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WO2019170086A1 - 一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用 - Google Patents

一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用 Download PDF

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WO2019170086A1
WO2019170086A1 PCT/CN2019/077026 CN2019077026W WO2019170086A1 WO 2019170086 A1 WO2019170086 A1 WO 2019170086A1 CN 2019077026 W CN2019077026 W CN 2019077026W WO 2019170086 A1 WO2019170086 A1 WO 2019170086A1
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compound
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Inventor
张强
于善楠
王中祥
冯守业
郑南桥
杨海龙
杨磊夫
张宏波
周利凯
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Beijing Scitech MQ Pharmaceuticals Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the invention belongs to the technical field of medicine and relates to an acyl substituted oxazinoquinazoline compound, a preparation method and application thereof.
  • Protein kinases are important signalling agents of cell life activities, catalyzing the transfer of ⁇ -phosphate groups at the ATP end to hydroxyl acceptors in substrate amino acid residues (serine, threonine, tyrosine) to activate targets Protein (Johnson LN, and Lewis RJ, (2001) Structural basis for control by phosphorylation. Cheminform. 101, 2209.). Protein kinases are involved in numerous physiological processes including cell proliferation, survival, apoptosis, metabolism, transcription, and differentiation (Adams J.A., (2001) Kinetic and catalytic mechanisms of protein kinases. Chemical reviews. 101, 2271.). Among the existing drug targets in the human body, members of the protein kinase family account for up to 10% (Santos R.,
  • the epidermal growth factor receptor (ErbB) tyrosine kinase regulates cell proliferation, migration, differentiation, apoptosis, and cell migration through a variety of pathways.
  • ErbB epidermal growth factor receptor
  • members of the ErbB family, as well as some of its ligands, are often overexpressed, amplified or mutated, making it an important therapeutic target.
  • the family of protein kinases include: ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4.
  • EGFR is an important target for the development of non-small cell lung cancer (Brumann R., et. al., (2001) Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer. ONCOTARGET. 2 (3), 165.).
  • Gefitinib, Erlotinib, and Icotinib are the first generation of reversible kinase inhibitors targeting EGFR for the treatment of non-small cell carcinoma. These inhibitors have both inhibitory effects on wild-type and activating mutant EGFR, and have achieved great clinical success, but the emergence of drug resistance in recipient patients after a period of use, especially resistance caused by T790M mutation Sexuality reduces or disables efficacy.
  • the second-generation EGFR inhibitor, Afatinib is a non-reversible inhibitor that contains a Michael receptor that is covalently bonded to a cysteine residue (Cys797) located at the entrance to the ATP-binding pocket.
  • the inhibitor showed strong activity against both T790M mutant EGFR kinase and wild-type EGFR kinase, and the inhibitory activity against T790M mutant EGFR kinase was higher than that of wild-type EGFR kinase, which made the therapeutic window narrower in clinical application of the drug.
  • the effect of use is not satisfactory (Camidge, DR, et. al. (2014) Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nature Reviews Clinical Oncology. 11, 473.).
  • the third-generation EGFR kinase inhibitors achieved high selective inhibition of T790M mutant EGFR kinase compared to wild-type EGFR kinase, which amplified the clinical window of use. Effective treatment of patients with T790M mutations has been achieved.
  • One of the reasons why the known three-generation EGFR kinase inhibitors are clinically resistant is that the wild-type EGFR kinase is amplified in vivo after a patient has been administered for a period of time due to its weak inhibitory activity against wild-type EGFR. (Chen L., et.al.
  • the present invention provides a compound of the formula (I), an isomer thereof, a hydrate, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof,
  • X is O or NH
  • L is a C 1 -C 4 straight chain alkyl, or each independently are R 4, R 5 substituted C 1 -C 4 straight chain alkyl;
  • R 4 and R 5 are each independently H or C 1 -C 3 alkyl
  • R 3 is -H, C 1 -C 6 alkyl which is unsubstituted or substituted by halogen, hydroxy, cyano, carboxy, C 1 -C 6 alkoxy, C 3 -C 7 cycloalkyl, aryl, a 4-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a fluorene structure;
  • the cyclo-ring structure is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaryl ring group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, an aromatic ring and a 5-6 membered cycloalkyl group, and an aromatic ring a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl ring and a 5-6 membered cycloalkyl group or a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic group;
  • heterocyclic group, heteroaryl ring group contains 1-3 hetero atoms selected from N, O or S;
  • the aryl, heteroaryl, heterocyclic or bicyclic ring structure is unsubstituted or independently separated by 1-3 selected from the group consisting of halogen, cyano, hydroxy, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 2 -C 3 alkynyl, C 2 -C 3 alkenyl, -NR'R" or -MR 6 Substituent substitution;
  • R ', R " are independently H or a C 1 -C 3 alkyl
  • M is -O(CH 2 ) q - or -C(O)-, wherein q is an integer from 1 to 4;
  • R 6 is -H, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or -NR 7 R 8 ;
  • R 7 and R 8 are each independently -H, C 1 -C 3 alkyl, or R 7 and R 8 are bonded to form a 4-7 membered heterocyclic ring;
  • L 1 is selected from:
  • T 1 is C 1 -C 8 straight chain alkyl group, or each independently are R 9, R 10 is substituted C 1 -C 8 straight chain alkyl group;
  • R 9 and R 10 are each independently -H or C 1 -C 3 alkyl
  • R 11 is -H, hydroxy, C 1 -C 3 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 3 alkoxy, C 1 -C 3 alkylthio, 4-7 membered heterocyclic Or -NR 12 R 13 ,
  • R 12 and R 13 are each independently -H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl substituted by hydroxy or C 1 -C 3 alkoxy Substituted C 1 -C 6 alkyl;
  • the 4-7 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, which are unsubstituted or C 1 -C 3 alkyl, aldehyde a group of a C 1 -C 4 alkyl acyl group, an amino acyl group, a mono or disubstituted C 1 -C 3 amino acyl group, a C 1 -C 3 alkyl sulfone group, a C 1 -C 3 alkyl sulfoxide group
  • the sulfur in the or two substituted or heterocyclic rings is oxidized by one or two oxygen atoms.
  • L is a C 1 -C 3 straight chain alkyl group, or each independently be R 4, R 5 substituted C 1 -C 3 linear alkyl;
  • R 4 and R 5 are each independently -H or C 1 -C 3 alkyl
  • R 3 is -H, C 1 -C 3 alkyl which is unsubstituted or substituted by halogen, hydroxy, cyano, carboxy, C 1 -C 3 alkoxy, C 3 -C 6 cycloalkyl, aryl, a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group, or a fluorene structure;
  • the cyclo-ring structure is selected from the group consisting of a benzo-5-6 heteroaryl ring group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, a benzo-5-6 cycloalkyl group, and a benzo-5-6 heterocyclic ring. a 5-6 membered heteroaryl ring and a 5-6 cycloalkyl group, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic group,
  • heterocyclic group, heteroaryl ring group contains 1-3 hetero atoms selected from N, O or S;
  • the aryl, heteroaryl, heterocyclic or bicyclic ring structure is unsubstituted or independently independently from one to three selected from the group consisting of halogen, cyano, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, halo C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 2 -C 3 alkynyl, C 2 -C 3 alkenyl, -NR'R" or -MR 6 Substituent substitution;
  • R' and R" are each independently H or a C 1 -C 3 alkyl group
  • M is -O(CH 2 ) q - or -C(O)-, wherein q is an integer from 1 to 3;
  • R 6 is H, hydroxy, C 1 -C 3 alkyl, C 1 -C 3 alkoxy, or -NR 7 R 8 ;
  • R 7 and R 8 are each independently H, C 1 -C 3 alkyl or R 7 and R 8 are bonded to form a 5-6 membered heterocyclic ring.
  • L is a C 1 -C 3 linear alkyl group, or a C 1 -C 2 linear alkyl group each independently substituted with R 4 , R 5 ;
  • R 4 and R 5 are each independently -H or methyl
  • R 3 is selected from the group consisting of: -H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, hydroxy, carboxy, 1-hydroxy-1-methylethyl, or the following groups:
  • R 14 is -H or C 1 -C 3 alkyl
  • Q 1 , Q 2 , Q 3 , Q 4 , and Q5 are each independently N or CH;
  • (R 15 ) p is p identical or different R 15 substituents, p is 0, 1, 2 or 3;
  • R 15 is selected from the group consisting of -H, -F, -Cl, -Br, -CF 3 , -OCF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, iso Propyloxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, hydroxy, cyano, -NR'R" or -MR 6 ;
  • R', R" are independently H, methyl, ethyl, propyl or isopropyl
  • M is -O(CH 2 ) q - or -C(O)-, wherein q is 1, 2 or 3;
  • R 6 is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or -NR 7 R 8 ;
  • R 7 and R 8 are independently H, methyl, ethyl, propyl, isopropyl, or R 7 and R 8 are bonded to form a 5-6 membered heterocyclic ring, and the 5-6 membered heterocyclic ring is preferably:
  • R 1 is
  • L is a C 1 -C 3 straight chain alkyl group, or each independently are R 4, R 5 substituted C 1 -C 3 linear alkyl;
  • R 4 and R 5 are each independently -H or methyl
  • R 3 is selected from the group consisting of: -H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, hydroxy, carboxy, 1-hydroxy-1-methylethyl, or the following groups:
  • R 14 is -H or C 1 -C 3 alkyl
  • (R 15 ) p is p identical or different R 15 substituents, p is 0, 1, 2 or 3;
  • R 15 is selected from the group consisting of -H, -F, -Cl, -Br, -CF 3 , -OCF 3 , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, iso Propyloxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, hydroxy, cyano, -NR'R" or -MR 6 ;
  • R', R" are independently H, methyl, ethyl, propyl or isopropyl
  • M is -O(CH 2 ) q - or -C(O)-, wherein q is 1, 2 or 3;
  • R 6 is H, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or -NR 7 R 8 ;
  • R 7 and R 8 are independently H, methyl, ethyl, propyl, isopropyl, or R 7 and R 8 are bonded to each other to form
  • L 1 is selected from:
  • T 1 is C 1 -C 6 linear alkyl group, or each independently are R 9, R 10 is substituted C 1 -C 6 straight chain alkyl;
  • R 9 and R 10 are each independently -H or methyl
  • R 11 is -H, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropyl Oxyl, methylthio, ethylthio, propylthio, isopropylthio, 5-6 membered heterocyclyl or -NR 12 R 13 ;
  • R 12 and R 13 are independently -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isobutyl, 1-ethylpropyl, cyclopropane Base, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, B Oxypropyl, ethoxybutyl, propoxyethyl, propoxypropyl, propoxybutyl, isopropoxyethyl, isopropoxypropyl or isopropoxybutyl;
  • the 5-6 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, and the 5-6 membered heterocyclic group is unsubstituted or methyl, B.
  • Base propyl, isopropyl, aldehyde, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylamino, dimethylamino, methylsulfonyl, ethylsulfonyl, isopropyl
  • One or two of the sulfone group, the methanesulfoxide group, the ethyl sulfoxide group, the isopropyl sulfoxide group or the sulfur in the hetero ring is oxidized by one or two oxygen atoms;
  • the 5-6 membered heterocyclic ring is selected from the group consisting of
  • L 1 is selected from:
  • T 1 is C 1 -C 6 linear alkyl group, or each independently are R 9, R 10 is substituted C 1 -C 6 straight chain alkyl;
  • R 9 and R 10 are each independently -H or methyl
  • R 11 is -H, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropyl Oxyl, methylthio, ethylthio, propylthio, isopropylthio, 5-6 membered heterocyclyl or -NR 12 R 13 ;
  • R 12 and R 13 are each independently H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isobutyl, 1-ethylpropyl, cyclopropyl. , cyclobutyl, cyclopentyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxy Propyl, isopropoxyethyl or isopropoxypropyl;
  • the 5-6 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, and the 5-6 membered heterocyclic group is unsubstituted or methyl, B.
  • Base propyl, isopropyl, aldehyde, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylamino, dimethylamino, methylsulfonyl, ethylsulfonyl, isopropyl
  • One or two of the sulfone group, the methanesulfoxide group, the ethyl sulfoxide group, the isopropyl sulfoxide group or the sulfur in the hetero ring is oxidized by one or two oxygen atoms;
  • the 5-6 membered heterocyclic group is selected from the group consisting of
  • R 16 is H, amino, methylamino, dimethylamino, methyl, ethyl, propyl, isopropyl.
  • the invention also relates to a method of treating a kinase-mediated disease or condition, such as EGFR, HER2, HER3, HER4, comprising administering to a patient in need thereof (human or other mammal, especially a human) a therapeutically effective amount of (I) A compound or a salt thereof, wherein the kinase-mediated diseases or conditions such as EGFR, HER2, HER3, HER4 include those mentioned above.
  • a kinase-mediated disease or condition such as EGFR, HER2, HER3, HER4
  • the invention also provides methods of preparing the corresponding compounds, which can be prepared using a variety of synthetic methods, including the methods described below, the compounds of the invention or pharmaceutically acceptable salts, isomers or hydrates thereof
  • the synthesis is carried out using the methods described below in the art of organic chemical synthesis, or by variations of those methods as understood by those skilled in the art, and the preferred methods include, but are not limited to, the methods described below.
  • the present invention exemplifies the synthetic route of the compound of the formula I by the following scheme, and the present invention mainly describes the following three preparation schemes:
  • the chlorinating agent includes, but is not limited to, a combination of phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride and chlorine, or a combination of two or more thereof.
  • Reaction step c) Reduction reaction of 5-(2-chloroethoxy)-6-nitroquinazolin-4(3H)-one of formula III to give 5-(2- represented by formula IV) Chloroethoxy)-6-aminoquinazolin-4(3H)-one.
  • the conditions for the reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, iron powder, zinc powder or stannous chloride.
  • the solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). , one of dioxane and dichloroethane, and a combination of two or more;
  • the reaction can be carried out under base-catalyzed conditions, including but not limited to triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.
  • base-catalyzed conditions including but not limited to triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the Carter condensing agent is selected from the group consisting of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yl-oxy hexafluorophosphate One or a combination of two of tripyrrolidinylphosphorus (PyBOP);
  • the above reaction can also be carried out under basic conditions, including but not limited to triethylamine, diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo10 One or a combination of two or more of carbon-7-ene (DBU), pyridine, N-methylmorpholine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate and cesium carbonate.
  • basic conditions including but not limited to triethylamine, diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo10
  • DBU carbon-7-ene
  • pyridine N-methylmorpholine
  • 4-dimethylaminopyridine sodium carbonate
  • potassium carbonate potassium carbonate
  • cesium carbonate cesium carbonate
  • the chlorinating agent is selected from one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride;
  • the above reaction can be carried out under basic conditions including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.
  • basic conditions including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the above reaction can be carried out in an organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA). a combination of N-methylpyrrolidone (NMP), dioxane and dichloroethane, and a combination of two or more;
  • organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA).
  • NMP N-methylpyrrolidone
  • dioxane and dichloroethane and a combination of two or more;
  • the compound represented by the formula IX is obtained by the step f-C1
  • the compound of the formula IX is further The reaction of step f-C2 takes place to give the compound of formula I.
  • the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a cerium salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably N, N'-carbonyl group.
  • this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) and N-methylmorpholine.
  • organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) and N-methylmorpholine.
  • step f-C2 can occur in an aprotic solvent, under the action of a base.
  • the aprotic solvent includes, but is not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). a combination of one or more of dioxane; the base includes, but is not limited to, one of sodium hydride, lithium bistrimethylsilylamine, and a combination of the two.
  • step fA), the step fB) and the fC) are a step of juxtaposition selection, that is, the compound of the formula VIII can be prepared by the compound of the formula fA), the step fB) and the fC), ie, the formula VIII.
  • the compound can be prepared by fA) to prepare a compound of the formula (I), or a compound of the formula VIII by the step fB) to prepare a compound of the formula (I) or by fC) to prepare a compound of the formula (I).
  • the compound represented by the formula VI is obtained by thorough contact.
  • R 1 is a substituent as described in claim 1.
  • the Carter condensing agent is selected from the group consisting of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yl-oxy hexafluorophosphate
  • BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • PyBOP tripyrrolidinylphosphine
  • the above reaction can also be carried out under basic conditions including but not limited to triethylamine, diisopropylethylamine, triethylene Diamine, 1,8-diazabicycloundec-7-ene (DBU), pyridine, N-methylmorpholine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, cesium carbonate Or a combination of two or more.
