WO2015043515A1 - 喹唑啉衍生物及其制备方法 - Google Patents

喹唑啉衍生物及其制备方法 Download PDF

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Publication number
WO2015043515A1
WO2015043515A1 PCT/CN2014/087633 CN2014087633W WO2015043515A1 WO 2015043515 A1 WO2015043515 A1 WO 2015043515A1 CN 2014087633 W CN2014087633 W CN 2014087633W WO 2015043515 A1 WO2015043515 A1 WO 2015043515A1
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Prior art keywords
chloro
compound
alkyl
alkoxy
group
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PCT/CN2014/087633
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English (en)
French (fr)
Inventor
校登明
朱岩
胡远东
王虎庭
李继军
彭勇
张慧
罗鸿
孔凡胜
韩永信
Original Assignee
正大天晴药业集团股份有限公司
北京赛林泰医药技术有限公司
连云港润众制药有限公司
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Application filed by 正大天晴药业集团股份有限公司, 北京赛林泰医药技术有限公司, 连云港润众制药有限公司 filed Critical 正大天晴药业集团股份有限公司
Priority to BR112016006692-8A priority Critical patent/BR112016006692B1/pt
Priority to EA201600204A priority patent/EA034573B1/ru
Priority to KR1020167010753A priority patent/KR101843752B1/ko
Priority to AU2014327932A priority patent/AU2014327932B9/en
Priority to CA2924705A priority patent/CA2924705C/en
Priority to US15/024,472 priority patent/US9725439B2/en
Priority to EP14849754.8A priority patent/EP3050880B1/en
Priority to CN201480048074.0A priority patent/CN105555782B/zh
Priority to JP2016544710A priority patent/JP6207752B2/ja
Publication of WO2015043515A1 publication Critical patent/WO2015043515A1/zh
Priority to HK16109937.9A priority patent/HK1221720A1/zh

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a quinazoline derivative and a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition thereof, and use thereof in the prevention and treatment of a tumor.
  • lung cancer is the most malignant tumor with the highest morbidity and mortality.
  • Lung cancer can be divided into two main types: small cell lung cancer and non-small cell lung cancer, of which non-small cell lung cancer accounts for 80% of the total number of lung cancer patients.
  • non-small cell lung cancer traditional chemotherapy and radiotherapy lack specificity, and while achieving efficacy and prolonging the survival time of patients, it also brings more side effects. Therefore, targeted therapy that can avoid excessive damage to normal cells is increasingly recognized by cancer academics and patients, and EGFR inhibitors play an important role.
  • Epidermal growth factor receptor is a tyrosine kinase receptor and is a member of the HER/ErbB family.
  • the family includes EGFR, HER2, HER3 and HER4, which are composed of three parts: an extracellular ligand binding region, a transmembrane region composed of a single strand, and an intracellular tyrosine kinase region.
  • EGFR is widely distributed on the surface of mammalian epithelial cells, fibroblasts, glial cells, keratinocytes, etc.
  • EGFR signaling pathway plays an important role in the physiological processes such as cell growth, proliferation and differentiation. Loss of protein tyrosine kinase function such as EGFR or abnormal activity or cell localization of key factors in related signaling pathways can cause tumor, diabetes, immunodeficiency and cardiovascular disease.
  • EGFR-TKI selective EGFR tyrosine kinase inhibitor
  • Iressa Gefitinib
  • Tarceva Erlotinib
  • EGFR/HER2 Inhibitor lapatinib Lapatinib, Tykerb
  • the reversible EGFR inhibitors gefitinib and erlotinib have a good therapeutic effect on EGFR-mutant non-small cell lung cancer patients, which can significantly prolong the progression-free survival (PFS) and overall survival (OS) of patients.
  • PFS progression-free survival
  • OS overall survival
  • PFS progression-free survival
  • most patients with positive EGFR mutations have a PFS of no more than 12 to 14 months, and then develop resistance to the above EGFR-TKI.
  • the present invention provides a series of novel quinazoline derivatives or pharmaceutically acceptable salts thereof, and pharmaceutical compositions comprising the same, and methods of preventing and treating tumors using such compounds.
  • the present invention provides a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof,
  • Ring Ar is an aryl or heteroaryl group
  • n and m are each an arbitrary integer from 0 to 6, and m and n are not 0 at the same time;
  • p is any integer from 0 to 5;
  • q is any integer from 0 to 8.
  • R 1 is independently selected from C 1-6 alkyl, C 3-8 cycloalkyl, C 2-6 alkenyl, C 2-6 alkynyl, heterocycloalkyl, halo, amino, mono (C 1-6 Alkyl)amino, di(C 1-6 alkyl)amino, hydroxy, C 1-6 alkoxy, fluorenyl, C 1-6 alkylthio, C 1-6 alkylcarbonyl, aryl, heteroaryl , cyano, nitro, wherein C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl can be halogen, cyano, nitro, C 1-6 Alkyla, aryl, heteroaryl, heterocycloalkyl substituted, and aryl, heteroaryl, heterocycloalkyl can be further substituted by halogen, cyano, nitro, C 1-6 alkyl, C 1- 6 alkoxy, C 1-6 alkylcarbonyl
  • R 2 is selected from hydrogen, hydroxy, C 1-6 alkoxy, or heterocycloalkyl group is a substituted heterocyclyl C 1-6 alkoxy or C 1-6 alkoxy group;
  • R 3 is independently selected from halogen, cyano, decyl, C 1-6 alkylthio, C 1-6 alkyl, C 3-8 cycloalkyl, heterocycloalkyl, amino, mono (C 1-6 alkane) Amino, di(C 1-6 alkyl)amino, hydroxy, C 1-6 alkoxy, C 1-6 alkoxycarbonyl, C 1-6 alkylamido, mono(C 1-6 alkane Aminoacyl, di(C 1-6 alkyl)amino acyl;
  • R 4 , R 5 and R 6 are each independently selected from the group consisting of hydrogen, halogen, C 1-6 alkyl, C 3-8 cycloalkyl, heterocycloalkyl, amino, mono(C 1-6 alkyl)amino, Bis(C 1-6 alkyl)amino, C 1-6 alkylamido, mono(C 1-6 alkyl)amino, di(C 1-6 alkyl)amino, C 1-6 alkoxy Alkylcarbonyl;
  • R 7 and R 8 are each independently selected from hydrogen or C 1-6 alkyl.
  • X is selected from -NR 8 -, -S-; in some embodiments of the invention, X is -NR 8 -.
  • p is an integer from 0 to 3. In some embodiments, p is 1 or 2.
  • q is an integer from 0 to 3. In some embodiments, q is zero.
  • R 7, R 8 is hydrogen
  • Ring Ar is phenyl
  • R 1 is independently selected from C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen, amino, hydroxy, C 1-6 alkoxy, C 1-6 alkylcarbonyl, cyano, nitro, wherein C 1-6 alkyl, C 1-6 alkoxy, C 2-6 alkenyl, C 2-6 alkynyl may be halogen, cyano, Nitro, C 1-6 alkoxy, aryl, heteroaryl, heterocycloalkyl substituted, and aryl, heteroaryl, heterocycloalkyl may be further substituted by halogen, cyano, nitro, C 1- 6 alkyl, C 1-6 alkoxy, C 1-6 alkylcarbonyl substituted.
  • R 1 is independently selected from C 2-6 alkynyl, halo, C 1-6 alkoxy, C 1-6 alkylcarbonyl, wherein C 1-6 alkoxy can be aryl
  • the group, heteroaryl group, heterocycloalkyl group is substituted, and the aryl group, heteroaryl group, heterocycloalkyl group may be further substituted by halogen, cyano group or nitro group.
  • R 1 is independently selected from C 2-6 alkynyl, halo, heteroaryl substituted C 1-6 alkoxy, aryl substituted C 1-6 alkoxy, C A 1-6 alkylcarbonyl group in which an aryl group or a heteroaryl group may be further substituted with a halogen.
  • R 1 is independently selected from ethynyl, halo, pyridyl substituted C 1-6 alkoxy, halophenyl substituted C 1-6 alkoxy.
  • R 4 , R 5 and R 6 are hydrogen.
  • R 2 is selected from the group consisting of hydrogen, methoxy, tetrahydrofuranyloxy, ethoxy substituted by methoxy, ethoxy substituted with morpholinyl.
  • the invention relates to the following compounds or salts thereof:
  • the compound of formula (I) of the present invention can be prepared by the steps of Synthesizing Routes I and II or a method analogous thereto: Synthetic Route 1:
  • PG is an amino protecting group
  • the compound of formula 1 is reacted with thionyl chloride under reflux to form a compound of formula 2, and the compound of formula 2 is refluxed with the compound of formula 2' in acetonitrile to give a compound of formula 3 in the presence of potassium t-butoxide and DMSO with R 2 H reacts to form a compound of formula 4, which is reduced with hydrogen in the presence of Raney nickel to give a compound of formula 5, which is formed by reacting a compound of formula 5 with a compound of formula 5' in the presence of trifluoroacetic acid or acetic acid or sodium triacetoxyborohydride.
  • the compound of the formula 5 is reacted in the presence of sodium nitrite, sulfuric acid, potassium thiocyanate, ferric chloride and water to form a compound of the formula 9, which is reacted with a compound of the formula 9' in the presence of sodium borohydride, potassium carbonate or ethanol.
  • a compound of formula 10, a compound of formula 10, is heated to 60 ° C in the presence of trifluoroacetic acid to form a compound of formula 11 which is reacted with acryloyl chloride to form a compound of formula 12.
  • the compounds of the invention may be asymmetric, for example, having one or more stereoisomers. Unless otherwise stated, all stereoisomers include, for example, enantiomers and diastereomers.
  • the asymmetric carbon atom-containing compound of the present invention can be isolated in optically active pure form or in racemic form. The optically active pure form can be resolved from the racemic mixture or synthesized by using a chiral starting material or a chiral reagent.
  • a compound of the formula (I) of the present invention in the form of a pharmaceutically acceptable salt formed with an inorganic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid or lactic acid.
  • an inorganic or inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid or lactic acid.
  • malonic acid succinic acid, fumaric acid, malic acid, mandelic acid, tartaric acid, citric acid, ascorbic acid, palmitic acid, maleic acid, benzoic acid, phenylacetic acid, cinnamic acid, salicylic acid, methanesulfonic acid, Benzenesulfonic acid, methylbenzenesulfonic acid.
  • Another aspect of the invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I as defined herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • compositions of the present invention can be prepared by combining a compound of the present invention with a suitable pharmaceutically acceptable carrier, for example, as a solid, semi-solid, liquid or gaseous preparation such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • a suitable pharmaceutically acceptable carrier for example, as a solid, semi-solid, liquid or gaseous preparation such as tablets, pills, capsules, powders. , granules, ointments, emulsions, suspensions, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
  • Typical routes of administration of a compound of the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, transmucosal, enteral, or topical, transdermal, inhalation, parenteral, sublingual, vaginal Internal, intranasal, intraocular, intraperitoneal, intramuscular, subcutaneous, intravenous administration.
  • a preferred route of administration is oral administration.
  • the pharmaceutical composition of the present invention can be produced by a method well known in the art, such as a conventional mixing method, a dissolution method, a granulation method, a drag coating method, a grinding method, an emulsification method, a freeze drying method, and the like.
  • the pharmaceutical composition is in oral form.
  • the pharmaceutical composition can be formulated by admixing the active compound with apharmaceutically acceptable carrier which is well known in the art. These carriers enable the compounds of the present invention to be formulated into tablets, pills, troches, dragees, capsules, liquids, gels, slurries, suspensions and the like for oral administration to a patient.
  • Solid oral compositions can be prepared by conventional methods of mixing, filling or tabletting. For example, it can be obtained by mixing the active compound with a solid excipient, optionally milling the resulting mixture, adding other suitable adjuvants if necessary, and then processing the mixture into granules. The core of a tablet or dragee.
  • Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.
  • microcrystalline cellulose glucose solution, gum arabic, gelatin solution, sucrose and starch paste; talc, starch, magnesium stearate, calcium stearate or stearic acid; lactose, sucrose, starch, mannitol, sorbus Sugar alcohol or dicalcium phosphate; silica; croscarmellose sodium, pre-treated starch, sodium starch glycolate, alginic acid, corn starch, potato starch, methyl cellulose, agar, carboxymethyl fiber Or cross-linked polyvinylpyrrolidone.
  • the core may optionally be coated according to methods well known in the ordinary pharmaceutical practice, especially using an enteric coating.
  • compositions may also be suitable for parenteral administration, such as sterile solutions, suspensions or lyophilized products in a suitable unit dosage form.
  • suitable excipients such as fillers, buffers or surfactants can be used.
  • Another aspect of the invention also relates to the use of a compound of formula I according to the invention, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the prophylaxis or treatment of a tumor.
  • the daily dose is preferably from 0.01 to 200 mg/kg body weight.
  • halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • hydroxy refers to -OH.
  • mercapto refers to -SH.
  • cyano refers to -CN.
  • nitro refers to -NO 2 .
  • alkyl refers to a straight or branched saturated aliphatic hydrocarbon group consisting of a carbon atom and a hydrogen atom, which is attached to the remainder of the molecule by a single bond.
  • the alkyl group may have 1 to 6 carbon atoms (represented by a C 1-6 alkyl group), preferably having 1 to 4 carbon atoms.
  • Non-limiting examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, n-pentyl, 2-methylbutyl, neopentyl Base, n-hexyl.
  • alkoxy refers to -O-alkyl wherein alkyl is as defined above.
  • the alkoxy group may have 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
  • Non-limiting examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, n-pentyloxy , 2-methylbutoxy, neopentyloxy, n-hexyloxy.
  • alkylthio refers to -S-alkyl wherein alkyl is as defined above.
  • amino refers to -NH 2 .
  • di(alkyl)amino refers to -N(alkyl) 2 wherein alkyl is as defined above and the two alkyls may be the same or different.
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic cyclic hydrocarbon group.
  • Non-limiting examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.
  • alkenyl refers to a straight or branched alkene group, preferably a straight or branched alkene group containing from 2 to 6 carbon atoms.
  • alkenyl groups include, but are not limited to, ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl.
  • alkynyl refers to a straight or branched alkyne group, preferably a straight or branched alkyne group containing from 2 to 6 carbon atoms.
  • alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl.
  • aryl refers to an all-carbon monocyclic or fused polycyclic aromatic ring group having a conjugated ⁇ -electron system, preferably having from 6 to 14 carbon atoms, more preferably from 6 to 12 carbon atoms, most It preferably has 6 carbon atoms.
  • Non-limiting examples of aryl groups include, but are not limited to, phenyl, naphthyl, and anthracenyl.
  • heteroaryl refers to a monocyclic or fused ring having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein 1, 2, 3 or 4 are selected from N, O. , the ring atom of S, the remaining ring atoms are C, and have a fully conjugated ⁇ -electron system.
  • the heteroaryl group preferably has a 5- or 6-membered ring, more preferably a 5-membered ring.
  • heteroaryl groups include, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl, oxazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolinyl, isoquinolinyl , tetrazolyl, triazolyl, triazinyl.
  • heterocycloalkyl refers to a monocyclic or fused ring having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms, wherein 1, 2 or 3 ring atoms are A hetero atom selected from N, O, S(O) n (where n is 0, 1, or 2), and the remaining ring atoms are C.
  • Such rings may be saturated or unsaturated (eg, having one or more double bonds), but do not have a fully conjugated ⁇ -electron system.
  • Examples of the 3-membered heterocycloalkyl group include, but are not limited to, an oxiranyl group, an ethylenethio group, a cycloalkylethane group, and examples of the 4-membered heterocycloalkyl group include, but are not limited to, an azetidinyl group, an oxabutyl group, Examples of the thibutane group, a 5-membered heterocycloalkyl group include, but are not limited to, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, 1,1-di Examples of oxoisothiazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyrazolyl, pyrrolinyl, dihydrofuranyl, dihydrothienyl, 6-membered
  • terapéuticaally effective amount means that when administered to a mammal, preferably a human, the compound of the invention is sufficient to effectively treat a mammalian (preferably human) disease.
  • the amount of a compound of the invention that constitutes a “therapeutically effective amount” will vary depending on the compound, the condition and severity thereof, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art It is determined by its own knowledge and the present disclosure.
  • treating means administering a compound or formulation of the invention to prevent, ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • pharmaceutical composition refers to one or more compounds of the present invention or salts thereof and carriers, excipients and/or carriers generally accepted in the art for delivery of biologically active compounds to organisms such as humans. Preparation of the medium.
  • the purpose of the pharmaceutical composition is to facilitate administration of the compounds of the invention to an organism.
  • pharmaceutically acceptable carrier refers to those carriers and diluents which are not irritating to the organism and which do not impair the biological activity and properties of the active compound.
  • “Pharmaceutically acceptable carrier” includes, but is not limited to, any carrier, excipient, vehicle, glidant, sweetener, diluent, for human or livestock animals that is approved by the National Food and Drug Administration as acceptable. Preservatives, dyes/colorants, flavor enhancers, surfactants, wetting agents, dispersing agents, disintegrating agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
  • the instrument used for nuclear magnetic resonance spectroscopy was a Varian VNMRS-400 resonance spectrometer.
