CN110229172A - A kind of oxazines and quinazoline compounds, preparation method and applications of acyl group substitution - Google Patents

A kind of oxazines and quinazoline compounds, preparation method and applications of acyl group substitution Download PDF

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CN110229172A
CN110229172A CN201910162610.4A CN201910162610A CN110229172A CN 110229172 A CN110229172 A CN 110229172A CN 201910162610 A CN201910162610 A CN 201910162610A CN 110229172 A CN110229172 A CN 110229172A
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base
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propyl
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CN110229172B (en
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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 Saite Mingqiang Medicine Technology Co Ltd
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    • A—HUMAN NECESSITIES
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    • 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
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    • 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

Abstract

The oxazines and quinazoline compounds, preparation method and applications replaced the present invention provides a kind of acyl group; more particularly to compound shown in formula (I), its isomers, hydrate, solvate, its pharmaceutically acceptable salt and its prodrug, preparation method and its preparing the application in the drug as kinase inhibitor.The compounds of this invention has good inhibitory activity to mutant egf R kinases, while showing and also have appropriate inhibitory activity to Wild type EGFR kinases.

Description

A kind of oxazines and quinazoline compounds, preparation method and applications of acyl group substitution
Technical field
The invention belongs to pharmaceutical technology fields, are related to the oxazines and quinazoline compounds, preparation side of a kind of acyl group substitution Method and its application.
Background technique
Protein kinase is the important signal envoy of cell activities, can be catalyzed the γ of the end ATP-phosphate group transfer On hydroxyl receptor into substrate amino acid residue (serine, threonine, tyrosine), to activate target protein (Johnson L.N.,and Lewis R.J.,(2001)Structural basis for control by phosphorylation.Cheminform.101,2209.).Protein kinase takes part in numerous physiology courses, including cell increases It grows, survive, apoptosis, metabolism, (Adams J.A., (2001) Kinetic and catalytic such as transcription and differentiation mechanisms of protein kinases.Chemical reviews.101,2271.).In the existing drug target of human body In, protein kinase family member's accounting is up to 10% (Santos R., Ursu O., Gaulton A., etal. (2017) Acomprehensive map of molecular drug targets.Nature Reviews Drug Discovery.16,19.)。
EGF-R ELISA (ErbB) tyrosine kinase can adjust through a variety of ways cell Proliferation, migration, differentiation, Apoptosis and cell are mobile.In the malignant tumour of diversified forms, ErbB family member and its some ligands are usually overexpressed, Amplification or mutation, this becomes important therapeutic targets.The family protein kinases includes: ErbB1/EGFR/HER1, ErbB2/ HER2, ErbB3/HER3 and ErbB4/HER4.Wherein EGFR is the important target spot (Dienstmann for developing non-small cell lung cancer R.,et.al.,(2001)Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer.ONCOTARGET.2(3),165.)。
Gefitinib (Gefitinib), Erlotinib (Erlotinib), Conmana (Icotinib) are first generation targets To the reversible kinase inhibitor of EGFR, for treating non-small cell carcinoma.Such inhibitor is simultaneously to wild type and activated mutant Type EGFR is inhibited, and clinically achieves biggish success, but subject patient takes drug resistance after a period of time Property appearance, especially T790M be mutated caused by drug resistance make curative effect reduce or failure.Second generation EGFR inhibitor Afatinib It (Afatinib) is non-reversible type inhibitor, it, can be with the half Guang ammonia positioned at ATP binding pocket inlet containing michael acceptor Covalent bonding together occurs for sour residue (Cys797), which is directed to T790M mutant egf R kinases and Wild type EGFR kinases Extremely strong activity is shown, and Wild type EGFR kinases is higher than for the inhibitory activity of T790M mutant egf R kinases, this makes It is relatively narrow to obtain treatment window in clinical drug application, using effect unsatisfactory (Camidge, D.R., et.al. (2014) Acquired resistance to TKIs in solid tumours:learning from lung cancer.Nature Reviews Clinical Oncology.11,473.).EGFR kinase inhibitor Austria of the third generation is uncommon to replace Buddhist nun (Osimertinib) Wild type EGFR is compared to T790M mutant egf R kinases swash with difficult to understand do not realized for Buddhist nun (Olmutinib) The highly selective inhibition of enzyme, has widened clinical use window, realizes effective treatment to T790M mutated patient.Known three One of the reason of drug resistance is clinically generated for EGFR kinase inhibitor, be due to it to Wild type EGFR inhibitory activity excessively Caused by faint after patient's medication a period of time, amplification (the Chen L., et.al. of the Wild type EGFR kinases generated in vivo (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).It is based on This, exploitation has to the good inhibitory activity of T790M mutant egf R kinases, while showing to Wild type EGFR kinases appropriateness The novel active molecule of inhibitory activity be of great significance.
Summary of the invention
The present invention provides that compound shown in a kind of formula (I), its isomers, hydrate, solvate, its is pharmaceutically acceptable Salt and its prodrug,
In formula (I),
X is O or NH；
R1For
L is C1-C4Straight chained alkyl, or separately by R4、R5Substituted C1-C4Straight chained alkyl；
R4And R5It is independently H or C1-C3Alkyl；
R3For-H, the unsubstituted or C that is replaced by halogen, hydroxyl, cyano, carboxyl1-C6Alkyl, C1-C6Alkoxy, C3-C7 Naphthenic base, aryl, 4-7 circle heterocyclic ring base, 5-6 unit's heteroaryl, or simultaneously ring structure；
Described and ring structure is selected from aromatic ring and 5-6 member heteroaryl ring group, 5-6 member hetero-aromatic ring and 5-6 member heteroaryl ring group, and aromatic ring is simultaneously Simultaneously 5-6 member is miscellaneous for 5-6 member naphthenic base, aromatic ring and 5-6 circle heterocyclic ring base, 5-6 member hetero-aromatic ring and 5-6 member naphthenic base or 5-6 member hetero-aromatic ring Ring group；
The heterocycle, heteroaryl ring group are selected from the hetero atom of N, O or S containing 1-3；
The aryl, heteroaryl, heterocycle or simultaneously ring structure be it is non-substituted or independently be selected from halogen by 1-3 Element, cyano, hydroxyl, C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl, C3-C6Naphthenic base, C2-C3Alkynyl, C2-C3Alkene Base ,-NR'R " or-MR6Substituent group replace；
R', R " are independently H or C1-C3Alkyl；
M is-O (CH2)qOr-C (O)-, wherein q is the integer of 1-4；
R6For-H, hydroxyl, C1-C3Alkyl, C1-C3Alkoxy, or-NR7R8；
R7And R8It is independently-H, C1-C3Alkyl or R7、R8It is connected to form 4-7 circle heterocyclic ring；
R2For
L1It is selected from:
T1For C1-C8Straight chained alkyl, or separately by R9、R10Substituted C1-C8Straight chained alkyl；
R9And R10It is independently-H or C1-C3Alkyl；
R11For-H, hydroxyl, C1-C3Alkyl, C3-C7Naphthenic base, C1-C3Alkoxy, C1-C3Alkylthio group, 4-7 circle heterocyclic ring base Or-NR12R13,
R12And R13It is independently-H, C1-C6Alkyl, C3-C6Naphthenic base, the C being optionally substituted by a hydroxyl group1-C6Alkyl or by C1- C3The C that alkoxy replaces1-C6Alkyl；
The 4-7 circle heterocyclic ring base is the heteroatomic heterocycles that N, O or S are selected from containing 1-2, the heterocycle not by Replace or by C1-C3Alkyl, aldehyde radical, C1-C4Alkyl acyl, aminoacyl, single or double substituted C1-C3Aminoacyl, C1-C3Alkane Base sulfuryl, C1-C3Sulphur in the substitution of one or both of alkyl sulfoxide base or heterocycle is aoxidized by one to two oxygen atom.
In a preferred embodiment,
R1For
L is C1-C3Straight chained alkyl, or separately by R4、R5Substituted C1-C3Straight chained alkyl；
R4And R5It is independently-H or C1-C3Alkyl；
R3For-H, the unsubstituted or C that is replaced by halogen, hydroxyl, cyano, carboxyl1-C3Alkyl, C1-C3Alkoxy, C3-C6 Naphthenic base, aryl, 5-6 circle heterocyclic ring base, 5-6 unit's heteroaryl, or simultaneously ring structure；
Described and ring structure is selected from benzo 5-6 heteroaryl ring group, 5-6 member hetero-aromatic ring and 5-6 member heteroaryl ring group, benzo 5-6 ring Alkyl, benzo 5-6 heterocycle, 5-6 member hetero-aromatic ring and 5-6 naphthenic base, 5-6 member hetero-aromatic ring and 5-6 circle heterocyclic ring base,
The heterocycle, heteroaryl ring group are selected from the hetero atom of N, O or S containing 1-3；
The aryl, heteroaryl, heterocycle or simultaneously ring structure is non-substituted or is separately selected from halogen by 1-3 Element, cyano, hydroxyl, C1-C3Alkyl, C1-C3Alkoxy, halogenated C1-C3Alkyl, C3-C4Naphthenic base, C2-C3Alkynyl, C2-C3Alkene Base ,-NR'R " or-MR6Substituent group replace；
R' and R " is independently H or C1-C3Alkyl；
M is-O (CH2)qOr-C (O)-, wherein q is the integer of 1-3；
R6For H, hydroxyl, C1-C3Alkyl, C1-C3Alkoxy, or-NR7R8；
R7、R8It is independently H, C1-C3Alkyl or R7、R8It is connected to form 5-6 circle heterocyclic ring.