  • the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP) a combination of dioxane, dichloroethane, or a combination of two or more; preferably, the reaction can be carried out under base-catalyzed conditions, including but not limited to triethylamine, diisopropyl B A kind of amine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride Or a combination of two or more; preferably, the reaction can be carried out under acid-catalyzed conditions, including but not limited to one of methanesulfonic acid, p-toluenes
  • the chlorinating agent is preferably one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride;
  • the above reaction can be carried out under basic conditions including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.
  • basic conditions including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the above reaction can be carried out in an organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA). a combination of N-methylpyrrolidone (NMP), dioxane and dichloroethane, and a combination of two or more;
  • organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA).
  • NMP N-methylpyrrolidone
  • dioxane and dichloroethane and a combination of two or more;
  • the compound of the formula VIII is reacted with 2-(diethoxyphosphoryl)acetic acid under the action of a condensing agent, the compound of the formula IX is obtained by the step c-C1, and the compound of the formula IX is further Step c-C2 reaction occurs to give a compound of formula I;
  • the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a cerium salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably N, N'-carbonyl group.
  • this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine and 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.
  • organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine and 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.
  • step c-C2 can occur in an aprotic solvent, under the action of a base.
  • the aprotic solvent includes, but is not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). a combination of one or more of dioxane; the base includes, but is not limited to, one of sodium hydride, lithium bistrimethylsilylamine, and a combination of the two.
  • step cA), the steps cB) and cC) are a step of juxtaposition selection, that is, the compound of the formula VIII can be prepared by one of the compounds cA), cB) and cC), ie, the formula VIII
  • the compound can be prepared by preparing a compound of the formula (I) by cA), or a compound of the formula VIII, or a compound of the formula (I) by the step cB) or a compound of the formula (I).
  • the chlorinating agent includes, but is not limited to, phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, chlorine, or a combination of two or more.
  • the chlorinating agent is preferably one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride; preferably, the above reaction may be alkaline.
  • the base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, One or a combination of two or more of N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.
  • the above reaction can be carried out in an organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA). a combination of N-methylpyrrolidone (NMP), dioxane, dichloroethane, and a combination of two or more;
  • organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA).
  • NMP N-methylpyrrolidone
  • dioxane dioxane
  • dichloroethane dichloroethane
  • the compound of the formula VIII is reacted with 2-(diethoxyphosphoryl)acetic acid under the action of a condensing agent, the compound of the formula IX is obtained by the step c-C1, and the compound of the formula IX is further The reaction of step c-C2 takes place to give the compound of formula I.
  • the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a cerium salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably N, N'-carbonyl group.
  • this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.
  • organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.
  • step c-C2 can occur in an aprotic solvent, under the action of a base.
  • the aprotic solvent includes, but is not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). a combination of one or more of dioxane; the base includes, but is not limited to, one of sodium hydride, lithium bistrimethylsilylamine, and a combination of the two.
  • step cA), the steps cB) and cC) are a step of juxtaposition selection, that is, the compound of the formula VIII can be prepared by one of the compounds cA), cB) and cC), ie, the formula VIII
  • the compound can be prepared by preparing a compound of the formula (I) by cA), or a compound of the formula VIII, or a compound of the formula (I), or a compound of the formula (I), by the step cB).
  • substituted includes complex substituents (e.g., phenyl, aryl, heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3
  • substituents e.g., phenyl, aryl, heteroalkyl, heteroaryl
  • 1 to 5 substituents preferably 1 to 3
  • alkyl as used herein includes saturated monovalent hydrocarbon radicals having straight chain, branched or cyclic moieties.
  • alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl.
  • alkoxy group is an etherified ether consisting of a linear, branched or cyclic alkyl group as previously described.
  • alkenyl and alkynyl groups include straight chain, branched or cyclic alkenyl and alkynyl groups.
  • aryl refers to an unsubstituted or substituted aryl group, such as phenyl, naphthyl, anthracenyl.
  • aroyl refers to -C(O)-aryl.
  • heterocyclyl represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system selected from carbon atoms and from N, O, S.
  • the heterocyclic ring can be combined with any hetero atom or carbon atom to form a stable structure.
  • heterocyclic rings include, but are not limited to, azacyclohexane, pyrrolidinyl, piperidinyl, piperazinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, dioxolane Base, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morphinolinyl, thiomorphocyaninyl, thiamorphinoline sulfoxide, thiamorpholin sulfone and oxadiazolyl.
  • heteroaryl represents a stable 5 or 6 membered monocyclic aromatic ring system which is unsubstituted or substituted, and may also represent unsubstituted or substituted 9 or a 10-membered benzene-fused benzene heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of a carbon atom and one to four hetero atoms selected from N, O, and S, wherein the N, S hetero atom can be optionally oxidized. , N heteroatoms can also be quaternized at random.
  • the heteroaryl group can be attached to any hetero atom or carbon atom to form a stable structure.
  • heteroaryl groups include, but are not limited to, thioxyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl , pyridyl, pyridazinyl, fluorenyl, azaindole, carbazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, Benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenyl, quinolinyl or isoquinolyl.
  • carbonyl refers to a C(O) group.
  • alkyl or aryl or any of their prefix radicals appear in the name of a substituent (eg, aralkyl, dialkylamine), it will be considered to contain the above “alkane” Those limitations given by “base” and “aryl”.
  • base e.g., aralkyl, dialkylamine
  • aryl e.g., aralkyl, dialkylamine
  • the specified number of carbon atoms eg, C 1 -C 6
  • the compounds, isomers, crystalline forms or prodrugs of formula I, and pharmaceutically acceptable salts thereof may exist in both solvated and unsolvated forms.
  • the solvated form can be in a water soluble form.
  • the present invention includes all such solvated and unsolvated forms.
  • the compounds of the invention may have asymmetric carbon atoms which, depending on their physicochemical differences, may be separated by known techniques, such as by chromatography or fractional crystallization. Into a single diastereomer. Separation of the enantiomers can be carried out by first reacting the appropriate optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then separating the individual The enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including mixtures of diastereomers and pure enantiomers, are considered to be part of this invention.
  • the compound of the present invention as an active ingredient, and a method of preparing the same, are all contents of the present invention.
  • the crystalline form of some of the compounds may exist as polycrystals, and such forms may also be included in the current invention.
  • some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the invention.
  • the compounds of the invention may be used in the free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment.
  • pharmaceutically acceptable salt refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response, etc., and have reasonable Benefit/risk ratio.
  • Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art.
  • the salt can be formed by reacting a compound of the invention with a suitable free base or acid.
  • salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid,
  • inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, per-3-phenylpropionate, Phosphate, picrate, propionate
  • Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and the use of such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.
  • prodrug as used herein means that a compound can be converted into a compound of the formula (I) of the present invention in vivo. This transformation is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent compound in the blood or tissue.
  • the pharmaceutical composition of the present invention comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer drug, an antiviral agent, an antibiotic An additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.
  • a kinase inhibitor small molecule, polypeptide, antibody, etc.
  • an immunosuppressant an anticancer drug
  • an antiviral agent an antibiotic
  • an additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound an additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound.
  • the compounds of the invention may be used alone or in combination with one or more other compounds of the invention or with one or more other agents.
  • the therapeutic agents can be formulated for simultaneous administration or sequentially at different times, or the therapeutic agents can be administered as a single composition.
  • “combination therapy” is meant the use of a compound of the invention in combination with another agent in the form of co-administration of each agent or sequential administration of each agent, in either case, for the purpose Achieve the best results of the drug.
  • Co-administration includes simultaneous delivery of the dosage form, as well as separate dosage forms for each compound.
  • administration of the compounds of the invention can be used in conjunction with other therapies known in the art, for example, in the treatment of cancer using radiation therapy or cytostatic agents, cytotoxic agents, other anticancer agents, and the like to improve Cancer-like.
  • the invention is not limited to the order of administration; the compounds of the invention may be administered previously, simultaneously, or after other anticancer or cytotoxic agents.
  • one or more compounds or salts of the formula (I) as an active ingredient thereof can be intimately mixed with a pharmaceutical carrier, which is carried out according to a conventional pharmaceutical ingredient technique.
  • the carrier can be used in a wide variety of forms depending on the form of preparation which is designed for different modes of administration (for example, oral or parenteral administration).
  • Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the British Pharmaceutical Society.
  • the pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear solutions, suspensions, Emulsion; or for topical use such as creams, creams; or as a suppository for rectal administration.
  • the pharmaceutical ingredient may also be presented in unit dosage form for administration in a precise dosage.
  • the pharmaceutical ingredient will include a conventional pharmaceutical carrier or excipient and a compound as an active ingredient prepared according to the present invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.
  • Therapeutic compounds can also be administered to mammals other than humans.
  • the dosage of the drug to be administered to a mammal will depend on the species of the animal and its disease state or the disordered condition in which it is located.
  • the therapeutic compound can be administered to the animal in the form of a capsule, a bolus, or a pill.
  • the therapeutic compound can also be introduced into the animal by injection or infusion. We prepare these forms of the drug in a traditional manner consistent with veterinary practice standards.
  • the pharmaceutical synthetic drug can be mixed with the animal feed and fed to the animal, so that the concentrated feed additive or premix can be prepared by mixing ordinary animal feed.
  • the invention also encompasses the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of a tyrosine kinase EGFR, HER2, HER3, HER4 associated cancer and an autoimmune disease.
  • Said cancer including non-solid tumors, solid tumors, primary or metastatic cancers, as indicated elsewhere herein and including one or more other treatments in which the cancer is resistant or refractory
  • other diseases including but The agent is not limited to fundus diseases, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, and the like.
  • the cancer includes, but is not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Any of tumor, B cell and T cell lymphoma, lymphoma, multiple myeloma, cholangiocarcinoma, and cholangiocarcinoma.
  • the intermediate involved in the compound of the present invention can be produced by the following method, but is not limited to the following method.
  • the synthesis of a part of the intermediates of the present invention can be referred to the method of the patent CN104530063, a simple replacement of some functional groups, and the corresponding intermediates can be obtained by those skilled in the art according to the knowledge of the chemical synthesis field.
  • the following invention provides the preparation route of the intermediate, and the intermediate involved in the compound of the present invention can be produced by the following scheme, but is not limited to the following scheme.
  • N-(3-Bromophenyl)-5-(2-chloroethoxy)-6-nitroquinazolin-4-amine (3.7 g, 8.7 mmol) was added to a round bottom flask, and ethanol and water were added. Mixing solvent, then adding iron powder (1.3g, 22.7mmol), acetic acid (1.85mL, 32.27mmol), the reaction mixture is heated and stirred until the reaction is complete, the solvent is evaporated, ethyl acetate is extracted, concentrated, and purified by column chromatography. 2.0 g of solid, 65% yield.
  • Step 1) Step 1) of the synthetic route to VIII-1.
  • 3-bromoaniline was replaced by the same molar equivalent of 3-trifluoromethylaniline.
  • Step 1) Step 1) of the synthetic route to VIII-1.
  • Steps 1) to 4) are the same as steps 1) to 4) in the preparation method of VIII-3.
  • Steps 1) to 5) are the same as steps 1) to 5) of the preparation method of VIII-4.
  • Steps 1) to 4) are the same as steps 1) to 4) in the synthesis method of VIII-3.
  • Step 5) Refer to step 5) of the VIII-3 synthetic route, which operates exactly the same, using 2,3,4,9-tetrahydro-10H-[1,4]oxazine [2,3-f
  • the quinazolin-10-one (V) was used as a starting material, and the equivalent molar equivalents of R 1 XH in the following table were substituted for 4-methoxyaniline.
  • the specific implementation compounds are as follows:
  • Steps 1) to 5) are the same as the synthesis of compound VIII-4 from step 1) to step 5).
  • Step 6 With reference to the synthesis of the compound VIII-4, step 6), the operation is identical, and the method is carried out by 10-((1H-benzo[d][1,2,3]triazole-1-oxyl) -3,4-Dihydro-2H-[1,4]oxazino[2,3-f]quinazoline (VI) as starting material, replacing the same molar equivalent of R 1 XH in the table below P-fluoroaniline.
  • the specific implementation compounds are shown in the following table:
  • N-(3-bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1) (178 mg, 0.5 mmol) was dissolved in tetrahydrofuran, acryloyl chloride (45.3 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature until the reaction was completed. The solid was 164 mg in 80% yield.
  • Example 84 1-(10-((4-Hydroxybenzyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4- Preparation of propyl-2-en-1-one
  • Example 86 Refer to the preparation method of Example 86, which is carried out in the same molar equivalent of tert-butyl 3-((3,4-dihydro-2H-[1,4]oxazino[2,3-f] quinazole Phenyl-10-yl)aminopropionate (VIII-89) in place of tert-butyl (3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline-10- Glycine ester (VIII-86).
  • N-(3-(Trifluoromethyl)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII- 2) (173 mg, 0.5 mmol) was dissolved in a mixed solvent of tetrahydrofuran and dimethylformamide, and trans-4-dimethylamino crotonyl chloride hydrochloride (92 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature until the reaction was completed. After quenching with aqueous potassium carbonate solution, ethyl acetate was evaporated.
  • N-(3-Chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-4) (165mg, 0.5mmol), dissolved in a mixed solvent of dichloromethane and dimethylformamide, added 4-bromocrotonyl chloride (91mg, 0.5mmol), stirred at room temperature until the reaction is complete, quenched with water, acetic acid The organic phase was concentrated and dissolved in acetonitrile.
  • Example 107-122 Reference is made to the preparation of Example 106, which operates in exactly the same manner, in which N-(3-) is replaced by the same molar equivalent of the intermediate of the formula VIII wherein R 1 X is a substituent in the following table.
  • VIII-4 Chloro-4-fluorophenyl-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine
  • N-(3-chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-4) (165 mg, 0.5 mmol), 2-(diethoxyphosphoryl)acetic acid (0.5 mmol) was dissolved in tetrahydrofuran, and N,N'-carbonyldiimidazole (81 mg, 0.5 mmol) was added and stirred at room temperature until complete. Water and ethyl acetate were extracted, and the organic layer was concentrated. MS: 509 [M+H] + .
  • Step 2) (S,E)-1-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3 -f]Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one
  • Step 2) (E)-1-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f Preparation of quinazolin-4-yl)-9-methoxyindole-2-en-1-one
  • Reference Example 123, step 2) operates identically, in a manner equivalent to replacing (S)-1-methylpyrrolidinyl-2-carboxaldehyde with an equivalent molar equivalent of 7-methoxyheptanal.
  • Step 2) (S,E)-1-(10-((3-ethynylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-)prop-2-en-1-one
  • Step 1) diethyl(2-(10-((4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3-f]quinazoline Preparation of 4-yl)-2-oxoethyl)phosphonate
  • Step 2) (S,E)-1-(10-((4-fluorophenyl(amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one
  • Step 2) (S,E)-3-(1-Methylpyrrolidin-2-yl)-1-(10-(phenylamino)-2,3-dihydro-4H-[1,4] Preparation of oxazolo[2,3-f]quinazolin-4-yl)prop-2-en-1-one
  • Example 148 Prepared in a similar manner to Step 2) of Example 148, except that in an equivalent molar equivalent of diethyl (2-oxo-2-(10-(phenylamino)-2,3-dihydro- 4H-[1,4]oxazine [2,3-f]quinazolin-4-yl)ethyl)phosphonate in place of diethyl(2-(10-(4-fluorophenyl)amino) -2,3-Dihydro-4H-[1,4]oxazine [2,3-f]quinazolin-4-yl)-2-oxoethyl)phosphonate.
  • Example 150 (E)-1-(10-((3-chloro-2-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3- Preparation of f]quinazolin-4-yl)-4-(cyclopropyl(methyl)amino)but-2-en-1-one
  • N-(3-chloro-2-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine 165 mg, 0.5 Methyl acetate, dissolved in dimethylformamide, added 4-bromocrotonyl chloride (91 mg, 0.5 mmol), stirred at room temperature until the reaction was completed, quenched with water, extracted with ethyl acetate.
  • Example 151 (E)-1-(10-((3-chloro-2-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3- Preparation of f]quinazolin-4-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one
  • 96-well plate a the compound was diluted 3 times with DMSO solution to form 11 gradients, and the 12th gradient was a pure DMSO solution (as a positive control); a new 96-well plate b was taken and the solution was used. Ultrapure water was diluted 25 times (DMSO concentration was 4%).
  • the compound solution diluted with ultrapure water in the above 96-well plate b was placed in a corresponding well of a 384-well plate according to a standard well of 2 duplicate wells.
