2,114.4,113.3,112.0,111.2,105.8(d,J＝12.6Hz,1C),61.4,61.3,55.7,50.5.
HRMS(ESI)for C36H29F3N6O5[M+H]+,calcd:683.2224,found:683.2226.
HPLC analysis:MeOH-H2O(85:15),13.93min,95.12％purity.
实施例55：5-氨基-1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-7-(3,5-二甲基哌嗪-1-基)-6,8-二氟-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为TL4830044)的制备
Figure PCTCN2016095813-appb-000081
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)δ12.19(s,1H),8.58(s,1H),8.53(s,1H),7.96(d,J＝12.5Hz,1H),7.55(s,1H),7.44-7.37(m,5H),3.98(s,3H),3.97(s,3H),3.34(d,J＝12.0Hz,2H),3.10(s,2H),2.92(t,J＝11.5Hz,2H),1.90(s,2H),1.13-1.07(m,10H).
13C NMR(125MHz,d6-DMSO)δ178.9,172.7,164.5,162.8,156.4,154.0(d,J＝243.3Hz,1C),152.6,150.7,149.7,149.4,139.8(d,J＝230.5Hz,1C),137.9(d,J＝9.8Hz,1C),136.9(d,J＝13.3Hz,1C),135.1(d,J＝13.1Hz,1C),133.2,128.4,125.0,116.5,109.6,109.2,108.5(d,J＝23.5Hz,1C),107.3,107.2,101.0,56.7,56.5,56.1,21.6,17.9,9.0,9.0.
HRMS(ESI)for C35H34F3N7O5[M+H]+,calcd:690.2646,found:690.2622.
HPLC analysis:MeOH-H2O(85:15),10.22min,95.56％purity.
实施例56：1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-7-(4-乙基哌嗪-1-基)-6-氟-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000093)的制备
Figure PCTCN2016095813-appb-000082
合成方法如实施例48。
1H NMR(500MHz,CDCl3)δ12.50(s,1H),8.89(s,1H),8.63(s,1H),8.06(d,J＝13.5Hz,1H),8.00(dd,J＝2.5,12.5Hz,1H),7.58(s,1H),7.46(dd,J＝0.5,8.5Hz,1H),7.36(d,J＝7.0Hz,1H),7.33(s,1H)7.28(m,1H),4.08(s,3H),4.06(s,3H),3.52(m,1H),3.35(t,J＝4.5Hz,4H),2.69(s,4H),2.52(q,J＝7.0Hz,2H),1.36(t,J＝6.5Hz,2H),1.21(m,2H),1.15(t,J＝7.0Hz,3H).
13C NMR(125MHz,CDCl3)δ175.6,164.9,163.2,155.9,154.3(d,J＝246.1Hz,1C),153.6(d,J＝248.6Hz,1C),152.9,150.3,149.5,147.0,145.3(d,J＝10.4Hz,1C),138.6,137.8(d,J＝9.9Hz,1C),135.3(d,J＝13.0Hz,1C),123.8,121.5(d,J＝7.3Hz,1C),116.1(d,J＝2.6Hz,1C),112.7(d,J＝23.1Hz,1C),111.0,110.3,109.3(d,J＝23.3Hz,1C),106.9,104.7,101.1,56.4,56.4,52.5,52.3,50.0,50.0,35.0,12.0,8.2.
HRMS(ESI)for C35H34F2N6O5[M+H]+,calcd:657.2632,found:657.2625.
HPLC analysis:MeOH-H2O(85:15),20.53min,98.36％purity.
实施例57：7-(3-氨基吡咯烷-1-基)-1-(2,4-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-氟-4-氧代-1,4-二氢-1,8-萘啶-3-甲酰胺(命名为GDL5000101)的制备
Figure PCTCN2016095813-appb-000083
合成方法如实施例48。
1H NMR(500MHz,d6-DMSO)δ12.52(s,1H),8.75(s,1H),8.57(s,1H),8.06(d,J＝13.0Hz,1H),7.98(d,J＝12.5Hz,1H),7.85(m,1H),7.59(m,2H),7.47(d,J＝12.5Hz,2H),7.36(t,J＝8.0Hz,1H),4.62(s,2H),4.00(s,3H),3.99(s,3H),3.62(m,5H),2.02(s,1H),1.76(s,1H).
13C NMR(125MHz,CDCl3)δ176.0(d,J＝1.6Hz,1C),164.8,163.0(dd,J＝10.9,251.1Hz,1C),157.8(dd,J＝12.4,253.9Hz,1C),156.0,154.2(d,J＝246.1Hz,1C),152.8,150.3,149.4,148.9(d,J＝12.6Hz,1C),146.4(d,J＝256.3Hz,1C),146.2,146.0,137.6(d,J＝9.6Hz,1C),135.4(d,J＝13.3Hz,1C),130.0(d,J＝10.1Hz,1C),124.7(dd,J＝4.3,13.3Hz,1C),123.8,118.5(d,J＝20.6Hz,1C),116.1(d,J＝2.6Hz,1C),112.7,112.4(d,J＝2.5Hz,1C),112.0(dd,J＝3.4,22.5Hz,1C),110.2,109.2(d,J＝23.0Hz,1C),106.8,104.9(t,J＝23.5Hz,1C),101.0,56.6,56.6,56.4,56.4,46.9,30.3.
HRMS(ESI)for C35H27F4N7O5[M+H]+,calcd:702.2083,found:702.2074.
HPLC analysis:MeOH-H2O(85:15),12.42min,99.81％purity.
实施例58：N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-1-乙基-6-氟-4-氧代-7-(哌嗪-1-基)-1,4-二氢-1,8-萘啶-3-甲酰胺(命名为GDL5000102)的制备
Figure PCTCN2016095813-appb-000084
合成方法如实施例48。
1H NMR(500MHz,CDCl3)δ12.51(s,1H),8.79(s,1H),8.63(s,1H),8.13(d,J＝13.5Hz,1H),7.80(dd,J＝2.0,12.0Hz,1H),7.58(s,1H),7.46(d,J＝8.5Hz,1H),7.28(m,1H),4.41(q,J＝7.0Hz,2H),4.08(s,3H),4.06(s,3H),3.82(t,J＝4.5Hz,4H),3.04(t,J＝4.5Hz,4H),1.51(t,J＝7.0Hz,3H).
13C NMR(125MHz,CDCl3)δ175.7,164.9,163.1,156.0,154.3(d,J＝245.9Hz,1C),152.9,150.4(d,J＝9.0Hz,1C),150.3,149.5,147.4(d,J＝247.0Hz,1C),146.0,144.7,137.8(d,J＝9.6Hz,1C),135.3(d,J＝13.1Hz,1C),123.8,120.7(d,J＝21.9Hz,1C),116.1(d,J＝2.9Hz,1C),115.1(d,J＝3.0Hz,1C),112.2,110.3,109.3(d,J＝23.3Hz,1C),106.9,101.1,56.4,56.4,48.4,48.3,47.4,46.1,15.0.
HRMS(ESI)for C31H29F2N7O5[M+H]+,calcd:618.2271,found:618.2264.
HPLC analysis:MeOH-H2O(85:15),16.99min,96.81％purity.
实施例59：1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-基-4-氧代-7-(哌嗪-1-基)-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000110)的制备
Figure PCTCN2016095813-appb-000085
合成方法如实施例48。
1H NMR(500MHz,CDCl3)δ12.50(s,1H),8.89(s,1H),8.62(s,1H),8.05(d,J＝13.5Hz,1H),8.00(dd,J＝2.0,12.5Hz,1H),7.58(s,1H),7.46(d,J＝9.0Hz,1H),7.34(m,2H),7.27(m,1H),4.07(s,3H),4.06(s,3H),3.52(m,1H),3.28(t,J＝4.5Hz,4H),3.10(t,J＝4.5Hz,4H),1.37(q,J＝6.5Hz,2H),1.22(m,2H).
13C NMR(125MHz,CDCl3)δ175.6,164.9,163.2,156.0,154.3(d,J＝246.3Hz,1C),153.7(d,J＝248.5Hz,1C),152.9,150.3,149.4,147.0,145.7(d,J＝10.1Hz,1C),138.6,137.8(d,J＝9.8Hz,1C),135.3(d,J＝12.6Hz,1C),123.8,121.4(d,J＝7.3Hz,1C),116.1(d,J＝3.0Hz,1C),112.7(d,J＝23.3Hz,1C),111.0,110.3,109.3(d,J＝23.0Hz,1C),106.8,104.7(d,J＝2.8Hz,1C),101.1,56.4,56.4,51.2,51.1,46.0,35.0,8.2.
HRMS(ESI)for C33H30F2N6O5[M+H]+,calcd:629.2319,found:629.2306.
HPLC analysis:MeOH-H2O(85:15),17.78min,97.22％purity.
实施例60：N-(4-((2-氯吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800199)的制备
J.
Figure PCTCN2016095813-appb-000086
步骤J1：4-((2-氯吡啶-4-取代)氧基-3-氟苯胺(化合物32)
4-氨基-2-氟苯酚(4.3g，32mmol，1.1eq)溶于100mL DMF，室温下加入NaH(60％，32mmol，1.1eq)反应10min，搅拌下加入2-氯-4-硝基吡啶(5g，31mmol，1.0eq)，加热至90℃反应过夜。冷至室温，用饱和NaCl淬灭，DCM/H2O萃取多次，合并有机相，柱层析得产物5.5g(75％)。
步骤J2：N-(4-((2-氯吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物33，TL4800199)
其他合成步骤如实施例25。
1H NMR(500MHz,d6-DMSO)δ11.06(s,1H),8.31(d,J＝6.0Hz,1H),8.06(d,J＝2.0Hz,1H),8.00(dd,J＝2.0,13.0Hz,1H),7.79(d,J＝9.0Hz,1H),7.65(dd,J＝2.0,9.0Hz,1H),7.52(dd,J＝1.0,9.0Hz,1H),7.39(t,J＝9.0Hz,1H),7.09(d,J＝2.0Hz,1H),7.00(dd,J＝2.0Hz,J2＝6.0Hz,1H),3.81(s,3H),2.78-2.74(q,J＝7.5Hz,2H),2.63(s,3H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.2,166.3,166.1,153.7(d,J＝244.1Hz,1C),153.1,152.1,151.8, 140.1,139.6,139.2(d,J＝9.8Hz,1C),135.2(d,J＝12.3Hz,1C),133.3,126.3,124.2,124.0,118.3,117.5,116.6,111.4,111.2,108.6(d,J＝22.8Hz,1C),35.7,27.9,19.4,15.7.
HRMS(ESI)for C25H21ClFN3O3[M+H]+,calcd:466.1328,found:466.1325.
HPLC analysis:MeOH-H2O(85:15),5.44min,98.91％purity.
实施例61：N-(4-((2-苄基吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4800200)的制备
k.