In another preferred embodiment,
R1For
L is C1-C3Straight chained alkyl, or separately by R4、R5Substituted C1-C2Straight chained alkyl；
R4And R5It is independently-H or methyl；
R3It is selected from :-H, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyclopropyl, Cyclobutyl, cyclopenta, cyclohexyl, hydroxyl, carboxyl, 1- hydroxyl -1- Methylethyl or following group:
R14For-H or C1-C3Alkyl；
Q1、Q2、Q3、Q4, Q5 be independently N or CH；
(R15)pFor p identical or different R15Substituent group, p 0,1,2 or 3；
R15Selected from-H ,-F ,-Cl ,-Br ,-CF3,-OCF3, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, third Oxygroup, isopropoxy, acetenyl, vinyl, cyclopropyl, cyclobutyl, hydroxyl, cyano ,-NR'R " or-MR6；
R', R " are independently H, methyl, ethyl, propyl or isopropyl；
M is-O (CH2)qOr-C (O)-, wherein q is 1,2 or 3；
R6For H, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, or-NR7R8；
R7、R8It is independently H, methyl, ethyl, propyl, isopropyl or R7、R8It is connected to form 5-6 circle heterocyclic ring, it is described 5-6 circle heterocyclic ring is preferred:
In some preferred embodiments, R1For
L is C1-C3Straight chained alkyl, or separately by R4、R5Substituted C1-C3Straight chained alkyl；
R4And R5It is independently-H or methyl；
R3It is selected from :-H, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyclopropyl, Cyclobutyl, cyclopenta, cyclohexyl, hydroxyl, carboxyl, 1- hydroxyl -1- Methylethyl or following group:
R14For-H or C1-C3Alkyl；
(R15)pFor p identical or different R15Substituent group, p 0,1,2 or 3；
R15Selected from-H ,-F ,-Cl ,-Br ,-CF3,-OCF3, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, third Oxygroup, isopropoxy, acetenyl, vinyl, cyclopropyl, cyclobutyl, hydroxyl, cyano ,-NR'R " or-MR6；
R', R " are independently H, methyl, ethyl, propyl or isopropyl；
M is-O (CH2)qOr-C (O)-, wherein q is 1,2 or 3；
R6For H, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, or- NR7R8；
R7、R8It is independently H, methyl, ethyl, propyl, isopropyl or R7、R8It is connected to be formed
Preferably,
R2For
L1It is selected from:
T1For C1-C6Straight chained alkyl, or separately by R9、R10Substituted C1-C6Straight chained alkyl；
R9And R10It is independently-H or methyl；
R11For-H, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, 5-6 circle heterocyclic ring base or-NR12R13；
R12And R13It is independently-H, methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, sec-butyl is different Butyl, 1- ethyl propyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ethoxy, hydroxypropyl, hydroxyl butyl, methoxy ethyl, Methoxy-propyl, methoxybutyl, ethoxyethyl group, ethoxycarbonyl propyl, ethoxybutyl, Among, propoxypropyl, Propyloxybutyl, isopropoxyethyl, isopropoxide propyl or isopropoxy butyl；
The 5-6 circle heterocyclic ring base is the heteroatomic heterocycle that N, O or S are selected from containing 1-2, and the 5-6 member is miscellaneous Ring group is unsubstituted or by methyl, ethyl, propyl, isopropyl, aldehyde radical, formoxyl, acetyl group, propiono, bytyry, isobutyryl Base, aminoacyl, methylamino acyl group, dimethylamino acyl group, methylsulfonyl, ethyl sulfone, isopropyl sulfuryl, first sulfoxide group, second sulfoxide group, Sulphur in the substitution of one or both of isopropyl sulfoxide group or heterocycle is aoxidized by one to two oxygen atom；
The 5-6 circle heterocyclic ring is selected from:
Preferably,
R2For
L1It is selected from:
T1For C1-C6Straight chained alkyl, or separately by R9、R10Substituted C1-C6Straight chained alkyl；
R9And R10It is independently-H or methyl；
R11For-H, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methoxyl group, Ethyoxyl, propoxyl group, isopropoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, 5-6 circle heterocyclic ring base or-NR12R13；
R12And R13It is independently H, methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, sec-butyl, isobutyl Base, 1- ethyl propyl, cyclopropyl, cyclobutyl, cyclopenta, ethoxy, hydroxypropyl, methoxy ethyl, methoxy-propyl, ethyoxyl Ethyl, ethoxycarbonyl propyl, Among, propoxypropyl, isopropoxyethyl or isopropoxide propyl；
The 5-6 circle heterocyclic ring base is the heteroatomic heterocycle that N, O or S are selected from containing 1-2, and the 5-6 member is miscellaneous Ring group is unsubstituted or by methyl, ethyl, propyl, isopropyl, aldehyde radical, formoxyl, acetyl group, propiono, bytyry, isobutyryl Base, aminoacyl, methylamino acyl group, dimethylamino acyl group, methylsulfonyl, ethyl sulfone, isopropyl sulfuryl, first sulfoxide group, second sulfoxide group, Sulphur in the substitution of one or both of isopropyl sulfoxide group or heterocycle is aoxidized by one to two oxygen atom；
The 5-6 circle heterocyclic ring base is selected from:
R16For H, amino, methylamino, dimethylamino, methyl, ethyl, propyl, isopropyl.
The invention further relates to a kind of method for treating the kinase mediated disease such as EGFR, HER2, HER3, HER4 or illness, It include to formula (I) compound of patient in need (people or other mammals, especially people) dosage treatment effective amount or Its salt, described EGFR, HER2, HER3, HER4 etc. kinase mediated disease or illness include aforementioned those of refer to.
The present invention also provides preparation respective compound method, can be used a variety of synthetic methods prepare it is as described herein Compound, including following methods, the compound of the present invention or its pharmaceutically acceptable salt, isomers or hydrate can be with Using synthetic method known to following methods and organic chemical synthesis field, or by those skilled in the art understand that these sides The changing method of method synthesizes, and preferred method includes but is not limited to following methods.
The present invention illustrates that the synthetic route of compound of formula I, the present invention mainly illustrate following three kinds of systems by taking following scheme as an example Standby scheme:
The preparation route one of compound shown in Formulas I: where R1、R2、R8、R9、R10、R11、R12、R13、L1, X and T1As above It is defined.
Reaction step a): chloro- -4 (3H) -one of 6- nitro-quinazoline of 5- and the plus hydrogenated sodium of ethylene glycol are come into full contact with into acquisition formula Compound 5- (2- hydroxyl-oxethyl) -6- nitro-quinazoline -4 (3H) -one that II is indicated.
Reaction step b): by (2- hydroxyl-oxethyl) -6- nitro-quinazoline -4 (3H) -one of 5- represented by Formula II and chlorination Reagent is added water after coming into full contact with and obtains 5- (2- chloroethoxy) -6- nitro-quinazoline -4 (3H) -one shown in formula III,
The chlorination reagent is including but not limited to phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride and chlorine it One or both or more combination.
Reaction step c): 5- shown in formula III (2- chloroethoxy) -6- nitro-quinazoline -4 (3H) -one is restored Reaction obtains 5- shown in formula IV (2- chloroethoxy) -6- amido quinazoline -4 (3H) -one.
The condition of reduction reaction is including but not limited to hydrogen and Raney's nickel, hydrogen and palladium carbon, iron powder, zinc powder or protochloride Tin.
Reaction step d): 5- shown in formula IV (2- chloroethoxy) -6- amido quinazoline -4 (3H) -one is dissolved in solvent In, heating obtains simultaneously [2, the 3-f] quinazoline -10- ketone of 2,3,4,9- tetrahydro -10H- [Isosorbide-5-Nitrae] oxazines shown in Formula V；
The solvent is selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, N,N-dimethylformamide (DMF), N, N- bis- Combination more than one of methylacetamide (DMA), N-Methyl pyrrolidone (NMP), dioxane and dichloroethanes and the two；
Preferably, which can carry out under the conditions of base catalysis, and the alkali is including but not limited to triethylamine, diisopropyl Ethylamine, pyridine, 4-dimethylaminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo, N-methylmorpholine, sodium carbonate, potassium carbonate With a combination of one or more of cesium carbonate.
Reaction step e): by shown in Formula V 2,3,4,9- tetrahydro -10H- [Isosorbide-5-Nitrae] oxazines [2,3-f] quinazoline -10- ketone, R1XH and the special condensing agent of card come into full contact with and obtain oxazines shown in Formula VII and quinazoline compounds；
Preferably, block special condensing agent and be selected from benzotriazole -1- base oxygroup three (dimethylamino) phosphorus hexafluorophosphate (BOP) or hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP) one of them or both group It closes；
Preferably, above-mentioned reaction can also carry out under alkaline condition, and the alkali is different including but not limited to triethylamine, two Ethylamine, the dilute diamines of three second, 1,8- diazabicylo, 11 carbon -7- alkene (DBU), pyridine, N-methylmorpholine, 4- diformazan ammonia One or more kinds of combinations of yl pyridines, sodium carbonate, potassium carbonate and cesium carbonate.
Reaction step f-A): by Formula VIII compound represented and R2Condensation reaction or R occur for C (O) Cl2COOH and chlorination Condensation reaction occurs with Formula VIII compound represented again after reagent reaction and obtains compound shown in Formulas I；
The chlorination reagent is selected from phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride therein one Kind or two or more combinations；
Preferably, above-mentioned reaction can carry out under alkaline condition, and the alkali includes but is not limited to triethylamine, diisopropyl Base ethylamine, pyridine, 4-dimethylaminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo, N-methylmorpholine, sodium carbonate, carbonic acid The a combination of one or more of potassium and cesium carbonate.
Reaction step f-B): alternatively, working as R2ForAnd R11For HNR12R13, L1For When, by Formula VIII compound withIt is added after reaction and is connected with R12And R13The amine of substituent groupInstead Answer preparation of compounds of formula I；
Preferably, above-mentioned reaction can carry out in organic solvent, and the organic solvent is including but not limited to tetrahydrofuran (THF), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), N-Methyl pyrrolidone (NMP), dioxy six Combination more than one of ring and dichloroethanes and the two；
Reaction step f-C): alternatively, working as R2ForAnd L1ForWhen, step f-C1 is carried out under condensing agent effect by Formula VIII compound and 2- (diethoxy phosphoryl) acetic acid Reaction obtains compound shown in Formula IX, Formula IX compound further withGeneration step f- C2 reacts to obtain compound of formula I.
Preferably, the condensing agent includes but is not limited to carbodiimide type condensing agent, salt condensing agent, organic phosphates contracting The one or more of mixture and other classification condensing agents, preferably N, N'- carbonyl dimidazoles (CDI), N, N- dicyclohexyl carbon Diimine (DCC), N, N- diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), n,N-diisopropylethylamine (DIEA), 1- hydroxyl -7- azo benzotriazole (HOAt), O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid Ester (TBTU), three (dimethylamino) phosphorus hexafluorophosphate (BOP) of benzotriazole -1- base oxygroup, (7- aoxidizes benzo three to 2- Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluoro Phosphate (HCTU), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), propyl phosphoric acid Acid anhydride (T3P), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI), 1- ethyl (3- dimethylamino third Base) carbodiimide (EDC), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Wan Phosphonium (PyBOP), (3H-1,2,3 triazols [4,5-b] pyridine -3- oxygroup) three -1- Bi cough up a combination of one or more in Wan Ji Phosphonium hexafluorophosphate (PyAOP)；
Preferably, this step can carry out in organic base, and the organic base is including but not limited to triethylamine, diisopropyl Ethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2,6- lutidines (Lutidine), 1,8- diaza two 11 carbon -7- alkene (DBU) of ring and N-methylmorpholine a combination of one or more.
Preferably, step f-C2 can occur under the action of alkali in non-protonic solvent.The non-protonic solvent packet Contain but be not limited to tetrahydrofuran (THF), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), N- methyl pyrrole Combination more than one of pyrrolidone (NMP), dioxane and the two；The alkali is including but not limited to sodium hydride, double trimethyls The combination of one of silicon substrate amido lithium and the two.
Above-mentioned steps f-A), step f-B) and f-C) between for and the step of column selection, i.e., compound shown in Formula VIII can Pass through f-A), step f-B) and one of f-C) compound shown in preparation formula, i.e. compound shown in Formula VIII can pass through f-A) Prepare compound shown in compound shown in formula (I) or Formula VIII and pass through step f-B) prepare compound shown in formula (I), Huo Zhetong Cross f-C) prepare compound shown in formula (I).
The preparation route two of compound shown in Formulas I: where R1、R2、R8、R9、R10、R11、R12、R13、L1, X and T1As above It is defined.
Reaction step a): by shown in Formula V 2,3,4,9- tetrahydro -10H- [Isosorbide-5-Nitrae] oxazines [2,3-f] quinazoline -10- ketone, It is come into full contact with the special condensing agent of card and obtains Formula IV compound represented.Wherein R1For the substituent group described in claim 1.It is preferred that Ground blocks special condensing agent and is selected from three (dimethylamino) phosphorus hexafluorophosphate (BOP) of benzotriazole -1- base oxygroup or hexafluoro Phosphoric acid benzotriazole -1- base-oxygroup tripyrrole alkyl phosphorus (PyBOP) one of them or both combination；Above-mentioned reaction It can carry out under alkaline condition, the alkali is including but not limited to triethylamine, diisopropyl ethyl amine, triethylene diamine, and 1, 11 carbon -7- alkene (DBU) of 8- diazabicylo, pyridine, N-methylmorpholine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, carbon One or more kinds of combinations of sour caesium.
Reaction step b): by 10- shown in Formula IV ((1H- benzo [d] [1,2,3] triazole -1- base) oxygen) -3,4- two Hydrogen -2H- [1,4] oxazines [2,3-f] quinazoline and R1XH comes into full contact with to obtain compound shown in Formula VIII in organic solvent.It is preferred that Ground, organic solvent are selected from methanol, ethyl alcohol, isopropanol, tetrahydrofuran, n,N-Dimethylformamide (DMF), N, N- dimethylacetamide Combination more than one of amine (DMA), N-Methyl pyrrolidone (NMP), dioxane, dichloroethanes and the two；Preferably, this is anti- It should can be carried out under the conditions of base catalysis, the alkali is including but not limited to triethylamine, diisopropyl ethyl amine, pyridine, 4- diformazan Aminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo, N-methylmorpholine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride one Kind or two or more combinations；Preferably, which can carry out under acid catalysed conditions, and the acid is including but not limited to methylsulphur One of acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, trifluoroacetic acid, hydrochloric acid or two or more combinations.