  • the recording format of nuclear magnetic resonance data is: proton number, peak type (s, single peak; d, double peak; t, triplet; q, quartet; m, multiplet), coupling constant (in Hertz) ).
  • the Agilent LC 1200 Series (5 micron C18 column) instrument is used for LC/MS.
  • Step 3 N-(3-Chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-fluoro-6-nitroquinazolin-4-amine
  • Step 4 N-(3-Chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-methoxy-6-nitroquinazolin-4-amine
  • Step 5 N 4 -(3-chloro-4-fluorophenyl)-N 4 -(3,4-dimethoxybenzyl)-7-methoxyquinazoline-4,6-diamine
  • N-(3-Chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-methoxy-6-nitroquinazolin-4-amine (2.35 g 4.7 mmol) and Raney Nickel about 0.5 g were added to tetrahydrofuran (100 mL), replaced with hydrogen, and stirred under a hydrogen atmosphere (1 atm) at room temperature overnight. Filtration and concentration of the filtrate in vacuo gave the title compound (2 g, 90%).
  • Step 6 3- ⁇ 4-[(3-Chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino]-7-methoxyquinazolin-6-yl ⁇ amino ⁇ Azetidine-1-carboxylate
  • N 4 -(3-chloro-4-fluorophenyl)-N 4 -(3,4-dimethoxybenzyl)-7-methoxyquinazoline-4,6-diamine (1.10 g , 2.35 mmol) and a solution of benzyl 3-oxoazetidine-1-carboxylate (0.58 g, 2.83 mmol) in trifluoroacetic acid (7 mL). Sodium (0.52 g, 2.45 mmol).
  • Step 7 N 6 -(azetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 8 N 6 -(1-acryloylazetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6- Diamine
  • N 6 -(azetidin-3yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine trifluoroacetate (0.89 g, 1.82 mmol) and a suspension of triethylamine (1 mL) in tetrahydrofuran (20 mL) were stirred at room temperature for 30 min. After cooling to -40 ° C, a solution of acryloyl chloride (166 mg, 1.82 mmol) in tetrahydrofuran (2 mL) was slowly added dropwise, and the reaction was continued for 30 minutes. After completion of the reaction, the reaction was quenched by slowly adding a 5% NaHCO 3 solution and extracted with ethyl acetate. The organic layer was washed with EtOAc EtOAc m.
  • Step 1 4- ⁇ 4-[(3-Chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino]-7-methoxyquinazolin-6-yl ⁇ amino ⁇ piperidine-1-carboxylic acid tert-butyl ester
  • Step 2 N 6 -(piperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 3 N 6 -(1-acryloylpiperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine
  • N 6 -(piperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine monotrifluoroacetate A solution of 258 mg, 0.5 mmol) and triethylamine (202 mg, 2.0 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 30 min. After cooling to 0 ° C, a solution of acryloyl chloride (54 mg, 0.6 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the reaction was continued for 30 minutes. After completion of the reaction, the reaction was quenched by slowly adding a 5% NaHCO 3 solution and extracted with ethyl acetate. The obtained organic phase was washed with EtOAc EtOAc m.
  • N-(3-chloro-4fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine (37.1 g, 0.11 mol) and (S)-3-hydroxytetrahydrofuran (13.6 g, 0.154) Mol) was dissolved in dry DMSO (200 mL), and potassium t-butoxide (30.9 g, 0.275 mol) was added portionwise, and the internal temperature of the water bath was controlled below 30 °C. After stirring at normal temperature for 4 hours, the reaction solution was poured into 1.2 L of water, suction filtered, washed with water and dried. The crude product was beaten with ethanol and filtered (33.4 g, 75%).
  • Step 3 (S)-N 4 -(3-Chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)quinazoline-4,6-diamine
  • Step 4 (S)-3- ⁇ 4-[(3-Chloro-4-fluorophenyl)amino]-7-(tetrahydrofuran-3-yloxy)quinazolin-6-yl ⁇ amino ⁇ nitrogen Benzetane-1-carboxylate
  • Step 5 (S)-N 6 -(azetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy) quinazoline Porphyrin-4,6-diamine
  • Step 6 (S)-N 6 -(1-acryloylazetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy Quinazoline-4,6-diamine
  • Step 1 (S)-4-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)piperidine-1-carboxylic acid Tert-butyl ester
  • Step 2 (S)-N 6 -(azetidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy) quinazoline Porphyrin-4,6-diamine
  • Step 3 (S)-N 6 -(1-acryloyl azacyclohexane-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy Quinazoline-4,6-diamine
  • Step 1 (S)-3-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)piperidine-1-carboxylic acid Tert-butyl ester
  • Step 2 (S)-N 6 -(azetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy) quinazoline Porphyrin-4,6-diamine
  • Step 3 (S)-N 6 -(1-acryloyl azacyclohexane-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy Quinazoline-4,6-diamine
  • Step 1 (S)-3-(4-(3-Chloro-4-fluorophenylamino)-7-(tetrahydrofuran-3-yloxy)quinazolin-6-ylamino)azetane- 1-carboxylic acid tert-butyl ester
  • Step 2 (S)-N 6 -(azepan-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy)quinazole Porphyrin-4,6-diamine
  • Step 3 (S)-N 6 -(1-acryloylazolidine-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(tetrahydrofuran-3-yloxy Quinazoline-4,6-diamine
  • Step 4 N 4 -(3-Chloro-4-(3-fluorobenzyloxy)phenyl)-7-methoxy-quinazoline-4,6-diamine
  • Step 5 4-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-7-methoxyquinazolin-6-ylamino)piperidine-1-carboxylic acid tert-butyl ester
  • Step 6 N 4 -(3-Chloro-4-(3-fluorobenzyloxy)phenyl)-7-methoxy-N 6 -(piperidin-4-yl)quinazoline-4,6- Diamine
  • Step 7 1-(4-(4-(3-Chloro-4-(3-fluorobenzyloxy)phenylamino)-7-methoxyquinazolin-6-ylamino)piperidine-1- Prop-2-en-1-one
  • Step 4 N 4 -(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 5 4-(4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino-7-methoxyquinazolin-6-ylamino)piperidine-1-carboxylic acid Butyl ester
  • Step 6 N 4 -(3-chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-methoxy-N 6 -(piperidin-4-yl)quinazoline-4, 6-diamine
  • Step 7 1-(4-(4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-methoxyquinazolin-6-ylamino)piperidine- 1-yl)prop-2-en-1-one
  • Step 1 3-(4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino-7-methoxyquinazolin-6-ylamino)azetidine-1-carboxylic acid Benzyl ester
  • Step 2 N 4 -(3-Chloro-4-(pyridin-2-ylmethoxy)phenyl)-7-methoxy-N 6 -(azetidin-3-yl)quinazoline-4 ,6-diamine
  • Step 3 1-(3-(4-(3-Chloro-4-(pyridin-2-ylmethoxy)phenylamino)-7-methoxyquinazolin-6-ylamino)azetidine -1-yl)prop-2-en-1-one
  • Step 2 N 4 -(3-ethynylphenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 3 4- ⁇ [4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl]amino ⁇ piperidine-1-carboxylic acid benzyl ester
  • Step 4 N 4 -(3-ethynylphenyl)-7-methoxy-N 6 -(piperidin-4-yl)quinazoline-4,6-diamine
  • Step 5 N 6 -(1-acryloylpiperidin-4-yl)-N 4 -(3-ethynylphenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 1 3- ⁇ [4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yl]amino ⁇ azetidin-1-carboxylate
  • Step 2 N 6 -(azetidin-3-yl)-N 4 -(3-ethynylphenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 3 N 6 -(1-acryloylazetidin-3-yl)-N 4 -(3-ethynylphenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 1 N 4 -(3-Acetylphenyl)-7-methoxy-N 6 -(piperidin-4-yl)quinazoline-4,6-diamine
  • Step 2 N 4 -(3-Acetylphenyl)-N 6 -(1-acryloylpiperidin-4-yl)-7-methoxyquinazoline-4,6-diamine
  • Step 1 N 4 -(3-Acetylphenyl)-N 6 -(azetidin-3-yl)-7-methoxyquinazoline-4,6-diamine
  • N-(3-Acetylphenyl)-7-methoxy-6-nitroquinazolin-4-amine was prepared in a similar manner to Step 2 of Example 10 to give N-(3-acetylphenyl).
  • -7-Methoxy-quinazoline-4,6-diamine which was then synthesized in a similar manner to that of Steps 6 and 7 of Example 1, to give the title compound.
  • Step 2 N 4 -(3-Acetylphenyl)-N 6 -(1-acryloylazetidin-3-yl)-7-methoxyquinazoline-4,6-diamine
  • Step 2 N 4 -(3-bromophenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 3 3- ⁇ [4-(3-Bromophenylamino)-7-methoxyquinazolin-6-yl]amino ⁇ azetidin-1-carboxylate
  • Step 4 N 6 -(azetidin-3-yl)-N 4 -(3-bromophenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 5 N 6 -(1-acryloylazetidin-3-yl)-N 4 -(3-bromophenyl)-7-methoxyquinazolin-4,6-diamine
  • Step 1 4- ⁇ [4-(3-Bromophenylamino)-7-methoxyquinazolin-6-yl]amino ⁇ piperidine-1-carboxylic acid benzyl ester
  • Step 2 N 4 -(3-Bromophenyl)-7-methoxy-N 6 -(piperidin-4-yl)quinazoline-4,6-diamine
  • Step 3 N 6 -(1-acryloylpiperidin-4-yl)-N 4 -(3-bromophenyl)-7-methoxyquinazoline-4,6-diamine
  • Step 2 N 4 -(3-chloro-4fluorophenyl)-7-(2-methoxyethoxy)quinazoline-4,6-diamine
  • N-(3-chloro-4-fluorophenyl)-7-(2-methoxyethoxy)-6-nitroquinazolin-4- is similar to the method described in Step 5 of Example 1. Amine synthesis gave the compound shown in the title.
  • Step 3 3- ⁇ [4-(3-Chloro-4-fluorophenyl)-7-(2-methoxyethoxy)quinazolin-6-yl]amino ⁇ azetidin-1 - benzyl formate
  • Step 4 N 6 -(azetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(2-methoxyethoxy)quinazoline-4 ,6-diamine
  • Step 5 N 6 -(1-acryloylazetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(2-methoxyethoxy)quin Oxazoline-4,6-diamine
  • Step 1 4- ⁇ [4-(3-Chloro-4-fluorophenyl)-7-(2-methoxyethoxy)quinazolin-6-yl]amino ⁇ azetane-1 - tert-butyl formate
  • Step 2 N 6 -(azetidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(2-methoxyethoxy)quinazoline-4 ,6-diamine
  • Step 3 N 6 -(1-acryloyl azacyclohexane-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(2-methoxyethoxy)quin Oxazoline-4,6-diamine
  • Step 2 N 4 -(3-Chloro-4-fluorophenyl)-7-(2-morpholinylethoxy)quinazoline-4,6-diamine
  • N-(3-chloro-4-fluorophenyl)-7-(2-morpholinylethoxy)-6-nitroquinazolin-4 was synthesized in a similar manner to that described in Step 5 of Example 1. -Amine synthesis gives the compound shown in the title.
  • Step 3 3- ⁇ [4-(3-Chloro-4fluorophenyl)-7-(2-morpholinylethoxy)quinazolin-6-yl]amino ⁇ azetidin-1- Benzyl formate
  • N 4 -(3-chloro-4-fluorophenyl)-7-(2-morpholinylethoxy)quinazoline-4,6-di was similar to the method described in Step 6 of Example 1. Amine synthesis gave the compound shown in the title.
  • Step 4 N 6 -(azetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(2-morpholinylethoxy)quinazoline-4 ,6-diamine
  • Step 5 N 6 -(1-acryloylazetidin-3-yl)-N 4 -(3-chloro-4-fluorophenyl)-7-(2-morpholinylethoxy)quin Oxazoline-4,6-diamine
  • Step 1 N-(3-Chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-methoxy-6-thiocyanoquinazolin-4-amine
  • N 4 -(3-chloro-4-fluorophenyl)-N 4 -(3,4-dimethoxybenzyl)-7-methoxyquinazoline-4,6- at 0 °C The diamine (0.25 g, 0.5 mmol) was slowly added to 30% sulfuric acid (3 g) and stirred for 30 minutes to completely dissolve. Sodium nitrite (0.072 g, 1 mmol) was slowly added. The system was stirred at 0 ° C for 30 minutes and then warmed to room temperature for 30 minutes.
  • Step 2 3- ⁇ 4-[(3-Chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino]-7-methoxyquinazolin-6-yl ⁇ fluorenyl ⁇ Azetidine-1-carboxylic acid tert-butyl ester
  • Step 3 6-(Azetidin-3-yl)indolyl-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine
  • Step 4 6-(1-Aroylazetidin-3-yl)indolyl-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine
  • Step 1 3- ⁇ 4-[(3-Chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino]-7-methoxyquinazolin-6-yl ⁇ fluorenyl ⁇ pyrrolidine-1-carboxylic acid tert-butyl ester
  • N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-methoxy-6 was synthesized in a similar manner to that described in Step 2, Example 19.
  • Synthesis of thiocyanoquinazolin-4-amine and tert-butyl 3-iodoazolidine-1-carboxylate gave the title compound.
  • Step 2 N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(pyrrolidin-3-ylindenyl)quinazolin-4-amine
  • Step 3 6-(1-Acyrylpyrrolidin-3-yl)indolyl-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine
  • N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(pyrrolidin-3-ylindenyl)quinazoline-4 was obtained in a similar manner to that described in Step 3 of Example 2. Synthesis of the amine trifluoroacetate gives the title compound.
  • Step 1 4- ⁇ 4-[(3-Chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino]-7-methoxyquinazolin-6-yl ⁇ fluorenyl ⁇ piperidine-1-carboxylic acid tert-butyl ester
  • N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-methoxy-6 was synthesized in a similar manner to that described in Step 2, Example 19.
  • Synthesis of thiocyanoquinazolin-4-amine and tert-butyl 4-iodopiperidine-1-carboxylate gave the title compound.
  • Step 3 6-(1-Aroylpiperidin-4-yl)indolyl-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine
  • N-(3-Chloro-4-fluorophenyl)-6-(piperidin-4-ylindenyl)-7-methoxyquinazoline-4 was obtained in a similar manner to that described in Step 3 of Example 2. Synthesis of the amine trifluoroacetate gives the title compound.
  • Step 1 (R)-3- ⁇ 4-[(3-Chloro-4-fluorophenyl)(3,4-dimethoxybenzyl)amino]-7-methoxyquinazoline-6 -yl ⁇ hydrazino ⁇ piperidine-1-carboxylic acid tert-butyl ester
  • N-(3-chloro-4-fluorophenyl)-N-(3,4-dimethoxybenzyl)-7-methoxy-6 was synthesized in a similar manner to that described in Step 2, Example 19.
  • Synthesis of thiocyanoquinazolin-4-amine and tert-butyl (S)-3-iodopiperidine-1-carboxylate gave the title compound.
  • Step 2 (R)-N-(3-Chloro-4-fluorophenyl)-7-methoxy-6-(piperidin-3-ylindenyl)quinazolin-4-amine
  • Step 3 (R)-6-(1-Aroylpiperidin-3-yl)indolyl-N-(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4-amine
  • Step 2 N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine
  • Step 3 4- ⁇ 4-[(3-Chloro-4-fluorophenyl)amino]-quinazolin-6-yl ⁇ amino ⁇ piperidine-1-carboxylic acid benzyl ester
  • Step 4 N 6 -(piperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine
  • Step 5 N 6 -(1-acryloylpiperidin-4-yl)-N 4 -(3-chloro-4-fluorophenyl)-quinazoline-4,6-diamine
  • EGFR, EGFR (T790M, L858R), HER2 kinase was obtained by the expression of the insect expression system by the Ministry of Biology of Beijing Sailing Medical Technology Co., Ltd. or obtained by purchasing a commercially available product.
  • the ELISA, EGFR (T790M, L858R) and HER2 kinase activity detection platforms were established by Cisbio's homogeneous time-resolved fluorescence (HTRF) method for the determination of compound activity.
  • the compounds were diluted 3-fold with 100% DMSO starting from 100 nM (EGFR and HER2), 1 ⁇ M (EGFR-T790M/L858R), and 4 ⁇ L of each concentration was added to 96 ⁇ L of reaction buffer (50 mM 4-hydroxyl).
  • Piperazine ethanesulfonic acid (pH 7.0), 0.02% NaN 3 , 0.01% bovine serum albumin (BSA), 0.1 mM sodium orthovanadate (Sodium Orthovanadate), 5 mM MgCl 2 , 50 nM SEB (Cisbio, Item No.: 61SEBALB), 1 mM DTT), 2.5 ⁇ L was added to a 384-well plate (OptiPlate-384, PerkinElmer), then 2.5 ⁇ L of kinase was added, mixed by centrifugation, and 5 ⁇ L of ATP and TK substrate biotin (Substrate- Biotin) initiates the reaction.
