WO2019170086A1 - Acyl-substituted oxazino-quinazoline compound, preparation method therefor, and uses thereof - Google Patents

Abstract

Provided are an acyl-substituted oxazino-quinazoline compound, a preparation method therefor, and uses thereof. More particularly provided is a compound shown in formula (I), an isomer, a hydrate, a solvate, a pharmaceutically acceptable salt, a prodrug thereof, a preparation method therefor, and uses thereof in preparing a drug acting as a kinase inhibitor. Said compound has a good inhibitory activity on mutant EGFR kinases and a moderate inhibitory activity on wild-type EGFR kinases. (I)

Description

Acyl substituted oxazinoquinazoline compound, preparation method and application thereof Technical field

The invention belongs to the technical field of medicine and relates to an acyl substituted oxazinoquinazoline compound, a preparation method and application thereof.

Background technique

Protein kinases are important signalling agents of cell life activities, catalyzing the transfer of γ-phosphate groups at the ATP end to hydroxyl acceptors in substrate amino acid residues (serine, threonine, tyrosine) to activate targets Protein (Johnson LN, and Lewis RJ, (2001) Structural basis for control by phosphorylation. Cheminform. 101, 2209.). Protein kinases are involved in numerous physiological processes including cell proliferation, survival, apoptosis, metabolism, transcription, and differentiation (Adams J.A., (2001) Kinetic and catalytic mechanisms of protein kinases. Chemical reviews. 101, 2271.). Among the existing drug targets in the human body, members of the protein kinase family account for up to 10% (Santos R.,

Ursu O., Gaulton A., et al. (2017) Acomprehensive map of molecular drug targets. Nature Reviews Drug Discovery. 16, 19.).

The epidermal growth factor receptor (ErbB) tyrosine kinase regulates cell proliferation, migration, differentiation, apoptosis, and cell migration through a variety of pathways. In many forms of malignancy, members of the ErbB family, as well as some of its ligands, are often overexpressed, amplified or mutated, making it an important therapeutic target. The family of protein kinases include: ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4. Among them, EGFR is an important target for the development of non-small cell lung cancer (Dienstmann R., et. al., (2001) Personalizing Therapy with Targeted Agents in Non-Small Cell Lung Cancer. ONCOTARGET. 2 (3), 165.).

Gefitinib, Erlotinib, and Icotinib are the first generation of reversible kinase inhibitors targeting EGFR for the treatment of non-small cell carcinoma. These inhibitors have both inhibitory effects on wild-type and activating mutant EGFR, and have achieved great clinical success, but the emergence of drug resistance in recipient patients after a period of use, especially resistance caused by T790M mutation Sexuality reduces or disables efficacy. The second-generation EGFR inhibitor, Afatinib, is a non-reversible inhibitor that contains a Michael receptor that is covalently bonded to a cysteine residue (Cys797) located at the entrance to the ATP-binding pocket. The inhibitor showed strong activity against both T790M mutant EGFR kinase and wild-type EGFR kinase, and the inhibitory activity against T790M mutant EGFR kinase was higher than that of wild-type EGFR kinase, which made the therapeutic window narrower in clinical application of the drug. The effect of use is not satisfactory (Camidge, DR, et. al. (2014) Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nature Reviews Clinical Oncology. 11, 473.). The third-generation EGFR kinase inhibitors, Osimintinib and Olmutinib, achieved high selective inhibition of T790M mutant EGFR kinase compared to wild-type EGFR kinase, which amplified the clinical window of use. Effective treatment of patients with T790M mutations has been achieved. One of the reasons why the known three-generation EGFR kinase inhibitors are clinically resistant is that the wild-type EGFR kinase is amplified in vivo after a patient has been administered for a period of time due to its weak inhibitory activity against wild-type EGFR. (Chen L., et.al. (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). Based on this, it is important to develop a novel active molecule having a good inhibitory activity against T790M mutant EGFR kinase while exhibiting a moderate inhibitory activity against wild-type EGFR kinase.

Summary of the invention

The present invention provides a compound of the formula (I), an isomer thereof, a hydrate, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof,

In formula (I),

X is O or NH;

R ¹ is

L is a C ₁ -C ₄ straight chain alkyl, or each independently are R ^4, R ⁵ substituted C ₁ -C ₄ straight chain alkyl;

R ⁴ and R ⁵ are each independently H or C ₁ -C ₃ alkyl;

R ³ is -H, C ₁ -C ₆ alkyl which is unsubstituted or substituted by halogen, hydroxy, cyano, carboxy, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, aryl, a 4-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a fluorene structure;

The cyclo-ring structure is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaryl ring group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, an aromatic ring and a 5-6 membered cycloalkyl group, and an aromatic ring a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl ring and a 5-6 membered cycloalkyl group or a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic group;

The heterocyclic group, heteroaryl ring group contains 1-3 hetero atoms selected from N, O or S;

The aryl, heteroaryl, heterocyclic or bicyclic ring structure is unsubstituted or independently separated by 1-3 selected from the group consisting of halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₃ alkynyl, C ₂ -C ₃ alkenyl, -NR'R" or -MR ⁶ Substituent substitution;

R ', R "are independently H or a C ₁ -C ₃ alkyl;

M is -O(CH ₂ ) _q - or -C(O)-, wherein q is an integer from 1 to 4;

R ⁶ is -H, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or -NR ⁷ R ⁸ ;

R ⁷ and R ⁸ are each independently -H, C ₁ -C ₃ alkyl, or R ⁷ and R ⁸ are bonded to form a 4-7 membered heterocyclic ring;

R ² is

L _{1 is} selected from:

T ₁ is C ₁ -C ₈ straight chain alkyl group, or each independently are R ^9, R ¹⁰ is substituted C ₁ -C ₈ straight chain alkyl group;

R ⁹ and R ¹⁰ are each independently -H or C ₁ -C ₃ alkyl;

R ¹¹ is -H, hydroxy, C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, 4-7 membered heterocyclic Or -NR ¹² R ¹³ ,

R ¹² and R ¹³ are each independently -H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl substituted by hydroxy or C ₁ -C ₃ alkoxy Substituted C ₁ -C ₆ alkyl;

The 4-7 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, which are unsubstituted or C ₁ -C ₃ alkyl, aldehyde a group of a C ₁ -C ₄ alkyl acyl group, an amino acyl group, a mono or disubstituted C ₁ -C ₃ amino acyl group, a C ₁ -C ₃ alkyl sulfone group, a C ₁ -C ₃ alkyl sulfoxide group The sulfur in the or two substituted or heterocyclic rings is oxidized by one or two oxygen atoms.

In a preferred embodiment,

R ¹ is

L is a C ₁ -C ₃ straight chain alkyl group, or each independently be R ^4, R ⁵ substituted C ₁ -C ₃ linear alkyl;

R ⁴ and R ⁵ are each independently -H or C ₁ -C ₃ alkyl;

R ³ is -H, C ₁ -C ₃ alkyl which is unsubstituted or substituted by halogen, hydroxy, cyano, carboxy, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, aryl, a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group, or a fluorene structure;

The cyclo-ring structure is selected from the group consisting of a benzo-5-6 heteroaryl ring group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, a benzo-5-6 cycloalkyl group, and a benzo-5-6 heterocyclic ring. a 5-6 membered heteroaryl ring and a 5-6 cycloalkyl group, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic group,

The heterocyclic group, heteroaryl ring group contains 1-3 hetero atoms selected from N, O or S;

The aryl, heteroaryl, heterocyclic or bicyclic ring structure is unsubstituted or independently independently from one to three selected from the group consisting of halogen, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halo C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, C ₂ -C ₃ alkynyl, C ₂ -C ₃ alkenyl, -NR'R" or -MR ⁶ Substituent substitution;

R' and R" are each independently H or a C ₁ -C ₃ alkyl group;

M is -O(CH ₂ ) _q - or -C(O)-, wherein q is an integer from 1 to 3;

R ⁶ is H, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or -NR ⁷ R ⁸ ;

R ⁷ and R ⁸ are each independently H, C ₁ -C ₃ alkyl or R ⁷ and R ⁸ are bonded to form a 5-6 membered heterocyclic ring.

In another preferred embodiment,

R ¹ is

L is a C ₁ -C ₃ linear alkyl group, or a C ₁ -C ₂ linear alkyl group each independently substituted with R ⁴ , R ⁵ ;

R ⁴ and R ⁵ are each independently -H or methyl;

R ^{3 is} selected from the group consisting of: -H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, hydroxy, carboxy, 1-hydroxy-1-methylethyl, or the following groups:

R ¹⁴ is -H or C ₁ -C ₃ alkyl;

Q ₁ , Q ₂ , Q ₃ , Q ₄ , and Q5 are each independently N or CH;

(R ¹⁵ ) _p is p identical or different R ¹⁵ substituents, p is 0, 1, 2 or 3;

R ^{15 is} selected from the group consisting of -H, -F, -Cl, -Br, -CF ₃ , -OCF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, iso Propyloxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, hydroxy, cyano, -NR'R" or -MR ⁶ ;

R', R" are independently H, methyl, ethyl, propyl or isopropyl;

M is -O(CH ₂ ) _q - or -C(O)-, wherein q is 1, 2 or 3;

R ⁶ is H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or -NR ⁷ R ⁸ ;

R ⁷ and R ^{8 are} independently H, methyl, ethyl, propyl, isopropyl, or R ⁷ and R ⁸ are bonded to form a 5-6 membered heterocyclic ring, and the 5-6 membered heterocyclic ring is preferably:

In some preferred embodiments, R ¹ is

L is a C ₁ -C ₃ straight chain alkyl group, or each independently are R ^4, R ⁵ substituted C ₁ -C ₃ linear alkyl;

R ⁴ and R ⁵ are each independently -H or methyl;

R ^{3 is} selected from the group consisting of: -H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, hydroxy, carboxy, 1-hydroxy-1-methylethyl, or the following groups:

R ¹⁴ is -H or C ₁ -C ₃ alkyl;

(R ¹⁵ ) _p is p identical or different R ¹⁵ substituents, p is 0, 1, 2 or 3;

R ^{15 is} selected from the group consisting of -H, -F, -Cl, -Br, -CF ₃ , -OCF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, iso Propyloxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, hydroxy, cyano, -NR'R" or -MR ⁶ ;

R', R" are independently H, methyl, ethyl, propyl or isopropyl;

M is -O(CH ₂ ) _q - or -C(O)-, wherein q is 1, 2 or 3;

R ⁶ is H, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or -NR ⁷ R ⁸ ;

R ⁷ and R ^{8 are} independently H, methyl, ethyl, propyl, isopropyl, or R ⁷ and R ⁸ are bonded to each other to form

Preferably,

R ² is

L _{1 is} selected from:

T ₁ is C ₁ -C ₆ linear alkyl group, or each independently are R ^9, R ¹⁰ is substituted C ₁ -C ₆ straight chain alkyl;

R ⁹ and R ¹⁰ are each independently -H or methyl;

R ¹¹ is -H, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropyl Oxyl, methylthio, ethylthio, propylthio, isopropylthio, 5-6 membered heterocyclyl or -NR ¹² R ¹³ ;

R ¹² and R ¹³ are independently -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isobutyl, 1-ethylpropyl, cyclopropane Base, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, B Oxypropyl, ethoxybutyl, propoxyethyl, propoxypropyl, propoxybutyl, isopropoxyethyl, isopropoxypropyl or isopropoxybutyl;

The 5-6 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, and the 5-6 membered heterocyclic group is unsubstituted or methyl, B. Base, propyl, isopropyl, aldehyde, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylamino, dimethylamino, methylsulfonyl, ethylsulfonyl, isopropyl One or two of the sulfone group, the methanesulfoxide group, the ethyl sulfoxide group, the isopropyl sulfoxide group or the sulfur in the hetero ring is oxidized by one or two oxygen atoms;

The 5-6 membered heterocyclic ring is selected from the group consisting of

Preferably,

R ² is

L _{1 is} selected from:

T ₁ is C ₁ -C ₆ linear alkyl group, or each independently are R ^9, R ¹⁰ is substituted C ₁ -C ₆ straight chain alkyl;

R ⁹ and R ¹⁰ are each independently -H or methyl;

R ¹¹ is -H, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropyl Oxyl, methylthio, ethylthio, propylthio, isopropylthio, 5-6 membered heterocyclyl or -NR ¹² R ¹³ ;

R ¹² and R ¹³ are each independently H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isobutyl, 1-ethylpropyl, cyclopropyl. , cyclobutyl, cyclopentyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxy Propyl, isopropoxyethyl or isopropoxypropyl;

The 5-6 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, and the 5-6 membered heterocyclic group is unsubstituted or methyl, B. Base, propyl, isopropyl, aldehyde, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylamino, dimethylamino, methylsulfonyl, ethylsulfonyl, isopropyl One or two of the sulfone group, the methanesulfoxide group, the ethyl sulfoxide group, the isopropyl sulfoxide group or the sulfur in the hetero ring is oxidized by one or two oxygen atoms;

The 5-6 membered heterocyclic group is selected from the group consisting of

R ¹⁶ is H, amino, methylamino, dimethylamino, methyl, ethyl, propyl, isopropyl.

