WO2013131424A1

WO2013131424A1 - 4-quinazoline amine derivative and application thereof

Info

Publication number: WO2013131424A1
Application number: PCT/CN2013/071453
Authority: WO
Inventors: 李心; 陈阳; 白东栋; 董庆
Original assignee: 上海恒瑞医药有限公司; 江苏恒瑞医药股份有限公司
Priority date: 2012-03-09
Filing date: 2013-02-06
Publication date: 2013-09-12
Also published as: TWI586659B; CN103987700B; CN103987700A; TW201336835A

Abstract

A 4-quinazoline amine derivative as represented by formula (1), a pharmaceutical composition comprising the derivative, and an application thereof in preparing medicine for curing cancer. The cancer is a drug-resistant cancer, preferably a cancer resisting an EGFR reversible inhibitor, and more preferably, a cancer resisting gefitinib, erlotinib or lapatinib; alternatively, the cancer carries EGFR mutation.

Description

4-quinazolinamine derivatives and uses thereof

The present invention relates to the use of a quinazolinamine derivative and a pharmaceutical composition containing the same for the preparation of a medicament for treating cancer, wherein the cancer is a drug resistant cancer, preferably resistant to a reversible inhibitor of EGFR The cancer is particularly preferably cancer resistant to gefitinib, erlotinib or lapatinib, or the cancer carries an EGFR mutation. Background technique

As a basic regulatory mechanism of cells, signal transduction transmits various extracellular signals to the interior of cells, allowing cells to respond to biological processes such as proliferation, differentiation, and apoptosis. Intracellular control systems are disrupted by genetic and environmental factors, causing abnormal amplification or disruption of the signaling system, resulting in the production of tumor cells. Protein tyrosine kinases play an important role in such cell regulation, and abnormal expression or mutation has been observed in cancer cells.

The epidermal growth factor receptor (EGFR) is expressed by the protooncogene c-ErbB, a transmembrane glycoprotein receptor-type tyrosine kinase of about 170 kDa, which is a member of the ErbB protein family. Activation, affecting cell growth and differentiation. The ErbB family includes ErbB-1/EGFR, ErbB-2/Her2, ErbB-3/Her3, and ErbB-4/Her4. When the ligand binds to EGFR, the receptor dimerizes to form a homologous or heterodimer. Subsequently, the tyrosine residue on the dimerization receptor is phosphorylated, triggering the downstream signaling pathway to be activated. Abnormal EGFR activation mechanisms include amplification of the receptor itself, overexpression of receptor ligands, activating mutations, and lack of a negative regulatory pathway, so EGFR-induced cancer can at least through three mechanisms: EGFR ligand overexpression, EGFR Amplification or mutational activation of EGFR. Among these three mechanisms, mutational activation of EGFR is the most important factor leading to abnormal biological behavior of tumor cells. In malignant tumors, such as breast cancer, prostate cancer, non-small cell lung cancer, gastrointestinal cancer, esophageal cancer, ovarian cancer, pancreatic cancer, etc., there is overexpression of one or more of the above dimeric members. Furthermore, both EGFR and HER-2 are known to significantly promote the formation of heterodimeric signaling complexes, thereby further confirming their association with tumorigenesis.

Several small molecule drugs have been developed that inhibit EGFR tyrosine kinases, such as gefitinib, erlotinib, and lapatinib. Gefitinib or erlotinib selectively and reversibly inhibits EGFR, while lapatinib reversibly inhibits both EGFR and HER-2, thereby inhibiting tumor growth, thereby significantly prolonging patient life or Provide therapeutic benefits.

It is well known that resistance to the drug used reduces the activity of the drug. For example, about half of patients taking gefitinib or erlotinib develop resistance due to EGFR T790M mutation, failing to achieve the desired therapeutic effect. . The EGFR gene mutation is mainly concentrated in the Tyrosing kinase coding domain (18-21 exon). Mutations associated with EGFR inhibitor activity are known to be restricted to the following: G719X (18 exons), E746-A450 deletion (19 exons), L858R (21 exons), L861Q (21 exons) ), T790M (20 exons) and D770-N771 (20 exons). The currently reported mutations are mainly directed to the following two types: 45% of which are exon 19 sequence deletions, mainly base deletion mutations at codons 746-752, resulting in loss of amino acid sequence in EGFR protein, altering receptor ATP binding The angle of the pocket; 40% is the missense mutation of exon 21, mainly the change of codon 851, which causes the amino acid of this site in EGFR protein to change from leucine to arginine (L858R). In addition, the T790M mutation is a base pair change. At the protein level, the threonine at the 790 site of the kinase domain is converted to methionine (T790M), which leads to changes in the structure of EGFR, and the steric effect of TKI binding. , producing acquired resistance to TKI. The EGFR T790M mutation was detected in both in non-small cell lung cancer patient tumor cells with acquired resistant EGFR mutations and in in vitro cell lines with gefitinib-resistant EGFR mutations. Mutations make the structural activation of EGFR outperform other pathways, so that the survival of tumor cells depends mainly on the EGFR signaling pathway.

In terms of overcoming the problem of drug resistance, irreversible inhibitors against EGFR targets are more effective than conventional reversible inhibitors. A series of patent applications for selective inhibitors of EGFR mutations, including WO2008150118 and WO2005028443, are currently disclosed.

Although a series of EGFR tyrosine kinase mutant drugs for treating cancer have been disclosed, there is still a need to develop new compounds having better pharmacological effects and fewer adverse side effects, and the design of the present invention has a general formula through continuous efforts. (I) A compound of the structure shown, and a compound having such a structure was found to exhibit excellent effects and effects. Summary of the invention

The object of the present invention is to provide a compound represented by the formula (I) or a pharmaceutically acceptable salt thereof, and tautomers, mesomers, racemates, enantiomers thereof, The use of diastereomers, mixtures thereof, and pharmaceutically acceptable salts thereof, and metabolites and metabolic precursors or prodrugs for the preparation of a medicament for the treatment of cancer, wherein the compound of formula (I) The structure is as follows:

Its towel _:

R ¹ is an alkoxy group, wherein the alkoxy group is optionally further further selected from one or more selected from halogen or alkoxy Substituted by a substituent;

A is selected from a carbon atom or a nitrogen atom;

When A is a carbon atom, R ² is a self-cyano group;

When A is a nitrogen atom, R ² is unsubstituted;

R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are each independently selected from a hydrogen atom, a halogen, a hydroxyl group, an alkyl group or -(CH ₂ )r-Ar or -0(CH ₂ )r-Ar;

Ar is selected from aryl or heteroaryl, wherein each of said aryl or heteroaryl is independently, optionally, further substituted with one or more substituents of halo, alkyl or trifluoromethyl;

R is selected from aryl, pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinyl or -NR ⁸ R ⁹ wherein said aryl, pyridyl, tetrahydropyranyl, piperidine The pyridyl, pyrrolidinyl, morphinolyl group is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, oxo, hydroxy or hydroxyalkyl; or pyrrolidin Is an N-oxide;

R ⁸ and R ⁹ together with the N atom to which they are bonded form a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group, wherein the monospiroheterocyclic group, the bicyclic fused heterocyclic group or the bicyclic bridged The cyclo group is optionally further substituted with one or more substituents selected from alkyl, alkoxy, halogen, haloalkyl, hydroxy or hydroxyalkyl;

r is 0, 1 or 2;

n is 0 or 1. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the manufacture of a medicament for treating cancer, wherein the cancer is a cancer resistant. The drug-resistant cancer may be a drug resistant to a plurality of drugs, preferably a cancer resistant to a reversible inhibitor of EGFR, particularly preferably resistant to gefitinib, erlotinib or lapatinib. Cancer. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein the cancer is a solid tumor, preferably a head and neck tumor, a colorectal cancer, a bladder cancer, a lung cancer, a pancreatic cancer, a breast cancer, Prostate cancer, gastric cancer, oral cancer, liver cancer, glioblastoma, ovarian cancer or non-small cell lung cancer. More preferably, it is non-small cell lung cancer. Wherein the cancer carries an EGFR mutation, and/or carries a HER2 mutation; the EGFR mutation comprises a deletion mutation EGFR del 746-750 on the ELREA sequence, a T790M point mutation in exon 20, EGFR del 746-750/ T790M double mutation or L858R/T790M double mutation. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and Use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein R is selected from the group consisting of pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, a morphinolinyl group, preferably a pyrrolidinyl group, more preferably a chiral pyrrolidinyltetrahydro group; the pyridyl group, tetrahydropyranyl group, piperidinyl group, pyrrolidinyl group, morphinolyl group optionally further one or Substituted by a plurality of alkyl or oxo groups; or the pyrrolidinyl group is an N-oxide. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, in the manufacture of a medicament for the treatment of cancer, wherein A is preferably a nitrogen atom and R ² is unsubstituted. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein R ³ , R ⁶ and R ^{7 are} preferably a hydrogen atom; R ⁴ and R ^{5 are} preferably a halogen, more preferably fluorine or chlorine. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for the treatment of cancer, wherein Ar is preferably a pyridyl group. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein R ⁸ and R ⁹ together with the N atom to which they are attached form a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group Wherein the monospiroheterocyclyl, bicyclic fused heterocyclyl or bicyclic bridge heterocyclyl optionally further is taken from one or more substituents selected from alkyl, alkoxy, hydroxy or hydroxyalkyl

A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and The use of a mixture form, and a pharmaceutically acceptable salt, for the preparation of a medicament for treating cancer, wherein a typical compound represented by the formula (I) or a tautomer, a mesogen, a racemate, a pair thereof The enantiomers, diastereomers, and mixtures thereof include, but are not limited to:

Example No. Compound Structure and Nomenclature

(R,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(l-methyl-1- Oxo-pyrrolidin-2-yl)-acrylamide Another aspect of the invention provides a compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, a pair Isomers, non-, and pharmaceutically acceptable salts:

among them:

R ¹ is an alkoxy group, wherein the alkoxy group is optionally further substituted with one or more substituents selected from halogen or alkoxy;

A is selected from a carbon atom or a nitrogen atom;

When A is a carbon atom, R ² is a self-cyano group;

When A is a nitrogen atom, R ² is unsubstituted;

r is 0, 1 or 2;

And n is 0 or 1. Preferred embodiments of the invention, a compound of the formula (I), a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof Form, and pharmaceutically acceptable salts, of which R Is pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinolyl, preferably pyrrolidinyl, more preferably chiral pyrrolidine tetrahydro; pyridyl, tetrahydropyranyl The piperidinyl, pyrrolidinyl, morphinolyl group is optionally further substituted with one or more alkyl or oxo substituents; or the pyrrolidinyl group is an N-oxide. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and In the form of a mixture, and a pharmaceutically acceptable salt, wherein A is preferably a nitrogen atom and R ² is unsubstituted. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture form, and a pharmaceutically acceptable salt, wherein

R ³ , R ⁶ and R ^{7 are} preferably a hydrogen atom; R ⁴ and R ^{5 are} preferably a halogen, more preferably fluorine or chlorine. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and In the form of a mixture, and a pharmaceutically acceptable salt, wherein Ar is preferably a pyridyl group. Preferred embodiments of the invention, a compound of the formula (I), a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof a form, and a pharmaceutically acceptable salt, wherein R ⁸ and R ⁹ together with the N atom to which they are attached form a monospiroheterocyclyl, a bicyclic fused heterocyclyl or a bicyclic heterocyclyl, said monospiroheterocyclyl, The bicyclic fused heterocyclic group or the bicyclic bridged heterocyclic group is optionally further substituted with one or more substituents selected from an alkyl group, an alkoxy group, a hydroxyl group or a hydroxyalkyl group. A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, and a mixture form, and a pharmaceutically acceptable salt, selected from the group consisting of:

A typical compound of the formula (I) or a tautomer thereof, a mesogen, a racemate, an enantiomer The diastereomers, and mixtures thereof, include, but are not limited to:

Form, or a pharmaceutically acceptable salt thereof. Another aspect of the invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a racemate, an enantiomer, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts, and pharmaceutically acceptable carriers. The present invention also relates to a process for the preparation of the above composition, which comprises the compound of the formula (I) or a tautomer, a racemate, an enantiomer thereof, a diastereomer thereof. And combinations thereof, and pharmaceutically acceptable salts, in combination with a pharmaceutically acceptable carrier or diluent. A compound of the formula (I) of the present invention or a pharmaceutically acceptable salt thereof as a medicament for treating cancer. It exhibits outstanding efficacy and fewer side effects in the treatment of cancer, wherein the cancer is selected from the group consisting of head and neck cancer, colon cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, ovarian cancer or Non-small cell lung cancer, preferably colon cancer, breast cancer or non-small cell lung cancer, more preferably non-small cell lung cancer. The cancer cells of the cancer are mutated in EGFR, and/or mutated in HER-2; the EGFR mutation includes a L858R point mutation and a deletion/insertion mutation in the ELREA sequence, and T790M in exon 20 Point mutation, or L858R/T790 double mutation; the HER-2 mutation is M774_A775insAYVM.