Figure PCTCN2016095813-appb-000087
步骤k1：4-(4-氨基-2-氟苯氧基)-N-苄基吡啶-2-氨基(化合物34)
化合物33(1.5g，6mmol，1.0eq)，铜粉(384mg，6mmol，1.0eq)和K2CO3(834mg，6mmol，1eq)加入30mL苄胺，于160℃封管反应过夜。冷至室温，用饱和NaCl淬灭，DCM/H2O萃取多次，合并有机相，柱层析得产物(900mg，50％)。
步骤k2：N-(4-((2-苄基吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物35，TL4800200)
其他合成步骤如实施例25。
HPLC analysis:MeOH-H2O(85:15),6.08min,96.21％.
实施例62：6-乙基-N-((3-氟-4-((-苯基氟[2,3-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000039)的制备
l.
Figure PCTCN2016095813-appb-000088
步骤l1：2-氨基-4-苯基呋喃-3-甲腈(化合物36)
羟基苯乙酮5g(1eq)，丙二腈(2.426g，1eq)溶于12mLDMF，室温下滴加1.9mL二乙胺，混合液搅拌2h，然后0℃下加入100mL水，10℃搅拌30min，过滤，水洗两遍，真空干燥，得到5.8g。1H NMR(400MHz,d6-DMSO)δ7.61(m,2H),7.46(s,2H),7.42(m,2H),7.39(s,1H),7.33(m,1H).
步骤l2：5-苯基呋喃[2,3-d]嘧啶-4(3H)-酮(化合物37)
Ar保护，0℃下将37mLHCOOH缓慢滴加到76mLAc2O中，搅拌45min，5.8g(化合物36)分批加入，15min后反应液由黑色变为深蓝色，升温至室温，搅拌15min后，125℃回流过夜。旋干反应液，DCM：MeOH＝50:1柱层析，得到1.65g产物。1H NMR(400MHz,d6-DMSO)δ12.68(s,1H),8.23(s,1H),8.16(s,1H),7.97(d,2H),7.42(m,2H),7.33(m,1H).
步骤l3：4-氯-5-苯基呋喃[2,3-d]嘧啶(化合物38)
取1.65g化合物37放在25mL茄形瓶中，在冰浴下加入9mLPOCl3，115℃回流90min，反应液缓慢倒入冰水中淬灭，搅拌15min，加入EA萃取3次，旋干，PE：EA＝10:1过柱，得到1.35g白色固体。1HNMR(400MHz,d6-DMSO)δ8.90(s,1H),8.47(s,1H),7.61(m,2H),7.50(m,3H).
步骤l4：3-氟-4-((5-苯基呋喃[2,3-d]嘧啶-4-取代)氧基)苯胺(化合物39)
0℃Ar保护下，563mg4-氨基-2-氟苯酚溶于20mLDMF中，300mgNaH分批加入其中，搅拌30min，将600mg(化合物38)溶于10mLDMF中，然后滴加到反应体系中，0℃反应4h。加NH4Cl饱和溶液淬灭，EA萃取3遍，旋干，柱层析，得到产物628mg(75％)。1H NMR(400MHz,d6-DMSO)δ8.55(s,1H),8.46(s,1H),7.80(m,2H),7.48(m,2H),7.40(t,J＝7.2Hz,1H),7.06(t,J＝4.8Hz,1H),6.49(dd,J＝13.2,2.4Hz,1H),6.40(dd,J＝8.8,2.4Hz,1H),5.39(s,2H).
步骤l5：6-乙基-N-((3-氟-4-((-苯基氟[2,3-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物40，GDL5000039)
其他合成步骤如实施例25。
1H NMR(400MHz,d6-DMSO)δ11.04(s,1H),8.58(s,1H),8.51(s,1H),8.09(s,1H),7.94(d,J＝13.2Hz,1H),7.83(m,3H),7.66(dd,J＝1.6,8.8Hz,1H),7.52-7.48(m,4H),7.41(t,J＝7.2Hz,1H),3.84(s,3H),2.80-.74(q,J＝7.6Hz,2H),2.65(s,3H),1.24(t,J＝7.6Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,169.2,166.2,163.2,153.9(d,J＝243.8Hz,1C),153.4,152.5,142.3,140.0,139.7,139.0(d,J＝10.0Hz,1C),134.5(d,J＝12.5Hz,1C),133.4,130.2,129.1,128.9,128.6,126.3,124.7,124.1,120.8,119.0,117.6,116.0,108.0(d,J＝22.5Hz,1C),103.3,35.7,27.3,19.49,15.9.
HRMS(ESI)for C32H25FN4O4[M+H]+,calcd:549.1933,found:549.1936.
HPLC analysis:MeOH-H2O(85:15),6.91min,97.17％purity.
实施例63：N-(4-((2-氨基甲酰基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000045)的制备
m.
Figure PCTCN2016095813-appb-000089
步骤m1：4-((4-氨基-2-氟苯氧基)吡啶酰胺(化合物41)
Ar保护下，4-氨基-2-氟苯酚(2.43g，19mmol，1.5eq)溶于25mL DMSO，室温下加入t-BuOK(2.3g，21mmol，1.6eq)反应15min，搅拌下加入4-氯吡啶-2-甲酰胺(2g，13mmol，1.0eq)，加热至80℃反应1h。冷至室温，加入25mL 1M NaOH溶液，25mL水，搅拌5h，过滤，水洗，烘干得到产物2.7g(85％)。1H NMR(400MHz,d6-DMSO)δ8.49(d,J＝5.6Hz,1H),8.09(s,1H),7.68(s,1H),7.35(d,J＝2.4Hz,1H),7.14(q,J＝2.8Hz,1H),7.02(t,J＝8.8Hz,1H),6.53(dd,J＝13.2,2.4Hz,1H),6.53(dd,J＝13.2,2.4Hz,1H),6.44(dd,J＝8.4,1.6Hz,1H),5.50(s,2H).
步骤m2：N-(4-((2-氨基甲酰基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物42，GDL5000045)
其他合成步骤如实施例25。
1H NMR(400MHz,d6-DMSO)δ11.06(s,1H),8.54(d,J＝5.6Hz,1H),8.12(s,1H),8.08(s,1H),8.00(d,J＝13.2Hz,1H),7.82(d,J＝8.8Hz,1H),7.72(s,1H),7.67(d,J＝8.0Hz,1H),7.53(d,J＝8.8Hz,1H),7.41(m,2H),7.22(m,1H),3.84(s,3H),2.80-2.74(q,J＝7.6Hz,2H),2.64(s,3H),1.24(t,J＝7.6Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.0,166.3,165.8,165.7,153.9(d,J＝243.8Hz,1C),153.3,152.4, 151.1,140.0,139.6,139.2(d,J＝10.0Hz,1C),135.2(d,J＝12.5Hz,1C),133.4,126.2,124.4,124.1,119.0,117.6,116.6,113.9,108.7,108.4(d,J＝22.5Hz,1C),35.7,27.9,19.5,15.9.
HRMS(ESI)for C26H23FN4O4[M+H]+,calcd:475.1776,found:475.1772.
HPLC analysis:MeOH-H2O(75:25),4.92min,98.23％purity.
实施例64：N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000050)的制备
n.
Figure PCTCN2016095813-appb-000090
步骤n1：N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物43，GDL5000050)
N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(106mg，0.22mmol，1.0eq)溶于DMF 2mL，H2O(11mg，0.60mmol，2.6eq)，吡啶(70mg,，0.88mmol，3.9eq)中，加入[双(三氟乙酰氧基)碘]苯(135mg，0.31mmol，1.4eq)，室温搅拌4h，加水50mL搅拌30min，过滤，滤渣经柱层析得产物。
1H NMR(400MHz,d6-DMSO)δ10.94(s,1H),8.08(s,1H),7.95(d,J＝13.2Hz,1H),7.81(m,2H),7.67(m,1H),7.48(d,J＝8.8Hz,1H),7.30(t,J＝8.8Hz,1H),6.19(dd,J＝2.0,5.6Hz,1H),5.95(s,2H),5.80(s,1H),3.83(s,3H),2.79-2.74(q,J＝7.6Hz,2H),2.62(s,3H),1.24(t,J＝7.6Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.4,166.6,166.2,154.5(d,J＝243.6Hz,1C),152.6,150.3,140.4,140.1,139.0(d,J＝9.8Hz,1C),136.3(d,J＝12.1Hz,1C),133.8,126.7,124.9,124.6,119.7,118.0,116.7,108.7(d,J＝23.1Hz,1C),102.1,93.3,28.4,19.9,16.4.
HRMS(ESI)for C25H23FN4O3[M+H]+,calcd:447.1827,found:447.1822.
HPLC analysis:MeOH-H2O(75:25),4.92min,95.41％purity.
实施例65：6-乙基-N-(3-氟基-4-(5-(1-甲基-1H-吡唑-4-取代)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000038)的制备
o.
Figure PCTCN2016095813-appb-000091
步骤o1：4-氯-5-碘-7H-吡咯[2,3-d]嘧啶(化合物44)
将4-氯-7H-吡咯[2,3-d]嘧啶(8.0g，52.32mmol，1.0eq)溶于DMF(40mL)，在0℃加入NIS(15.7g，57.55mmol，1.1eq)，室温搅拌过夜，加入200mL饱和Na2S2O3溶液，过滤，用水洗涤三次，真空干燥，得到产物14.6g(100％)。1H NMR(400MHz,d6-DMSO):δ12.94(s,1H),8.59(s,1H),7.93(d,J＝2.4Hz,1H).
步骤o2：4-氯-5-碘-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(化合物45)
将NaH(60％，160mg，4mmol，1.10eq)加入无水THF(20mL)中，将4-氯-5-碘-7H-吡咯[2,3-d]嘧啶(1.00g，3.6mmol，1.00eq)溶于THF(10mL)中后滴加进去，反应15min后，冷却至0℃，将SEMCl(0.7mL，3.8mmol，1.05eq)缓慢滴加进去，搅拌过夜。加入饱和NH4Cl溶液淬灭反应，用EtOAc萃取三次，合并有机相，柱层析得到产物1.1g(75％)。1H NMR(400MHz,d6-DMSO):δ8.69(s,1H),8.13(s,1H),5.60(s,2H),3.52(t,J＝8.0Hz,2H)；0.82(t,J＝8.0Hz,2H)；-0.09(s,9H).
步骤o3：4-氯-5-(1-甲基-1H-吡唑-4-基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(化合物46)
将4-氯-5-碘-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(200mg，0.5mmol，1.0eq)，1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑(124mg，0.6mmol，1.2eq)，K3PO4(126mg，0.6mmol，1.2eq)，PdCl2dppfDCM(40mg，0.05mmol，0.1eq)，H2O(0.64mL)，Et3N(0.4mL)加入THF(6.4mL)中，回流18h，冷却至室温，用乙酸乙酯萃取，通过柱层析得到产物85mg(48％)。1HNMR(400MHz,d6-DMSO):δ8.68(s,1H),7.94(s,1H),7.88(s,1H),7.64(s,1H),5.66(s,2H),3.90(s,3H),3.56(t,J＝8.0Hz,2H)；0.85(t,J＝8.0Hz,2H)；-0.09(s,9H).