Reaction step c-A): by Formula VIII compound represented and R2C (O) Cl or R2COOH is sent out after reacting with chlorination reagent Raw condensation reaction obtains compound shown in Formulas I；
It is therein that the chlorination reagent is preferable over phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride One or more kinds of combinations；
Preferably, above-mentioned reaction can carry out under alkaline condition, and the alkali includes but is not limited to triethylamine, diisopropyl Base ethylamine, pyridine, 4-dimethylaminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo, N-methylmorpholine, sodium carbonate, carbonic acid The a combination of one or more of potassium, cesium carbonate.
Reaction step c-B): alternatively, working as R2ForAnd R11For HNR12R13, when L is vinyl, By Formula VIII compound withIt is added after reaction and is connected with R12And R13The amine of substituent groupInstead Answer preparation of compounds of formula I；
Preferably, above-mentioned reaction can carry out in organic solvent, and the organic solvent is including but not limited to tetrahydrofuran (THF), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), N-Methyl pyrrolidone (NMP), dioxy six Combination more than one of ring and dichloroethanes and the two；
Reaction step c-C): alternatively, working as R2ForAnd L1ForWhen, step c-C1 is carried out under condensing agent effect by Formula VIII compound and 2- (diethoxy phosphoryl) acetic acid Reaction obtains compound shown in Formula IX, Formula IX compound further withGeneration step c- C2 reacts to obtain compound of formula I；
Preferably, the condensing agent includes but is not limited to carbodiimide type condensing agent, salt condensing agent, organic phosphates contracting The one or more of mixture and other classification condensing agents, preferably N, N'- carbonyl dimidazoles (CDI), N, N- dicyclohexyl carbon Diimine (DCC), N, N- diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), n,N-diisopropylethylamine (DIEA), 1- hydroxyl -7- azo benzotriazole (HOAt), O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid Ester (TBTU), three (dimethylamino) phosphorus hexafluorophosphate (BOP) of benzotriazole -1- base oxygroup, (7- aoxidizes benzo three to 2- Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluoro Phosphate (HCTU), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), propyl phosphoric acid Acid anhydride (T3P), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI), 1- ethyl (3- dimethylamino third Base) carbodiimide (EDC), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Wan Phosphonium (PyBOP), (3H-1,2,3 triazols [4,5-b] pyridine -3- oxygroup) three -1- Bi cough up a combination of one or more in Wan Ji Phosphonium hexafluorophosphate (PyAOP)；
Preferably, this step can carry out in organic base, and the organic base is including but not limited to triethylamine, diisopropyl Ethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2,6- lutidines (Lutidine) and 1,8- diaza two 11 carbon -7- alkene (DBU) of ring or N-methylmorpholine a combination of one or more.
Preferably, step c-C2 can occur under the action of alkali in non-protonic solvent.The non-protonic solvent packet Contain but be not limited to tetrahydrofuran (THF), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), N- methyl pyrrole Combination more than one of pyrrolidone (NMP), dioxane and the two；The alkali is including but not limited to sodium hydride, double trimethyls The combination of one of silicon substrate amido lithium and the two.
Above-mentioned steps c-A), step c-B) and c-C) between for and the step of column selection, i.e., compound shown in Formula VIII can Pass through c-A), step c-B) and one of c-C) compound shown in preparation formula, i.e. compound shown in Formula VIII can pass through c-A) Prepare compound shown in compound shown in formula (I) or Formula VIII and pass through step c-B) prepare compound shown in formula (I), Huo Zhetong Cross c-C) prepare compound shown in formula (I).
The preparation route three of target compound, wherein R1、R2、R8、R9、R10、R11、R12、R13、L1, X and T1As determined above Justice.
Reaction step a): by Formula II indicate compound 5- (2- hydroxyl-oxethyl) -6- nitro-quinazoline -4 (3H) -one with Chlorination reagent reaction after again with R1XH contact obtains quinazoline compounds shown in Formula VII.Chlorination reagent including but not limited to Phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, combination more than one of chlorine or both.
Reaction step b): quinazoline compounds shown in Formula VII are obtained into oxazines shown in Formula VIII under the reducing conditions And quinazoline compounds, the reducing condition is including but not limited to hydrogen and Raney's nickel, hydrogen and palladium carbon, iron powder, zinc powder, Stannous chloride.
Reaction step c-A): by Formula VIII compound represented and R2C (O) Cl or R2COOH is sent out after reacting with chlorination reagent Raw condensation reaction obtains compound shown in Formulas I；
It is therein that the chlorination reagent is preferable over phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride One or more kinds of combinations；Preferably, above-mentioned reaction can carry out under alkaline condition, and the alkali includes but unlimited In triethylamine, diisopropyl ethyl amine, pyridine, 4-dimethylaminopyridine, 11 carbon -7- alkene of 1,8- diazabicylo, N- methyl The a combination of one or more of morpholine, sodium carbonate, potassium carbonate, cesium carbonate.
Reaction step c-B): alternatively, reaction step c-B): alternatively, working as R2ForAnd R11For HNR12R13, L be vinyl when, by Formula VIII compound withIt is added after reaction and is connected with R12And R13Substituent group AmineReact preparation of compounds of formula I；
Preferably, above-mentioned reaction can carry out in organic solvent, and the organic solvent is including but not limited to tetrahydrofuran (THF), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), N-Methyl pyrrolidone (NMP), dioxy six Combination more than one of ring, dichloroethanes and the two；
Reaction step c-C): alternatively, working as R2ForAnd L1ForWhen, step c-C1 is carried out under condensing agent effect by Formula VIII compound and 2- (diethoxy phosphoryl) acetic acid Reaction obtains compound shown in Formula IX, Formula IX compound further withGeneration step c- C2 reacts to obtain compound of formula I.
Preferably, the condensing agent includes but is not limited to carbodiimide type condensing agent, salt condensing agent, organic phosphates contracting The one or more of mixture and other classification condensing agents, preferably N, N'- carbonyl dimidazoles (CDI), N, N- dicyclohexyl carbon Diimine (DCC), N, N- diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), n,N-diisopropylethylamine (DIEA), 1- hydroxyl -7- azo benzotriazole (HOAt), O- benzotriazole-N, N, N', N'- tetramethylurea tetrafluoro boric acid Ester (TBTU), three (dimethylamino) phosphorus hexafluorophosphate (BOP) of benzotriazole -1- base oxygroup, (7- aoxidizes benzo three to 2- Nitrogen azoles)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HBTU), 6- Chloro-Benzotriazole -1,1,3,3- tetramethylurea hexafluoro Phosphate (HCTU), 2- (7- aoxidizes benzotriazole)-N, N, N', N'- tetramethylurea hexafluorophosphoric acid ester (HATU), propyl phosphoric acid Acid anhydride (T3P), 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride (EDCI), 1- ethyl (3- dimethylamino third Base) carbodiimide (EDC), hexafluorophosphoric acid benzotriazole -1- base-oxygroup tripyrrole Wan Phosphonium (PyBOP), (3H-1,2,3 triazols [4,5-b] pyridine -3- oxygroup) three -1- Bi cough up a combination of one or more in Wan Ji Phosphonium hexafluorophosphate (PyAOP)；
Preferably, this step can carry out in organic base, and the organic base is including but not limited to triethylamine, diisopropyl Ethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2,6- lutidines (Lutidine), 1,8- diaza two 11 carbon -7- alkene (DBU) of ring or N-methylmorpholine a combination of one or more.
Preferably, step c-C2 can occur under the action of alkali in non-protonic solvent.The non-protonic solvent packet Contain but be not limited to tetrahydrofuran (THF), N,N-dimethylformamide (DMF), DMAC N,N' dimethyl acetamide (DMA), N- methyl pyrrole Combination more than one of pyrrolidone (NMP), dioxane and the two；The alkali is including but not limited to sodium hydride, double trimethyls The combination of one of silicon substrate amido lithium and the two.
Above-mentioned steps c-A), step c-B) and c-C) between for and the step of column selection, i.e., compound shown in Formula VIII can Pass through c-A), step c-B) and one of c-C) compound shown in preparation formula, i.e. compound shown in Formula VIII can pass through c-A) Prepare compound shown in compound shown in formula (I) or Formula VIII and pass through step c-B) prepare compound shown in formula (I), Huo Zhetong Cross c-C) prepare compound shown in formula (I).
Detailed description of the invention
Term " substitution " referred to here, including complicated substituent group (for example, phenyl, aryl, miscellaneous alkyl, heteroaryl), Proper is 1 to 5 substituent group, preferably 1 to 3, preferably 1 to 2, can freely be selected from substituent group list It selects.
Unless there are specified otherwise, alkyl as used herein includes the alkyl of saturation unit price, these alkyl have a straight chain, branch or Annulus.For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n- butyl, isobutyl group, sec-butyl, tert- Butyl, cyclobutyl, n- amyl, 3- (2- methyl) butyl, 2- amyl, 2- methyl butyl, neopentyl, cyclopenta, n- hexyl, 2- oneself Base, 2- methyl amyl and cyclohexyl.Alkoxy is by previously described straight chain, the oxide ether of branch or cyclic alkyl composition.It is similar , alkenyl and alkynyl include straight chain, branch or cyclic alkenyl radical and alkynyl.
Term " aryl " used herein refers to unsubstituted or substituted virtue unless otherwise specified Perfume base, such as phenyl, naphthalene, anthryl.Term " aroyl " refers to-C (O)-aryl.
Term " heterocycle " used herein represents unsubstituted or substituted steady unless there are specified otherwise 3 to 8 fixed unit monocycle saturated ring systems, they are made of carbon atom and 1 to 3 hetero atom selected from N, O, S, wherein N, S hetero atom can be aoxidized arbitrarily, and N hetero atom can also be by arbitrarily quaternized.Heterocycle can be with any hetero atom or carbon atom In conjunction with thus one stable structure of composition.The example of this kind of heterocycle includes but is not limited to piperidine base, pyrroles Alkyl, piperidyl, piperazinyl, oxidation piperazinyl, oxyl base, tetrahydrofuran base, dioxolanyl, imidazolidine base, four Hydrogen thiazolyl, tetrahydro oxazolyl, THP trtrahydropyranyl, morpholine base, thio-morpholine group, thiophene morpholine sulfoxide, thiophene morpholine sulfone And oxadiazoles base.
Term " heteroaryl " used herein represents unsubstituted or substituted stabilization unless otherwise specified 5 or 6 unit monocycle aromatic ring systems, unsubstituted or substituted thick benzene heteroaromatic ring systems of 9 or 10 yuan of benzene can also be represented Or bicyclic heteroaromatic ring system, they are formed by carbon atom and by 1 to 4 hetero atom selected from N, O, S, wherein N, the miscellaneous original of S Son can be aoxidized arbitrarily, and N hetero atom can also be by arbitrarily quaternized.Heteroaryl can stick with any hetero atom or carbon atom Get up, thus one stable structure of composition.The example of heteroaryl includes but is not limited to thianthrene group, furyl, imidazoles Base, isoxazolyl, oh oxazolyl, pyrazolyl, pyrrole radicals, thiazolyl, thiadiazolyl group, triazolyl, pyridyl group, pyridazinyl, indyl, Azaindolyl, indazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzo isoxazolyl, benzoxazolyl, benzene And pyrazolyl, benzothiazolyl, diazosulfide base, benzotriazole base, adenyl, quinolyl or isoquinolyl.
Term " carbonyl " refers to C (O) base.
No matter when term " alkyl " or " aryl " or they any prefix root appear in the title of a substituent In (for example, aralkyl, dialkyl amino), those of it will be considered containing the above are " alkyl " and " aryl " and provide limit System.The specified quantity of carbon atom is (for example, C1-C6) indicate independent in a moieties or in a bigger substituent group In moieties (wherein alkyl is as its prefix root) in carbon atom quantity.
It is clear that the compound of Formulas I, isomers, crystal form or prodrug and its officinal salt there may be solvation form and Nonsolvated forms.Such as solvation form can be water-soluble form.The present invention include all these solvations and non-solvent The form of change.
