TW201336835A - Pharmaceutical use of 4-quinazolone amide derivatives - Google Patents

Abstract

The present invention relates to pharmaceutical use of 4-quinazolone amide derivatives. Specifically, the present invention relates to a use of 4-quinazolone amide derivatives of general formula (I) and pharmaceutical compositions containing same, in the preparation of a medicament for the treatment of cancer, wherein the said cancer is cancer with drug resistance, preferably drug resistant to reversible inhibitor of EGFR, more preferably drug resistant to Gefitinib, Erlotinib or Lapatinib; or wherein the said cancer carries EGFR mutation. And all substitutes of general formula (I) are defined as those in the specification.

Description

Application of 4-quinazolinamine derivatives in medicine

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, which is a cancer resistant, preferably resistant to a reversible inhibitor of EGFR The cancer is particularly preferably a cancer resistant to gefitinib, erlotinib or lapatinib, or the cancer carries an EGFR mutation.

Signal transduction, as a basic regulatory mechanism of cells, transmits extracellular signals to the interior of cells, allowing cells to respond to biological responses 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 proto-oncogene c-ErbB and is a transmembrane glycoprotein receptor type tyrosine kinase of about 170 kDa. It is a member of the ErbB protein family and is derived from the epidermal growth factor. Start up, 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 occurs two. Polymerization forms homologous or heterodimers. Subsequently, phosphorylation of the tyrosine residue on the dimerization receptor initiates the initiation of a downstream signaling pathway. 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 be through three mechanisms: overexpression of EGFR ligands, 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 dimer 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 kinase, 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 to EGFR T790M mutation and fail to achieve the desired therapeutic effect. .

The EGFR gene mutation is mainly concentrated in the Tyrosing kinase coding domain (18-21 exon). Gene mutations known to be involved in EGFR inhibitor activity are limited 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 mutations currently reported are mainly for the following two Species: 45% of them are missing from the exon 19 sequence, mainly the base deletion mutation of the 746-752 codon, resulting in the loss of the amino acid sequence in the EGFR protein, changing the angle of the receptor ATP binding pocket; % is a missense mutation of exon 21, mainly due to the conversion of the 851th codon, causing the amino acid of this site in the EGFR protein to be converted from leucine to arginine (L858R). In addition, the T790M mutation is a base pair change, and the conversion of threonine at the protein level to the 790 site of the kinase domain to methionine (T790M) leads to a change in the structure of EGFR, causing a 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 cause the structural activation of EGFR to exceed that of other pathways, so that the survival of tumor cells depends mainly on the EGFR signaling pathway.

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

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 undesirable 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.

The object of the present invention is to provide a compound of the formula (I) or a pharmaceutically acceptable salt thereof, and tautomers, meso-, racemates, enantiomers thereof, non-pairs thereof And the use thereof, and a pharmaceutically acceptable salt thereof, and the use of a metabolite and a metabolic precursor or prodrug for the preparation of a medicament for treating cancer, wherein the compound of the formula (I) has the following structure :

Wherein: 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; and when A is a carbon atom , R ² is a self-cyano group; when A is a nitrogen atom, R ² is unsubstituted; and 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 -O(CH ₂ )r-Ar; Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl are each independently optionally further substituted with one or more halogens, alkanes Substituted by a substituent of a trifluoromethyl group; R is selected from aryl, pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl or -NR ⁸ R ⁹ wherein the aryl group, Pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl optionally further substituted by one or more substituents selected from alkyl, halo, haloalkyl, pendant oxy, hydroxy or hydroxyalkyl Substituted; or the pyrrolidinyl group is an N-oxide; 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 bridge heterocyclyl, wherein the monospiro Ring base, double ring thick The cyclo or bicyclic bridge heterocyclic 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, and mixtures thereof The use of a form, and a pharmaceutically acceptable salt, for the manufacture of a medicament for treating cancer, wherein the cancer is a cancer resistant. The cancer resistant to cancer may be a drug resistant to a plurality of drugs, preferably a cancer resistant to a reversible inhibitor of EGFR, particularly preferably gefitinib, erlotinib or lapatinib. Cancer resistant.

A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof The use of a 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, a 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, an 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, and mixtures thereof Use of a form, and a pharmaceutically acceptable salt, for the manufacture of a medicament for the treatment of cancer, wherein R is selected from the group consisting of pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, preferably Is pyrrolidinyl, more preferably chiral pyrrolidine tetrahydro; the pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholyl group is optionally further substituted by one or more alkyl groups or Substituted by an oxy group; 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, and mixtures thereof The use of a form, and a pharmaceutically acceptable salt, for 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, and mixtures thereof The use of a form, and a pharmaceutically acceptable salt, for the preparation of a medicament for the treatment of 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 a fluorine or a chlorine. .

A preferred embodiment of the invention, a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof The use of a form, and a pharmaceutically acceptable salt, for the manufacture 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, and mixtures thereof Use of a form, and a pharmaceutically acceptable salt, in the manufacture of a medicament for the treatment of cancer, 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 bridged heterocyclyl, Wherein 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 groups, wherein the single A spiroheterocyclyl, a bicyclic fused heterocyclyl or a bicyclic bridged heterocyclic group is selected from the group consisting of

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

Another aspect of the invention provides a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, and mixtures thereof Form, and pharmaceutically acceptable salts:

Wherein: 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; and when A is a carbon atom , R ² is a self-cyano group; when A is a nitrogen atom, R ² is unsubstituted; and 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 -O(CH ₂ )r-Ar; Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl are each independently optionally further substituted with one or more halogens, alkanes Substituted by a substituent of a trifluoromethyl group; R is selected from aryl, pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl or -NR ⁸ R ⁹ wherein the aryl group, Pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl optionally further substituted by one or more substituents selected from alkyl, halo, haloalkyl, pendant oxy, hydroxy or hydroxyalkyl Substituted; or the pyrrolidinyl group is an N-oxide; 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 bridge heterocyclyl, wherein the monospiro Ring base, double ring thick The cyclo or bicyclic bridge heterocyclic 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), a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and a mixture thereof And a pharmaceutically acceptable salt, wherein R is pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl, preferably pyrrolidinyl, more preferably chiral pyrrolidine tetrahydro The pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl group is optionally further substituted with one or more alkyl or pendant oxy substituents; or the pyrrolidinyl group is 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, and mixtures thereof Form, and pharmaceutically acceptable salts, 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, and mixtures thereof Form, and pharmaceutically acceptable salts, wherein R ³ , R ⁶ and R ^{7 are} preferably a hydrogen atom; R ⁴ and R ^{5 are} preferably 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, and mixtures thereof Form, and pharmaceutically acceptable salts, wherein Ar is preferably pyridyl.

A preferred embodiment of the invention, a compound of the formula (I), a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and 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 monospiroheterocyclic group, a bicyclic fused heterocyclic group or a bicyclic bridged heterocyclic group, which is monospirocyclic and bicyclic The cyclo or bicyclic bridge heterocyclyl is optionally further substituted with 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, and mixtures thereof a form, and a pharmaceutically acceptable salt, wherein the monospiroheterocyclyl, bicyclic fused heterocyclyl or bicyclic bridged heterocyclyl is selected from the group consisting of

The compounds of the general formula (I) or their tautomers, meso, racemate, enantiomers, diastereomers, and mixtures thereof include, but are not limited to: Or a tautomer, a meso form, a racemate, an enantiomer, a diastereomer, and mixtures thereof, 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 And 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, a diastereomer thereof, and The mixture, and the pharmaceutically acceptable salt, are combined 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, which is selected from the group consisting of head and neck cancer, colon cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, stomach cancer, ovarian cancer or non-small cells. Lung cancer, preferably colon cancer, breast cancer or non-small cell lung cancer, more preferably non-small cell lung cancer. The cancer cell of the cancer is mutated in EGFR, and/or is mutated in HER-2; the EGFR mutation includes a L858R point mutation and a deletion/insertion mutation in the ELREA sequence, a T790M point mutation in exon 20, or L858R/T790 double mutation; the HER-2 mutation is M774_A775insAYVM.