The invention also relates to a method of treating a kinase-mediated disease or condition, such as EGFR, HER2, HER3, HER4, comprising administering to a patient in need thereof (human or other mammal, especially a human) a therapeutically effective amount of (I) A compound or a salt thereof, wherein the kinase-mediated diseases or conditions such as EGFR, HER2, HER3, HER4 include those mentioned above.

The invention also provides methods of preparing the corresponding compounds, which can be prepared using a variety of synthetic methods, including the methods described below, the compounds of the invention or pharmaceutically acceptable salts, isomers or hydrates thereof The synthesis is carried out using the methods described below in the art of organic chemical synthesis, or by variations of those methods as understood by those skilled in the art, and the preferred methods include, but are not limited to, the methods described below.

The present invention exemplifies the synthetic route of the compound of the formula I by the following scheme, and the present invention mainly describes the following three preparation schemes:

Preparation of a compound of formula I: wherein R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , L ₁ , X and T _{1 are} as defined above.

Reaction step a): 5-chloro-6-nitroquinazolin-4(3H)-one is sufficiently contacted with sodium glycolate to obtain a compound of formula II 5-(2-hydroxyethoxy) -6-Nitroquinazolin-4(3H)-one.

Reaction step b): 5-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one represented by formula II is sufficiently contacted with a chlorinating reagent, and then added to water to obtain a formula III. 5-(2-chloroethoxy)-6-nitroquinazolin-4(3H)-one,

The chlorinating agent includes, but is not limited to, a combination of phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride and chlorine, or a combination of two or more thereof.

Reaction step c): Reduction reaction of 5-(2-chloroethoxy)-6-nitroquinazolin-4(3H)-one of formula III to give 5-(2- represented by formula IV) Chloroethoxy)-6-aminoquinazolin-4(3H)-one.

The conditions for the reduction reaction include, but are not limited to, hydrogen and Raney nickel, hydrogen and palladium carbon, iron powder, zinc powder or stannous chloride.

Reaction step d): Dissolving 5-(2-chloroethoxy)-6-aminoquinazolin-4(3H)-one of formula IV in a solvent and heating to obtain 2,3 represented by formula V , 4,9-tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one;

The solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). , one of dioxane and dichloroethane, and a combination of two or more;

Preferably, the reaction can be carried out under base-catalyzed conditions, including but not limited to triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.

Reaction step e): 2,3,4,9-tetrahydro-10H-[1,4]oxazine [2,3-f]quinazolin-10-one of formula V, R ¹ XH and The Carter condensing agent is sufficiently contacted to obtain the oxazinoquinazoline compound represented by the formula VII;

Preferably, the Carter condensing agent is selected from the group consisting of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yl-oxy hexafluorophosphate One or a combination of two of tripyrrolidinylphosphorus (PyBOP);

Preferably, the above reaction can also be carried out under basic conditions, including but not limited to triethylamine, diisopropylethylamine, triethylenediamine, 1,8-diazabicyclo10 One or a combination of two or more of carbon-7-ene (DBU), pyridine, N-methylmorpholine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate and cesium carbonate.

Reaction step fA): condensation reaction of a compound represented by formula VIII with R ² C(O)Cl or reaction of R ² COOH with a chlorinating reagent followed by condensation with a compound of formula VIII to give a formula I Compound

The chlorinating agent is selected from one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride;

Preferably, the above reaction can be carried out under basic conditions including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.

且R ¹¹为HNR ¹²R ¹³，L ₁为

时，由式VIII化合物与

反应后加入连有R ¹²和R ¹³取代基的胺

反应制备式I化合物； Reaction step fB): or, when R ² is

And R ¹¹ is HNR ¹² R ¹³ , and L ₁ is

By the compound of formula VIII and

After the reaction, an amine to which a substituent of R ¹² and R ^{13 is} attached is added.

Preparing a compound of formula I;

Preferably, the above reaction can be carried out in an organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA). a combination of N-methylpyrrolidone (NMP), dioxane and dichloroethane, and a combination of two or more;

且L ₁为

时，由式VIII化合物与2-(二乙氧基磷酰基)乙酸在缩合剂作用下进行步骤f-C1反应得到式IX所示化合物，式IX化合物进一步与

发生步骤f-C2反应得到式I化合物。 Reaction step fC): or, when R ² is

And L ₁ is

When the compound of the formula VIII is reacted with 2-(diethoxyphosphoryl)acetic acid under the action of a condensing agent, the compound represented by the formula IX is obtained by the step f-C1, and the compound of the formula IX is further

The reaction of step f-C2 takes place to give the compound of formula I.

Preferably, the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a cerium salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably N, N'-carbonyl group. Diimidazole (CDI), N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), N,N- Diisopropylethylamine (DIEA), 1-hydroxy-7-azobenzotriazole (HOAt), O-benzotriazole-N,N,N',N'-tetramethylurea IV Fluoroborate (TBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(7-oxobenzotriazole)-N ,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), propylphosphoric anhydride (T3P), 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl(3-dimethylaminopropyl)carbodiimide (EDC), benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinium (PyBOP), (3H-1,2,3 triazolo[4,5-b]pyridin-3-yloxy)tri-1-pyrrolidinium hexafluorophosphate (PyAOP) of one or a combination of two or more;

Preferably, this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) and N-methylmorpholine.

Preferably, step f-C2 can occur in an aprotic solvent, under the action of a base. The aprotic solvent includes, but is not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). a combination of one or more of dioxane; the base includes, but is not limited to, one of sodium hydride, lithium bistrimethylsilylamine, and a combination of the two.

The above step fA), the step fB) and the fC) are a step of juxtaposition selection, that is, the compound of the formula VIII can be prepared by the compound of the formula fA), the step fB) and the fC), ie, the formula VIII. The compound can be prepared by fA) to prepare a compound of the formula (I), or a compound of the formula VIII by the step fB) to prepare a compound of the formula (I) or by fC) to prepare a compound of the formula (I).

Preparation of a compound of formula I: wherein R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , L ₁ , X and T _{1 are} as defined above.

Reaction step a): 2,3,4,9-tetrahydro-10H-[1,4]oxazine [2,3-f]quinazolin-10-one represented by formula V, and Carter condensing agent The compound represented by the formula VI is obtained by thorough contact. Wherein R ¹ is a substituent as described in claim 1. Preferably, the Carter condensing agent is selected from the group consisting of benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yl-oxy hexafluorophosphate One or a combination of two of tripyrrolidinylphosphine (PyBOP); the above reaction can also be carried out under basic conditions including but not limited to triethylamine, diisopropylethylamine, triethylene Diamine, 1,8-diazabicycloundec-7-ene (DBU), pyridine, N-methylmorpholine, 4-dimethylaminopyridine, sodium carbonate, potassium carbonate, cesium carbonate Or a combination of two or more.

Reaction step b): 10-((1H-benzo[d][1,2,3]triazol-1-yl)oxy)-3,4-dihydro-2H-[ 1,4] Oxazine [2,3-f]quinazoline is sufficiently contacted with R ¹ XH in an organic solvent to give a compound of the formula VIII. Preferably, the organic solvent is selected from the group consisting of methanol, ethanol, isopropanol, tetrahydrofuran, N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP) a combination of dioxane, dichloroethane, or a combination of two or more; preferably, the reaction can be carried out under base-catalyzed conditions, including but not limited to triethylamine, diisopropyl B A kind of amine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride Or a combination of two or more; preferably, the reaction can be carried out under acid-catalyzed conditions, including but not limited to one of methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, trifluoroacetic acid, hydrochloric acid Or a combination of two or more.

Reaction step cA): a compound represented by formula VIII is reacted with R ² C(O)Cl or R ² COOH with a chlorinating reagent to form a compound of formula I;

The chlorinating agent is preferably one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride and phosphorus pentachloride;

Preferably, the above reaction can be carried out under basic conditions including, but not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diaza One or a combination of two or more of cycloundec-7-ene, N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.

且R ¹¹为HNR ¹²R ¹³，L为乙烯基时，由式VIII化合物与

反应后加入连有R ¹²和R ¹³取代基的胺

反应制备式I化合物； Reaction step cB): or, when R ² is

And R ¹¹ is HNR ¹² R ¹³ , and when L is a vinyl group, the compound of formula VIII is

After the reaction, an amine to which a substituent of R ¹² and R ^{13 is} attached is added.

Preparing a compound of formula I;

Preferably, the above reaction can be carried out in an organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA). a combination of N-methylpyrrolidone (NMP), dioxane and dichloroethane, and a combination of two or more;

且L ₁为

时，由式VIII化合物与2-(二乙氧基磷酰基)乙酸在缩合剂作用下进行步骤c-C1反应得到式IX所示化合物，式IX化合物进一步与

发生步骤c-C2反应得到式I化合物； Reaction step cC): or, when R ² is

And L ₁ is

When the compound of the formula VIII is reacted with 2-(diethoxyphosphoryl)acetic acid under the action of a condensing agent, the compound of the formula IX is obtained by the step c-C1, and the compound of the formula IX is further

Step c-C2 reaction occurs to give a compound of formula I;

Preferably, the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a cerium salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably N, N'-carbonyl group. Diimidazole (CDI), N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), N,N- Diisopropylethylamine (DIEA), 1-hydroxy-7-azobenzotriazole (HOAt), O-benzotriazole-N,N,N',N'-tetramethylurea IV Fluoroborate (TBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(7-oxobenzotriazole)-N ,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), propylphosphoric anhydride (T3P), 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl(3-dimethylaminopropyl)carbodiimide (EDC), benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinium (PyBOP), (3H-1,2,3 triazolo[4,5-b]pyridin-3-yloxy)tri-1-pyrrolidinium hexafluorophosphate (PyAOP) of one or a combination of two or more;

Preferably, this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine and 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.

Preferably, step c-C2 can occur in an aprotic solvent, under the action of a base. The aprotic solvent includes, but is not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). a combination of one or more of dioxane; the base includes, but is not limited to, one of sodium hydride, lithium bistrimethylsilylamine, and a combination of the two.