The compound of the present invention may have asymmetric carbon atom, according to their physical and chemical difference, by known technology Mature method, for example, this diastereoisomeric mixture can be separated into single by chromatography or Steppecd crystallization Diastereoisomer.The separation of enantiomter can be by first with suitably there is the compound of optically active to be reacted, right The mixture for reflecting isomery is converted to diastereoisomeric mixture, separates diastereoisomer, then single diastereoisomer (hydrolysis) is converted into corresponding pure enantiomter.All such isomers, including non-enantiomer mixture and pure Enantiomer is considered as a part of the invention.
As the compound of the present invention of active constituent, and the method for preparing the compound, it is all the contents of the present invention. Moreover, the crystalline forms of some compounds can be used as polycrystal presence, this form may also be included in that current invention In.In addition, some compounds can be formed together solvate, this solvent with water (i.e. hydrate) or common organic solvent Compound is also included in the scope of the present invention.
The compound of the present invention can be used to treat in a free form, or in the appropriate case with pharmaceutically acceptable Salt or other derivatives form for treating.As used herein, term " pharmaceutically acceptable salt " refers to of the invention The organic salt and inorganic salts of compound, this salt be suitable for the mankind and lower animal, no excessive toxicity, irritation, allergic reaction etc., With reasonable interests/Hazard ratio.The pharmaceutically acceptable salt of amine, carboxylic acid, phosphonate and other types of compound is in institute Category is well-known in field.The salt can be reacted by the compound of the present invention with suitable free alkali or acid.Including But be not limited to, with inorganic acid for example hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acid for example acetic acid, oxalic acid, maleic acid, The salt that tartaric acid, citric acid, succinic acid, malonic acid are formed, or by using method well known in the art, such as ion exchange Method, to obtain these salt.Other pharmaceutically acceptable salts include adipate, alginates, ascorbate, aspartic acid Salt, benzene sulfonate, benzoate, disulfate, borate, butyrate, camphor hydrochlorate, camsilate, citrate, two Portugals Sugar lime, lauryl sulfate, esilate, formates, fumarate, gluceptate, glycerophosphate, gluconic acid Salt, Hemisulphate, caproate, hydriodate, 2- isethionate, Lactobionate, lactate, laruate, lauryl sulphur It is hydrochlorate, malate, maleate, methane sulfonates, 2- naphthalene sulfonate, nicotinate, nitrate, oleate, palmitate, double Hydroxynaphthoate, persulfate, crosses 3- phenylpropionic acid salt, phosphate, picrate, propionate, stearate, sulphur at pectate Hydrochlorate, rhodanate, tosilate, undecanoate etc..Representative alkaline or alkaline-earth salts include sodium, lithium, potassium, Calcium, magnesium etc..Other pharmaceutically acceptable salts include nontoxic ammonium appropriate, quaternary ammonium, and using such as halogen ion, hydroxyl, The amido cation that carboxylate radical, sulfate radical, phosphate radical, nitrate anion, low-grade alkane sulfonate and arylsulphonate are formed.
In addition, terms used herein " prodrug ", which refers to a compound in vivo, can be converted into shown in formula (I) of the present invention Compound.This conversion is hydrolyzed in blood by pro-drug or the shadow in blood or tissue through enzymatic conversion for parent compound It rings.
Pharmaceutical composition of the invention includes structure formula (I) compound described herein or its pharmaceutically acceptable salt, swashs Enzyme inhibitor (small molecule, polypeptide, antibody etc.), immunosuppressor, anticarcinogen, antivirotic, anti-inflammatory agent, antifungal agent, antibiosis The other activating agent of plain or anti-angiogenic antihyperproliferative compound；And any pharmaceutically acceptable carrier, adjuvant or figuration Agent.
The compound of the present invention can be used as exclusive use, can also with one or more other the compound of the present invention or It is used with one or more other drug combinations.When being administered in combination, therapeutic agent can be configured to be administered simultaneously or sequentially exist Different time administrations or the therapeutic agent can be used as single composition administration.So-called " combination treatment ", refer to using The compound of the present invention is used together with another medicament, and administration mode is that co-administered or every kind of medicament are suitable simultaneously for every kind of medicament Sequence administration, no matter which kind of situation, purpose is all the optimum efficiency of drug to be reached.Co-administered includes while delivering dosage form, with And the independent dosage form of every kind of compound respectively.Therefore, the compound of the present invention administration can with known this field other Therapy uses simultaneously, for example, using radiotherapy or cytostatic agent, cytotoxic agent, Qi Takang in cancer treatment The adjunctive therapies such as cancer agent improve cancerous symptom.The present invention is not limited to the sequences of administration；The compound of the present invention can be applied previously With being administered simultaneously, or applied after other anticancer agents or cytotoxic agent.
In order to prepare the Pharmaceutical Compositions of this invention, one or more chemical combination of the molecule formula (I) as its active constituent Object or salt can be mixed closely with pharmaceutical carriers, this be carried out according to traditional pharmacy ingredients technical, wherein Carrier can be used a variety of more according to by different administration mode (for example, oral or parenteral administration) designed preparation form The form of sample.Pharmaceutically acceptable carrier appropriate is technically well-known.To some of such pharmaceutically acceptable The description of carrier can be found " pharmaceutical excipient handbook " is inner, and the book is by American Pharmaceutical Association and pharmacy society, Britain combined publication.
Pharmaceutical composition of the present invention can have following form, such as, it is suitble to oral administration, such as tablet, capsule, medicine Ball, medicinal powder, the form of sustained release, solution or suspension；For parental injection such as transparent liquid, suspension, emulsion；Or For local application's such as cream, frost；Or rectally is used for as suppository.Pharmaceutical Compositions can also be suitble in the form of unit dose Once daily for exact dose.The Pharmaceutical Compositions will be including a kind of traditional pharmaceutical carriers or excipient and according to mesh Compound made of preceding invention as active constituent, alternatively, it is also possible to include others medicine or pharmaceutical formulations, carrier, Adjuvant, etc..
Therapeutic compound can also award mammal and non-human.It will be taken to drug dose used in a mammal Certainly in the type of the animal and its disease condition or the de-synchronization state locating for it.Therapeutic compound can be with capsule, greatly The form of pill, tablet liquid medicine is fed for animal.Therapeutic compound can also be allowed to enter animal by way of injecting or inculcating In vivo.We prepare these medicament forms according to the traditional mode for meeting veterinary practice standard.As a kind of selectable Mode, pharmacy synthetic drug can mix with animal feed and be fed for animal, therefore, the feed addictive of concentration or mix and stir in advance Material can be in case of to mix common animal feed.
A further object of the present invention is to be to provide a kind of method for treating cancer in subject in need, packet Include a kind of method that the therapeutically effective amount of the composition containing the compound of the present invention is applied to subject.
The invention also includes the use of the compound of the present invention or its pharmaceutically acceptable derivates, preparation treatment and junket Application in the drug of the relevant cancer of histidine kinase EGFR, HER2, HER3, HER4 and autoimmune disease.The cancer (including non-physical knurl, solid tumor, primary or metastatic cancer, as pointed by the other places this paper and including cancer it is resistant or Refractory one or more other treatments) and Other diseases (including but not limited to fundus oculi disease, psoriasis, atheroma, Pulmonary fibrosis, liver fibrosis, myelofibrosis etc.) medicament.The cancer includes but is not limited to: non-small cell lung cancer, small thin Born of the same parents' lung cancer, breast cancer, cancer of pancreas, glioma, glioblastoma, oophoroma, cervix cancer, colorectal cancer, black Plain tumor, carcinoma of endometrium, prostate cancer, bladder cancer, leukaemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic grain are thin Born of the same parents' leukaemia, acute myelocytic leukemia, non-Hodgkin lymphoma, nasopharyngeal carcinoma, cancer of the esophagus, brain tumor, B cell and T cell leaching Any one of bar tumor, lymthoma, Huppert's disease, biliary tract carcinosarcoma, cholangiocarcinoma.
Examples provided below can better illustrate the present invention, and unless stated otherwise, all temperature are degree Celsius.
Specific embodiment
The intermediate that the compounds of this invention is related to can be prepared by the following method, but be not limited to following methods.The present invention Moiety intermediate synthesis can be with the method for referenced patent CN104530063, the simple replacement of some functional groups, art technology Personnel can accordingly adjust according to the field of chemical synthesis knowledge of grasp and obtain corresponding intermediate.During following present invention provides The preparation path of mesosome, the intermediate that the compounds of this invention is related to can be prepared by following scheme, but be not limited to lower section Case.
The synthesis of midbody compound shown in Formula VIII
Intermediate N (3- bromophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-1)
The preparation of step 1) 5- (2- hydroxyl-oxethyl) -6- nitro-quinazoline -4 (3H) -one (II)
Ethylene glycol (352.7g, 5.7mol) is dissolved in 1 liter of DMF, ice-water bath is cooling, addition sodium hydride (68.2g, 2.8mol), chloro- 6- nitro-quinazoline -4 (3H) -one of 5- is added after stirring 0.5 hour, (128g, 0.57mol) is slowly increased to room Temperature, stirring to end of reaction.Ethyl acetate is added to there are a large amount of solids to be precipitated, filters, obtained solid is beaten with water, and hydrochloric acid is adjusted to It is filtered after faintly acid, obtains 129.7 grams of white solid, yield 91%.1H NMR(DMSO-d6,400MHz)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]+。
The preparation of step 2) N- (3- bromophenyl) -5- (2- chloroethoxy) -6- nitro-quinazoline -4- amine (VII-1)
5- (2- hydroxyl-oxethyl) -6- nitro-quinazoline -4 (3H) -one (3g, 11.94mmol) is added in round-bottomed flask, Thionyl chloride stirring and dissolving is added, instills catalytic amount dimethylformamide, heating reaction solution is back to raw material fully reacting, depressurizes Be evaporated yellow solid is directly dissolved in methylene chloride, then be added 3- bromaniline (2g, 11.94mmol) ethanol solution, stir It mixes to fully reacting, n-hexane is added and stirs to there is a large amount of solids to be precipitated, suction filtration, petroleum ether dry to obtain yellow solid 3.7 Gram, yield 88%.MS:423[M+H]+。
Step 3) N- (3- bromophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-1) Preparation
N- (3- bromophenyl) -5- (2- chloroethoxy) -6- nitro-quinazoline -4- amine (3.7g, 8.7mmol) is added to round bottom In flask, be added second alcohol and water mixed solvent, then sequentially add iron powder (1.3g, 22.7mmol), acetic acid (1.85mL, 32.27mmol), reaction solution heating stirring is to fully reacting, boils off solvent, ethyl acetate extraction, concentration, column chromatograph yellow is solid 2.0 grams of body, yield 65%.1H NMR(500MHz,DMSO-d6) δ 10.03 (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]+。
Intermediate N (3- (trifluoromethyl) phenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-2) preparation
Step 1) of the step 1) with VIII-1 synthetic route.
Step 2) N- (3- (trifluoromethyl) phenyl) -5- (2- chloroethoxy) -6- nitro-quinazoline -4- amine (VII-2) Preparation
With reference to the preparation method of N- (3- bromophenyl) -5- (2- chloroethoxy) -6- nitro-quinazoline -4- amine (VII-1) Step 2), specific embodiment are to substitute 3- bromaniline with the 3- 5-trifluoromethylaniline of identical molar equivalent.MS:413[M+H]+。
Step 3) N- (3- (trifluoromethyl) phenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-2) preparation
With reference to N- (3- bromophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-1) The step 3) of preparation method, specific embodiment are with N- (3- (trifluoromethyl) phenyl) -5- (2- chloroethene of identical molar equivalent Oxygroup) -6- nitro-quinazoline -4- amine (VII-2) substitution N- (3- bromophenyl) -5- (2- chloroethoxy) -6- nitro-quinazoline -4- Amine (VII-1), yield 60%.1H NMR(500MHz,DMSO-d6)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]+。
Intermediate N (4- methoxyphenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-3) preparation
Step 1) of the step 1) with VIII-1 synthetic route.