EGFR mutation-activated cancer cells, such as mutations occur in the EGF receptor region of tyrosine kinases, which It can be sensitive to the treatment of EGFR inhibitors. Similarly, cancer cells activated by HER-2 mutations, such as M774_A775insAYVM, may be sensitive to the treatment of HER-2 inhibitors. Cancer cells that are mutated by both EGFR and HER-2 mutations may be sensitive to the treatment of dual inhibitors of EGFR and HER-2.

For patients with non-small cell lung cancer treated with gefitinib and erlotinib, the emergence of specific functional mutations in the tyrosine kinase region of the EGFR receptor is associated with a sustained increase in the sensitivity of cancer cells to their treatment. (Sdewce 304, 1497 (2004)). In particular, the L858R point mutation (exon 21) and the deletion/insertion mutation (exon 19) in the ELREA sequence are the main causes of gefitinib. Another T790M point mutation in exon 20 is associated with the acquisition of resistance to gefitinib and erlotinib. This mutation is similar to the T325I mutation in CML patients who are resistant to imatinib.

Non-reversible tyrosine kinase inhibitors such as HKI-272, which are capable of inhibiting the proliferation and EGF induction of EGFR receptors that express double mutations on the cell line, compared to reversible tyrosine kinase inhibitors such as gefitinib EGFR ^- .V (Proceedings of the National Acadamy of Science of the United States 102 7665 (2005).

A method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. It exhibits outstanding efficacy and fewer side effects in the treatment of cancer, wherein the cancer is selected from the group consisting of head and neck cancer, colon cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, ovarian cancer or Non-small cell lung cancer, preferably colon cancer, breast cancer or non-small cell lung cancer, more preferably non-small cell lung cancer. The cancer cells of the cancer described therein are mutated in EGFR, and/or mutated in HER-2; the EGFR mutation includes a L858R point mutation and a deletion/insertion mutation in the ELREA sequence, and T790M in exon 20 Point mutation, or L858R/T790 double mutation; the HER-2 mutation is M774_A775insAYVM.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture. Oral compositions can be prepared according to any method known in the art for preparing a pharmaceutical composition, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing. These excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic and a lubricant such as magnesium stearate, stearic acid or talc. These tablets may be uncoated or may be coated by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time. For example, a water-soluble taste masking substance such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or an extended-time substance such as ethylcellulose or cellulose acetate butyrate may be used.

It is also possible to use hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or the active ingredient with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, Soft gelatin capsules mixed with liquid paraffin or olive oil provide oral preparations.

The aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing. Such excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents can be naturally occurring a phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of ethylene oxide with a long chain fatty alcohol, such as heptadecyl ethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitan monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols A condensation product of a partial ester such as polyethylene oxide sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agents such as sucrose, saccharin or aspartame.

The oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin. The oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. The above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or alpha-tocopherol.

The dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweeteners, flavoring agents, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion. The oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and ethylene oxide, For example, polyethylene oxide sorbitol monooleate. The emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants. Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.

The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. The oil solution is then added to a mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local injection. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.

The pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration. The suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injection solution or a mixture prepared in a non-toxic parenterally acceptable diluent or solvent. A suspension, such as a solution prepared in 1,3-butanediol. In addition, sterile fixed oils may be conveniently employed as a solvent or suspending medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used. In addition, fatty acids such as oleic acid can also be prepared as an injection.

The compounds of the invention may be administered in the form of a suppository for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug. Such materials include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, The patient's diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment such as the mode of treatment, the daily dose of the compound of formula (I) or the type of pharmaceutically acceptable salt It can be verified according to traditional treatment options. Detailed description of the invention

Terms used in the specification and claims have the following meanings unless stated to the contrary.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 , 5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl group, 2-methyl-2-ethylpentyl, 2- 3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3 , 3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, and non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, sec-butyl Base, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Base, 2,3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups independently selected from the group consisting of alkane Base, alkenyl, block, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, ring Alkoxy, heterocycloalkoxy, A cycloalkylthio group, a heterocycloalkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms. One carbon atom. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Polycyclic cycloalkyl groups include spiro, fused, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6 yuan monospirocycloalkyl. Non-limiting real

The term "fused cycloalkyl" refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyl group, preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to 5 to 20 members, any two rings sharing two carbon-free all-carbon polycyclic groups, which may contain one or more double bonds, but none of the rings have complete Conjugate π electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Bridged cycloalkyl

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the parent structure is attached The ring that is joined together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like. The cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group. Thio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide a heterocyclic alkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms, wherein one or more of the ring atoms is selected from nitrogen, oxygen or S(0) A hetero atom of _m (where m is an integer of 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are hetero atoms; more preferably, the cycloalkyl ring contains 3 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, morphinolinyl, homopiperazinyl and the like. The polycyclic heterocyclic group includes a spiro ring, a fused ring, and a bridged ring heterocyclic group; preferably a bicyclic heterocyclic group, and a non-limiting example includes a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a specific ring bridged heterocyclic group.

The term "spiroheterocyclyl" refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (0). _m ) (where m is an integer 0 to 2) of a hetero atom, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. The spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispirocyclic heterocyclic group or a polyspirocyclic group according to the number of the shared spiro atoms between the rings, preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6

The term "fused heterocyclyl" refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(0) _m (where m is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. The bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5- to 5- or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups:

Hekou.

The term "bridge heterocyclyl" refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total π electron conjugated system in which one or more ring atoms selected from nitrogen, oxygen, or S (0) _m hetero atoms (wherein m is an integer of 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. bridge

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is heterogeneous, non-limiting examples of which include:

Wait. The heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group. Thio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide a heterocyclic alkylthio group, an oxo group, a carboxyl group or a carboxylate group.

The term "aryl" refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:

The aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkylthio, Alkylamino, thiol, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, Heterocycloalkylthio, carboxy or carboxylate groups.

The term "heteroaryl" refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen. The heteroaryl group is preferably 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the parent structure is attached

The heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of alkyl, alkenyl, block, alkoxy, alkane Thio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide a heterocyclic alkylthio group, a carboxyl group or a carboxylate group.

The term "decyloxy" refers to -0-(fluorenyl) and -0-(unsubstituted cycloalkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an alkyl group, an alkenyl group, a block group, an alkoxy group, and an alkane group. Thio group, alkylamino group, halogen, thiol, hydroxy group, nitro group, cyano group, cycloalkyl group, heterocycloalkyl group, aryl group, heteroaryl group, cycloalkoxy group, heterocycloalkoxy group, cycloalkyl sulfide a heterocyclic alkylthio group, a carboxyl group or a carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted by one or more halogens, wherein the alkyl group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.

The term "N-oxide", also known as "amine-N-oxide", is an organic compound of the formula R ₃ N+-0_ (also written as R ₃ N=0 or R ₃ N→0) Wherein R is a substituent on the N atom); The pyrrolidinyl group is an N-oxide and refers to a pyrrolidine-N-oxide.

The term "hydroxy" refers to an -OH group.

The term "halogen" means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "nitro" refers to -N0 ₂ .

The term "oxo" refers to =0 or →0; when "oxo" is →0, the substitution occurs on the N or S atom of the substituent.

The term "carboxy" refers to -C(0)OH.

The term "carboxylate group" means -c(o)o(alkyl) or -c(o)o(cycloalkyl), wherein alkyl, cycloalkyl are as defined above.

"Optional" or "optionally" means that the subsequently described event or environment may, but need not, occur, including where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may be, but not necessarily, present, including the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group. .

"Substituted" means one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory) substitutions that may or may not be possible without undue effort. For example, an amino or hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients. The purpose of the pharmaceutical composition is to promote the administration of the organism, which facilitates the absorption of the active ingredient and thereby the biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the present invention which is safe and effective for use in a mammal and which has the desired biological activity. Method for synthesizing the compound of the present invention

In order to accomplish the object of the present invention, the present invention adopts the following technical solutions:

Synthesis A: a preparation method of the compound of the formula (I) or a salt thereof of the present invention, comprising the following steps:

( IA) ( I ) The compound of the formula (I) is reacted with RH or a salt thereof with sodium iodide or potassium iodide under basic conditions in a solvent to obtain a compound of the formula (I);

The reagents providing basic conditions include organic bases including, but not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium t-butoxide, and the like. Inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, potassium carbonate or cesium carbonate;

Wherein R is - NR ⁸ R ⁹ ;

X is a halogen;

A, n, and 〜11 ⁷ are as defined in the general formula (I). Next steps:

(IB)

(I)

a phosphate compound of the formula (IB) is reacted with an aldehyde RCHO under lithium hexamethyldisilazide under an acetone bath to obtain a compound of the formula (I);

Wherein R is selected from pyrrolidinyl, pyridyl, tetrahydropyranyl, piperidinyl, or morpholinyl, A, R~ R ⁷ as defined in formula (I) of the, n is 1. detailed description

The invention is further described in the following examples, but these examples are not intended to limit the scope of the invention.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS). The NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide ( ) 3⁄4>- ), deuterated chloroform (CDC1 ₃ ) deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl. silane CTMS), chemical shifts are given 10- ⁶ Cppm) as a unit.

For the determination of MS FINMGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan

LCQ advantage MAX).

The HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column).

The average inhibition rate of the kinase and the IC _5Q value were determined using a NovoStar plate reader (BMG, Germany).

Thin layer chromatography silica gel plate using Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate, thin layer chromatography

(TLC) The silica gel plate used has a specification of 0.15 mm~0.2 mm, and the thin layer chromatography separation and purification product is adopted. The specifications are 0.4 mm to 0.5 mm silica gel plates.

Column chromatography generally uses Yantai Yellow Sea 200~300 mesh silica gel as a carrier.

The known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organnics, Aldrich Chemical Company, ela远化学科技 (; Accela ChemBio Inc, Companies such as Dare Chemicals.

In the examples, the reactions were all carried out under an argon atmosphere or a nitrogen atmosphere unless otherwise specified.

An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.

The pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.

The hydrogenation reaction is usually evacuated, charged with hydrogen, and operated three times.

The microwave reaction was carried out using a CEM Discover-S Model 908860 microwave reactor.

In the examples, the solution in the reaction means an aqueous solution unless otherwise specified.

In the examples, the temperature of the reaction was room temperature unless otherwise specified.

Room temperature is the optimum reaction temperature, and the temperature range is from 20 ° C to 30 ° C.

The progress of the reaction in the examples was monitored by thin layer chromatography (TLC). The system used for the reaction was: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.

The system of the eluent for column chromatography and the system for developing the thin layer chromatography of the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and acetone System, D: hexamethylene, E: ethyl acetate, the volume ratio of the solvent is adjusted depending on the polarity of the compound, and may be adjusted by adding a small amount of triethylamine and an acidic or alkaline reagent.

Example 1

(^VW- -O-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(Y3aR,5r,6a-5-hydroxyhexahydrocyclopentyl W-pyrrole -2(1H)-yl)-2-butenamide

OH

Br

O first step

1a

Step

first step

(EH-bromo-2-butenoic acid

Under ice bath, methyl (E)-4-bromo-2-butenoate la (10 g, 0.056 mol) was dissolved in 30 mL of tetrahydrofuran, and 30 mL of an aqueous lithium hydroxide solution was slowly added dropwise to the reaction solution ( 3.05 g, 0.073 mol), after the addition, the reaction solution was stirred for 3 hours. The reaction mixture was extracted with 50 mL of EtOAc. EtOAc (EtOAc m. -Bromo-2-butenoic acid lb (5.93 g, yellow oil), Yield: 64.3%.

Second step

7-fluoroquinazoline-4 (3H ketone)

2-Amino-4-fluorobenzoic acid lcC 10 g, 0.065 mol) was dissolved in 150 mL of 2-methoxyethanol, and formazan acetate (16.79 g, 0.16 mol) was added thereto, the temperature was raised to 120 ° C, and the reaction was stirred for 22 hours. . The reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj ), Yield: 80%.

MS m/z (ESI): 165.1 [M+l] third step

7-fluoro-6-nitroquinazoline-4 (3H ketone)

Under ice bath, stir 20 mL concentrated sulfuric acid and 20 mL concentrated nitric acid, and slowly add 7-fluoroquinazoline-4 (3H ketone Id (8.42 g, 0.051 mol), stir evenly. Remove the ice bath and stir at room temperature for 1 hour. The temperature was raised to 110 ° C and stirring was continued for 2 hours. The heating was stopped, the reaction solution was cooled to room temperature, slowly added to 150 mL of ice water, a large amount of yellow solid was precipitated, stirred for 30 minutes, filtered, and the filter cake was washed with water and beaten with 50 mL of methanol 30 After a few minutes, the mixture was filtered and dried to give crystals crystals.