Cancer cells initiated by EGFR mutations, such as mutations, occur in the EGF receptor region of tyrosine kinase, which may be sensitive to the treatment of EGFR inhibitors. Similarly, cancer cells initiated by HER-2 mutations, such as M774_A775insAYVM, may It is sensitive to the treatment of HER-2 inhibitors. Cancer cells that are mutated by mutations such as EGFR and HER-2 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. ( Science 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 cause 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 develop resistance to imatinib.

Non-reversible tyrosine kinase inhibitors such as HKI-272, which are capable of inhibiting the proliferation of double-mutated EGFR receptors on the cell line and EGF-induced, compared to reversible tyrosine kinase inhibitors such as gefitinib EGFR phosphorylation ( 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 the compound of formula (I) or a pharmaceutically acceptable salt thereof. It exhibits outstanding efficacy and fewer side effects in the treatment of cancer, which is selected from the group consisting of head and neck cancer, colon cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, stomach cancer, ovarian cancer or non-small cells. Lung cancer, preferably colon cancer, breast cancer or non-small cell lung cancer, more preferably non-small cell lung cancer. The cancer cell of the cancer is mutated in EGFR, and/or is mutated in HER-2; the EGFR mutation includes a L858R point mutation and a deletion/insertion mutation in the ELREA sequence, a T790M point mutation in exon 20, 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, water or oil 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 pharmaceutical compositions, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring, coloring, and preservatives to provide a pleasing And delicious pharmaceutical preparations. Tablet containing active ingredient and suitable preparation tablets for mixing A non-toxic pharmaceutically acceptable excipient. 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 a known technique which provides a sustained release effect over a longer period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract. For example, water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, 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 in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil. Soft gelatin capsules 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 acacia; dispersing or wetting agents may 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 heptadecanoethyloxy 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 sorbitol 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 a plurality of flavoring agents and one or more sweeteners 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 oily 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 sweetening, flavoring, and coloring agents may also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.

The pharmaceutical composition of the present 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 can 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 oily 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. Can be injected by local injection The liquid or microemulsion is injected into the bloodstream of the patient. Alternatively, the solution and microemulsion are preferably administered in a manner that maintains a constant loop 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 can 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 injectable solution or suspension, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent. In addition, sterile fixed oils may conveniently be employed as a solvent or suspension 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 mixtures of cocoa butter, glycerin gelatin, hydrogenated vegetable oils, 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 activity of the particular compound employed, the age of the patient, the weight of the patient, the health of the patient, the conduct of the patient, the patient 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 amount of the compound of formula (I) or the type of pharmaceutically acceptable salt may be Validated according to traditional treatment protocols.

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, t-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-di Methylpentyl, 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 -ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-decyl, 2-methyl-2-ethylhexyl, 2-methyl-3 -ethylhexyl , 2,2-diethyl-pentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl group, and various branched chain isomers thereof. More preferred are lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, Second butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methyl Butyl, 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-ethyl Butyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 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, alkynyl, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, A cycloalkoxy group, a heterocycloalkoxy group, a cycloalkylthio group, a heterocycloalkylthio group, a pendant oxy 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 3 Up to 10 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene A polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.

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 are 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 ring and the ring. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members or 5 members/6 members of the monospirocycloalkyl group. Non-limiting examples of spirocycloalkyl groups include: The term "fused cycloalkyl" refers to 5 to 20 members, each ring of the system sharing 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. The bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl group may be classified according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 5 member/5 member or 5 member/6 member bicycloalkyl group. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of which has a complete Conjugate 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 bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, 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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamine, halogen, Mercaptan, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, side An oxy 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 ring atoms are selected from nitrogen, oxygen or S(O). A hetero atom of _m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains from 3 to 12 ring atoms, of which from 1 to 4 are heteroatoms; more preferably the cycloalkyl ring contains from 3 to 10 ring atoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, morphinolinyl, homopiperazinyl and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups; preferred bicyclic heterocyclic groups, non-limiting examples include monospiroheterocyclyl, bicyclic fused heterocyclyl or specific cyclic heterocyclic .

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 (O). ) _m (where m is an integer 0 to 2) heteroatoms, 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 monospiroheterocyclyl group, a dispiroheterocyclic group or a polyspiroheterocyclic group, preferably a monospiroheterocyclic group and a dispiroheterocyclic group, depending on the number of common spiro atoms between the ring and the ring. . More preferably, it is 4 members/4 members, 4 members/5 members, 4 members/6 members, 5 members/5 members, or 5 members/6 members of a single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl groups include:

The term "fused heterocyclyl" refers to 5 to 20 members, each ring of the system sharing 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(O) _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. It may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic group according to the number of constituent rings, preferably a bicyclic or tricyclic ring, more preferably a 5 member/5 member or a 5 member/6 member bicyclic fused heterocyclic ring. base. Non-limiting examples of fused heterocyclic groups include:

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 A π-electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _m (where m is an integer from 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. Non-limiting examples of bridge heterocyclic groups include:

The heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, 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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring An alkylthio group, a heterocycloalkylthio group, a pendant oxy 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 (i.e., a ring that shares a pair of adjacent carbon atoms) having a conjugated π-electron system, preferably from 6 to 10 members, for example, Phenyl 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, alkynyl, alkoxy, alkylthio. , alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

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 from 5 to 10 members, more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl. , tetrazolyl and the like. The heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include: 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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring An alkylthio group, a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "alkoxy" refers to -O-(alkyl) and -O-(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 alkyl, alkenyl, alkynyl, alkoxy, Alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, ring An alkylthio group, a heterocycloalkylthio group, a carboxyl group or a carboxylate group.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl 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+-O- (also referred to as R ₃ N=O or R ₃ N→O) Here, R is a substituent on the N atom; in the present invention, 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 -NO ₂ .

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

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

The term "carboxylate group" refers to -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, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group. .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted 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 amine group or a 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 comprising 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, and to facilitate the absorption of the active ingredient to exert biological activity.

"Pharmaceutically acceptable salt" refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses 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:

Synthetic Route 1: The preparation method of the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:

The compound of the formula (IA) is reacted with RH or a salt thereof with sodium iodide or potassium iodide in a solvent under basic conditions to give a compound of the formula (I); and a reagent for providing basic conditions includes an organic base and an inorganic base. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, potassium butoxide, and the 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; and A, n, R ¹ to R ⁷ are as defined in the general formula (I).

Synthetic Route 2: A method for preparing the compound of the formula (I) or a salt thereof according to the present invention, comprising the steps of:

The phosphate compound of the formula (IB) is reacted with an aldehyde RCHO under lithium hexamethyldidecylamine in an acetone bath to give a compound of the formula (I); wherein R is selected from pyrrolidinyl, pyridyl, tetrahydrogen A pyranyl, piperidinyl or morpholinyl group, A, R ¹ to R ⁷ are as defined in the formula (I), and 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. The solvent was deuterated dimethyl hydrazine ( DMSO-d6 ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was tetramethyl. For decane (TMS), the chemical shift is given in units of 10 ^-6 (ppm).