  • Add 2 ⁇ substrate/ATP mixture Take 5 ⁇ l of the above 2 ⁇ substrate/ATP mixture into the corresponding reaction well of a 384-well plate with a lance.
  • Negative control wells were placed in 384-well plates, 2.5 ⁇ l of 4 ⁇ substrate, 2.5 ⁇ l of 4 ⁇ enzyme solution, 2.5 ⁇ l of 1 ⁇ Kinase Assay Buffer and 2.5 ⁇ l of ultrapure water containing 4% DMSO were added to each well. .
  • Inhibition rate (positive control well reading - experimental well reading value) / (positive control well reading - negative control well reading) * 100%
  • the final concentration of EGFR kinase was 0.35 nM in the reaction system, the final concentration of ATP was 150 ⁇ M, the final concentration of substrate ULight TM -labeled JAK-1 (Tyr1023) Peptide was 100 nM, and the enzymatic reaction time was 2 hours.
  • the maximum final concentration of the compound in the reaction system was 2.5 ⁇ M, and a total of 11 concentrations were diluted by a 3-fold gradient, and the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO was 1%.
  • the final concentration of EGFR (T790M) kinase was 0.05 nM in the reaction system, the final concentration of ATP was 5 ⁇ M, the final concentration of substrate ULight TM -labeled PolyGT was 100 nM, and the enzymatic reaction time was 2 hours.
  • the maximum final concentration of the compound in the reaction system was 2.5 ⁇ M, and a total of 11 concentrations were diluted by a 3-fold gradient, and the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO was 1%.
  • HER2 kinase reaction system in a final concentration of 10nM, ATP final concentration 10 ⁇ M, (TM) -labeled substrate PolyGT final concentration ULight is 100nM, enzymatic reaction time was 2 hours.
  • the maximum final concentration of the compound in the reaction system was 2.5 ⁇ M, and a total of 11 concentrations were diluted by a 3-fold gradient, and the lowest final concentration was 0.042 nM.
  • the final concentration of DMSO was 1%.
  • Table (1) lists the results of the determination of tyrosine kinase inhibitory activity by some of the compounds in this patent, wherein A represents an IC 50 of less than or equal to 50 nM, B represents an IC 50 of greater than 50 nM but less than or equal to 500 nM, and C represents an IC 50 greater than 500 nM but less than or equal to 5000 nM, D indicates an IC 50 greater than 5000 nM, and NT indicates that no corresponding kinase was tested.
  • test for inhibition of cell proliferation by small molecule compounds is as follows:
  • the BT474 and HCC827 cell lines were inoculated in 96-well plates at a cell density of 10,000 and 3000/well/80 ⁇ L, respectively.
  • the 96-well plates were not filled with sterile water in the outer circumference of 36 wells, only 60 wells were used. In cell experiments and controls;
  • Table (2) lists the results of assays for the activity of representative compounds of the present invention against HCC827 and BT474 cancer cells.
  • A represents an IC 50 of less than or equal to 50 nM
  • B represents an IC 50 of greater than 50 nM but less than or equal to 500 nM
  • C represents an IC 50 of greater than 500 nM but less than or equal to 5000 nM
  • D represents an IC 50 of greater than 5000 nM
  • NT indicates that no corresponding cells have been tested.

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Abstract

一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用，具体涉及式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其制备方法及其在制备作为激酶抑制剂的药物中的应用。化合物对突变型EGFR激酶具有良好的抑制活性，同时展示出对野生型EGFR激酶也具有适度的抑制活性。

Description

一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用 技术领域
本发明属于医药技术领域，涉及一种酰基取代的噁嗪并喹唑啉类化合物、制备方法及其应用。
背景技术
蛋白激酶是细胞生命活动重要的信号使者，可催化将ATP末端的γ-磷酸基团转移至底物氨基酸残基(丝氨酸、苏氨酸、酪氨酸)中的羟基受体上，从而激活目标蛋白(Johnson L.N.,and Lewis R.J.,(2001)Structural basis for control by phosphorylation.Cheminform.101,2209.)。蛋白激酶参与了众多的生理过程，包括细胞增殖、存活、凋亡、代谢、转录以及分化等(Adams J.A.,(2001)Kinetic and catalytic mechanisms of protein kinases.Chemical reviews.101,2271.)。在人体现有药物靶点中，蛋白激酶家族成员占比高达10％(Santos R.,
Ursu O.,Gaulton A.,et al.(2017)Acomprehensive map of molecular drug targets.Nature Reviews Drug Discovery.16,19.)。
表皮生长因子受体(ErbB)酪氨酸激酶可通过多种途径调节细胞增殖、迁移、分化、凋亡以及细胞移动。在多种形式的恶性肿瘤中，ErbB家族成员以及其部分配体通常过表达、扩增或突变，这使其成为重要的治疗靶标。该家族蛋白激酶包括：ErbB1/EGFR/HER1、ErbB2/HER2、ErbB3/HER3和ErbB4/HER4。其中EGFR是开发非小细胞肺癌的重要靶点(Dienstmann R.,et.al.,(2001)Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer.ONCOTARGET.2(3),165.)。
Figure PCTCN2019077026-appb-000001
吉非替尼(Gefitinib)、埃罗替尼(Erlotinib)、埃克替尼(Icotinib)是第一代靶向EGFR的可逆型激酶抑制剂，用于治疗非小细胞癌。该类抑制剂同时对野生型和激活突变型EGFR具有抑制作用，且在临床上取得了较大的成功，但是受体患者服用一段时间后耐药性的出现，尤其是T790M突变导致的耐药性使疗效降低或失效。第二代EGFR抑制剂阿法替尼(Afatinib)为非可逆型抑制剂，其含有迈克尔受体，可与位于ATP结合口袋入口处的半胱氨酸残基(Cys797)发生共价键结合，该抑制剂针对T790M突变型EGFR激酶和野生型EGFR激酶均表现出极强的活性，且对于T790M突变型EGFR激酶的抑制活性高于野生型EGFR激酶，这使得该药物临床应用中治疗窗口较窄，使用效果并不理想(Camidge,D.R.,et.al.(2014)Acquired resistance to TKIs in solid tumours:learning from lung cancer.Nature Reviews Clinical Oncology.11,473.)。第三代的EGFR激酶抑制剂奥希替尼(Osimertinib)和奥莫替尼(Olmutinib)实现了对T790M突变型EGFR激酶相比野生型EGFR激酶的高选择性抑制，拉大了临床使用窗口，实现了对T790M突变病人的有效治疗。已知的三代EGFR激酶抑制剂在临床上产生耐药性的原因之一，是由于其对野生型EGFR抑制活性过于微弱而导致的病人服药一段时间后，体内产生的野生型EGFR激酶的扩增(Chen L.,et.al.(2017)Recent Progress of Small-Molecule Epidermal Growth Factor Receptor(EGFR)Inhibitors against C797S Resistance in Non-Small-Cell Lung Cancer.Journal of Medicinal Chemistry.DOI:10.1021/acs.jmedchem.7b01310)。基于此，开发具有对T790M突变型EGFR激酶良好的抑制活性，同时展示出对野生型EGFR激酶适度的抑制活性的新型活性分子具有重要意义。
发明内容
本发明提供一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，
Figure PCTCN2019077026-appb-000002
式(I)中，
X为O或NH；
R 1为
Figure PCTCN2019077026-appb-000003
L为C 1-C 4直链烷基，或分别独立地被R 4、R 5取代的C 1-C 4直链烷基；
R 4和R 5分别独立的为H或C 1-C 3烷基；
R 3为-H，未被取代或被卤素、羟基、氰基、羧基取代的C 1-C 6烷基，C 1-C 6烷氧基，C 3-C 7环烷基，芳基，4-7元杂环基，5-6元杂芳基，或者并环结构；
所述并环结构选自芳环并5-6元杂芳环基，5-6元杂芳环并5-6元杂芳环基，芳环并5-6元环烷基，芳环并5-6元杂环基，5-6元杂芳环并5-6元环烷基或5-6元杂芳环并5-6元杂环基；
所述杂环基、杂芳环基含1-3个选自N、O或S的杂原子；
所述的芳基、杂芳基、杂环基或并环结构为非取代或分别独立的被1-3个选自卤素、氰基、羟基、C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、C 3-C 6环烷基、C 2-C 3炔基、C 2-C 3烯基、-NR'R”或-MR 6的取代基取代；
R'、R”分别独立的为H或C 1-C 3的烷基；
M为-O(CH 2) q-或-C(O)-，其中q为1-4的整数；
R 6为-H，羟基，C 1-C 3烷基，C 1-C 3烷氧基，或-NR 7R 8；
R 7和R 8分别独立的为-H，C 1-C 3烷基，或者R 7、R 8相连接形成4-7元杂环；
R 2为
Figure PCTCN2019077026-appb-000004
L 1选自：
Figure PCTCN2019077026-appb-000005
T 1为C 1-C 8直链烷基，或分别独立地被R 9、R 10取代的C 1-C 8直链烷基；
R 9和R 10分别独立的为-H或C 1-C 3烷基；
R 11为-H，羟基，C 1-C 3烷基，C 3-C 7环烷基，C 1-C 3烷氧基，C 1-C 3烷硫基，4-7元杂环基或-NR 12R 13，
R 12和R 13分别独立的为-H，C 1-C 6烷基，C 3-C 6环烷基，被羟基取代的C 1-C 6烷基或被C 1-C 3烷氧基取代的C 1-C 6烷基；
所述的4-7元杂环基为含有1-2个选自N、O或S的杂原子的杂环基，所述杂环基未被取代或被C 1-C 3烷基、醛基、C 1-C 4烷基酰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基中的一种或两种取代或杂环中的硫被一至二个氧原子氧化。
在一个优选的实施方案中，
R 1为
Figure PCTCN2019077026-appb-000006
L为C 1-C 3直链烷基，或分别独立地被R 4、R 5取代的C 1-C 3直链烷基；
R 4和R 5分别独立的为-H或C 1-C 3烷基；
R 3为-H，未被取代或被卤素、羟基、氰基、羧基取代的C 1-C 3烷基，C 1-C 3烷氧基，C 3-C 6环烷基，芳基，5-6元杂环基，5-6元杂芳基，或者并环结构；
所述并环结构选自苯并5-6杂芳环基，5-6元杂芳环并5-6元杂芳环基，苯并5-6环烷基，苯并5-6杂环基，5-6元杂芳环并5-6环烷基，5-6元杂芳环并5-6元杂环基，
所述杂环基、杂芳环基含1-3个选自N、O或S的杂原子；
所述的芳基、杂芳基、杂环基或并环结构为非取代或分别独立地被1-3个选自卤素、氰基、羟基、C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷基、C 3-C 4环烷基、C 2-C 3炔基、C 2-C 3 烯基、-NR'R”或-MR 6的取代基取代；
R'和R”分别独立的为H或C 1-C 3的烷基；
M为-O(CH 2) q-或-C(O)-，其中q为1-3的整数；
R 6为H，羟基，C 1-C 3烷基，C 1-C 3烷氧基，或-NR 7R 8；
R 7、R 8分别独立的为H，C 1-C 3烷基或者R 7、R 8相连接形成5-6元杂环。
在另一个优选的实施方案中，
R 1为
Figure PCTCN2019077026-appb-000007
L为C 1-C 3直链烷基，或分别独立地被R 4、R 5取代的C 1-C 2直链烷基；
R 4和R 5分别独立的为-H或甲基；
R 3选自：-H，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，环丙基，环丁基，环戊基，环己基，羟基，羧基，1-羟基-1-甲基乙基，或以下基团：
Figure PCTCN2019077026-appb-000008
R 14为-H或C 1-C 3烷基；
Q 1、Q 2、Q 3、Q 4、Q5分别独立的为N或CH；
(R 15) p为p个相同或不同的R 15取代基，p为0，1，2或3；
R 15选自-H，-F，-Cl，-Br，-CF 3，-OCF 3，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，乙炔基，乙烯基，环丙基，环丁基，羟基，氰基，-NR'R”或-MR 6；
R'、R”分别独立的为H，甲基，乙基，丙基或异丙基；
M为-O(CH 2) q-或-C(O)-，其中q为1，2或3；
R 6为H，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，或-NR 7R 8；
R 7、R 8独立的为H、甲基，乙基，丙基，异丙基，或R 7、R 8相连接形成5-6元杂环，所述的5-6元杂环优选：
Figure PCTCN2019077026-appb-000009
在一些优选的实施方案中，R 1为
Figure PCTCN2019077026-appb-000010
L为C 1-C 3直链烷基，或分别独立地被R 4、R 5取代的C 1-C 3直链烷基；
R 4和R 5分别独立的为-H或甲基；
R 3选自：-H，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，环丙基，环丁基，环戊基，环己基，羟基，羧基，1-羟基-1-甲基乙基，或以下基团：
Figure PCTCN2019077026-appb-000011
R 14为–H或C 1-C 3烷基；
(R 15) p为p个相同或不同的R 15取代基，p为0，1，2或3；
R 15选自-H，-F，-Cl，-Br，-CF 3，-OCF 3，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，乙炔基，乙烯基，环丙基，环丁基，羟基，氰基，-NR'R”或-MR 6；
R'、R”分别独立的为H，甲基，乙基，丙基或异丙基；
M为-O(CH 2) q-或-C(O)-，其中q为1，2或3；
R 6为H，羟基，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，或-NR 7R 8；