The above step cA), the steps cB) and cC) are a step of juxtaposition selection, that is, the compound of the formula VIII can be prepared by one of the compounds cA), cB) and cC), ie, the formula VIII The compound can be prepared by preparing a compound of the formula (I) by cA), or a compound of the formula VIII, or a compound of the formula (I) by the step cB) or a compound of the formula (I).

The third aspect of the preparation of the object compound, wherein R ¹ , R ² , R ⁸ , R ⁹ , R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , L ₁ , X and T _{1 are} as defined above.

Reaction step a): reacting the compound 5-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one represented by the formula II with a chlorinating reagent and then contacting with R ¹ XH A quinazoline compound represented by VII. The chlorinating agent includes, but is not limited to, phosphorus oxychloride, thionyl chloride, phosphorus trichloride, phosphorus pentachloride, chlorine, or a combination of two or more.

Reaction step b): the quinazoline compound of the formula VII is obtained under reducing conditions to obtain an oxazine quinazoline compound represented by the formula VIII, and the reducing conditions include, but are not limited to, hydrogen and Raney nickel. Hydrogen and palladium carbon, iron powder, zinc powder, stannous chloride.

Reaction step cA): a compound represented by formula VIII is reacted with R ² C(O)Cl or R ² COOH with a chlorinating reagent to form a compound of formula I;

The chlorinating agent is preferably one or a combination of two or more of phosphorus oxychloride, thionyl chloride, oxalyl chloride, phosphorus trichloride, and phosphorus pentachloride; preferably, the above reaction may be alkaline. Under conditions, the base includes, but is not limited to, triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, 1,8-diazabicycloundec-7-ene, One or a combination of two or more of N-methylmorpholine, sodium carbonate, potassium carbonate, and cesium carbonate.

且R ¹¹为HNR ¹²R ¹³，L为乙烯基时，由式VIII化合物与

反应后加入连有R ¹²和R ¹³取代基的胺

反应制备式I化合物； Reaction step cB): or, reaction step cB): or, when R ² is

And R ¹¹ is HNR ¹² R ¹³ , and when L is a vinyl group, the compound of formula VIII is

After the reaction, an amine to which a substituent of R ¹² and R ^{13 is} attached is added.

Preparing a compound of formula I;

Preferably, the above reaction can be carried out in an organic solvent including, but not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA). a combination of N-methylpyrrolidone (NMP), dioxane, dichloroethane, and a combination of two or more;

且L ₁为

时，由式VIII化合物与2-(二乙氧基磷酰基)乙酸在缩合剂作用下进行步骤c-C1反应得到式IX所示化合物，式IX化合物进一步与

发生步骤c-C2反应得到式I化合物。 Reaction step cC): or, when R ² is

And L ₁ is

When the compound of the formula VIII is reacted with 2-(diethoxyphosphoryl)acetic acid under the action of a condensing agent, the compound of the formula IX is obtained by the step c-C1, and the compound of the formula IX is further

The reaction of step c-C2 takes place to give the compound of formula I.

Preferably, the condensing agent includes, but not limited to, a carbodiimide type condensing agent, a cerium salt type condensing agent, an organic phosphorus type condensing agent, and one or more kinds of other types of condensing agents, preferably N, N'-carbonyl group. Diimidazole (CDI), N,N-dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide (DIC), hydroxybenzotriazole (HOBt), N,N- Diisopropylethylamine (DIEA), 1-hydroxy-7-azobenzotriazole (HOAt), O-benzotriazole-N,N,N',N'-tetramethylurea IV Fluoroborate (TBTU), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 2-(7-oxobenzotriazole)-N ,N,N',N'-tetramethylurea hexafluorophosphate (HBTU), 6-chlorobenzotriazole-1,1,3,3-tetramethyluronium hexafluorophosphate (HCTU), 2-(7-oxobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), propylphosphoric anhydride (T3P), 1-(3-dimethyl Aminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 1-ethyl(3-dimethylaminopropyl)carbodiimide (EDC), benzotriazole hexafluorophosphate- 1-yl-oxytripyrrolidinium (PyBOP), (3H-1,2,3 triazolo[4,5-b]pyridin-3-yloxy)tri-1-pyrrolidinium hexafluorophosphate (PyAOP) of one or a combination of two or more;

Preferably, this step can be carried out in an organic base including, but not limited to, triethylamine, diisopropylethylamine (DIEA), pyridine, 4-dimethylaminopyridine (DMAP), 2, One or a combination of two or more of 6-lutidine, 1,8-diazabicycloundec-7-ene (DBU) or N-methylmorpholine.

Preferably, step c-C2 can occur in an aprotic solvent, under the action of a base. The aprotic solvent includes, but is not limited to, tetrahydrofuran (THF), N,N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), N-methylpyrrolidone (NMP). a combination of one or more of dioxane; the base includes, but is not limited to, one of sodium hydride, lithium bistrimethylsilylamine, and a combination of the two.

The above step cA), the steps cB) and cC) are a step of juxtaposition selection, that is, the compound of the formula VIII can be prepared by one of the compounds cA), cB) and cC), ie, the formula VIII The compound can be prepared by preparing a compound of the formula (I) by cA), or a compound of the formula VIII, or a compound of the formula (I), or a compound of the formula (I), by the step cB).

Detailed description of the invention

The term "substituted" as used herein, includes complex substituents (e.g., phenyl, aryl, heteroalkyl, heteroaryl), suitably 1 to 5 substituents, preferably 1 to 3 One, preferably one or two, can be freely selected from the list of substituents.

Unless otherwise specified, alkyl as used herein includes saturated monovalent hydrocarbon radicals having straight chain, branched or cyclic moieties. For example, alkyl includes methyl, ethyl, propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, cyclobutyl, n-pentyl, 3-(2-methyl)butyl, 2-pentyl, 2-methylbutyl, neopentyl, cyclopentyl, n-hexyl, 2-hexyl, 2-methylpentyl and cyclohexyl. An alkoxy group is an etherified ether consisting of a linear, branched or cyclic alkyl group as previously described. Similarly, alkenyl and alkynyl groups include straight chain, branched or cyclic alkenyl and alkynyl groups.

The term "aryl" as used herein, unless otherwise specified, refers to an unsubstituted or substituted aryl group, such as phenyl, naphthyl, anthracenyl. The term "aroyl" refers to -C(O)-aryl.

The term "heterocyclyl" as used herein, unless otherwise specified, represents an unsubstituted or substituted stable 3 to 8 membered monocyclic saturated ring system selected from carbon atoms and from N, O, S. The composition of one to three heteroatoms, wherein the N, S heteroatoms can be arbitrarily oxidized, and the N heteroatoms can also be quaternized at random. The heterocyclic ring can be combined with any hetero atom or carbon atom to form a stable structure. Examples of such heterocyclic rings include, but are not limited to, azacyclohexane, pyrrolidinyl, piperidinyl, piperazinyl, piperazinyl, piperidinyl, tetrahydrofuranyl, dioxolane Base, tetrahydroimidazolyl, tetrahydrothiazolyl, tetrahydrooxazolyl, tetrahydropyranyl, morphinolinyl, thiomorphocyaninyl, thiamorphinoline sulfoxide, thiamorpholin sulfone and oxadiazolyl.

The term "heteroaryl" as used herein, unless otherwise specified, represents a stable 5 or 6 membered monocyclic aromatic ring system which is unsubstituted or substituted, and may also represent unsubstituted or substituted 9 or a 10-membered benzene-fused benzene heteroaromatic ring system or a bicyclic heteroaromatic ring system consisting of a carbon atom and one to four hetero atoms selected from N, O, and S, wherein the N, S hetero atom can be optionally oxidized. , N heteroatoms can also be quaternized at random. The heteroaryl group can be attached to any hetero atom or carbon atom to form a stable structure. Examples of heteroaryl groups include, but are not limited to, thioxyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiazolyl, thiadiazolyl, triazolyl , pyridyl, pyridazinyl, fluorenyl, azaindole, carbazolyl, benzimidazolyl, benzofuranyl, benzothienyl, benzisoxazolyl, benzoxazolyl, Benzopyrazolyl, benzothiazolyl, benzothiadiazolyl, benzotriazolyl, adenyl, quinolinyl or isoquinolyl.

The term "carbonyl" refers to a C(O) group.

Whenever the terms "alkyl" or "aryl" or any of their prefix radicals appear in the name of a substituent (eg, aralkyl, dialkylamine), it will be considered to contain the above "alkane" Those limitations given by "base" and "aryl". The specified number of carbon atoms (eg, C ₁ -C ₆ ) will independently represent a carbon atom in an alkyl moiety or an alkyl moiety in a larger substituent (wherein the alkyl group is the prefix root) Quantity.

It will be apparent that the compounds, isomers, crystalline forms or prodrugs of formula I, and pharmaceutically acceptable salts thereof, may exist in both solvated and unsolvated forms. For example, the solvated form can be in a water soluble form. The present invention includes all such solvated and unsolvated forms.

The compounds of the invention may have asymmetric carbon atoms which, depending on their physicochemical differences, may be separated by known techniques, such as by chromatography or fractional crystallization. Into a single diastereomer. Separation of the enantiomers can be carried out by first reacting the appropriate optically active compound, converting the enantiomeric mixture into a diastereomeric mixture, separating the diastereomers, and then separating the individual The enantiomers are converted (hydrolyzed) to the corresponding pure enantiomers. All such isomers, including mixtures of diastereomers and pure enantiomers, are considered to be part of this invention.

The compound of the present invention as an active ingredient, and a method of preparing the same, are all contents of the present invention. Moreover, the crystalline form of some of the compounds may exist as polycrystals, and such forms may also be included in the current invention. Additionally, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also included within the scope of the invention.

The compounds of the invention may be used in the free form for treatment or, where appropriate, in the form of a pharmaceutically acceptable salt or other derivative for treatment. As used herein, the term "pharmaceutically acceptable salt" refers to organic and inorganic salts of the compounds of the present invention which are suitable for use in humans and lower animals without undue toxicity, irritation, allergic response, etc., and have reasonable Benefit/risk ratio. Pharmaceutically acceptable salts of amines, carboxylic acids, phosphonates, and other types of compounds are well known in the art. The salt can be formed by reacting a compound of the invention with a suitable free base or acid. Including, but not limited to, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, malonic acid, These salts are obtained either by methods well known in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, hydrogen sulfate, borate, butyrate, camphoric acid Salt, camphor sulfonate, citrate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerol phosphate, gluconic acid Salt, hemisulfate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methane Sulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulphate, per-3-phenylpropionate, Phosphate, picrate, propionate, stearate, sulfate, thiocyanate, p-toluenesulfonate, undecanoate, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include suitable non-toxic ammonium, quaternary ammonium, and the use of such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates. An amine cation formed by the acid salt.

Further, the term "prodrug" as used herein means that a compound can be converted into a compound of the formula (I) of the present invention in vivo. This transformation is affected by hydrolysis of the prodrug in the blood or enzymatic conversion to the parent compound in the blood or tissue.

The pharmaceutical composition of the present invention comprises a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a kinase inhibitor (small molecule, polypeptide, antibody, etc.), an immunosuppressant, an anticancer drug, an antiviral agent, an antibiotic An additional agent of an inflammatory, antifungal, antibiotic or anti-vascular hyperproliferative compound; and any pharmaceutically acceptable carrier, adjuvant or excipient.