The measurement of the MS was carried out using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

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

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The thin layer chromatography tantalum sheet uses Yantai Yellow Sea HSGF254 or Qingdao GF254 tannin sheet, and the thin layer chromatography (TLC) used for the tannin sheet is 0.15 mm to 0.2 mm. The specification for thin layer chromatography separation and purification is 0.4. Mm to 0.5 mm silicone board.

Pipe column chromatography generally uses Yantai Yellow Sea 200~300 mesh silicone as 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, Accela ChemBio Inc, Companies such as Dare Chemicals.

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

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 the operation is repeated 3 times.

The microwave reaction used 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 The ether and ethyl acetate systems, 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 the developer of the thin layer chromatography using the purified compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane and Acetone system, D: n-hexane, 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

( E ) -N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((3a R , 5 r , 6a) S )-5-hydroxyhexahydrocyclopenta[ c ]pyrrole-2(1 H )-yl)-2-butenylamine

first step

( E )-4-bromo-2-butenoic acid

Under ice bath, methyl ( E )-4-bromo-2-butenoate 1a (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 completion, the reaction solution was stirred for 3 hours. The reaction solution was extracted with 50 mL ethyl acetate, the aqueous phase was adjusted with 6 M HCl pH <1 and extracted with dichloromethane (100 mL × 2), the combined organic phases, the organic phase was concentrated under reduced pressure to give the title product (E) - 4-bromo-2-butenoic acid 1b (5.93 g, yellow oil), yield: 64.3%.

Second step

7-fluoroquinazoline-4(3 H )-one

2-Amino-4-fluorobenzoic acid 1c (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, and the temperature was raised to 120 ° C, and the reaction was stirred. 22 hours. The reaction solution was concentrated under reduced pressure, the residue was slurried with 50 mL of water, filtered, the filter cake was rinsed with a small amount of ethanol, and drying, to give the title product 7-fluoro-quinazolin -4 (3 H) - -one 1d (8.42 g, Gray Powder solid), yield: 80%.

MS m/z (ESI): 165.1 [M+1]

third step

7-fluoro-6-nitroquinazolin-4(3 H )-one

Under ice bath, stir 20 mL concentrated sulfuric acid and 20 mL concentrated nitric acid, and slowly add 7-fluoroquinazoline-4( 3H )-one 1d (8.42 g, 0.051 mol) and mix well. The ice bath was removed, stirred at room temperature for 1 hour, warmed 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, beaten with 50 mL of methanol for 30 minutes, filtered, and the filter cake was dried to obtain a title. Product 7-Fluoro-6-nitroquinazolin-4( 3H )-one 1e (7.60 g, yellow solid), yield: 51.1%.

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

the fourth step

4-chloro-7-fluoro-6-nitroquinazoline

7-Fluoro-6-nitroquinazolin-4(3 H )-one 1e (7.60 g, 0.036 mol), 65 mL of hydrazine chloride, 200 mL of phosphorus oxychloride and 0.5 mL of DMF were mixed and stirred. The mixture was heated, stirred at 100 ° C for 2 hours, and stirred at 50 ° C for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjj %.

the fifth step

N- (3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine

4-Chloro-7-fluoro-6-nitroquinazoline 1f (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 solution was concentrated under reduced pressure, was added 30 mL of dichloromethane, filtered and the filtrate was concentrated under reduced pressure to give the title product N - (3- chloro-4-fluorophenyl) -7-fluoro-6-nitro-quinazolin-4 - 1 g of amine (10.50 g, yellow solid), yield: 100%.

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

Step 6

N- (3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine

Add 1 g (1.30 g, 3.86 mmol) of N- (3-chloro-4-fluorophenyl)-7-fluoro-6-nitroquinazolin-4-amine to 15 mL of methanol, stir to dissolve, add 0.5 Aqueous sodium hydroxide (0.19 g, 4.63 mmol) was added, stirred well, warmed to 70 ° C, and stirred for 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 obtain the title product N- (3-chloro-4-fluorophenyl)-7-methoxy- 6-Nitroquinazolin-4-amine 1 h (1.50 g, yellow solid), mp.

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

Seventh step

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

The starting material N- (3-chloro-4-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine 1 h (1.50 g, 4.30 mmol) was added to 30 mL of tetrahydrofuran and stirred to dissolve. Raney nickel (1 g) was added, the hydrogen was replaced three times, and the reaction was stirred for 3 hours. The reaction was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure to give the title product N ⁴ - (3- chloro-4-fluorophenyl) -7-methoxy-quinazolin-4,6-diamine 1i (1 g , brown solid), total yield: 73%.

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

Eighth step

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

( E )-4-Bromo-2-butenoic acid 1b (8.5 g, 51.50 mmol) was dissolved in 100 mL of dichloromethane, cooled to 0 ° C in an ice bath, and re-steamed of saponin (8.77 mL) 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-butene chloride in tetrahydrofuran. Dissolving N ⁴ -(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4,6-diamine 1i (1 g, 3.14 mmol) and 2.5 mL of triethylamine in 50 mL of tetrahydrofuran The mixture was cooled to 0 ° C in an ice-bath, and a solution of (E) -4-chloro-2-butene chloride in tetrahydrofuran was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give the title product (E) -4- chloro - N - (4 - (( 3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) 2-butenylamine 1j (2.4 g, brown solid) was used directly in the next step.

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

Step 9

(3a R , 6a S )-5-hydroxy-hexahydro-cyclopenta[ c ]pyrrole-2-carboxylic acid tert-butyl ester

(3a R , 6a S )-5-Phenoxy-hexahydro-cyclopenta[ c ]pyrrole-2-carboxylic acid tert-butyl ester 1k (500 mg, 2.22 mmol, prepared according to the existing document WO2008089636) Dissolved in 100 mL of methanol, cooled to 0 ° C in an ice bath, slowly added sodium borohydride (168 mg, 4.44 mmol), and stirred for 30 min. 1 mL of water was added, and the reaction mixture was evaporated. EtOAcj~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ The crude product (3a R , 6a S )-5-hydroxy-hexahydro-cyclopenta[ c ]pyrrole-2-carboxylic acid tert-butyl ester 1 l (441 mg, light brown oil) was obtained without isolation Go directly to the next step.

Step 10

(3a R , 6a S )-octahydro-cyclopenta[ c ]pyrrole-5-ol hydrochloride

The crude (3a R , 6a S )-5-hydroxy-hexahydro-cyclopenta[ c ]pyrrole-2-carboxylic acid tert-butyl ester 1 l (441 mg, 1.94 mmol) was dissolved in 5 mL of 2M hydrogen chloride. The reaction was stirred for 12 hours in a 4-dioxane solution. The reaction solution was concentrated under reduced pressure, to give (3a R, 6a S) - octahydro - cyclopenta [c] pyrrole-5-ol hydrochloride 1m (318 mg, yellow solid), yield: 100%.

The eleventh step

( E ) -N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-((3a R , 5 r , 6a) S )-5-hydroxyhexahydrocyclopenta[ c ]pyrrole-2(1 H )-yl)-2-butenylamine

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenylamine 1j (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 To the amine, (3a R , 6a S )-octahydro-cyclopenta[ c ]pyrrol-5-ol hydrochloride 1 m (500 mg, 2.20 mmol) was added, and the mixture was stirred for 12 hours. The reaction mixture was poured into 50 mL of ice water, EtOAc (EtOAc) A thin layer chromatography and the obtained residue was purified by developing solvent system, to give the title product (E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazoline Phenyl-6-yl)-4-((3a R ,5 r ,6a S )-5-hydroxyhexahydrocyclopenta[ c ]pyrrole-2(1 H )-yl)-2-butenoxime 1 (3 mg, yellow solid), yield: 1.6%.