  • HEPES Piperazine ethanesulfonic acid
  • Anchorage-independent cell proliferation assay anchor-independent cell proliferation assay
  • Human non-small cell lung cancer cells NCI-H1975, human breast cancer cell line BT474 were cultured in a cell culture incubator (37 ° C, 5% CO 2 ) with RPIM-1640 or DMEM medium plus 10% fetal bovine serum (FBS).
  • FBS fetal bovine serum
  • concentration of the underlying substrate was 0.6%, and after the cells were reselected with 0.3% of low melting point agar, 10,000 cells per well (100 ⁇ L) were plated in 96-well plates.
  • the compound was subjected to 3-fold serial dilution from 10 mM, and 2 ⁇ L of each concentration was added to 98 ⁇ L of the medium, and then 5.3 ⁇ L was added to the cell culture medium (final concentration of DMSO 0.1%, v/v) for one week (7 days). ), add 20 ⁇ L (Promega) reagent, incubated for 4 hours at 37 ° C, read the fluorescence signal on Envison (Perkin Elmer), and calculate the IC 50 value of the compound for cell proliferation inhibition using GraphPad Prism 5.0.
  • the study used 6 healthy adult male rats from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd. Animals were fasted overnight before the experiment. The fasting time was from 12 hours before the administration to 4 hours after the administration.
  • the single dose was administered at a dose of 5 mg/kg, and the test compound was dissolved in 20% sulfobutyl- ⁇ . - aqueous solution of cyclodextrin (SBE). Blood was collected at 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after administration. Animals were bled with anesthesia machine through a mild anesthesia with isoflurane, and about 0.5 mL of whole blood was collected through the orbital venous plexus into a heparin anticoagulation tube.
  • the samples were centrifuged at 4 ° C, 4000 rpm for 5 min, the plasma was transferred to a centrifuge tube and stored at -80 ° C until analysis. Quantification of plasma drug concentrations by liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Analysis of the sample The pharmacokinetic parameters of the compound were calculated by WinNonlin (WinNonlin Professional, version. 6.3).

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Abstract

本发明涉及式（I）的喹唑啉衍生物及其制备方法、包含式（I）化合物的药物组合物及其用于制备治疗和预防肿瘤的药物中的用途。本发明化合物可以不可逆地阻止EGFR的自身磷酸化，并且有效的抑制癌细胞的信号传导，显示出更高的体外和体内抗肿瘤活性。

Description

喹唑啉衍生物及其制备方法 技术领域
本发明涉及喹唑啉衍生物和其药学上可接受的盐、其制备方法、其药物组合物、及其在预防和治疗肿瘤中的用途。
背景技术
世界范围内，肺癌是目前发病率和死亡率最高的恶性肿瘤。肺癌可以划分为两种主要的类型：小细胞肺癌和非小细胞肺癌，其中非小细胞肺癌占到肺癌患者总数的80％。针对非小细胞肺癌，传统的化疗和放疗缺乏特异性，在取得疗效、适当延长患者生存时间的同时，也带来了较多的副作用。因此，可避免对正常细胞过度伤害的靶向性治疗越来越被肿瘤学术界和广大患者所认同，其中EGFR抑制剂占有重要地位。
表皮生长因子受体(EGFR)是一种酪氨酸激酶受体，是HER/ErbB家族成员之一。该家族包括EGFR、HER2、HER3和HER4，它们由三部分组成：胞外的配体结合区、由单链构成的跨膜区以及胞内的酪氨酸激酶区。EGFR广泛分布于哺乳动物上皮细胞、成纤维细胞、胶质细胞、角质细胞等细胞表面，EGFR信号通路对细胞的生长、增殖和分化等生理过程发挥重要的作用。EGFR等蛋白酪氨酸激酶功能缺失或其相关信号通路中关键因子的活性或细胞定位异常，均会引起肿瘤、糖尿病、免疫缺陷及心血管疾病的发生。
目前，已经上市的相关药物有以下几种，选择性EGFR酪氨酸激酶抑制剂(EGFR-TKI)吉非替尼(Gefitinib，Iressa)、厄洛替尼(Erlotinib，Tarceva)以及EGFR/HER2双重抑制剂拉帕替尼(Lapatinib，Tykerb)。它们通过竞争性结合胞内段酪氨酸激酶的磷酸化位点，阻断其与ATP的相互作用，抑制酪氨酸磷酸化及下游一系列的信号传导，继而抑制肿瘤细胞的生长。其中，可逆型EGFR抑制剂吉非替尼、厄洛替尼对EGFR突变的非小细胞肺癌患者有着良好的治疗作用，可以显著延长患者的无进展生存期(PFS)和总生存期(OS)。然而，近些年的临床应用表明，大部分EGFR突变阳性患者的PFS不超过12～14个月，随即对上述EGFR-TKI产生耐药性。
现有研究表明，大约有一半左右EGFR-TKI治疗后耐药性的产生与EGFR的20位外显子发生的二次突变(T790M)相关。针对这种情况，近些年开发了诸多不可逆EGFR抑制剂，如Afatinib(BIBW-2992)、Canertinib(CI-1033)、Neratinib(HKI-272)、CO-1686、HM781-36B等，可解决上述EGFR-TKI的耐药性问题。这些药物分子具有共同的结构特征，既存在一个丙烯酰胺官能团，该官能团可与EGFR的ATP结合区的半胱氨酸773(Cys733)形成共价键。这种共价结合可以不可逆地阻止EGFR的自身磷酸化，并且有效的抑制癌细胞的信号传导，显示出更高的体外和体内抗肿瘤活性。
发明内容
本发明提供了一系列新型喹唑啉衍生物或其药学上可接受的盐，并包含这些化合物的药物组合物，以及用此类化合物预防和治疗肿瘤的方法。
根据本发明的一个方面，本发明提供式(I)表示的化合物或其药学上可接受的盐，
Figure PCTCN2014087633-appb-000001
其中：
环Ar为芳基或杂芳基；
X选自-NR8-、-S-、-S(＝O)-或者-S(＝O)2-；
n和m各自为从0到6的任意整数，且m、n不同时为0；
p为从0到5的任意整数；
q为从0到8的任意整数；
R1独立地选自C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、杂环烷基、卤素、氨基、单(C1-6烷基)氨基、二(C1-6烷基)氨基、羟基、C1-6烷氧基、巯基、C1-6烷硫基、C1-6烷基羰基、芳基、杂芳基、氰基、硝基，其中C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基可被卤素、氰基、硝基、C1-6烷氧基、芳基、杂芳基、杂环烷基取代，且芳基、杂芳基、杂环烷基可进一步被卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基羰基取代；
R2选自氢、羟基、C1-6烷氧基、杂环烷基氧基或者是被C1-6烷氧基或杂环烷基取代的C1-6烷氧基；
R3独立地选自卤素、氰基、巯基、C1-6烷硫基、C1-6烷基、C3-8环烷基、杂环烷基、氨基、单(C1-6烷基)氨基、二(C1-6烷基)氨基、羟基、C1-6烷氧基、C1-6烷氧基羰基、C1-6烷基酰氨基、单(C1-6烷基)氨基酰基、二(C1-6烷基)氨基酰基；
R4、R5和R6各自独立的选自氢、卤素、C1-6烷基、C3-8环烷基、杂环烷基、氨基、单(C1-6烷基)氨基、二(C1-6烷基)氨基、C1-6烷基酰氨基、单(C1-6烷基)氨基酰基、二(C1-6烷基)氨基酰基、C1-6烷氧基羰基；
R7、R8各自独立地选自氢或C1-6烷基。
在本发明的一些实施方案中，X选自-NR8-、-S-；在本发明的一些实施方案中，X为-NR8-。
在本发明的一些实施方案中，n和m各自为从0到3的任意整数，且m、n不同时为0。在本发明的一些实施方案中，n和m各自为从0到3的任意整数，且n+m＝2、3或4。
在本发明的一些实施方案中，p为从0到3的整数。在一些实施方案中，p为1或2。
在本发明的一些实施方案中，q为从0到3的整数。在一些实施方案中，q为0。
在本发明的一些实施方案中，R7、R8为氢。
在本发明的一些实施方案中，环Ar为苯基。
在本发明的一些实施方案中，R1独立地选自C1-6烷基、C2-6烯基、C2-6炔基、卤素、氨基、羟基、C1-6烷氧基、C1-6烷基羰基、氰基、硝基，其中C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基可被卤素、氰基、硝基、C1-6烷氧基、芳基、杂芳基、杂环烷基取代，且芳基、杂芳基、杂环烷基可进一步被卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基羰基取代。
本发明的一些实施方案中，R1独立地选自C2-6炔基、卤素、C1-6烷氧基、C1-6烷基羰基，其中C1-6烷氧基可被芳基、杂芳基、杂环烷基取代，且芳基、杂芳基、杂环烷基可进一步被卤素、氰基、硝基取代。
在本发明的一些实施方案中，R1独立地选自C2-6炔基、卤素、杂芳基取代的C1-6烷氧基、芳基取代的C1-6烷氧基、C1-6烷基羰基，其中芳基、杂芳基可进一步被卤素取代。
在本发明的一些实施方案中，R1独立地选自乙炔基、卤素、吡啶基取代的C1-6烷氧基、卤代苯基取代的C1-6烷氧基。
在本发明的一些实施方案中，R4、R5和R6为氢。
在本发明的一些实施方案中，R2选自氢、甲氧基、四氢呋喃基氧基、被甲氧基取代的乙氧基、被吗啉基取代的乙氧基。
在本发明的一些实施方案，涉及以下化合物或其盐：
Figure PCTCN2014087633-appb-000002
Figure PCTCN2014087633-appb-000003
例如，通过合成路线一、二的步骤或与其类似的方法，可以制备本发明的式(I)化合物：合成路线一：
Figure PCTCN2014087633-appb-000004
PG为氨基保护基。
式1化合物在回流条件下与二氯亚砜反应生成式2化合物，式2化合物与式2’化合物在乙腈中回流得到式3化合物，式3化合物在叔丁醇钾和DMSO存在下与R2H反应生成式4化合物，式4化合物在雷尼镍存在下用氢气还原得式5化合物，式5化合物与式5’化合物在三氟乙酸或醋酸、三乙酰氧基硼氢化钠存在下反应生成式6化合物，式6化合物在三氟乙酸存在下加热至60℃或在盐酸甲醇溶液中生成式7化合物，式7化合物在二异丙基乙基胺、四氢呋喃存在下与丙烯酰氯反应生成式8化合物。
合成路线二：
Figure PCTCN2014087633-appb-000005
式5化合物在亚硝酸钠、硫酸、硫氰酸钾、三氯化铁、水存在下反应生成式9化合物，式9化合物在硼氢化钠、碳酸钾、乙醇存在下与式9’化合物反应生成式10化合物，式10化合物在三氟乙酸存在下加热至60℃生成式11化合物，式11化合物与丙烯酰氯反应生成式12化合物。
上述合成方法只是列举了本发明中部分化合物的制备方法，按照本领域的公知技术，技术人员在上述合成方案的基础上，采用类似的方法也可以合成本发明的化合物。
本发明化合物可以是不对称的，例如，具有一个或多个立体异构体。除非另有说明，所有立体异构体都包括，如对映异构体和非对映异构体。本发明的含有不对称碳原子的化合物可以以光学活性纯的形式或外消旋形式被分离出来。光学活性纯的形式可以从外消旋混合物拆分，或通过使用手性原料或手性试剂合成。
还可以使用与无机酸或有机酸形成的药学可接受的盐形式的本发明式(I)的化合物，所述有机酸或无机酸例如盐酸、氢溴酸、硫酸、磷酸、硝酸、乙酸、乳酸、丙二酸、丁二酸、富马酸、苹果酸、扁桃酸、酒石酸、柠檬酸、抗坏血酸、棕榈酸、马来酸、苯甲酸、苯乙酸、肉桂酸、水杨酸、甲磺酸、苯磺酸、甲基苯磺酸。
本发明另一方面还涉及药物组合物，其包含本发明所定义的式I化合物或其药学上可接受的盐和药学上可接受的载体。
本发明的药物组合物可通过将本发明的化合物与适宜的药学上可接受的载体组合而制备，例如可配制成固态、半固态、液态或气态制剂，如片剂、丸剂、胶囊剂、粉剂、颗粒剂、膏剂、乳剂、悬浮剂、溶液剂、栓剂、注射剂、吸入剂、凝胶剂、微球及气溶胶等。
给予本发明化合物或其药物可接受的盐或其药物组合物的典型途径包括但不限于口服、直肠、透黏膜、经肠给药，或者局部、经皮、吸入、肠胃外、舌下、阴道内、鼻内、眼内、腹膜内、肌内、皮下、静脉内给药。优选的给药途径是口服给药。
本发明的药物组合物可以采用本领域众所周知的方法制造，如常规的混合法、溶解法、制粒法、制糖衣药丸法、磨细法、乳化法、冷冻干燥法等等。
在优选的实施方案中，药物组合物是口服形式。对于口服给药，可以通过将活性化合物与本领域熟知的药学上可接受的载体混合，来配制该药物组合物。这些载体能使本发明的化合物被配制成片剂、丸剂、锭剂、糖衣剂、胶囊剂、液体、凝胶剂、浆剂、悬浮剂等，用于对患者的口服给药。
可以通过常规的混合、填充或压片方法来制备固体口服组合物。例如，可通过下述方法获得：将所述的活性化合物与固体赋形剂混合，任选地碾磨所得的混合物，如果需要则加入其它合适的辅剂，然后将该混合物加工成颗粒，得到了片剂或糖衣剂的核心。适合的辅料包括但不限于：粘合剂、稀释剂、崩解剂、润滑剂、助流剂、甜味剂或矫味剂等。如微晶纤维素、葡萄糖溶液、阿拉伯胶浆、明胶溶液、蔗糖和淀粉糊；滑石、淀粉、硬脂酸镁、硬脂酸钙或硬脂酸；乳糖、蔗糖、淀粉、甘露糖醇、山梨糖醇或磷酸二钙；二氧化硅；交联羧甲基纤维素钠、预交化淀粉、淀粉羟乙酸钠、藻酸、玉米淀粉、马铃薯淀粉、甲基纤维素、琼脂、羧甲基纤维素、交联聚乙烯吡咯烷酮等。可以根据通常药物实践中公知的方法任选地对片芯进行包衣，尤其使用肠溶包衣。
药物组合物还可适用于肠胃外给药，如合适的单位剂型的无菌溶液剂、混悬剂或冻干产品。能够使用适当的赋形剂，例如填充剂、缓冲剂或表面活性剂。
本发明另一方面还涉及本发明的式Ⅰ化合物或其药学上可接受的盐或其药物组合物在制备预防或者治疗肿瘤的药物中的用途。
本文所述的通式Ⅰ化合物的所有施用方法中，每天给药的剂量优选为0.01到200mg/Kg体重。
除非另有定义，否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明，本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。
还应注意，除非另有说明，否则所用“或”、“或者”表示“和/或”。此外，所用术语“包括”以及其它形式，例如“包含”、“含”和“含有”并非限制性。
除非另有说明，本文中所用的术语具有如下含义：
术语“卤素”是指氟、氯、溴或碘，优选氟或氯。
术语“羟基”指-OH。
术语“巯基”指-SH。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“烷基”是指由碳原子和氢原子组成的直链或支链的饱和的脂肪烃基团，其通过单键与分子的其余部分连接。例如所述烷基可具有1-6个碳原子(以C1-6烷基表示)，优选具有1-4个碳原子。烷基的非限制性实例包括但不限于甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、正戊基、2-甲基丁基、新戊基、正己基。
术语“烷氧基”是指-O-烷基，其中烷基与上文定义的相同。所述烷氧基可具有1-6个碳原子，优选含有1-4个碳原子。烷氧基的非限制性实例包括但不限于甲氧基、乙氧基、丙氧基、异丙氧基、正丁氧基、异丁氧基、叔-丁氧基、正-戊氧基、2-甲基丁氧基、新戊氧基、正己氧基。
术语“烷硫基”是指-S-烷基，其中烷基与上文定义的相同。
术语“氨基”是指-NH2。
术语“单(烷基)氨基”是指-NH(烷基)，其中烷基与上文定义相同。
术语“二(烷基)氨基”是指-N(烷基)2，其中烷基与上文定义相同，并且这两个烷基可以相同或不同。
术语“环烷基”是指饱和或不饱和的非芳香环状烃基。环烷基的非限制性实例包括但不限于环丙基、环丁基、环戊基、环己基和环庚基等。
术语“烯基”是指直链或者支链的烯烃基，优选含有2-6个碳原子的直链或者支链的烯烃基。烯基的非限制性实例包括但不限于乙烯基、1-丙烯基、2-丙烯基、1-丁烯基、异丁烯基。
术语“炔基”是指直链或者支链的炔烃基，优选含有2-6个碳原子的直链或者支链的炔烃基。炔基的非限制性实例包括但不限于乙炔基、1-丙炔基、2-丙炔基。
术语“芳基”是指具有共轭的π电子体系的全碳单环或稠合多环的芳香环基团，优选具有6-14个碳原子，更优选具有6-12个碳原子，最优选具有6个碳原子。芳基的非限制性实例包括但不限于苯基、萘基和蒽基。
术语“杂芳基”是指具有5、6、7、8、9、10、11或12个环原子的单环或稠合环，其中含有1、2、3或4个选自N、O、S的环原子，其余环原子为C，且具有完全共轭的π-电子体系。所述杂芳基优选具有5或6元环，较优选为5元环。杂芳基的非限制性实例包括但不限于吡咯基、呋喃基、噻吩基、咪唑基、噁唑基、吡唑基、吡啶基、嘧啶基、吡嗪基、喹啉基、异喹啉基、四唑基、三唑基、三嗪基。
术语“杂环烷基”是指具有3、4、5、6、7、8、9、10、11或12个环原子的单环或稠合环，其中1、2或3个环原子是选自N、O、S(O)n(其中n为0、1或2)的杂原子，其余环原子为C。这样的环可以是饱和的或不饱和的(例如具有一个或多个双键)，但是不具有完全共轭的π-电子体系。3元杂环烷基的实例包括但不限于环氧乙烷基、环硫乙烷基、环氮乙烷基，4元杂环烷基的实例包括但不限于吖丁啶基、噁丁环基、噻丁环基，5元杂环烷基的实例包括但不限于四氢呋喃基、四氢噻吩基、吡咯烷基、异噁唑烷基、噁唑烷基、异噻唑烷基、1,1-二氧代异噻唑烷基、噻唑烷基、咪唑烷基、四氢吡唑基、吡咯啉基、二氢呋喃基、二氢噻吩基，6元杂环烷基的实例包括但不限于哌啶基、四氢吡喃基、四氢噻喃基、吗啉基、哌嗪基、1,4-噻噁烷基、1,4-二氧六环基、硫代吗啉基、1,2-、1,4-二噻烷基、二氢吡啶基、四氢吡啶基、二氢吡喃基、四氢吡喃基、二氢噻喃基，7元杂环烷基的实例包括但不限于氮杂环庚烷基、氧杂环庚烷基、硫杂环庚烷基。优选为具有5或6个环原子的单环杂环烷基。