The preparation of step 2) 5- (2- chloroethoxy) -6- nitro-quinazoline -4 (3H) -one (III)
By 5- (2- hydroxyl-oxethyl) -6- nitro-quinazoline -4 (3H) -one, (129.7g, 0.52mol) is placed in flask, 200 milliliters of phosphorus oxychloride are added, are heated to reflux to end of reaction.Phosphorus oxychloride is boiled off, adds water to be beaten to a large amount of solids are precipitated, takes out Filter, obtains 120.8 grams of white solid, yield 87%.1H NMR(400MHz,DMSO-d6)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]+。
The preparation of step 3) 5- (2- chloroethoxy) -6- amido quinazoline -4 (3H) -one (IV)
5- (2- chloroethoxy) -6- nitro-quinazoline -4 (3H) -one (120.8g, 0.45mol) is dissolved in methanol and tetrahydro The in the mixed solvent of furans is added 40 grams of Raney's nickels, is stirred at room temperature under hydrogen environment to end of reaction.It filters, is concentrated to give yellow 107.4 grams of solid, yield 100%.1H NMR(400MHz,DMSO-d6) δ 11.76 (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]+。
The preparation of step 4) 2,3,4,9- tetrahydro -10H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- ketone (V)
5- (2- chloroethoxy) -6- amido quinazoline -4 (3H) -one (107.4g, 0.45mol) is dissolved in 1 liter of DMF, is added Enter triethylamine (94mL, 0.68mol), be heated to boiling off DMF after completion of the reaction, addition methylene chloride stirs a large amount of solid to being precipitated Body filters, obtains 80 grams of white solid, yield 88%.1H NMR(DMSO-d6,300MHz)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]+。
Step 5) N- (4- methoxyphenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-3) preparation
By 2,3,4,9- tetrahydro -10H- [Isosorbide-5-Nitrae] oxazines simultaneously [2,3-f] quinazoline -10- ketone (0.5g, 2.46mmol), 4- first Oxygroup aniline (605mg, 4.92mmol), three (dimethylamino) phosphorus hexafluorophosphate (BOP) of benzotriazole -1- base oxygroup (1.4g, 3.20mmol) is set in a round bottom flask, and 5 milliliters of acetonitriles are added, are stirring evenly and then adding into 1,8- diazabicylo 11 Carbon -7- alkene (DBU) (0.56g, 3.69mmol), is stirred at room temperature to end of reaction, boils off solvent, gained mixture silica gel column layer Analysis, obtains 568 milligrams of brown solid, yield 75%.1H NMR(400MHz,DMSO-d6)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]+。
Intermediate N (3- chlorine 4- fluorophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-4) preparation
Step 1) is to step 4) with the step 1) in the preparation method of VIII-3 to step 4).
- 3,4- dihydro -2H- [1,4] oxazines is simultaneously by step 5) 10- ((1H- benzo [d] [1,2,3] triazole -1- base) oxygen) The preparation of [2,3-f] quinazoline (VI)
By 2,3,4,9- tetrahydro -10H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- ketone (20.3g, 100mmol) and benzene And three (dimethylamino) phosphorus hexafluorophosphate (BOP) (44.2g, 100mmol) of triazole -1- base oxygroup is placed in round-bottomed flask In, acetonitrile is added and is stirring evenly and then adding into 1,8- diazabicylo, 11 carbon -7- alkene (DBU) (15.2g, 100mmol), room temperature is stirred It mixes to end of reaction, adds water and stirs to a large amount of solids, suction filtration are precipitated, obtain 28 grams of yellow solids, yield 87%.1H NMR (400MHz,DMSO-d6) δ 8.26 (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]+。
Step 6) N- (3- chlorine 4- fluorophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-4) preparation
By 10- ((1H- benzo [d] [1,2,3] triazole -1- base) oxygen) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3- F] quinazoline (320mg, 1mmol) and m-chloro para-fluoroaniline (145mg, 1mmol), p-methyl benzenesulfonic acid monohydrate (17mg, It 0.1mmol) is dissolved in isopropanol, is stirred at room temperature to end of reaction, add water and stir, filter, obtain 300 milligrams of yellow solid products, Yield 91%.1H NMR(400MHz,DMSO-d6) δ 10.20 (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-d6)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]+。
Intermediate 10- (4- (3- fluorine benzyloxy) phenoxy group) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline (VIII-5) preparation
Step 1) to step 5) with the preparation method of VIII-4 step 1) to step 5).
Step 6) 10- ((3- methoxy-benzyl) oxygroup) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline (VIII-5) preparation
It is dissolved in 138 milligrams of meta-methoxy benzyl alcohol (1mmol) in 5 milliliters of dimethylformamides, 24 milli of sodium hydride is added Gram, it is stirred at room temperature to after being generated there is no gas and 10- ((1H- benzo [d] [1,2,3] triazole -1- base) oxygen) -3,4- bis- is added Hydrogen -2H- [Isosorbide-5-Nitrae] oxazines simultaneously 320 milligrams of [2,3-f] quinazoline (VI) (1mmol), is stirred at room temperature to end of reaction, water quenching is added to go out, 290 milligrams of yellow solid products, yield 89% are obtained after suction filtration.MS:324[M+H]+。
Intermediate VIII-6 to VIII-93 preparation
Step 1) is to step 4) with the step 1) in the synthetic method of VIII-3 to step 4).
Step 5) refers to the step 5) of VIII-3 synthetic route, and operation is identical, and implementation method is with 2,3,4,9- Simultaneously [2,3-f] quinazoline -10- ketone (V) is starting material to tetrahydro -10H- [Isosorbide-5-Nitrae] oxazines, by equal mole equivalent in following table R1XH substitutes 4- aminoanisole.It is as follows that compound is embodied:
Intermediate VIII-94 to VIII-103 preparation
Step 1) is to step 5) with the synthesis step 1 of compound VIII-4) to step 5).
The synthesis step 6 of step 6) reference compound VIII-4), operation is identical, and implementation method is with 10- (simultaneously [2,3-f] quinazoline (VI) is (1H- benzo [d] [1,2,3] triazole -1- oxygroup) -3,4- dihydro -2H- [1,4] oxazines Starting material, by the R of molar equivalent identical in following table1XH substitutes m-chloro para-fluoroaniline.It is as shown in the table that compound is embodied:
The preparation of embodiment compound
Embodiment 1
1- (10- ((3- bromophenyl) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinazoline -4- base) propyl- The preparation of 2- alkene -1- ketone
By N- (3- bromophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-1) (178mg, 0.5mmol) is dissolved in tetrahydrofuran, is added acryloyl chloride (45.3mg, 0.5mmol), is stirred at room temperature to having reacted Finish, wet chemical is added to be quenched, ethyl acetate extraction, silica gel column chromatography purifies after organic phase concentration, obtains off-white powder 164 milligrams, yield 80%.1H NMR(500MHz,DMSO-d6)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/z 411.0457calcdfor C19H15BrN4O2[M+H]+,found 411.0455.
Embodiment 2-82
The preparation method of reference implementation example 1, operation is identical, and embodiment is with the formula of identical molar equivalent R in VIII1X is that the intermediate of substituent group in following table substitutes N- (3- bromophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3- F] quinazoline -10- amine (VIII-1), the compound of specific implementation is as shown in the table:
83 1- of embodiment (10- ((4- aminobenzyl) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinoline azoles Quinoline -4- base) propyl- 2- alkene -1- ketone preparation
By tert-butyl (4- (((3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- base) amino) methyl) benzene Amine t-butyl formate (VIII-34) (203mg, 0.5mmol) is dissolved in tetrahydrofuran, addition acryloyl chloride (45.3mg, 0.5mmol), it being stirred at room temperature to raw material after disappearing and 1 milliliter of hydrochloric acid is added, stirring to end of reaction adds wet chemical to be quenched, Ethyl acetate extraction, silica gel column chromatography purifies after organic phase concentration, obtains 95 milligrams of off-white powder, yield 53%.1H NMR (400MHz,DMSO-d6) δ 8.49-8.42 (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]+。
Embodiment 84:1- (10- ((4- hydroxybenzyl) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinoline azoles Quinoline -4- base) propyl- 2- alkene -1- ketone preparation
By 4- (((3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- base) amino) methyl) phenylacetate (VIII-36) (175mg, 0.5mmol) is dissolved in 5 milliliters of tetrahydrofurans, and ice bath is cooling, addition acryloyl chloride (45.3mg, 0.5mmol), it is stirred at room temperature to raw material after disappearing and is added 1 milliliter of concentrated hydrochloric acid, continue stirring to end of reaction, it is solid to obtain off-white color 63 milligrams of body, yield 35%.1H NMR(400MHz,DMSO-d6)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]+
Embodiment 85:1- (10- ((4- hydroxyl-3-methoxybenzy) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2, 3-f] quinazoline -4- base) propyl- 2- alkene -1- ketone preparation
The preparation method of reference implementation example 84 operates identical.Specific embodiment is with equal mole equivalent Compound VIII-37 replaces VIII-36.1H NMR(400MHz,DMSO-d6)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]+。
Embodiment 86:(4- acryloyl group -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- base) sweet ammonia The preparation of acid
By tert-butyl (3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- base) glycinate (VIII-86) (158mg, 0.5mmol) is dissolved in 5mL tetrahydrofuran, and ice bath is cooling, is added acryloyl chloride 45.3mg (0.5mmol), room temperature is stirred It mixes to end of reaction, water quenching is added to go out, ethyl acetate extraction, silica gel column chromatography purifies after organic phase concentration, obtains target compound 63mg, yield 40%.1H NMR(400MHz,DMSO-d6)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]+。
Embodiment 87:3- ((4- acryloyl group -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- base) ammonia Base) propionic acid preparation
The preparation method of reference implementation example 86, specific implementation method are with the tert-butyl 3- ((3,4- bis- of identical molar equivalent Hydrogen -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- base) aminopropan acid esters (VIII-89) substitutes tert-butyl (3,4- dihydro - 2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- base) glycinate (VIII-86).1H NMR(400MHz,DMSO-d6)δ 12.67 (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]+。
Embodiment 88
(E) -4- (dimethylamino) -1- (10- ((3- (trifluoromethyl) phenyl) amino) -2,3- dihydro -4H- [1,4] oxazines And [2,3-f] quinazoline -4- base) but-2-ene -1- ketone preparation
By N- (3- (trifluoromethyl) phenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-2) (173mg, 0.5mmol) is dissolved in the in the mixed solvent of tetrahydrofuran and dimethylformamide, and trans- -4- diformazan is added Base amido crotonyl chloride hydrochloride (92mg, 0.5mmol), is stirred at room temperature to end of reaction, wet chemical is added to be quenched, acetic acid Ethyl ester extraction, silica gel column chromatography purifies after organic phase concentration, obtains 173 milligrams of off-white powder, yield 76%.1H NMR (500MHz,DMSO-d6) δ 10.07 (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]+。
Embodiment 89-105
Embodiment 89-105 preparation reference implementation example 88 preparation method, operate it is identical, embodiment be with R in the Formula VIII of identical molar equivalent1X is that the intermediate of substituent group in following table substitutes N- (3- (trifluoromethyl) phenyl) -3, Simultaneously [2,3-f] quinazoline -10- amine (VIII-2), the compound of specific implementation are as shown in the table for 4- dihydro -2H- [Isosorbide-5-Nitrae] oxazines:
Embodiment 106
(E) -1- (10- ((the chloro- 4- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinazoline - 4- yl) -4- morpholine but-2-ene -1- ketone preparation
By N- (the chloro- 4- fluorophenyl of 3-) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII- 4) (165mg, 0.5mmol) is dissolved in the in the mixed solvent of methylene chloride and dimethylformamide, 4- bromo crotonyl chloride is added (91mg, 0.5mmol) is stirred at room temperature to end of reaction, water quenching is added to go out, and ethyl acetate extraction is directly dissolved in after organic phase concentration In acetonitrile, diisopropyl ethyl amine (129mg, 1mmol) and morpholine (87mg, 1mmol) is added, is stirred at room temperature to end of reaction, Water quenching is added to go out, ethyl acetate extraction, silica gel column chromatography purifies after organic phase concentration, obtains 61 milligrams of off-white powder, yield 25%.1HNMR(500MHz,DMSO-d6) δ 9.92 (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 C24H23ClFN5O3[M+H]+,found484.1550.