步骤o4：3-氟-4-((5-(1-甲基-1H-吡唑-4-基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶-4-基)氧基)苯胺(化合物47)
Ar保护下，4-氨基-2-氟苯酚(430mg,3.4mmol,1.7eq)溶于20mL DMF，0℃下加入NaH(230mg,5.8mmol,2.9eq)反应15min,搅拌下加入4-氯-5-(1-甲基-1H-吡唑-4-基)-7-((2-(三甲基硅基)乙氧基)甲基)-7H-吡咯[2,3-d]嘧啶(720mg,2.0mmol,1.0eq)，搅拌过夜。加入饱和NH4Cl溶液淬灭反应，用EtOAc萃取三次，柱层析得到产物580mg(64％)。1H NMR(400MHz,d6-DMSO):δ8.34(s,1H),7.99(s,1H),7.82(m,2H),7.07(t,J＝7.2Hz,1H),6.49(dd,J＝10.4,2.0Hz,1H),6.42(dd,J＝6.8,2.0Hz,1H),5.61(s,2H),5.36(s,2H),3.85(s,3H),3.55(t,J＝6.4Hz,2H)；0.85(t,J＝6.4Hz,2H)；-0.08(s,9H).
步骤o5：6-乙基-N-(3-氟基-4-(5-(1-甲基-1H-吡唑-4-取代)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物48，GDL5000038)
其他合成步骤如实施例25。
1H NMR(400MHz,d6-DMSO)δ12.30(s,1H),11.00(s,1H),8.28(s,1H),8.09(s,1H),8.00(s,1H),7.90(m,1H),7.83(m,2H),7.66(m,2H),7.49-7.42(m,2H),3.85(s,3H),3.84(s,3H),2.78(q,J＝7.5Hz,2H),2.65(s,3H),1.2(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.4,166.6,162.1,154.7(d.J＝242.5Hz,1C),154.5,152.8,151.0,140.4,140.1,139.0(d,J＝10.0Hz,1C),138.4,135.4(d,J＝12.5Hz,1C),133.8,129.4,126.7,125.4,124.6,122.5,119.5,118.0,116.4(d,J＝1.3Hz,1C),115.6,108.4(d,J＝22.5Hz,1C),107.4,102.6,40.0,39.5,36.1,28.2,19.9,16.4.
HRMS(ESI)for C30H26FN7O3[M+H]+,calcd:552.2154,found:552.2156.
HPLC analysis:MeOH-H2O(75:25),5.34min,99.20％purity.
实施例66：2,6-二乙基-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为TL4830005)的制备
p.
Figure PCTCN2016095813-appb-000092
步骤p1：2,6-二乙基-1-甲基-4-氧基-1,4-二氢喹啉-3-羧酸甲酯(化合物49)
6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-羧酸(化合物16)(780mg，3.18mmol)溶于50mL DMF，冰浴下加入NaH(190mg，4.8mmol，1.5eq)，搅拌下加入MeI(900mg，6.63mmol，2eq)，于80℃反应过夜。冷至室温，加水有固体析出，过滤，固体用DCM/H2O萃取多次，合并有机相，旋干柱层析得产物440mg(51％)。1H NMR(500MHz,d6-DMSO)δ7.96(d,J＝2.0Hz,1H),7.77(d,J＝8.5Hz,1H),7.64(dd,J＝2.0,8.5Hz,1H),3.79(s,3H),3.78(s 3H),2.77-2.50(m,4H),1.24-1.20(m,6H).
步骤p2：2,6-二乙基-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物50，TL4830005)
其他合成步骤如实施例25。
HPLC analysis:MeOH-H2O(85:15),5.75min,98.06％.
实施例67：N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-2,6-二乙基-1-甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为TL4830074)的制备
合成步骤如实施例66。
Figure PCTCN2016095813-appb-000093
实施例68：N-(4-((2-氨基甲酰基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000056)的制备
q.
Figure PCTCN2016095813-appb-000094
步骤q1：3,4-二氯-2-吡啶甲酰胺(化合物51)
-78℃条件下，n-BuLi(2.4M，19.5mL，31mol，1.15eq)缓慢滴加到2,2,6,6-四甲基哌啶(4.4g，31mmol，1.15eq)的乙醚(50mL)溶液中，反应2h后，将3,4-二氯吡啶(4g，27mol，1.0eq)的乙醚(5mL)溶液滴加到反应液中，-78℃度下继续反应2h，将三甲基硅基异氰酸酯(95％pure，5.6mL，40mol，1.5eq)滴加到反应体系中，缓慢升至室温后反应2h。加入醋酸(5.4g，90mmol)和水(27mL)淬灭反应，混合物搅拌过夜，过滤，用少量乙醚洗涤得到产物2.51g(49％)。1H NMR(400MHz,d6-DMSO)δ8.48(d,J＝5.2Hz,1H),8.07(s,1H),7.82(m,2H).
步骤q2：4-((4-氨基-2-氟苯氧基)-3-氯吡啶酰胺(化合物52)
Ar保护下，4-氨基-2-氟苯酚(0.93g，7.3mmol，1.4eq)溶于10mL DMF，室温下加入t-BuOK(0.88g，7.8mmol，1.6eq)反应30min，搅拌下加入3,4-二氯-2-吡啶甲酰胺(1g，5.2mmol，1.0eq)，加热至50℃反应3h。冷至室温，加入饱和NaHCO3溶液，用乙酸乙酯萃取，柱层析得到产物440mg(30％)。
1H NMR(400MHz,d6-DMSO)δ8.30(d,J＝5.6Hz,1H),8.01(s,1H),7.71(s,1H),7.03(t,J＝8.8Hz,1H),6.72(d,J＝5.2Hz,1H),6.54(dd,J＝13.6,2.4Hz,1H),6.45(m,1H),5.53(s,2H).
步骤q3：N-(4-((2-氨基甲酰基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(化合物53，GDL5000056)
其他合成步骤如实施例25。
1H NMR(400MHz,d6-DMSO)δ11.05(s,1H),8.33(d,J＝5.6Hz,1H),8.08-8.00(m,3H),7.83(d,J＝8.8Hz,1H),7.74(s,1H),7.67(m,1H),7.53(d,J＝8.8Hz,1H),7.42(t,J＝8.8Hz,1H),6.87(d,J＝5.2Hz,1H),3.84(s,3H),2.80-2.74(q,J＝7.2Hz,2H),2.64(s,3H),1.25(t,J＝7.2Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.4,167.4,166.7,161.0,155.1,153.9(d,J＝244.3Hz,1C),152.8,149.6,140.5,140.1,139.8(d,J＝9.5Hz,1C),135.6(d,J＝12.4Hz,1C),133.8,126.7,124.6,124.5,119.5,118.0,117.3,117.0,111.6,108.9(d,J＝22.8Hz,1C),36.1,28.4,19.9,16.4.
HRMS(ESI)for C26H22ClFN4O4[M+H]+,calcd:509.1386,found:509.1380.
HPLC analysis:MeOH-H2O(70:30),6.43min,99.81％purity.
实施例69:N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000059)的制备
Figure PCTCN2016095813-appb-000095
0℃下，N-(4-((2-氨基甲酰基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(100mg，0.19mmol，1.0eq)，乙酸乙酯2mL，乙腈2mL，H2O1mL，PhI(OCCH3)2(80mg，0.25mmol，1.3eq)，搅拌过夜，柱层析得到产物50mg。
1H NMR(400MHz,d6-DMSO)δ10.99(s,1H),8.08(s,1H),7.98-7.94(dd,J1＝2.4Hz,J2＝13.6Hz,1H),7.82(d,J＝8.8Hz,1H),7.75(d,J＝5.6Hz,1H),7.68-7.65(dd,J＝2.0,8.8Hz,1H),7.48(d,J＝9.6Hz,1H),7.42(t,J＝8.8Hz,1H),6.40(s,2H),5.95(d,J＝5.6Hz,1H),3.83(s,3H),2.80-2.74(q,J＝7.2Hz,2H),2.63(s,3H),1.25(t,J＝7.2Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.4,166.6,160.7,158.3,154.1(d,J＝243.8Hz,1C),152.8,148.1,140.4,140.1 139.2(d,J＝9.9Hz,1C),136.4(d,J＝12.1Hz,1C),133.8,126.6,124.5,124.3,119.5,118.0,116.7,108.7(d,J＝22.8Hz,1C),101.1,101.0,36.1,28.3,19.9,16.3.
HRMS(ESI)for C25H22ClFN4O3[M+H]+,calcd:481.1437,found:481.1435.
HPLC analysis:MeOH-H2O(80:20),5.43min,99.59％purity.
实施例70：N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2,6-二甲基-4-氧代-1-苯基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000083)的制备
r.
Figure PCTCN2016095813-appb-000096
步骤r1：2-氯-5-甲基苯甲酰氯(化合物54)
0℃条件下，草酰氯(2.6mL，30.5mmol，5.2eq)缓慢滴加到2-氯-5-甲基-苯甲酸(1g，5.9mmol，1.0eq)的CH2Cl2(15mL)溶液中，加入一滴DMF，室温搅拌过夜，旋干。
步骤r2：(E)-3-(苯氨基)丁烯酸甲酯(化合物55)
乙酰乙酸甲酯(5g，43mmol，1.0eq)加入苯胺(4g，43mmol，1.0eq)中，再加入乙酸(260mg，4.3mmol，0.1eq),加热至90℃，过夜。柱层析得到产物5.1g(62％)。1H NMR(400MHz,CDCl3)δ10.35(s,1H),7.32(t,J＝7.6Hz,2H),7.16(t,J＝7.6Hz,1H),7.09(d,J＝7.6Hz,2H),4.70(s,1H),3.69(s,3H),2.00(s,3H).
步骤r3：2,6-二甲基-4-氧基-1-苯基-1,4-二氢喹啉-3-羧酸甲酯(化合物56)
0℃，Ar保护下，2-氯-5-甲基-苯甲酰氯(1.1g，5.8mmol，1.0eq)溶于无水二氧六环(4mL)中，缓慢滴加3-Phenylamino-but-2-enoic acid methyl ester(1.1g，5.8mmol，1.0eq)和Et3N(587mg，5.8mmol，1.0eq)，室温搅拌30min后升至65℃，搅拌1h，冷却至室温，再在0℃下加入t-BuOK(1.3g，11.6mmol，2.0eq)和DBU(1.8g，11.6mmol，2.0eq)，加热回流6h，冷却至室温，加水淬灭反应，用乙酸乙酯萃取，柱层析都到产物100mg(6％)。1H NMR(400MHz,d6-DMSO)δ7.99(s,1H),7.65-7.72(m,3H),7.51(m,2H),7.40(dd,J＝8.8,2.0Hz,1H),6.53(d,J＝8.8Hz,1H),3.79(s,3H),2.39(s,3H),2.00(s,3H).