术语“治疗有效量”是指当对哺乳动物，优选对人给药时，本发明化合物足以有效地治疗哺乳动物的(优选人的)疾病。构成“治疗有效量”的本发明化合物的量取决于该化合物、疾病状态及其严重性、给药方式以及待被治疗的哺乳动物的年龄而改变，但可例行性地由本领域技术人员根据其自身的知识及本公开内容而确定。
术语“治疗”意为将本发明所述化合物或制剂进行给药以预防、改善或消除疾病或与所述疾病相关的一个或多个症状，且包括：
(i)预防疾病或疾病状态在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病状态，但尚未被诊断为已患有该疾病状态时；
(ii)抑制疾病或疾病状态，即遏制其发展；
(iii)缓解疾病或疾病状态，即使该疾病或疾病状态消退。
术语“药物组合物”是指一种或多种本发明的化合物或其盐与在本领域中通常接受的用于将生物活性化合物输送至有机体(例如人)的载体、赋形剂和/或介质的制剂。药物组合物的目的是有利于对有机体给予本发明的化合物。
术语“药学上可接受的载体”是指对有机体无明显刺激作用，而且不会损害该活性化合物的生物活性及性能的那些载体和稀释剂。“药学上可接受的载体”包括但不限于被国家食品药品管理局许可为可接受的用于人或家畜动物的任何载体、赋形剂、介质、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味增强剂、表面活性剂、润湿剂、分散剂、崩解剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。
实验部分
涉及对水和/或氧气敏感的实验的所有操作都在预干燥玻璃仪器中于氮气氛下进行。除非另有说明，所有原料均为商业原料，并且在使用前未作进一步纯化。
柱层析采用的是青岛海洋化工所生产的硅胶(200-300目)。薄层色谱采用默克公司(E.Merck)预涂色谱板(硅胶60PF254,0.25毫米)。
核磁共振光谱分析使用的仪器为瓦里安VNMRS-400共振光谱仪。化学位移以四甲基硅烷(TMS＝δ0.00)为内标。核磁共振氢谱数据的记录格式为：质子数，峰型(s，单峰；d，双重峰；t，三重峰；q，四重峰；m，多重峰)，耦合常数(以赫兹为单位)。
液质联用使用的是安捷伦LC 1200系列(5微米C18色谱柱)仪器。
实施例1 N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺(化合物E1)的合成
步骤1：4-氯-7-氟-6-硝基喹唑啉
7-氟-6-硝基喹唑啉-4(3H)-酮(2.0g,9.6mmol)和一滴N,N-二甲基甲酰胺在二氯亚砜(6mL)中回流过夜，真空浓缩。加入甲苯后再次真空浓缩去除多余的二氯亚砜，得标题所示化合物(2g,92％)。
1H NMR(CDCl3):δ9.18(1H,s),9.05(1H,d,J＝7.6 Hz),7.95(1H,d,J＝10.4)。
步骤2：3-氯-N-(3,4-二甲氧基苄基)-4-氟苯胺
将3-氯-4-氟苯胺(2.9g,20mmol)和3,4-二甲氧基苯甲醛(3.3g,20mmol)加入1,2-二氯乙烷(30mL)中，室温搅拌1小时。加入三乙酰基硼氢化钠(10g,50mmol)，混合液在室温下搅拌过夜。将反应液倾入100mL水中，二氯甲烷萃取。分离有机相，饱和食盐水洗，干燥，真空浓缩得到标题所示化合物(5.5g,93％)。
1H NMR(CDCl3):δ6.94-6.82(4H,m),6.63-6.61(1H,m),6.45-6.41(1H,m),4.18(2H,s),3.98(1H,br),3.87(3H,s),3.86(3H,s)。
步骤3：N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-氟-6-硝基喹唑啉-4-胺
将4-氯-7-氟-6-硝基喹唑啉(2.1g,9.2mmol)和3-氯-N-(3,4-二甲氧基苄基)-4-氟苯胺(2.7g，9.2mmol)加入乙腈(20mL)中，回流3小时。冷却后，加入碳酸钠溶液中和，乙酸乙 酯萃取，分离有机相，饱和食盐水洗，干燥，真空浓缩得到标题所示化合物(3.6g,80％)。
步骤4：N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-甲氧基-6-硝基喹唑啉-4-胺
将金属钠(113mg,5.0mmol)加入无水甲醇(20mL)中，室温搅拌10分钟，然后加入N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-氟-6-硝基喹唑啉-4-胺(2.4g,5.0mmol)，混合液在40℃下搅拌6小时。冷却后，将混合液倾入100mL水中，乙酸乙酯萃取，有机相用饱和食盐水洗，干燥，真空浓缩得到标题所示化合物(2.35g,94％)。
1H NMR(CDCl3):δ8.85(1H,s),7.57(1H,s),7.35(1H,s),7.23-7.19(2H,m),7.00-6.96(1H,m),6.84-6.78(2H,m),5.35(2H,s),4.05(3H,s),3.88(3H,s),3.83(3H,s)。
步骤5：N4-(3-氯-4-氟苯基)-N4-(3,4-二甲氧基苄基)-7-甲氧基喹唑啉-4,6-二胺
将N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-甲氧基-6-硝基喹唑啉-4-胺(2.35g,4.7mmol)和雷尼镍约0.5g加入四氢呋喃(100mL)中，氢气置换，在氢气氛下(1atm)室温搅拌过夜。过滤，滤液真空浓缩得到标题所示化合物(2g,90％)。
1H NMR(CDCl3):δ8.72(1H,s),7.17(1H,s),7.09-7.06(1H,m),7.00-6.95(2H,m),6.86-6.83(1H,m),6.79-6.74(2H,m),6.33(1H,s),5.30(2H,s),3.98-3.97(5H,m),3.83(3H,s),3.78(3H,s)。
步骤6：3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}氨基}氮杂环丁烷-1-甲酸苄酯
将N4-(3-氯-4-氟苯基)-N4-(3,4-二甲氧基苄基)-7-甲氧基喹唑啉-4,6-二胺(1.10g,2.35mmol)和3-氧代氮杂环丁烷-1-甲酸苄酯(0.58g,2.83mmol)的三氟醋酸(7mL)溶液在室温搅拌10分钟,然后一次性加入三乙酰基硼氢化钠(0.52g,2.45mmol)。反应半小时后，补加3-氧代氮杂环丁烷-1-甲酸苄酯(0.24g,1.17mmol)和三乙酰基硼氢化钠(0.25g,1.17mmol)，继续反应半小时。反应完毕，慢慢加入水淬灭反应，乙酸乙酯萃取。所得有机相依次用水、5％NaHCO3溶液和饱和食盐水洗，无水硫酸钠干燥并真空浓缩。残余物物用乙醚打浆，过滤得标题所示化合物(1.3g,84％)。
1H NMR(CDCl3):δ8.79(1H,s),7.68(1H,br),7.31-7.37(5H,m),7.05-7.11(2H,m),6.86-6.88(2H,m),6.79-6.82(1H,m),6.73-6.75(1H,m),5.77(1H,s),5.32(2H,s),5.10(2H,s),4.83(1H,d,J＝5.6 Hz),3.83-3.97(5H,m),3.83(3H,s),3.77(3H,s),3.55-3.62(3H,m)。
步骤7：N6-(氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺
将3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}氨基}氮杂环丁烷-1-甲酸苄酯(1.2g,1.82mmol)的三氟醋酸(8mL)溶液在70℃下搅拌6小时。反应完毕，冷却，真空浓缩，残余物用乙酸乙酯打浆、过滤得到标题所示化合物的三氟醋酸盐(0.74g,84％)。
1H NMR(DMSO-d6):δ10.50(1H,s),9.04(1H,s),8.80(1H,s),8.70(1H,s),7.95-7.98(1H,m),7.65-7.68(1H,m),7.52-7.57(1H,m),7.24(1H,s),7.14(1H,s),6.86-6.89(1H,m),4.50-4.56(1H,m),4.41-4.44(2H,m),4.04-4.11(5H,m)。
步骤8：N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺
将N6-(氮杂环丁烷-3基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺三氟醋酸盐(0.89g,1.82mmol)和三乙胺(1mL)的四氢呋喃(20mL)混悬液在室温下搅拌30分钟。冷却至-40℃，慢慢滴加丙烯酰氯(166mg,1.82mmol)的四氢呋喃(2mL)溶液，继续反应30分钟。反应完毕，慢慢加入5％NaHCO3溶液淬灭反应，乙酸乙酯萃取。所得有机相用饱和食盐水洗，无水硫酸钠干燥并真空浓缩，残余物用乙酸乙酯打浆得到标题所示化合物(0.32g,41％)。
1H NMR(CDCl3):δ8.59(1H,s),7.92(1H,s),7.83-7.85(1H,m),7.57-7.59(1H,m),7.19(1H,s),7.10-7.15(1H,m),6.68(1H,s),6.35-6.38(1H,m),6.17-6.31(1H,m),5.68-5.71(1H,m),5.05(1H,d,J＝6.4 Hz),4.58-4.63(2H,m),4.42-4.48(1H,m),4.10-4.14(1H,m),4.01-4.03(4H,m)。
实施例2 N6-(1-丙烯酰基氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺(化合物E2)的合成
步骤1：4-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}氨基}哌啶-1-甲酸叔丁酯
将N4-(3-氯-4-氟苯基)-N4-(3,4-二甲氧基苄基)-7-甲氧基喹唑啉-4,6-二胺(469mg,1.0mmol)和4-氧代哌啶-1-甲酸叔丁酯(239mg,1.2mmol)的醋酸(10mL)溶液在室温下搅拌2小时,然后一次性加入三乙酰氧基硼氢化钠(254mg,1.2mmol)。反应半小时后，慢慢加入水淬灭反应，乙酸乙酯萃取。所得有机相依次用水、5％NaHCO3水溶液和饱和食盐水洗，无水硫酸钠干燥并真空浓缩。余物经硅胶柱层析分离得到标题所示化合物(404mg,62％)。
1H NMR(DMSO-d6):δ8.57(1H,s),7.33-7.27(2H,m),7.09(1H,s),6.99(1H,m),6.84-6.80(1H,m),6.81-6.80(1H,m),6.79-6.78(1H,m),5.99(1H,m),5.29(2H,s),3.91(3H,m),3.85-3.82(2H,m),3.64(3H,m),3.61(3H,m),2.80-2.75(1H,m),2.59-2.53(2H,m),1.42-1.37(11H,m),1.20-1.17(2H,m)。
步骤2：N6-(哌啶-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由步骤1的产物来合成标题所示化合物。
1H NMR(DMSO-d6):δ10.62(1H,s),8.75(1H,s),8.68-8.60(1H,br),8.50-8.41(1H,br),7.96-7.94(1H,m),7.66-7.64(1H,m),7.58-7.56(1H,m),7.39(1H,s),7.20(1H,s),6.19-6.17(1H,m),4.05(3H,s),3.80-3.60(2H,m),3.05-2.96(2H,m),2.16-2.12(2H,m),1.78-1.74(2H,m)。
步骤3：N6-(1-丙烯酰基哌啶-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺
将N6-(哌啶-4-基)-N4-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4,6-二胺单三氟醋酸盐(258mg,0.5mmol)和三乙胺(202mg,2.0mmol)的四氢呋喃(10mL)溶液于室温下搅拌30分钟。冷却至0℃后，滴加丙烯酰氯(54mg,0.6mmol)的四氢呋喃溶液(2mL)，加完继续反应30分钟。反应完毕，慢慢加入5％NaHCO3溶液淬灭反应，乙酸乙酯萃取。所得有机相用饱和食盐水洗，无水硫酸钠干燥并真空浓缩，余物经硅胶柱层析分离得到目标产物(150mg,66％)。
1H NMR(DMSO-d6):δ9.24(1H,s),8.33(1H,s),8.09-8.08(1H,m),7.77-7.74(1H,m),7.42-7.40(1H,m),7.23(1H,s),7.06(1H,s),6.85-6.81(1H,m),6.10-6.06(1H,m),5.66-5.64(1H,m),5.32-5.29(1H,m),4.41-4.38(1H,m),4.09-4.06(1H,m),3.93(3H,s),3.79-3.78(1H,m),3.35-3.34(1H,m),2.87-2.84(1H,m),2.03-2.01(2H,m),1.44-1.41(2H,m)。
实施例3(S)-N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺(化合物E3)的合成
步骤1:N-(3-氯-4氟苯基)-7-氟-6-硝基喹唑啉-4-胺
将4-氯-7-氟-6-硝基喹唑啉(2.28g,10mmol)和3-氯-4-氟苯胺(1.46g,10mmol)溶于乙腈(50mL)中，加热回流1小时，真空浓缩去除溶剂。向残余物中加入饱和碳酸钠和乙酸乙酯，搅拌10分钟，分液。水相用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，真空浓缩去除溶剂。所得残余物用乙醚打浆、过滤得标题所示化合物(3.01g,90％)。
1H NMR(DMSO-d6):δ10.51(1H,s),9.58(1H,d,J＝8.0 Hz),8.73(1H,s),8.13(1H,dd,J＝6.8 Hz,2.8 Hz),7.85(1H,d,J＝12.4 Hz),7.77-7.61(1H,m),7.49(1H,t,J＝9.2 Hz)。
步骤2：(S)-N-(3-氯-4氟苯基)-7-(四氢呋喃-3-基氧基)-6-硝基喹唑啉-4-胺
将N-(3-氯-4氟苯基)-7-氟-6-硝基喹唑啉-4-胺(37.1g,0.11mol)和(S)-3-羟基四氢呋喃(13.6g,0.154mol)溶于干燥的DMSO(200mL)中，分批加入叔丁醇钾(30.9g,0.275mol)，期间水浴控制内温于30℃以下。常温搅拌4小时，反应液倾倒于1.2L水中，抽滤，水洗并干燥的粗产品。粗品用乙醇打浆、抽滤后的标题所示化合物(33.4g,75％)。
1H NMR(DMSO-d6):δ10.08(1H,s),9.15(1H,s),8.61(1H,s),8.11-8.09(1H,m),7.77-7.74(1H,m),7.43-7.39(2H,m),5.41-5.38(1H,m),3.96-3.92(1H,m),3.87-3.73(3H,m),2.33-2.28(1H,m),2.06-2.01(1H,m)。
步骤3：(S)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例1步骤5中所描述的方法由(S)‐N‐(3‐氯‐4‐氟苯基)‐7‐(四氢呋喃‐3‐基氧基)‐6‐硝基喹唑啉‐4‐胺合成标题所示化合物。
1H NMR(DMSO-d6):δ8.55(1H,s),7.96-7.93(1H,m),7.56-7.51(1H,m),7.18-7.13(3H,m),6.97(1H,s),5.13-5.10(1H,m),4.30(1H,br),4.13-4.03(3H,m),3.96-3.91(1H,m),2.39-2.34(1H,m),2.26-2.22(1H,m)。
步骤4：(S)-3-{{4-[(3-氯-4-氟苯基)氨基]-7-(四氢呋喃-3-基氧基)喹唑啉-6-基}氨基}氮杂环丁烷-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由(S)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺合成标题所示化合物。
1H NMR(CDCl3):δ10.63(1H,br),8.08-8.10(1H,m),8.02(1H,s),7.69-7.73(1H,m),7.31-7.37(5H,m),7.15-7.19(1H,m),7.00(1H,s),6.76(1H,s),5.12(2H,s),5.03-5.05(1H,m),4.52-4.60(3H,m),4.30-4.35(1H,m),3.91-4.00(2H,m),3.74-3.85(4H,m),2.14-2.20(1H,m),1.95-2.00(1H,m)。
步骤5：(S)-N6-(氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由(S)-3-{{4-[(3-氯-4-氟苯基)氨基]-7-(四氢呋喃-3-基氧基)喹唑啉-6-基}氨基}氮杂环丁烷-1-甲酸苄酯合成标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.80(1H,s),9.10(1H,br),8.90(1H,br),8.69(1H,s),7.90-7.93(1H,m),7.60-7.63(1H,m),7.50-7.574(1H,m),7.23(1H,s),7.11(1H,s),6.68(1H,d,J＝5.6 Hz),5.22-2.24(1H,m),4.40-4.5(3H,m),3.90-4.09(5H,m),3.76-3.81(1H,m),2.43-2.48(1H,m),2.14-2.18(1H,m)。
步骤6：(S)-N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例1步骤8中所描述的方法由(S)-N6-(氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺的三氟醋酸盐合成标题所示化合物。
1H NMR(CDCl3):δ8.59(1H,s),7.97(1H,s),7.85-7.87(1H,m),7.56-7.59(1H,m),7.10-7.15(2H,m),6.70(1H,s),6.30-6.35(1H,m),6.19-6.26(1H,m),5.68-5.71(1H,m),5.13(1H,s),5.01(1H,d,J＝6.4 Hz),4.60-4.63(2H,m),4.42-4.46(1H,m),4.01-4.19(5H,m),3.91-3.94(1H,m),2.35-2.41(1H,m),2.22-2.29(1H,m)。
实施例4(S)-N6-(1-丙烯酰基氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺(化合物E4)的合成
步骤1：(S)-4-(4-(3-氯-4-氟苯氨基)-7-(四氢呋喃-3-基氧基)喹唑啉-6-基氨基)哌啶-1-甲酸叔丁酯