R 7、R 8独立的为H、甲基、乙基、丙基、异丙基，或R 7、R 8相连接形成
Figure PCTCN2019077026-appb-000012
优选地，
R 2为
Figure PCTCN2019077026-appb-000013
L 1选自：
Figure PCTCN2019077026-appb-000014
T 1为C 1-C 6直链烷基，或分别独立地被R 9、R 10取代的C 1-C 6直链烷基；
R 9和R 10分别独立的为–H或甲基；
R 11为-H，羟基，甲基，乙基，丙基，异丙基，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，甲硫基，乙硫基，丙硫基，异丙硫基，5-6元杂环基或-NR 12R 13；
R 12和R 13分别独立的为-H，甲基，乙基，丙基，丁基，戊基，己基，异丙基，仲丁基，异丁基，1-乙基丙基，环丙基，环丁基，环戊基，环己基，羟乙基，羟丙基，羟丁基，甲氧基乙基，甲氧基丙基，甲氧基丁基，乙氧基乙基，乙氧基丙基，乙氧基丁基，丙氧基乙基，丙氧基丙基，丙氧基丁基，异丙氧基乙基，异丙氧基丙基或异丙氧基丁基；
所述的5-6元杂环基为含有1-2个选自N、O或S的杂原子的杂环基，所述的5-6元杂环基未被取代或被甲基，乙基，丙基，异丙基，醛基，甲酰基，乙酰基，丙酰基，丁酰基，异丁酰基，氨基酰基，甲氨基酰基，二甲氨基酰基，甲砜基，乙砜基，异丙砜基，甲亚砜基，乙亚砜基，异丙亚砜基中的一种或两种取代或杂环中的硫被一至二个氧原子氧化；
所述的5-6元杂环选自：
Figure PCTCN2019077026-appb-000015
优选地，
R 2为
Figure PCTCN2019077026-appb-000016
L 1选自：
Figure PCTCN2019077026-appb-000017
T 1为C 1-C 6直链烷基，或分别独立地被R 9、R 10取代的C 1-C 6直链烷基；
R 9和R 10分别独立的为–H或甲基；
R 11为-H，羟基，甲基，乙基，丙基，异丙基，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，甲硫基，乙硫基，丙硫基，异丙硫基，5-6元杂环基或-NR 12R 13；
R 12和R 13分别独立的为H，甲基，乙基，丙基，丁基，戊基，己基，异丙基，仲丁基，异丁基，1-乙基丙基，环丙基，环丁基，环戊基，羟乙基，羟丙基，甲氧基乙基，甲氧基丙基，乙氧基乙基，乙氧基丙基，丙氧基乙基，丙氧基丙基，异丙氧基乙基或异丙氧基丙基；
所述的5-6元杂环基为含有1-2个选自N、O或S的杂原子的杂环基，所述的5-6元杂环基未被取代或被甲基，乙基，丙基，异丙基，醛基，甲酰基，乙酰基，丙酰基，丁酰基，异丁酰基，氨基酰基，甲氨基酰基，二甲氨基酰基，甲砜基，乙砜基，异丙砜基，甲亚砜基，乙亚砜基，异丙亚砜基中的一种或两种取代或杂环中的硫被一至二个氧原子氧化；
所述的5-6元杂环基选自：
Figure PCTCN2019077026-appb-000018
R 16为H，氨基，甲氨基，二甲氨基，甲基，乙基，丙基，异丙基。
本发明还涉及一种治疗EGFR、HER2、HER3、HER4等激酶介导的疾病或病症的方法，其包括对有需要的患者(人或其他哺乳动物，尤其是人)给药治疗有效量的式(I)化合物或其盐，所述EGFR、HER2、HER3、HER4等激酶介导的疾病或病症包括前述提及的那些。
本发明还提供了制备相应化合物的方法，可以使用多种合成方法制备本文所述的化合物，包括下述的方法，本发明的化合物或者其药学上可接受的盐，异构体或水合物可以使用下述方法与有机化学合成领域已知的合成方法，或通过本领域技术人员理解对这些方法的变化方法合成，优选方法包括但不限于下述方法。
本发明以以下方案为例阐述式I化合物的合成路线，本发明主要阐述以下三种制备方案：
式I所示化合物的制备路线一：其中，R 1、R 2、R 8、R 9、R 10、R 11、R 12、R 13、L 1、X 和T 1如前文所定义。
Figure PCTCN2019077026-appb-000019
反应步骤a)：将5-氯-6-硝基喹唑啉-4(3H)-酮与乙二醇加氢化钠充分接触获得式II表示的化合物5-(2-羟基乙氧基)-6-硝基喹唑啉-4(3H)-酮。
反应步骤b)：将式II所表示的5-(2-羟基乙氧基)-6-硝基喹唑啉-4(3H)-酮与氯化试剂充分接触后加入水获得式III所示的5-(2-氯乙氧基)-6-硝基喹唑啉-4(3H)-酮，
所述的氯化试剂包含但不限于三氯氧磷，氯化亚砜，三氯化磷，五氯化磷和氯气之一或者两者以上的联用。
反应步骤c)：将式III所示的5-(2-氯乙氧基)-6-硝基喹唑啉-4(3H)-酮进行还原反应得到式IV所示的5-(2-氯乙氧基)-6-氨基喹唑啉-4(3H)-酮。
还原反应的条件包含但不限于氢气与雷尼镍，氢气与钯碳，铁粉，锌粉或氯化亚锡。
反应步骤d)：将式IV所示的5-(2-氯乙氧基)-6-氨基喹唑啉-4(3H)-酮溶于溶剂中，加热获得式V所示的2,3,4,9-四氢-10H-[1,4]噁嗪并[2,3-f]喹唑啉-10-酮；
所述的溶剂选自甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环和二氯乙烷之一及两者以上的组合；
优选地，该反应可在碱催化条件下进行，所述的碱包含但不限于三乙胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯、N-甲基吗啉、碳酸钠、碳酸钾和碳酸铯的一种或两种以上的组合。
反应步骤e)：将式V所示的2,3,4,9-四氢-10H-[1,4]噁嗪[2,3-f]喹唑啉-10-酮，R 1XH与卡特缩合剂充分接触获得式VII所示的噁嗪并喹唑啉类化合物；
优选地，卡特缩合剂选自苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)或者六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)的其中一个或者两者的组合；
优选地，上述反应也可以在碱性条件下进行，所述的碱包含但不限于三乙胺，二异丙基乙基胺，三乙稀二胺，1,8-二氮杂二环十一碳-7-烯(DBU)，吡啶，N-甲基吗啉，4-二甲氨基吡啶，碳酸钠，碳酸钾和碳酸铯的一种或者两种以上的联用。
反应步骤f-A)：将式VIII所示的化合物与R 2C(O)Cl发生缩合反应，或R 2COOH与氯化试剂反应后再与式VIII所示的化合物发生缩合反应得到式I所示化合物；
所述的氯化试剂选自三氯氧磷、氯化亚砜、草酰氯、三氯化磷和五氯化磷其中的一种或者两种以上的组合；
优选地，上述反应可以在碱性条件下进行，所述的碱包括但不限于三乙胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯、N-甲基吗啉、碳酸钠、碳酸钾和碳酸铯的一种或两种以上的组合。
反应步骤f-B)：或者，当R 2为
Figure PCTCN2019077026-appb-000020
且R 11为HNR 12R 13，L 1为
Figure PCTCN2019077026-appb-000021
时，由式VIII化合物与
Figure PCTCN2019077026-appb-000022
反应后加入连有R 12和R 13取代基的胺
Figure PCTCN2019077026-appb-000023
反应制备式I化合物；
优选地，上述反应可在有机溶剂中进行，所述的有机溶剂包含但不限于四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环和二氯乙烷之一及两者以上的组合；
反应步骤f-C)：或者，当R 2为
Figure PCTCN2019077026-appb-000024
且L 1为
Figure PCTCN2019077026-appb-000025
时，由式VIII化合物与2-(二乙氧基磷酰基)乙酸在缩合剂作用下进行步骤f-C1反应得到式IX所示化合物，式IX化合物进一步与
Figure PCTCN2019077026-appb-000026
发生步骤f-C2反应得到式I化合物。
Figure PCTCN2019077026-appb-000027
优选地，所述缩合剂包括但不限于碳二亚胺型缩合剂，鎓盐类缩合剂，有机磷类缩合剂及其他类别缩合剂的一种或两种以上，优选N,N'-羰基二咪唑(CDI)，N,N-二环己基碳二亚胺(DCC)，N,N-二异丙基碳二亚胺(DIC)，羟基苯并三唑(HOBt)，N,N-二异丙基乙胺(DIEA)，1-羟基-7-偶氮苯并三氮唑(HOAt)，O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)，苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)，丙基磷酸酐(T3P)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，1-乙基(3-二甲基氨基丙基)碳二亚胺(EDC)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷鏻(PyBOP)，(3H-1,2,3三唑并[4,5-b]吡啶-3-氧基)三-1-吡咯烷基鏻六氟磷酸盐(PyAOP)中一种或两种以上的组合；
优选地，此步骤可在有机碱中进行，所述的有机碱包含但不限于三乙胺、二异丙基乙基胺(DIEA)，吡啶，4-二甲氨基吡啶(DMAP)，2,6-二甲基吡啶(Lutidine)，1,8-二氮杂二环十一碳-7-烯(DBU)和N-甲基吗啉一种或两种以上的组合。
优选地，步骤f-C2可在非质子性溶剂中，碱的作用下发生。所述的非质子性溶剂包含但不限于四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环之一及两者以上的组合；所述的碱包含但不限于氢化钠、双三甲基硅基胺基锂之一及两者的组合。
上述步骤f-A)、步骤f-B)和f-C)之间为并列选择的步骤，即式VIII所示化合物可通过f-A)、步骤f-B)和f-C)其中之一制备式所示化合物，即式VIII所示化合物可通过f-A)制备 式(I)所示化合物，或式VIII所示化合物通过步骤f-B)制备式(I)所示化合物，或者通过f-C)制备式(I)所示化合物。
式I所示化合物的制备路线二：其中，R 1、R 2、R 8、R 9、R 10、R 11、R 12、R 13、L 1、X和T 1如前文所定义。
Figure PCTCN2019077026-appb-000028
反应步骤a)：将式V所示的2,3,4,9-四氢-10H-[1,4]噁嗪[2,3-f]喹唑啉-10-酮，与卡特缩合剂充分接触获得式VI所示的化合物。其中R 1为权利要求1中所述的取代基。优选地，卡特缩合剂选自苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)或者六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷(PyBOP)的其中一个或者两者的组合；上述反应也可以在碱性条件下进行，所述的碱包含但不限于三乙胺，二异丙基乙基胺，三乙烯二胺，1,8-二氮杂二环十一碳-7-烯(DBU)，吡啶，N-甲基吗啉，4-二甲氨基吡啶，碳酸钠，碳酸钾，碳酸铯的一种或者两种以上的联用。
反应步骤b)：将式VI所示的10-((1H-苯并[d][1,2,3]三氮唑-1-基)氧)-3,4-二氢-2H-[1,4]噁嗪[2,3-f]喹唑啉与R 1XH在有机溶剂中充分接触得式VIII所示化合物。优选地，有机溶剂选自甲醇、乙醇、异丙醇、四氢呋喃、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环、二氯乙烷之一及两者以上的组合；优选地，该反应可在碱催化条件下进行，所述的碱包含但不限于三乙胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯、N-甲基吗啉、碳酸钠、碳酸钾、碳酸铯、氢化钠的一种或两种以上的组合；优选地，该反应可在酸催化条件下进行，所述的酸包含但不限于 甲磺酸、对甲苯磺酸、苯磺酸、三氟乙酸、盐酸中的一种或者两种以上的组合。
反应步骤c-A)：将式VIII所示的化合物与R 2C(O)Cl或R 2COOH与氯化试剂反应后发生缩合反应得到式I所示化合物；
所述的氯化试剂优选于三氯氧磷、氯化亚砜、草酰氯、三氯化磷和五氯化磷其中的一种或者两种以上的组合；
优选地，上述反应可以在碱性条件下进行，所述的碱包括但不限于三乙胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯、N-甲基吗啉、碳酸钠、碳酸钾、碳酸铯的一种或两种以上的组合。
反应步骤c-B)：或者，当R 2为
Figure PCTCN2019077026-appb-000029
且R 11为HNR 12R 13，L为乙烯基时，由式VIII化合物与
Figure PCTCN2019077026-appb-000030
反应后加入连有R 12和R 13取代基的胺
Figure PCTCN2019077026-appb-000031
反应制备式I化合物；
优选地，上述反应可在有机溶剂中进行，所述的有机溶剂包含但不限于四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环和二氯乙烷之一及两者以上的组合；
反应步骤c-C)：或者，当R 2为
Figure PCTCN2019077026-appb-000032
且L 1为
Figure PCTCN2019077026-appb-000033
时，由式VIII化合物与2-(二乙氧基磷酰基)乙酸在缩合剂作用下进行步骤c-C1反应得到式IX所示化合物，式IX化合物进一步与
Figure PCTCN2019077026-appb-000034
发生步骤c-C2反应得到式I化合物；
优选地，所述缩合剂包括但不限于碳二亚胺型缩合剂，鎓盐类缩合剂，有机磷类缩合剂及其他类别缩合剂的一种或两种以上，优选N,N'-羰基二咪唑(CDI)，N,N-二环己基碳二亚胺(DCC)，N,N-二异丙基碳二亚胺(DIC)，羟基苯并三唑(HOBt)，N,N-二异丙基乙胺(DIEA)，1-羟基-7-偶氮苯并三氮唑(HOAt)，O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)，苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)，丙基磷酸酐(T3P)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，1-乙基(3-二甲基氨基丙基)碳二亚胺(EDC)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷鏻(PyBOP)，(3H-1,2,3三唑并[4,5-b]吡啶-3-氧基)三-1-吡咯烷基鏻六氟磷酸盐(PyAOP)中一种或两种以上的组合；
优选地，此步骤可在有机碱中进行，所述的有机碱包含但不限于三乙胺、二异丙基乙基胺(DIEA)，吡啶，4-二甲氨基吡啶(DMAP)，2,6-二甲基吡啶(Lutidine)和1,8-二氮杂二环十一碳-7-烯(DBU)或N-甲基吗啉一种或两种以上的组合。
优选地，步骤c-C2可在非质子性溶剂中，碱的作用下发生。所述的非质子性溶剂包含 但不限于四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环之一及两者以上的组合；所述的碱包含但不限于氢化钠、双三甲基硅基胺基锂之一及两者的组合。
上述步骤c-A)、步骤c-B)和c-C)之间为并列选择的步骤，即式VIII所示化合物可通过c-A)、步骤c-B)和c-C)其中之一制备式所示化合物，即式VIII所示化合物可通过c-A)制备式(I)所示化合物，或式VIII所示化合物通过步骤c-B)制备式(I)所示化合物，或者通过c-C)制备式(I)所示化合物。
目标化合物的制备路线三，其中，R 1、R 2、R 8、R 9、R 10、R 11、R 12、R 13、L 1、X和T 1如前文所定义。
Figure PCTCN2019077026-appb-000035
反应步骤a)：将式II表示的化合物5-(2-羟基乙氧基)-6-硝基喹唑啉-4(3H)-酮与氯化试剂反应后再与R 1XH接触获得式VII所示的喹唑啉类化合物。氯化试剂包含但不限于三氯氧磷，氯化亚砜，三氯化磷，五氯化磷，氯气之一或者两者以上的联用。
反应步骤b)：将式VII所示的喹唑啉类化合物在还原条件下得式VIII所示的噁嗪并喹唑啉类化合物，所述的还原条件包含但不限于氢气与雷尼镍，氢气与钯碳，铁粉，锌粉，氯化亚锡。
反应步骤c-A)：将式VIII所示的化合物与R 2C(O)Cl或R 2COOH与氯化试剂反应后发生缩合反应得到式I所示化合物；
所述的氯化试剂优选于三氯氧磷、氯化亚砜、草酰氯、三氯化磷、五氯化磷其中的一种或者两种以上的组合；优选地，上述反应可以在碱性条件下进行，所述的碱包括但不限于三乙胺、二异丙基乙基胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂二环十一碳-7-烯、N-甲 基吗啉、碳酸钠、碳酸钾、碳酸铯的一种或两种以上的组合。
反应步骤c-B)：或者，反应步骤c-B)：或者，当R 2为
Figure PCTCN2019077026-appb-000036
且R 11为HNR 12R 13，L为乙烯基时，由式VIII化合物与
Figure PCTCN2019077026-appb-000037
反应后加入连有R 12和R 13取代基的胺
Figure PCTCN2019077026-appb-000038
反应制备式I化合物；
优选地，上述反应可在有机溶剂中进行，所述的有机溶剂包含但不限于四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环、二氯乙烷之一及两者以上的组合；
反应步骤c-C)：或者，当R 2为
Figure PCTCN2019077026-appb-000039
且L 1为
Figure PCTCN2019077026-appb-000040
时，由式VIII化合物与2-(二乙氧基磷酰基)乙酸在缩合剂作用下进行步骤c-C1反应得到式IX所示化合物，式IX化合物进一步与
Figure PCTCN2019077026-appb-000041
发生步骤c-C2反应得到式I化合物。
优选地，所述缩合剂包括但不限于碳二亚胺型缩合剂，鎓盐类缩合剂，有机磷类缩合剂及其他类别缩合剂的一种或两种以上，优选N,N'-羰基二咪唑(CDI)，N,N-二环己基碳二亚胺(DCC)，N,N-二异丙基碳二亚胺(DIC)，羟基苯并三唑(HOBt)，N,N-二异丙基乙胺(DIEA)，1-羟基-7-偶氮苯并三氮唑(HOAt)，O-苯并三氮唑-N,N,N',N'-四甲基脲四氟硼酸酯(TBTU)，苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HBTU)、6-氯苯并三氮唑-1,1,3,3-四甲基脲六氟磷酸酯(HCTU)，2-(7-氧化苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)，丙基磷酸酐(T3P)，1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)，1-乙基(3-二甲基氨基丙基)碳二亚胺(EDC)，六氟磷酸苯并三唑-1-基-氧基三吡咯烷鏻(PyBOP)，(3H-1,2,3三唑并[4,5-b]吡啶-3-氧基)三-1-吡咯烷基鏻六氟磷酸盐(PyAOP)中一种或两种以上的组合；