步骤r4：2,6-二甲基-4-氧基-1-苯基-1,4-二氢喹啉-3-羧酸(化合物57)
将2,6-Dimethyl-4-oxo-1-phenyl-1,4-dihydro-quinoline-3-carboxylic acid methyl ester(200mg，0.65mmol，1.0eq)溶于5mLTHF和5mLH2O中，加入1gNaOH，加热回流72h。冷却，旋干THF，加1M HCl将溶液调至酸性，析出白色固体，过滤洗涤得到产物180mg(95％)。1H NMR(400MHz,d6-DMSO)δ8.21(s,1H),7.76-7.69(m,3H),7.56(m,3H),6.63(d,J＝8.8Hz,1H),2.62(s,3H),2.46(s,3H).MS(ESI),m/z 294[M+H]+.
步骤r5：N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2,6-二甲基-4-氧代-1-苯基-1,4-二氢喹啉-3-甲酰胺(化合物58，GDL5000083)
其他合成步骤如实施例1。
1H NMR(500MHz,d6-DMSO)δ11.25(s,1H),8.29(s,1H),8.11(s,1H),7.90-7.93(dd,J＝2.0,12.5Hz,1H),7.78-7.68(m,6H),7.47(m,3H),7.38-7.44(m,4H),7.25(t,J＝7.5Hz,1H),6.57(d,J＝9.0Hz,1H),2.42 (s,3H),2.22(s,3H).
13C NMR(125MHz,d6-DMSO)δ175.0,165.9,162.0,156.0,154.6(d,J＝242.8Hz,1C),152.2,150.6,140.7,139.4,138.7(d,J＝9.6Hz,1C),135.7(d,J＝12.8Hz,1C),135.4,134.7,134.6,131.6,130.8,129.8,129.2,129.1,126.8,126.1,125.9,125.6,125.4,118.9,118.8,116.4,116.0,108.5(d,J＝23.5Hz,1H),102.8,21.3,20.8.
HRMS(ESI)for C36H26FN5O3[M+H]+,calcd:596.2092,found:596.2098.
HPLC analysis:MeOH-H2O(85:15),8.93min,97.96％purity.
实施例71：6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-吗啉代丙氧基)喹唑啉-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000123)的制备
s.
Figure PCTCN2016095813-appb-000097
步骤s1：4-((7-(卞氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯胺(化合物59)的制备
向反应瓶中加入7-卞氧基-4-氯-6-甲氧基喹唑啉(4.5g，15mmol)、4-氨基-2-氟苯酚(2.3g，18mmol)、叔丁醇钾(2.4g，21mmol)、DMF(250mL)，加热至80℃反应2小时，停止反应，减压去除溶剂后，干法过柱，得到4-((7-(卞氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯胺3.6g(62％)。1H NMR(400MHz,d6-DMSO)δ8.53(s,1H),7.55(s,1H),7.52(m,2H),7.49(s,1H),7.44(t,J＝7.2Hz,2H),7.37(t,J＝7.2Hz,1H),7.04(t,J＝8.8Hz,1H),6.50(dd,J＝2.4,13.2Hz,1H),6.42(dd,J＝2.4,8.8Hz,1H),5.39(s,2H),5.35(s,2H),3.97(s,3H).MS(ESI),m/z:391[M+H]+.
步骤s2：4-(4-氨基-2-氟苯氧基)-6-甲氧基喹唑啉-7-醇(化合物60)的制备
将4-((7-(卞氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯胺(化合物59，5.2g,13.3mmol)，Pd/C(0.4g)，甲醇(250mL)，在氢气作用下于0℃反应过夜，过滤除去Pd/C，滤液浓缩过柱，得到4-(4-氨基-2-氟苯氧基)-6-甲氧基喹唑啉-7-醇2.4g(60％)。1H NMR(400MHz,d6-DMSO)δ10.72(s,1H),8.45(s,1H),7.52(s,1H),7.22(d,J＝3.2Hz,1H),7.02(t,J＝8.8Hz,1H),6.49(dd,J＝2.4,12.8Hz,1H),6.41(dd,J＝2.0,8.8Hz,1H),5.37(s,2H),3.97(s,3H).MS(ESI),m/z:301[M+H]+。
步骤s3：3-氟-4-((6-甲氧基-7-(3-吗啉代丙氧基)喹唑啉-4-基)氧基)苯胺(化合物61)的制备
将4-(4-氨基-2-氟苯氧基)-6-甲氧基喹唑啉-7-醇(化合物60，400mg，1.3mmol)、4-(3-氯丙基)吗啉(3-5a)(640mg，3.9mmol)、碳酸钾(540mg，3.9mmol)加入DMF(50mL)中，加热至80℃反应两小时，用乙酸乙酯萃取三次，合并有机相，然后以饱和食盐水洗涤，有机相旋干过柱，得3-氟-4-((6-甲氧基-7-(3-吗啉代丙氧基)喹唑啉-4-基)氧基)苯胺380mg(67％)。1H NMR(400MHz,CDCl3)δ8.60(s,1H),7.53(s,1H),7.31(s,1H),7.05(t,J＝8.8Hz,1H),6.49(dd,J＝2.4,12.0Hz,1H),6.41(dd,J＝2.4,8.8Hz,1H),4.26(t,J＝6.4Hz,2H),4.02(s, 3H),3.71(t,J＝4.4Hz,4H),2.56(t,J＝7.2Hz,2H),2.47(s,4H),2.11(m,2H).MS(ESI),m/z:428[M+H]+.
步骤s4：6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-吗啉代丙氧基)喹唑啉-4-取代)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(化合物62，GDL5000123)的制备
其他合成步骤如实施例25。
1H NMR(500MHz,d6-DMSO)δ11.01(s,1H),8.56(s,1H),8.08(d,J＝1.5Hz,1H),7.97-7.94(dd,J＝2.0,13.0Hz,1H),7.81(d,J＝9.0Hz,1H),7.67-7.65(dd,J＝2.0,8.5Hz,1H),7.58(s,1H),7.50(m,1H),7.44(t,J＝9.0Hz,1H),7.40(s,1H),4.26(t,J＝6.0Hz,2H),3.99(s,3H),3.83(s,3H),3.60(s,4H),2.77(q,J＝7.5Hz,2H),2.65(s,3H),2.50(m,2H),2.41(s,4H),1.99(t,J＝6.5Hz,2H),1.25(t,J＝7.5Hz,2H).
13C NMR(125MHz,d6-DMSO)δ174.4,166.6,165.0,156.2,154.4(d,J＝243.0Hz,1C),153.0,152.7,151.3,149.8,140.4,140.1,139.3(d,J＝9.8Hz,1C),135.3(d,J＝12.9Hz,1C),133.8,126.7,125.2,124.6,119.6,118.0,116.4,109.9,108.4,108.2,101.6,68.0,67.1,57.0,55.6,54.2,36.1,28.4,26.4,19.9,16.4.
HRMS(ESI)for C36H38FN5O6[M+H]+,calcd:656.2879,found:656.2882.
HPLC analysis:MeOH-H2O(85:15),7.87min,98.65％purity.
实施例72：N-(4-((7-(2-(二甲氨基)乙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000128)的制备
Figure PCTCN2016095813-appb-000098
合成步骤如实施例71。
1H NMR(500MHz,d6-DMSO)δ11.07(s,1H),8.61(s,1H),8.12(s,1H),7.99(d,J＝13.0Hz,1H),7.84(d,J＝8.5Hz,1H),7.69(d,J＝8.5Hz,1H),7.64(s,1H),7.54(d,J＝9.0Hz,1H),7.51-7.45(m,2H),4.42(t,J＝5.0Hz,2H),4.04(s,3H),3.87(s,3H),3.05(s,2H),2.80(q,J＝7.5Hz,2H),2.69(s,3H),2.53(s,2H),1.28(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.4,166.6,165.0,155.7,154.4(d,J＝243.1Hz,1C),153.0,152.8,151.2,149.7,140.4,140.1,139.3(d,J＝10.0Hz,1C),135.25(d,J＝12.9Hz,1C),133.8,126.7,125.2,124.5,119.5,118.0,116.4,110.2,108.6,108.4(d,J＝23.0Hz,1C),101.7,67.1,57.6,57.1,45.8,36.1,28.3,19.9,16.4.
HRMS(ESI)for C33H34FN5O5[M+H]+,calcd:600.2617,found:600.2621.
HPLC analysis:MeOH-H2O(85:15),7.17min,98.97％purity.
实施例73：6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-(4-甲基哌嗪1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为GDL5000138)的制备
Figure PCTCN2016095813-appb-000099
合成步骤如实施例71。
1H NMR(500MHz,d6-DMSO)δ11.00(s,1H),8.56(s,1H),8.08(s,1H),7.96(m,1H),7.82(d,J＝8.5Hz,1H),7.66(dd,J＝2.0,8.5Hz,1H),7.58(s,1H),7.50(d,J＝9.0Hz,1H),7.44(t,J＝9.0Hz,1H),7.39(s,1H),4.24(t,J＝6.5Hz,2H),3.99(s,3H),3.83(s,3H),2.77(q,J＝7.5Hz,2H),2.64(s,3H),2.50-2.33(m,8H),2.15(s,3H),1.97(t,J＝6.5Hz,2H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ174.4,166.6,165.0,156.2,154.4(d,J＝243.0Hz,1C),153.0,152.7,151.3,149.9,140.4,140.1,139.3(d,J＝10.3Hz,1C),135.3(d,J＝12.6Hz,1C),133.8,126.7,125.3,124.6,119.6,118.0,116.4,109.9,108.4,108.2,101.6,68.1,57.0,55.7,55.2,53.6,46.7,36.1,28.4,26.9,19.9,16.4.
HRMS(ESI)for C37H41FN6O5[M+H]+,calcd:669.3195,found:669.3182.
HPLC analysis:MeOH-H2O(85:15),15.65min,99.55％purity.
实施例74：6-乙基-N-(3-氟-4-((6-甲氧基-7-(2-(吡咯烷-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为TL4830058)的制备
Figure PCTCN2016095813-appb-000100
合成步骤如实施例71。
1H NMR(500MHz,d6-DMSO)δ10.99(s,1H),8.56(s,1H),8.09(s,1H),7.96(d,J＝13.0Hz,1H),7.83(d,J＝8.5Hz,1H),7.67(d,J＝9.0Hz,1H),7.59(s,1H),7.50(d,J＝9.0Hz,1H),7.44(m,2H),4.30(t,J＝5.0Hz,2H),3.99(s,3H),3.84(s,3H),2.89(t,J＝5.5Hz,2H),2.77(q,J＝7.5Hz,2H),2.64(s,3H),2.56(s,4H),1.70(s,4H),1.24(t,J＝7.5Hz,3H).