以类似于实施例2步骤1中所描述的方法由(S)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺合成标题所示化合物。
1H NMR(CDCl3):δ8.53(1H,s),7.84-7.82(1H,m),7.54-7.50(1H,m),7.18-7.10(3H,m),6.62(1H,s),5.10-5.09(1H,m),4.62(1H,d,J＝8.0 Hz),4.10-3.88(6H,m),3.61-3.57(1H,m),3.05-2.98(2H,m),2.38-2.07(4H,m),1.53-1.43(11H,m)。
步骤2：(S)-N6-(氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
将(S)-4-(4-(3-氯-4-氟苯氨基)-7-(四氢呋喃-3-基氧基)喹唑啉-6-基氨基)哌啶基-1-甲酸叔丁酯(1.0g,1.79mmol)加到1mol/L的HCl甲醇溶液(10mL)中，室温搅拌过夜。将真空浓缩后加入碳酸氢钠溶液搅拌1小时，乙酸乙酯、甲醇混合溶液萃取。有机相干燥、真空浓缩得标题所示化合物(500mg,61％)。
步骤3：(S)-N6-(1-丙烯酰基氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由(S)-N6-(氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺合成标题所示化合物。
1H NMR(CDCl3):δ8.40(1H,s),7.74-7.71(1H,m),7.49-7.45(1H,m),7.07-7.03(2H,m), 6.76(1H,s),6.56-6.49(1H,m),6.25-6.20(1H,m),5.66-5.63(1H,m),5.01-4.98(1H,m),4.55-4.41(2H,m),4.00-3.65(6H,m),3.28-3.21(1H,m),3.00-2.89(1H,m),1.53-1.43(2H,m)。
实施例5(S)-N6-(1-丙烯酰基氮杂环己烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺(化合物E5)的合成
步骤1：(S)-3-(4-(3-氯-4-氟苯氨基)-7-(四氢呋喃-3-基氧基)喹唑啉-6-基氨基)哌啶-1-甲酸叔丁酯
以类似于实施例2步骤1中所描述的方法由(S)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺与3-氧代哌啶-1-甲酸叔丁酯来合成标题所示化合物。
1H NMR(CDCl3):δ8.56(1H,s),8.26-8.37(1H,brs),8.03-8.05(1H,m),7.90-7.94(1H,m),7.41(1H,s),7.12(1H,t,J＝8.8 Hz),6.98(1H,s),5.14(1H,s),5.02(1H,s),4.56-4.60(1H,m),3.93-4.06(4H,m),3.80-3.90(2H,m),3.26-3.33(1H,m),2.87-2.94(1H,m),2.37-2.47(1H,m),2.27-2.32(1H,m),2.17-2.22(2H,m),1.65-1.75(2H,m),1.43(9H,s)。
步骤2：(S)-N6-(氮杂环己烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例4步骤2中所描述的方法由(S)-3-(4-(3-氯-4-氟苯氨基)-7-(四氢呋喃-3-基氧基)喹唑啉-6-基氨基)哌啶-1-甲酸叔丁酯合成得到标题所示化合物。
步骤3：(S)-N6-(1-丙烯酰基氮杂环己烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由(S)-N6-(氮杂环己烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(CDCl3):δ8.89-9.07(1H,brs),8.64(1H,s),8.35-8.39(1H,m),8.21-8.27(1H,m),7.76-7.86(1H,m),7.16-7.22(2H,m),6.71(1H,dd,J＝17.2 Hz,10.4 Hz),6.54(1H,dd,J＝47.2Hz,1.2 Hz),5.89(1H,dd,J＝10.8 Hz,1.2 Hz),5.23-5.29(2H,m),4.66-4.74(1H,m),4.05-4.19(4H,m),3.87-3.97(1H,m),3.26-3.43(3H,m),2.46-2.60(1H,m),2.21-2.35(1H,m),2.01-2.10(2H,m),1.64-1.78(2H,m)。
实施例6(S)-N6-(1-丙烯酰基氮杂环戊烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺(化合物E6)的合成
步骤1：(S)-3-(4-(3-氯-4-氟苯氨基)-7-(四氢呋喃-3-基氧基)喹唑啉-6-基氨基)氮杂环戊烷-1-甲酸叔丁酯
以类似于实施例2步骤1中所描述的方法由(S)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺与3-氧代氮杂环戊烷-1-甲酸叔丁酯来合成标题所示化合物。
步骤2：(S)-N6-(氮杂环戊烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例4步骤2中所描述的方法由(S)-3-(4-(3-氯-4-氟苯氨基)-7-(四氢呋喃-3-基氧基)喹唑啉-6-基氨基)氮杂环戊烷-1-甲酸叔丁酯合成得到标题所示化合物。
步骤3：(S)-N6-(1-丙烯酰基氮杂环戊烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由(S)-N6-(氮杂环戊烷-3-基)-N4-(3-氯-4-氟苯基)-7-(四氢呋喃-3-基氧基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(CDCl3):δ8.97-8.57(1H,m),8.54-8.48(1H,m),7.84-7.76(1H,m),7.66-7.62(1H,m),7.40-7.20(1H,m),7.11-6.98(2H,m),6.49-6.32(2H,s),5.74-5.67(1H,s),5.10-5.09(1H,s),4.66-4.63(1H,m),4.30-3.20(8H,m),2.42-1.91(3H,m),1.43-1.42(1H,m)。
实施例71-(4-(4-(3-氯-4-(3-氟苄氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)哌啶-1-基)丙-2-烯-1-酮(化合物E7)的合成
步骤1：2-氯-1-(3-氟苄氧基)-4-硝基苯
2-氯-4-硝基苯酚(3.4g,20mmol)，3-氟苄氯(2.8g,20mmol)和碳酸钾(3.3g,24mmol)在乙腈(30mL)中回流过夜。将反应液倾入100mL水中，用乙酸乙酯萃取。有机相用饱和食盐水洗涤，干燥，真空浓缩得粗产品。粗产品用石油醚洗涤过滤干燥得标题所示化合物(3.2g，57％)。
1H NMR(CDCl3):δ8.35(1H,d,J＝2.8 Hz),8.17-8.14(1H,m),7.44-7.38(1H,m),7.25-7.19(2H,m),7.10-7.06(1H,m),7.03(1H,d,J＝9.2 Hz),5.26(2H,s)。
步骤2：3-氯-4-(3-氟苄氧基)-苯胺
将2-氯-1-(3-氟苄氧基)-4-硝基苯(3.2g,11.4mmol)，锌粉(4.5g,68.4mmol)和氯化铵(1.52g,28.5mmol)加入乙醇(60mL)和水(10mL)的混合溶液中。该混合液在60℃下搅拌过夜。然后将反应液倾入200mL水中，用乙酸乙酯萃取。有机相分离，用饱和食盐水洗，干燥，真空除去溶剂得到标题所示化合物(2.8g,98％)。
1H NMR(CDCl3):δ7.36-7.30(1H,m),7.22-7.18(2H,m),7.02-6.97(1H,m),6.79-6.76(2H,m),6.52-6.49(1H,m),5.03(2H,s),3.49(2H,br)。
步骤3：N-(3-氯-4-(3-氟苄氧基)苯基)-7-甲氧基-6-硝基喹唑啉-4-胺
将3-氯-4-(3-氟苄氧基)-苯胺(2.82g,11.1mmol)，4-氯-7-甲氧基-6-硝基喹唑啉(2.68g,11.2mmol)加入异丙醇(30mL)中，在60℃下搅拌3小时。然后过滤，用异丙醇洗涤，干燥得到标题所示化合物(4.8g,95％)。
1H NMR(DMSO-d6):δ10.94(1H,br),9.33(1H,s),8.79(1H,s),7.91(1H,d,J＝2.4 Hz),7.64-7.61(1H,m),7.47-7.40(2H,m),7.31-7.27(3H,m),7.18-7.13(1H,m),5.25(2H,s),4.06(3H,s)。
步骤4：N4-(3-氯-4-(3-氟苄氧基)苯基)-7-甲氧基-喹唑啉-4,6-二胺
将N-(3-氯-4-(3-氟苄氧基)苯基)-7-甲氧基-6-硝基喹唑啉-4-胺(4.8g,10.5mmol)，铁粉(3.54g,63mmol)，醋酸(6mL)与乙醇(60mL)的混合液在85℃下搅拌过夜。然后将混合液倾入300mL水中，过滤得粗产品。粗产品用乙酸乙酯洗涤，过滤干燥得到标题所示化合物(3.8g,85％)。
1H NMR(DMSO-d6):δ10.70(1H,br),8.68(1H,s),7.84(1H,d,J＝2.4 Hz),7.59-7.45(3H,m),7.32-7.30(3H,m),7.19-7.16(2H,m),5.93(2H,br),5.29(2H,s),4.02(3H,s)。
步骤5：4-(4-(3-氯-4-(3-氟苄氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)哌啶-1-甲酸叔丁酯
以类似于实施例2步骤1中所描述的方法由N4-(3-氯-4-(3-氟苄氧基)苯基)-7-甲氧基-喹唑啉-4,6-二胺合成标题所示化合物。
1H NMR(CDCl3):δ8.47(1H,s),7.78(1H,d,J＝2.4 Hz),7.58-7.55(1H,m),7.40-7.35(1H,m),7.26-7.22(2H,m),7.17(1H,s),7.06-7.01(1H,m),6.97(1H,d,J＝8.8 Hz),6.71(1H,br),5.16(2H,s),4.68(1H,d,J＝8.0 Hz),4.10-4.05(2H,m),3.96(3H,s),3.68(1H,br),3.11-3.04(2H,m),2.15-2.11(2H,m),1.52-1.43(11H,m)。
步骤6：N4-(3-氯-4-(3-氟苄氧基)苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺
以类似于实施例4步骤2中所描述的方法由4-(4-(3-氯-4-(3-氟苄氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)哌啶-1-甲酸叔丁酯合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.62(1H,s),8.29(1H,s),8.07(1H,s),7.82(1H,d,J＝9.2 Hz),7.55(1H,s),7.49-7.43(1H,m),7.33-7.29(2H,m),7.23-7.14(2H,m),7.05(1H,s),5.23(2H,s),5.14(1H,d,J＝8.4 Hz),4.04-4.00(1H,m),3.95(3H,s),3.12-3.09(2H,m),2.92-2.86(2H,m),2.05-2.01(2H,m),1.53-1.50(2H,m)。
步骤7：1-(4-(4-(3-氯-4-(3-氟苄氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)哌啶-1-基)丙-2-烯-1-酮
以类似于实施例2步骤3中所描述的方法由N4-(3-氯-4-(3-氟苄氧基)苯基)-7-甲氧基 -N6-(哌啶-4-基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.14(1H,s),8.30(1H,s),7.90(1H,d,J＝2.8 Hz),7.67-7.64(1H,m),7.32-7.23(4H,m),7.19-7.14(1H,m),7.06(1H,s),6.87-6.80(1H,m),6.12-6.07(1H,m),5.68-5.65(1H,m),5.27(1H,d,J＝8.4 Hz),5.24(1H,s),4.44-4.38(1H,m),4.12-4.07(1H,m),3.94(3H,s),3.81-3.77(1H,m),2.92-2.83(1H,m),2.07-2.02(2H,m),1.46-1.40(2H,m)。
实施例81-(4-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)哌啶-1-基)丙-2-烯-1-酮(化合物E8)的合成
步骤1：2-((2-氯-4-硝基苯氧基)甲基)吡啶
2-氯-4-硝基苯酚(3.4g,20mmol)，2-氯甲基吡啶盐酸盐(3.4g,21mmol)，碳酸钾(3.3g,24mmol)和碘化钠(3.0g,20mmol)在乙腈(30mL)中回流过夜。将反应液倾入100mL水中，用乙酸乙酯萃取。有机相用饱和食盐水洗涤，干燥，旋干得粗产品。粗产品用石油醚洗涤过滤干燥得标题所示化合物(3.9g，74％)。
1H NMR(CDCl3):δ8.63(1H,d,J＝4.8 Hz),8.34(1H,d,J＝2.8 Hz),8.16-8.14(1H,m),7.79-7.76(1H,m),7.62-7.60(1H,m),7.31-7.27(1H,m),7.11(1H,d,J＝9.2 Hz),5.49(2H,s)。
步骤2：3-氯-4-(吡啶-2-基甲氧基)苯胺
将2-((2-氯-4-硝基苯氧基)甲基)吡啶(3.9g,15mmol)，锌粉(5.8g,88mmol)和氯化铵(2.4g,44mmol)加入乙醇(60mL)和水(10mL)的混合溶液中。该混合液在60℃下搅拌过夜。然后将反应液倾入200mL水中，用乙酸乙酯萃取。有机相分离，用饱和食盐水洗，干燥，真空除去溶剂得到标题所示化合物(3.4g,98％)。
1H NMR(CDCl3):δ8.57(1H,d,J＝4.8 Hz),7.75-7.70(1H,m),7.65-7.63(1H,m),7.23-7.20(1H,m),6.81(1H,d,J＝9.2 Hz),6.77(1H,d,J＝2.8 Hz),5.18(2H,s),3.48(2H,br)。
步骤3：N-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基-6-硝基喹唑啉-4-胺
将3-氯-4-(吡啶-2-基甲氧基)苯胺(3.5g,14mmol)，4-氯-7-甲氧基-6-硝基喹唑啉(3.4g,14mmol)加入异丙醇(40mL)中，在60℃下搅拌3小时。然后过滤，滤饼用异丙醇洗涤，干燥得到标题所示化合物(5.6 g,92％)。
1H NMR(DMSO-d6):δ10.91(1H,br),9.34(1H,s),8.80(1H,s),8.63(1H,d,J＝4.4 Hz),7.97-7.91(2H,m),7.68-7.61(2H,m),7.50(1H,s),7.44-7.40(1H,m),7.34(1H,d,J＝9.2 Hz),5.34(2H,s),4.09(3H,s)。
步骤4：N4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基喹唑啉-4,6-二胺
将N-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基-6-硝基喹唑啉-4-胺(5.6g,13mmol)，铁粉(4.5g,81mmol)，醋酸(8mL)与乙醇(60mL)的混合液在85℃下搅拌过夜。然后将混合液倾入300mL水中，过滤得粗产品。粗产品用乙酸乙酯洗涤，过滤干燥得到标题所示化合物(4.5g,86％)。
1H NMR(DMSO-d6):δ10.66(1H,br),8.67(1H,s),8.59(1H,d,J＝4.4 Hz),7.90-7.84(2H,m),7.58-7.54(2H,m),7.51(1H,s),7.38-7.35(1H,m),7.30(1H,d,J＝9.2 Hz),7.15(1H,s),5.92(2H,br),5.31(2H,s),4.00(3H,s)。
步骤5：4-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基-7-甲氧基喹唑啉-6-基氨基)哌啶-1-甲酸叔丁酯
以类似于实施例2步骤1中所描述的方法由N4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基喹唑啉-4,6-二胺合成标题所示化合物。
1H NMR(CDCl3):δ8.60(1H,d,J＝4.8 Hz),8.50(1H,s),7.77-7.73(2H,m),7.66(1H,d,J＝7.6 Hz),7.49-7.46(1H,m),7.26-7.23(1H,m),7.16(1H,s),7.00(1H,d,J＝8.8 Hz),6.61(1H,br),5.28(2H,s),4.64(1H,d,J＝8.0 Hz),4.08-3.98(5H,m),3.62-3.59(1H,m),3.06-3.00(2H,m),2.11-2.07(2H,m),1.49-1.46(11H,m)。
步骤6：N4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺
以类似于实施例4步骤2中所描述的方法由4-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基-7- 甲氧基喹唑啉-6-基氨基)哌啶-1-甲酸叔丁酯合成得到标题所示化合物。
步骤7：1-(4-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)哌啶-1-基)丙-2-烯-1-酮
以类似于实施例2步骤3中所描述的方法由N4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ8.60(1H,d,J＝4.8 Hz),8.47(1H,s),7.78-7.74(2H,m),7.66-7.64(1H,m),7.49-7.47(1H,m),7.26-7.24(1H,m),7.16(1H,s),6.97(1H,d,J＝8.8 Hz),6.79(1H,br),6.63-6.56(1H,m),6.32-6.27(1H,m),5.72-5.69(1H,m),5.26(2H,s),4.65(1H,d,J＝8.0 Hz),4.55-4.50(1H,m),4.01-3.95(4H,m),3.76-3.74(1H,m),3.36-3.29(1H,s),3.08-3.00(1H,m),2.22-2.14(2H,m),1.52-1.46(2H,m)。
实施例9 1-(3-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)吖丁啶-1-基)丙-2-烯-1-酮(化合物E9)的合成
步骤1：3-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基-7-甲氧基喹唑啉-6-基氨基)吖丁啶-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由N4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基喹唑啉-4,6-二胺合成得到标题所示化合物。