MS m/z (ESI): 208.1 [M+1]

the fourth step

4-chloro-7-fluoro-6-nitroquinazoline

Mix 7-fluoro-6-nitroquinazolin-4 (3H ketone le (7.60 g, 0.036 mol), 65 mL of thionyl chloride, 200 mL of phosphorus oxychloride and 0.5 mL of DMF, and heat, The mixture was stirred at 100 ° C for 2 hours, and stirred at 50 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure, and then toluene was taken from toluene 2 to 3 times to give the title product 4-chloro-7-fluoro-6-nitroquinazole. Porphyrin lf (7.15 g, pale yellow solid), Yield: 86%.

the fifth step

ΛΚ3-Chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine 4-chloro-7-fluoro-6-nitroquinazoline If (7.15 g, 0.031 mol) 4-Fluoro-3-chloroaniline (4.58 g, 0.031 mol), triethylamine (3.52 g, 0.035 mol) was added to 70 mL of isopropanol and stirred for 1.5 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjj -amine lgC 10.50 g, yellow solid), Yield: 100%.

MS m/z (ESI) 337.0 [M+1]

Step 6

ΛΚ3-Chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine ΛΜ chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazoline 4-Amine lg (1.30 g, 3.86 mmol) was added to 15 mL of methanol, stirred and dissolved. Add 0.5 mL of sodium hydroxide C 0.19 g, 4.63 mmol), stir well, warm to 70 ° C, stir the reaction 2 hours. The reaction solution was poured into 50 mL of water, stirred vigorously for 1 hour, filtered, and the filter cake was washed with water and dried in a vacuum oven at 60 ° C to give the title product N-(3-chloro-4-fluorophenyl)-7-methoxy. -6-Nitroquinazolin-4-amine lhC 1.50 g, yellow solid), total yield: 100%.

MS m/z (ESI) 349.0 [M+1]

Seventh step

-(3-Chloro-4-fluorophenyl)-7-methoxyquinazoline-4,6-diamine starting material ΛΜchloro-4-fluorophenyl)-7-methoxy-6-nitro The quinazolin-4-amine 1h (1.50 g, 4.30 mmol) was added to 30 mL of tetrahydrofuran, dissolved by stirring, and Raney nickel (lg) was added, and the hydrogen was replaced three times, and the reaction was stirred for 3 hours. The reaction mixture was filtered over EtOAc (EtOAc)EtOAc. Solid), Total yield: 73%.

MS m/z (ESI) 319.3 [M+1] Eighth step

-4-Chloro-N-(4- 3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide (E)-4-bromo 2-butenoic acid lb (8.5 g, 51.50 mmol) was dissolved in 100 mL of dichloromethane, cooled to 0 ° C in ice-bath, and re-steamed oxalyl chloride (8.77 mL, 103 mmol) and 0.05 mL N After stirring at 0 ° C for 2 hours, the reaction mixture was warmed to room temperature and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and 50 mL of anhydrous tetrahydrofuran was added to give (E 4-chloro-2-butenoyl chloride in tetrahydrofuran as a solution. -(3-chloro-4-fluorophenyl)-7-methoxy Base quinazoline-4,6-diamine li (lg, 3.14 mmol) and 2.5 mL of triethylamine dissolved in 50 mL of tetrahydrofuran, cooled to 0 ° C in an ice bath, and added dropwise (E)- A solution of 4-chloro-2-butenoyl chloride in tetrahydrofuran was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure to give the title product (E)-4-chloro-N-(4- 3-chloro-4-fluoro Phenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide lj (2.4 g, brown solid) was used directly in the next step.

MS m/z (ESI) 421.3 [M+1]

Step 9

(3aR,6a-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester C3aR,6a-5-oxo-hexahydro-cyclopenta[c]pyrrole-2- The tert-butyl carboxylate lk (500 mg, 2.22 mmol, prepared according to the existing literature WO2008089636) was dissolved in 100 mL of methanol, cooled to 0 ° C in an ice bath, slowly added sodium borohydride C168 mg, 4.44 mmol), stirred Reaction for 30 minutes. After adding 1 mL of water, the reaction mixture was evaporated. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The crude product (3aR, 6a-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 11 (441 mg, yield, brown oil) was obtained.

Step 10

(3aR,6a-octahydro-cyclopenta[c]pyrrole-5-ol hydrochloride salt crude OR, 6a-5-hydroxy-hexahydro-cyclopenta[c]pyrrole-2-carboxylic acid tert-butyl ester 11 (441 mg, 1.94 mmol) was dissolved in 5 mL of 2M hydrogen chloride in 1,4-dioxane, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure to give C3aR, 6a- octahydro-cyclopenta[ c] pyrrol-5-alcohol hydrochloride lm (318 mg, yellow solid), yield: 100%.

The eleventh step

(£)-W-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((3aR,5r,6a -5- Hydroxy hexahydrocyclopenta Mpyrrole-2(1H-yl)-2-butenamide

(E)-4-Chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide lj

(150 mg, 0.36 mmol), sodium iodide (30 mg, 0.18 mmol) and N,N-diisopropylethylamine (100 mg, 0.70 mmol) dissolved in 5 mL of N,N-dimethylformamide C3aR, 6a-octahydro-cyclopenta[c]pyrrole-5-ol hydrochloride lm (500 mg, 2.20 mmol) was added, and the reaction was stirred for 12 hours. The reaction mixture was poured into 50 mL of ice water, EtOAc (EtOAc (EtOAc) The resulting residue was purified by EtOAc EtOAc (EtOAc) -( 3aR,5r,6a -5- Hydroxyhexahydrocyclopenta[c]pyrrole-2(1H-yl)-2-butenamide 1 (3 mg, yellow solid), Yield: 1.6%. MS m/z (ESI): 512.4 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.41 (s, 1H), 9.34 (s, 1H), 8.41 (s, 1H), 8.06-8.04 (m, 1H), 7.64-7.63 (m, 1H) ), 7.31 (s, 1H), 6.94-6.80 (m, 2H), 6.37-6.18 (m, 2H), 3.60-3.59 (m, 1H), 3.51 (s, 3H), 3.43 (s, 1H), 3.28-3.25 (m, 2H), 2.56-2.54 (m, 2H), 2.27-2.25 (m, 2H), 1.36-1.34 (m, 2H), 1.08-1.05 (m, 2H), 0.72-0.74 (m , 2H). Example 2

(-^4-((3-chloro-4-fluorophenyl)amino 7-methoxyquinazolin-6-yl 4-(2-oxa-8-azaspiro"4.51 decane

(E)-4-Chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide lj ( 150 mg, 0.36 mmol), 2-oxa-8-azaspiro[4.5]decane hydrochloride 2a (100 mg, 0.71 mmol, using well-known method "Bioorganic & Medicinal Chemistry Letters, 12 (13), 1759 -1762; 2002 "prepared", sodium iodide (30 mg, 0.18 mmol) and triethylamine (0.1 mL, 0.71 mmol) were added to 2 mL of N,N-dimethylacetamide and stirred for 12 hours. . The reaction mixture was poured into 10 mL of ice water and extracted with ethyl acetate (15 mL×3), and the organic phase was combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue obtained gives (E)-AK4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-P-oxa-8-nitro Heterospiro[4.5]decane-8-yl)-2-butenamide 2 (17 mg, yellow solid), Yield: 10.0%.

MS m/z (ESI): 526.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.07 (s, 1H), 8.67 (s, 1H), 8.24 (s, 1H), 8.15 (s, 1H), 7.95-8.02 (m, 1H), 7.57-7.65 (m, 1H), 7.17 (t, J= 8 Hz, 1H), 6.31 (t, J= 16 Hz, 1H), 7.01-7.12 (m, 1H), 4.09 (s, 3H), 3.91 (t, J= 4 Hz, 3H), 3.61 (s, 2H), 3.35 (d, J= 8 Hz, 2H), 2.52-2.71 (m, 4H), 1.72-1.85 (m, 4H), 1.31 - 1.40 (m, 2H). Example 3

EVN-i4-(Y3-chloro-4-fluorophenyl)amino 7-methoxyquinazolin-6-yl 4-(-hydroxy-8-azabicyclo"3.2.11 octane-8-yl 2 -buteneamine

(E)-4-Chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide lj ( 100 mg, 0.24 mmol), 8-azabicyclo[3.2.1]octane-3-ol 3a (77 mg, 0.48 mmol), sodium iodide (18 mg, 0.12 mmol) and triethylamine (48 mg, 0.48 mmol) was added to 2 mL of N,N-dimethylacetamide, and the reaction was stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and purified to purified crystals eluted eluted eluted elution -6-yl)-4--3-hydroxy-8-azabicyclo[3.2.1]octane-8-yl)-2-butenamide 3 (20 mg, pale yellow solid), yield: 16.6% .

MS m/z (ESI): 512.4 [M+l]

iHNMR (400 MHz, DMSO-J ₆ ): δ 10.16 (s, 1H), 9.87 (d, 1H), 8.91 (s, 1H), 8.59 (s, 1H) 8.23 (s, 1H), 8.16 (d, 1H), 7.45 (s, 1H), 7.29 (s, 1H), 6.99 (d, 1H), 6.75 (d, 1H), 4.01 (s, 3H), 3.93 (d, 2H), 2.33-1.75 (m , 8H), 1.27-0.92 (m, 3H). Example 4

( )-N-(4-(Y3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-methylhexahydropyrrole

tert-Butyl 3-bromo-4-(2-hydroxyethoxy)pyrrolidine-1-carboxylate N-Boc-3-pyrroline 4a (100 g, 0.59 mol) was dissolved in 300 mL of ethylene glycol. Add bromine in batches Desuccinimide C108.0 g, 0.61 mol), about 10.0 g per batch, added in about 2 hours, stirred for 16 hours. After adding 500 mL of water, extracting with ethyl acetate (300 mL of EtOAc), EtOAc (EtOAc) tert-Butyl 4-bromo-4-(2-hydroxyethoxy)pyrrolidine-l-carboxylate 4b (178.0 g, pale yellow oily). Yield: 97%.

MS m/z (ESI): 256.0 [M-55]

Second step

tert-Butyl 3-bromo-4-(2-p-toluenesulfonyloxyethoxy)pyrrolidine-1-carboxylate 3-bromo-4-(2-hydroxyethoxy)b-pyrrolidine-1- tert-Butyl carboxylic acid 4b (178.0 g, 574 mmol), triethylamine (96 mL, 690 mmol) and 4-dimethylaminopyridine (2.0 g, 16 mmol) were added to 600 mL of toluene. °C, 200 mL of 4-toluenesulfonyl chloride (131.5 g, 58 mmol) in toluene was slowly added dropwise, and the dropwise addition was completed in about 1 hour. The ice bath was removed and naturally allowed to react to room temperature for 16 hours. 500 mL of water was added to the reaction mixture, and the organic layer was washed with 0.1 M hydrochloric acid (200 mL), saturated sodium hydrogen carbonate solution (200 mL), saturated sodium chloride solution (250 mL), dried over anhydrous sodium sulfate Filtration and concentration of the filtrate under reduced pressure afforded the title product 3-bromo-4-(2-p-toluenesulfonyloxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester 4c (240 g, brown oil). Rate: 90%.

MS m/z (ESI): 256.0 [M-55]

third step

Hexahydro-4-benzyl-B-pyrolo[3,4-b]-l,4-oxazine-6 (tert-butyl 2H carboxylic acid 3-bromo-4-(2-p-toluenesulfonyloxy) Ethoxy) B-terrolidine-1-carboxylic acid tert-butyl ester 4c (350 g, 0.75 mol) was dissolved in 2 L of p-xylene to give a brown solution, benzylamine (250 g, 2.26 mol) was added, The white solid was formed and heated under reflux for 7 hours. The reaction mixture was obtained as a pale yellow turd. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (500 mL). Wash with saturated sodium chloride solution (600 mL), filter, and concentrate the filtrate under reduced pressure. The residue was dissolved in 316 mL of methanol, cooled to 0 ° C, 6.9 M hydrogen chloride in dioxane solution (170 mL) The white solid was precipitated, the temperature was controlled to 0 ° C, stirred for 1.5 hours, and filtered to give the title product hexahydro-4-benzyl-B-pyrolo[3,4-b]-l,4-oxazine-6 (2H carboxylic acid tert-butyl ester 4d (134 g, white solid), yield 50%.

MS m/z (ESI): 319.2 [M+l]

the fourth step

Hexahydropyrrolo[3,4-b][l,4]oxazine-6 (tert-butyl 2H carboxylic acid hexahydro-4-benzyl-B is compared to [3,4-b]-l, 4-oxazine-6 (2H carboxylic acid tert-butyl ester 4d (50 g, 157 mmol) was dissolved in 7 L of methanol, palladium/carbon (5 g, 10%) was added, and the mixture was replaced with hydrogen three times, and the reaction was stirred for 16 hours. The reaction mixture was filtered, and the filtrate was evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj Used in the next step of the reaction.