13C NMR(125MHz,d6-DMSO)δ173.9,166.2,164.6,155.7,154.0(d,J＝242.8Hz,1C),152.6,152.2,150.8,149.4,140.0,139.7,138.9(d,J＝19.4Hz,1C),134.9(d,J＝12.6Hz,1C),133.4,126.3,124.8,124.2,119.3,117.6,116.0,109.6,107.9(d,J＝23.1Hz,1C),107.9,101.1,68.5,56.6,54.5,54.4,35.7,27.9,23.7,19.5,16.0.
HRMS(ESI)for C35H36FN5O5[M+H]+,calcd:626.2773,found:626.2777.
HPLC analysis:MeOH-H2O(85:15),15.28min,98.83％purity.
实施例75：6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-甲氧丙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为TL4830073)的制备
Figure PCTCN2016095813-appb-000101
合成步骤如实施例71。
1H NMR(500MHz,CDCl3)δ12.70(s,1H),8.62(s,1H),8.35(s,1H),8.01-7.98(dd,J＝2.0,12.0Hz,1H),7.62-7.60(dd,J＝2.0,9.0Hz,1H),7.56(m,2H),7.45(d,J＝8.5Hz,1H),7.34(s,1H),7.27(t,J＝9.0Hz,1H),4.31(t,J＝6.5Hz,2H),4.06(s,3H),3.92(s,3H),3.62(t,J＝6.0Hz,2H),3.38(s,3H),3.09(s,3H),2.82(q,J＝7.5Hz,2H),2.21(m,2H),1.33(t,J＝7.5Hz,2H).
13C NMR(125MHz,CDCl3)δ165.0,164.9,158.3,155.4,154.3(d,J＝245.5Hz,1C),152.8,150.5,149.4,141.5,138.7,138.2(d,J＝9.6Hz,1C),135.2(d,J＝12.9Hz,1C),133.6,126.4,125.4,123.7,116.3,116.3,115.8,113.6,110.2,109.4(d,J＝24.4Hz,1C),107.6,101.2,69.1,66.3,58.8,56.4,35.8,29.2,28.3,20.4,15.4.
HRMS(ESI)for C33H33FN4O6[M+H]+,calcd:601.2457,found:601.24553.
HPLC analysis:MeOH-H2O(85:15),7.64min,98.54％purity.
实施例76：N-(4-((7-(2-(二甲氨基)丙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为TL4830076)的制备
Figure PCTCN2016095813-appb-000102
合成步骤如实施例71。
1H NMR(500MHz,CDCl3)δ12.68(s,1H),8.61(s,1H),8.32(s,1H),7.97(d,J＝12.5Hz,1H),7.57(m,2H),7.51(m,1H),7.44(d,J＝8.5Hz,1H),7.33(s,1H),7.26(m,1H),4.26(t,J＝6.5Hz,2H),4.05(s,3H),3.88(m,3H),3.05(m,3H),2.80(q,J＝7.5Hz,2H),2.50(t,J＝7.5Hz,2H),2.27(s,6H),2.11(t,J＝7.0Hz,2H),1.32(t,J＝7.5Hz,3H).
13C NMR(125MHz,CDCl3)δ176.6,165.0,164.9,158.2,155.4,154.3(d,J＝245.8Hz,1C),152.8,150.5,149.4,141.4,138.6,138.2(d,J＝9.8Hz,1C),135.2(d,J＝13.3Hz,1C),133.6,126.3,125.3,123.7,116.2,115.8,113.6,110.2,109.4(d,J＝22.9Hz,1C),107.6,101.2,67.7,56.3,56.2,45.5,35.7,28.3,27.1,20.3,15.3.
HRMS(ESI)for C34H36FN5O5[M+H]+,calcd:614.2778,found:614.2769.
HPLC analysis:MeOH-H2O(85:15),14.10min,97.25％purity.
实施例77：N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-7-(4-甲基哌嗪-1-基)-4-氧代-1,4-二氢喹啉-3-甲酰胺(命名为TL4830071)的制备
Figure PCTCN2016095813-appb-000103
步骤t1：2-溴-1-乙基-4-硝基苯(化合物63)
向反应瓶中加入对硝基乙苯(16g，106mmol)、硫酸银(33g，106mmol)、浓硫酸(95mL)、水(12mL)，向上述混合液中缓慢滴加液溴(5.4mL，106mmol)，室温反应4小。将反应液倒入亚硫酸钠溶液中，用纱布过滤，滤液用二氯甲烷萃取2遍，柱层析得出产物15g。(68％)。1H NMR(400MHz,CDCl3)δ8.40(d,J＝2.4Hz,1H),8.10(dd,J＝2.4,8.4Hz,1H),7.39(d,J＝8.4Hz,1H),2.88-2.83(q,J＝7.6Hz,2H),1.27(t,J＝7.6Hz,3H).MS(ESI),m/z:229[M+H]+.
步骤t2：3-溴-4-乙基苯胺(化合物64)
将2-溴-1-乙基-4-硝基苯(化合物63，15g,66mmol)加入乙醇(75mL)和水(75mL)混合溶液中，然后缓慢加入5mL盐酸和铁粉(14g，264mmol)，回流反应过夜。冷至室温，过滤，旋干溶剂，柱层析得产物9g(69％)。MS(ESI),m/z:200[M+H]+.
步骤t3：2-(1-((3-溴-4-乙基苯基)氨基)乙叉基丙二酸二乙酯(化合物65)
将对3-溴-4-乙基苯胺(化合物64，9g，45mmol)，乙酰基丙二酸二乙酯(9.1g，45mmol)溶于150mL正戊烷，加入催化量对甲基苯磺酸(40mg)，回流反应过夜。降至室温，加少量饱和NaHCO3，用EA萃取两次，合并有机相，用饱和食盐水洗涤一遍，无水Na2SO4干燥，过滤旋干，柱层析得固体14.5g(85％)。1HNMR(400MHz,CDCl3),δ11.14(s,1H),7.29(d,J＝2.0Hz,1H),7.19(d,J＝8.0Hz,1H),6.98(dd,J＝2,8Hz,1H),4.27-4.16(m,4H),2.76-2.71(q,J＝7.6Hz,2H),2.07(s,3H),1.33-1.26(m,6H),1.21(t,J＝7.6Hz,3H).MS(ESI),m/z:385[M+H]+.
步骤t4：7-溴-6-乙基-2-甲基-4-氧代-1,4-二氢喹啉-3-羧酸乙酯(化合物66)
2-(1-((3-溴-4-乙基苯基)氨基)乙叉基丙二酸二乙酯(化合物65，14g，37mmol)溶于75mL二苯醚，搅拌下加热至200℃反应2小时。降至室温，有固体析出，过滤，用PE洗，柱层析得产物5.6g(45％)。1HNMR(400MHz,CDCl3),δ11.84(s,1H),7.95(s,1H),7.75(s,1H),4.23(q,J＝8.0Hz,2H),2.81-2.75(q,J＝8.0Hz,2H),2.37(s,3H),1.26(t,J＝8.0Hz,3H),1.21(t,J＝8.0Hz,3H).MS(ESI),m/z:338[M+H]+.
步骤t5：7-溴-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酸乙酯(化合物67)
7-溴-6-乙基-2-甲基-4-氧代-1,4-二氢喹啉-3-羧酸乙酯(化合物66，5.6g，17mmol)，K2CO3,(7g，51mmol)溶于75mL DMF，搅拌下加入MeI(1.6mL，25.5mmol)，50℃反应过夜。降至室温，加水淬灭，有固体析出，用水洗多次，固体用DCM多次萃取，合并有机相旋干，柱层析得白色固体4.5g(75％)。1HNMR(400MHz,d6-DMSO),δ8.09(s,1H),8.04(s,1H),4.25(q,J＝7.2Hz,2H),3.74(s,3H),2.80(q,J＝7.2Hz,2H),2.44(s,3H),1.27(t,J＝7.2Hz,3H),1.22(t,J＝7.2Hz,3H).MS(ESI),m/z:352[M+H]+.
步骤t6：6-乙基-1,2-二甲基-7-(-4-甲基哌嗪-1取代)-4-氧取代--1,4-二氢喹啉-3-羧酸乙酯(化合物68)
在封管中加入7-溴-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-羧酸乙酯(化合物67，4g,11mmol)，N-甲基哌嗪(2.4mL，22mmol)，Pd(OAc)2(123mg，0.55mmol)，X-Phos(367mg，0.77mmol)，Cs2CO3(7.2g，22mmol)，dioxane(60mL)，氩气置换后于90℃反应过夜。冷至室温，过滤，水洗两遍，DCM萃取多次，合并有机相，旋干，柱层析得产物780mg(19％)。MS(ESI),m/z:372[M+H]+.
步骤t7：6-乙基-1,2-二甲基-7-(-4-甲基哌嗪-1取代)-4-氧取代--1,4-二氢喹啉-3-羧酸(化合物69)
在6-乙基-1,2-二甲基-7-(-4-甲基哌嗪-1取代)-4-氧取代--1,4-二氢喹啉-3-羧酸乙酯(化合物68，780mg，2mmol)的乙醇(15mL)和水(10mL)混合溶液中加入氢氧化钠(240mg，6mmol)，回流反应过夜。冷至室温，旋干溶剂，直接投入下一步反应。
步骤t8：N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-7-(4-甲基哌嗪-1-基)-4-氧代-1,4-二氢喹啉-3-甲酰胺(化合物70，TL4830071)
其他合成步骤如实施例48。
1H NMR(500MHz,d6-DMSO)δ11.19(s,1H),8.57(s,1H),8.08(s,1H),7.95(d,J＝13.0Hz,1H),7.59(s,1H),7.49(d,J＝9Hz,1H),7.44(t,J＝9.0Hz,1H),7.42(s,1H),7.21(s,1H),4.00(s,3H),3.99(s,3H),3.03(s,4H),2.74(q,J＝7.5Hz,2H),2.66(s,3H),2.53(s,4H),2.27(s,3H),1.27(t,J＝7.5Hz,3H).13C NMR(125MHz,d6-DMSO)δ173.7,166.2,164.6,156.4,156.1,154.4(d,J＝243.0Hz,1C),152.7,152.6,151.8,149.5,140.6,138.9(d,J＝11.1Hz,1C),135.1,134.8(d,J＝12.8Hz,1C),125.8,124.8,121.7,118.3,116.0,109.6,108.1,107.9,107.3,106.5,101.1,56.7,56.6,55.5,52.1,46.3,35.6,23.1,19.6,14.9.HPLCanalysis:MeOH-H2O(85:15),10.76min,97.64％purity.