The compounds of the invention may be used alone or in combination with one or more other compounds of the invention or with one or more other agents. When administered in combination, the therapeutic agents can be formulated for simultaneous administration or sequentially at different times, or the therapeutic agents can be administered as a single composition. By "combination therapy" is meant the use of a compound of the invention in combination with another agent in the form of co-administration of each agent or sequential administration of each agent, in either case, for the purpose Achieve the best results of the drug. Co-administration includes simultaneous delivery of the dosage form, as well as separate dosage forms for each compound. Thus, administration of the compounds of the invention can be used in conjunction with other therapies known in the art, for example, in the treatment of cancer using radiation therapy or cytostatic agents, cytotoxic agents, other anticancer agents, and the like to improve Cancer-like. The invention is not limited to the order of administration; the compounds of the invention may be administered previously, simultaneously, or after other anticancer or cytotoxic agents.

In order to prepare the pharmaceutical ingredient of the present invention, one or more compounds or salts of the formula (I) as an active ingredient thereof can be intimately mixed with a pharmaceutical carrier, which is carried out according to a conventional pharmaceutical ingredient technique. The carrier can be used in a wide variety of forms depending on the form of preparation which is designed for different modes of administration (for example, oral or parenteral administration). Suitable pharmaceutically acceptable carriers are well known in the art. A description of some of these pharmaceutically acceptable carriers can be found in the Handbook of Pharmaceutical Excipients, published jointly by the American Pharmaceutical Association and the British Pharmaceutical Society.

The pharmaceutical composition of the present invention may have the following forms, for example, suitable for oral administration, such as tablets, capsules, pills, powders, sustained release forms, solutions or suspensions; for parenteral injections such as clear solutions, suspensions, Emulsion; or for topical use such as creams, creams; or as a suppository for rectal administration. The pharmaceutical ingredient may also be presented in unit dosage form for administration in a precise dosage. The pharmaceutical ingredient will include a conventional pharmaceutical carrier or excipient and a compound as an active ingredient prepared according to the present invention, and may also include other medical or pharmaceutical preparations, carriers, adjuvants, and the like.

Therapeutic compounds can also be administered to mammals other than humans. The dosage of the drug to be administered to a mammal will depend on the species of the animal and its disease state or the disordered condition in which it is located. The therapeutic compound can be administered to the animal in the form of a capsule, a bolus, or a pill. The therapeutic compound can also be introduced into the animal by injection or infusion. We prepare these forms of the drug in a traditional manner consistent with veterinary practice standards. As an alternative, the pharmaceutical synthetic drug can be mixed with the animal feed and fed to the animal, so that the concentrated feed additive or premix can be prepared by mixing ordinary animal feed.

It is a further object of the present invention to provide a method for treating cancer in a subject in need thereof which comprises administering to the subject a method of administering a therapeutically effective amount of a composition comprising a compound of the present invention.

The invention also encompasses the use of a compound of the invention, or a pharmaceutically acceptable derivative thereof, for the manufacture of a medicament for the treatment of a tyrosine kinase EGFR, HER2, HER3, HER4 associated cancer and an autoimmune disease. Said cancer (including non-solid tumors, solid tumors, primary or metastatic cancers, as indicated elsewhere herein and including one or more other treatments in which the cancer is resistant or refractory) and other diseases (including but The agent is not limited to fundus diseases, psoriasis, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, and the like. The cancer includes, but is not limited to, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma, ovarian cancer, cervical cancer, colorectal cancer, melanoma, intrauterine Membrane cancer, prostate cancer, bladder cancer, leukemia, gastric cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain Any of tumor, B cell and T cell lymphoma, lymphoma, multiple myeloma, cholangiocarcinoma, and cholangiocarcinoma.

The invention is better illustrated by the examples provided below, all temperatures being in degrees Celsius unless otherwise stated.

Detailed ways

The intermediate involved in the compound of the present invention can be produced by the following method, but is not limited to the following method. The synthesis of a part of the intermediates of the present invention can be referred to the method of the patent CN104530063, a simple replacement of some functional groups, and the corresponding intermediates can be obtained by those skilled in the art according to the knowledge of the chemical synthesis field. The following invention provides the preparation route of the intermediate, and the intermediate involved in the compound of the present invention can be produced by the following scheme, but is not limited to the following scheme.

Synthesis of Intermediate Compounds of Formula VIII

Intermediate N-(3-Bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1)

Step 1) Preparation of 5-(2-hydroxyethoxy)-6-nitroquinazolin-4(3H)-one (II)

Ethylene glycol (352.7 g, 5.7 mol) was dissolved in 1 liter of DMF, cooled in an ice water bath, sodium hydride (68.2 g, 2.8 mol) was added, and after stirring for 0.5 hour, 5-chloro-6-nitroquinazoline was added. 4(3H)-one, (128g, 0.57 mol), slowly warmed to room temperature and stirred until the reaction was completed. Ethyl acetate was added until a large amount of solid was precipitated and suction filtered, and the obtained solid was beaten with water, hydrochloric acid was adjusted to weak acid, and then filtered to give a white solid, 129.7 g, yield 91%. ¹ H NMR (DMSO-d ₆ , 400 MHz) δ 12.55 (1H, s), 8.13 - 8.28 (2H, m), 7.52 (1H, d, J = 8.9 Hz), 4.76 (1H, s), 4.04– 4.32 (2H, m), 3.60 - 3.84 (2H, m); MS: 252 [M+H] ⁺ .

Step 2) Preparation of N-(3-bromophenyl)-5-(2-chloroethoxy)-6-nitroquinazolin-4-amine (VII-1)

5-(2-Hydroxyethoxy)-6-nitroquinazolin-4(3H)-one (3g, 11.94mmol) was added to a round bottom flask, dissolved in thionyl chloride, and dissolved in a catalytic amount. Dimethylformamide, the reaction mixture was heated to reflux until the reaction was completed. The residue was evaporated to dryness. After adding n-hexane, stirring was carried out until a large amount of solid was precipitated, suction filtration, petroleum ether washing, and drying to obtain 3.7 g of a yellow solid, yield 88%. MS: 423 [M+H] ⁺ .

Step 3) N-(3-bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1) preparation

N-(3-Bromophenyl)-5-(2-chloroethoxy)-6-nitroquinazolin-4-amine (3.7 g, 8.7 mmol) was added to a round bottom flask, and ethanol and water were added. Mixing solvent, then adding iron powder (1.3g, 22.7mmol), acetic acid (1.85mL, 32.27mmol), the reaction mixture is heated and stirred until the reaction is complete, the solvent is evaporated, ethyl acetate is extracted, concentrated, and purified by column chromatography. 2.0 g of solid, 65% yield. ¹ H NMR (500 MHz, DMSO-d ₆ ) δ 10.03 (s, 1H), 8.35 (dd, J = 6.5, 4.5 Hz, 2H), 7.81 (dd, J = 8.1, 1.0 Hz, 1H), 7.40- 7.28 (m, 1H), 7.29-7.21 (m, 3H), 6.29 (s, 1H), 4.48 (t, J = 4.3 Hz, 2H), 3.46 (dd, J = 7.0, 4.1 Hz, 2H). ¹³ C NMR (125 MHz, DMSO) δ 156.23, 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]oxazino[2,3-f]quinazolin-10-amine (VIII -2) preparation

Step 1) Step 1) of the synthetic route to VIII-1.

Step 2) Preparation of N-(3-(trifluoromethyl)phenyl)-5-(2-chloroethoxy)-6-nitroquinazolin-4-amine (VII-2)

Refer to step 2) of the preparation method of N-(3-bromophenyl)-5-(2-chloroethoxy)-6-nitroquinazolin-4-amine (VII-1), and the specific embodiment is The 3-bromoaniline was replaced by the same molar equivalent of 3-trifluoromethylaniline. MS: 413 [M+H] ⁺ .

Step 3) N-(3-(Trifluoromethyl)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine ( Preparation of VIII-2)

Preparation method of N-(3-bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1) Step 3), in a specific molar ratio of N-(3-(trifluoromethyl)phenyl)-5-(2-chloroethoxy)-6-nitroquinazolin-4- The amine (VII-2) was substituted for N-(3-bromophenyl)-5-(2-chloroethoxy)-6-nitroquinazolin-4-amine (VII-1) in a yield of 60%. ^{1 H NMR (500MHz, DMSO-} d 6) δ10.15 (s, 1H), 8.45 (s, 1H), 8.37 (s, 1H), 8.10 (d, J = 8.3Hz, 1H), 7.64-7.56 ( m,1H), 7.43 (d, J = 7.7 Hz, 1H), 7.28-7.22 (m, 2H), 6.30 (s, 1H), 4.51-4.46 (m, 2H), 3.51-3.43 (m, 2H) ¹³ C NMR (125 MHz, DMSO) δ 156.39, 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]oxazino[2,3-f]quinazolin-10-amine (VIII-3) Preparation

Step 1) Step 1) of the synthetic route to VIII-1.

Step 2) Preparation of 5-(2-chloroethoxy)-6-nitroquinazolin-4(3H)-one (III)

5-(2-Hydroxyethoxy)-6-nitroquinazolin-4(3H)-one, (129.7 g, 0.52 mol) was placed in a flask, 200 ml of phosphorus oxychloride was added, and the mixture was heated to reflux. The reaction is completed. The phosphorus oxychloride was distilled off, and water was added to be slurried to precipitate a large amount of solid, which was filtered under suction to give a white solid, 120.8 g, yield 87%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 12.55 (s, 1H), 8.24 - 8.21 (m, 2H), 7.56 (d, J = 9.0 Hz, 1H), 4.41 (t, J = 5.4 Hz, 2H), 3.96 (t, J = 5.4 Hz, 2H); MS: 270 [M+H] ⁺ .

Step 3) Preparation of 5-(2-chloroethoxy)-6-aminoquinazolin-4(3H)-one (IV)

5-(2-Chloroethoxy)-6-nitroquinazolin-4(3H)-one (120.8 g, 0.45 mol) was dissolved in a mixed solvent of methanol and tetrahydrofuran, and 40 g of Raney nickel was added. Stir at room temperature under hydrogen atmosphere until the reaction is complete. Filtration and concentration gave 107.4 g of a yellow solid. ^{1 H NMR (400MHz, DMSO-} d 6) δ11.76 (s, 1H), 7.74 (s, 1H), 7.24 (d, J = 2.2Hz, 2H), 5.32 (s, 2H), 4.15 (t, J = 5.6 Hz, 2H), 3.97 (t, J = 5.6 Hz, 2H); MS: 240 [M+H] ⁺ .

Step 4) Preparation of 2,3,4,9-tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one (V)

5-(2-Chloroethoxy)-6-aminoquinazolin-4(3H)-one (107.4 g, 0.45 mol) was dissolved in 1 L of DMF and triethylamine (94 mL, 0.68 mol) was added. After heating to completion of the reaction, DMF was evaporated, and dichloromethane was added to the mixture to dissolve a large amount of solid, which was filtered to give a white solid. ¹ H NMR (DMSO-d ₆ , 300 MHz) δ 11.66 (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]oxazino[2,3-f]quinazolin-10-amine (VIII-3) Preparation

2,3,4,9-Tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one (0.5 g, 2.46 mmol), 4-methoxyaniline (605 mg, 4.92 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (1.4 g, 3.20 mmol) in a round bottom flask, add 5 ML acetonitrile, stir well, add 1,8-diazabicycloundec-7-ene (DBU) (0.56 g, 3.69 mmol), stir at room temperature until the reaction is complete, distill off the solvent, the mixture is obtained by silica gel column chromatography , 568 mg of a brown solid was obtained with a yield of 75%. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.97 (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 = 4.4 Hz, 2H), 3.77 (s, 3H), 3.49 - 3.44 (m, 2H); MS: 309 [M+H] ⁺ .

Intermediate N-(3-chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-4 Preparation

Steps 1) to 4) are the same as steps 1) to 4) in the preparation method of VIII-3.