MS m/z (ESI): 512.4 [M+1]

¹ H NMR (400 MHz, DMSO- d 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

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (2-oxa-aza Heterospiro[4.5]decane-8-yl)-2-butenylamine

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenylamine 1j (150 mg, 0.36 mmol), 2-oxa-8-azaspiro[4.5]decane hydrochloride 2a (100 mg, 0.71 mmol, using a 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, stirred Reaction for 12 hours. The reaction solution was poured into 10 mL of ice water and extracted with ethyl acetate (15 mL×3). The resulting residue was obtained (E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (2-oxo Hetero-8-azaspiro[4.5]decane-8-yl)-2-butenoxime 2 (17 mg, yellow solid), yield: 10.0%.

MS m/z (ESI): 526.2 [M+1]

¹ H NMR (400 MHz, DMSO- d 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

( E ) -N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-4-(3-hydroxy-8-aza Bicyclo[3.2.1]octane-8-yl)-2-butenylamine

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenylamine 1j (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, purified by thin layer chromatography in a developing solvent system A resulting residue was obtained (E) - N - (4 -) ((3- chloro-4-fluorophenyl) 7-amine Oxyquinazolin-6-yl)-4-(3-hydroxy-8-azabicyclo[3.2.1]octane-8-yl)-2-butenoxime 3 (20 mg, pale yellow solid ), yield: 16.6%.

MS m/z (ESI): 512.4 [M+1]

¹ H NMR (400 MHz, DMSO- d 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

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (4-methyl-hexahydro-pyrrolo [3,4-b][1,4] Pyrazine-6(2 H )-yl)-2-butenylamine

first step

3-bromo-4-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

N- Boc-3-pyrroline 4a (100 g, 0.59 mol) was dissolved in 300 mL of ethylene glycol, and bromobutaneimine (108.0 g, 0.61 mol) was added in portions, about 10.0 g per batch. The addition was completed in about 2 hours and stirred for 16 hours. After adding 500 mL of water and extracting with ethyl acetate (300 mL × 3), the organic phase was combined, washed with a saturated sodium chloride solution (300 mL × 1), dried over anhydrous sodium sulfate, filtered, 4-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester 4b (178.0 g, pale yellow oily liquid), yield: 97%.

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

Second step

3-bromo-4-(2-p-toluenesulfonyloxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester

3-Bromo-4-(2-hydroxyethoxy)pyrrolidine-1-carboxylic acid tert-butyl ester 4b (178.0 g, 574 mmol), triethylamine (96 mL, 690 mmol) and 4-dimethyl Add the amino-aminopyridine (2.0 g, 16 mmol) to 600 mL of toluene, ice-cooled to 0 °C, and slowly add 200 mL of 4-toluenesulfonium chloride (131.5 g, 58 mmol) in toluene solution for about 1 hour. After the addition was completed, the ice bath was removed and naturally raised 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), and 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) : 90%.

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

third step

Hexahydro-4-benzyl-pyrrolo[3,4-b]-1,4- Pyridin-6( 2H )-carboxylic acid tert-butyl ester

3-Bromo-4-(2-p-toluenesulfonyloxyethoxy)pyrrolidine-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, and a large amount of a white solid was formed, which was heated under reflux for 7 hours, and the reaction mixture was pale yellow turbid. The reaction solution was cooled to room temperature, filtered, and the filter cake was washed with ethyl acetate (500 mL). The filtrate was washed with saturated sodium bicarbonate (600 mL) and saturated sodium chloride solution (600 mL) and filtered. Concentrated by pressure. The residue was dissolved in 316 mL of methanol, cooled to 0 ° C, 6.9 M hydrogen chloride in dioxane solution (170 mL) was added dropwise, and a white solid was precipitated. The mixture was stirred at 0 ° C, stirred for 1.5 hours, and filtered to give the title product. Hexahydro-4-benzyl-pyrrolo[3,4-b]-1,4- Pyridin-6( 2H )-carboxylic acid tert-butyl ester 4d (134 g, white solid), yield 50%.

MS m/z (ESI): 319.2 [M+1]

the fourth step

Hexahydropyrrolo[3,4-b][1,4] Pyridin-6( 2H )-carboxylic acid tert-butyl ester

Hexahydro-4-benzyl-pyrrolo[3,4-b]-1,4- Pyridyl-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 solution was filtered, and the filtrate was concentrated to give the title product hexahydropyrrolo[3,4-b][1,4] Pyridin-6( 2H )-carboxylic acid tert-butyl ester 4e (30 g, colorless oil) was used directly in the next step.

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

the fifth step

4-methylhexahydropyrrolo[3,4-b][1,4] Pyridin-6( 2H )-carboxylic acid tert-butyl ester

Hexahydropyrrolo[3,4-b][1,4] Pyridyl-6( 2H )-carboxylic acid tert-butyl ester 4e (1.8 g, 7.80 mmol) was dissolved in 60 mL of 1,2-dichloroethane, and 38% formaldehyde solution (1.0 g, 11.80 mmol) was added. After the addition was completed, the reaction was stirred for 1 hour, and ice-cooled to 0 ° C, and sodium triacetoxyborohydride (5.0 g, 23.60 mmol) was added portionwise, and a large amount of air bubbles were added, and 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 pH of the reaction mixture was 9 and dichloromethane (100 mL×3) was extracted. The organic phase was combined and washed with saturated sodium chloride solution (100 mL×1) Drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to give the title product 4-methylhexahydropyrrolo[3,4-b][1,4] Pyridin-6( 2H )-carboxylic acid tert- butyl ester 4f (2.0 g, colorless oil) was used directly in the next step.

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

Step 6

4-methyloctahydropyrrolo[3,4-b][1,4] Oxazine

4-methylhexahydropyrrolo[3,4-b][1,4] Pyridyl-6( 2H )-carboxylic acid tert- butyl ester 4f (2.0 g, 8.26 mmol) was dissolved in 2M MeOH MeOH (30 mL). The reaction mixture was concentrated under reduced pressure to give the title product 4-methyl succinol[3,4-b][1,4] 4 g (1.0 g, colorless oil), yield: 85%.

MS m/z (ESI): 143.1 [M+1]

Seventh step

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (4-methyl-hexahydro-pyrrolo [3,4-b][1,4] Pyrazine-6(2 H )-yl)-2-butenylamine

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenylamine 1j (150mg, 0.36 mmol), 4-methyloctahydropyrrolo[3,4-b][1,4] 4 g (202 mg, 1.43 mmol), sodium iodide (53.4 mg, 0.36 mmol) and N,N-diisopropylethylamine (100 mg, 0.70 mmol) were added to 2 mL of N,N-dimethyl The reaction was stirred for 12 hours in the guanamine. To the reaction mixture, 20 mL of ice water was added, and the mixture was combined with ethyl acetate (30 mL × 3). A thin layer chromatography and the obtained residue was purified by developing solvent system, to give the title product (E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazoline Phenyl-6-yl)-4-(4-methylhexahydropyrrolo[3,4-b][1,4] Pyrazin-6( 2H )-yl)-2-butenylamine 4 (6.7 mg, light brown solid), yield: 3.5%.

MS m/z (ESI): 527.4 [M+1]

¹ H NMR (400 MHz, DMSO- d 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 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (8-hydroxy-2-aza Spiro[4.5]decane-2-yl)-2-butenylamine

first step

Ethyl 1,4-dioxospiro[4.5]decane-8-carboxylate

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) were dissolved in 70 mL The reaction was stirred for 16 hours in toluene. The reaction solution was concentrated under reduced pressure. EtOAc (EtOAc m.) dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1,4-spiro [4.5] decane-8-carboxylic acid ethyl ester 5b (25 g, colorless oil) is used directly in the next step reaction.