实施例78：喹诺酮类衍生物对AXL及FLT3激酶IC50测试
激酶活性检测：应用Z′-LYTETM技术(采用荧光进行检测、酶偶联形式，以磷酸化和非磷酸化多肽对蛋白水解切割的敏感性差异为基础)，采用荧光共振能量转移(FRET)原理，使用Z′-LYTETM FRET肽类底物，二级反应检测化合物对激酶活性。(Invitrogen,Z′-LYTETM KINASE ASSAY KIT–TYR 2PEPTIDE,PV3191)将AXL激酶(invitrogen,PV4803)逐级稀释后加入FRET肽，ATP，再加入不同浓度化合物，反应1h后，加入位点特异性蛋白酶，识别并切割非磷酸化的FRET肽，反应1h，使用400nm激发波长，检测445nm及520nm吸收。得出抑制率与药物浓度成正相关，做出激酶活性与浓度关系曲线，计算IC50值，结果见表1。
Figure PCTCN2016095813-appb-000104
喹诺酮类衍生物与ATP的竞争实验中，部分化合物(例如TL4800075，TL4800172，TL4830005，TL4800191，TL4800144，TL4800116，TL4830073，TL4830074，GDL5000037，GDL5000038，GDL5000123，GDL5000128，GDL5000138等)对AXL激酶表现出强烈的抑制活性。对通式(Ⅰ)中R5取代基的改造，发现当R5为疏水性取代基时，活性更好，且为乙基时，活性最好；当R6取代基为甲基时，活性更好，且活性能容忍取代基的较大改造；当R4取代基为疏水基团时，活性较好且也能容取代基的较大改造。
表1化合物编号以及对应激酶活性结果。
Compds AXL IC50(μM) Compds AXL IC50(μM) Compds AXL IC50(μM)
TL50115 0.102 TL4800116 0.061 TL4830040 0.224
TL50025 0.569 TL4800117 0.075 TL4830042 0.038
TL50046 >10 TL4830014 0.105 TL4830044 0.503
TL50053 1.889 TL4830016 1.122 GDL5000093 0.277
TL50054 >10 GDL5000091 0.042 GDL5000101 0.081
TL50080 >10 TL4800147 0.157 GDL5000102 0.064
TL50081 >10 TL4800172 0.0298 GDL5000110 0.020
TL50086 >10 GDL5000037 0.016 TL4800199 >10
TL50087 >10 TL4800178 0.056 TL4800200 >10
TL50090 2.629 TL4800160 0.129 GDL5000039 0.192
TL50121 0.153 TL4830032 0.0265 GDL5000045 4.377
TL50128 0.211 TL4800167 0.152 GDL5000050 0.888
TL50133 3.118 TL50167 0.324 GDL5000038 0.034
TL50198 >10 TL50148 0.227 TL4830005 0.023
TL4800005 0.099 TL50160 4.53 TL4830074 0.009
TL4800025 0.557 TL50163 >10 GDL5000056 >10
TL4800067 0.146 TL50180 >10 GDL5000059 0.072
TL4800104 0.533 TL50172 0.026 GDL5000083 0.618
TL4800080 0.476 TL50161 0.195 GDL5000123 0.008
TL4800139 0.078 TL4800019 >10 GDL5000128 0.006
TL4800144 0.078 TL50134 >10 GDL5000138 0.003
TL4800088 0.429 TL4800191 0.004 TL4830058 0.008
TL4800095 0.110 GDL5000082 0.720 TL4830073 0.005
GDL5000076 0.627 TL4830031 0.028 TL4830076 0.0011
TL4800075 0.006 GDL5000111 1.084 TL4830071 0.0148
TL4800062 0.042 TL4830039 0.058    
实施例79：喹诺酮类衍生物对FLT3激酶抑制率的测试
采用常规的酶联免疫吸附测定(ELISA)方法，具体步骤如下
化合物配制：
化合物12000g离心5min，加入DMSO配制成10-2M储液,涡旋均匀后超声10min待用，-40℃保存。测试时将化合物用DMSO从储液稀释到所测试浓度的100倍(体系中DMSO浓度为1％)。
试验方法：
1.酶反应底物Poly(Glu,Tyr)4:1用无钾离子的PBS(10mM磷酸钠缓冲液，150mM NaCl，pH7.2-7.4)稀释成20μg/mL，125μL/孔包被酶标板，置37℃反应12-16小时。弃去孔中液体。洗板，用T-PBS(含0.1％Tween-20的无钾离子的PBS，200μL/孔)洗板三次，每次5分钟。于37℃烘箱中干燥酶标板1-2小时。
2.每孔加入以反应缓冲液(50mM HEPES pH 7.4,50mM MgCl2,0.5mM MnCl2,0.2mM Na3VO4,1mM DTT)稀释的ATP溶液49μL，每孔中加入1μL待测试化合物，再加入50μL以反应缓冲液稀释的 FLT-3激酶域重组蛋白启动反应，每次实验需设无ATP对照孔两孔。置37℃摇床(100rpm)反应1小时。弃去孔中液体，T-PBS洗板三次。
3.加入抗体PY99稀释液(抗体用含BSA 5mg/mL的T-PBS 1:500稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。
4.加入辣根过氧化物酶标记的羊抗鼠二抗稀释液(抗体用含BSA 5mg/ml的T-PBS 1:2000稀释)，100μL/孔，37℃摇床反应0.5小时。弃去孔中液体，T-PBS洗板三次。
5.加入2mg/ml的OPD显色液100μL/孔【用含有0.03％H2O2的0.1M柠檬酸－柠檬酸钠缓冲液(pH＝5.4)稀释】，25℃避光反应1-10分钟。
6.加入2M H2SO4 50μL/孔中止反应，用可调波长式微孔板酶标仪VERSAmax读数，波长为490nm。
7.结果分析
Figure PCTCN2016095813-appb-000105
实验结果：
1.该批次化合物对FLT-3酶活抑制率如表2所示，大部分化合物对FLT-3酶活有较强的抑制作用；
2.阳性化合物对FLT-3酶活抑制活性与文献报导相近。
表2.化合物对受体酪氨酸激酶FLT-3酶活抑制率(％)
Figure PCTCN2016095813-appb-000106
Figure PCTCN2016095813-appb-000107
实施例80：喹诺酮类衍生物对Molm-13和MV4-11细胞增殖的抑制作用
化合物配制：
化合物12000g离心5min，加入DMSO配制成10-2M储液，涡旋均匀后超声10min待用，-40℃保存。测试时将化合物用生理盐水从储液稀释到所测试浓度的10倍(体系中DMSO浓度不超过0.5％)。
试验方法：
化合物对MV4-11细胞的增殖抑制作用以CCK-8细胞计数试剂盒(Dojindo)检测。具体步骤如下：处于对数生长期的MV4-11细胞按合适密度接种至96孔培养板中，每孔90μL，培养过夜后，加入不同浓度的化合物作用72hr，并设定溶剂对照组(阴性对照)。待化合物作用细胞72h后，化合物对细胞增殖的影响采用CCK-8细胞计数试剂盒(Dojindo)检测，每孔加入10μL CCK-8试剂，置于37℃培养箱中放置2-4小时后，用全波长式微孔板酶标仪SpectraMax 190读数，测定波长为450nm。
采用以下列公式计算化合物对肿瘤细胞生长的抑制率(％)：
抑制率(％)＝(OD对照孔-OD给药孔)/OD对照孔×100％
IC50值采用酶标仪随机附带软件以四参数法回归求得。
实验结果：
该批次化合物对MV4-11细胞增殖影响如下表所示，部分化合物对MV4-11细胞增殖有较强的抑制作用；阳性化合物活性与文献报导相近。(结果见表3)
表3化合物对Molm-13和MV4-11细胞株增殖抑制的IC50值(nM)
Figure PCTCN2016095813-appb-000108
化合物对各细胞增殖抑制IC50来自两次独立重复试验，展示结果为均值±标准差。
实施例81：喹诺酮类衍生物对MDA-MB-231和4T1细胞AXL激酶磷酸化的影响
使用常规Western Blot(免疫印迹法)，其包括四个步骤：样品制备；电泳分离；蛋白的膜转移；免疫杂交与显色(蛋白检测)。
样品制备
1.将MDA-MB-231细胞以合适密度接种到6孔板中，培养24小时，使其细胞汇合度达到80％左右，分别加入相应浓度的含药培养基，共培养2-24小时；
2.在预定的时间点，弃去培养基，用4℃预冷过的PBS清洗孔板两遍，洗去残留液体；
3.加入1x SDS样品缓冲液(CST推荐，6孔板，300μL)，用细胞刮刀将皿中的细胞全部刮下，转移到1.5mL EP管中，冰上操作；
4.细胞裂解液用超声处理10-15秒，切断DNA以降低样品的粘性；
5.煮沸样品5min；
6.在4℃下，离心12000g,5min，取上清,储存于-20℃或-80℃，用于蛋白免疫印迹分析；
蛋白样品的检测
1.电泳分离：使用8％～12％的SDS-PAGE聚丙烯酰胺凝胶，上样15-20μL，90v电泳上层胶，120v电泳下层胶。
2.装配转移三明治：将聚丙烯酰胺凝胶浸置于转移缓冲液中平衡10min。依据聚丙烯酰胺凝胶的大小剪取PVDF膜(Mili pore)和滤纸6片，放入转移缓冲液中平衡10min。PVDF膜需用甲醇浸泡3-5秒。按海绵→3层滤纸→胶→膜→3层滤纸→海绵的顺序放好，确保没有气泡。
3.转膜：将转移槽置于冰浴中，放入三明治，确保将胶面对着负极，PVDF面对着正极。加入1x转膜缓冲液，恒压，根据需要检测的蛋白分子量大小，110V转膜0.5-2h。
4.封闭：转膜结束后取出PVDF膜，用封闭液(1×TBS，含0.5％Tween-20和5％脱脂奶粉)进行封闭，水平摇床缓慢摇动2h。
5.孵育一抗：封闭完毕，1:200～1:1000稀释一抗(抗体AXL，phosphor-AXL，AKT，phosphor-AKT，GAPDH等)。将PVDF膜与抗体在湿盒中于4℃孵育过夜，使抗体与目的蛋白充分结合。
6.孵育二抗：将PVDF膜取出，1×TBST洗膜4次，每次5min。1×TBST溶液配制5％脱脂奶粉溶液，将辣根过氧化物酶(HRP,sigma)标记的二抗稀释1000倍，PVDF膜放入湿盒中，室温孵育2h。用1×TBST洗涤4次，每次10min。
7.显影：PVDF膜上的条带通过用ECL Western Blotting Detection Kit(Thermo Scientific,USA)按照 说明书进行化学发光。在X-射线胶片上通过增强化学发光(Thermo)进行显影、定影，最后用自来水冲洗，烘干保存。扫描胶片记录结果。
通过图1可以发现，喹诺酮类化合物中，TL4800075和TL4800191能显著抑制MDA-MB-231细胞AXL及其下游信号蛋白AKT的磷酸化。
通过图2可以发现，大部分喹诺酮类化合物能显著抑制A549细胞中GAS6诱导的AXL磷酸化水平。
实施例82：喹诺酮类衍生物对TGF-β1诱导的MDA-MB-231细胞EMT转化，以及侵袭和迁移的影响
使用免疫荧光实验检测化合物对EMT标志蛋白的影响
免疫荧光显微实验(Immunofluorescence Microscopy Assay)
将MDA-MB-231细胞接种到事先置于6孔板的载玻片上，然后用加或不加TGF-β1(10ng/ml)的不同浓度待测化合物(0.04，0.2，1.5μM)处理96小时。室温下，使用4％的甲醛溶液固定15分钟，0.5％TritonX-100处理10分钟，并用含3％的羊血清清蛋白的PBS溶液封闭一小时，然后，用抗E-cadherin和N-cadherin抗体(1:1000；Abcam,ab10983)在室温下孵育1.5小时。然后用PBST洗涤并用Alexa Fluor 555标记的兔二抗(4413；CST,USA)或Alexa Fluor 488标记的鼠二抗(4408；CST,USA)在室温于黑暗条件下共同孵育一小时，细胞核用ProLong Gold antifade reagent(P36931；Invitrogen,USA)染色5分钟，用玻璃片覆盖载玻片，使用激光扫描共焦显微镜(Zeiss710；Germany)观察样品。
实验结果显示，化合物TL4800075和TL4800191能够剂量依赖地抑制AXL的磷酸化水平，并显著上调E-cadherin的表达，同时下调N-cadherin的表达。(见图3，4)
使用常规的transwell以及wound-healing实验，检测化合物对EMT的影响。
划痕实验(Wound-healing Assay)
将MDA-MB-231乳腺癌细胞接种到6孔培养板上，每孔5×105个细胞数，培养至占满100％培养基时，除去培养基，用200-μL吸液头在单层细胞中间划出宽度恒定的划痕。用磷酸缓冲液(PBS)洗涤三遍，以除去细胞碎片，然后加入含或不含TGF-β1(10ng/mL)的2％FBS以及不同浓度待测物在RPMI-1640中培养24小时。在0和24小时的时间点，选择三个划痕区，用相差倒置荧光显微镜(CKX41；Olympus)和Image-ProPlus图像捕获软件进行检测和拍照。用Adobe Photoshop 7.0.1(Adobe Systems Inc.,San Jose,CA)软件计算划痕闭合程度。最终结果取三次平均值。
细胞侵袭和迁移抑制实验