优选地，此步骤可在有机碱中进行，所述的有机碱包含但不限于三乙胺、二异丙基乙基胺(DIEA)，吡啶，4-二甲氨基吡啶(DMAP)，2,6-二甲基吡啶(Lutidine)，1,8-二氮杂二环十一碳-7-烯(DBU)或N-甲基吗啉一种或两种以上的组合。
优选地，步骤c-C2可在非质子性溶剂中，碱的作用下发生。所述的非质子性溶剂包含但不限于四氢呋喃(THF)、N,N-二甲基甲酰胺(DMF)、N,N-二甲基乙酰胺(DMA)、N-甲基吡咯烷酮(NMP)、二氧六环之一及两者以上的组合；所述的碱包含但不限于氢化钠、双三甲基硅基胺基锂之一及两者的组合。
上述步骤c-A)、步骤c-B)和c-C)之间为并列选择的步骤，即式VIII所示化合物可通过c-A)、步骤c-B)和c-C)其中之一制备式所示化合物，即式VIII所示化合物可通过c-A)制备式(I)所示化合物，或式VIII所示化合物通过步骤c-B)制备式(I)所示化合物，或者通过c-C) 制备式(I)所示化合物。
发明详述
在这里所指的术语“取代”，包括复杂取代基(比如，苯基，芳基，杂烷基，杂芳基)，比较合适的是1至5个取代基，较好的是1到3个，最好是1到2个，可从取代基列表上自由选择。
除非有特殊说明，在此使用的烷基包括饱和单价的烃基，这些烃基有直链，支链或环状部分。比如，烷基包括甲基，乙基，丙基，异丙基，环丙基，n-丁基，异丁基，仲-丁基，叔-丁基，环丁基，n-戊基，3-(2-甲基)丁基，2-戊基，2-甲基丁基，新戊基，环戊基，n-己基，2-己基，2-甲基戊基和环己基。烷氧基由先前描述的直链，支链或环状烷基组成的氧化醚。类似的，烯基和炔基包括直链，支链或环状烯基和炔基。
在这里使用的术语“芳基”，除非有特别说明，指的是未被取代的或已被取代的芳香基，例如苯基，萘基，蒽基。术语“芳酰基”指-C(O)-芳基。
在这里使用的术语“杂环基”，除非有特殊说明，代表未被取代的或已被取代的稳定的3至8元单环饱和环体系，它们由碳原子以及从N，O，S中选的1至3个杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。杂环可以和任何杂原子或碳原子结合，从而组成一个稳定的结构。这类杂环的例子包括(但并不局限于)氮杂环己烷基，吡咯烷基，哌啶基，哌嗪基，氧化哌嗪基，氧化哌啶基，四氢呋喃基，二氧戊环基，四氢咪唑基，四氢噻唑基，四氢噁唑基，四氢吡喃基，吗啡啉基，硫代吗啡啉基，噻吗啡啉亚砜，噻吗啡啉砜以及噁二唑基。
在这里使用的术语“杂芳基”，除非有特别说明，代表未被取代或已被取代的稳定的5或6元单环芳香环体系，也可以代表未被取代或已被取代的9或10元苯稠苯杂芳环体系或二环杂芳环体系，它们由碳原子和由1至4个从N，O，S中选择的杂原子组成，其中N，S杂原子可以被随意氧化，N杂原子还可以被随意季铵化。杂芳基可以和任何杂原子或碳原子黏附起来，从而组成一个稳定的结构。杂芳基的例子包括(但并不局限于)噻蒽基，呋喃基，咪唑基，异噁唑基，呃唑基，吡唑基，吡咯基，噻唑基，噻二唑基，三唑基，吡啶基，哒嗪基，吲哚基，氮杂吲哚基，吲唑基，苯并咪唑基，苯并呋喃基，苯并噻吩基，苯并异噁唑基，苯并噁唑基，苯并吡唑基，苯并噻唑基，苯并噻二唑基，苯并三唑基，腺嘌呤基，喹啉基或异喹啉基。
术语“羰基”指的是C(O)基。
无论何时术语“烷基”或“芳基”或任何它们的前缀词根出现在一个取代物的名称中(例如，芳烷基，二烷基氨)，它将被认为包含了以上为“烷基”和“芳基”而给出的那些限制。碳原子的指定数量(比如，C 1-C 6)将独立的表示在一个烷基部分或在一个更大的取代基中的烷基部分(其中烷基作为其前缀词根)中的碳原子的数量。
很清楚，式I的化合物、异构体、晶型或前药及其可药用盐可以存在溶剂化形式和非溶剂化形式。例如溶剂化形式可以是水溶形式。本发明包括所有这些溶剂化的和未溶剂化 的形式。
本发明的化合物可能有不对称的碳原子，根据它们的理化差异，通过已知技术上已成熟的方法，比如，通过色谱或分步结晶法，这种非对映异构的混合物可以被分离成单一的非对映异构体。对映异构体的分离可通过先用适当有旋光活性的化合物进行反应，把对映异构的混合物转化成非对映异构的混合物，分离非对映异构体，再把单一非对映异构体转化(水解)成相应的纯的对映异构体。所有这样的异构体，包括非对映异构体混合物和纯对映体被认为是该发明的一部分。
作为活性成分的本发明的化合物，以及制备该化合物的方法，都是本发明的内容。而且，一些化合物的晶型形式可以作为多晶体存在，这种形式也可以被包括在目前的发明里。另外，一些化合物可以和水(即水合物)或普通的有机溶剂一起形成溶剂化物，这种溶剂化物也被包括在此项发明的范畴内。
本发明的化合物可以以游离的形式用于治疗，或者在适当情况下以药学上可接受的盐或其它衍生物的形式用于治疗。如本文所用，术语“药学上可接受的盐”是指本发明的化合物的有机盐及无机盐，此盐适用于人类和低等动物，无过度毒性、刺激性、过敏反应等，具有合理的利益/风险比。胺，羧酸，膦酸盐，和其它类型的化合物的药学上可接受的盐在所属领域中是众所周知的。该盐可以由本发明的化合物与合适的游离碱或酸反应而成。包括但不限于，与无机酸如盐酸、氢溴酸、磷酸、硫酸、高氯酸或与有机酸如乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸、丙二酸形成的盐，或通过使用本领域熟知的方法，例如离子交换法，来得到这些盐。其他药学上可接受的盐包括己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、己酸盐、氢碘酸盐、2‐羟基乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、甲烷磺酸盐、2‐萘磺酸盐、烟酸盐、硝酸盐、油酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、过硫酸盐、过3‐苯基丙酸盐、磷酸盐、苦味酸盐、丙酸盐、硬脂酸盐、硫酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐等。代表性的碱或碱土金属盐包括钠、锂、钾、钙、镁等。其他药学上可接受的盐包括适当的无毒的铵、季铵，和使用诸如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根，低级烷基磺酸盐和芳基磺酸盐形成的胺基阳离子。
另外，本文所用术语“前药”是指一个化合物在体内可以转化为本发明式(I)所示的化合物。此转化受前体药物在血液中水解或在血液或组织中经酶转化为母体化合物的影响。
本发明的药物组合物包含本文所述结构式(I)化合物或其药学上可接受的盐、激酶抑制剂(小分子，多肽，抗体等)、免疫抑制剂、抗癌药、抗病毒剂、抗炎剂、抗真菌剂、抗生素或抗血管过度增生化合物的另外的活性剂；以及任何药学上可接受的载体、佐剂或赋形剂。
本发明的化合物可以作为单独使用，也可以与一种或多种其它本发明的化合物或与一种或多种其它药剂联合使用。当联合给药时，治疗剂可以配制成同时给药或顺序地在不同的时间给药，或者所述治疗剂可以作为单一组合物给药。所谓“组合疗法”，指的是使用本发明的化合物与另一种药剂一起使用，给药方式为每种药剂同时共同给药或每种药剂顺序给药，无论哪种情况，目的都是要达到药物的最佳效果。共同给药包括同时递送剂型，以及每种化合物分别的单独剂型。因此，本发明的化合物的给药可以与已知的本领域的其他疗法同时使用，例如，在癌症治疗中使用放射治疗或细胞生长抑制剂、细胞毒性剂、其它抗癌剂等附加疗法来改善癌症状。本发明并不限于给药的顺序；本发明的化合物可以先前施用，同时施用，或在其他抗癌剂或细胞毒性剂之后施用。
为了制备这一发明的药学成分，作为其活性成分的分子式(I)的一种或多种化合物或盐类可紧密的与药学载体混合在一起，这是根据传统的制药配料技术而进行的，其中的载体可根据按不同的给药方式(例如，口服或肠外给药)设计好的制备形式而采用多种多样的形式。适当的药学上可接受的载体在技术上是众所周知的。对一些这类药学可接受的载体的描述可以在《药学赋形剂手册》里找到，该书由美国药学会和英国药学社联合出版。
本发明药物组合物可以有以下形式，比如说，适合口服给药，例如药片，胶囊，药丸，药粉，持续释放的形式，溶液或悬浮液；用于胃肠外注射如透明液，悬浮液，乳状液；或者用于局部用药如膏，霜；亦或作为栓剂用于直肠给药。药学成分也可以单位剂量的形式适合用于精确剂量的一次性给药。该药学成分将包括一种传统的药学载体或赋形剂以及根据目前的发明制成的作为活性成分的化合物，另外，也可以包括其他的医学或药学制剂，载体，辅助剂，等等。
治疗性化合物也可给于哺乳动物而非人类。给一个哺乳动物所用的药物剂量将取决于该动物的种类以及它的疾病状况或其所处的失调状态。治疗性化合物可以以胶囊，大丸药，药片药水的形式喂给动物。也可以通过注射或灌输的方式让治疗性化合物进入动物体内。我们根据符合兽医实践标准的传统的方式制备好这些药物形式。作为一种可选择的方式，药学合成药可以同动物饲料混合在一起喂给动物，因此，浓缩的饲料添加剂或预拌和料可以备以混合普通的动物饲料。
本发明的又一目的是在于提供一种用于治疗有需要的受试者中癌症的方法，其包括给受试者施用含本发明的化合物的组合物的治疗有效量的一种方法。
本发明还包括本发明的化合物或其药学上可接受的衍生物的使用，制备治疗与酪氨酸激酶EGFR、HER2、HER3、HER4相关的癌症及自身免疫疾病的药物中的应用。所述的癌症(包括非实体瘤、实体瘤、原发性或转移性癌症，如本文别处所指出和包括癌症具有抗性或难治的一种或多种其它治疗)以及其它疾病(包括但不限于眼底疾病、银屑病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化等)的药剂。所述癌症包括但不限于：非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结 肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌中的任一种。
下面提供的实施例可以更好的说明本发明，除非特别说明，所有的温度为摄氏度。
具体实施方式
本发明化合物涉及的中间体，可以通过以下方法制备，但不限于以下方法。本发明的部分中间体合成可以参考专利CN104530063的方法，一些官能团的简单替换，本领域技术人员根据掌握的化学合成领域知识可以相应调整而获得相应的中间体。以下本发明提供中间体的制备路径，本发明化合物涉及的中间体，可以通过以下方案制备，但不限于以下方案。
式VIII所示的中间体化合物的合成
中间体N-(3-溴苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-1)
Figure PCTCN2019077026-appb-000042
步骤1)5-(2-羟基乙氧基)-6-硝基喹唑啉-4(3H)-酮(II)的制备
Figure PCTCN2019077026-appb-000043
将乙二醇(352.7g,5.7mol)溶于1升DMF中，冰水浴冷却，加入氢化钠(68.2g,2.8mol)，搅拌0.5小时后加入5-氯-6-硝基喹唑啉-4(3H)-酮，(128g,0.57mol)，缓慢升至室温，搅拌至反应完毕。加入乙酸乙酯至有大量固体析出，抽滤，所得固体用水打浆，盐酸调至弱酸性后抽滤，得白色固体129.7克，产率91％。 1H NMR(DMSO-d 6,400MHz)δ12.55(1H,s),8.13–8.28(2H,m),7.52(1H,d,J＝8.9Hz),4.76(1H,s),4.04–4.32(2H,m),3.60–3.84(2H,m)；MS:252[M+H] +。
步骤2)N-(3-溴苯基)-5-(2-氯乙氧基)-6-硝基喹唑啉-4-胺(VII-1)的制备
Figure PCTCN2019077026-appb-000044
5-(2-羟基乙氧基)-6-硝基喹唑啉-4(3H)-酮(3g,11.94mmol)加入到圆底烧瓶中，加入二氯亚砜搅拌溶解，滴入催化量二甲基甲酰胺，加热反应液回流至原料反应完全，减压蒸干得黄色固体直接溶于二氯甲烷中，然后加入3-溴苯胺(2g,11.94mmol)的乙醇溶液，搅拌至反应完全，加入正己烷搅拌至有大量固体析出，抽滤、石油醚洗涤、晾干得黄色固体3.7克，产率88％。MS:423[M+H] +。
步骤3)N-(3-溴苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-1)的制备
N-(3-溴苯基)-5-(2-氯乙氧基)-6-硝基喹唑啉-4-胺(3.7g，8.7mmol)加入到圆底烧瓶中，加入乙醇和水的混合溶剂，然后依次加入铁粉(1.3g,22.7mmol)、醋酸(1.85mL,32.27mmol)，反应液加热搅拌至反应完全，蒸去溶剂，乙酸乙酯萃取、浓缩、柱层析得黄色固体2.0克,产率65％。 1H NMR(500MHz,DMSO-d 6)δ10.03(s,1H),8.35(dd,J＝6.5,4.5Hz,2H),7.81(dd,J＝8.1,1.0Hz,1H),7.40-7.28(m,1H),7.29-7.21(m,3H),6.29(s,1H),4.48(t,J＝4.3Hz,2H),3.46(dd,J＝7.0,4.1Hz,2H). 13C NMR(125MHz,DMSO)δ156.23,150.81,143.54,141.31,135.47,132.35,130.91,125.99,123.70,123.50,121.97,121.18,120.48,107.23,65.92；MS:357[M+H] +。
中间体N-(3-(三氟甲基)苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-2)的制备
Figure PCTCN2019077026-appb-000045
步骤1)同VIII-1合成路线的步骤1)。
步骤2)N-(3-(三氟甲基)苯基)-5-(2-氯乙氧基)-6-硝基喹唑啉-4-胺(VII-2)的制备
Figure PCTCN2019077026-appb-000046
参考N-(3-溴苯基)-5-(2-氯乙氧基)-6-硝基喹唑啉-4-胺(VII-1)的制备方法的步骤2)，具体实施方式为以相同摩尔当量的3-三氟甲基苯胺替代3-溴苯胺。MS:413[M+H] +。
步骤3)N-(3-(三氟甲基)苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-2)的制备
参考N-(3-溴苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-1)的制备方法的步骤3)，具体实施方式为以相同摩尔当量的N-(3-(三氟甲基)苯基)-5-(2-氯乙氧基)-6-硝基喹唑啉-4-胺(VII-2)替代N-(3-溴苯基)-5-(2-氯乙氧基)-6-硝基喹唑啉-4-胺(VII-1)，产率60％。 1H NMR(500MHz,DMSO-d 6)δ10.15(s,1H),8.45(s,1H),8.37(s,1H),8.10(d,J＝8.3Hz,1H),7.64-7.56(m,1H),7.43(d,J＝7.7Hz,1H),7.28-7.22(m,2H),6.30(s,1H),4.51-4.46(m,2H),3.51-3.43(m,2H). 13C NMR(125MHz,DMSO)δ156.39,150.69,143.35,140.46,135.54,132.42,130.08,129.92,125.80,125.52,123.59,121.03,119.75,117.8,107.20,65.94；MS:347[M+H] +。
中间体N-(4-甲氧基苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-3)的制备
Figure PCTCN2019077026-appb-000047
步骤1)同VIII-1合成路线的步骤1)。
步骤2)5-(2-氯乙氧基)-6-硝基喹唑啉-4(3H)-酮(III)的制备
Figure PCTCN2019077026-appb-000048
将5-(2-羟基乙氧基)-6-硝基喹唑啉-4(3H)-酮，(129.7g,0.52mol)置于烧瓶中，加入200毫升三氯氧磷，加热回流至反应完毕。蒸去三氯氧磷，加水打浆至析出大量固体，抽滤，得白色固体120.8克，产率87％。 1H NMR(400MHz,DMSO-d 6)δ12.55(s,1H),8.24–8.21(m,2H),7.56(d,J＝9.0Hz,1H),4.41(t,J＝5.4Hz,2H),3.96(t,J＝5.4Hz,2H)；MS:270[M+H] +。
步骤3)5-(2-氯乙氧基)-6-氨基喹唑啉-4(3H)-酮(IV)的制备
Figure PCTCN2019077026-appb-000049
将5-(2-氯乙氧基)-6-硝基喹唑啉-4(3H)-酮(120.8g,0.45mol)溶于甲醇与四氢呋喃的混合溶剂中，加入40克雷尼镍，氢气环境下室温搅拌至反应完毕。抽滤，浓缩得黄色固体107.4克，产率100％。 1H NMR(400MHz,DMSO-d 6)δ11.76(s,1H),7.74(s,1H),7.24(d,J＝2.2Hz, 2H),5.32(s,2H),4.15(t,J＝5.6Hz,2H),3.97(t,J＝5.6Hz,2H)；MS:240[M+H] +。
步骤4)2,3,4,9-四氢-10H-[1,4]噁嗪并[2,3-f]喹唑啉-10-酮(V)的制备
Figure PCTCN2019077026-appb-000050
将5-(2-氯乙氧基)-6-氨基喹唑啉-4(3H)-酮(107.4g,0.45mol)溶于1升DMF中，加入三乙胺(94mL,0.68mol)，加热至反应完毕后蒸去DMF，加入二氯甲烷搅拌至析出大量固体，抽滤，得白色固体80克，产率88％。 1H NMR(DMSO-d 6,300MHz)δ11.66(1H,s),7.67(1H,s),6.96–7.03(2H,m),6.11(1H,s),4.13–4.21(2H,m),3.25–3.33(2H,m)；MS:204[M+H] +。
步骤5)N-(4-甲氧基苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-3)的制备
将2,3,4,9-四氢-10H-[1,4]噁嗪并[2,3-f]喹唑啉-10-酮(0.5g,2.46mmol)，4-甲氧基苯胺(605mg,4.92mmol)，苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)(1.4g,3.20mmol)置于圆底烧瓶中，加入5毫升乙腈，搅拌均匀后加入1,8-二氮杂二环十一碳-7-烯(DBU)(0.56g,3.69mmol)，室温搅拌至反应完毕，蒸去溶剂，所得混合物硅胶柱层析，得到棕色固体568毫克，产率75％。 1H NMR(400MHz,DMSO-d 6)δ9.97(s,1H),8.29(s,1H),7.75–7.60(m,2H),7.25–7.17(m,2H),7.01–6.87(m,2H),6.32(s,1H),4.44(t,J＝4.4Hz,2H),3.77(s,3H),3.49–3.44(m,2H)；MS:309[M+H] +。
中间体N-(3-氯4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-4)的制备
Figure PCTCN2019077026-appb-000051
步骤1)至步骤4)同VIII-3的制备方法中的步骤1)至步骤4)。