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

Second step

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

Ethyl 4-oxocyclohexanecarboxylate 5b (10 g, 0.047 mol) was dissolved in 55 mL of tetrahydrofuran, cooled to -78 ° C with dry ice-acetone bath, and lithium hexamethyldidecylamine was added dropwise. (1 M, 57 mL), the reaction was stirred for 1 hour, 3-bromopropene (4.9 mL, 56.20 mmol) was added dropwise, and the reaction was stirred at room temperature for 16 hours. The reaction was quenched with a protective ammonium chloride solution, and the reaction mixture was concentrated under reduced pressure, and ethyl acetate (400 mL), and then water (100 mL), saturated ammonium chloride (100 mL) and saturated sodium chloride mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 8-allyl-1,4-dioxaspiro [4.5] decane-8-carboxylic acid ethyl ester 5c (11.5 g, colorless Oil), used directly in the next step.

third step

Ethyl 8-(2-oxoethyl)-1,4-dioxospiro[4.5]decane-8-carboxylate

Ethyl 8-allyl-1,4-dioxospiro[4.5]decane-8-carboxylate 5c (11.5 g, 45.27 mmol) was dissolved in 300 mL dichloromethane and cooled with a dry ice-acetone bath. At -78 ° C, the ozone was replaced three times, the reaction was stirred for 5 to 6 hours, the air was replaced three times, the reaction was stirred for 1 hour, triphenylphosphine (15.4 g, 58.71 mmol) was added, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure and purified tolululululululululululululululululululululululululu Ethyl ester 5d (9.1 g, yellow oil), yield: 78%.

the fourth step

10-benzyl-1,4-dioxo-10-aza-bispiro[4.2.4.2]tetradecane-11-one

Ethyl 8-(2-oxoethyl)-1,4-dioxospiro[4.5]decane-8-carboxylate 5d (9.1 g, 35.55 mmol) was dissolved in 90 mL of 1,2-dichloroethyl In the alkane, benzylamine (4.7 mL, 42.62 mmol), 2 mL of acetic acid and sodium triacetoxyborohydride (22.6 g, 106.60 mmol) were added, and the mixture was stirred at room temperature for 16 hours. The reaction was quenched with water. EtOAc (EtOAc) (EtOAc) The resulting residue was purified by EtOAc EtOAc (EtOAc) 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]tetradecane-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 to pH 7 of the reaction mixture, and concentrated under reduced pressure. EtOAc (EtOAc) dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product, 2-benzyl-2-aza-spiro [4.5] decane-3,8-dione 5f (4.2g, yellow oil), yield : 98%.

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

Step 6

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

Dissolve 2-benzyl-2-azaspiro[4.5]decane-3,8-dione 5f (1 g, 3.89 mmol) in 15 mL of tetrahydrofuran, cool in ice bath, slowly add 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 and evaporated. Alkan-8-alcohol 5 g (0.5 g, yellow oil), yield: 53%.

Seventh step

2-azaspiro[4.5]decane-8-ol

Dissolve 2-benzyl-2-azaspiro[4.5]nonane-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 at ° C for 16 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure to give the title product as 2-aza-spiro [4.5] decan-8-ol 5h (0.28 g, yellow oil). Yield: 87.5%.

Eighth step

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (8-hydroxy-2-aza Spiro[4.5]decane-2-yl)-2-butenylamine

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenylamine 1j (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 Ethylethylamine (370 mg, 2.84 mmol) was added to 15 mL of N,N-dimethylformamide and the reaction was stirred for 16 hours. 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 with water (30 mL×1) and brine (30 mL×2) , filtered, and the filtrate was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxyquinazolin-6-yl)-4-(8-hydroxy-2-azaspiro[4.5]decane-2-yl)-2-butenoxime 5 (25 mg, yellow Solid), yield: 5.6%.

MS m/z (ESI): 540.2 [M+1]

¹ H NMR (400 MHz, DMSO- d 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 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (2-oxa-7 nitrogen Heterospiro[4.5]decane-7-yl)-2-butenylamine

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-2-butenylamine 1j (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 mmol) 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, filtered, and the filtrate was concentrated under reduced pressure. , to give the title product (E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -4- (2-oxo Hetero-7-azaspiro[4.5]decane-7-yl)-2-butenoxime 6 (2 mg, light brown solid), yield: 1%.

MS m/z (ESI): 526.4 [M+1]

¹ H NMR (400 MHz, DMSO- d 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 = 8 Hz, 1H), 6.30 (t, J = 16 Hz, 1H), 7.01 - 7.13 (m, 1H), 4.08 (s, 3H), 3.90 ( t, J = 4 Hz, 3H), 3.61 (s, 2H), 3.35 (d, J = 8 Hz, 2H), 2.51-2.71 (m, 4H), 1.72-1.86 (m, 4H), 1.30-1.40 (m , 2H).

Example 7

( S,E )- N -(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidine -2-yl) acrylamide

first step

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

N,N'-carbonyldiimidazole (3 g, 18.80 mmol) was added to 30 mL of tetrahydrofuran, the temperature was raised to 40 ° C, the reaction was stirred for 1 hour, and diethylphosphoric acid (3.69 g, 18.80 mmol) was added dropwise. The reaction was stirred for 1 hour and used. Dissolve N ⁴ -(3-chloro-4-fluorophenyl)-7-methoxyquinazolin-4,6-diamine 1i (2 g, 6.28 mmol) in 20 mL of tetrahydrofuran, stir to dissolve, warm up The above reaction mixture was added dropwise to 40 ° C, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc m. -((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

( S,E )- N -(4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidine -2-yl) acrylamide

(2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl 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 hexamethyldidecylamine lithium (1 M, 0.4 mL) was added dropwise. Reaction for 1 hour. ( S )-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 liquid naturally rose. Stir for 16 hours to room temperature. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (S, E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-Methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenylamine 7 (30 mg, yellow solid), yield: 16%.

MS m/z (ESI): 456.2 [M+1]

¹ H NMR (400 MHz, DMSO- d 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 = 8 Hz, 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), 1.7-1.28 (m, 2H).

Example 8

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -3-cyano-7-methoxy-quinazolin-6-yl) -4- (2-oxo Hetero-8-azaspiro[4.5]decane-8-yl)-2-butenylamine

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, sodium methoxide (13.5 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, and add N,N-diisopropylethylamine (65 mL, 0.37) Mol), after the addition, the reaction was stirred for 3 hours for use. 2,4-Dimethoxy-5-nitrobenzoic acid 8b (10.4 g, 0.046 mol) was dissolved in 100 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (8.9 g, 0.055 mol) was added. After stirring for 20 minutes, the temperature was raised to 60 ° C, and the reaction was stirred for 2 hours. The reaction solution was naturally cooled to room temperature, and slowly added to the above-mentioned standby 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 with 4 M hydrochloric acid dropwise, and stirred for 15 minutes, and saturated sodium hydrogencarbonate solution was added thereto to adjust the pH to 7. Up to 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-carbonylprop. Nitrile 8c (8 g, yellow solid), yield: 70%.

