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WO2019170086A1 - Composé d'oxazino-quinazoline à substitution acyle, son procédé de préparation et ses applications - Google Patents

Composé d'oxazino-quinazoline à substitution acyle, son procédé de préparation et ses applications Download PDF

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Publication number
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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group
compound
alkyl
independently
formula
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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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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

Font l'objet de la présente invention un composé d'oxazino-quinazoline à substitution acyle, son procédé de préparation et ses applications. Fait plus particulièrement l'objet de la présente invention un composé de formule (I), son isomère, son hydrate, son solvate, son sel pharmaceutiquement acceptable et son promédicament, son procédé de préparation et ses applications dans la préparation d'un médicament agissant comme inhibiteur de la kinase. Ledit composé présente une bonne activité inhibitrice sur la kinase du récepteur de l'EGF muté et une activité inhibitrice modérée sur la kinase du récepteur de l'EGF sauvage. (I)
PCT/CN2019/077026 2018-03-06 2019-03-05 Composé d'oxazino-quinazoline à substitution acyle, son procédé de préparation et ses applications Ceased WO2019170086A1 (fr)

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CN102875570A (zh) * 2012-10-23 2013-01-16 浙江大学 喹唑啉衍生物及其制备方法和用途
CN103965213A (zh) * 2013-02-02 2014-08-06 江苏奥赛康药业股份有限公司 7,8-二氢-6H-[1,4]噁嗪[3,2-g]喹唑啉类衍生物及其制备方法和用途
CN104530063A (zh) * 2015-01-13 2015-04-22 北京达立泰制药科技有限公司 喹唑啉并杂环类化合物及其制备方法和作为用于治疗癌症的表皮生长因子受体抑制剂的应用

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US7576074B2 (en) * 2002-07-15 2009-08-18 Rice Kenneth D Receptor-type kinase modulators and methods of use
CN103965211A (zh) * 2013-02-02 2014-08-06 江苏奥赛康药业股份有限公司 含喹唑啉结构的三环类衍生物及其制备方法和用途
WO2017148391A1 (fr) * 2016-03-01 2017-09-08 上海医药集团股份有限公司 Composé hétérocyclique azoté, procédé de préparation, intermédiaire, composition et utilisation

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CN102875570A (zh) * 2012-10-23 2013-01-16 浙江大学 喹唑啉衍生物及其制备方法和用途
CN103965213A (zh) * 2013-02-02 2014-08-06 江苏奥赛康药业股份有限公司 7,8-二氢-6H-[1,4]噁嗪[3,2-g]喹唑啉类衍生物及其制备方法和用途
CN104530063A (zh) * 2015-01-13 2015-04-22 北京达立泰制药科技有限公司 喹唑啉并杂环类化合物及其制备方法和作为用于治疗癌症的表皮生长因子受体抑制剂的应用

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