步骤5)10-((1H-苯并[d][1,2,3]三氮唑-1-基)氧)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉(VI)的制备
Figure PCTCN2019077026-appb-000052
将2,3,4,9-四氢-10H-[1,4]噁嗪并[2,3-f]喹唑啉-10-酮(20.3g,100mmol)和苯并三氮唑-1-基氧基三(二甲基氨基)磷鎓六氟磷酸盐(BOP)(44.2g,100mmol)置于圆底烧瓶中，加入乙腈搅拌均匀后加入1,8-二氮杂二环十一碳-7-烯(DBU)(15.2g,100mmol)，室温搅拌至反应完毕，加水搅拌至析出大量固体、抽滤，得28克黄色固体，产率87％。 1H NMR(400MHz,DMSO-d 6)δ8.26(s,1H),8.19(d,J＝8.4Hz,1H),7.78(d,J＝8.3Hz,1H),7.68–7.60(m,1H), 7.58–7.47(m,3H),6.70(s,1H),4.41(t,J＝4.2Hz,2H),3.58–3.47(m,2H)；MS:321[M+H] +。
步骤6)N-(3-氯4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-4)的制备
将10-((1H-苯并[d][1,2,3]三氮唑-1-基)氧)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉(320mg,1mmol)和间氯对氟苯胺(145mg,1mmol)，对甲苯磺酸一水合物(17mg,0.1mmol)溶于异丙醇中，室温搅拌至反应完毕，加水搅拌、抽滤，得300毫克黄色固体产品，产率91％。 1H NMR(400MHz,DMSO-d 6)δ10.20(s,1H),8.41(d,J＝3.6Hz,1H),8.26–8.14(m,1H),7.83–7.71(m,1H),7.45–7.38(m,1H),7.33–7.17(m,2H),6.41(s,1H),4.46(t,4.3Hz,2H),3.58–3.56(m,2H)； 13C NMR(125MHz,DMSO-d 6)δ156.26,153.52,150.81,143.53,136.93,135.55,132.29,123.47,123.21,122.27,121.12,119.41,117.04,107.11,65.90；MS:331[M+H] +。
中间体10-(4-(3-氟苄氧基)苯氧基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉(VIII-5)的制备
Figure PCTCN2019077026-appb-000053
步骤1)至步骤5)同VIII-4的制备方法的步骤1)至步骤5)。
步骤6)10-((3-甲氧基苄基)氧基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉(VIII-5)的制备
将间甲氧基苯甲醇138毫克(1mmol)，溶于5毫升二甲基甲酰胺中，加入氢化钠24毫克，室温搅拌至不再有气体产生后加入10-((1H-苯并[d][1,2,3]三氮唑-1-基)氧)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉(VI)320毫克(1mmol)，室温搅拌至反应完毕，加水淬灭，抽滤后得到290毫克黄色固体产品，产率89％。MS:324[M+H] +。
中间体VIII-6至VIII-93制备
Figure PCTCN2019077026-appb-000054
步骤1)至步骤4)同VIII-3的合成方法中的步骤1)至步骤4)。
步骤5)参考VIII-3合成路线的步骤5)，其操作完全相同，实施方法为以2,3,4,9-四氢-10H-[1,4]噁嗪并[2,3-f]喹唑啉-10-酮(V)为起始原料，将下表中相等摩尔当量的R 1XH替代4-甲氧基苯胺。具体实施化合物如下：
Figure PCTCN2019077026-appb-000055
Figure PCTCN2019077026-appb-000056
Figure PCTCN2019077026-appb-000057
Figure PCTCN2019077026-appb-000058
Figure PCTCN2019077026-appb-000059
Figure PCTCN2019077026-appb-000060
Figure PCTCN2019077026-appb-000061
Figure PCTCN2019077026-appb-000062
Figure PCTCN2019077026-appb-000063
Figure PCTCN2019077026-appb-000064
中间体VIII-94至VIII-103制备
Figure PCTCN2019077026-appb-000065
步骤1)至步骤5)同化合物VIII-4的合成步骤1)至步骤5)。
步骤6)参考化合物VIII-4的合成步骤6)，其操作完全相同，实施方法为以10-((1H-苯并[d][1,2,3]三氮唑-1-氧基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉(VI)为起始原料，将下表中相同摩尔当量的R 1XH替代间氯对氟苯胺。具体实施化合物如下表所示：
Figure PCTCN2019077026-appb-000066
Figure PCTCN2019077026-appb-000067
实施例化合物的制备
实施例1
1-(10-((3-溴苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000068
将N-(3-溴苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-1)(178mg,0.5mmol)溶于四氢呋喃中，加入丙烯酰氯(45.3mg,0.5mmol)，室温搅拌至反应完毕，加碳酸钾水溶液淬灭，乙酸乙酯萃取，有机相浓缩后硅胶柱层析纯化，得到类白色固体164毫克，产率80％。 1H NMR(500MHz,DMSO-d 6)δ10.91(s,1H),8.82(s,1H),8.18(s,1H),7.95-7.90(m,1H),7.68-7.65(m,1H),7.56(dd,J＝8.0,0.9Hz,1H),7.52-7.45(m,2H),6.78-6.81(m,1H),6.35-6.30(m,1H),5.95-5.91(m,1H),4.71(t,J＝4.5Hz,2H),4.10(t,J＝4.5Hz,2H)； 13C NMR(125MHz,DMSO)δ164.73,159.84,151.01,144.14,138.83,133.14,131.11,130.22,129.97,129.30,128.50,125.08,124.18,121.67,114.41,104.95,100.00,69.07；HRMS(ESI):m/z411.0457calcd for C 19H 15BrN 4O 2[M+H] +,found 411.0455.
实施例2-82
Figure PCTCN2019077026-appb-000069
参考实施例1的制备方法，其操作完全相同，实施方式为以相同的摩尔当量的式VIII中R 1X为下表中取代基的中间体替代N-(3-溴苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-1)，具体实施的化合物如下表所示：
Figure PCTCN2019077026-appb-000070
Figure PCTCN2019077026-appb-000071
Figure PCTCN2019077026-appb-000072
Figure PCTCN2019077026-appb-000073
Figure PCTCN2019077026-appb-000074
Figure PCTCN2019077026-appb-000075
Figure PCTCN2019077026-appb-000076
Figure PCTCN2019077026-appb-000077
Figure PCTCN2019077026-appb-000078
Figure PCTCN2019077026-appb-000079
Figure PCTCN2019077026-appb-000080
Figure PCTCN2019077026-appb-000081
Figure PCTCN2019077026-appb-000082
Figure PCTCN2019077026-appb-000083
Figure PCTCN2019077026-appb-000084
Figure PCTCN2019077026-appb-000085
Figure PCTCN2019077026-appb-000086
Figure PCTCN2019077026-appb-000087
Figure PCTCN2019077026-appb-000088
Figure PCTCN2019077026-appb-000089
实施例83 1-(10-((4-氨基苄基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000090
将叔丁基(4-(((3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-基)氨基)甲基)苯胺甲酸叔丁酯(VIII-34)(203mg,0.5mmol)溶于四氢呋喃中，加入丙烯酰氯(45.3mg,0.5mmol)，室温搅拌至原料消失后加入1毫升盐酸，搅拌至反应完毕，加碳酸钾水溶液淬灭，乙酸乙酯萃取，有机相浓缩后硅胶柱层析纯化，得到类白色固体95毫克，产率53％。 1H NMR(400MHz,DMSO-d 6)δ8.49–8.42(m,1H),8.33(s,1H),7.70(s,1H),7.20(d,J＝9.2Hz,1H),7.06–7.01(m,2H),6.81–6.68(m,1H),6.54–6.48(m,2H),6.33–6.25(m,1H),5.87–5.82(m,1H),4.94(s,2H),4.63–4.57(m,2H),4.53(t,J＝4.8Hz,2H),4.00(t,J＝4.8Hz,2H)；MS:362[M+H] +。
实施例84：1-(10-((4-羟基苄基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000091
将4-(((3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-基)氨基)甲基)乙酸苯酯(VIII-36)(175mg,0.5mmol)溶于5毫升四氢呋喃中，冰浴冷却，加入丙烯酰氯(45.3mg,0.5mmol)，室温搅拌至原料消失后加入浓盐酸1毫升，继续搅拌至反应完毕，得到类白色固体63毫克，产率35％。 1H NMR(400MHz,DMSO-d 6)δ9.26(s,1H),8.62–8.56(m,1H),8.32(s,1H),7.70(s,1H),7.22–7.15(m,3H),6.79–6.68(m,3H),6.33–6.26(m,1H),5.85(dd,J＝10.4,2.0Hz,1H),4.70–4.64(m,2H),4.54(t,J＝4.8Hz,2H),4.01(t,J＝4.8Hz,2H)；MS:363[M+H] +
实施例85：1-(10-((4-羟基-3-甲氧基苄基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000092
参考实施例84的制备方法，其操作完全相同。具体实施方式为以相等摩尔当量的化 合物VIII-37替换VIII-36。 1H NMR(400MHz,DMSO-d 6)δ8.82(s,1H),8.59–8.52(m,1H),8.34(s,1H),7.71(s,1H),7.20(d,J＝8.8Hz,1H),7.01–6.98(m,1H),6.79–6.69(m,3H),6.33–6.26(m,1H),5.88–5.83(m,1H),4.67(d,J＝5.6Hz,2H),4.54(t,J＝4.8Hz,2H),4.01(t,J＝4.8Hz,2H),3.74(s,3H)；MS:393[M+H] +。
实施例86：(4-丙烯酰基-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-基)甘氨酸的制备
Figure PCTCN2019077026-appb-000093
将叔丁基(3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-基)甘氨酸酯(VIII-86)(158mg，0.5mmol)溶于5mL四氢呋喃中，冰浴冷却，加入丙烯酰氯45.3mg(0.5mmol)，室温搅拌至反应完毕，加水淬灭，乙酸乙酯萃取，有机相浓缩后硅胶柱层析纯化，得到目标化合物63mg，产率40％。 1H NMR(400MHz,DMSO-d 6)δ13.13(s,1H),9.78-9.68(m,1H),8.78(s,1H),8.09(s,1H),7.33(d,J＝9.0Hz,1H),6.83–6.73(m,1H),6.33(d,J＝16.8Hz,1H),5.91(d,J＝10.4Hz,1H),4.64(t,J＝4.6Hz,2H),4.37(d,J＝5.6Hz,2H),4.07(t,J＝4.6Hz,2H)；MS:315[M+H] +。
实施例87：3-((4-丙烯酰基-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-基)氨基)丙酸的制备
Figure PCTCN2019077026-appb-000094
参考实施例86的制备方法，具体实施方法为以相同摩尔当量的叔丁基3-((3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-基)氨基丙酸酯(VIII-89)替代叔丁基(3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-基)甘氨酸酯(VIII-86)。 1H NMR(400MHz,DMSO-d 6)δ12.67(s,1H),9.78-9.68(m,1H),8.78(s,1H),8.05(s,1H),7.31(dd,J＝9.2,2.6Hz,1H),6.82–6.70(m,1H),6.32(d,J＝16.6Hz,1H),5.90(d,J＝10.4Hz,1H),4.61(d,J＝4.8Hz,2H),4.05(t,J＝4.6Hz,2H),3.95–3.89(m,2H),2.68(t,J＝7.1Hz,2H)；MS:329[M+H] +。
实施例88
(E)-4-(二甲氨基)-1-(10-((3-(三氟甲基)苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丁-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000095
将N-(3-(三氟甲基)苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-2)(173mg，0.5mmol)溶于四氢呋喃和二甲基甲酰胺的混合溶剂中，加入反式-4-二甲基胺基巴豆酰氯盐酸盐(92mg,0.5mmol)，室温搅拌至反应完毕，加碳酸钾水溶液淬灭，乙酸乙酯萃取，有机相浓缩后硅胶柱层析纯化，得到类白色固体173毫克，产率76％。 1H NMR(500MHz,DMSO-d 6)δ10.07(s,1H),8.55(s,1H),8.35(s,1H),8.12(d,J＝8.5Hz,1H),7.89(s,1H),7.69-7.58(m,1H),7.49(d,J＝7.8Hz,1H),7.35(d,J＝9.0Hz,1H),6.83(dt,J＝15.2,5.9Hz,1H),6.60(d,J＝15.2Hz,1H),4.70(t,J＝4.6Hz,2H),4.11-4.03(m,2H),3.10(d,J＝5.4Hz,2H),2.19(s,6H)； 13C NMR(125MHz,DMSO)δ164.30,157.61,154.31,149.24,144.55,142.70,139.98,130.57,130.01,129.83,126.84,125.75,123.57,122.39,120.65,119.35,119.16,106.49,68.80,60.35,45.63；MS:458[M+H] +。
实施例89-105
Figure PCTCN2019077026-appb-000096
实施例89-105的制备参考实施例88的制备方法，其操作完全相同，实施方式为以相同的摩尔当量的式VIII中R 1X为下表中取代基的中间体替代N-(3-(三氟甲基)苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-2)，具体实施的化合物如下表所示：
Figure PCTCN2019077026-appb-000097
Figure PCTCN2019077026-appb-000098
Figure PCTCN2019077026-appb-000099
Figure PCTCN2019077026-appb-000100
Figure PCTCN2019077026-appb-000101
实施例106
(E)-1-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-4-吗啉丁-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000102
将N-(3-氯-4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-4)(165mg,0.5mmol)，溶于二氯甲烷和二甲基甲酰胺的混合溶剂中，加入4-溴代巴豆酰氯(91mg,0.5mmol)，室温搅拌至反应完毕，加水淬灭，乙酸乙酯萃取，有机相浓缩后直接溶于乙腈中，加入二异丙基乙基胺(129mg,1mmol)和吗啉(87mg,1mmol)，室温搅拌至反应完毕，加水淬灭，乙酸乙酯萃取，有机相浓缩后硅胶柱层析纯化，得到类白色固体61毫克，产率25％。 1H NMR(500MHz,DMSO-d 6)δ9.92(s,1H),8.52(s,1H),8.18(dd,J＝6.8,2.5Hz,1H),7.96-7.72(m,2H),7.49-7.40(m,1H),7.33(d,J＝9.0Hz,1H),6.82(dt,J＝15.1,5.8Hz,1H),6.62(d,J＝15.0Hz,1H),4.68(t,J＝4.5Hz,2H),4.10-4.04(m,2H),3.70-3.48(m,4H),3.15(d,J＝5.4Hz,2H),2.44-2.38(m,4H). 13C NMR(125MHz,DMSO)δ157.58,154.35,153.14,149.22,143.74,142.71,136.38,130.52,124.75,123.77,123.72,122.28,119.44,119.25,117.07,116.90,106.37,68.77,66.64,59.37,53.79；HRMS(ESI):m/z 484.1552calcd for C 24H 23ClFN 5O 3[M+H] +,found 484.1550.