Embodiment 107-122
The preparation method of the preparation reference implementation example 106 of embodiment 107-122, operation is identical, and embodiment is With R in the Formula VIII of identical molar equivalent1X is that the intermediate of substituent group in following table substitutes N- (the chloro- 4- fluorophenyl of 3-) -3,4- Dihydro -2H- [Isosorbide-5-Nitrae] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-4), with equal molar equivalentSubstitution Quinoline.The compound of specific implementation is as shown in the table:
Embodiment 123
(S, E) -1- (10- ((the chloro- 4- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinoline azoles Quinoline -4- base) -3- (1- methylpyrrolidin- 2- yl) propyl- 2- alkene -1- ketone preparation
Step 1) diethyl (2- (10- ((the chloro- 4- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3- F] quinazoline -4- base) -2- oxoethyl) and phosphate preparation (IX-1)
By N- (3- chlorine 4- fluorophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-4) (165mg, 0.5mmol), 2- (diethoxy phosphoryl) acetic acid (0.5mmol) are dissolved in tetrahydrofuran, and N, N'- carbonyl two is added Imidazoles (81mg, 0.5mmol) is stirred at room temperature to fully reacting, and water and ethyl acetate extraction, organic phase concentration, column chromatography is added 218 milligrams of yellow solid are obtained, yield 86%.MS:509[M+H]+。
Step 2) (S, E) -1- (10- ((the chloro- 4- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3- F] quinazoline -4- base) -3- (1- methylpyrrolidin- 2- yl) propyl- 2- alkene -1- ketone preparation
By diethyl (2- (10- ((the chloro- 4- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinoline Oxazoline -4- base) -2- oxoethyl) phosphate (IX-1) (218mg, 0.43mmol) is dissolved in tetrahydrofuran, -78 DEG C are cooled to, drop The lithium hexamethyldisilazide toluene solution (0.65mL, 0.65mmol) for entering 1 mole every liter continues stirring to raw material and disappears, It is added (S) -1- methylpyrrole alkyl -2- formaldehyde (48.6mg, 0.43mmol), is warmed to room temperature and continues stirring to end of reaction, add Enter water and ethyl acetate extraction, organic phase concentration, column chromatographs to obtain 148 milligrams of off-white powder, yield 74%.1H NMR (300MHz,DMSO-d6)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]+。
Embodiment 124
(E) -1- (10- ((the chloro- 4- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinazoline - 4- yl) -9- methoxyl group nonyl- 2- alkene -1- ketone
Step 1) is the same as 123 step 1) of embodiment
(- 2,3- dihydro -4H- [1,4] oxazines is simultaneously [2,3-f] by 10- ((the chloro- 4- fluorophenyl of 3-) amino) by step 2) (E) -1- Quinazoline -4- base) -9- methoxyl group nonyl- 2- alkene -1- ketone preparation
123 step 2) of reference implementation example, operation is identical, and specific embodiment is with the 7- first of equal mole equivalent Oxygroup enanthaldehyde substitutes (S) -1- methylpyrrole alkyl -2- formaldehyde.1HNMR(400MHz,DMSO-d6)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]+。
Embodiment 125
(S, E) -1- (10- ((3- ethynyl phenyl) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinoline azoles Quinoline -4- base) -3- (1- methylpyrrolidin- 2- yl) propyl- 2- alkene -1- ketone preparation
Step 1) diethyl (2- (10- ((3- ethynyl phenyl) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3- F] quinazoline -4- base) -2- oxoethyl) and phosphate preparation (IX-2)
123 step 1) of reference implementation example, operation is identical, and specific embodiment is with the N- of equal mole equivalent Simultaneously [2,3-f] quinazoline -10- amine (VIII-7) substitutes N- (3- chlorine to (3- ethynyl phenyl) -3,4- dihydro -2H- [1,4] oxazines 4- fluorophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-4).Yield 85%.MS:481 [M+H]+。
(10- ((3- ethynyl phenyl) amino) -2,3- dihydro -4H- [1,4] oxazines is simultaneously [2,3-f] by step 2) (S, E) -1- Quinazoline -4- base) -3- (1- methylpyrrolidin- 2-) propyl- 2- alkene -1- ketone preparation
123 step 2) of reference implementation example, operation is identical, and specific embodiment is with the diethyl of equal mole equivalent Base (2- (10- ((3- ethynyl phenyl) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinazoline -4- base) -2- oxygen For ethyl) ((10- ((the chloro- 4- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] is disliked 2- phosphate (IX-2) substitution diethyl Piperazine simultaneously [2,3-f] quinazoline -4- base) -2- oxoethyl) phosphate (IX-1).Yield 70%.1H NMR(300MHz,DMSO- d6) δ 9.95 (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]+。
Embodiment 126
1- (10- (the chloro- 4- fluorophenoxy of 3-) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinazoline -4- base) butyl- The preparation of 2- alkynes -1- ketone
2- tetrolic acid (42mg, 0.5mmol) is dissolved in methylene chloride, 0.05 milliliter of dimethylformamide, ice bath are instilled Oxalyl chloride (32mg, 0.25mmol) is added after cooling, 10- (the chloro- 4- fluorophenoxy of 3-) -3 is added after continuing stirring 0.5 hour, 4- dihydro -2H- [Isosorbide-5-Nitrae] oxazines simultaneously [2,3-f] quinazoline -10- amine (VIII-4) (165mg, 0.5mmol), is warmed to room temperature continuation Stirring adds wet chemical to be quenched, ethyl acetate extraction, organic phase concentration rear pillar chromatographs to obtain off-white powder to end of reaction 69 milligrams of product, yield 34%.1H NMR(400MHz,DMSO-d6)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]+。
Embodiment 127-147
The preparation method of the preparation reference implementation example 126 of embodiment 127-147, operates identical, specific embodiment party Formula is with R in the Formula VIII of identical molar equivalent1X is that the intermediate of substituent group in following table substitutes 10- (the chloro- 4- fluorobenzene oxygen of 3- Base) -3,4- dihydro -2H- [Isosorbide-5-Nitrae] oxazines simultaneously [2,3-f] quinazoline -10- amine, with the R of equal mole equivalent2For shown in following table The carboxylic acid of substituent group substitutes 2- tetrolic acid.The compound of specific implementation is as shown in the table:
Embodiment 148:(S, E) (((4- fluorophenyl (amino) -2,3- dihydro -4H- [1,4] oxazines is simultaneously [2,3-f] by 10- by -1- Quinazoline -4- base) -3- (1- methylpyrrolidin- 2- yl) propyl- 2- alkene -1- ketone preparation
Step 1): diethyl (2- (10- ((4- fluorophenyl) amino) -2,3- dihydro -4H- [1,4] oxazines [2,3-f] quinoline azoles Quinoline -4- base) -2- oxoethyl) phosphonate ester preparation
By N- (4- fluorophenyl) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (148mg, 0.5mmol), 2- (diethoxy phosphoryl) acetic acid (98mg, 0.5mmol) is dissolved in tetrahydrofuran, and N, two miaow of N'- carbonyl is added Water and ethyl acetate extraction, organic phase concentration, column layer is added in azoles (81mg, 0.5mmol), 40 DEG C of oil bath stirrings to fully reacting 168 milligrams of yellow solid are analysed to obtain, yield 71%.MS:475[M+H]+。
Step 2): (S, E) -1- (10- ((4- fluorophenyl (amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinoline Oxazoline -4- base) -3- (1- methylpyrrolidin- 2- yl) propyl- 2- alkene -1- ketone preparation
By diethyl (2- (10- ((4- fluorophenyl) amino) -2,3- dihydro -4H- [1,4] oxazines [2,3-f] quinazoline -4- Base) -2- oxoethyl) phosphonate ester (168mg, 0.35mmol) is dissolved in tetrahydrofuran, is cooled to -78 DEG C, instill 1 mole every liter Lithium hexamethyldisilazide toluene solution (0.53mL, 0.53mmol) continues stirring to raw material and disappears, (R) -1- methyl is added Pyrrolidinyl -2- formaldehyde (39.6mg, 0.35mmol) is warmed to room temperature and continues stirring to end of reaction, water and ethyl acetate is added Extraction, organic phase concentration, through 83 milligrams of the isolated white solid of high performance liquid preparative chromatography, yield 54%.1H NMR (400MHz,DMSO-d6) δ 9.86 (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]+。
Embodiment 149:(S, E) -3- (1- methylpyrrolidin- 2- yl) -1- (10- (phenyl amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2,3-f] quinazoline -4- base) propyl- 2- alkene -1- ketone preparation
Step 1) diethyl (2- oxo -2- (10- (phenyl amino) -2,3- dihydro -4H- [1,4] oxazines [2,3-f] quinoline azoles Quinoline -4- base) ethyl) phosphonate ester preparation
It is prepared using method similar with 148 step 1) of embodiment, the difference is that with equal mole equivalent Simultaneously [2,3-f] quinazoline -10- amine replaces N- (4- fluorophenyl) -3,4- dihydro-to N- phenyl -3,4- dihydro -2H- [1,4] oxazines 2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine.Yield 77%.MS:457[M+H]+。
Step 2) (S, E) -3- (1- methylpyrrolidin- 2- yl) -1- (10- (phenyl amino) -2,3- dihydro -4H- [1,4] Oxazines simultaneously [2,3-f] quinazoline -4- base) propyl- 2- alkene -1- ketone preparation
It is prepared using method similar with 148 step 2) of embodiment, the difference is that with equal mole equivalent Diethyl (2- oxo -2- (10- (phenyl amino) -2,3- dihydro -4H- [1,4] oxazines [2,3-f] quinazoline -4- base) ethyl) Phosphonate ester replaces diethyl (2- (10- ((4- fluorophenyl) amino) -2,3- dihydro -4H- [1,4] oxazines [2,3-f] quinazoline -4- Base) -2- oxoethyl) phosphonate ester.1H NMR(400MHz,DMSO-d6)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]+。
Embodiment 150:(E) -1- (10- ((the chloro- 2- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2, 3-f] quinazoline -4- base) -4- (cyclopropyl (methyl) amino) but-2-ene -1- ketone preparation
By N- (the chloro- 2- fluorophenyl of 3-) -3,4- dihydro -2H- [1,4] oxazines simultaneously [2,3-f] quinazoline -10- amine (165mg, 0.5mmol), it is dissolved in dimethylformamide, is added 4- bromo crotonyl chloride (91mg, 0.5mmol), be stirred at room temperature to having reacted To finish, water quenching is added to go out, ethyl acetate extraction is directly dissolved in acetonitrile after organic phase concentration, addition diisopropyl ethyl amine (129mg, It 1mmol) with N- methyl cyclopropylamine (71mg, 1mmol), is stirred at room temperature to end of reaction, water quenching is added to go out, ethyl acetate extraction has Machine purifies after being mutually concentrated through high performance liquid preparative chromatography, obtains 84 milligrams of white solid, yield 36%.1H NMR(400MHz, DMSO-d6) δ 10.00 (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]+。
Embodiment 151:(E) -1- (10- ((the chloro- 2- fluorophenyl of 3-) amino) -2,3- dihydro -4H- [1,4] oxazines simultaneously [2, 3-f] quinazoline -4- base) -4- (cyclobutyl (methyl) amino) but-2-ene -1- ketone preparation
It is prepared using method similar with embodiment 150, the difference is that with the N- methyl of equal mole equivalent Ring butylamine hydrochloride replaces N- methyl cyclopropylamine.1H NMR(400MHz,DMSO-d6)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]+。
Experimental example 1.
Small molecule compound inhibits EGFRWT、EGFRT790MAnd the test of HER2 kinase activity, test method are as follows:
1) dilution of compound
In 96 orifice plate a, compound DMSO solution is pressed into 3 times of dilution proportions, forms 11 gradients, the 12nd gradient is Pure DMSO solution (as positive control)；One piece of 96 new orifice plate b is taken, above-mentioned solution ultrapure water is diluted 25 times, and (DMSO is dense 4%) degree is.