MS m/z (ESI): 251.1 [M+1]

third step

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

3-(2,4-Dimethoxy-5-nitrophenyl)-3-carbonylpropanenitrile 8c (8 g, 0.032 mol) was dissolved in 100 mL of N,N-dimethylformamide N,N-dimethylformamide dimethyl acetal (7.9 g, 0.064 mol) was added dropwise, stirred for 30 minutes, ammonia was replaced 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, and slowly added phosphorus oxychloride (5.6 mL, 45 mmol). After the addition, the ice bath was removed, heated to 100 ° C, and the reaction was 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-nitroquinoline-3-carbonitrile. 8e (4.74 g, yellow solid), yield: 80.3%.

the fifth step

4-((3-chloro-4-fluorophenyl)amino)-7-methoxy-6-nitroquinoline-3-carbonitrile

Dissolve 4-chloro-7-methoxy-6-nitroquinoline-3-carbonitrile 8e (4.74 g, 18 mmol) and 3-chloro-4-fluoroaniline in 60 mL isopropanol and warm to 90 The reaction was stirred for 3 hours at °C. The reaction solution was cooled to room temperature, then concentrated, evaporated, evaporated, evaporated, evaporated. 50 mL), dried over anhydrous sodium sulfate, filtered and evaporated. 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-((3-Chloro-4-fluorophenyl)amino)-7-methoxy-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 a mixed solvent of 120 mL of methanol and water (V/V = 1:1), replaced with hydrogen 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). dried, filtered, and the filtrate was concentrated under reduced pressure to give the title product 6-amino-4 - ((3-chloro-4-fluorophenyl) amino) -7-methoxy-quinoline-3-carbonitrile 8g (4.3 g, Yellow solid), Yield: 68%.

Seventh step

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-2-butene Enamine

( E )-4-Bromo-2-butenoic acid 1b (1 g, 6 mmol) was dissolved in 20 mL of dichloromethane, cooled to 0 ° C in ice-bath, and re-steamed After stirring at 0 ° C for 2 hours, 9 mmol) and 0.05 mL of N,N-dimethylformamide were stirred at room temperature and stirring was continued for 1 hour. The reaction solution was concentrated under reduced pressure, and then 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 The mixture was cooled to 0 ° C in 10 mL of dichloromethane, and then a mixture of methylene chloride (E) -4-chloro-2-butene chloride was added dropwise, and the mixture was stirred at room temperature for 4 hours. The reaction was concentrated under reduced pressure to give the title product (E) -4- chloro - N - (4 - (( 3- chloro-4-fluorophenyl) amino) -3-cyano-7-methoxy-quinoline - 6-yl)-2-butenylamine 8h (2 g, black solid) was used directly in the next step.

Eighth step

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -3-cyano-7-methoxy-quinazolin-6-yl) -4- (2-oxo Hetero-8-azaspiro[4.5]decane-8-yl)-2-butenylamine

( E )-4-Chloro- N- (4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-2- Butenoin 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) 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, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -3 -Cyano-7-methoxyquinazolin-6-yl)-4-(2-oxa-8-azaspiro[4.5]decane-8-yl)-2-butenylamine 8 ( 25 mg, gray solid), yield: 20.3%.

MS m/z (ESI): 550.4 [M+1]

¹ H NMR (400 MHz, DMSO- d 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

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -3- (4-methylmorpholine -3 -yl) acrylamide

first step

4-methylmorpholine-3-carbaldehyde

Dimethyl hydrazine (0.65 mL, 9.16 mmol) was dissolved in 15 mL of dichloromethane at -78 ° C, and chloroform (0.58 mL, 6.87 mmol) was added dropwise, and the reaction was stirred for 1 hour. 10 mL (4-methylmorpholin-3-yl)methanol 9a (600 mg, 4.58 mmol, prepared according to the existing literature WO2009072658) in dichloromethane, added, stirred for 1 hour, added triethylamine ( 1.9 mL, 13.70 mmol), the reaction was stirred for 15 minutes, warmed to 0 ° C and stirring was continued for 1 hour. The reaction mixture was diluted with aq. The resulting residue was purified to give crystalljjjjjjjjj

Second step

(E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazolin-6-yl) -3- (4-methylmorpholine -3 -yl) acrylamide

(2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl 7a (200 mg, 0.40 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and hexamethyldidecylamine lithium (1 M, 0.41 mL) was added dropwise. Reaction for 1 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 solution, added, stirred for 0.5 hour, the reaction solution was naturally warmed to room temperature, stirred. 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc (EtOAc m. A thin layer chromatography and the obtained residue was purified by developing solvent system, to give the title product (E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-methoxy-quinazoline -6-yl)-3-(4-methylmorpholin-3-yl)propenamide 9 (100 mg, pale yellow solid), yield: 53%.

MS m/z (ESI): 472.3 [M+1]

¹ H NMR (400 MHz, DMSO- d 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 -(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-3-(1- Methyl pyrrolidin-2-yl) acrylamide

first step

(2-((4-(3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)amino)-2-oxoethyl) Phosphate diethyl ester

N,N'-carbonyldiimidazole (1.89 g, 11.70 mmol) was added to 40 mL of tetrahydrofuran, diethylphosphoacetic acid (2.3 g, 11.70 mmol) was slowly added dropwise, and the reaction was stirred for 1 hour, and 6- Amino-4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinoline-3-carbonitrile 8 g (2 g, 5.84 mmol). The reaction mixture was concentrated under reduced vacuo. EtOAc m. -((4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)amino)-2-oxoethyl)phosphate Diethyl 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- Methyl pyrrolidin-2-yl) acrylamide

(2-((4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)amino)-2-oxoethyl Diethyl phosphate 10a (250 mg, 0.48 mmol) was added to 20 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and hexamethyldidecylamine lithium (1 M, 0.72 mL) was added dropwise. After the addition was completed, the reaction was stirred for 1 hour. ( R )-1-Methylpyrrolidine-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. 16 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (R, E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) 3-cyano-7-methoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenamide 10 (20 mg, yellow solid), yield: 8.7% .

MS m/z (ESI): 480.2 [M+1]

¹ H NMR (400 MHz, DMSO- d 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

( S,E )- N -(4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)-3-(1- Methyl pyrrolidin-2-yl) acrylamide

(2-((4-((3-chloro-4-fluorophenyl)amino)-3-cyano-7-methoxyquinolin-6-yl)amino)-2-oxoethyl Diethyl phosphate 10a (100 mg, 0.19 mmol) was added to 5 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and hexamethyldidecylamine lithium (1 M, 0.2 mL) was added dropwise. After the addition was completed, the reaction was stirred for 1 hour. ( S )-1-Methyl-pyrrolidine-2-carbaldehyde 7b (150 mg, 1.32 mmol) was dissolved in 5 mL of tetrahydrofuran, added dropwise to the above reaction mixture, and the reaction solution was allowed to rise to room temperature. Stir for 16 hours. The reaction mixture was concentrated under reduced pressure, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (S, E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) 3-cyano-7-methoxyquinolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenylamine 11 (20 mg, yellow solid), yield: 21.7% .

MS m/z (ESI): 480.4 [M+1]

¹ H NMR (400 MHz, DMSO- d 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) , 1H), 6.69-6.67 (m, 2H), 4.04 (s, 3H), 3.25-3.1 (m, 1H), 2.33 (s, 3H), 2.15 - 1.95 (m, 1H), 1.85-1.75 (m , 2H), 1.7-1.5 (m, 1H), 1.3-1.2 (m, 2H).

Example 12

( R,E )- N -(4-((3-Chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-A Pyrrolidin-2-yl)propenylamine

first step

N- (3-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 the literature 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 Polin-4-amine 12c (1.5 g, pale yellow solid), yield: 99%.

MS m/z (ESI): 364.8 [M-1]

Second step

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

Add N- (3-chloro-2,4-difluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine 12c (1.5 g, 4.09 mmol) to 100 mL of THF. 800 mg of Raney nickel was added, 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 N ⁴ -(3-chloro-2,4-difluorophenyl)-7 -Methoxyquinazoline-4,6-diamine 12d (1.1 g, yellow solid), yield: 80%.