步骤2：N4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基-N6-(吖丁啶-3-基)喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由3-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基-7-甲氧基喹唑啉-6-基氨基)吖丁啶-1-甲酸苄酯合成得到标题所示化合物。
步骤3：1-(3-(4-(3-氯-4-(吡啶-2-基甲氧基)苯基氨基)-7-甲氧基喹唑啉-6-基氨基)吖丁啶-1-基)丙-2-烯-1-酮
以类似于实施例2步骤3中所描述的方法由N4-(3-氯-4-(吡啶-2-基甲氧基)苯基)-7-甲氧基-N6-(吖丁啶-3-基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ8.58(1H,d,J＝4.8 Hz),8.45(1H,s),8.30(1H,br),7.77-7.75(2H,m),7.64-7.62(1H,m),7.51-7.48(1H,m),7.26-7.24(1H,m),7.18(1H,s),6.92(1H,d,J＝9.2 Hz),6.79(1H,s),6.35-6.30(1H,m),6.22-6.15(1H,m),5.69-5.66(1H,m),5.23(2H,s),5.05(1H,d,J＝6.8 Hz),4.69-4.53(3H,m),4.08-4.04(1H,m),3.99-3.95(4H,m)。
实施例10 N6-(1-丙烯酰基哌啶-4-基)-N4-(3-乙炔基苯基)-7-甲氧基喹唑啉-4,6-二胺(化合物E10)的合成
步骤1：N-(3-乙炔基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺
将4-氯-7-甲氧基-6-硝基喹唑啉(1.00g,4.17mmol)加入3-乙炔基苯胺(0.49g,4.17mmol)的异丙醇溶液(15mL)中加热回流1小时。反应完毕后冷却，过滤得到标题所示化合物(1.12g,84％)。
1H NMR(DMSO-d6):δ11.08(1H,br),9.47(1H,s),8.89(1H,s),7.95(1H,s),7.79-7.82(1H,m),7.56(1H,s),7.47-7.52(1H,m),7.37-7.40(1H,m),4.27(1H,s),4.10(3H,s)。
步骤2:N4-(3-乙炔基苯基)-7-甲氧基喹唑啉-4,6-二胺
室温下，向铁粉(1.00g,17.9mmol)和N-(3-乙炔基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺(1.12g，3.5mmol)的乙醇(30mL)混悬溶液中缓慢滴加饱和氯化铵溶液(10mL)，加毕慢慢升温，加热回流4小时。反应完毕后，冷却，真空浓缩，残余物加入N,N-二甲基甲酰胺(40 mL)中搅拌30分钟。垫硅藻土过滤，滤液减压浓缩至干，余物用水打浆，过滤，水洗，干燥后得到黄色固体(0.78g,86％)。
1H NMR(DMSO-d6):δ9.77(1H,br),8.49(1H,s),7.99(1H,s),7.81-7.84(1H,m),7.46(1H,s),7.37-7.41(1H,m),7.20-7.23(1H,m),7.12(1H,s),5.56(2H,br),4.19(1H,s),3.99(3H,s)。
步骤3：4-{[4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基]氨基}哌啶-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由N4‐(3‐乙炔基苯基)‐7‐甲氧基喹唑啉‐4,6‐二胺与4‐氧代氮杂环己烷‐1‐甲酸苄酯合成得到标题所示化合物。
步骤4：N4-(3-乙炔基苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺
将40％氢氧化钾水溶液(4mL)加入4-{[4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基]氨基}哌啶-1-甲酸苄酯(200mg,0.39mmol)的甲醇(5mL)溶液中，加热到100℃搅拌3小时。反应完毕，慢慢加入水，乙酸乙酯萃取。所得有机相用饱和食盐水洗，无水硫酸钠干燥并真空浓缩，余物用乙醚打浆、过滤得到标题所示化合物(116mg,79％)。
1H NMR(DMSO-d6):δ9.17(1H,s),8.36(1H,s),7.98(1H,s),7.89-7.91(1H,m),7.36-7.40(1H,m),7.28(1H,s),7.16-7.19(1H,m),7.09(1H,s),5.10(1H,d,J＝8.8 Hz),4.19(1H,s),3.98(3H,s),3.62-3.72(1H,m),2.97-3.02(2H,m),2.64-2.71(2H,m),1.96-2.01(2H,m),1.30-1.40(2H,m)。
步骤5：N6-(1-丙烯酰基哌啶-4-基)-N4-(3-乙炔基苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N4‐(3‐乙炔基苯基)‐7‐甲氧基‐N6‐(哌啶‐4‐基)喹唑啉‐4,6‐二胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.13(1H,s),8.38(1H,s),7.97(1H,s),7.90-7.93(1H,m),7.37-7.41(1H,m)7.31(1H,s),7.18-7.21(1H,m),7.10(1H,s),6.81-6.89(1H,m),6.09-6.13(1H,m),5.66-5.70(1H,m),5.34(1H,d,J＝8.8 Hz),4.40-4.44(1H,m),4.19(1H,s),4.08-4.13(1H,m),3.97(3H,s),3.81-3.88(1H,m),2.82-2.91(2H,m),2.02-2.11(2H,m),1.40-1.48(2H,m)。.
实施例11 N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-乙炔基苯基)-7-甲氧基喹唑啉-4,6-二胺(化合物E11)的合成
步骤1:3-{[4-(3-乙炔基苯氨基)-7-甲氧基喹唑啉-6-基]氨基}氮杂环丁烷-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由N4‐(3‐乙炔基苯基)‐7‐甲氧基喹唑啉‐4,6‐二胺合成得到标题所示化合物。
1H NMR(CDCl3):δ8.54(1H,s),7.81(1H,s),7.71-7.73(1H,m),7.22-7.38(8H,m)7.14(1H,s),6.44(1H,s),5.10(2H,s),5.01-5.04(1H,m),4.43-4.49(2H,m),4.32-4.40(1H,m),3.99(1H,s),3.96(3H,s),3.89-3.94(2H,m)。
步骤2:N6-(氮杂环丁烷-3-基)-N4-(3-乙炔基苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由3‐{[4‐(3‐乙炔基苯氨基)‐7‐甲氧基喹唑啉‐6‐基]氨基}氮杂环丁烷‐1‐甲酸苄酯合成得到标题所示化合物。
步骤3:N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-乙炔基苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N6-(氮杂环丁烷-3-基)-N4-(3-乙炔基苯基)-7-甲氧基喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(CD3OD):δ8.40(1H,s),7.83(1H,s),7.70-7.72(1H,m),7.31-7.38(2H,m),7.24-7.27(1H,m),7.04(1H,s),6.34-6.38(1H,m),6.22-6.27(1H,m),5.72-5.75(1H,m),4.80-4.82(2H,m),4.54-4.58(2H,m),4.20-4.23(1H,m),3.98-4.03(4H,m)。
实施例12 N4-(3-乙酰基苯基)-N6-(1-丙烯酰基哌啶-4-基)-7-甲氧基喹唑啉-4,6-二胺(化合物E12)的合成
步骤1:N4-(3-乙酰基苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺
参照实施例10步骤1的方法，4-氯-7-甲氧基-6-硝基喹唑啉与3-乙酰基苯胺制备N-(3-乙酰基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺，接着依次参照实施例10的步骤2-4的方法制备得到标题化合物。
步骤2:N4-(3-乙酰基苯基)-N6-(1-丙烯酰基哌啶-4-基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N4-(3-乙酰基苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(CDCl3):δ8.58(1H,s),8.20-8.22(1H,m),8.10(1H,s),7.69-7.72(1H,m),7.50-7.54(1H,m),7.18-7.21(2H,m),6.59-6..62(2H,m),6.28-6.333(1H,m),5.70-5.75(1H,m),4.69(1H,d,J＝7.2 Hz),4.50-4.57(1H,m),4.00-4.03(4H,m),3.73-3.80(1H,m),3.34-3.42(1H,m),3.07-3.14(1H,m),2.65(3H,s),2.17-2.24(2H,m),1.40-1.48(2H,m)。
实施例13 N4-(3-乙酰基苯基)-N6-(1-丙烯酰基氮杂环丁烷-3-基)-7-甲氧基喹唑啉-4,6-二胺(化合物E13)的合成
步骤1：N4-(3-乙酰基苯基)-N6-(氮杂环丁烷-3-基)-7-甲氧基喹唑啉-4,6-二胺
N-(3-乙酰基苯基)-7-甲氧基-6-硝基喹唑啉-4-胺以类似于实施例10步骤2的方法制备得到N-(3-乙酰基苯基)-7-甲氧基-喹唑啉-4,6-二胺，然后依次以类似实施例1步骤6和7的方法合成得到标题所示化合物。
1H NMR(DMSO-d6):δ10.85(1H,s),9.24(1H,br),8.98(1H,br),8.75(1H,s),8.17(1H,s),7.96-8.00(1H,m),7.90-7.94(1H,m),7.33(1H,s),7.25(1H,s),6.95-6.98(1H,m),4.50-4.56(1H,m),4.41-4.44(2H,m),4.04-4.11(5H,m)。
步骤2：N4-(3-乙酰基苯基)-N6-(1-丙烯酰基氮杂环丁烷-3-基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N4-(3-乙酰基苯基)-N6-(氮杂环丁烷-3-基)-7-甲氧基喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(CDCl3):δ8.60(1H,s),8.14-8.20(2H,m),7.68-7.72(1H,m),7.47-7.52(1H,m),6.64(1H,s),6.31-6.36(1H,m),6.17-6.25(1H,m),5.66-5.70(1H,m),5.13(1H,d,J＝6.8 Hz),4.50-4.73(3H,m),3.90-4.12(4H,m),2.62(3H,s)。.
实施例14 N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺(化合物E14)的合成
步骤1：N-(3-溴苯基)-7-甲氧基-6-硝基喹唑啉-4-胺
以类似于实施例3步骤1中所描述的方法由4-氯-7-甲氧基-6-硝基喹唑啉与3-溴苯胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ11.10(1H,br),9.43(1H,s),8.87(1H,s),8.04-8.05(1H,m),7.74-7.78(1H,m),7.52(1H,s),7.38-7.44(2H,m),4.07(3H,s)。
步骤2:N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例7步骤4中所描述的方法由N-(3-溴苯基)-7-甲氧基-6-硝基喹唑啉-4-胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ10.09(1H,br),8.57(1H,s),8.05(1H,s),7.72-7.75(1H,m),7.47(1H,s),7.30-7.38(2H,m),7.13(1H,s),5.62(2H,br),3.97(3H,s)。
步骤3:3-{[4-(3-溴苯氨基)-7-甲氧基喹唑啉-6-基]氨基}氮杂环丁烷-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺合成得到标题所示化合物。
步骤4:N6-(氮杂环丁烷-3-基)-N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由3-{[4-(3-溴苯氨基)-7-甲氧基喹唑啉-6-基]氨基}氮杂环丁烷-1-甲酸苄酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.40(1H,br),8.97(1H,br),8.72(1H,br),8.66(1H,s),7.95(1H,s),7.68-7.71(1H,m),7.38-7.45(2H,m),7.16-7.19(2H,m),6.80-6.82(1H,m),4.44-4.56(1H,m),4.38-4.43(2H,m),3.99-4.08(5H,m)。
步骤5:N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N6-(氮杂环丁烷-3-基)-N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.23(1H,s),8.38(1H,s),8.08(1H,s),7.82-7.85(1H,m),7.29-7.34(1H,m),7.22-7.25(1H,m),7.10(1H,s),7.03(1H,s),6.30-6.38(2H,m),6.07-6.12(1H,m),5.62-5.67(1H,m),4.65-4.68(1H,m),4.38-4.51(2H,m),4.09-4.13(1H,m),3.90-3.96(4H,m)。
实施例15 N6-(1-丙烯酰基哌啶-4-基)-N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺(化合物E15)的合成
步骤1:4-{[4-(3-溴苯氨基)-7-甲氧基喹唑啉-6-基]氨基}哌啶-1-甲酸苄酯
以类似于实施例10步骤3中所描述的方法由N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.42(1H,br),8.44(1H,s),8.10(1H,s),7.84(1H,d,J＝8.0),7.29-7.39(8H,m),7.11(1H,s),5.40-5.42(1H,m),5.10(2H,s),4.04-4.08(2H,m),3.99(3H,s),3.75-3.81(1H,m),3.00-3.15(2H,m),1.98-2.05(2H,m),4.42-1.48(2H,m)。
步骤2:N4-(3-溴苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由4-{[4-(3-溴苯氨基)-7-甲氧基喹唑啉-6-基]氨基}哌啶-1-甲酸苄酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.40(1H,br),8.70(1H,s),8.61(1H,br),8.44(1H,br),7.97(1H,s),7.72-7.74(1H,m),7.42-7.498(2H,m),7.38(1H,s),7.19(1H,s),6.02-6.05(1H,m),4.04(3H,s),3.75-3.80(1H,m),3.32-3.38(2H,m),2.98-3.04(2H,m),2.12-2.18(2H,m),1.70-1.81(2H,m)。
步骤3:N6-(1-丙烯酰基哌啶-4-基)-N4-(3-溴苯基)-7-甲氧基喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N4-(3-溴苯基)-7-甲氧基-N6-(哌啶-4-基)喹唑啉-4,6-二胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.26(1H,s),8.39(1H,s),8.13(1H,s),7.86-7.90(1H,m),7.25-7.37(3H,m),7.10(1H,s),6.82-6.89(1H,m),6.09-6.14(1H,m),5.66-5.70(1H,m),5.37(1H,d,J＝8.8Hz),4.39-4.45(1H,m),4.09-4.13(1H,m),3.97(3H,s),3.79-3.88(1H,m),3.21-3.27(1H,m),2.83-2.92(1H,m),2.02-2.09(2H,m),1.41-1.50(2H,m)。
实施例16 N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺(化合物E16)的合成
步骤1:N-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)-6-硝基喹唑啉-4-胺
以类似于实施例3步骤2中所描述的方法由N-(3-氯-4-氟苯基)-7-氟-6-硝基喹唑啉-4-胺与2-甲氧基乙醇合成得到标题所示化合物。
1H NMR(DMSO-d6):δ10.13(1H,s),9.18(1H,s),8.65(1H,s),8.14(1H,dd,J＝6.8 Hz,2.4Hz),7.75-7.79(1H,m),7.49(1H,s),7.45(1H,t,J＝9.2 Hz),4.42(2H,t,J＝4.8 Hz),3.72(2H,t,J＝4.8 Hz),3.32(3H,s)。
步骤2:N4-(3-氯-4氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺
以类似于实施例1步骤5中所描述的方法由N-(3-氯-4氟苯基)-7-(2-甲氧基乙氧基)-6-硝基喹唑啉-4-胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.38(1H,s),8.36(1H,s),8.17(1H,dd,J＝6.8 Hz,2.4 Hz),7.77-7.81(1H,m),7.39(1H,s),7.37(1H,t,J＝9.2 Hz),7.10(1H,s),5.29(2H,s),4.28(2H,t,J＝4.4 Hz),3.77(2H,t,J＝4.4 Hz),3.34(3H,s)。