2) by compound turntable to 384 orifice plates
By the compound solution diluted in above-mentioned 96 orifice plate b with ultrapure water according to the standard turntable of 2 multiple holes to 384 orifice plates In corresponding hole.
3) add 4 × kinase solution: taking the 2.5 above-mentioned 4 × kinase solutions of μ l to be added to the corresponding reacting hole of 384 orifice plates with the volley of rifle fire In, it mixes room temperature pre-reaction 5 minutes.
4) add 2 × substrate/ATP mixed liquor: taking the 5 above-mentioned 2 × substrates of μ l/ATP mixed liquor corresponding to 384 orifice plates with the volley of rifle fire In reacting hole.
5) negative control: being arranged negative control hole in 384 orifice plates, every hole be added 2.5 4 × substrates of μ l, 2.5 μ l 4 × Enzyme solutions, 2.5 μ l 1 × Kinase Assay Buffer and 2.5 ultrapure waters of the μ l containing 4%DMSO.
6) centrifugation mixes, and is protected from light room temperature reaction 2 hours.
7) enzymatic reaction is terminated:
The 5 above-mentioned 4 × terminate liquids of μ l to 384 orifice plate corresponding apertures are drawn, centrifugation mixes, and reacts at room temperature 5 minutes.
8) chromogenic reaction:
It draws 5 μ l above-mentioned 4 × detection liquid and is added to 384 orifice plate corresponding apertures, centrifugation mixes, and reacts at room temperature 1 hour.
9) 384 orifice plates are put into plate reader, transfer corresponding Programmable detection signal.
10)IC50Analysis:
Hole readings=10000*EU665 value/EU615 value
Inhibiting rate=(Positive control wells readings-experimental port readings)/(Positive control wells readings-negative control hole readings) * 100%
Drug concentration and the input processing of GraphPad Prism 5 of corresponding inhibiting rate can be calculated into corresponding IC50。
EGFRWTKinase activity inhibits molecule to screen experiment condition:
Final concentration of 150 μM of EGFR kinases final concentration 0.35nM, ATP, substrate ULight in reaction systemTM-labeled The final concentration 100nM of JAK-1 (Tyr1023) Peptide, time of enzymatic reacting are 2 hours.
Final concentration of 2.5 μM of compound highest in reaction system, totally 11 concentration, minimum end are dense after 3 times of gradient dilutions Degree is 0.042nM.DMSO final concentration of 1%.
EGFRT790MKinase activity inhibits molecule to screen experiment condition:
Final concentration of 5 μM of EGFR (T790M) kinases final concentration 0.05nM, ATP, substrate ULight in reaction systemTM- The final concentration 100nM of labeled PolyGT, time of enzymatic reacting are 2 hours.
Final concentration of 2.5 μM of compound highest in reaction system, totally 11 concentration, minimum end are dense after 3 times of gradient dilutions Degree is 0.042nM.DMSO final concentration of 1%.
HER2 kinase activity inhibits molecule to screen experiment condition:
10 μM of the final concentration of the final concentration of 10nM of HER2 kinases in reaction system, ATP, substrate ULightTM-labeled The final concentration of 100nM of PolyGT, time of enzymatic reacting are 2 hours.
Final concentration of 2.5 μM of compound highest in reaction system, totally 11 concentration, minimum end are dense after 3 times of gradient dilutions Degree is 0.042nM.DMSO final concentration of 1%.
Table (one) lists in this patent part of compounds to the measurement result of tyrosine-kinase enzyme inhibition activity, wherein A table Show IC50IC is indicated less than or equal to 50nM, B50Greater than 50nM but it is less than or equal to 500nM, C indicates IC50Greater than 500nM but small In or equal to 5000nM, D expression IC50Greater than 5000nM, NT is indicated without testing corresponding kinases.
Table (one), the compounds of this invention are to EGFR and HER2 kinase inhibiting activity measurement result
Experimental example 2.
Small molecule compound inhibits the test of cell Proliferation, and the specific method is as follows:
1. 600 μ L pancreatin are added in T75 Tissue Culture Flask, about 1min is digested in 37 DEG C of incubators, 5mL is then added The complete culture solution of DMEM, piping and druming uniformly, are transferred in 15mL centrifuge tube, 1000rpm, 4min centrifugation；
2. discarding supernatant liquid, 5mL DMEM complete culture solution is added, piping and druming uniformly, takes 10 μ L cell suspending liquids and 10 μ L 0.4% tire expects blue mixing, is counted under cell counter；
3. BT474 and HCC827 cell line is inoculated according to 10000 and 3000/hole/80 μ L cell density respectively Overnight incubation in 96 orifice plates, 96 orifice plate periphery, 36 hole are not added cell and only add sterile water, and only 60 holes of the inside are for cell experiment and right According to；
4. diluted chemical compound: compound carries out 3 times of dilutions by initial concentration of 10mM, totally 10 concentration；
5. the compound of 20 μ L variety classes various concentrations is added in every hole, remaining hole is added 20 μ L complete culture solutions and shakes Even, the middle concentration of DMSO is 0.25% in every hole；
6. cultivating every hole after 72h is added 10 μ L CCK-8 reagents, 37 DEG C of culture 1-2h；Its OD value is read at 450nm；
7. cell survival rate (%)=[(As-Ab)/(Ac-Ab)] * 100%
As: experimental port (containing cell culture medium, CCK-8, compound)
Ac: control wells (containing cell culture medium, CCK-8)
Ab: blank well (culture medium, CCK-8 without cell and compound)
8. numerical value, which is imported Graphpad Prism5 software, carries out IC50(compound concentration when highest survival rate 50%) It calculates.
Table (two) lists in the present invention representative compound to the determination of activity result of HCC827 and BT474 cancer cell. Wherein A indicates IC50IC is indicated less than or equal to 50nM, B50Greater than 50nM but it is less than or equal to 500nM, C indicates IC50It is greater than 500nM but be less than or equal to 5000nM, D indicate IC50Greater than 5000nM, NT is indicated without testing corresponding cell.
Table (two), representative compound of the present invention are to the measurement result of cell activity
The above is a preferred embodiment of the present invention, it is noted that for those skilled in the art For, under the premise of not departing from principle of the present invention, embodiments of the present invention can also make several improvements and modify, These improvement and modification also should be regarded as protection scope of the present invention.

Claims (13)

1. compound shown in a kind of formula (I), its isomers, hydrate, solvate, its pharmaceutically acceptable salt and its preceding Medicine,
In formula (I),
X is O or NH；
R1For
L is C1-C4Straight chained alkyl, or separately by R4、R5Substituted C1-C4Straight chained alkyl；
R4And R5It is independently H or C1-C3Alkyl；
R3For-H, the unsubstituted or C that is replaced by halogen, hydroxyl, cyano, carboxyl1-C6Alkyl, C1-C6Alkoxy, C3-C7Cycloalkanes Base, aryl, 4-7 circle heterocyclic ring base, 5-6 unit's heteroaryl, or simultaneously ring structure；
Described and ring structure is selected from aromatic ring and 5-6 member heteroaryl ring group, 5-6 member hetero-aromatic ring and 5-6 member heteroaryl ring group, aromatic ring and 5-6 First naphthenic base, aromatic ring and 5-6 circle heterocyclic ring base, 5-6 member hetero-aromatic ring and 5-6 member naphthenic base or 5-6 member hetero-aromatic ring and 5-6 circle heterocyclic ring Base；
The heterocycle, heteroaryl ring group are selected from the hetero atom of N, O or S containing 1-3；
The aryl, heteroaryl, heterocycle or simultaneously ring structure be it is non-substituted or independently be selected from halogen, cyanogen by 1-3 Base, hydroxyl, C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl, C3-C6Naphthenic base, C2-C3Alkynyl, C2-C3Alkenyl ,-NR' R " or-MR6Substituent group replace；
R', R " are independently H or C1-C3Alkyl；
M is-O (CH2)qOr-C (O)-, wherein q is the integer of 1-4；
R6For-H, hydroxyl, C1-C3Alkyl, C1-C3Alkoxy, or-NR7R8；
R7And R8It is independently-H, C1-C3Alkyl or R7、R8It is connected to form 4-7 circle heterocyclic ring；
R2For
L1It is selected from:
T1For C1-C8Straight chained alkyl, or separately by R9、R10Substituted C1-C8Straight chained alkyl；
R9And R10It is independently-H or C1-C3Alkyl；
R11For-H, hydroxyl, C1-C3Alkyl, C3-C7Naphthenic base, C1-C3Alkoxy, C1-C3Alkylthio group, 4-7 circle heterocyclic ring base or- NR12R13,
R12And R13It is independently-H, C1-C6Alkyl, C3-C6Naphthenic base, the C being optionally substituted by a hydroxyl group1-C6Alkyl or by C1-C3Alkane The C that oxygroup replaces1-C6Alkyl；
The 4-7 circle heterocyclic ring base is the heteroatomic heterocycle that N, O or S are selected from containing 1-2, and the heterocycle is unsubstituted Or by C1-C3Alkyl, aldehyde radical, C1-C4Alkyl acyl, aminoacyl, single or double substituted C1-C3Aminoacyl, C1-C3Alkyl sulfone Base, C1-C3Sulphur in the substitution of one or both of alkyl sulfoxide base or heterocycle is aoxidized by one to two oxygen atom.
2. compound according to claim 1, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug, which is characterized in that
R1For
L is C1-C3Straight chained alkyl, or separately by R4、R5Substituted C1-C3Straight chained alkyl；
R4And R5It is independently-H or C1-C3Alkyl；
R3For-H, the unsubstituted or C that is replaced by halogen, hydroxyl, cyano, carboxyl1-C3Alkyl, C1-C3Alkoxy, C3-C6Cycloalkanes Base, aryl, 5-6 circle heterocyclic ring base, 5-6 unit's heteroaryl, or simultaneously ring structure；
Described and ring structure is selected from benzo 5-6 heteroaryl ring group, 5-6 member hetero-aromatic ring and 5-6 member heteroaryl ring group, benzo 5-6 naphthenic base, Benzo 5-6 heterocycle, 5-6 member hetero-aromatic ring and 5-6 naphthenic base, 5-6 member hetero-aromatic ring and 5-6 circle heterocyclic ring base,
The heterocycle, heteroaryl ring group are selected from the hetero atom of N, O or S containing 1-3；
The aryl, heteroaryl, heterocycle or simultaneously ring structure is non-substituted or is separately selected from halogen, cyanogen by 1-3 Base, hydroxyl, C1-C3Alkyl, C1-C3Alkoxy, halogenated C1-C3Alkyl, C3-C4Naphthenic base, C2-C3Alkynyl, C2-C3Alkenyl ,-NR' R " or-MR6Substituent group replace；
R' and R " is independently H or C1-C3Alkyl；
M is-O (CH2)qOr-C (O)-, wherein q is the integer of 1-3；
R6For H, hydroxyl, C1-C3Alkyl, C1-C3Alkoxy, or-NR7R8；
R7、R8It is independently H, C1-C3Alkyl or R7、R8It is connected to form 5-6 circle heterocyclic ring.