实施例107-122
Figure PCTCN2019077026-appb-000103
实施例107-122的制备参考实施例106的制备方法，其操作完全相同，实施方式为以相同的摩尔当量的式VIII中R 1X为下表中取代基的中间体替代N-(3-氯-4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-4)，以相等的摩尔当量的
Figure PCTCN2019077026-appb-000104
替代吗啉。具体实施的化合物如下表所示：
Figure PCTCN2019077026-appb-000105
Figure PCTCN2019077026-appb-000106
Figure PCTCN2019077026-appb-000107
Figure PCTCN2019077026-appb-000108
Figure PCTCN2019077026-appb-000109
Figure PCTCN2019077026-appb-000110
实施例123
(S,E)-1-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-3-(1-甲基吡咯烷-2-基)丙-2-烯-1-酮的制备
步骤1)二乙基(2-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-2-氧代乙基)磷酸酯的制备(IX-1)
Figure PCTCN2019077026-appb-000111
将N-(3-氯4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-4)(165mg,0.5mmol)，2-(二乙氧基磷酰基)乙酸(0.5mmol)溶于四氢呋喃中，加入N,N'-羰基二咪唑(81mg,0.5mmol)，室温搅拌至反应完全，加入水和乙酸乙酯萃取，有机相浓缩，柱层析得黄色固体218毫克，产率86％。MS:509[M+H] +。
步骤2)(S,E)-1-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-3-(1-甲基吡咯烷-2-基)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000112
将二乙基(2-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-2-氧代乙基)磷酸酯(IX-1)(218mg,0.43mmol)溶于四氢呋喃，冷却至-78℃，滴入1摩尔每升的双三甲基硅基胺基锂甲苯溶液(0.65mL,0.65mmol)，继续搅拌至原料消失，加入(S)-1-甲基吡咯烷基-2-甲醛(48.6mg,0.43mmol)，升至室温继续搅拌至反应完毕，加入水和乙酸乙酯萃取，有机相浓缩，柱层析得到类白色固体148毫克，产率74％。 1H NMR(300MHz,DMSO-d 6)δ9.93(s,1H),8.51(s,1H),8.21–8.11(m,1H),7.80(s,2H),7.50-7.40(m,1H),7.32(d,J＝9.1Hz,1H),6.76–6.64(m,1H),6.62–6.47(m,1H),4.73-4.62(m,2H),4.11–3.97(m,2H),3.09–2.94(m,1H),3.00–2.76(m,1H),2.28–2.19(m,4H),2.03–1.96(m,1H),1.77–1.68(m,2H),1.61–1.55(m,1H)；MS:468[M+H] +。
实施例124
(E)-1-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-9-甲氧基壬-2-烯-1-酮
Figure PCTCN2019077026-appb-000113
步骤1)同实施例123步骤1)
步骤2)(E)-1-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-9-甲氧基壬-2-烯-1-酮的制备
参考实施例123步骤2)，其操作完全相同，具体实施方式为以相等摩尔当量的7-甲氧基庚醛替代(S)-1-甲基吡咯烷基-2-甲醛。 1HNMR(400MHz,DMSO-d 6)δ9.92(s,1H),8.51(s,1H),8.21–8.15(m,1H),7.96–7.77(m,2H),7.49–7.40(m,1H),7.36–7.29(m,1H),6.95–6.84(m,1H),6.44(d,J＝15.1Hz,1H),4.66(t,J＝4.6Hz,2H),4.05(t,J＝4.6Hz,2H),3.33–3.29(m,2H),3.27(s,3H),2.27–2.20(m,2H),1.58–1.41(m,8H)；MS:499[M+H] +。
实施例125
(S,E)-1-(10-((3-乙炔基苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-3-(1-甲基吡咯烷-2-基)丙-2-烯-1-酮的制备
步骤1)二乙基(2-(10-((3-乙炔基苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-2-氧代乙基)磷酸酯的制备(IX-2)
Figure PCTCN2019077026-appb-000114
参考实施例123步骤1)，其操作完全相同，具体实施方式为以相等摩尔当量的N-(3-乙炔基苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-7)替代N-(3-氯4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-4)。产率85％。MS:481[M+H] +。
步骤2)(S,E)-1-(10-((3-乙炔基苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-3-(1-甲基吡咯烷-2-)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000115
参考实施例123步骤2)，其操作完全相同，具体实施方式为以相等摩尔当量的二乙基(2-(10-((3-乙炔基苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-2-氧代乙基)磷酸酯(IX-2)替代二乙基(2-(10-((3-氯-4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-2-氧代乙基)磷酸酯(IX-1)。产率70％。 1H NMR(300MHz,DMSO-d 6)δ9.95(s,1H),8.52(s,1H),8.29–7.96(m,2H),7.88(d,J＝8.3Hz,1H),7.44–7.22(m,3H),6.52–6.27(m,1H),6.11–5.88(m,1H),4.70-4.64(m,2H),4.24(s,1H),4.08-4.00(m,2H),3.10–2.97(m,1H),2.27–2.12(m,4H),2.06–1.96(m,1H),1.79–1.67(m,2H),1.58–1.39(m,2H)；MS:440[M+H] +。
实施例126
1-(10-(3-氯-4-氟苯氧基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丁-2-炔-1-酮的制备
Figure PCTCN2019077026-appb-000116
将2-丁炔酸(42mg,0.5mmol)溶于二氯甲烷中，滴入0.05毫升二甲基甲酰胺，冰浴冷却后加入草酰氯(32mg,0.25mmol)，继续搅拌0.5小时后加入10-(3-氯-4-氟苯氧基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(VIII-4)(165mg,0.5mmol)，升至室温继续搅拌至反应完毕，加碳酸钾水溶液淬灭，乙酸乙酯萃取，有机相浓缩后柱层析得类白色固体产品69毫克，产率34％。 1H NMR(400MHz,DMSO-d 6)δ8.60(s,1H),8.57–8.38(m,1H),7.71–7.60(m,1H),7.57–7.46(m,2H),7.37–7.28(m,1H),4.64–4.50(m,2H),4.34–4.13(m,2H),1.84(s,3H)；MS:398[M+H] +。
实施例127-147
Figure PCTCN2019077026-appb-000117
实施例127-147的制备参考实施例126的制备方法，其操作完全相同，具体实施方式为以相同的摩尔当量的式VIII中R 1X为下表中取代基的中间体替代10-(3-氯-4-氟苯氧基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺，以相等摩尔当量的R 2为下表中所示取代 基的羧酸替代2-丁炔酸。具体实施的化合物如下表所示：
Figure PCTCN2019077026-appb-000118
Figure PCTCN2019077026-appb-000119
Figure PCTCN2019077026-appb-000120
Figure PCTCN2019077026-appb-000121
Figure PCTCN2019077026-appb-000122
Figure PCTCN2019077026-appb-000123
实施例148：(S,E)-1-(10-((4-氟苯基(氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-3-(1-甲基吡咯烷-2-基)丙-2-烯-1-酮的制备
步骤1):二乙基(2-(10-((4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪[2,3-f]喹唑啉-4-基)-2-氧代乙基)膦酸酯的制备
Figure PCTCN2019077026-appb-000124
将N-(4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(148mg,0.5mmol)，2-(二乙氧基磷酰基)乙酸(98mg,0.5mmol)溶于四氢呋喃中，加入N,N'-羰基二咪唑(81mg,0.5mmol)，油浴40℃搅拌至反应完全，加入水和乙酸乙酯萃取，有机相浓缩，柱层析得黄色固体168毫克，产率71％。MS:475[M+H] +。
步骤2):(S,E)-1-(10-((4-氟苯基(氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-3-(1-甲基吡咯烷-2-基)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000125
将二乙基(2-(10-((4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪[2,3-f]喹唑啉-4-基)-2-氧代乙基)膦酸酯(168mg,0.35mmol)溶于四氢呋喃，冷却至-78℃，滴入1摩尔每升的双三甲基硅基胺基锂甲苯溶液(0.53mL,0.53mmol)，继续搅拌至原料消失，加入(R)-1-甲基吡咯烷基-2-甲醛(39.6mg,0.35mmol)，升至室温继续搅拌至反应完毕，加入水和乙酸乙酯萃取，有机相浓缩，经高效液相制备色谱分离得到白色固体83毫克，产率54％。 1H NMR(400MHz,DMSO-d 6)δ9.86(s,1H),8.44(s,1H),8.08–7.51(m,3H),7.30(d,J＝9.0Hz,1H),7.24(t,J＝8.8Hz,2H),6.74–6.63(m,1H),6.54(d,J＝17.3Hz,1H),4.78–4.52(m,2H),4.20–3.86(m,2H),3.05–2.95(m,1H),2.83–2.73(m,1H),2.20(s,3H),2.18–2.10(m,1H),2.05–1.92(m,1H),1.79–1.63(m,2H),1.62–1.50(m,1H)；MS:434[M+H] +。
实施例149：(S,E)-3-(1-甲基吡咯烷-2-基)-1-(10-(苯基氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丙-2-烯-1-酮的制备
步骤1)二乙基(2-氧代-2-(10-(苯基氨基)-2,3-二氢-4H-[1,4]噁嗪[2,3-f]喹唑啉-4-基)乙基)膦酸酯的制备
Figure PCTCN2019077026-appb-000126
采用与实施例148步骤1)相似的方法进行制备，不同之处在于以相等摩尔当量的N-苯基-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺代替N-(4-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺。产率77％。MS:457[M+H] +。
步骤2)(S,E)-3-(1-甲基吡咯烷-2-基)-1-(10-(苯基氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)丙-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000127
采用与实施例148步骤2)相似的方法进行制备，不同之处在于以相等摩尔当量的二乙基(2-氧代-2-(10-(苯基氨基)-2,3-二氢-4H-[1,4]噁嗪[2,3-f]喹唑啉-4-基)乙基)膦酸酯代替二乙基(2-(10-((4-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪[2,3-f]喹唑啉-4-基)-2-氧代乙基)膦酸酯。 1H NMR(400MHz,DMSO-d 6)δ9.90(s,1H),8.48(s,1H),8.10–7.69(m,3H),7.40(t,J＝7.8Hz,2H),7.31(d,J＝9.0Hz,1H),7.16(t,J＝7.4Hz,1H),6.76–6.64(m,1H),6.55(d,J＝ 15.1Hz,1H),4.93–4.53(m,2H),4.20–3.89(m,2H),3.12–2.93(m,1H),2.87–2.68(m,1H),2.20(s,3H),2.18–2.09(m,1H),2.07–1.90(m,1H),1.78–1.62(m,2H),1.59–1.45(m,1H)；MS:416[M+H] +。
实施例150：(E)-1-(10-((3-氯-2-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-4-(环丙基(甲基)氨基)丁-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000128
将N-(3-氯-2-氟苯基)-3,4-二氢-2H-[1,4]噁嗪并[2,3-f]喹唑啉-10-胺(165mg,0.5mmol)，溶于二甲基甲酰胺中，加入4-溴代巴豆酰氯(91mg,0.5mmol)，室温搅拌至反应完毕，加水淬灭，乙酸乙酯萃取，有机相浓缩后直接溶于乙腈中，加入二异丙基乙基胺(129mg,1mmol)和N-甲基环丙胺(71mg,1mmol)，室温搅拌至反应完毕，加水淬灭，乙酸乙酯萃取，有机相浓缩后经高效液相制备色谱纯化，得到白色固体84毫克，产率36％。 1H NMR(400MHz,DMSO-d 6)δ10.00(d,J＝1.7Hz,1H),8.49(s,1H),8.16–8.11(m,1H),7.91–7.80(m,1H),7.45–7.40(m,1H),7.36–7.33(m,1H),7.32–7.27(m,1H),6.90–6.81(m,1H),6.56(d,J＝15.2Hz,1H),4.65(t,2H),4.06(t,J＝4.6Hz,2H),3.31(d,J＝1.6Hz,2H),2.28(s,3H),1.78–1.73(m,1H),0.47–0.42(m,2H),0.34–0.30(m,2H)；MS:468[M+H] +。
实施例151：(E)-1-(10-((3-氯-2-氟苯基)氨基)-2,3-二氢-4H-[1,4]噁嗪并[2,3-f]喹唑啉-4-基)-4-(环丁基(甲基)氨基)丁-2-烯-1-酮的制备
Figure PCTCN2019077026-appb-000129
采用与实施例150相似的方法进行制备，不同之处在于以相等摩尔当量的N-甲基环丁胺盐酸盐代替N-甲基环丙胺。 1H NMR(400MHz,DMSO-d 6)δ10.00(s,1H),8.50(s,1H),8.15–8.10(m,1H),7.92–7.81(m,1H),7.46–7.41(m,1H),7.37–7.33(m,1H),7.33–7.28(m,1H),6.86–6.79(m,1H),6.61–6.54(m,1H),4.65(t,J＝4.7Hz,2H),4.06(t,J＝4.5Hz,2H),3.04(dd,J＝6.3,1.4Hz,2H),2.86(t,J＝7.8Hz,1H),2.05(s,3H),2.00–1.93(m,2H),1.81–1.72(m,2H),1.63–1.55(m,2H)；MS:482[M+H] +。
实验例1.
小分子化合物抑制EGFR WT、EGFR T790M及HER2激酶活性的测试，测试方法如下：
1)化合物的稀释
在96孔板a中，将化合物用DMSO溶液按3倍比例稀释，形成11个梯度，第12个梯度为纯 DMSO溶液(作为阳性对照)；取一块新的96孔板b，将上述溶液用超纯水稀释25倍(DMSO浓度为4％)。
2)将化合物转盘到384孔板
将上述96孔板b中用超纯水稀释过的化合物溶液按照2复孔的标准转盘到384孔板相应的孔中。
3)加4×激酶溶液：用排枪取2.5μl上述4×激酶溶液加入到384孔板相应的反应孔中，混匀室温预反应5分钟。
4)加2×底物/ATP混合液:用排枪取5μl上述2×底物/ATP混合液到384孔板相应的反应孔中。
5)阴性对照：在384孔板中设置阴性对照孔，每孔加入2.5μl 4×底物、2.5μl 4×酶溶液、2.5μl 1×Kinase Assay Buffer和2.5μl含4％DMSO的超纯水。
6)离心混匀，避光室温反应2小时。
7)终止酶促反应：
吸取5μl上述4×终止液到384孔板相应孔，离心混匀，室温反应5分钟。
8)显色反应：
吸取5μl上述4×检测液加入到384孔板相应孔，离心混匀，室温反应1小时。
9)将384孔板放入读板仪，调取相应的程序检测信号。
10)IC 50分析：
孔读值＝10000*EU665值/EU615值
抑制率＝(阳性对照孔读值-实验孔读值)/(阳性对照孔读值-阴性对照孔读值)*100％
将药物浓度和相应抑制率输入GraphPad Prism 5处理可计算出相应的IC 50。
EGFR WT激酶活性抑制分子筛选实验条件：
反应体系中EGFR激酶终浓度0.35nM，ATP的终浓度为150μM，底物ULight TM-labeled JAK-1(Tyr1023)Peptide的终浓度100nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
EGFR T790M激酶活性抑制分子筛选实验条件：
反应体系中EGFR(T790M)激酶终浓度0.05nM，ATP的终浓度为5μM，底物ULight TM-labeled PolyGT的终浓度100nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
HER2激酶活性抑制分子筛选实验条件：
反应体系中HER2激酶终浓度为10nM，ATP的终浓度10μM，底物ULight TM-labeled PolyGT终浓度为100nM，酶促反应时间为2小时。
反应体系中化合物最高终浓度为2.5μM，经3倍梯度稀释后共11个浓度，最低终浓度为0.042nM。DMSO终浓度为1％。
表(一)列出了本专利中部分化合物对酪氨酸激酶抑制活性的测定结果，其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM，NT表示没有测试相对应的激酶。
表(一)、本发明化合物对EGFR及HER2激酶抑制活性测定结果
Figure PCTCN2019077026-appb-000130
Figure PCTCN2019077026-appb-000131
Figure PCTCN2019077026-appb-000132
实验例2.