按照厂商说明书使用Transwell chambers(353097,353504；Corning Costar)或者Magrigel Invasion chambers(354480；Corning Costar)小室开展迁移和侵袭研究。具体步骤如下：
1、细胞胰酶消化离心后重悬计数，用无血清培养基重悬，稀释成5×104～5×105个/mL，用细胞悬液配制不同浓度的AXL抑制剂溶液加入到上室，下室加入800μL含10％FBS的培养基。
2、4小时后，去除上下室中的培养基，使用甲醇固定30min，用棉签小心去除上室的贴壁细胞。用PBS洗2遍。
3、用0.2％结晶紫染色30min。
4、使用清水洗涤去掉多余的染料。
5、显微镜下拍照。
6、Photoshop计数，Excell统计各组均数和标准差，SPSS1.0统计组间差异。
实验结果显示，化合物TL4800075和TL4800191能够剂量依赖地抑制TGF-β1诱导的乳腺癌细胞MDA-MB-231的侵袭和迁移。(见图5，6)
实施例83：喹诺酮类衍生物抑制体内移植瘤的迁移
选取BALB/c小鼠进行右侧皮下接种4T1细胞(0.5×106/mouse)。接种24天后，将小鼠随机分为治疗组和对照组(每组10只)。每组小鼠口服给药21天，治疗组药物剂量分别为每天30mg/kg和90mg/kg的化合物2-1in。每两天检测一次小鼠体重和肿瘤体积。小鼠到达给药终点后，切除并收集小鼠肝脏组 织，用10％的甲醛液固定，石蜡包埋，切片，肝脏组织切片用伊红染色。用显微镜检测至少3个视野范围内的微转移情况并计算肝脏微转移数目。
肿瘤体积计算公式为：TV＝W2(L/2)，其中，L为长度，W为宽度。
结果显示，化合物TL4800191对原位瘤的生长没有明显抑制作用，但能够剂量依赖性地抑制肿瘤肝转移的数目和大小。(见图7)
实施例84：喹诺酮类衍生物体内药代动力学实验
大鼠药代动力学和生物利用度试验。SD大鼠，单次口服(25mg/kg)和静脉(2.5～5mg/kg)给药，给药后在合适的时间点采集动物血样，肝素抗凝，8000转/分钟，离心6分钟，取上清，-20℃保存备HPLC-MS分析。血样采用乙腈沉淀蛋白，12000rpm*10min，上清用于HPCL-MS分析。数据采用DAS2.0进行参数拟合，分别获得房室模型和非房室模型参数。根据AUC数据计算化合物的口服生物利用度。结果见下表，其中TL4900191，GDL5000123，GDL5000128，GDL5000138以及TL4830058的盐酸盐等均具有合适的药动参数，能够满足体内药效试验需要。
表4.部分化合物药代动力学数据
Figure PCTCN2016095813-appb-000109
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，其特征在于具有式(Ⅰ)所示结构：
    Figure PCTCN2016095813-appb-100001
    其中，X任选自：CH或N；
    R1任选自：氢或卤素；
    R2任选自：
    Figure PCTCN2016095813-appb-100002
    R9任选自：氢、C1～C5烷基或C3～C6环烷基；
    或者R1、R2与A环组成含1～3个N的取代或未取代并5～6元杂环
    Figure PCTCN2016095813-appb-100003
    m＝2～3，X任选自CH或N，Y任选自C、N或O；
    B任选自：芳基、杂芳基、单环或多环烷基；
    R3任选自：氢、卤素、三氟甲基或C1～C3烷基；
    R4任选自：氢、C1～C5烷基、C3～C6环烷基、C1～C3烷氧基、取代或未取代苯基；
    R5任选自：氢、-(CH2)r-COOR22、-(CH2)r-NR23R24、-L-杂芳基或
    Figure PCTCN2016095813-appb-100004
    R5中，r、s1、s2、s3各自独立的选自0、1、2或3；
    V任选自：CH或N；
    U任选自：O、S、CR23R24或NR23；
    R22任选自：氢或C1～C4烷基；
    R23、R24任选自：H、C1～C3烷基、C3～C6环烷基、-NH(C1～C3烷基)、-N(C1～C3烷基)(C1～C3烷基)或-C(＝O)(C1～C3烷基)；
    L任选自：C1～C3烷基、-NR25-、-NR25CO-、-CONR25-、-O-、-CO-、-SO-或-SO2-；R25选自：C1～C3烷基；
    R6任选自：氢、卤素、C1～C5烷基、C2～C6烯基、C3～C6环烷基、C4～C6环烯基、C1～C5烷氧基、三氟甲基或三氟甲氧基；
    R7任选自：氢、C1～C5烷基或C3～C6环烷基；
    R8为氢；
    或者R7、R8与C、D环组成含有或不含有杂原子的5～7元脂肪环烷
    Figure PCTCN2016095813-appb-100005
    其中，n＝0～2；W任选自CH2或O；R10任选自H或CH3。
  2. 根据权利要求1所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，其特征在于当所述R1、R2与A环组成并5～6元取代杂环，所述的并5～6元取代杂环为如下结构中的一种：
    Figure PCTCN2016095813-appb-100006
    其中，X为CH2或N；
    R11任选自：氢、卤素、甲基、乙基、丙基、异丙基、环丙基、甲氧基、乙氧基、丙氧基或异丙氧基；
    R12、R13相同或不同地任选自：氢、卤素、-(CR15R16)OR14、-O(CR15R16)OR14、-(CR17＝CR18)pR14、-O(CR17＝CR18)pR14、
    Figure PCTCN2016095813-appb-100007
    其中，o、p、q＝0～6，R14、R15、R16、R17、R18相同或不同地任选自：-H、-F、-Cl、-Br、-I、-CF3、-OCF3、-OH、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH(CH3)2、-COOC(CH3)3、-(C＝O)-NR19R20、-SOm-NR19R20、-CHR19R20、-OR19或-NR19R20；m＝1～2；
    R19、R20相同或不同地任选自：氢、卤素、C1～C6烷基；或者，R19与R20组成饱和或不饱和的5～8元杂环基团；
    或者，R12、R13组成含1～4个杂原子的取代或未取代C5～C18脂肪环烷基。
  3. 根据权利要求1所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，其特征在于：所述R4选自以下结构：氢、甲基、乙基、丙基、异丙基、丁基、异丁基、戊基、异戊基、环丙基、环丁基、环戊基、环己基、甲氧基、乙氧基、丙氧基、异丙氧基或
    Figure PCTCN2016095813-appb-100008
    其中，R21任选自：氢、卤素、C1～C5烷基、C3～C6环烷基或C1～C5烷基；
    所述R5选自以下结构：氢、
    Figure PCTCN2016095813-appb-100009
    Figure PCTCN2016095813-appb-100010
    所述R6选自以下结构：氢，氟，氯，溴，甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，异戊基，丙烯基，异丙烯基，丁烯基，戊烯基，环丙基，环丁基，环戊基，环己基，环丁烯基，环戊烯基，环己烯基，甲氧基，乙氧基，丙氧基，异丙氧基，三氟甲基或三氟甲氧基；
    当所述R8为H时，R7选自以下结构：氢，甲基，乙基，丙基，异丙基，丁基，环丙基，环丁基，环戊基或环己基；
    当所述R7、R8与C、D环组成三元并环，所述三元并环为以下结构之一：
    Figure PCTCN2016095813-appb-100011
  4. 根据权利要求1所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，其特征在于：具有如下所示结构：
    Figure PCTCN2016095813-appb-100012
    Figure PCTCN2016095813-appb-100013
    其中，n＝0～2，W为CH2或O；
    X任选自：CH或N；
    R1任选自：氢或卤素；
    R2任选自：
    Figure PCTCN2016095813-appb-100014
    R9任选自：氢、C1～C5烷基或C3～C6环烷基；
    R3任选自：氢、卤素、三氟甲基或C1～C3烷基；
    R4任选自：氢、C1～C5烷基、C3～C6环烷基、C1～C3烷氧基、取代或未取代苯基；
    R5任选自：氢、-(CH2)r-COOR22、-(CH2)r-NR23R24、-L-杂芳基或
    Figure PCTCN2016095813-appb-100015
    R5中，r、s1、s2、s3各自独立的选自0、1、2或3；
    V任选自：CH或N；
    U任选自：O、S、CR23R24或NR23；
    R22任选自：氢或C1～C4烷基；
    R23、R24任选自：H、C1～C3烷基、C3～C6环烷基、-NH(C1～C3烷基)、-N(C1～C3烷基)(C1～C3烷基)或-C(＝O)(C1～C3烷基)；
    L任选自：C1～C3烷基、-NR25-、-NR25CO-、-CONR25-、-O-、-CO-、-SO-或-SO2-；R25选自：C1～C3烷基；
    R6任选自：氢、卤素、C1～C5烷基、C2～C6烯基、C3～C6环烷基、C4～C6环烯基、C1～C5烷氧基、三氟甲基或三氟甲氧基；
    R7任选自：氢、C1～C5烷基或C3～C6环烷基；
    或者R7与C、D环组成三元并环
    Figure PCTCN2016095813-appb-100016
    R10任选自H或CH3；
    所述的三元并环为以下结构之一：
    Figure PCTCN2016095813-appb-100017
  5. 根据权利要求4所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，其特征在于：
    R4任选自：氢，甲基，乙基，丙基，异丙基，丁基，异丁基，戊基，异戊基，环丙基，环丁基，环戊基，环己基，甲氧基，乙氧基，丙氧基，异丙氧基，
    Figure PCTCN2016095813-appb-100018
    其中，R21任选自：氢，卤素，C1～C5烷基，C3～C6环烷基或C1～C5烷基；
    R5任选自：氢，
    Figure PCTCN2016095813-appb-100019
    Figure PCTCN2016095813-appb-100020
    Figure PCTCN2016095813-appb-100021
    R6任选自：氢，氟，氯，溴，甲基，乙基，丙基，异丙基，丁基，异丁基，叔丁基，戊基，异戊基，丙烯基，异丙烯基，丁烯基，戊烯基，环丙基，环丁基，环戊基，环己基，环丁烯基，环戊烯基，环己烯基，甲氧基，乙氧基，丙氧基，异丙氧基，三氟甲基或三氟甲氧基。
  6. 根据权利要求4所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，其特征在于：所述E与A环组成并5～6元取代杂环，为以下结构：
    Figure PCTCN2016095813-appb-100022
    其中，X为CH或N；
    R11任选自：氢，卤素，甲基，乙基，丙基，异丙基，环丙基，甲氧基，乙氧基，丙氧基或异丙氧基；
    R12、R13相同或不同地任选自：氢，卤素，-(CR15R16)OR14、-O(CR15R16)OR14、-(CR17＝CR18)pR14、-O(CR17＝CR18)pR14、
    Figure PCTCN2016095813-appb-100023
    其中，o、p、q＝0～6；R14、R15、R16、R17、R18相同或不同地任选自：-H、-F、-Cl、-Br、-I、-CF3、-OCF3、-OH、-COOH、-COOCH3、-COOC2H5、-COOC3H7、-COOCH(CH3)2、-COOC(CH3)3、-(C＝O)-NR19R20、-SOm-NR19R20、-CHR19R20、-OR19或-NR19R20；
    R19、R20相同或不同地任选自：氢、卤素、C1～C6烷基；或者，R19与R20组成饱和或不饱和的5～8元杂环基团；
    或者，R12、R13组成含1～4个杂原子的取代或未取代C5～C18脂肪环烷基。
  7. 根据权利要求1所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体，其特征在于为以下化合物中的一种：
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-氯-N-(3-氟-4-((3-苯基-1H-吡唑[3,4-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((7H-吡咯[2,3-d]嘧啶-4-取代)氧基)-3氟苯基)-6-氯-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    7-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    5-氯-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-7-(三氟甲基)-1,4-二氢喹啉-3-甲酰胺