MS m/z (ESI): 337.1 [M+1]

third step

(2-((4-Chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphoric acid Ester diethyl ester

N,N'-carbonyldiimidazole (144 mg, 0.89 mmol) was added to 5 mL of tetrahydrofuran, diethylphosphoacetic acid (174 mg, 0.89 mmol) was slowly added dropwise, and the mixture was stirred for 1 hour, and was taken. Add N ⁴ -(3-chloro-2,4-difluorophenyl)-7-methoxyquinazolin-4,6-diamine 12d (100 mg, 0.30 mmol) to 5 mL of tetrahydrofuran and heat The mixture was added dropwise to the above-mentioned alternate reaction solution at 40 ° C, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced vacuo. EtOAc m. (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+1]

the fourth step

( R,E )- N -(4-((3-Chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-A Pyrrolidin-2-yl)propenylamine

(2-((4-(3-Chloro-2,4-difluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl) Diethyl phosphate 12e (153 mg, 0.30 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and hexamethyldidecylamino lithium (1 M, 0.3 mL) was added dropwise. After completion, the reaction was stirred for 1 hour. ( R )-1-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 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, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (R, E) - N - (4 - ((-2,4- difluorophenyl 3-chloro) Amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenamide 12 (122 mg, pale yellow solid), yield: 88% .

MS m/z (ESI): 473.8 [M-1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 9.79 (s, 1H), 9.71 (s, 1H), 8.92 (s, 1H), 8.54 (s, 1H), 8.13 (d, J = 8 Hz, 1H), 7.78-7.85 (m, 1H), 7.43 (t, J = 8 Hz, 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

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

first step

N- (3-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) Triethylamine (1.86 g, 18.37 mmol) was added to 80 mL of acetic acid, 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 the filter cake was 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+1]

Second step

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

Add N- (3-chloro-2-fluorophenyl)-7-methoxy-6-nitroquinazolin-4-amine 13b (2.73 g, 7.84 mmol) to 200 mL of methanol and tetrahydrofuran (V/ In a mixed solvent of V = 1:1), 1 g of Raney nickel was added, and the hydrogen was replaced three times. The reaction was stirred for 16 hours, filtered, and the cake was washed with methanol, and the filtrate was concentrated under reduced pressure to give the title product N ⁴ -(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+1]

third step

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

N,N'-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. Add N ⁴ -(3-chloro-2-fluorophenyl)-7-methoxyquinazolin-4,6-diamine 13c (100 mg, 0.31 mmol) to 5 mL of tetrahydrofuran and warm 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 m. Product (2-((4-(3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl 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-methylpyrrolidine -2-yl) acrylamide

(2-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl ester 13d (133 mg, 0.27 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and hexamethyldidecylamino lithium (1 M, 0.3 mL) was added dropwise. 1 hour. ( R )-1-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 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, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (R, E) - N - (4 - ((3- chloro-2-fluorophenyl) amino) -7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenamide 13 (55 mg, pale yellow solid), yield: 45%.

MS m/z (ESI): 455.9 [M-1]

¹ H NMR (400 MHz, DMSO- d 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-((3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidine -2-yl) acrylamide

first step

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

N,N'-carbonyldiimidazole (526 mg, 3.24 mmol) was added to 5 mL of tetrahydrofuran, diethylphosphoacetic 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 m. Product (2-((4-(3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl ester 14b (400 mg, grey solid), yield: 62.5%.

Second step

( R,E )- N -(4-((3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)-3-(1-methylpyrrolidine -2-yl) acrylamide

(2-((4-((3-chloro-4-hydroxyphenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl 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 hexamethyldidecylamine lithium (1 M, 0.3 mL) was added dropwise. Reaction for 1 hour. ( R )-1-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, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (R, E) - N - (4 - ((3- chloro-4-hydroxyphenyl) amino) -7-Methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenamide 14 (10 mg, yellow solid), yield: 21.7%.

MS m/z (ESI): 454.2 [M+1]

¹ H NMR (400 MHz, DMSO- d ₆ ): δ 10.5 (s, 1H), 9.9 (s, 1H), 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 -(4-((3-Chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)-3-(1-A Pyrrolidin-2-yl)propenylamine

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, prepared according to the literature "Bioorganic & Medicinal Chemistry, 2007, 15 (11), 3635-3648") was dissolved in To 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, and a large amount of solid was precipitated. The reaction solution was poured into 50 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-ethoxy-6-nitroquinazole Polin-4-amine 15b (1.4 g, yellow solid), yield: 73.7%.

Second step

N ⁴ -(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. 1 g of Raney nickel was added, 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 N ⁴ -(3-chloro-2,4-difluorophenyl)-7 Ethoxyquinazoline-4,6-diamine 15c (1.2 g, yellow solid), yield: 92.3%.

MS m/z (ESI): 351.2 [M+1]

third step

(2-((4-Chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphoric acid Ester diethyl ester

N,N'-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 N ⁴ -(3-chloro-2,4-difluorophenyl)-7-ethoxyquinazoline-4,6-diamine 15c (300 mg, 0.85 mmol) to 5 mL of tetrahydrofuran and heat The mixture was added dropwise to the above-mentioned alternate reaction solution at 40 ° C, and the reaction was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure. EtOAc m. Product (2-((4-(3-chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)-2-oxoethyl) Diethyl phosphate 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-(1-A Pyrrolidin-2-yl)propenylamine

(2-((4-(3-chloro-2,4-difluorophenyl)amino)-7-ethoxyquinazolin-6-yl)amino)-2-oxoethyl) Diethyl phosphate 15d (270 mg, 0.51 mmol) was added to 10 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and hexamethyldidecylamino lithium (1 M, 0.6 mL) was added dropwise. After completion, the reaction was stirred for 1 hour. ( R )-1-Methylpyrrolidine-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 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, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (R, E) - N - (4 - ((-2,4- difluorophenyl 3-chloro) Amino)-7-ethoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenamide 15 (80 mg, yellow solid), yield: 32%.

MS m/z (ESI): 488.2 [M+1]

¹ H NMR (400 MHz, DMSO- d 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

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

(2-((4-((3-chloro-4-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)amino)-2-oxoethyl)phosphate Ethyl 7a (200 mg, 0.41 mmol) was added to 2.5 mL of tetrahydrofuran, cooled to -78 ° C with dry ice acetone bath, and hexamethyldidecylamine lithium (1 M, 0.41 mL) was added dropwise. Reaction for 1 hour. ( R )-1-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, resulting in a thin layer chromatography developing solvent system A and the residue was purified to give the title product (R, E) - N - (4 - ((3- chloro-4-fluorophenyl) amino) -7-Methoxyquinazolin-6-yl)-3-(1-methylpyrrolidin-2-yl)propenylamine 16 (88 mg, white solid), yield: 48%.

MS m/z (ESI): 456.3 [M+1]

¹ H NMR (400 MHz, DMSO- d 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,E )- N -{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-anilino]-3-hydro-7-ethoxy-quinolin-6-yl }-3-(1-Methyl-pyrrolidin-2-yl)-acrylamide

first step

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

N,N'-carbonyldiimidazole (486.45 mg, 3 mmol) was dissolved in 4 mL of tetrahydrofuran at 40 ° C, the temperature was raised to 40 ° C in an oil bath, and 4 mL of diethyl phosphate-based acetic acid (588.42 mg) was added dropwise to the reaction solution. , 3 mmol) of tetrahydrofuran solution, stirred for 30 minutes for use. 6-Amino-4-[3-chloro-4-(pyridin-2-ylmethoxy)-anilino]-7-ethoxy-quinoline-3-carbonitrile 17a (445.9 mg, at 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 under reduced pressure. EtOAcjjjjjjjjjjjjjjjj The residue obtained was purified by chromatography to give the title product ({4-[3-chloro-4-(pyridin-2-ylmethoxy)-anilinyl]-3-cyano-7-ethoxy-quinoline- 6-Aminoaminoformamidine}-methyl)-diethyl phosphate 17b (624 mg, pale yellow solid), yield: 99.9%.