小分子化合物抑制细胞增殖的测试，具体方法如下：
1.在T75细胞培养瓶中加入600μL胰酶，于37℃培养箱中消化约1min，随后加入5mL DMEM的完全培养液，吹打均匀，转移至15mL离心管中，1000rpm,4min离心；
2.弃去上清液，加入5mL DMEM完全培养液，吹打均匀，取10μL细胞悬浮液和10μL 0.4％胎盼蓝混匀，在细胞计数仪下进行计数；
3.分别将BT474和HCC827细胞系按照10000和3000个/孔/80μL的细胞密度接种于96孔板中培养过夜，96孔板外周36孔不加细胞仅加无菌水，仅里面60孔用于细胞实验和对照；
4.化合物稀释：化合物以10mM为起始浓度进行3倍稀释，共10个浓度；
5.在每孔中加入20μL不同种类不同浓度的化合物，其余孔加入20μL完全培养液摇匀，每孔中DMSO的中浓度为0.25％；
6.培养72h后每孔加入10μL CCK-8试剂，37℃培养1-2h；于450nm处读其OD值；
7.细胞存活率(％)＝[(As-Ab)/(Ac-Ab)]*100％
As：实验孔(含有细胞的培养基、CCK-8、compound)
Ac：对照孔(含有细胞的培养基、CCK-8)
Ab：空白孔(不含细胞和compound的培养基、CCK-8)
8.将数值导入Graphpad Prism5软件进行IC 50(最高存活率50％时的化合物浓度)计算。
表(二)列出了本发明中代表性化合物对HCC827和BT474癌细胞的活性测定结果。其中A表示IC 50小于或等于50nM，B表示IC 50大于50nM但小于或等于500nM，C表示IC 50大于500nM但小于或等于5000nM，D表示IC 50大于5000nM，NT表示没有测试相对应的细胞。
表(二)、本发明代表性化合物对细胞活性的测定结果
Figure PCTCN2019077026-appb-000133
Figure PCTCN2019077026-appb-000134
以上所述是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明所述原则的前提下，本发明的实施方式还可以作出若干改进和修饰，这些改进和修饰也应视为本发明的保护范围。

Claims (13)

  1. 一种式(I)所示化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，
    Figure PCTCN2019077026-appb-100001
    式(I)中，
    X为O或NH；
    R 1为
    Figure PCTCN2019077026-appb-100002
    L为C 1-C 4直链烷基，或分别独立地被R 4、R 5取代的C 1-C 4直链烷基；
    R 4和R 5分别独立的为H或C 1-C 3烷基；
    R 3为-H，未被取代或被卤素、羟基、氰基、羧基取代的C 1-C 6烷基，C 1-C 6烷氧基，C 3-C 7环烷基，芳基，4-7元杂环基，5-6元杂芳基，或者并环结构；
    所述并环结构选自芳环并5-6元杂芳环基，5-6元杂芳环并5-6元杂芳环基，芳环并5-6元环烷基，芳环并5-6元杂环基，5-6元杂芳环并5-6元环烷基或5-6元杂芳环并5-6元杂环基；
    所述杂环基、杂芳环基含1-3个选自N、O或S的杂原子；
    所述的芳基、杂芳基、杂环基或并环结构为非取代或分别独立的被1-3个选自卤素、氰基、羟基、C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、C 3-C 6环烷基、C 2-C 3炔基、C 2-C 3烯基、-NR'R”或-MR 6的取代基取代；
    R'、R”分别独立的为H或C 1-C 3的烷基；
    M为-O(CH 2) q-或-C(O)-，其中q为1-4的整数；
    R 6为-H，羟基，C 1-C 3烷基，C 1-C 3烷氧基，或-NR 7R 8；
    R 7和R 8分别独立的为-H，C 1-C 3烷基，或者R 7、R 8相连接形成4-7元杂环；
    R 2为
    Figure PCTCN2019077026-appb-100003
    L 1选自：
    Figure PCTCN2019077026-appb-100004
    T 1为C 1-C 8直链烷基，或分别独立地被R 9、R 10取代的C 1-C 8直链烷基；
    R 9和R 10分别独立的为-H或C 1-C 3烷基；
    R 11为-H，羟基，C 1-C 3烷基，C 3-C 7环烷基，C 1-C 3烷氧基，C 1-C 3烷硫基，4-7元杂 环基或-NR 12R 13，
    R 12和R 13分别独立的为-H，C 1-C 6烷基，C 3-C 6环烷基，被羟基取代的C 1-C 6烷基或被C 1-C 3烷氧基取代的C 1-C 6烷基；
    所述的4-7元杂环基为含有1-2个选自N、O或S的杂原子的杂环基，所述杂环基未被取代或被C 1-C 3烷基、醛基、C 1-C 4烷基酰基、氨基酰基、单或双取代的C 1-C 3氨基酰基、C 1-C 3烷基砜基、C 1-C 3烷基亚砜基中的一种或两种取代或杂环中的硫被一至二个氧原子氧化。
  2. 根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 1为
    Figure PCTCN2019077026-appb-100005
    L为C 1-C 3直链烷基，或分别独立地被R 4、R 5取代的C 1-C 3直链烷基；
    R 4和R 5分别独立的为-H或C 1-C 3烷基；
    R 3为-H，未被取代或被卤素、羟基、氰基、羧基取代的C 1-C 3烷基，C 1-C 3烷氧基，C 3-C 6环烷基，芳基，5-6元杂环基，5-6元杂芳基，或者并环结构；
    所述并环结构选自苯并5-6杂芳环基，5-6元杂芳环并5-6元杂芳环基，苯并5-6环烷基，苯并5-6杂环基，5-6元杂芳环并5-6环烷基，5-6元杂芳环并5-6元杂环基，
    所述杂环基、杂芳环基含1-3个选自N、O或S的杂原子；
    所述的芳基、杂芳基、杂环基或并环结构为非取代或分别独立地被1-3个选自卤素、氰基、羟基、C 1-C 3烷基、C 1-C 3烷氧基、卤代C 1-C 3烷基、C 3-C 4环烷基、C 2-C 3炔基、C 2-C 3烯基、-NR'R”或-MR 6的取代基取代；
    R'和R”分别独立的为H或C 1-C 3的烷基；
    M为-O(CH 2) q-或-C(O)-，其中q为1-3的整数；
    R 6为H，羟基，C 1-C 3烷基，C 1-C 3烷氧基，或-NR 7R 8；
    R 7、R 8分别独立的为H，C 1-C 3烷基或者R 7、R 8相连接形成5-6元杂环。
  3. 根据权利要求1所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 1为
    Figure PCTCN2019077026-appb-100006
    L为C 1-C 3直链烷基，或分别独立地被R 4、R 5取代的C 1-C 3直链烷基；
    R 4和R 5分别独立的为-H或甲基；
    R 3选自：-H，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，环丙基，环丁基，环戊基，环己基，羟基，羧基，1-羟基-1-甲基乙基，或以下基团：
    Figure PCTCN2019077026-appb-100007
    Figure PCTCN2019077026-appb-100008
    R 14为–H或C 1-C 3烷基；
    Q 1、Q 2、Q 3、Q 4、Q5分别独立的为N或CH；
    (R 15) p为p个相同或不同的R 15取代基，p为0，1，2或3；
    R 15选自-H，-F，-Cl，-Br，-CF 3，-OCF 3，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，乙炔基，乙烯基，环丙基，环丁基，羟基，氰基，-NR'R”或-MR 6；
    R'、R”分别独立的为H，甲基，乙基，丙基或异丙基；
    M为-O(CH 2) q-或-C(O)-，其中q为1，2或3；
    R 6为H，羟基，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，或-NR 7R 8；
    R 7、R 8独立的为H、甲基，乙基，丙基，异丙基，或R 7、R 8相连接形成5-6元杂环，所述的5-6元杂环优选：
    Figure PCTCN2019077026-appb-100009
  4. 根据权利要求3所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 1为
    Figure PCTCN2019077026-appb-100010
    L为C 1-C 3直链烷基，或分别独立地被R 4、R 5取代的C 1-C 3直链烷基；
    R 4和R 5分别独立的为-H或甲基；
    R 3选自：-H，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，环丙基，环丁基，环戊基，环己基，羟基，羧基，1-羟基-1-甲基乙基，或以下基团：
    Figure PCTCN2019077026-appb-100011
    R 14为–H或C 1-C 3烷基；
    (R 15) p为p个相同或不同的R 15取代基，p为0，1，2或3；
    R 15选自-H，-F，-Cl，-Br，-CF 3，-OCF 3，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，乙炔基，乙烯基，环丙基，环丁基，羟基，氰基，-NR'R”或-MR 6；
    R'、R”分别独立的为H，甲基，乙基，丙基或异丙基；
    M为-O(CH 2) q-或-C(O)-，其中q为1，2或3；
    R 6为H，羟基，甲基，乙基，丙基，异丙基，甲氧基，乙氧基，丙氧基，异丙氧基，或-NR 7R 8；
    R 7、R 8独立的为H、甲基，乙基，丙基，异丙基，或R 7、R 8相连接形成
    Figure PCTCN2019077026-appb-100012
  5. 根据权利要求1至4中任一项所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 2为
    Figure PCTCN2019077026-appb-100013
    L 1选自：
    Figure PCTCN2019077026-appb-100014
    T 1为C 1-C 6直链烷基，或分别独立地被R 9、R 10取代的C 1-C 6直链烷基；
    R 9和R 10分别独立的为-H或甲基；
    R 11为-H，羟基，甲基，乙基，丙基，异丙基，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，甲硫基，乙硫基，丙硫基，异丙硫基，5-6元杂环基或-NR 12R 13；
    R 12和R 13分别独立的为-H，甲基，乙基，丙基，丁基，戊基，己基，异丙基，仲丁基，异丁基，1-乙基丙基，环丙基，环丁基，环戊基，环己基，羟乙基，羟丙基，羟丁基，甲氧基乙基，甲氧基丙基，甲氧基丁基，乙氧基乙基，乙氧基丙基，乙氧基丁基，丙氧基乙基，丙氧基丙基，丙氧基丁基，异丙氧基乙基，异丙氧基丙基或异丙氧基丁基；
    所述的5-6元杂环基为含有1-2个选自N、O或S的杂原子的杂环基，所述的5-6元杂环基未被取代或被甲基，乙基，丙基，异丙基，醛基，甲酰基，乙酰基，丙酰基，丁酰基，异丁酰基，氨基酰基，甲氨基酰基，二甲氨基酰基，甲砜基，乙砜基，异丙砜基，甲亚砜基，乙亚砜基，异丙亚砜基中的一种或两种取代或杂环中的硫被一至二个氧原子氧化；
    所述的5-6元杂环选自：
    Figure PCTCN2019077026-appb-100015
  6. 根据权利要求1至5中任一项所述的化合物、其异构体、水合物、溶剂化物、其药学上可接受的盐及其前药，其特征在于，
    R 2为
    Figure PCTCN2019077026-appb-100016
    L 1选自：
    Figure PCTCN2019077026-appb-100017
    T 1为C 1-C 6直链烷基，或分别独立地被R 9、R 10取代的C 1-C 6直链烷基；
    R 9和R 10分别独立的为-H或甲基；
    R 11为-H，羟基，甲基，乙基，丙基，异丙基，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，甲硫基，乙硫基，丙硫基，异丙硫基，5-6元杂环基或-NR 12R 13；
    R 12和R 13分别独立的为-H，甲基，乙基，丙基，丁基，戊基，己基，异丙基，仲丁基，异丁基，1-乙基丙基，环丙基，环丁基，环戊基，羟乙基，羟丙基，甲氧基乙基，甲氧基丙基，乙氧基乙基，乙氧基丙基，丙氧基乙基，丙氧基丙基，异丙氧基乙基或异丙氧基丙基；
    所述的5-6元杂环基为含有1-2个选自N、O或S的杂原子的杂环基，所述的5-6元杂环基未被取代或被甲基，乙基，丙基，异丙基，醛基，甲酰基，乙酰基，丙酰基，丁酰基，异丁酰基，氨基酰基，甲氨基酰基，二甲氨基酰基，甲砜基，乙砜基，异丙砜基，甲亚砜基，乙亚砜基，异丙亚砜基中的一种或两种取代或杂环中的硫被一至二个氧原子氧化；
    所述的5-6元杂环基选自：
    Figure PCTCN2019077026-appb-100018
    R 16为H，氨基，甲氨基，二甲氨基，甲基，乙基，丙基，异丙基。
  7. 一种制备权利要求1-6所述的化合物、其异构体、溶剂化物、其药学上可接受的盐及其前药的制备方法，包含以下步骤，
    由R 2C(O)Cl与式(VIII)化合物反应，或R 2COOH发生氯化反应后与式(VIII)化合物反应制备式(I)化合物；
    Figure PCTCN2019077026-appb-100019
    或者，当R 2为
    Figure PCTCN2019077026-appb-100020
    且L 1为
    Figure PCTCN2019077026-appb-100021
    R 11为-NR 12R 13时，由式(VIII)化合物与
    Figure PCTCN2019077026-appb-100022
    及连有R 12和R 13取代基的胺(HNR 12R 13)反应制备式(I)化合物；
    Figure PCTCN2019077026-appb-100023
    或者，R 2为
    Figure PCTCN2019077026-appb-100024
    且L 1为
    Figure PCTCN2019077026-appb-100025
    由式(IX)化合物与
    Figure PCTCN2019077026-appb-100026
    反应制备式(I)化合物，
    Figure PCTCN2019077026-appb-100027
    R 1、R 2、R 11、R 12、R 13、X、L 1和T 1如权利要求1-6所定义。
  8. 一种式(VIII)所示的化合物，
    Figure PCTCN2019077026-appb-100028
    X和R 1如权利要求1-6所定义。
  9. 一种制备权利要求8所述的化合物的方法，包含以下步骤：
    方法A：
    Figure PCTCN2019077026-appb-100029
    将式(V)所示的2,3,4,9-四氢-10H-[1,4]噁嗪并[2,3-f]喹唑啉-10-酮，R 1XH，与卡特缩合剂充分接触获得式(VIII)所示化合物，其中X和R 1如权利要求1-6所定义，
    或者方法B：
    Figure PCTCN2019077026-appb-100030
    将式(V)所示的2,3,4,9-四氢-10H-[1,4]噁嗪并[2,3-f]喹唑啉-10-酮与卡特缩合剂充分接触获得式(VI)所示的化合物，化合物(VI)进一步与R 1XH反应得到式(VIII)所示化合物，其中X和R 1如权利要求1-6所定义，
    或者方法C：
    Figure PCTCN2019077026-appb-100031
    将式(II)所示的化合物与氯化试剂反应后与R 1XH反应得到式(VII)所示化合物，式(VII)所示化合物进一步发生还原关环反应后得到式(VIII)所示化合物，其中X和R 1如权利要求1-6所定义。
  10. 根据权利要求1至6中任一项所述的化合物、其药学上可接受的盐、异构体、水合物、溶剂化物、或前药，其中，所述化合物的药学上可接受的盐为选自所述化合物的盐酸盐、氢溴酸盐、氢碘酸盐、高氯酸盐、硫酸盐、硝酸盐、磷酸盐、甲酸盐、乙酸盐、丙酸盐、羟基乙酸盐、乳酸盐、琥珀酸盐、马来酸盐、酒石酸盐、苹果酸盐、柠檬酸盐、富马酸盐、葡萄糖酸盐、安息香酸盐、扁桃酸盐、甲磺酸盐、羟乙基磺酸盐、苯磺酸盐、草酸盐、棕榈酸盐、2-萘磺酸盐、对甲苯磺酸盐、环己氨基磺酸盐、水杨酸盐、己糖酸盐、三氟乙酸盐、铝盐、钙盐、氯普鲁卡因盐、胆碱盐、二乙醇胺盐、乙二胺盐、锂盐、镁盐、钾盐、钠盐和锌盐中的一种或多种。
  11. 一种治疗与酪氨酸激酶EGFR、HER2、HER3、HER4相关疾病的药用组合物，其由权利要求1-6所述的式(I)的化合物或其药学上可接受的盐或其水合物或其溶剂化物或其前药与药学上可接受的载体或赋形剂组成。
  12. 一种药用组合物:其中包含如权利要求1-6所述的式(I)的化合物或其药学上可接受的盐、水合物、溶剂化物、或前药作为活性成分，一个或多个其它的治疗剂，以及一种或多种药学上可接受的载体或赋形剂。
  13. 根据权利要求1-6中任一项所述的式(I)的化合物或其药学上可接受的盐或其前药用于制备治疗与酪氨酸激酶EGFR、HER2、HER3、HER4相关的癌症及自身免疫疾病的药物中的应用，其中所述癌症及自身免疫疾病包括：眼底疾病、干眼症、银屑病、白癜风、皮炎、斑秃、类风湿性关节炎、结肠炎、多重硬化、系统性红斑狼疮、克罗恩病、动脉粥样化、肺纤维化、肝纤维化、骨髓纤维化、非小细胞肺癌、小细胞肺癌、乳腺癌、胰腺癌、神经胶质瘤、胶质母细胞瘤、卵巢癌、子宫颈癌、结肠直肠癌、黑色素瘤、子宫内膜癌、前列腺癌、膀胱癌、白血病、胃癌、肝癌、胃肠间质瘤、甲状腺癌、慢性粒细胞白血病、急性髓细胞性白血病、非霍奇金淋巴瘤、鼻咽癌、食道癌、脑瘤、B细胞和T细胞淋巴瘤、淋巴瘤、多发性骨髓瘤、胆道癌肉瘤、胆管癌。
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