    6-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((1H-吡咯[2,3-b]吡啶-4-取代)氧基)-3氟苯基)-6-氯-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-三氟甲基-1,4-二氢喹啉-3-甲酰胺
    6-氯-N-(3-氟-4-((3-苯基-1H-吡咯[2,3-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-溴-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢苯并[g]喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-6甲氧基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    1-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1-丙基-1,4-二氢喹啉-3-甲酰胺
    1-丁基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-2,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    2-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-2-苯基-1,4-二氢喹啉-3-甲酰胺
    9-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-3-甲基-10-(4-甲基哌嗪-1-取代)-7-氧基-3,7-二氢-[1,4]氧氮卓[2,3,4-ij]喹啉-6-甲酰胺
    1-环丙基-6-氟-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-4-氧基-7-(哌嗪-1-取代)-1,4-二氢喹啉-3-甲酰胺
    9-氟-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-8-(4-羟基哌啶-1-基)-5-甲基-1-氧代-1,5,6,7-四氢吡啶并[3,2,1-ij]喹啉-2-甲酰胺
    6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-叔丁基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-丙基-1,4-二氢喹啉 -3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-三氟甲氧基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-1,2-二甲基-4-氧基-N-(4((5-苯基-7H-吡咯[2,3,d]嘧啶-4-取代)氧基)-1,4-二氢喹啉-3-甲酰胺
    6-乙基-12-二甲基-N-(3-甲基-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(2-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((7H-吡咯[2,3-d]嘧啶-4-取代)氧基)-3-三氟苯基)-6-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟-4-((3-苯基-1H-吡咯[2,3-d]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟-4-((5-(4-甲氧基苯基)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-9-甲基-1-氧基-1,5,6,7-四氢吡啶[3,2,1-ij]喹啉-2-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-9-甲基-1-氧代-6,7-二氢-1H,5H-吡啶并[3,2,1-ij]喹啉-2-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,6-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-(丙基-1-烯基-2-取代)-1,4-二氢喹啉-3-甲酰胺
    6-环丙基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-(环戊基-1-烯基-1-取代)-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-苯基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-6-(1-哌啶-4-取代)-1H-吡唑-4-取代)-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-6-异丙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-环戊基-N-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    3-(3-氟-4-((5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)氨甲酰基-1,2-二甲基-4-氧基-1,4-二氢喹啉-6-羧酸甲酯
    N-(3-氟-4-((7-甲基-5-苯基-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2,6-三甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-6-氟-1-甲基-7-(4-((5-甲基-2-氧代-1,3-二氧杂环戊烯-4-基)甲基)哌嗪-1-基)-4-氧代-1,4-二氢-[1,3]硫氮杂环丁烷并[3,2-a]喹啉-3-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-取代)氧基)-3-氟苯基)-9-氟-8-(4-羟基哌啶-1-取代)-5-甲基-1-氧基-1,5,6,7-四氢吡咯[3,2,2-ij]喹啉-2-甲酰胺
    (S)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-9-氟-3-甲基-10-(4-甲基哌嗪-1-基)-7-氧代-2,3-二氢-7H-[1,4]恶嗪[2,3,4-ij]喹啉-6-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-9-氟-3-甲基-10-(4-甲基哌嗪-1-基)-7-氧代-2,3-二氢-7H-[1,3,4]恶二嗪[6,5,4-ij]喹啉-6-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6,8-二氟-1-(2-氟乙基)-7-(4-甲基哌嗪-1-基)-4-氧代-1,4-二氢喹啉-3-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-氟-1-(4-氟苯基)-4-氧代-7-(哌嗪-1-基)-1,4-二氢喹啉-3-甲酰胺
    5-氨基-1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-7-(3,5-二甲基哌嗪-1-基)-6,8-二氟-4-氧代-1,4-二氢喹啉-3-甲酰胺
    1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-7-(4-乙基哌嗪-1-基)-6-氟-4-氧代-1,4-二氢喹啉-3-甲酰胺
    7-(3-氨基吡咯烷-1-基)-1-(2,4-二氟苯基)-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-氟-4-氧代-1,4-二氢-1,8-萘啶-3-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-1-乙基-6-氟-4-氧代-7-(哌嗪-1-基)-1,4-二氢-1,8-萘啶-3-甲酰胺
    1-环丙基-N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-基-4-氧代-7-(哌嗪-1-基)-1,4-二氢喹啉-3-甲酰胺
    N-(4-((2-氯吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((2-苄基吡啶-4-取代)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-((3-氟-4-((-苯基氟[2,3-b]吡啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((2-氨基甲酰基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((2-氨基吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟基-4-(5-(1-甲基-1H-吡唑-4-取代)-7H-吡咯[2,3-d]嘧啶-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    2,6-二乙基-N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-取代)氧基)苯基)-1-甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-2,6-二乙基-1-甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
    N-(4-((2-氨基甲酰基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((2-氨基-3-氯吡啶-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(3-氟-4-((5-苯基-7H-吡咯并[2,3-d]嘧啶-4-基)氧基)苯基)-2,6-二甲基-4-氧代-1-苯基-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-吗啉代丙氧基)喹唑啉-4-取代)氧基)苯基)-1,2-二甲基-4-氧基-1,4-二氢喹啉-3-甲酰胺
    N-(4-((7-(2-(二甲氨基)乙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-(4-甲基哌嗪1-基)丙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟-4-((6-甲氧基-7-(2-(吡咯烷-1-基)乙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
    6-乙基-N-(3-氟-4-((6-甲氧基-7-(3-甲氧丙氧基)喹唑啉-4-基)氧基)苯基)-1,2-二甲基-4-氧代-1,4-二氢喹啉-3-甲酰胺
    N-(4-((7-(2-(二甲氨基)丙氧基)-6-甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-4-氧代-1,4- 二氢喹啉-3-甲酰胺
    N-(4-((6,7-二甲氧基喹唑啉-4-基)氧基)-3-氟苯基)-6-乙基-1,2-二甲基-7-(4-甲基哌嗪-1-基)-4-氧代-1,4-二氢喹啉-3-甲酰胺
  8. 一种治疗肿瘤的药用组合物，其特征在于包括权利要求1～7任一项所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体或其前药分子及药学上可接受的载体。
  9. 根据权利要求1～7任一项所述的取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体或其前药分子在制备治疗或预防肿瘤的药物中的应用。
  10. 根据权利要求9所述的应用，其特征在于所述肿瘤为血液性肿瘤、胃肠间质瘤、组织细胞性淋巴癌、非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、胰腺癌、乳腺癌、前列腺癌、肝癌、皮肤癌、上皮细胞癌、鼻咽癌中的任意一种。
PCT/CN2016/095813 2015-08-18 2016-08-18 取代喹诺酮类衍生物或其药学上可接受的盐或立体异构体及其药用组合物和应用 WO2017028797A1 (zh)

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AU2016309833B2 (en) 2019-05-23
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IL257481B (en) 2021-06-30
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JP6530857B2 (ja) 2019-06-12
CN108473434B (zh) 2021-11-23
KR20180052640A (ko) 2018-05-18
EP3339294B1 (en) 2021-04-14
JP2018528195A (ja) 2018-09-27
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