MS m/z (ESI): 229.09 [M+1]

the fifth step

4-methylhexahydropyrrolo[3,4-b][l,4]oxazine-6 (tert-butyl 2H carboxylic acid) Dissolving hexahydropyrrolo[3,4-b][l,4]oxazine-6C2H)-carboxylic acid tert-butyl ester 4e C1.8 g, 7.80 mmol) in 60 mL of 1,2-dichloroethane Add 38% formaldehyde solution (1.0 g, 11.80 mmol), add, stir the reaction for 1 hour, ice bath to 0 V, add sodium triacetoxyborohydride (5.0 g, 23.60 mmol) in portions, with a large number of bubbles After the addition, the reaction was stirred at room temperature for 16 hours. The reaction solution was cooled to 0 ° C, 10 M sodium hydroxide solution was added dropwise until the reaction liquid was 9 , and dichloromethane (100 mL X 3 ) was extracted. The organic phase was combined and washed with saturated sodium chloride solution (100 mL X) l), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 4-methylhexahydropyrrolo[3,4-b][l,4]oxazin-6 (2H carboxylic acid tert-butyl ester) 4f (2.0 g, colorless oil), used directly in the next step.

MS m/z (ESI): 243.1 [M+1]

Step 6

4-methyloctahydropyrrolo[3,4-b][l,4]oxazine

Dissolve 4-methylhexahydropyrrolo[3,4-b][l,4]oxazin-6C2H)-carboxylic acid tert-butyl ester 4f (2.0 g, 8.26 mmol) in 2M hydrogen chloride in methanol (30) In mL), stir at room temperature for 1 hour. The reaction mixture was concentrated under reduced vacuo. mjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj MS m/z (ESI): 143.1 [M+1]

Seventh step

(E)-AK4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(4-methylhexahydropyrrole

[3,4-b][l,4]oxazine-6(2H-yl)-2-butenamide

(E)-4-Chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide lj ( 150 mg, 0.36 mmol), 4-methyloctahydropyrrolo[3,4-b][l,4]oxazine 4g (202 mg, 1.43 mmol), sodium iodide (53.4 mg, 0.36 mmol) and N N-Diisopropylethylamine (100 mg, 0.70 mmol) was added to 2 mL of N,N-dimethylformamide, and the reaction was stirred for 12 hours. 20 mL of ice water was added to the reaction mixture, and the mixture was combined with ethyl acetate (30 mL×3), and the organic phase was combined, washed with brine (30 mL×2), dried over anhydrous sodium sulfate The resulting residue was purified by EtOAc EtOAc (EtOAc) -4-(4-methylhexahydropyrrolo[3,4-b][l,4]oxazin-6(2H-yl)-2-butenamide 4 (6.7 mg, light brown solid yield: 3.5%.

MS m/z (ESI): 527.4 [M+l]

iHNMR (400 MHz, DMSO-J ₆ ): δ 9.81 (s, 1H), 9.69 (s, 1H), 8.94 (s, 1H), 8.54 (s, 1H), 8.15-8.12 (m, 1H), 7.83 -7.79 (m, 1H), 7.45-7.41 (m, 1H), 7.29 (s, 1H), 6.84-6.77 (m, 1H), 6.60 (d, 1H), 4.02 (s, 3H), 3.93-3.91 (m, 1H), 3.72 (d, 2H), 3.47-3.38 (m, 1H),

3.36-3.35 (m, 1H), 3.10-3.03 (m, 2H), 2.77-2.70 (m, 2H), 2.55-2.48 (m, 2H), 2.46-2.34 (m, 1H), 2.27 (s, 3H Example 5.

(E-N-(4-i(3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(8-hydroxy-2-azaspiro) 4.51癸垸

-2-yl 2-butenamide

First step

1,4-Dioxo[4.5]decane-8-carboxylic acid ethyl ester

Ethyl 4-oxocyclohexanecarboxylate 5a (20 g, 0.12 mol), ethylene glycol (23 mL, 0.41 mol) and p-toluenesulfonic acid monohydrate (224 mg, 1.18 mmol) dissolved in 70 mL of toluene The reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc) (EtOAc (EtOAc) The lacquer was dried over anhydrous sodium sulfate, filtered, and then filtered, evaporated, evaporated. Used in the next step of the reaction.

MS m/z (ESI): 214.6 [M+1]

Second step

Ethyl 8-allyl-1,4-dioxospiro[4.5]decane-8-carboxylate Ethyl 4-oxocyclohexanecarboxylate 5b (10 g, 0.047 mol) was dissolved in 55 mL of tetrahydrofuran In the dry ice-acetone bath, the mixture was cooled to -78 ° C, and hexamethyldisilazide lithium C1 M (57 mL) was added dropwise. After the addition, the reaction was stirred for 1 hour, and 3-bromopropene (4.9 mL, 56.20 mmol), after completion, the reaction was stirred at room temperature for 16 hours. The reaction was quenched with aq. aq. ammonium chloride, and the mixture was concentrated under reduced pressure. <RTI ID=0.0>> After washing with 100 mL), dried over anhydrous sodium sulfate, filtered and evaporated. g, colorless oil), used directly in the next step.

third step

Ethyl 8-(2-oxoethyl)-1,4-dioxospiro[4.5]decane-8-carboxylate 8-Allyl-1,4-dioxospiro[4.5]decane-8 - Ethyl carboxylate 5c (11.5 g, 45.27 mmol) was dissolved in 300 mL of dichloromethane, cooled to -78 °C with dry ice-acetone bath, three times with ozone, stirred for 5 to 6 hours, air was exchanged three times, stirred After reacting for 1 hour, triphenylphosphine (15.4 g, 58.71 mmol) was added, and the reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and the residue obtained was purified by EtOAc (EtOAc) To the title product oxyethyl)-1,4-dioxospiro[4.5]decane-8-carboxylic acid ethyl ester 5d (9.1 g, yellow oil), yield: 78%

the fourth step

10-benzyl-1,4-dioxo-10-azabicyclo[4.2.4.2]tetradecane-11-one 8-(2-oxoethyl)-1,4-dioxo[4.5 Ethyl decane-8-carboxylate 5d (9.1 g, 35.55 mmol) was dissolved in

In 90 mL of 1,2-dichloroethane, under ice bath, benzylamine (4.7 mL, 42.62 mmol), 2 mL of acetic acid and sodium triacetoxyborohydride (22.6 g, 106.60 mmol), After completion, the reaction was stirred at room temperature for 16 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The resulting residue was purified by EtOAc (EtOAc) elut elut elut eluting elut g, yellow oil), Yield: 66%.

the fifth step

2-benzyl -2-azaspiro [4.5] decane -3,8-dione

Dissolve 10-benzyl-1,4-dioxo-10-azaspiro[4.2.4.2]tetradec-11-one 5e (5 g, 16.61 mmol) in 100 mL of acetone and add 2M hydrochloric acid. (20 mL), the reaction was stirred for 16 hours. Saturated sodium bicarbonate solution was added dropwise until the pH of the reaction mixture was 7 and concentrated under reduced pressure. <RTI ID=0.0>> After washing, it was dried over anhydrous sodium sulfate and filtered and evaporated.]]]]]]]]]]]] , Yield: 98%.

MS m/z (ESI): 258.2 [M+1]

Step 6

2-benzyl-2-azaspiro[4.5]decane-8-ol

2-Benzyl-2-azaspiro[4.5]decane-3,8-dione 5f (I g, 3.89 mmol) was dissolved in 15 mL of tetrahydrofuran, cooled in an ice bath, and slowly added with lithium aluminum hydride (0.75) g, 19.47 mmol), after completion, the reaction was stirred at room temperature for 5 hours. The reaction was quenched with a saturated aqueous solution of sodium chloride, and the mixture was filtered. 5% decane-8-ol (0.5 g, yellow oil), Yield: 53%.

Seventh step

2-Azaspiro[4.5]decane-8-ol

Dissolve 2-benzyl-2-azaspiro[4.5]decane-8-ol 5g (0.5 g, 2.04 mmol) in 15 mL of tetrahydrofuran, add palladium hydroxide (0.25 g, 20%), heat to 50 The reaction was stirred for 16 hours at °C. The reaction mixture was filtered, and then evaporated tolulululululululululululululululululululululululululululululululululu

Eighth step

(E)-N-(4 3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4 8-hydroxy-2-azaspiro[4.5]decane

2-yl) - ₂ - butenamide (E)-4-Chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide lj ( 400 mg, 0.94 mmol), 2-azaspiro[4.5]decane-8-ol 5 h (300 mg, 1.93 mmol), sodium iodide (150 mg, 0.95 mmol) and N,N-diisopropyl The amine (370 mg, 2.84 mmol) was added to 15 mL of N,N-dimethylformamide and the reaction was stirred 16 hr. 15 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×4). The organic phase was combined, washed sequentially with water (30 mL×l) and brine (30 mL×2), dried over anhydrous sodium sulfate The residue was purified by EtOAc (EtOAc) elut elut Oxyquinazolin-6-yl)-4-(8-hydroxy-2-azaspiro[4.5]decane-2-yl)-2-butenamide 5 (25 mg, yellow solid), yield : 5.6%.

MS m/z (ESI): 540.2 [M+l]

iHNMR (400 MHz, DMSO-J ₆ ): δ 9.84 (s, 1H), 9.78 (s, 1H), 8.91 (s, 1H), 8.53 (s, 1H), 8.14 (d, 1H), 7.82 (d , 1H), 7.42 (t, 1H), 7.28 (s, 1H), 6.82 (d, 1H), 6.60 (d, 1H), 4.47 (s, 1H), 4.15 (s, 1H), 4.01 (s, 3H), 3.15 (d, 2H), 1.50-1.64 (m, 8H), 1.20-1.48 (m, 6H). Example 6

(E-N-(4-i(3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(2-oxa-7-aza snail "4.51癸垸

(E)-4-Chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenamide lj ( 150 mg, 0.36 mmol), 2-oxa-7-azaspiro[4.5]decane 6a (100 mg, 0.71 mmol), sodium iodide (30 mg, 0.18 mmol) and triethylamine (0.1 mL, 0.71 Methyl) was added to 2 mL of N,N-dimethylacetamide and the reaction was stirred for 16 hours. 6 mL of ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL×1). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure and purified by thin layer chromatography The residue gave the title product (EHV-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-P-oxa-7- Azaspiro[4.5]decane-7-yl)-2-butenamide 6 (2 mg, light brown solid), Yield: 1%.

MS m/z (ESI): 526.4 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.06 (s, 1H), 8.68 (s, 1H), 8.23 (s, 1H), 8.16 (s, 1H), 7.93-8.00 (m, 1H), 7.58-7.66 (m, 1H), 7.18 (t, J=8Hz, 1H), 6.30 (t, J=16Hz, 1H), 7.01-7.13 (m, 1H), 4.08 (s, 3H), 3.90 (t , J=4Hz, 3H), 3.61 (s, 2H), 3.35 (d, J=8Hz, 2H), 2.51-2.71 (m, 4H), 1.72-1.86 (m, 4H), 1.30-1.40 (m, 2H). Example

, E -N-i4-ii 垸 -2-yl) propylene

first step

(2-((4-Chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester

Add hydrazine, Ν'-carbonyldiimidazole (3 g, 18.80 mmol) to 30 mL of tetrahydrofuran, warm to 40 ° C, stir the reaction for 1 hour, add diethylphosphoric acid (3.69 g, 18.80 mmol) dropwise After completion, the reaction was stirred for 1 hour and used. -0-chloro-4-fluorophenyl 7-methoxyquinazoline-4,6-diamine li (2 g, 6.28 mmol) was dissolved in 20 mL of tetrahydrofuran, stirred and dissolved, warmed to 40 ° C, The above alternate reaction solution was added, and after completion, the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc m. Product (2-((4-(3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester 7a (3.20 g, yellow solid), Yield: 100%.

MS m/z (ESI) 497.3 [M+1]

Second step

(&E)-N-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2- Acrylamide

(2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester 7a (200 mg, 0.40 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and lithium hexamethyldisilazide (1 M, 0.4 mL) was added dropwise. 1 hour. (-1-Methyl-pyrrolidine-2-carbaldehyde 7b (150 mg, 1.33 mmol) was dissolved in 2.5 mL of tetrahydrofuran, added dropwise to the above reaction solution, added, stirred for 0.5 hour, and the reaction solution was allowed to rise to room temperature. After stirring for 16 hours, the reaction mixture was concentrated under reduced pressure. EtOAc mjjjjjj -7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 7 (30 mg, yellow solid) Body), Yield: 16%.