步骤3:3-{[4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-6-基]氨基}氮杂环丁烷-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由N4-(3-氯-4氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(CDCl3):δ8.54(1H,s),7.84(1H,dd,J＝6.8 Hz,2.4 Hz),7.48-7.52(1H,m),7.29-7.37(5H,m),7.18(1H,s),7.15(1H,t,J＝8.8 Hz),6.37(1H,s),5.09-5.13(3H,m),4.47(2H,dd,J＝9.2 Hz,7.2 Hz),4.25-4.38(3H,m),3.96(2H,dd,J＝9.2 Hz,4.8 Hz),3.83(2H,t,J＝4.8Hz),3.46(3H,s)。
步骤4:N6-(氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由3-{[4-(3-氯-4氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-6-基]氨基}氮杂环丁烷-1-甲酸苄酯合成得到标题所示化合物的三氟醋酸盐。
步骤5:N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉 -4,6-二胺
以类似于实施例1步骤8中所描述的方法由N6-(氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(DMSO):δ9.27(1H,s),8.37(1H,s),8.08(1H,dd,J＝6.8 Hz,2.4 Hz),7.75-7.79(1H,m),7.42(1H,t,J＝9.2 Hz),7.14(1H,s),7.04(1H,s),6.36(1H,dd,J＝17.2 Hz,10.4 Hz),6.16(1H,d,J＝6.8 Hz),6.11(1H,dd,J＝16.4 Hz,2.4 Hz),5.66(1H,dd,J＝10.4 Hz,2.4 Hz),4.71(1H,t,J＝8.0 Hz),4.41-4.53(2H,m),4.31(2H,t,J＝4.8 Hz),4.13-4.16(1H,m),3.93-3.97(1H,m),3.79(2H,t,J＝4.8 Hz),3.34(3H,s)。
实施例17 N6-(1-丙烯酰基氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺(化合物E17)的合成
步骤1:4-{[4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-6-基]氨基}氮杂环己烷-1-甲酸叔丁酯
将N4‐(3‐氯‐4氟苯基)‐7‐(2‐甲氧基乙氧基)喹唑啉‐4,6‐二胺(100mg,0.28mmol)和4‐氧代哌啶‐1‐甲酸叔丁酯(167mg,0.84mmol)的醋酸(4mL)溶液在室温下搅拌2小时,然后加入三乙酰氧基硼氢化钠(178mg,0.84mmol)。反应1小时后，慢慢加入水淬灭反应，乙酸乙酯萃取。所得有机相依次用水、5％NaHCO3水溶液和饱和食盐水洗，无水硫酸钠干燥并真空浓缩。余物经硅胶柱层析分离得到标题所示化合物(85mg,56％)。
1H NMR(CDCl3):δ8.52(1H,s),7.83(1H,dd,J＝6.8 Hz,2.4 Hz),7.51-7.55(1H,m),7.17(1H,s),7.16(1H,t,J＝8.8 Hz),6.57(1H,s),4.72-4.76(1H,brs),4.29(2H,t,J＝4.4 Hz),4.02-4.11(2H,m),3.82(2H,t,J＝4.4 Hz),3.57-3.64(1H,m),3.46(3H,s),3.01-3.08(2H,m),2.08-2.03(2H,m),1.45-1.53(11H,m)。
步骤2:N6-(氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺
以类似于实施例4步骤2中所描述的方法由4-{[4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-6-基]氨基}氮杂环己烷-1-甲酸叔丁酯合成得到标题所示化合物。
步骤3:N6-(1-丙烯酰基氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N6-(氮杂环己烷-4-基)-N4-(3-氯-4-氟苯基)-7-(2-甲氧基乙氧基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(DMSO):δ9.68-9.75(1H,brs),8.40(1H,s),8.08(1H,dd,J＝6.8 Hz,2.4 Hz),7.75-7.79(1H,m),7.42(1H,t,J＝8.8 Hz),7.40(1H,s),7.11(1H,s),6.82(1H,dd,J＝16.8 Hz,10.8 Hz),6.08(1H,dd,J＝16.8 Hz,2.4 Hz),5.65(1H,dd,J＝10.8 Hz,2.4 Hz),5.21(1H,d,J＝8.8 Hz),4.37-4.42(1H,m),4.28(2H,t,J＝4.4 Hz),4.05-4.10(1H,m),3.82-3.91(1H,m),3.76(2H,t,J＝4.4 Hz),3.31(3H,s),3.20-3.26(1H,m),2.85-2.92(1H,m),2.00-2.06(2H,m),1.35-1.46(2H,m)。
实施例18 N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-4,6-二胺(化合物E18)的合成
步骤1:N-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)-6-硝基喹唑啉-4-胺
以类似于实施例3步骤2中所描述的方法由N-(3-氯-4-氟苯基)-7-氟-6-硝基喹唑啉-4-胺与2-吗啉乙醇合成得到标题所示化合物。
1H NMR(DMSO):δ10.17(1H,s),9.19(1H,s),8.65(1H,s),8.14(1H,dd,J＝6.8 Hz,2.4Hz),7.76-7.80(1H,m),7.51(1H,s),7.45(1H,t,J＝9.2 Hz),4.41(2H,t,J＝5.6 Hz),3.54-3.56(4H,m),2.76(2H,t,J＝5.6 Hz),2.49-2.52(4H,m)。
步骤2:N4-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-4,6-二胺
以类似于实施例1步骤5中所描述的方法由N-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)-6-硝基喹唑啉-4-胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.36(1H,s),8.34(1H,s),8.15(1H,dd,J＝7.2 Hz,2.8 Hz),7.75-7.79(1H,m),7.37(1H,s),7.36(1H,t,J＝9.2 Hz),7.09(1H,s),5.29(2H,s),4.25(2H,t,J＝5.6 Hz),3.55-3.57(4H,m),2.79(2H,t,J＝5.6 Hz),2.48-2.50(4H,m)。
步骤3:3-{[4-(3-氯-4氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-6-基]氨基}氮杂环丁烷-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由N4-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-4,6-二胺合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.36-9.39(1H,brs),8.38(1H,s),8.11-8.13(1H,m),7.79-7.84(1H,m),7.43(1H,t,J＝9.2 Hz),7.30-7.39(5H,m),7.16(1H,s),7.13(1H,s),6.06-6.14(1H,brs),5.07(2H,s),4.41-4.48(3H,m),4.31(2H,t,J＝5.6 Hz),3.90-4.01(2H,m),3.56-3.64(4H,m),2.86(2H,t,J＝5.6 Hz),2.50-2.54(4H,m)。
步骤4:N6-(氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由3-{[4-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-6-基]氨基}氮杂环丁烷-1-甲酸苄酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.32-10.47(1H,brs),9.14-9.24(1H,brs),9.03-9.12(1H,brs),8.63(1H,s),7.97(1H,dd,J＝6.8 Hz,2.4 Hz),7.65-7.70(1H,m),7.49(1H,t,J＝9.2 Hz),7.31(1H,s),7.17(1H,s),6.91-6.95(1H,brs),4.51-4.64(3H,m),4.39-4.48(2H,m),4.08-4.16(2H,m),3.40-3.97(10H,m)。
步骤5:N6-(1-丙烯酰基氮杂环丁烷-3-基)-N4-(3-氯-4-氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-4,6-二胺
以类似实施例2步骤3中所描述的方法由N6-(氮杂环丁烷-3-基)-N4-(3-氯-4氟苯基)-7-(2-吗啉基乙氧基)喹唑啉-4,6-二胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.47(1H,s),8.37(1H,s),8.14(1H,dd,J＝6.8 Hz,2.4 Hz),7.82-7.86(1H,m),7.41(1H,t,J＝9.2 Hz),7.18(1H,S),7.14(1H,s),6.35(1H,dd,J＝13.2 Hz,9.2 Hz),6.11(1H,dd,J＝13.2 Hz,2.4 Hz),5.66(1H,dd,J＝10.0 Hz,2.4 Hz),4.72(1H,t,J＝7.6 Hz),4.52-4.59(1H,m),4.43(1H,t,J＝7.6 Hz),4.27-4.36(2H,m),4.09-4.17(1H,m),3.92-3.99(1H,m),3.53-3.68(4H,m),2.77-2.90(2H,m),2.50-2.58(4H,m)。
实施例196-(1-丙烯酰基氮杂环丁烷-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺(化合物E19)的合成
步骤1：N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-甲氧基-6-硫氰基喹唑啉-4-胺
在0℃下，将N4-(3-氯-4-氟苯基)-N4-(3,4-二甲氧基苄基)-7-甲氧基喹唑啉-4,6-二胺(0.25g,0.5mmol)慢慢加入到30％的硫酸(3g)中，搅拌30分钟使其完全溶解。慢慢加入亚硝酸钠(0.072g,1mmol)。体系在0℃继续搅拌30分钟，然后升至室温搅拌30分钟。在室温下将上述溶液慢慢滴加到剧烈搅拌的硫氰酸钾(0.5g,5mmol)和三氯化铁(0.25g,1.5mmol)的水溶液(30mL)中，加完继续搅拌过夜。抽滤，水洗，干燥后得到黄色的标题所示化合物(0.25g,92％)。
1H NMR(DMSO-d6):δ9.03(1H,s),7.83(1H,s),7.44(1H,t,J＝8.0 Hz),7.29-7.38(2H,m),7.24(1H,s),6.92(1H,s),6.81(1H,s),5.48(3H,s),4.05(3H,s),3.69(3H,s),3.66(3H,s)。
步骤2：3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}氮杂环丁烷-1-甲酸叔丁酯
将硼氢化钠(16mg,0.43mmol)加入到N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-甲氧基-6-硫氰基喹唑啉-4-胺(44mg,0.086mmol)的乙醇溶液(2mL)中，室温搅拌1小时，再补加硼氢化钠(5mg)，继续搅拌30分钟。TLC检测原料消失后，依次加入无水碳酸钾(120mg)和3-碘代氮杂环丁烷-1-甲酸叔丁酯(30mg,0.106mmol)，然后加热反应混合物至50℃反应5小时。反应完毕，冷却，慢慢加入水淬灭反应，乙酸乙酯萃取。所得有机相依次用水和饱和食盐水洗，无水硫酸钠干燥并真空浓缩。余物用制备薄层(二氯甲烷:乙酸乙酯(v/v)＝1:2)纯化得到标题所示化合物(15mg,27％)。
1H NMR(CDCl3):δ8.82(1H,s),7.38(1H,br),7.10-7.20(2H,m),6.80-6.93(2H,m),6.72-6.77(3H,m),5.33(2H,s),4.10-4.15(2H,m),3.98(3H,s),3.84(3H,s),3.79(3H,s),3.60-6.68(2H,m),3.30-3.35(1H,m),1.45(9H,s)。
步骤3：6-(氮杂环丁烷-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺
以类似于实施例1步骤7中所描述的方法由3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}氮杂环丁烷-1-甲酸叔丁酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.30(1H,s),8.97-9.03(2H,m),8.64(1H,s),8.16(1H,s),8.02-8.04(1H,m),7.70-7.72(1H,m),7.46-7.49(1H,m),7.27(1H,s),4.42-4.47(3H,m),3.99(3H,s),3.82-3.88(3H,m)。
步骤4：6-(1-丙烯酰基氮杂环丁烷-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺
以类似于实施例2步骤3中所描述的方法由6-(氮杂环丁烷-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(CD3OD):δ8.39(1H,s),8.03(1H,s),7.88-7.90(1H,m),7.54-7.56(1H,m),7.16-7.20(1H,m),7.11(1H,s),6.17-6.24(2H,m),5.64-5.67(1H,m),4.71-4.73(1H,m),4.45-4.48(1H,m),4.26-4.29(1H,m),4.11-4.13(1H,m),3.95(3H,s),3.86-3.89(1H,m)。
实施例206-(1-丙烯酰基氮杂环戊烷-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺(化合物E20)的合成
步骤1：3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}吡咯烷-1-甲酸叔丁酯
以类似于实施例19步骤2中所描述的方法由N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-甲氧基-6-硫氰基喹唑啉-4-胺与3-碘代氮杂环戊烷-1-甲酸叔丁酯合成得到标题所示化合物。
1H NMR(CDCl3):δ8.81(1H,s),7.15-7.26(2H,m),7.05-7.12(1H,m),7.04(1H,s),6.95(1H,s),6.90-6.94(1H,m),6.78-6.82(1H,m),6.74-6.77(1H,m),5.30-5.35(2H,m),3.98(3H,s),3.84(3H,s),3.79(3H,s),3.35-3.60(3H,m),3.12-3.21(2H,m),1.92-2.05(1H,m),1.60-1.70(1H,m),1.45(9H,s)。
步骤2:N-(3-氯-4-氟苯基)-7-甲氧基-6-(吡咯烷-3-基巯基)喹唑啉-4-胺
以类似于实施例1步骤7中所描述的方法由3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}吡咯烷-1-甲酸叔丁酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.50(1H,br),9.03-9.09(2H,br),8.73(1H,s),8.40(1H,s),8.02-8.04(1H,m),7.70-7.75(1H,m),7.49-7.55(1H,m),7.32(1H,s),4.22-4.28(1H,m),4.04(3H,s),3.52-3.80(3H,m),3.12-3.20(1H,m),2.42-2.50(1H,m),1.92-2.01(1H,m)。
步骤3:6-(1-丙烯酰基吡咯烷-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺
以类似于实施例2步骤3中所描述的方法由N-(3-氯-4-氟苯基)-7-甲氧基-6-(吡咯烷-3-基巯基)喹唑啉-4-胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(CD3OD):δ8.46(1H,s),8.31-8.34(1H,m),7.94-7.98(1H,m),7.61-7.65(1H,m),7.21-7.26(1H,m),7.15(1H,s),6.45-6.61(1H,m),6.20-6.28(1H,m),5.65-5.75(1H,m),4.17-4.25(1H,m),3.99(3H,s),3.79-3.88(1H,m),3.65-3.78(1H,m),3.35-3.42(2H,m),2.30-2.48(1H,m),1.90-2.08(1H,m)。
实施例216-(1-丙烯酰基哌啶-4-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺(化合物E21)的合成
步骤1：4-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}哌啶-1-甲酸叔丁酯
以类似于实施例19步骤2中所描述的方法由N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-甲氧基-6-硫氰基喹唑啉-4-胺与4-碘代哌啶-1-甲酸叔丁酯合成得到标题所示化合物。
1H NMR(CDCl3):δ8.82(1H,s),7.10-7.18(4H,m),6.88-6.93(2H,m),6.78-6.82(1H,m),6.74-6.77(1H,m),5.33(2H,s),3.98(3H,s),3.84(3H,s),3.79(3H,s),2.86-2.96(3H,m),1.50-1.70(4H,m),1.45(9H,s),1.30-1.40(2H,m)。
步骤2:N-(3-氯-4-氟苯基)-6-(哌啶-4-基巯基)-7-甲氧基喹唑啉-4-胺