Step 5) 10-((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)-3,4-dihydro-2H-[1,4]oxazine[ Preparation of 2,3-f]quinazoline (VI)

2,3,4,9-Tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one (20.3 g, 100 mmol) and benzotriazole-1 - oxyl tris(dimethylamino)phosphonium hexafluorophosphate (BOP) (44.2 g, 100 mmol) was placed in a round bottom flask, stirred with acetonitrile and then added to 1,8-diazabicyclo-11 Carbon-7-ene (DBU) (15.2 g, 100 mmol) was stirred at room temperature until the reaction was completed, stirred with water to give a large solid, and filtered, to give 28 g of a yellow solid. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.26 (s, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.68 - 7.60 (m, 1H), 7.58 - 7.47 (m, 3H), 6.70 (s, 1H), 4.41 (t, J = 4.2 Hz, 2H), 3.58 - 3.47 (m, 2H); MS: 321 [M+H] ⁺ .

Step 6) N-(3-chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII- 4) Preparation

10-((1H-Benzo[d][1,2,3]triazol-1-yl)oxy)-3,4-dihydro-2H-[1,4]oxazine [2, 3-f]quinazoline (320 mg, 1 mmol) and m-chloro-p-fluoroaniline (145 mg, 1 mmol), p-toluenesulfonic acid monohydrate (17 mg, 0.1 mmol) were dissolved in isopropyl alcohol and stirred at room temperature until the reaction was completed. After stirring with water and suction filtration, 300 mg of a yellow solid product was obtained with a yield of 91%. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.20 (s, 1H), 8.41 (d, J = 3.6Hz, 1H), 8.26-8.14 (m, 1H), 7.83-7.71 (m, 1H), 7.45–7.38 (m, 1H), 7.33–7.17 (m, 2H), 6.41 (s, 1H), 4.46 (t, 4.3 Hz, 2H), 3.58–3.56 (m, 2H); ¹³ C NMR (125 MHz, DMSO-d ₆ ) δ 156.26, 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-Fluorobenzyloxy)phenoxy)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline (VIII- 5) Preparation

Steps 1) to 5) are the same as steps 1) to 5) of the preparation method of VIII-4.

Step 6) 10-((3-Methoxybenzyl)oxy)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline (VIII-5 Preparation

138 mg (1 mmol) of m-methoxybenzyl alcohol was dissolved in 5 ml of dimethylformamide, and 24 mg of sodium hydride was added. After stirring at room temperature until no more gas was produced, 10-((1H-benzo[d] was added. ][1,2,3]triazol-1-yl)oxy)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline (VI) 320 Milliol (1 mmol) was stirred at room temperature until the reaction was completed, quenched with water and filtered to give 290 mg of yel. MS: 324 [M+H] ⁺ .

Preparation of intermediates VIII-6 to VIII-93

Steps 1) to 4) are the same as steps 1) to 4) in the synthesis method of VIII-3.

Step 5) Refer to step 5) of the VIII-3 synthetic route, which operates exactly the same, using 2,3,4,9-tetrahydro-10H-[1,4]oxazine [2,3-f The quinazolin-10-one (V) was used as a starting material, and the equivalent molar equivalents of R ¹ XH in the following table were substituted for 4-methoxyaniline. The specific implementation compounds are as follows:

Preparation of intermediates VIII-94 to VIII-103

Steps 1) to 5) are the same as the synthesis of compound VIII-4 from step 1) to step 5).

Step 6) With reference to the synthesis of the compound VIII-4, step 6), the operation is identical, and the method is carried out by 10-((1H-benzo[d][1,2,3]triazole-1-oxyl) -3,4-Dihydro-2H-[1,4]oxazino[2,3-f]quinazoline (VI) as starting material, replacing the same molar equivalent of R ¹ XH in the table below P-fluoroaniline. The specific implementation compounds are shown in the following table:

Preparation of example compounds

Example 1

1-(10-((3-bromophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)propane- Preparation of 2-en-1-one

N-(3-bromophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1) (178 mg, 0.5 mmol) was dissolved in tetrahydrofuran, acryloyl chloride (45.3 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature until the reaction was completed. The solid was 164 mg in 80% yield. ^{1 H NMR (500MHz, DMSO-} d 6) δ10.91 (s, 1H), 8.82 (s, 1H), 8.18 (s, 1H), 7.95-7.90 (m, 1H), 7.68-7.65 (m, 1H ), 7.56 (dd, J=8.0, 0.9 Hz, 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 = 4.5 Hz, 2H), 4.10 (t, J = 4.5 Hz, 2H); ¹³ C NMR (125 MHz, DMSO) δ 164.73, 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 411.0457calcd for C ₁₉ H ₁₅ BrN ₄ O ₂ [M+H] ⁺ , found 411.0455.

Example 2-82

Referring to the preparation method of Example 1, the operation is identical, in that N-(3-bromophenyl)-3 is replaced by the same molar equivalent of the intermediate of the formula VIII in which R ¹ X is a substituent in the following table, 4-Dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-1), the specific compounds are shown in the following table:

Example 83 1-(10-((4-Aminobenzyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl Preparation of prop-2-en-1-one

tert-Butyl (4-((3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-yl)amino)methyl)phenyl) Butyl ester (VIII-34) (203 mg, 0.5 mmol) was dissolved in tetrahydrofuran, acryloyl chloride (45.3 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature until the disappearance of the starting material, 1 ml of hydrochloric acid was added, and the mixture was stirred until the reaction was completed. off, extracted with ethyl acetate, purified by silica gel column chromatography after organic phase was concentrated to give an off-white solid 95 mg, yield ^{53%. 1 H NMR (400MHz} , DMSO-d 6) δ8.49-8.42 (m, 1H) , 8.33 (s, 1H), 7.70 (s, 1H), 7.20 (d, J = 9.2 Hz, 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 = 4.8 Hz, 2H), 4.00 (t, J = 4.8 Hz, 2H); MS: 362 [M+H] ⁺ .

Example 84: 1-(10-((4-Hydroxybenzyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4- Preparation of propyl-2-en-1-one

4-((3,4-Dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-yl)amino)methyl)acetate phenyl ester (VIII-36) (175 mg, 0.5 mmol) was dissolved in 5 ml of tetrahydrofuran, cooled in an ice bath, acryloyl chloride (45.3 mg, 0.5 mmol) was added, and stirred at room temperature until the starting material disappeared, then 1 ml of concentrated hydrochloric acid was added and stirring was continued until the reaction was completed to give an off-white The solid was 63 mg in a yield of 35%. ^{1 H NMR (400MHz, DMSO-} d 6) δ9.26 (s, 1H), 8.62-8.56 (m, 1H), 8.32 (s, 1H), 7.70 (s, 1H), 7.22-7.15 (m, 3H ), 6.79–6.68 (m, 3H), 6.33–6.26 (m, 1H), 5.85 (dd, J = 10.4, 2.0 Hz, 1H), 4.70–4.64 (m, 2H), 4.54 (t, J=4.8) Hz, 2H), 4.01 (t, J = 4.8 Hz, 2H); MS: 363 [M+H] ⁺

Example 85: 1-(10-((4-Hydroxy-3-methoxybenzyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] Preparation of quinazolin-4-yl)prop-2-en-1-one

The preparation method of Reference Example 84 was carried out in exactly the same manner. A specific embodiment is to replace VIII-36 with an equivalent molar equivalent of compound VIII-37. ^{1 H NMR (400MHz, DMSO-} d 6) δ8.82 (s, 1H), 8.59-8.52 (m, 1H), 8.34 (s, 1H), 7.71 (s, 1H), 7.20 (d, J = 8.8 Hz, 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=5.6 Hz, 2H), 4.54 (t, J = 4.8 Hz, 2H), 4.01 (t, J = 4.8 Hz, 2H), 3.74 (s, 3H); MS: 393 [M+H] ⁺ .

Example 86: Preparation of (4-acryloyl-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-yl)glycine

tert-Butyl (3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-yl)glycine (VIII-86) (158 mg, 0.5 mmol) Dissolve in 5 mL of tetrahydrofuran, cool in an ice bath, add 45.3 mg (0.5 mmol) of acryloyl chloride, stir at room temperature until the reaction is completed, quench with water, extract with ethyl acetate. The yield was 40%. ^{1 H NMR (400MHz, DMSO-} d 6) δ13.13 (s, 1H), 9.78-9.68 (m, 1H), 8.78 (s, 1H), 8.09 (s, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.83–6.73 (m, 1H), 6.33 (d, J = 16.8 Hz, 1H), 5.91 (d, J = 10.4 Hz, 1H), 4.64 (t, J = 4.6 Hz, 2H), 4.37 (d, J = 5.6 Hz, 2H), 4.07 (t, J = 4.6 Hz, 2H); MS: 315 [M+H] ⁺ .

Example 87: 3-((4-Acryloyl-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-yl)amino)propanoic acid preparation

Refer to the preparation method of Example 86, which is carried out in the same molar equivalent of tert-butyl 3-((3,4-dihydro-2H-[1,4]oxazino[2,3-f] quinazole Phenyl-10-yl)aminopropionate (VIII-89) in place of tert-butyl (3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline-10- Glycine ester (VIII-86). ¹ H NMR (400 MHz, DMSO-d ₆ ) 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, 2.6 Hz, 1H), 6.82–6.70 (m, 1H), 6.32 (d, J = 16.6 Hz, 1H), 5.90 (d, J = 10.4 Hz, 1H), 4.61 (d, J = 4.8 Hz, 2H), 4.05 (t, J = 4.6 Hz, 2H), 3.95 - 3.89 (m, 2H), 2.68 (t, J = 7.1 Hz, 2H); MS: 329 [M +H] ⁺ .

Example 88

(E)-4-(dimethylamino)-1-(10-((3-(trifluoromethyl)phenyl)amino)-2,3-dihydro-4H-[1,4]oxazine Preparation of [2,3-f]quinazolin-4-yl)but-2-en-1-one

N-(3-(Trifluoromethyl)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII- 2) (173 mg, 0.5 mmol) was dissolved in a mixed solvent of tetrahydrofuran and dimethylformamide, and trans-4-dimethylamino crotonyl chloride hydrochloride (92 mg, 0.5 mmol) was added, and the mixture was stirred at room temperature until the reaction was completed. After quenching with aqueous potassium carbonate solution, ethyl acetate was evaporated. ^{1 H NMR (500MHz, DMSO-} d 6) δ10.07 (s, 1H), 8.55 (s, 1H), 8.35 (s, 1H), 8.12 (d, J = 8.5Hz, 1H), 7.89 (s, 1H), 7.69-7.58 (m, 1H), 7.49 (d, J = 7.8 Hz, 1H), 7.35 (d, J = 9.0 Hz, 1H), 6.83 (dt, J = 15.2, 5.9 Hz, 1H), 6.60 (d, J = 15.2 Hz, 1H), 4.70 (t, J = 4.6 Hz, 2H), 4.11-4.03 (m, 2H), 3.10 (d, J = 5.4 Hz, 2H), 2.19 (s, 6H) ¹³ C NMR (125 MHz, DMSO) δ 164.30, 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] ⁺ .