3. compound according to claim 1, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug, which is characterized in that
R1For
L is C1-C3Straight chained alkyl, or separately by R4、R5Substituted C1-C3Straight chained alkyl；
R4And R5It is independently-H or methyl；
R3It is selected from :-H, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, hydroxyl, carboxyl, 1- hydroxyl -1- Methylethyl or following group:
R14For-H or C1-C3Alkyl；
Q1、Q2、Q3、Q4, Q5 be independently N or CH；
(R15)pFor p identical or different R15Substituent group, p 0,1,2 or 3；
R15Selected from-H ,-F ,-Cl ,-Br ,-CF3,-OCF3, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, Isopropoxy, acetenyl, vinyl, cyclopropyl, cyclobutyl, hydroxyl, cyano ,-NR'R " or-MR6；
R', R " are independently H, methyl, ethyl, propyl or isopropyl；
M is-O (CH2)qOr-C (O)-, wherein q is 1,2 or 3；
R6For H, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, or-NR7R8；
R7、R8It is independently H, methyl, ethyl, propyl, isopropyl or R7、R8It is connected to form 5-6 circle heterocyclic ring, the 5-6 member Heterocycle is preferred:
4. compound according to claim 3, its isomers, hydrate, solvate, its pharmaceutically acceptable salt and Its prodrug, which is characterized in that
R1For
L is C1-C3Straight chained alkyl, or separately by R4、R5Substituted C1-C3Straight chained alkyl；
R4And R5It is independently-H or methyl；
R3It is selected from :-H, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, cyclopropyl, ring fourth Base, cyclopenta, cyclohexyl, hydroxyl, carboxyl, 1- hydroxyl -1- Methylethyl or following group:
R14For-H or C1-C3Alkyl；
(R15)pFor p identical or different R15Substituent group, p 0,1,2 or 3；
R15Selected from-H ,-F ,-Cl ,-Br ,-CF3,-OCF3, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, Isopropoxy, acetenyl, vinyl, cyclopropyl, cyclobutyl, hydroxyl, cyano ,-NR'R " or-MR6；
R', R " are independently H, methyl, ethyl, propyl or isopropyl；
M is-O (CH2)qOr-C (O)-, wherein q is 1,2 or 3；
R6For H, hydroxyl, methyl, ethyl, propyl, isopropyl, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, or-NR7R8；
R7、R8It is independently H, methyl, ethyl, propyl, isopropyl or R7、R8It is connected to be formed
5. compound according to any one of claim 1 to 4, its isomers, hydrate, solvate, its pharmaceutically Acceptable salt and its prodrug, which is characterized in that
R2For
L1It is selected from:
T1For C1-C6Straight chained alkyl, or separately by R9、R10Substituted C1-C6Straight chained alkyl；
R9And R10It is independently-H or methyl；
R11For-H, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methoxyl group, ethoxy Base, propoxyl group, isopropoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, 5-6 circle heterocyclic ring base or-NR12R13；
R12And R13It is independently-H, methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, sec-butyl, isobutyl group, 1- ethyl propyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, ethoxy, hydroxypropyl, hydroxyl butyl, methoxy ethyl, methoxyl group Propyl, methoxybutyl, ethoxyethyl group, ethoxycarbonyl propyl, ethoxybutyl, Among, propoxypropyl, propoxyl group Butyl, isopropoxyethyl, isopropoxide propyl or isopropoxy butyl；
The 5-6 circle heterocyclic ring base is the heteroatomic heterocycle that N, O or S are selected from containing 1-2, the 5-6 circle heterocyclic ring base It is unsubstituted or by methyl, ethyl, propyl, isopropyl, aldehyde radical, formoxyl, acetyl group, propiono, bytyry, isobutyryl, Aminoacyl, methylamino acyl group, dimethylamino acyl group, methylsulfonyl, ethyl sulfone, isopropyl sulfuryl, first sulfoxide group, second sulfoxide group are different Sulphur in the substitution of one or both of third sulfoxide group or heterocycle is aoxidized by one to two oxygen atom；
The 5-6 circle heterocyclic ring is selected from:
6. compound according to any one of claim 1 to 5, its isomers, hydrate, solvate, its pharmaceutically Acceptable salt and its prodrug, which is characterized in that
R2For
L1It is selected from:
T1For C1-C6Straight chained alkyl, or separately by R9、R10Substituted C1-C6Straight chained alkyl；
R9And R10It is independently-H or methyl；
R11For-H, hydroxyl, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, methoxyl group, ethoxy Base, propoxyl group, isopropoxy, methyl mercapto, ethylmercapto group, rosickyite base, isopropyisulfanyl, 5-6 circle heterocyclic ring base or-NR12R13；
R12And R13It is independently-H, methyl, ethyl, propyl, butyl, amyl, hexyl, isopropyl, sec-butyl, isobutyl group, 1- ethyl propyl, cyclopropyl, cyclobutyl, cyclopenta, ethoxy, hydroxypropyl, methoxy ethyl, methoxy-propyl, ethyoxyl second Base, ethoxycarbonyl propyl, Among, propoxypropyl, isopropoxyethyl or isopropoxide propyl；
The 5-6 circle heterocyclic ring base is the heteroatomic heterocycle that N, O or S are selected from containing 1-2, the 5-6 circle heterocyclic ring base It is unsubstituted or by methyl, ethyl, propyl, isopropyl, aldehyde radical, formoxyl, acetyl group, propiono, bytyry, isobutyryl, Aminoacyl, methylamino acyl group, dimethylamino acyl group, methylsulfonyl, ethyl sulfone, isopropyl sulfuryl, first sulfoxide group, second sulfoxide group are different Sulphur in the substitution of one or both of third sulfoxide group or heterocycle is aoxidized by one to two oxygen atom；
The 5-6 circle heterocyclic ring base is selected from:
R16For H, amino, methylamino, dimethylamino, methyl, ethyl, propyl, isopropyl.
7. it is a kind of prepare compound described in claim 1-6, its isomers, solvate, its pharmaceutically acceptable salt and The preparation method of its prodrug, comprises the steps of,
By R2C (O) Cl is reacted with formula (VIII) compound or R2COOH reacts after chlorination reaction occurs with formula (VIII) compound Prepare formula (I) compound；
Alternatively, working as R2For
And L1ForR11For-NR12R13When, by formula (VIII) compound withAnd it is connected with R12With R13Amine (the HNR of substituent group12R13) reaction preparation formula (I) compound；
Alternatively, R2ForAnd L1ForBy formula (IX) compound WithReaction preparation formula (I) compound,
R1、R2、R11、R12、R13、X、L1And T1As claim 1-6 is defined.
8. a kind of formula (VIII) compound represented,
X and R1As claim 1-6 is defined.
9. a kind of method for preparing compound according to any one of claims 8 comprising the steps of:
Method A:
By simultaneously [2, the 3-f] quinazoline -10- ketone of 2,3,4,9- tetrahydro -10H- [Isosorbide-5-Nitrae] oxazines shown in formula (V), R1XH contracts with Ka Te Mixture comes into full contact with compound shown in acquisition formula (VIII), wherein X and R1If claim 1-6 is defined,
Or method B:
2,3,4,9- tetrahydro -10H- [1,4] oxazines shown in formula (V) simultaneously [2,3-f] quinazoline -10- ketone and is blocked into special condensing agent Come into full contact with acquisition formula (VI) compound represented, compound (VI) further with R1XH reacts to obtain chemical combination shown in formula (VIII) Object, wherein X and R1If claim 1-6 is defined,
Or method C:
After formula (II) compound represented is reacted with chlorination reagent with R1XH reacts to obtain compound shown in formula (VII), formula (VII) compound shown in formula (VIII) is obtained after the reduction ring closure reaction of compound further occurrence shown in, wherein X and R1Such as right It is required that 1-6 is defined.
10. compound according to any one of claim 1 to 6, its pharmaceutically acceptable salt, isomers, hydrate, Solvate or prodrug, wherein the pharmaceutically acceptable salt of the compound is hydrochloride, hydrogen selected from the compound Bromate, hydriodate, perchlorate, sulfate, nitrate, phosphate, formates, acetate, propionate, hydroxyacetic acid Salt, lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, peace Cease fragrant hydrochlorate, mandelate, mesylate, isethionate, benzene sulfonate, oxalates, palmitate, 2- naphthalene sulfonate, Tosilate, cyclamate, salicylate, hexose hydrochlorate, trifluoroacetate, aluminium salt, calcium salt, chloroprocanine One of salt, choline salt, diethanolamine salt, ethylenediamine salt, lithium salts, magnesium salts, sylvite, sodium salt and zinc salt are a variety of.
11. a kind of Pharmaceutical composition for the treatment of and tyrosine kinase EGFR, HER2, HER3, HER4 related disease, is wanted by right Ask formula described in 1-6 (I) compound or its pharmaceutically acceptable salt or its hydrate or its solvate or its prodrug with Pharmaceutically acceptable carrier or excipient composition.
12. a kind of Pharmaceutical composition: wherein the compound comprising formula (I) as described in claim 1-6 or its can pharmaceutically connect Salt, hydrate, solvate or the prodrug received are as active constituent, one or more of the other therapeutic agent, and one kind or more Kind pharmaceutically acceptable carrier or excipient.
13. the compound or its pharmaceutically acceptable salt of formula (I) according to claim 1 to 6 or its prodrug It is used to prepare in the drug for the treatment of cancer relevant to tyrosine kinase EGFR, HER2, HER3, HER4 and autoimmune disease Using, wherein the cancer and autoimmune disease include: fundus oculi disease, xerophthalmia, psoriasis, leucoderma, dermatitis, alopecia areata, Rheumatoid arthritis, colitis, multiple sclerosis, systemic loupus erythematosus, Crohn disease, atheroma, pulmonary fibrosis, liver Fibrosis, myelofibrosis, non-small cell lung cancer, Small Cell Lung Cancer, breast cancer, cancer of pancreas, glioma, glioblast Tumor, oophoroma, cervix cancer, colorectal cancer, melanoma, carcinoma of endometrium, prostate cancer, bladder cancer, leukaemia, stomach Cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myelocytic leukemia, acute myelocytic leukemia, non-Hodgkin's lymph Tumor, nasopharyngeal carcinoma, cancer of the esophagus, brain tumor, B cell and t cell lymphoma, lymthoma, Huppert's disease, biliary tract carcinosarcoma, bile duct Cancer.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021515768A (en) * 2018-03-06 2021-06-24 北京賽特明強医薬科技有限公司 Oxadinoquinazoline and oxadinoquinoline compounds, as well as preparation methods and their use

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006846A2 (en) * 2002-07-15 2004-01-22 Exelixis, Inc. Receptor-type kinase modulators and methods of use
CN103965211A (en) * 2013-02-02 2014-08-06 江苏奥赛康药业股份有限公司 Quinazoline structure-containing ricyclic derivative, preparation method and application thereof
CN103965213A (en) * 2013-02-02 2014-08-06 江苏奥赛康药业股份有限公司 7,8-Dihydro-6H-[1,4]oxazine[3,2-g]quinazoline derivatives, and preparation method and use thereof
CN104530063A (en) * 2015-01-13 2015-04-22 北京达立泰制药科技有限公司 Quinazoline and heterocyclic ring compounds, preparing method of compounds, and application of compounds serving as epidermal growth factor receptor inhibitors used for treating cancer
CN107141293A (en) * 2016-03-01 2017-09-08 上海医药集团股份有限公司 A kind of nitrogen-containing heterocycle compound, preparation method, intermediate, composition and application

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102875570B (en) * 2012-10-23 2015-11-04 浙江大学 Quinazoline derivant and its production and use

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004006846A2 (en) * 2002-07-15 2004-01-22 Exelixis, Inc. Receptor-type kinase modulators and methods of use
CN103965211A (en) * 2013-02-02 2014-08-06 江苏奥赛康药业股份有限公司 Quinazoline structure-containing ricyclic derivative, preparation method and application thereof
CN103965213A (en) * 2013-02-02 2014-08-06 江苏奥赛康药业股份有限公司 7,8-Dihydro-6H-[1,4]oxazine[3,2-g]quinazoline derivatives, and preparation method and use thereof
CN104530063A (en) * 2015-01-13 2015-04-22 北京达立泰制药科技有限公司 Quinazoline and heterocyclic ring compounds, preparing method of compounds, and application of compounds serving as epidermal growth factor receptor inhibitors used for treating cancer
CN107141293A (en) * 2016-03-01 2017-09-08 上海医药集团股份有限公司 A kind of nitrogen-containing heterocycle compound, preparation method, intermediate, composition and application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
XIANGFENG CHEN等: "Synthesis and biological evaluation of novel tricyclic oxazine and oxazepine fused quinazolines. Part 1: Erlotinib analogs", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2021515768A (en) * 2018-03-06 2021-06-24 北京賽特明強医薬科技有限公司 Oxadinoquinazoline and oxadinoquinoline compounds, as well as preparation methods and their use
JP7190755B2 (en) 2018-03-06 2022-12-16 北京賽特明強医薬科技有限公司 Oxazinoquinazoline and oxazinoquinoline compounds, and methods of preparation and uses thereof

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