以类似于实施例1步骤7中所描述的方法由4-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}哌啶-1-甲酸叔丁酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.54(1H,br),8.74(1H,s),8.63(1H,br),8.56(1H,s),8.48(1H,br),8.05-8.09(1H,m),7.72-7.78(1H,m),7.48-7.55(1H,m),7.30(1H,s),4.03(3H,s),3.72-3.80(1H,m),3.26-3.35(2H,m),2.98-3.05(2H,m),2.06-2.15(2H,m),1.65-1.78(2H,m)。
步骤3:6-(1-丙烯酰基哌啶-4-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺
以类似于实施例2步骤3中所描述的方法由N-(3-氯-4-氟苯基)-6-(哌啶-4-基巯基)-7-甲氧基喹唑啉-4-胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(CD3OD):δ8.46(1H,s),8.38(1H,s),7.94-7.98(1H,m),7.61-7.65(1H,m),7.21-7.26(1H,m),7.15(1H,s),6.69-6.74(1H,m),6.14-6.19(1H,m),5.68-5.72(1H,m),4.24-4.29(1H,m),3.98-4.06(4H,m),3.68-3.75(1H,m),3.30-3.40(1H,m),3.12-3.20(1H,m),1.97-2.03(2H,m),1.50-1.60(2H,m)。
实施例22(R)-6-(1-丙烯酰基哌啶-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺(化合物E22)的合成
步骤1：(R)-3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}哌啶-1-甲酸叔丁酯
以类似于实施例19步骤2中所描述的方法由N-(3-氯-4-氟苯基)-N-(3,4-二甲氧基苄基)-7-甲氧基-6-硫氰基喹唑啉-4-胺与(S)-3-碘代哌啶-1-甲酸叔丁酯合成得到标题所示化合物。
1H NMR(CDCl3):δ8.83(1H,s),7.08-7.18(1H,m),7.07(1H,s),6.85-95(3H,m),6.78-6.85(1H,m),6.74-6.78(2H,m),5.33(2H,s),3.97(3H,s),3.84(3H,s),3.75-3.80(4H,m),2.45-3.00(2H,m),1.65-1.92(4H,m),1.30-1.50(11H,m)。
步骤2：(R)-N-(3-氯-4-氟苯基)-7-甲氧基-6-(哌啶-3-基巯基)喹唑啉-4-胺
以类似于实施例1步骤7中所描述的方法由(R)-3-{{4-[(3-氯-4-氟苯基)(3,4-二甲氧基苄基)氨基]-7-甲氧基喹唑啉-6-基}巯基}哌啶-1-甲酸叔丁酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(CD3OD):δ8.65(1H,s),8.61(1H,s),7.92-7.95(1H,m),7.61-7.65(1H,m),7.27-7.33(1H,m),7.25(1H,s),4.09(3H,s),3.74-3.80(1H,m),3.51-3.58(2H,m),2.99-3.06(2H,m),2.16-2.22(1H,m),2.00-2.06(1H,m),1.80-1.92(2H,m),1.62-1.73(1H,m)。
步骤3:(R)-6-(1-丙烯酰基哌啶-3-基)巯基-N-(3-氯-4-氟苯基)-7-甲氧基喹唑啉-4-胺
以类似于实施例2步骤3中所描述的方法由(R)-N-(3-氯-4-氟苯基)-7-甲氧基-6-(哌啶-3-基巯基)喹唑啉-4-胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(CD3OD):δ8.44(1H,s),8.22(1H,s),8.14-8.17(1H,m),7.95-8.00(1H,m),7.16-7.20(1H,m),7.06(1H,s),6.77-6.85(1H,m),6.26-6.31(1H,m),5.78-5.81(1H,m),4.78-4.82(1H,m),4.04-4.12(1H,m),3.98(3H,s),3.38-3.45(2H,m),2.73-2.79(1H,m),2.12-2.18(1H,m),1.93-1.97(1H,m),1.62-1.80(2H,m)。
实施例23 N6-(1-丙烯酰基哌啶-4-基)-N4-(3-氯-4-氟苯基)-喹唑啉-4,6-二胺(化合物E23)的合成
步骤1：6-硝基喹唑啉-4(3H)-酮
冰水浴下，缓慢将喹唑啉-4(3H)-酮(1.46g,10mmol)分批加入混酸(浓硫酸:浓硝酸＝4:1)(8mL)中。加毕，将反应体系缓慢升至95℃。反应1小时后，将反应物倒入冰水(100mL)中，搅拌至固体析出。过滤，所得固体经硅胶柱层析分离的到标题所示化合物(1.45g,76％)。
1H NMR(DMSO-d6):δ12.90(1H,br),8.78(1H,d,J＝2.4 Hz),8.52(1H,dd,J＝2.4 Hz,8.8Hz),8.28(1H,s),7.83(1H,d,J＝8.8 Hz)。
步骤2：N4-(3-氯-4-氟苯基)-喹唑啉-4,6-二胺
将6-硝基喹唑啉-4(3H)-酮(1.34g,7.0mmol)和五氯化磷(1.46g,7.0mmol)的三氯化磷(5mL)溶液于160℃搅拌6小时。冷至室温，将反应物倒入冷的正己烷中，搅拌至固体析出。过滤，滤饼经乙醚洗涤后真空干燥得到白色固体。向所得白色固体和3-氯-4-氟-苯胺(1.02g,7.0mmol)的混合物中加入乙腈(20mL)后，将反应体系缓慢升至80℃。反应2小时后，降至室温，减压蒸除溶剂，加入饱和NaHCO3溶液(50mL)后用乙酸乙酯萃取。所得有机相用饱和食盐水洗，无水硫酸钠干燥并真空浓缩至干。将残余物溶于DMF:甲醇＝1:1的混合液(20mL)后，向所得混合物中加入雷尼镍(70mg)。体系氢气置换，并在氢气氛中(1atm)于40℃搅拌4小时。过滤，滤液经减压浓缩，所得油状物经硅胶柱层析分离的到目标产物(303mg,15％)。
1H NMR(DMSO-d6):δ9.90(1H,br),8.45(1H,s),8.11-8.09(1H,m),7.75-7.73(1H,m),7.55-7.53(1H,m),7.42-7.39(1H,m),7.28-7.27(1H,m),5.17(2H,br)。
步骤3：4-{{4-[(3-氯-4-氟苯基)氨基]-喹唑啉-6-基}氨基}哌啶-1-甲酸苄酯
以类似于实施例1步骤6中所描述的方法由N4-(3-氯-4-氟苯基)-喹唑啉-4,6-二胺与4-氧代哌啶-1-甲酸苄酯合成得到标题所示化合物。
1H NMR(d6-DMSO):δ10.63(1H,br),8.63(1H,s),7.96-7.94(1H,m),7.65-7.61(2H,m),7.56-7.52(1H,m),7.24-7.21(1H,m),7.38-7.34(5H,m),6.64(1H,s),5.07(2H,s),3.98-3.95(2H,m),3.65-3.62(1H,m),3.18-3.14(2H,m),1.99-1.95(2H,m),1.36-1.34(2H,m)。
步骤4：N6-(哌啶-4-基)-N4-(3-氯-4-氟苯基)-喹唑啉-4,6-二胺
以类似于实施例1步骤7中所描述的方法由4-{{4-[(3-氯-4-氟苯基)氨基]-喹唑啉-6-基}氨基}哌啶-1-甲酸苄酯合成得到标题所示化合物的三氟醋酸盐。
1H NMR(DMSO-d6):δ10.79(1H,s),8.67-8.52(3H,m),7.96-7.93(1H,m),7.64-7.61(2H,m),7.54-7.51(1H,m),7.48-7.45(1H,m),7.34-7.31(1H,m),6.84(1H,s),3.70-3.68(2H,m),3.04-2.98(3H,m),2.14-2.11(2H,m),1.66-1.64(2H,m)。
步骤5：N6-(1-丙烯酰基哌啶-4-基)-N4-(3-氯-4-氟苯基)-喹唑啉-4,6-二胺
以类似于实施例2步骤3中所描述的方法由N6-(哌啶-4-基)-N4-(3-氯-4-氟苯基)-喹唑啉-4,6-二胺的三氟醋酸盐合成得到标题所示化合物。
1H NMR(DMSO-d6):δ9.55(1H,s),8.30(1H,s),8.16-8.14(1H,m),7.84-7.83(1H,m),7.46-7.43(1H,m),7.42-7.39(1H,m),7.31-7.29(1H,m),7.24-7.22(1H,m),6.85-6.81(1H,m),6.15-6.05(2H,m),5.66-5.63(1H,m),4.29-4.26(1H,m),4.02-3.98(1H,m),3.84-3.79(2H,m),3.01-2.97(1H,m),2.02-1.98(2H,m),1.20-1.18(2H,m)。
体外活性试验
1.体外酶学检测方法
EGFR,EGFR(T790M，L858R)，HER2激酶由北京赛林泰医药技术有限公司生物部通过昆虫表达系统表达纯化得到或通过购买市售产品得到。
采取Cisbio公司的均相时间分辨荧光(HTRF)方法建立了EGFR,EGFR(T790M，L858R),HER2的激酶活性检测平台，进行化合物活性的测定。将化合物分别从100nM(EGFR和HER2)，1μM(EGFR-T790M/L858R)开始用100％DMSO进行3倍的梯度稀释，每个浓度取4μL加入到96μL的反应缓冲液中(50mM 4-羟乙基哌嗪乙磺酸(HEPES)(pH 7.0),0.02％NaN3,0.01％牛血清白蛋白(BSA),0.1mM原钒酸钠(Sodium Orthovanadate)，5mM MgCl2,50nM SEB(Cisbio公司，货号：61SEBALB)，1mM DTT)，取2.5μL加入到384孔板(OptiPlate-384,PerkinElmer)，然后加入2.5μL的激酶，离心混匀，再加入5μL的ATP和TK底物生物素(Substrate-biotin)启动反应。将384孔板放于孵育箱中23℃反应一定时间后，加入5μL的Eu3+-Cryptate标记的TK-Antibody，5μL的链霉亲和素(streptavidin)-XL665停止反应。在 孵育箱中孵育1小时后，在Envision(PerkinElmer)上读取荧光值。化合物的IC50值使用GraphPad Prism 5.0软件计算得到。
2.Anchorage-independent细胞增殖试验(锚定非依赖性细胞增殖试验)
人非小细胞肺癌细胞NCI-H1975，人乳腺癌细胞系BT474在细胞培养箱(37℃，5％CO2)中用RPIM-1640或者DMEM培养基加10％胎牛血清(FBS)进行培养。在化合物的检测中，底层基质浓度为0.6％,细胞用0.3％的低熔点琼脂重选后，10,000个细胞每孔(100μL)铺于96孔板中。化合物从10mM进行3倍梯度稀释，每个浓度取2μL加入到98μL的培养基中，然后取5.3μL加入到细胞培养液中(DMSO终浓度为0.1％，v/v)，处理一周(7天)后，加入20μL
Figure PCTCN2014087633-appb-000006
(Promega)试剂，37℃孵育4个小时，在Envison(Perkin Elmer)上读取荧光信号，使用GraphPad Prism 5.0计算化合物对细胞增殖抑制的IC50值。
生物活性列表
Figure PCTCN2014087633-appb-000007
注：NT为未测定
大鼠药动学测试
研究使用6只健康成年雄性大鼠，来源于北京维通利华实验动物技术有限公司。动物在实验前禁食过夜，禁食时间从给药前12小时至给药后4小时，单次灌胃给药，剂量为5mg/kg，将待测化合物溶于20％磺丁基-β-环糊精(SBE)水溶液。在给药后0.25、0.5、1、2、4、6、8和24小时采血。动物采血时用麻醉机通过异氟醚浅麻醉，通过眼眶静脉丛采集约0.5mL全血放入肝素抗凝管中。样品于4℃、4000rpm离心5min，血浆转移至离心管中，并放于-80℃保存直到分析。使用液相色谱-串联质谱联用方法(LC-MS/MS)对血浆中药品浓度进行定量 分析。样品的分析结果通过WinNonlin(WinNonlin Professional,version.6.3)算得化合物的药代动力学参数。
化合物 T1/2(hr) Tmax(hr) Cmax(ng/mL) AUC0-∞(hr*ng/mL)
实施例1 1.30 0.50 588 1346
实施例2 2.39 1.00 1972 11040

Claims (16)

  1. 式(I)表示的化合物或其药学上可接受的盐，
    Figure PCTCN2014087633-appb-100001
    其中：
    环Ar为芳基或杂芳基；
    X选自-NR8-、-S-、-S(＝O)-或者-S(＝O)2-；
    n和m各自为从0到6的任意整数，且m、n不同时为0；
    p为从0到5的任意整数；
    q为从0到8的任意整数；
    R1独立地选自C1-6烷基、C3-8环烷基、C2-6烯基、C2-6炔基、杂环烷基、卤素、氨基、单(C1-6烷基)氨基、二(C1-6烷基)氨基、羟基、C1-6烷氧基、巯基、C1-6烷硫基、C1-6烷基羰基、芳基、杂芳基、氰基、硝基，其中C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基可被卤素、氰基、硝基、C1-6烷氧基、芳基、杂芳基、杂环烷基取代，且芳基、杂芳基、杂环烷基可进一步被卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基羰基取代；
    R2选自氢、羟基、C1-6烷氧基、杂环烷基氧基或者是被C1-6烷氧基或杂环烷基取代的C1-6烷氧基；
    R3独立地选自卤素、氰基、巯基、C1-6烷硫基、C1-6烷基、C3-8环烷基、杂环烷基、氨基、单(C1-6烷基)氨基、二(C1-6烷基)氨基、羟基、C1-6烷氧基、C1-6烷氧基羰基、C1-6烷基酰氨基、单(C1-6烷基)氨基酰基、二(C1-6烷基)氨基酰基；
    R4、R5和R6各自独立的选自氢、卤素、C1-6烷基、C3-8环烷基、杂环烷基、氨基、单(C1-6烷基)氨基、二(C1-6烷基)氨基、C1-6烷基酰氨基、单(C1-6烷基)氨基酰基、二(C1-6烷基)氨基酰基、C1-6烷氧基羰基；
    R7、R8各自独立地选自氢或C1-6烷基。
  2. 权利要求1所述的化合物或其药学上可接受的盐，其中，X选自-NR8-、-S-。
  3. 权利要求1或2所述的化合物或其药学上可接受的盐，其中，n和m各自为从0到3的任意整数，且m、n不同时为0。
  4. 权利要求1-3任一项所述的化合物或其药学上可接受的盐，其中，R7、R8为氢。
  5. 权利要求1-4任一项所述的化合物或其药学上可接受的盐，其中，环Ar为苯基。
  6. 权利要求1-5任一项所述的化合物或其药学上可接受的盐，其中，p为从0到3的整数。
  7. 权利要求1-6任一项所述的化合物或其药学上可接受的盐，其中，q为从0到3的整数。
  8. 权利要求1-7任一项所述的化合物或其药学上可接受的盐，其中，R1独立地选自C1-6烷基、C2-6烯基、C2-6炔基、卤素、氨基、羟基、C1-6烷氧基、C1-6烷基羰基、氰基、硝基，其中C1-6烷基、C1-6烷氧基、C2-6烯基、C2-6炔基可被卤素、氰基、硝基、C1-6烷氧基、芳基、杂芳基、杂环烷基取代，且芳基、杂芳基、杂环烷基可进一步被卤素、氰基、硝基、C1-6烷基、C1-6烷氧基、C1-6烷基羰基取代。
  9. 权利要求8所述的化合物或其药学上可接受的盐，其中，R1独立地选自C2-6炔基、卤素、C1-6烷氧基、C1-6烷基羰基，其中C1-6烷氧基可被芳基、杂芳基、杂环烷基取代，且芳基、杂芳基、杂环烷基可进一步被卤素、氰基、硝基取代。
  10. 权利要求9所述的化合物或其药学上可接受的盐，其中，R1独立地选自C2-6炔基、卤素、杂芳基取代的C1-6烷氧基、芳基取代的C1-6烷氧基、C1-6烷基羰基，其中芳基、杂芳基可进一步被卤素取代。
  11. 权利要求10所述的化合物或其药学上可接受的盐，其中，R1独立地选自乙炔基、卤素、吡啶基取代的C1-6烷氧基、卤代苯基取代的C1-6烷氧基。
  12. 权利要求1-11任一项所述的化合物或其药学上可接受的盐，其中，R4、R5和R6为氢。
  13. 权利要求1-12任一项所述的化合物或其药学上可接受的盐，其中，R2选自氢、甲氧基、四氢呋喃基氧基、被甲氧基取代的乙氧基、被吗啉基取代的乙氧基。
  14. 下列化合物或其药学上可接受的盐：
    Figure PCTCN2014087633-appb-100002
    Figure PCTCN2014087633-appb-100003
  15. 药物组合物，其包含权利要求1-14中任一项所述的化合物或其药学上可接受的盐和药学上可接受的载体。
  16. 权利要求1-14中任一项所述的化合物或其药学上可接受的盐或权利要求15所述的组合物在制备预防或者治疗肿瘤的药物中的用途。
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EP3272746A4 (en) * 2015-03-20 2018-11-07 Chai Tai Tianqing Pharmaceutical Group Co., Ltd. Salts of quinazoline derivative and method for preparing same
JP2019524857A (ja) * 2016-08-25 2019-09-05 正大天晴▲藥▼▲業▼集▲団▼股▲フン▼有限公司 キナゾリン誘導体の塩の結晶
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US10858340B2 (en) * 2016-08-25 2020-12-08 Chia Tai Tianqing Pharmaceutical Group Co. Ltd. Crystal of salt of quinazoline derivative
JP7036798B2 (ja) 2016-08-25 2022-03-15 正大天晴▲藥▼▲業▼集▲団▼股▲フン▼有限公司 キナゾリン誘導体の塩の結晶
WO2019120213A1 (zh) 2017-12-19 2019-06-27 南京明德新药研发股份有限公司 喹唑啉衍生物及其应用
US11034672B1 (en) 2018-09-25 2021-06-15 Black Diamond Therapeutics, Inc. Tyrosine kinase inhibitor compositions, methods of making and methods of use
WO2020253836A1 (zh) 2019-06-19 2020-12-24 南京明德新药研发有限公司 喹唑啉类化合物的晶型、盐型及其制备方法
WO2021083346A1 (zh) 2019-11-01 2021-05-06 正大天晴药业集团股份有限公司 包含喹唑啉衍生物或其盐的药物组合物
CN114787151A (zh) * 2019-11-01 2022-07-22 正大天晴药业集团股份有限公司 喹唑啉衍生物或其盐、或其药物组合物的用途
CN114787151B (zh) * 2019-11-01 2024-04-16 正大天晴药业集团股份有限公司 喹唑啉衍生物或其盐、或其药物组合物的用途

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US9725439B2 (en) 2017-08-08
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