MS m/z (ESI): 456.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.81 (s, 1H), 9.77 (s, 1H), 8.92 (s, 1H), 8.55 (s, 1H), 8.11-8.18 (m, 1H), 7.78-7.84 (m, 1H), 7.43 (t, J=8Hz, 1H), 7.30 (s, 1H), 6.59-6.80 (m, 2H), 4.05-4.12 (m, 1H), 4.02 (s, 3H) ), 2.27-2.47 (m, 3H), 2.05-2.15 (m, 1H), 1.77-1.92 (m, 2H), 1.62-1.74 (m, 1H), 1.17-1.28 (m, 2H). Example 8

^-Κ4-ίί3-chloro-4-fluorophenyl)amino 3-cyano-7-methoxyquinazoline-6-yl 4-(2-oxa-8-aza snail

First step

2,4-dimethoxy-5-nitrobenzoic acid

2,4-Dichloro-5-nitrobenzoic acid 8a (11.8 g, 0.05 mol) was dissolved in 150 mL of methanol, and sodium methoxide G3.5 g, 0.25 mol) was added in portions, and the mixture was heated to 80 °. C, The reaction was stirred for 16 hours. The reaction solution was concentrated under reduced pressure, and 50 mL of ice water was added to the residue, and 20% hydrochloric acid was added dropwise to adjust the pH to 2 to 3, and a large amount of solid was precipitated, filtered, and the filter cake was washed with water (100 mL) and dried to give the title product. 2,4-Dimethoxy-5-nitrobenzoic acid 8b (10.4 g, white solid), Yield: 92%.

Second step

3-(2,4-dimethoxy-5-nitrophenyl)-3-carbonylpropionitrile

Dissolve 2-cyanoacetic acid (9.7 g, 0.11 mol) in 150 mL of acetonitrile, add magnesium chloride (17.4 g, 0.18 mol), cool in ice bath, add N,N-diisopropylethylamine C65 mL, 0.37 mol ), after the addition, the reaction was stirred for 3 hours for use. Dissolve 2,4-dimethoxy-5-nitrobenzoic acid 8b (10.4 g, 0.046 mol) in 100 mL of tetrahydrofuran In the middle, hydrazine, Ν'-carbonyldiimidazole (8.9 g, 0.055 mol) was added, and the mixture was stirred for 20 minutes, heated to 60 ° C, and stirred for 2 hours. The reaction solution was naturally cooled to room temperature, and slowly added to the above-mentioned alternate suspension. After the addition, the temperature was raised to 80 ° C, and the reaction was stirred for 3 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 1 L of ice water was added to the residue, and the mixture was adjusted to pH 1 by dropwise addition of 4 M hydrochloric acid, and stirred for 15 minutes, and the pH was adjusted to 7 by dropwise addition of saturated sodium hydrogen carbonate solution. ~8, a large amount of solid precipitated. 50 mL of ethyl acetate was added, stirred for 15 minutes, filtered, and the filter cake was washed with water (50 mL) and dried to give the title product 3-(2,4-dimethoxy-5-nitrophenyl)-3-carbonylpropane Nitrile 8c (8 g, yellow solid), Yield: 70%.

MS m/z (ESI): 251.1 [M+l]

third step

4-hydroxy-7-methoxy-6-nitroquinoline-3-carbonitrile

3-C2,4-dimethoxy-5-nitrophenyl 3-carbonylpropionitrile 8c (8 g, 0.032 mol) was dissolved in 100 mL of N,N-dimethylformamide, and N was added dropwise. N-dimethylformamide dimethyl acetal (7.9 g, 0.064 mol), stirred for 30 minutes, replaced with ammonia three times, and stirred for 3 hours under ice bath. Potassium carbonate (11 g, 0.080 mol) was added, and after completion, the temperature was raised to 80 ° C, and the reaction was stirred for 2 hours. The reaction solution was naturally cooled to room temperature, filtered, and 200 mL of water was added to the filtrate. 20% hydrochloric acid was added dropwise to adjust the pH to 5 to 6. A large amount of yellow solid was precipitated, filtered, and the filter cake was washed with water (50 mL) and dried to give the title product. 4-Hydroxy-7-methoxy-6-nitroquinoline-3-carbonitrile 8d (5.5 g, yellow solid), yield: 71%.

the fourth step

4-chloro-7-methoxy-6-nitroquinoline-3-carbonitrile

Dissolve 4-hydroxy-7-methoxy-6-nitroquinoline-3-carbonitrile 8d (5.5 g, 22.50 mmol) in 50 mL of acetonitrile and add N,N-diisopropylethylamine (12 mL) , 67.50 mmol), cooled to 0 ° C in an ice bath, slowly added dropwise phosphorus oxychloride (5.6 mL, 45 mmol). After the addition, the ice bath was removed, heated to 100 ° C, and stirred for 3 hours. The reaction solution was naturally cooled to room temperature, poured slowly into 400 mL of ice water, and a large amount of solid was precipitated, filtered, and dried to give the title product 4-chloro-7-methoxy-6-nitroquinolin-3-carbonitrile 8e. (4.74 g, yellow solid), Yield: 80.3%.

the fifth step

4-chloro-4-fluorophenyl)amino)-7-methoxy-6-nitroquinoline-3-carbonitrile 4-chloro-7-methoxy-6-nitroquinoline-3 - Nitrile 8e (4.74 g, 18 mmol) and 3-chloro-4-fluoroaniline were dissolved in 60 mL of isopropanol, warmed to 90 ° C, and stirred for 3 hours. The reaction solution was cooled to room temperature, then concentrated, evaporated, evaporated, evaporated, evaporated. 50 mL), dried over anhydrous sodium sulfate, filtered, EtOAcjjjjjjj 3-carbonitrile 8f (7 g, yellow solid) was used directly in the next step.

Step 6

6-Amino-4-(3-chloro-4-fluorophenyl)amino)-7-methoxyquinoline-3-carbonitrile 4-(0-chloro-4-fluorophenyl)amino)-7- Oxy-6-nitroquinoline-3-carbonitrile 8f (7 g, 18.80 mmol), iron powder (4.7 g, 84.60 mmol) and ammonium chloride (7.5 g, 141 mmol) were added to 120 mL of methanol and water ( V/V=l : l) In the mixed solvent, the hydrogen was replaced three times, heated to 100 ° C, and stirred for 5 hours. The reaction solution was cooled to room temperature, filtered, and the filtered cake was washed with methanol (200 mL). Drying, filtration, and EtOAc~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ ), Yield: 68%.

Seventh step

(£)-4-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-2-butene The amide (E)-4-bromo-2-butenoic acid lb (1 g, 6 mmol) was dissolved in 20 mL of dichloromethane, cooled to 0 ° C in an ice-bath, and re-steamed oxalyl chloride (0.80) After stirring for 2 hours at 0 °C, mL, 9 mmol) and 0.05 mL of N,N-dimethylformamide, the reaction mixture was warmed to room temperature and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure and dichloromethane (10 mL) was evaporated. 6-Amino-4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinoline-3-carbonitrile 8 g (2.3 g, 6.72 mol) and 0.5 mL of triethylamine dissolved in 10 It was cooled to 0 ° C in an ice-cooled dichloromethane, and a solution of dichloromethane (E)-4-chloro-2-butenoyl chloride in dichloromethane was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure to give the title compound (E)-4-chloro-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinoline- 6-yl)-2-butenamide 8h (2 g, black solid), used directly in the next step.

Eighth step

Chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinazoline-6-yl)-4-P-oxa-8-aza snail

[4.5] decane-8-yl)-2-butenamide

^ -4-Chloro-indole 4 3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-2-butenamide

8h (100 mg, 0.23 mmol), 2-oxa-8-azaspiro[4.5]decane hydrochloride 2a (80 mg, 0.45 mmol), sodium iodide (17 mg, 0.11 mmol) and triethylamine (0.1 mL, 0.71 mmol) was added to 2 mL of N,N-dimethylacetamide, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj -7-methoxyquinazolin-6-yl)-4-P-oxa-8-azaspiro[4.5]decane-8-yl-2-butenamide 8 (25 mg, gray solid yield : 20.3%.

MS m/z (ESI): 550.4 [M+l]

iHNMR (400 MHz, DMSO-J ₆ ): δ 9.96 (s, 1H), 9.84-9.72 (m, 2H), 8.95 (s, 1H), 8.56 (s, 1H), 7.49-7.45 (m, 2H) , 7.27 (s, 1H), 6.91 (d, 1H), 6.77-6.73 (m, 1H), 4.04 (s, 3H), 3.75-3.65 (m, 3H), 3.63-3.5 (m, 3H), 1.85 -1.6 (m, 5H), 1.3-1.25 (m, 5H). Example 9

(-W-i4-ii3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl 3-(4-methylmorphinolin-3-yl)acrylamide

first step

4-methylmorpholine-3-carbaldehyde

Dimethyl sulfoxide (0.65 mL, 9.16 mmol) was dissolved in 15 mL of dichloromethane at -78 ° C, oxalyl chloride (0.58 mL, 6.87 mmol) was added dropwise, and the reaction was stirred for 1 hour. 10 mL of C4-methylmorpholine-3-yl)methanol 9a (600 mg, 4.58 mmol, prepared according to the existing literature WO2009072658) in dichloromethane, after completion, the reaction was stirred for 1 hour, and triethylamine (1.9) was added. mL, 13.70 mmol), stir the reaction for 15 minutes, warm to 0 ° C and continue stirring for 1 hour. 200 mL of dichloromethane was added to the reaction mixture, and the mixture was washed with brine (50 mL) and saturated sodium chloride (50 mL). The resulting residue was purified by chromatography tolululululululululululululululululululululu

Second step

(£)-W-(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(4-methylmorpholine-3- Acrylamide

(2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester 7a (200 mg, 0.40 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and lithium hexamethyldisilazide (IM, 0.41 mL) was added dropwise, and the reaction was stirred. hour. 4-methylmorpholine-3-carbaldehyde 9b (185 mg, 1.43 mmol) was dissolved in 2.5 mL of tetrahydrofuran, added dropwise to the above reaction mixture, added, stirred for 0.5 hour, the reaction solution was naturally warmed to room temperature, stirred 16 hour. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The resulting residue was purified by EtOAc (EtOAc) elut elut Phenyl-6-yl)-3-(4-methylmorphinolin-3-yl)acrylamide 9 (100 mg, pale yellow solid), yield: 53%.

MS m/z (ESI): 472.3 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 8.13 (s, 1H), 7.69 (s, 1H), 7.21-7.25 (m, 1H), 6.85-6.92 (m, 1H), 6.42-6.49 (m , 1H), 5.97-6.05 (m, 1H), 5.82-5.88 (m, 1H), 3.29 (s, 3H), 3.04-3.09 (m, 1H), 2.84-2.96 (m, 2H), 2.58-2.64 (m, 1H), 2.56 (s, 1H), 2.11-2.17 (m, 1H), 2.11-2.06 (m, 1H), 1.87 (s, 1H), 1.48-1.61 (m, 4H). Example 10 (R,E)-N-i4-ii3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-3-indole-methylpyrrole- 2-base)

first step

(2-((4-(4-chloro-4-fluorophenyl)amino)-3-cyanoquinolin-6-yl)amino)-2-oxoethyl)phosphate

Add hydrazine, Ν'-carbonyldiimidazole C1.89 g, 11.70 mmol) to 40 mL of tetrahydrofuran, slowly add diethylphosphoric acid (2.3 g, 11.70 mmol), drop, stir the reaction for 1 hour, add 6 -Amino-4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinoline-3-carbonitrile 8 g C2 g, 5.84 mmol). The reaction mixture was concentrated under reduced vacuo. EtOAc m. Product (2-((4-(3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)amino)-2-oxoethyl)phosphoric acid Ethyl ester 10a (1 g, yellow solid), Yield: 33.3%.

Second step

(R,E)-N-(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-3-(1-A Pyrrolidine

-2-yl)acrylamide

Ρ 4- 4-Chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester 10a (250 mg, 0.48 mmol) was added to 20 mL of tetrahydrofuran, cooled to -78 °C with dry ice acetone bath, and lithium hexamethyldisilazide (1 M, 0.72 mL) was added dropwise, and the reaction was stirred. hour. (R)-l-methylpyrrolidin-2-carbaldehyde 10b (112 mg, 0.96 mmol) was dissolved in 25 mL of tetrahydrofuran, and added dropwise to the above reaction solution. After the addition, the reaction solution was naturally warmed to room temperature and stirred. hour. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj Cyano-7-methoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 10 (20 mg, yellow solid), yield: 8.7%.

MS m/z (ESI): 480.2 [M+l]

iHNMR (400 MHz, DMSO-J ₆ ): δ 9.75-9.74 (d, 2H), 8.98 (s, 1H), 8.56 (s, 1H),

7.47-7.40 (m, 3H), 7.26 (s, 1H), 6.69-6.66 (m, 2H), 4.04 (s, 3H), 3.15-2.8 (m, 2H), 2.3 (s, 3H), 2.1- 1.95 (m, 1H), 1.81-1.71 (m, 2H), 1.70-1.55 (m, 1H), 1.3-1.15 (m, 1H). Example 11

, E-N-i4-ii3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-3-indole-methylpyrrole-2-yl )

P- 4-Chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester 10a (100 mg, 0.19 mmol) was added to 5 mL of tetrahydrofuran and cooled to -78 with dry ice acetone. C, lithium hexamethyldisilazide (1 M, 0.2 mL) was added dropwise, and the reaction was stirred for 1 hour. (-1-Methyl-pyrrolidine-2-carbaldehyde 7b (150 mg, 1.32 mmol) was dissolved in 5 mL of tetrahydrofuran, added dropwise to the above reaction solution, and the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Base-7-methoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 11 (20 mg, yellow solid), yield: 21.7%.