Examples 89-105

Preparation of Examples 89-105 The preparation of Reference Example 88 was carried out in exactly the same manner by substituting N-(3-) for the same molar equivalent of the intermediate of the formula VIII in which R ¹ X is a substituent in the following table. (Trifluoromethyl)phenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-2), The compounds are shown in the following table:

Example 106

(E)-1-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] quinazole Preparation of phenyl-4-yl)-4-morpholinbut-2-en-1-one

N-(3-Chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-4) (165mg, 0.5mmol), dissolved in a mixed solvent of dichloromethane and dimethylformamide, added 4-bromocrotonyl chloride (91mg, 0.5mmol), stirred at room temperature until the reaction is complete, quenched with water, acetic acid The organic phase was concentrated and dissolved in acetonitrile. Diisopropylethylamine (129 mg, 1 mmol) and morpholine (87 mg, 1 mmol) were added and stirred at room temperature until the reaction was completed, quenched with water and ethyl acetate. The organic phase was concentrated and purified by silica gel column chromatography toiel ^{1 H NMR (500MHz, DMSO-} d 6) δ9.92 (s, 1H), 8.52 (s, 1H), 8.18 (dd, J = 6.8,2.5Hz, 1H), 7.96-7.72 (m, 2H), 7.49-7.40 (m, 1H), 7.33 (d, J = 9.0 Hz, 1H), 6.82 (dt, J = 15.1, 5.8 Hz, 1H), 6.62 (d, J = 15.0 Hz, 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). ¹³ C NMR (125MHz, DMSO) δ 157.58, 154.35, 153.14, 149.22, 143.74, 142.71, 136.38, 130.52, 124.75, 123.77, 123.72, 122.28, 119.44, 119.25, 117.07, 116.90, 106.37, 68.77, 66.64, 59.37, 53.79; HRMS ( ESI): m/z 484.1552calcd for C ₂₄ H ₂₃ ClFN ₅ O ₃ [M+H] ⁺ , found 484.1550.

Examples 107-122

替代吗啉。具体实施的化合物如下表所示： Preparation of Examples 107-122 Reference is made to the preparation of Example 106, which operates in exactly the same manner, in which N-(3-) is replaced by the same molar equivalent of the intermediate of the formula VIII wherein R ¹ X is a substituent in the following table. Chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-4), in equal molars Equivalent

Replace morpholine. The specific compounds are shown in the following table:

Example 123

(S,E)-1-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

Step 1) Diethyl(2-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f Preparation of quinazolin-4-yl)-2-oxoethyl)phosphate (IX-1)

N-(3-chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-4) (165 mg, 0.5 mmol), 2-(diethoxyphosphoryl)acetic acid (0.5 mmol) was dissolved in tetrahydrofuran, and N,N'-carbonyldiimidazole (81 mg, 0.5 mmol) was added and stirred at room temperature until complete. Water and ethyl acetate were extracted, and the organic layer was concentrated. MS: 509 [M+H] ⁺ .

Step 2) (S,E)-1-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3 -f]Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

Diethyl(2-(10-(3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quina Oxazolin-4-yl)-2-oxoethyl)phosphate (IX-1) (218 mg, 0.43 mmol) was dissolved in tetrahydrofuran, cooled to -78 ° C, and 1 mol per liter of ditrimethylsilane was added dropwise. A solution of lithium amide in toluene (0.65 mL, 0.65 mmol), stirring was continued until the starting material disappeared, and (S)-1-methylpyrrolidin-2-carbaldehyde (48.6 mg, 0.43 mmol) was added. After the reaction was completed, water and ethyl acetate were added and the organic layer was concentrated. ^{1 H NMR (300MHz, DMSO-} d 6) δ9.93 (s, 1H), 8.51 (s, 1H), 8.21-8.11 (m, 1H), 7.80 (s, 2H), 7.50-7.40 (m, 1H ), 7.32 (d, J = 9.1 Hz, 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] ⁺ .

Example 124

(E)-1-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] quinazole Phenyl-4-yl)-9-methoxyindol-2-en-1-one

Step 1) Same as Example 123 Step 1)

Step 2) (E)-1-(10-((3-chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f Preparation of quinazolin-4-yl)-9-methoxyindole-2-en-1-one

Reference Example 123, step 2), operates identically, in a manner equivalent to replacing (S)-1-methylpyrrolidinyl-2-carboxaldehyde with an equivalent molar equivalent of 7-methoxyheptanal. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 9.92 (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 = 15.1 Hz, 1H), 4.66 (t, J = 4.6 Hz, 2H), 4.05 (t, J = 4.6 Hz, 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] ⁺ .

Example 125

(S,E)-1-(10-((3-ethynylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazoline Preparation of 4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

Step 1) Diethyl(2-(10-(3-ethynylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazoline Preparation of phenyl-4-yl)-2-oxoethyl)phosphate (IX-2)

Reference Example 123, step 1), which operates identically, in an equivalent molar equivalent of N-(3-ethynylphenyl)-3,4-dihydro-2H-[1,4]oxazine. [2,3-f]quinazolin-10-amine (VIII-7) replaces N-(3-chloro-4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazine [2,3-f]quinazolin-10-amine (VIII-4). The yield was 85%. MS: 481 [M+H] ⁺ .

Step 2) (S,E)-1-(10-((3-ethynylphenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-)prop-2-en-1-one

Reference Example 123, step 2), which operates identically, in an equivalent molar equivalent of diethyl (2-(10-(3-ethynylphenyl)amino)-2,3-dihydro- 4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-2-oxoethyl)phosphate (IX-2) instead of diethyl (2-(10-) ((3-Chloro-4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl)-2- Oxoethyl phosphate (IX-1). The yield was 70%. ^{1 H NMR (300MHz, DMSO-} d 6) δ9.95 (s, 1H), 8.52 (s, 1H), 8.29-7.96 (m, 2H), 7.88 (d, J = 8.3Hz, 1H), 7.44- 7.22(m,3H), 6.52–6.27(m,1H), 6.11–5.88(m,1H), 4.70-4.64(m,2H), 4.24(s,1H),4.08-4.00(m,2H), 3.10–2.97 (m, 1H), 2.27–2.12 (m, 4H), 2.06–1.96 (m, 1H), 1.79–1.67 (m, 2H), 1.58–1.39 (m, 2H); MS: 440 [M +H] ⁺ .

Example 126

1-(10-(3-chloro-4-fluorophenoxy)-2,3-dihydro-4H-[1,4]oxazino[2,3-f]quinazolin-4-yl) Preparation of but-2-yn-1-one

2-butynoic acid (42 mg, 0.5 mmol) was dissolved in dichloromethane, and 0.05 ml of dimethylformamide was added dropwise. After cooling in ice-cooling, oxalyl chloride (32 mg, 0.25 mmol) was added, and stirring was continued for 0.5 hr. -(3-chloro-4-fluorophenoxy)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (VIII-4) (165 mg, 0.5 mmol), the mixture was stirred at room temperature and then stirred until the reaction was completed, and then the mixture was evaporated. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 8.60 (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] ⁺ .

Examples 127-147

Preparation of Examples 127-147 The preparation method of Reference Example 126 was carried out in exactly the same manner, and the specific embodiment was to replace 10-(3) with the same molar equivalent of the intermediate of the formula VIII in which R ¹ X is a substituent in the following table. -chloro-4-fluorophenoxy)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine in equal molar equivalents of R ² The 2-butynoic acid was replaced by a carboxylic acid of the substituent shown in the table below. The specific compounds are shown in the following table:

Example 148: (S,E)-1-(10-((4-fluorophenyl(amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

Step 1): diethyl(2-(10-((4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3-f]quinazoline Preparation of 4-yl)-2-oxoethyl)phosphonate

N-(4-Fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (148 mg, 0.5 mmol), 2 -(Diethoxyphosphoryl)acetic acid (98 mg, 0.5 mmol) was dissolved in tetrahydrofuran, N,N'-carbonyldiimidazole (81 mg, 0.5 mmol) was added, and the mixture was stirred at 40 ° C until the reaction was completed. Water and acetic acid were added. The ethyl ester was extracted, and the organic phase was concentrated. MS: 475 [M + H] ⁺ .

Step 2): (S,E)-1-(10-((4-fluorophenyl(amino)-2,3-dihydro-4H-[1,4]oxazino[2,3-f] Preparation of quinazolin-4-yl)-3-(1-methylpyrrolidin-2-yl)prop-2-en-1-one

Diethyl(2-(10-(4-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3-f]quinazoline-4- 2-oxoethyl)phosphonate (168 mg, 0.35 mmol) was dissolved in tetrahydrofuran, cooled to -78 ° C, and 1 mol of bis trimethylsilylamino lithium toluene solution (0.53 mL) was added dropwise. , 0.53 mmol), stirring was continued until the starting material disappeared, (R)-1-methylpyrrolidinyl-2-carbaldehyde (39.6 mg, 0.35 mmol) was added, and the mixture was warmed to room temperature and stirred until the reaction was completed. Water and ethyl acetate were added. The extract was concentrated, and the organic phase was concentrated. ^{1 H NMR (400MHz, DMSO-} d 6) δ9.86 (s, 1H), 8.44 (s, 1H), 8.08-7.51 (m, 3H), 7.30 (d, J = 9.0Hz, 1H), 7.24 ( t, J = 8.8 Hz, 2H), 6.74 - 6.63 (m, 1H), 6.54 (d, J = 17.3 Hz, 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] ⁺ .

Example 149: (S,E)-3-(1-methylpyrrolidin-2-yl)-1-(10-(phenylamino)-2,3-dihydro-4H-[1,4] Preparation of oxazolo[2,3-f]quinazolin-4-yl)prop-2-en-1-one

Step 1) Diethyl(2-oxo-2-(10-(phenylamino)-2,3-dihydro-4H-[1,4]oxazine [2,3-f]quinazoline- Preparation of 4-yl)ethyl)phosphonate

Prepared in a similar manner to Step 1) of Example 148, except that in an equivalent molar equivalent of N-phenyl-3,4-dihydro-2H-[1,4]oxazine [2,3- f] quinazoline-10-amine in place of N-(4-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazoline-10- amine. The yield was 77%. MS: 457 [M+H] ⁺ .

Step 2) (S,E)-3-(1-Methylpyrrolidin-2-yl)-1-(10-(phenylamino)-2,3-dihydro-4H-[1,4] Preparation of oxazolo[2,3-f]quinazolin-4-yl)prop-2-en-1-one

Prepared in a similar manner to Step 2) of Example 148, except that in an equivalent molar equivalent of diethyl (2-oxo-2-(10-(phenylamino)-2,3-dihydro- 4H-[1,4]oxazine [2,3-f]quinazolin-4-yl)ethyl)phosphonate in place of diethyl(2-(10-(4-fluorophenyl)amino) -2,3-Dihydro-4H-[1,4]oxazine [2,3-f]quinazolin-4-yl)-2-oxoethyl)phosphonate. ^{1 H NMR (400MHz, DMSO-} d 6) δ9.90 (s, 1H), 8.48 (s, 1H), 8.10-7.69 (m, 3H), 7.40 (t, J = 7.8Hz, 2H), 7.31 ( d, J = 9.0 Hz, 1H), 7.16 (t, J = 7.4 Hz, 1H), 6.76 - 6.64 (m, 1H), 6.55 (d, J = 15.1 Hz, 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] ⁺ .

Example 150: (E)-1-(10-((3-chloro-2-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3- Preparation of f]quinazolin-4-yl)-4-(cyclopropyl(methyl)amino)but-2-en-1-one

N-(3-chloro-2-fluorophenyl)-3,4-dihydro-2H-[1,4]oxazino[2,3-f]quinazolin-10-amine (165 mg, 0.5 Methyl acetate, dissolved in dimethylformamide, added 4-bromocrotonyl chloride (91 mg, 0.5 mmol), stirred at room temperature until the reaction was completed, quenched with water, extracted with ethyl acetate. Add diisopropylethylamine (129mg, 1mmol) and N-methylcyclopropylamine (71mg, 1mmol), stir at room temperature until the reaction is complete, add water to quench, extract with ethyl acetate, concentrate the organic phase and pass the high-performance liquid phase Purification by preparative chromatography gave a white solid, 84 mg, yield 36%. ^{1 H NMR (400MHz, DMSO-} d 6) δ10.00 (d, J = 1.7Hz, 1H), 8.49 (s, 1H), 8.16-8.11 (m, 1H), 7.91-7.80 (m, 1H), 7.45–7.40 (m, 1H), 7.36–7.33 (m, 1H), 7.32–7.27 (m, 1H), 6.90–6.81 (m, 1H), 6.56 (d, J = 15.2 Hz, 1H), 4.65 ( t, 2H), 4.06 (t, J = 4.6 Hz, 2H), 3.31 (d, J = 1.6 Hz, 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] ⁺ .