MS m/z (ESI): 480.4 [M+l]

¹ H NMR (400 MHz, DMSO-J ₆ ): δ 9.73-9.72 (d, 2H), 8.98 (s, 1H), 8.58 (s, 1H), 7.47-7.41 (m, 3H), 7.26-7.23 (m , (1,1H) 2H), 1.7-1.5 (m, 1H), 1.3-1.2 (m, 2H). Example 12

(R, EVN-i4-(Y3-chloro-2,4-difluorophenyl)amino 7-methoxyquinazolin-6-yl)-3-indole-methylpyrrolidin-2-yl)

First step

-Chloro-2,4-difluorophenyl 7-methoxy-6-nitroquinazolin-4-amine 4-Chloro-7-methoxy-6-nitroquinazoline 12a (1 g, 4.17 mmol, prepared according to document WO2008033749) was dissolved in 25 mL of acetic acid, and 3-chloro-2,4-difluoro was added. Aniline 12b (683 mg, 4.17 mmol) was stirred for 2 hours and a large amount of solid precipitated. The reaction solution was poured into 200 mL of water, stirred for 0.5 hour, filtered, and the filter cake was dried in vacuo to give the title product N-(3-chloro-2,4-difluorophenyl)-7-methoxy-6-nitroquinazole Benzyl-4-amine 12c (1.5 g, pale yellow solid), Yield: 99%.

MS m/z (ESI): 364.8 [M-l]

Second step

-(3-chloro-2,4-difluorophenyl)-7-methoxyquinazoline-4,6-diamine

Add NO Chloro-2,4-difluorophenyl) -7-methoxy-6-nitroquinazolin-4-amine 12c (1.5 g, 4.09 mmol) to 100 mL of tetrahydrofuran, add 800 mg of blue Nickel-nickel, hydrogen was replaced three times, the reaction was stirred for 16 hours, filtered, and the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give the title product -(3-chloro-2,4-difluorophenyl)-7-methoxyquin. Oxazoline-4,6-diamine 12d (1. lg, yellow solid), Yield: 80%.

MS m/z (ESI): 337.1 [M+l]

third step

(2-((4-Chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl ester

Ν,Ν'-carbonyldiimidazole (144 mg, 0.89 mmol) was added to 5 mL of tetrahydrofuran, and diethylphosphoric acid (174 mg, 0.89 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour, and was taken. Add -(3-chloro-2,4-difluorophenyl)-7-methoxyquinazoline-4,6-diamine 12d (100 mg, 0.30 mmol) to 5 mL of tetrahydrofuran and heat to 40 °C, dropwise added to the above-mentioned alternate reaction solution, after completion, the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc m. 4-((3-Chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester 12e (150 Mg, yellow oil), used directly in the next step.

MS m/z (ESI) 515.2 [M+l]

the fourth step

(R,E)-N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methyl Pyrrolidine

-2-yl)acrylamide

(2-((4-(3-chloro-2,4-difluorophenyl)amino 7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl Ester 12e (153 mg, 0.30 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 °C with dry ice acetone bath, and lithium hexamethyldisilazide (1 M, 0.3 mL) was added dropwise. The reaction was carried out for 1 hour. (R)-l-methylpyrrolidin-2-carbaldehyde 10b (150 mg, 1.33 mmol) was dissolved in 2.5 mL of tetrahydrofuran, added dropwise to the above reaction mixture, and the reaction was stirred for 0.5 hour. The dry ice acetone bath was removed, and the reaction mixture was warmed to room temperature and stirred for 16 hr. The reaction mixture was concentrated under reduced pressure. ((3-Chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 12 ( 122 mg, pale yellow solid), Yield: 88%. MS m/z (ESI): 473.8 [Ml]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.79 (s, 1H), 9.71 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H) _: 8.13 (d, J=8Hz, 1H ), 7.78-7.85 (m, 1H), 7.43 (t, J=8Hz, 1H), 6.66-6.73 (m, 1H) _: 6.53-6.62 (m, 1H), 4.02 (s, 3H), 3.01-3.07 (m, 1H), 2.55 (s, 2H), 2.14-2.18 (m, 2H) _: 1.97-2.05 (m, 1H), 1.70-1.80 (m, 2H), 1.53-1.63 (m, 1H), 1.24 (s, 1H). Example 13

Alkan-2-yl)propane

First step

ΛΚ3-Chloro-2-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

Dissolve 4-chloro-7-methoxy-6-nitroquinazoline 12a (2 g, 8.35 mmol, prepared according to document WO2008033749) and 3-chloro-2-fluoroaniline 13a (1.22 g, 8.35 mmol) To 80 mL of acetic acid, triethylamine G.86 g, 18.37 mmol) was added, and the reaction was stirred for 48 hours, and a large amount of solid was precipitated. The reaction solution was poured into 250 mL of water, stirred for 0.5 hr, filtered, and then filtered and dried in vacuo to give the title product N-(3-chloro-2-fluorophenyl)-7-methoxy-6-nitroquinazoline-4 -Amine 13b (2.73 g, pale yellow solid), Yield: 94%.

MS m/z (ESI): 348.9 [M+l]

Second step

-(3-chloro-2-fluorophenyl)-7-methoxyquinazoline-4,6-diamine

Add NOchloro-2-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine 13b (2.73 g, 7.84 mmol) to lj 200 mL methanol and tetrahydrofuran (V/V=l: In the mixed solvent of l), 1 g of Raney nickel was added, and the hydrogen was replaced three times. The reaction was stirred for 16 hours, filtered, and the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give the title product - (3-chloro-2-fluorophenyl) 7-Methoxyquinazoline-4,6-diamine 13c (2.49 g, yellow-green solid), Yield: 99%.

MS m/z (ESI): 319.1 [M+l]

third step

(2-((4-(3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl Ν, Ν '-carbonyldiimidazole (152 mg, 0.94 mmol) was added to 5 mL of tetrahydrofuran, diethylphosphoacetic acid (184 mg, 0.94 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour, and was taken. -(3-Chloro-2-fluorophenyl)-7-methoxyquinazolin-4,6-diamine 13c (100 mg, 0.31 mmol) was added to 5 mL of tetrahydrofuran and heated to 40 °C. The mixture was added dropwise to the above-mentioned alternate reaction solution, and after completion, the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title product was obtained (2-((4-(3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl) phosphate Diethyl ester 13d (133 mg, yellow oil), yield: 85%.

MS m/z (ESI) 497.3 [M+1]

the fourth step

(R,E)-N-(4-((3-chloro-2-fluorophenyl)amino 7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2- Acrylamide

(2-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl) phosphate diethyl ester 13d (133 mg, 0.27 mmol) was added to 2.5 mL of tetrahydrofuran and cooled to -78 with dry ice acetone. C, lithium hexamethyldisilazide (1 M, 0.3 mL) was added dropwise, and the reaction was stirred for 1 hour. (R)-l-methylpyrrolidin-2-carbaldehyde 10b (150 mg, 1.33 mmol) was dissolved in 2.5 mL of tetrahydrofuran, added dropwise to the above reaction solution, added, stirred for 0.5 hour, and the acetone bath was removed. The reaction solution was naturally warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjj 7-Methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 13 (55 mg, pale yellow solid), yield: 45%.

MS m/z (ESI): 455.9 [M-l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.80 (s, 1H), 9.70 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.14 (s, 1H), 7.78- 7.85 (m, 1H), 7.38-7.42 (m, 1H), 7.24-7.28 (m, 1H), 6.65-6.73 (m, 1H), 6.53-6.62 (m, 1H), 4.02 (s, 3H), 3.01-3.07 (m, 1H), 2.55 (s, 2H), 2.14-2.18 (m, 2H), 1.98-2.05 (m, 1H), 1.71-1.80 (m, 2H), 1.53-1.63 (m, 1H) ), 1.24 (s, 1H). Example 14

(R,E)-N-(4-(Y3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-indole-methylpyrrole-2- Base)

first step

(2-((4-(3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl) phosphate diethyl ester

Ν,Ν'-carbonyldiimidazole (526 mg, 3.24 mmol) was added to 5 mL of tetrahydrofuran, and diethylphosphoric acid (700 mg, 3.57 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour, and was taken. 4-((6-Amino-7-methoxyquinazolin-4-yl)amino)-2-chlorophenol 14a (633 mg, 2.00 mmol, prepared according to document WO2011095053) was added to 5 mL of tetrahydrofuran. The mixture was heated to 40 ° C, added dropwise to the above-mentioned alternate reaction solution, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title product was obtained (2-((4-(3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl) phosphate Diethyl 14b (400 mg, grey solid), Yield: 62.5%.

Second step

(R,E)-N-(4-((3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-0-methylpyrrolidin-2- Acrylamide

(2-((4-((3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl) phosphate diethyl ester 14b (50 mg, 0.10 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 °C with dry ice acetone bath, and lithium hexamethyldisilazide (1 M, 0.3 mL) was added dropwise, and the reaction was stirred. 1 hour. (R)-l-methylpyrrolidine-2-carbaldehyde 10b (23 mg, 0.20 mmol) was dissolved in 2.5 mL of tetrahydrofuran, added dropwise to the above reaction solution, added, stirred for 0.5 hour, and the dry ice acetone bath was removed. The reaction solution was naturally warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjj -7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 14 (10 mg, yellow solid), yield: 21.7%.

MS m/z (ESI): 454.2 [M+l]

iHNMR (400 MHz, DMSO-J ₆ ): δ 10.5 (s, 1H), 9.9 (s, lH), 8.41 (s, 1H), 8.23-8.18 (m, 2H), 7.86 (s, 1H), 6.52 (d, 1H), 6.68-6.66 (m, 2H), 6.42-6.3 (m, 2H), 4.01 (s, 3H), 3.25-2.8 (m, 2H), 2.5 (s, 3H), 2.18-2.05 (m, 1H), 1.91-1.81 (m, 2H), 1.79-1.65 (m, 1H), 1.3-1.18 (m, 1H). Example 15

(R,E-N-i4-(Y3-chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-3-indole-methylpyrrole-2 -yl) acrylamide

First step

N-(3-chloro-2,4-difluorophenyl)-7-ethoxy-6-nitroquinazolin-4-amine

4-chloro-7-ethoxy-6-nitroquinazoline 15a (1.3 g, 5.10 mmol, according to the literature "Bioorganic &

Medicinal Chemistry, 2007, 15(11), 3635-3648 "Prepared" was dissolved in 30 mL of acetic acid, 3-chloro-2,4-difluoroaniline 12b (835 mg, 5.10 mmol) was added, and the reaction was stirred for 2 hours. A large amount of solid was precipitated. The reaction mixture was poured into 50 mL of water, stirred for 0.5 hr, filtered, and then filtered to dryness to give the title product N-(3-chloro-2,4-difluorophenyl)-7-ethoxy-6 -Nitroquinazolin-4-amine 15b (1.4 g, yellow solid), Yield: 73.7%.

Second step

-(3-chloro-2,4-difluorophenyl)-7-ethoxyquinazoline-4,6-diamine

Add N-(3-chloro-2,4-difluorophenyl)-7-ethoxy-6-nitroquinazolin-4-amine 15b (1.4 g, 3.70 mmol) to 30 mL of tetrahydrofuran. After adding lg of Raney nickel, the hydrogen was replaced three times, the reaction was stirred for 16 hours, filtered, and the filter cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give the title product -(3-chloro-2,4-difluorophenyl)-7- Oxyquinazoline-4,6-diamine 15c (1.2 g, yellow solid), Yield: 92.3%.

MS m/z (ESI): 351.2 [M+l]

third step

(2-((4-Chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl ester

Ν,Ν'-carbonyldiimidazole (416 mg, 2.87 mmol) was added to 5 mL of tetrahydrofuran, diethylphosphoacetic acid (503 mg, 2.57 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour, and was taken. Add -(3-chloro-2,4-difluorophenyl)-7-ethoxyquinazoline-4,6-diamine 15c (300 mg, 0.85 mmol) to 5 mL of tetrahydrofuran and heat to 40 °C, dropwise added to the above-mentioned alternate reaction solution, after completion, the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. The title product was obtained (2-((4-chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)-2-oxoethyl Phosphate diethyl ester 15d (800 mg, white solid) was used directly in the next step. MS m/z (ESI) 529.3 [M+1]

the fourth step

(R,E)-N-(4-((3-chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-3-0-methylpyrrolidine

-2-yl)acrylamide

(2-((4-(3-Chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Diethyl ester 15d (270 mg, 0.51 mmol) was added to 10 mL of tetrahydrofuran, cooled to -78 °C with dry ice acetone bath, and lithium hexamethyldisilazide (1 M, 0.6 mL) was added dropwise. The reaction was stirred for 1 hour. (R)-l-methylpyrrolidin-2-carbaldehyde 10b (200 mg, 1.53 mmol) was dissolved in 5 mL of tetrahydrofuran, added dropwise to the above reaction solution, added, stirred for 0.5 hour, and the acetone bath was removed. The reaction solution was naturally warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Amino)-7-ethoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 15 (80 mg, yellow solid), yield: 32%.