Example 151: (E)-1-(10-((3-chloro-2-fluorophenyl)amino)-2,3-dihydro-4H-[1,4]oxazine [2,3- Preparation of f]quinazolin-4-yl)-4-(cyclobutyl(methyl)amino)but-2-en-1-one

The preparation was carried out in a similar manner to Example 150 except that N-methylcyclopropylamine was replaced by an equivalent molar equivalent of N-methylcyclobutylamine hydrochloride. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ 10.00 (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=4.7 Hz, 2H) ), 4.06 (t, J = 4.5 Hz, 2H), 3.04 (dd, J = 6.3, 1.4 Hz, 2H), 2.86 (t, J = 7.8 Hz, 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 compounds inhibit EGFR ^WT , EGFR ^T790M and HER2 kinase activity tests as follows:

1) dilution of the compound

In 96-well plate a, the compound was diluted 3 times with DMSO solution to form 11 gradients, and the 12th gradient was a pure DMSO solution (as a positive control); a new 96-well plate b was taken and the solution was used. Ultrapure water was diluted 25 times (DMSO concentration was 4%).

2) Turn the compound to the 384-well plate

The compound solution diluted with ultrapure water in the above 96-well plate b was placed in a corresponding well of a 384-well plate according to a standard well of 2 duplicate wells.

3) Add 4×kinase solution: 2.5 μl of the above 4×kinase solution was added to the corresponding reaction well of a 384-well plate with a lance, and the mixture was pre-reacted at room temperature for 5 minutes.

4) Add 2× substrate/ATP mixture: Take 5 μl of the above 2× substrate/ATP mixture into the corresponding reaction well of a 384-well plate with a lance.

5) Negative control: Negative control wells were placed in 384-well plates, 2.5 μl of 4× substrate, 2.5 μl of 4× enzyme solution, 2.5 μl of 1×Kinase Assay Buffer and 2.5 μl of ultrapure water containing 4% DMSO were added to each well. .

6) Mix by centrifugation and react at room temperature for 2 hours.

7) Termination of the enzymatic reaction:

Pipette 5 μl of the above 4× stop solution into the corresponding well of a 384-well plate, mix by centrifugation, and react at room temperature for 5 minutes.

8) Color reaction:

Pipette 5 μl of the above 4× test solution into the corresponding well of a 384-well plate, mix by centrifugation, and react at room temperature for 1 hour.

9) Put the 384-well plate into the plate reader and call the corresponding program detection signal.

10) IC ₅₀ analysis:

Hole reading = 10000 * EU665 value / EU 615 value

Inhibition rate = (positive control well reading - experimental well reading value) / (positive control well reading - negative control well reading) * 100%

The corresponding drug concentration and the inhibition rate calculated process input GraphPad Prism 5 the corresponding IC _50.

EGFR ^WT kinase activity inhibition molecule screening experimental conditions:

The final concentration of EGFR kinase was 0.35 nM in the reaction system, the final concentration of ATP was 150 μM, the final concentration of substrate ULight ^TM -labeled JAK-1 (Tyr1023) Peptide was 100 nM, and the enzymatic reaction time was 2 hours.

The maximum final concentration of the compound in the reaction system was 2.5 μM, and a total of 11 concentrations were diluted by a 3-fold gradient, and the lowest final concentration was 0.042 nM. The final concentration of DMSO was 1%.

EGFR ^T790M kinase activity inhibition molecule screening experimental conditions:

The final concentration of EGFR (T790M) kinase was 0.05 nM in the reaction system, the final concentration of ATP was 5 μM, the final concentration of substrate ULight ^TM -labeled PolyGT was 100 nM, and the enzymatic reaction time was 2 hours.

The maximum final concentration of the compound in the reaction system was 2.5 μM, and a total of 11 concentrations were diluted by a 3-fold gradient, and the lowest final concentration was 0.042 nM. The final concentration of DMSO was 1%.

HER2 kinase activity inhibition molecule screening experimental conditions:

HER2 kinase reaction system in a final concentration of 10nM, ATP final concentration 10μM, ^(TM) -labeled substrate PolyGT final concentration ULight is 100nM, enzymatic reaction time was 2 hours.

The maximum final concentration of the compound in the reaction system was 2.5 μM, and a total of 11 concentrations were diluted by a 3-fold gradient, and the lowest final concentration was 0.042 nM. The final concentration of DMSO was 1%.

Table (1) lists the results of the determination of tyrosine kinase inhibitory activity by some of the compounds in this patent, wherein A represents an IC _{50 of} less than or equal to 50 nM, B represents an IC _{50 of} greater than 50 nM but less than or equal to 500 nM, and C represents an IC ₅₀ greater than 500 nM but less than or equal to 5000 nM, D indicates an IC ₅₀ greater than 5000 nM, and NT indicates that no corresponding kinase was tested.

Table (I), results of determination of EGFR and HER2 kinase inhibitory activity of the compounds of the present invention

Experimental example 2.

The test for inhibition of cell proliferation by small molecule compounds is as follows:

1. Add 600 μL of trypsin to a T75 cell culture flask, digest it in a 37 ° C incubator for about 1 min, then add 5 mL of DMEM in complete medium, blow evenly, transfer to a 15 mL centrifuge tube, centrifuge at 1000 rpm for 4 min;

2. Discard the supernatant, add 5 mL of DMEM complete medium, blow evenly, mix 10 μL of cell suspension and 10 μL of 0.4% trypan blue, and count under the cell counter;

3. The BT474 and HCC827 cell lines were inoculated in 96-well plates at a cell density of 10,000 and 3000/well/80 μL, respectively. The 96-well plates were not filled with sterile water in the outer circumference of 36 wells, only 60 wells were used. In cell experiments and controls;

4. Compound dilution: the compound was diluted 3-fold at a starting concentration of 10 mM for a total of 10 concentrations;

5. Add 20 μL of different kinds of compounds in different concentrations to each well, and shake the remaining wells with 20 μL of complete medium, and the concentration of DMSO in each well is 0.25%;

6. After incubation for 72 h, add 10 μL of CCK-8 reagent to each well, incubate at 37 ° C for 1-2 h; read the OD value at 450 nm;

7. Cell viability (%) = [(As-Ab) / (Ac-Ab)] * 100%

As: experimental well (cell-containing medium, CCK-8, compound)

Ac: Control well (cell-containing medium, CCK-8)

Ab: blank well (cell and compound-free medium, CCK-8)

8. The value introduced into Graphpad Prism5 software IC ₅₀ (concentration of compound highest survival rate of 50%) is calculated.

Table (2) lists the results of assays for the activity of representative compounds of the present invention against HCC827 and BT474 cancer cells. Wherein A represents an IC _{50 of} less than or equal to 50 nM, B represents an IC _{50 of} greater than 50 nM but less than or equal to 500 nM, C represents an IC _{50 of} greater than 500 nM but less than or equal to 5000 nM, and D represents an IC _{50 of} greater than 5000 nM, and NT indicates that no corresponding cells have been tested.

Table (2), results of determination of cell activity of representative compounds of the present invention

The above is a preferred embodiment of the present invention, and it should be noted that those skilled in the art can make several improvements and modifications to the embodiments of the present invention without departing from the principles of the present invention. These modifications and modifications are also considered to be within the scope of the invention.

Claims (13)

a compound of the formula (I), an isomer thereof, a hydrate, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof,

In formula (I), X is O or NH; R ¹ is

L is a C ₁ -C ₄ straight chain alkyl, or each independently are R ^4, R ⁵ substituted C ₁ -C ₄ straight chain alkyl; R ⁴ and R ⁵ are each independently H or C ₁ -C ₃ alkyl; R ³ is -H, C ₁ -C ₆ alkyl which is unsubstituted or substituted by halogen, hydroxy, cyano, carboxy, C ₁ -C ₆ alkoxy, C ₃ -C ₇ cycloalkyl, aryl, a 4-7 membered heterocyclic group, a 5-6 membered heteroaryl group, or a fluorene structure; The cyclo-ring structure is selected from the group consisting of an aromatic ring and a 5-6 membered heteroaryl ring group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, an aromatic ring and a 5-6 membered cycloalkyl group, and an aromatic ring a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl ring and a 5-6 membered cycloalkyl group or a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic group; The heterocyclic group, heteroaryl ring group contains 1-3 hetero atoms selected from N, O or S; The aryl, heteroaryl, heterocyclic or bicyclic ring structure is unsubstituted or independently separated by 1-3 selected from the group consisting of halogen, cyano, hydroxy, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halo C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₂ -C ₃ alkynyl, C ₂ -C ₃ alkenyl, -NR'R" or -MR ⁶ Substituent substitution; R ', R "are independently H or a C ₁ -C ₃ alkyl; M is -O(CH ₂ ) _q - or -C(O)-, wherein q is an integer from 1 to 4; R ⁶ is -H, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or -NR ⁷ R ⁸ ; R ⁷ and R ⁸ are each independently -H, C ₁ -C ₃ alkyl, or R ⁷ and R ⁸ are bonded to form a 4-7 membered heterocyclic ring; R ² is

L _{1 is} selected from:

T ₁ is C ₁ -C ₈ straight chain alkyl group, or each independently are R ^9, R ¹⁰ is substituted C ₁ -C ₈ straight chain alkyl group; R ⁹ and R ¹⁰ are each independently -H or C ₁ -C ₃ alkyl; R ¹¹ is -H, hydroxy, C ₁ -C ₃ alkyl, C ₃ -C ₇ cycloalkyl, C ₁ -C ₃ alkoxy, C ₁ -C ₃ alkylthio, 4-7 membered heterocyclic Or -NR ¹² R ¹³ , R ¹² and R ¹³ are each independently -H, C ₁ -C ₆ alkyl, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl substituted by hydroxy or C ₁ -C ₃ alkoxy Substituted C ₁ -C ₆ alkyl; The 4-7 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, which are unsubstituted or C ₁ -C ₃ alkyl, aldehyde a group of a C ₁ -C ₄ alkyl acyl group, an amino acyl group, a mono or disubstituted C ₁ -C ₃ amino acyl group, a C ₁ -C ₃ alkyl sulfone group, a C ₁ -C ₃ alkyl sulfoxide group The sulfur in the or two substituted or heterocyclic rings is oxidized by one or two oxygen atoms. The compound according to claim 1, an isomer, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof, characterized in that R ¹ is