MS m/z (ESI): 488.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.90 (s, 1H), 8.93 (s, 1H), 8.40 (s, 1H), 7.55-7.49 (m, 1H), 7.40-7.35 (m, 1H ), 7.27 (s, 1H), 6.87-6.71 (m, 2H), 4.33-4.28 (m, 2H), 4.24 (s, 1H) 3.03-3.00 (m, 1H), 3.13 (s, 3H), 1.91 -1.64 (m, 6H), 1.49-1.45 (m, 3H). Example 16

iR,E N-i4-i(3-chloro-4-fluorophenyl)amino 7-oxazoline-6-yl)-3-indole-methylpyrrolidin-2-yl)propane

(2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate diethyl ester 7a (200 mg, 0.41 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 °C with dry ice acetone bath, and lithium hexamethyldisilazide (1 M, 0.41 mL) was added dropwise, and the reaction was stirred. 1 hour. (R)-l-methylpyrrolidine-2-carbaldehyde 10b (150 mg, 1.33 mmol) was dissolved in 2.5 mL of tetrahydrofuran, added dropwise to the above reaction solution, added, stirred for 0.5 hour, and the reaction solution was naturally raised to Stir at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjj Oxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)acrylamide 16 (88 mg, white solid), yield: 48%.

MS m/z (ESI): 456.3 [M+l] NMR NMR (400 MHz, DMSO-J ₆ ): δ 9.80 (s, 1H), 9.70 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.14 (d, J = 8 Hz, 1H), 7.78-7.85 (m, 1H), 7.43 (t, J= 8 Hz, 1H), 7.29 (s, 1H), 6.65-6.73 (m, 1H), 6.53-6.62 (m, 1H), 4.02 (s, 3H), 3.01-3.07 (m, 1H), 2.55 (s, 2H), 2.14-2.18 (m, 2H), 1.98-2.05 (m, 1H), 1.71-1.80 (m, 2H), 1.53 -1.63 (m, 1H), 1.24 (s, 1H). Example 17

(R, EVN-i4-"3-chloro-4-(pyridin-2-ylmethoxy)-phenylamine 1-3-hydrogen-7-ethoxy-quinoline-6-ylmethyl

-pyrrole-2-yl V acrylamide

First step

({4-[3-Chloro-4-(pyridin-2-ylmethoxy)-anilino]-3-cyano-7-ethoxy-quinolin-6-ylcarbamoyl}-methyl ) -Diethyl phosphate

The hydrazine, Ν'-carbonyldiimidazole (486.45 mg, 3 mmol) was dissolved in 4 mL of tetrahydrofuran at 40 ° C, the oil bath was heated to 40 ° C, and 4 mL of diethyl phosphate-based acetic acid was added dropwise to the reaction solution. A solution of 588.42 mg, 3 mmol) in tetrahydrofuran was stirred for 30 minutes. 6-Amino-4-[3-chloro-4-(pyridin-2-ylmethoxy)-anilino]-7-ethoxy-quinoline-3-carbonitrile 17a (445.9 mg, 40 ° C, 1 mmol, prepared according to the literature "WO2005028443") was dissolved in 4 mL of tetrahydrofuran, and the above-mentioned alternate reaction solution was added dropwise, and the reaction was stirred for 12 hours. The reaction mixture was concentrated with EtOAc EtOAc (EtOAc m. The residue obtained gave the title product ({4-[3-chloro-4-(pyridin-2-ylmethoxy)-anilinyl]-3-cyano-7-ethoxy-quinolin-6-yl Carbamoylmethyl)-diethyl phosphate 17b (624 mg, pale yellow solid), Yield: 99.9%.

MS m/z (ESI): 624 [M+l]

Second step

(E)-N-{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-aniline]-3-hydro-7-ethoxy-quinolin-6-yl}-3 -(1-methyl

-pyrrolidin-2-yl)-acrylamide

«4-[3-Chloro-4-(pyridin-2-ylmethoxy)-anilino]-3-cyano-7-ethoxy-quinolin-6-ylcarbamoyl group in a dry ice bath Diethyl phosphate 17b (250 mg, 0.4 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and a 1 M solution of bistrimethylsilylamide lithium in toluene (0.44 mL, 0.44 mmol) was added dropwise. After 30 minutes, 5 mL of (R)-N-methyl-2-Bpyrrolidine 10b (90 mg, 0.8 mmol) in tetrahydrofuran was added dropwise, the reaction was stirred for 30 minutes, and the reaction was continued for 12 hours at room temperature. Pressure concentration, using silicon The residue obtained is purified by column chromatography to give the title product (R, E)-AM4-[3-chloro-4-(pyridin-2-ylmethoxy)-aniline]-3-hydro-7-ethoxy Base-quinolin-6-yl}-3-(1-methyl-pyrrolidin-2-yl)-acrylamide 17 (46 mg, yellow solid), yield: 19.7%.

MS m/z (ESI): 584 [M+1]

¹ H NMR (400 MHz, DMSO-J ₆ ): 9.156 (s, 1H), 8.628 (d, 1H, J = 4.4 Hz), 8.555 (s, 1H), 8.261 (s, 1H), 7.828 (t, 1H, J=9.2Hz), 7.759 (m, 2H), 7.574 (m, 1H), 7.404 (d, 2H, J = 10.8Hz), 7.187 (d, 1H, J=8.8Hz), 7.060 (m, 2H) , 6.343 (d, 1H, J=15.2Hz), 5.353 (s, 2H), 4.390 (m, 2H, J=6.8Hz, J=14Hz), 3.323 (m, 1H), 3.100 (m, 1H), 2.734 (s, 3H), 2.371 (m, 2H), 2.076 (m, 2H), 1.642 (t, 3H, J=6.8Hz). Example 18

(^ -^-"4-"3-Chloro-4-(2-pyridylmethoxy)phenyl 1amino 1-3-cyano-7-ethoxy-6-quinoline

N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolinyl group at -78 °C Diethyl 2-phosphate-acetamide 17b (50 mg, 0.08 mmol) was dissolved in 2 mL of tetrahydrofuran, and 1 M solution of ditrimethylsilylamine lithium in toluene (80 μ, 0.08 mmol) was added dropwise. After stirring for 45 minutes, (2 -1-methyl-B-pyrrolidine-2-carbaldehyde 7b (20 mg, 0.17 mmol) was added to the reaction mixture, and stirring was continued for 1 hour, and the reaction was carried out at room temperature for 12 hours. 1 mL of water and 1 mL of methanol. Extracted with dichloromethane (50 mL×3), EtOAc (EtOAc) The residue obtained was purified by chromatography to afford the title product (EHV-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano- 7-Ethoxy-6-quinolinyl]-3-[(2-1-methylpyrrolidin-2-yl)prop-2-enamide 18 (25 mg, yellow solid), yield: 53.5 % .

MS m/z (ESI): 583 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.63 (s, 2H), 8.95 (s, 1H), 8.60 (d, 1H), 8.48 (s, 1H), 7.89 (t, 1H), 7.59 ( d, 1H), 7.37 (m, 3H), 7.27-7.20 (m, 2H), 6.80-6.60 (m, 2H), 5.29 (s, 2H), 4.34 (dd, 2H), 2.33-2.24 (m, 3H), 2.23-2.15 (m, 2H), 1.99-1.88 (m, 3H), 1.80-1.78 (m, 2H), 1.49 (t, 3H). Example 19

(£)-W-"4-"(-Chloro-4-fluoro-phenyl)amino 1-7-ethoxy-quinazolin-6-yl l-3-"(2R)-l-methyl Pyrrolidine

First step

W-[4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl-acetamide will be Ν,Ν'- The carbonyl diimidazole (292 mg, 1.80 mmol) was dissolved in 4 mL of tetrahydrofuran, the oil bath was heated to 50 ° C, and 3 mL of a solution of diethyl phosphate phosphate (353 mg, 1.8 mmol) in tetrahydrofuran was added dropwise to the reaction solution. The reaction was allowed to stand for 1.5 hours. -(3-Chloro-4-fluoro-phenyl)-7-ethoxy-quinazoline-4,6-diamine 19a (200 mg, 0.60 mmol, prepared according to the literature "WO2005028443") dissolved in 10 mL The above-mentioned alternate reaction solution was added dropwise to the tetrahydrofuran at 50 ° C, and reacted at 40 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. Chromatography The residue obtained was purified using eluent (EtOAc) to give the title product N-[4-[(3-chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazoline-6-yl] Diethyl-2-phosphate-acetamide 19b (100 mg, pale yellow solid), Yield: 303.

MS m/z (ESI): 511.1 [M+1]

Second step

(£)-W-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2R)-l-- Pyrrolidine

-2-yl]prop-2-enamide

N-[4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 19b (300 mg, 0.59 mmol) dissolved in 10 mL of tetrahydrofuran, cooled to -78 °C in a dry ice bath, and added 1 M solution of ditrimethylsilylamino lithium in toluene (1.2 mL, 1.18 mmol) under argon. After stirring for 30 minutes, (R)-l-methyl-pyrrolidine-2-carbaldehyde 10b (133 mg, 1.18 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour and then allowed to react at room temperature for 12 hours. Concentrate the reaction solution, add 10 mL of water, extract with dichloromethane (25 mL×3), combine the organic phase, wash with saturated sodium chloride solution (30 mL><2), dry over anhydrous sodium sulfate, filter The residue was purified by silica gel column chromatography eluting elut elut elut elut Oxy-quinazolin-6-yl]-3-[(2R)-l-methylpyrrolidin-2-yl]prop-2-enamide 19 (130 mg, yellow solid yield: 47.3%.

MS m/z (ESI): 470.2 [M+1]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.79 (s, 1H), 9.53 (s, 1H), 8.93 (s, 1H), 8.53 (s, 1H), 8.12-8.15 (m, 1H), 7.79-7.83 (m, 1H), 7.40-7.45 (m, 1H), 7.27 (s, 1H), 6.67-6.73 (m, 1H), 6.56-6.60 (m, 1H), 4.27-4.32 (m, 2H) ), 4.09-4.10 (m, 1H), 3.17 (m, 2H), 3.04 (m, 1H), 2.77-2.79 (m, 1H), 2.18-2.16 (m, 1H), 2.21 (s, 3H), 1.74-1.76 (m, 1H), 1.47 (t 3H). Example 20

(£)-W-"4-"(-Chloro-4-fluoro-phenyl)amino 1-7-ethoxy-quinazolin-6-yl 1-3-"ί2 -1-methylpyrrole

N-[4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 19b (100 mg, 0.20 mmol) dissolved in 10 mL of tetrahydrofuran, cooled to -78 °C in a dry ice bath, and added 1 M solution of ditrimethylsilylamine lithium in toluene (400 μ, 0.40 mmol), and stirred for 45 minutes. (2 -1-methyl-B-pyrrolidine-2-carbaldehyde 7b (100 mg, 0.85 mmol) was added to the reaction mixture, and stirring was continued for 1 hour, and the reaction was carried out for 12 hours at room temperature. 1 mL of water and 1 were added to the reaction solution. The mixture was extracted with methylene chloride (100 mL×3), EtOAc (EtOAc) The resulting residue was purified to give the title product (£)-W-[4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazoline-6-yl. -3-[(2 -1-Methylpyrrolidin-2-yl)prop-2-enamide 20 (60 mg, yellow solid), yield: 65.2%.

MS m/z (ESI): 470.2 [M+l]

1H NMR (400 MHz, DMSO-J ₆ ): δ 9.78 (s, 1H), 9.53 (s, 1H), 8.91 (s, 1H), 8.52 (s, 1H), 8.13-8.15 (m, 1H), 7.79-7.81 (m, 1H), 7.39-7.43 (m, lH), 7.26 (s, lH), 6.67-6.69 (m, 2H), 4.26-4.31 (m, 2H), 4.09-4.10 (m, lH ), 3.17-3.15 (m, 2H), 3.08-3.04 (m, lH), 2.77-2.79 (m, lH), 2.87-2.82 (m, lH), 2.23 (s, 3H), 1.74-1.76 (m , lH), 1.47 (m, 3H). Using the procedure of Synthesis Scheme 1, the compounds of Examples 21-31 were synthesized using the appropriate reactants in accordance with the procedures of Examples 1 through 8. Using the synthetic route II, the compounds of Examples 32-38 were synthesized using the appropriate reactants in accordance with the procedures of Examples 9 through 20.

CSM.0/CT0ZN3/X3d

CSM.0/CT0ZN3/X3d

£SnLO/£lOZSLJ/∑Jd Biological evaluation

The invention is further described below in conjunction with the test examples, but these examples are not intended to limit the scope of the invention.

Some sources of materials used in this test case:

Company source and item number

EGFR Invitrogen, PV3872

EGFR T790M Invitrogen, PV4803

EGFR L858R Invitrogen, PV4128

EGFR T790M/ L858R Invitrogen, PV4879

EGFR del 746-750 Carna Biosciences, 08-527

EGFR del 746-750/T790M Carna Biosciences, 08-528

EGFR mutant human non-small cell lung adenocarcinoma cells NCI-H-1975, human lung cancer cells PC-9, gefitinib-resistant human lung cancer cells PC-9 GR: purchased from the Chinese Academy of Sciences cell bank.

The experimental methods in which the specific conditions are not specified in the test examples of the present invention are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer of the product. Reagents not specified for specific sources, are routine reagents purchased by the market. Test Example 1. Determination of inhibition of activity of EGFR mutant kinase by the compound of the present invention

The following method was used to determine the inhibitory effects of the compounds of the present invention on the activities of EGFR, EGFR T790M, EGFR L858R, EGFR T790M/L858R, EGFR del 746-750, EGFR del 746-750/T790M, respectively. The experimental method is briefly described as follows:

In vitro activity assays of VEGFR-2 inhibitors were performed using Invitrogen's U-box Z'-LYTE® Kinase Assay Kit- Tyrosine 4 Peptide (Invitrogen, PV3193). According to the kit instructions, configure the enzyme buffer (50mM HEPES PH7.5, 0.01% BRIJ-35, 10mM MgCl ₂ , 4mM MnCl ₂ , ImM EGTA, 2mMDTT), enzyme/substrate peptide solution, ATP solution. And completely phosphorylate the substrate peptide, mix gently; dilute water to prepare 4X concentration of the test compound solution, mix well.

The configured enzyme/substrate peptide solution and the fully phosphorylated substrate peptide 5uL were added to a 384-well plate, then 2.5 uL ATP solution and 2.5 uL compound solution were added to the experimental group, and 2.5 uL was added to the completely inhibited control group. Enzyme buffer and 2.5uL of the corresponding concentration of DMSO solution, 2.5uL ATP solution and 2.5uL corresponding DMSO solution were added to the non-inhibited control group, 2.5uL enzyme buffer and 2.5uL corresponding concentration were added to the completely phosphorylated substrate control group. DMSO solution; paste the plate and shake it on the shaker for 30 seconds to mix the solutions uniformly, and incubate for 1 hour at room temperature.

According to the instructions, the developing solution was prepared according to the corresponding ratio. After mixing, add 5 uL of each reaction well, and attach the sealing plate to the shaker for 30 seconds to mix the solutions uniformly, and incubate for 1 hour at room temperature. Every The wells were added with 5 uL of stop solution, and after mixing uniformly, fluorescence was read at 445 nm and 520 nm by excitation at 400 nm. Biochemical activity of the compounds of the present invention measured by the above test, measured EGFR and mutant EGFR activity inhibition value IC _5Q 1 to Table 3 in the table below.

Table 1 IC _5Q inhibition of EGFR enzyme activity by the compounds of the present invention

Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the proliferation of EGFR kinase. Table 2 ICs for inhibition of EGFR T790M, L858R and T790M/L858R enzyme activities by the compounds of the present invention

3 138 41 453

4 41 7.2 237

5 57 11 250

6 65 21 307

7 58 2.4 158

16 6.6 2.3 27

17 65 69 258

19 18 5.9 86

21 113 22 311

23 77 11 311

24 361 91 844

25 145 5.6 664

26 111 25

29 83 30 331

35 97

36 125

37 19 5.8 26

38 217 3.2 259 Conclusion: The compounds of the present invention have significant inhibitory effects on the proliferation of EGFR T790M, L858R and T790M/L858R kinases. Table 3 IC ₅ o inhibition of EGFR del 746-750, EGFR del 746-750/T790M enzyme activity by the compounds of the invention

15 22 219

16 5.3 80

17 273 315

19 16 97

30 41

31 73

33 1.9

34 50

35 10 153

37 7.8 19

38 3.3

Conclusion: The compounds of the present invention have significant inhibitory effects on the proliferation of EGFR del 746-750 and EGFR del 746-750/T790M kinases. Test Example 2. Determination of the inhibition of the activity of the compound of the present invention on EGFR mutant cells

The following method was used to determine the inhibitory effect of the compound of the present invention on the proliferation of EGFR mutant cells NCI-H-1975 and PC-9 GR. Briefly read as follows:

EGFR mutant cells (NCI-H-1975 or PC-9 GR) were cultured in IMDM medium (Hyclone, SH30228.01B) (containing 20% FBS, 100 units/ml P/S, 5 ng/ml VEGF). When cells cover 80 to 90%, they are digested with 0.25% trypsin (EDTA) and then planted in 96-well plates at 2000 cells per well (ΙΟΟμΙ IMDM (2% FBS, P/S) medium), placed at 37°. C. Incubate for 24 hours in a 5% CO ₂ incubator. Dispense the drug into a 20 mM stock solution, dilute to a 200 X concentration gradient with 100% DMSO, and dilute 20 times with IMDM (2% FBS, 100 units/ml P/S) to ensure DMSO concentration in each culture system. Both were 0.5%) After 24 hours, the medium was removed, and 90 μl (IMDM, 10% FBS, 100 units/ml P/S, 5 ng/ml VEGF) and ΙΟμΙ drug were added to each well, gently shaken and mixed, control group and blank. The group only contained ΙΟΟμΙ (IMDM, 10% FBS, P/S, 5ng/ml VEGF), and was placed in a 37°C, 5% CO ₂ incubator. After 72 hours, add ΙΟμΙ CCK-8 to each well, then add 37 Incubate for 4 hours at °C, 5% CO ₂ incubator, and absorb the absorbance at 450 nm.

The biochemical activity of the compounds of the present invention was determined by the above test, and the measured IC _5Q values are shown in Table 4 below.

Table 4 ICs for inhibiting the activity of EGFR mutant cells by the compounds of the present invention:

10 279 146

11 197 123

12 88

13 207

14 71

15 57

16 112 51

17 192 89

18 131 204

19 259 20

33 763 157

35 345 29

36 356 28

37 60 29

Inventive Example Compounds for NCI-H-1975, PC-9 GR Cell Proliferation

Claims

Claims:

1. A compound of the formula (I), a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable drug Use of a salt for the preparation of a medicament for treating cancer:

(I)

Its towel:

A is selected from a carbon atom or a nitrogen atom;

When A is a carbon atom, R ² is a cyano group;

When A is a nitrogen atom, R ² is unsubstituted;

r is 0, 1 or 2;

n is 0 or 1.

The use according to claim 1, wherein the cancer is a cancer resistant, preferably a cancer resistant to a reversible inhibitor of EGFR, particularly preferably gefitinib, erlotinib or pull Patinib is resistant to cancer.

3. Use according to claim 1 or 2, wherein the cancer is a solid tumor, preferably a head and neck Tumor, colorectal cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, oral cancer, liver cancer, glioblastoma, ovarian cancer or non-small cell lung cancer.

The use according to any one of claims 1 to 3, wherein the cancer is non-small cell lung cancer.

The use according to any one of claims 1 to 4, wherein the cancer carries an EGFR mutation.

6. The use according to claim 5, wherein the EGFR mutation comprises a deletion mutation EGFR del 746-750 on an ELREA sequence, a T790M point mutation in exon 20, an EGFR del 746-750/T790M double mutation or L858R/T790M double mutation.

The use according to any one of claims 1 to 4, wherein the cancer carries a HER2 mutation.

The use according to any one of claims 1 to 7, wherein R is pyridinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinolyl, preferably pyrrolidinyl; The base, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinolyl are optionally further substituted with one or more alkyl or oxo groups; or the pyrrolidinyl group is an N-oxide.

The use according to any one of claims 1 to ⁸ , wherein R ⁸ and R ⁹ together with the N atom to which they are bonded form a monospiroheterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group, The monospiroheterocyclyl, bicyclic fused heterocyclyl or bicyclic bridge heterocyclyl is optionally further substituted with one or more substituents selected from alkyl, alkoxy, hydroxy or hydroxyalkyl.

10. The use according to claim 9, wherein the monospiroheterocyclic group, the bicyclic fused heterocyclic group or

The use according to any one of claims 1 to 10, wherein the compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof Construct, diastereomer, and

66

12. A method of treating cancer which comprises administering to a subject in need thereof a therapeutically effective amount of a compound of the formula (I), a tautomer, a mesogen, a racemate, an enantiomer. , diastereomers, mixtures thereof, and pharmaceutically acceptable salts:

(I)

Wherein: 1^~1 ⁷ , R, A, n are as defined in claim 1.

13. The method according to claim 12, wherein the cancer is a cancer resistant, preferably a cancer resistant to a reversible inhibitor of EGFR, particularly preferably gefitinib, erlotinib or pull Patinib is resistant to cancer.

14. The method according to claim 12 or 13, wherein the cancer is a solid tumor, preferably a head and neck tumor, colorectal cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, oral cavity. Cancer, liver cancer, glioblastoma, ovarian cancer or non-small cell lung cancer, more preferably non-small cell lung cancer.

The method according to any one of claims 12 to 14, wherein said cancer carries EGFR Mutation, and / or carry a HER2 mutation.

16. The method according to claim 15, wherein said EGFR mutation comprises a deletion mutation EGFR del 746-750 on an ELREA sequence, a T790M point mutation in exon 20, an EGFR del 746-750/T790M double mutation or L858R/T790M double mutation.

17. A compound, tautomer, mesogen, racemate, enantiomer, form, and pharmaceutically acceptable salt of the formula (I) as a medicament for treating cancer :

(I)

Wherein: 1^~1 ⁷ , R, A, n are as defined in claim 1.

The compound of the formula (I), the tautomer, the mesogen, the racemate, the enantiomer, the diastereomer, and the a mixture form, and a pharmaceutically acceptable salt, wherein the cancer is a cancer resistant, preferably a cancer resistant to a reversible inhibitor of EGFR, particularly preferably gefitinib, erlotinib or rapa Titanic cancer resistant to cancer.

The compound of the formula (I), the tautomer, the mesogen, the racemate, the enantiomer, the diastereomer, or the like, according to claim 17 or 18. And a mixture thereof, and a pharmaceutically acceptable salt, wherein the cancer is a solid tumor, preferably a head and neck tumor, colorectal cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, gastric cancer, oral cancer , liver cancer, glioblastoma, ovarian cancer or non-small cell lung cancer, more preferably non-small cell lung cancer.

The compound of the formula (I), the tautomer, the mesogen, the racemate, the enantiomer, the diastereomer according to any one of claims 17 to 19 A construct, and mixtures thereof, and a pharmaceutically acceptable salt, wherein the cancer carries an EGFR mutation, and/or carries a HER2 mutation.

The compound of the formula (I), the tautomer, the mesogen, the racemate, the enantiomer, the diastereomer, and the a mixture form, and a pharmaceutically acceptable salt, wherein the EGFR mutation comprises a deletion mutation EGFR del 746-750 on an ELREA sequence, a T790M point mutation in exon 20, an EGFR del 746-750/T790M double mutation or L858R /T790M double mutation.

22. A compound of the formula (I), a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, a mixture thereof, and Medicinal salt:

(I)

Its towel:

A is selected from a carbon atom or a nitrogen atom;

When A is a carbon atom, R ² is a cyano group;

When A is a nitrogen atom, R ² is unsubstituted;

r is 0, 1 or 2;

n is 0 or 1.

23. A compound of the formula (I) according to claim 22, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and mixtures thereof a form, and a pharmaceutically acceptable salt, wherein R is pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinolyl, preferably pyrrolidinyl, more preferably chiral pyrrolidine tetrahydro; The pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morphinolyl group is optionally further substituted with one or more alkyl or oxo substituents; or the pyrrolidinyl group It is an N-oxide.

24. A compound of the formula (I), a tautomer, a mesogen, according to claim 22, a racemate, an enantiomer, a diastereomer, a mixture thereof, and a pharmaceutically acceptable salt, wherein R ⁸ and R ⁹ together with the N atom to which they are attached form a monospiroheterocyclyl group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group, said monospiroheterocyclic group, bicyclic fused heterocyclic group or bicyclic bridged heterocyclic group optionally further selected from one or more selected from the group consisting of a fluorenyl group, an alkoxy group, and a hydroxy group Substituted by a substituent of a hydroxyalkyl group.

25. A compound of the formula (I), a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and mixtures thereof according to claim 24. Form, and pharmaceutically acceptable salt, wherein

The compound of the formula (I) or the tautomer, racemate, enantiomer, diastereomer thereof, and the compound of the formula (I) according to any one of claims 22 to 25 In the form of a mixture, and a pharmaceutically acceptable salt,

27. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 22 to 26, or a tautomer, racemate, enantiomer, diastereomer thereof. Isomers, mixtures thereof, and pharmaceutically acceptable salts, and pharmaceutically acceptable carriers.

A method of preparing a pharmaceutical composition according to claim 27, which comprises the compound according to any one of claims 22 to 26, or a tautomer, racemate or enantiomer thereof. The complexes, diastereomers, mixtures thereof, and pharmaceutically acceptable salts are combined with a pharmaceutically acceptable carrier or diluent.