L is a C ₁ -C ₃ straight chain alkyl group, or each independently be R ^4, R ⁵ substituted C ₁ -C ₃ linear alkyl; R ⁴ and R ⁵ are each independently -H or C ₁ -C ₃ alkyl; R ³ is -H, C ₁ -C ₃ alkyl which is unsubstituted or substituted by halogen, hydroxy, cyano, carboxy, C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, aryl, a 5-6 membered heterocyclic group, a 5-6 membered heteroaryl group, or a fluorene structure; The cyclo-ring structure is selected from the group consisting of a benzo-5-6 heteroaryl ring group, a 5-6 membered heteroaryl ring and a 5-6 membered heteroaryl ring group, a benzo-5-6 cycloalkyl group, and a benzo-5-6 heterocyclic ring. a 5-6 membered heteroaryl ring and a 5-6 cycloalkyl group, a 5-6 membered heteroaryl ring and a 5-6 membered heterocyclic group, The heterocyclic group, heteroaryl ring group contains 1-3 hetero atoms selected from N, O or S; The aryl, heteroaryl, heterocyclic or bicyclic ring structure is unsubstituted or independently independently from one to three selected from the group consisting of halogen, cyano, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, halo C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, C ₂ -C ₃ alkynyl, C ₂ -C ₃ alkenyl, -NR'R" or -MR ⁶ Substituent substitution; R' and R" are each independently H or a C ₁ -C ₃ alkyl group; M is -O(CH ₂ ) _q - or -C(O)-, wherein q is an integer from 1 to 3; R ⁶ is H, hydroxy, C ₁ -C ₃ alkyl, C ₁ -C ₃ alkoxy, or -NR ⁷ R ⁸ ; R ⁷ and R ⁸ are each independently H, C ₁ -C ₃ alkyl or R ⁷ and R ⁸ are bonded to form a 5-6 membered heterocyclic ring. The compound according to claim 1, an isomer, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof, characterized in that R ¹ is

L is a C ₁ -C ₃ straight chain alkyl group, or each independently be R ^4, R ⁵ substituted C ₁ -C ₃ linear alkyl; R ⁴ and R ⁵ are each independently -H or methyl; R ^{3 is} selected from the group consisting of: -H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, hydroxy, carboxy, 1-hydroxy-1-methylethyl, or the following groups:

R ¹⁴ is -H or C ₁ -C ₃ alkyl; Q ₁ , Q ₂ , Q ₃ , Q ₄ , and Q5 are each independently N or CH; (R ¹⁵ ) _p is p identical or different R ¹⁵ substituents, p is 0, 1, 2 or 3; R ^{15 is} selected from the group consisting of -H, -F, -Cl, -Br, -CF ₃ , -OCF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, iso Propyloxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, hydroxy, cyano, -NR'R" or -MR ⁶ ; R', R" are independently H, methyl, ethyl, propyl or isopropyl; M is -O(CH ₂ ) _q - or -C(O)-, wherein q is 1, 2 or 3; R ⁶ is H, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or -NR ⁷ R ⁸ ; R ⁷ and R ^{8 are} independently H, methyl, ethyl, propyl, isopropyl, or R ⁷ and R ⁸ are bonded to form a 5-6 membered heterocyclic ring, and the 5-6 membered heterocyclic ring is preferably:

The compound according to claim 3, an isomer, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof, characterized in that R ¹ is

L is a C ₁ -C ₃ straight chain alkyl group, or each independently be R ^4, R ⁵ substituted C ₁ -C ₃ linear alkyl; R ⁴ and R ⁵ are each independently -H or methyl; R ^{3 is} selected from the group consisting of: -H, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, hydroxy, carboxy, 1-hydroxy-1-methylethyl, or the following groups:

R ¹⁴ is -H or C ₁ -C ₃ alkyl; (R ¹⁵ ) _p is p identical or different R ¹⁵ substituents, p is 0, 1, 2 or 3; R ^{15 is} selected from the group consisting of -H, -F, -Cl, -Br, -CF ₃ , -OCF ₃ , methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, iso Propyloxy, ethynyl, vinyl, cyclopropyl, cyclobutyl, hydroxy, cyano, -NR'R" or -MR ⁶ ; R', R" are independently H, methyl, ethyl, propyl or isopropyl; M is -O(CH ₂ ) _q - or -C(O)-, wherein q is 1, 2 or 3; R ⁶ is H, hydroxy, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy or -NR ⁷ R ⁸ ; R ⁷ and R ^{8 are} independently H, methyl, ethyl, propyl, isopropyl, or R ⁷ and R ⁸ are bonded to each other to form

The compound according to any one of claims 1 to 4, an isomer, a hydrate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof, characterized in that R ² is

L _{1 is} selected from:

T ₁ is C ₁ -C ₆ linear alkyl group, or each independently are R ^9, R ¹⁰ is substituted C ₁ -C ₆ straight chain alkyl; R ⁹ and R ¹⁰ are each independently -H or methyl; R ¹¹ is -H, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropyl Oxyl, methylthio, ethylthio, propylthio, isopropylthio, 5-6 membered heterocyclyl or -NR ¹² R ¹³ ; R ¹² and R ¹³ are independently -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isobutyl, 1-ethylpropyl, cyclopropane Base, cyclobutyl, cyclopentyl, cyclohexyl, hydroxyethyl, hydroxypropyl, hydroxybutyl, methoxyethyl, methoxypropyl, methoxybutyl, ethoxyethyl, B Oxypropyl, ethoxybutyl, propoxyethyl, propoxypropyl, propoxybutyl, isopropoxyethyl, isopropoxypropyl or isopropoxybutyl; The 5-6 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, and the 5-6 membered heterocyclic group is unsubstituted or methyl, B. Base, propyl, isopropyl, aldehyde, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylamino, dimethylamino, methylsulfonyl, ethylsulfonyl, isopropyl One or two of the sulfone group, the methanesulfoxide group, the ethyl sulfoxide group, the isopropyl sulfoxide group or the sulfur in the hetero ring is oxidized by one or two oxygen atoms; The 5-6 membered heterocyclic ring is selected from the group consisting of

The compound, an isomer, a hydrate, a solvate thereof, a pharmaceutically acceptable salt thereof, and a prodrug thereof according to any one of claims 1 to 5, wherein R ² is

L _{1 is} selected from:

T ₁ is C ₁ -C ₆ linear alkyl group, or each independently are R ^9, R ¹⁰ is substituted C ₁ -C ₆ straight chain alkyl; R ⁹ and R ¹⁰ are each independently -H or methyl; R ¹¹ is -H, hydroxy, methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, propoxy, isopropyl Oxyl, methylthio, ethylthio, propylthio, isopropylthio, 5-6 membered heterocyclyl or -NR ¹² R ¹³ ; R ¹² and R ¹³ are independently -H, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, isobutyl, 1-ethylpropyl, cyclopropane Base, cyclobutyl, cyclopentyl, hydroxyethyl, hydroxypropyl, methoxyethyl, methoxypropyl, ethoxyethyl, ethoxypropyl, propoxyethyl, propoxy Propyl, isopropoxyethyl or isopropoxypropyl; The 5-6 membered heterocyclic group is a heterocyclic group containing 1-2 hetero atoms selected from N, O or S, and the 5-6 membered heterocyclic group is unsubstituted or methyl, B. Base, propyl, isopropyl, aldehyde, formyl, acetyl, propionyl, butyryl, isobutyryl, aminoacyl, methylamino, dimethylamino, methylsulfonyl, ethylsulfonyl, isopropyl One or two of the sulfone group, the methanesulfoxide group, the ethyl sulfoxide group, the isopropyl sulfoxide group or the sulfur in the hetero ring is oxidized by one or two oxygen atoms; The 5-6 membered heterocyclic group is selected from the group consisting of

R ¹⁶ is H, amino, methylamino, dimethylamino, methyl, ethyl, propyl, isopropyl. A process for preparing the compound according to claims 1-6, an isomer thereof, a solvate thereof, a pharmaceutically acceptable salt thereof and a prodrug thereof, comprising the following steps, Preparing a compound of formula (I) by reacting R ² C(O)Cl with a compound of formula (VIII) or chlorination of R ² COOH with a compound of formula (VIII);

Or when R ² is

And L ₁ is

When R ¹¹ is -NR ¹² R ¹³ , the compound of formula (VIII)

And a compound of formula (I) is prepared by reacting an amine (HNR ¹² R ¹³ ) having a substituent of R ¹² and R ¹³ ;

Or, R ² is

And L ₁ is

From the compound of formula (IX)

Reaction to prepare a compound of formula (I),

R ¹ , R ² , R ¹¹ , R ¹² , R ¹³ , X, L ₁ and T _{1 are} as defined in claims 1-6. a compound of the formula (VIII),

X and R ^{1 are} as defined in claims 1-6. A method of preparing the compound of claim 8 comprising the steps of: Method A:

2,3,4,9-tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one, R ¹ XH, represented by formula (V), and Carter The condensing agent is sufficiently contacted to obtain a compound of the formula (VIII), wherein X and R ^{1 are} as defined in claims 1-6, Or method B:

The 2,3,4,9-tetrahydro-10H-[1,4]oxazino[2,3-f]quinazolin-10-one represented by the formula (V) is sufficiently contacted with the Carter condensing agent to obtain The compound of the formula (VI), the compound (VI) is further reacted with R ¹ XH to give a compound of the formula (VIII) wherein X and R ^{1 are} as defined in claims 1-6. Or method C:

The compound represented by the formula (II) is reacted with a chlorinating reagent and reacted with R ¹ XH to obtain a compound of the formula (VII), and the compound of the formula (VII) is further subjected to a reduction ring-closing reaction to obtain a formula (VIII). A compound wherein X and R ^{1 are} as defined in claims 1-6. The compound according to any one of claims 1 to 6, a pharmaceutically acceptable salt, isomer, hydrate, solvate or prodrug thereof, wherein the pharmaceutically acceptable salt of the compound is a hydrochloride, hydrobromide, hydroiodide, perchlorate, sulfate, nitrate, phosphate, formate, acetate, propionate, glycolate selected from the compounds , lactate, succinate, maleate, tartrate, malate, citrate, fumarate, gluconate, benzoate, mandelate, methanesulfonate, hydroxyethyl Sulfonate, besylate, oxalate, palmitate, 2-naphthalenesulfonate, p-toluenesulfonate, cyclamate, salicylate, hexanoate, trifluoroethyl One or more of an acid salt, an aluminum salt, a calcium salt, a chloroprocaine salt, a choline salt, a diethanolamine salt, an ethylenediamine salt, a lithium salt, a magnesium salt, a potassium salt, a sodium salt, and a zinc salt . A pharmaceutical composition for treating a disease associated with tyrosine kinases EGFR, HER2, HER3, HER4, which comprises a compound of formula (I) according to claims 1-6, or a pharmaceutically acceptable salt thereof, or hydrated thereof Or a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable carrier or excipient. A pharmaceutical composition comprising a compound of formula (I) according to claims 1-6, or a pharmaceutically acceptable salt, hydrate, solvate or prodrug thereof as active ingredient, one or more Other therapeutic agents, as well as one or more pharmaceutically acceptable carriers or excipients. The compound of the formula (I) according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof or a prodrug thereof, for use in the preparation of a cancer associated with the tyrosine kinases EGFR, HER2, HER3, HER4 And a drug for use in an autoimmune disease, wherein the cancer and autoimmune diseases include: fundus diseases, dry eye syndrome, psoriasis, vitiligo, dermatitis, alopecia areata, rheumatoid arthritis, colitis, multiple sclerosis, system Lupus erythematosus, Crohn's disease, atheroma, pulmonary fibrosis, liver fibrosis, myelofibrosis, non-small cell lung cancer, small cell lung cancer, breast cancer, pancreatic cancer, glioma, glioblastoma Tumor, ovarian cancer, cervical cancer, colorectal cancer, melanoma, endometrial cancer, prostate cancer, bladder cancer, leukemia, stomach cancer, liver cancer, gastrointestinal stromal tumor, thyroid cancer, chronic myeloid leukemia, acute myeloid cells Leukemia, non-Hodgkin's lymphoma, nasopharyngeal carcinoma, esophageal cancer, brain tumor, B cell and T cell lymphoma, lymphoma, multiple myeloma, biliary sarcoma, cholangiocarcinoma.