MS m/z (ESI): 624 [M+1]

Second step

( R,E )- N -{4-[3-Chloro-4-(pyridin-2-ylmethoxy)-anilino]-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-ylaminomethyl under dry ice bath醯}-Methyl)-diethyl phosphate 17b (250 mg, 0.4 mmol) was dissolved in 10 mL of anhydrous tetrahydrofuran, and 1 M solution of bistrimethyldecylamine lithium in toluene (0.44 mL, 0.44 mmol) was added dropwise. The reaction was stirred for 30 minutes, and 5 mL of a solution of ( R )-N-methyl-2-pyrrolidinecarboxaldehyde 10b (90 mg, 0.8 mmol) in tetrahydrofuran was added dropwise, the reaction was stirred for 30 minutes, and the reaction was continued at room temperature for 12 hours. It was concentrated under reduced pressure, was purified by column chromatography of the residue on silica gel to give the title product (R, E) - N - {4- [3- chloro-4- (pyridin-2-ylmethoxy) - phenylamine 3-ylhydro-7-ethoxy-quinolin-6-yl}-3-(1-methyl-pyrrolidin-2-yl)-propenylamine 17 (46 mg, yellow solid) Yield: 19.7%.

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

^{_{1 HNMR (400MHz, DMSO- d 6}} ): 9.156 (s, 1H), 8.628 (d, 1H, J = 4.4Hz), 8.555 (s, 1H), 8.261 (s, 1H), 7.828 (t, 1H, J=9.2 Hz), 7.759 (m, 2H), 7.574 (m, 1H), 7.404 (d, 2H, J = 10.8 Hz), 7.187 (d, 1H, J = 8.8 Hz), 7.060 (m, 2H) , 6.343 (d, 1H, J = 15.2 Hz), 5.353 (s, 2H), 4.390 (m, 2H, J = 6.8 Hz, J = 14 Hz), 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 = 6.8 Hz).

Example 18

(E) - N - [4 - [[3- chloro-4- (2-pyridin ylmethoxy) phenyl] amino] -3-cyano-7-ethoxy-6-quinolinyl] -3-[(2 S )-1-methylpyrrolidin-2-yl]prop-2-enylamine

N- [4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl group at -78 °C Diethyl 2-phosphate-acetamide 17b (50 mg, 0.08 mmol) was dissolved in 2 mL of tetrahydrofuran, and a solution of 1 M bistrimethyldecylamine lithium in toluene (80 μL, 0.08 mmol) was added dropwise. After stirring for 45 minutes, ( 2S )-1-methyl-pyrrolidine-2-carbaldehyde 7b (20 mg, 0.17 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour and then reacted at room temperature for 12 hours. 1 mL of water and 1 mL of methanol were added to the reaction solution. Extracted with dichloromethane (50 mL×3), combined with EtOAc (EtOAc)EtOAc. A resultant residue was purified release agent system, to give the title product (E) - N - [4 - [[3- chloro-4- (2-pyridin ylmethoxy) phenyl] amino] -3-cyano - 7-ethoxy-6-quinolinyl]-3-[( 2S )-1-methylpyrrolidin-2-yl]prop-2-enylamine 18 (25 mg, yellow solid) : 53.5%.

MS m/z (ESI): 583 [M+1]

¹ H NMR (400 MHz, DMSO- d 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

( E ) -N- [4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2 R )-1 -methylpyrrolidin-2-yl]prop-2-enylamine

first step

N- [4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl ester-acetamide

Dissolve N,N'-carbonyldiimidazole (292 mg, 1.80 mmol) in 4 mL of tetrahydrofuran, warm to 50 ° C in an oil bath, and add 3 mL of diethyl phosphate phosphate (353 mg, 1.8 mmol) to the reaction solution. The tetrahydrofuran solution was reacted for 1.5 hours for use. N ⁴ -(3-Chloro-4-fluoro-phenyl)-7-ethoxy-quinazolin-4,6-diamine 19a (200 mg, 0.60 mmol, prepared according to the literature "WO2005028443") was dissolved in The above-mentioned alternate reaction solution was added dropwise to 10 mL of tetrahydrofuran at 50 ° C, and reacted at 40 ° C for 3 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj The resulting residue was purified by column chromatography eluting to afford the title product N- [4-[(3-chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazoline- 6-yl]-2-phosphate diethyl ester-acetamide 19b (100 mg, pale yellow solid), yield: 33.3%.

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

Second step

( E ) -N- [4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2 R )-1 -methylpyrrolidin-2-yl]prop-2-enylamine

N- [4-[(3-Chloro-4-fluoro-phenyl)amino-7-ethoxy-quinazolin-6-yl]-2-phosphate diethyl ester-acetamide 19b (300 Mg, 0.59 mmol) was dissolved in 10 mL of tetrahydrofuran, cooled to -78 ° C in a dry ice bath, and a 1 M solution of ditrimethylguanidino lithium in toluene (1.2 mL, 1.18 mmol) was added dropwise under argon. After stirring for 30 minutes, ( R )-1-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 reacted at room temperature for 12 hours. The reaction mixture was concentrated, EtOAc (EtOAc) (EtOAc m. The residue obtained is purified by eluent column chromatography eluting to afford the title product ( E ) -N- [4-[(3-chloro-4-fluoro-phenyl)amino]-7- Ethoxy-quinazolin-6-yl]-3-[(2 R )-1-methylpyrrolidin-2-yl]prop-2-enylamine 19 (130 mg, yellow solid), yield : 47.3%.

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

¹ H NMR (400 MHz, DMSO- d 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

( E ) -N- [4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazolin-6-yl]-3-[(2 S )-1 -methylpyrrolidin-2-yl]prop-2-enylamine

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 ditrimethylguanidino lithium in toluene (400 μL, 0.40 mmol), and stirred for 45 minutes. ( 2S )-1-Methyl-pyrrolidine-2-carbaldehyde 7b (100 mg, 0.85 mmol) was added to the reaction mixture, and the mixture was stirred for 1 hour, and then reacted at room temperature for 12 hours. 1 mL of water and 1 mL of methanol were added to the reaction solution. The mixture was extracted with methylene chloride (100 mL×3), EtOAc (EtOAc m. The residue obtained was purified by eluent system A to give the title product ( E ) -N- [4-[(3-chloro-4-fluoro-phenyl)amino]-7-ethoxy-quinazoline-6 -yl]-3-[( 2S )-1-methylpyrrolidin-2-yl]prop-2-enylamine 20 (60 mg, yellow solid), yield: 65.2%.

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

¹ H NMR (400 MHz, DMSO- d 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, 1H), 7.26 (s, 1H), 6.67-6.69 (m, 2H), 4.26-4.31 (m, 2H), 4.09-4.10 (m, 1H), 3.17-3.15 (m, 2H), 3.08-3.04 (m, 1H), 2.77-2.79 (m, 1H), 2.87-2.82 (m, 1H), 2.23 (s, 3H), 1.74-1.76 ( m, 1H), 1.47 (m, 3H).

Using the synthetic route one, the compounds of Examples 21 to 31 were synthesized using the appropriate reactants with reference to the procedures of Examples 1 to 8. Using the synthetic route 2, the compounds of Examples 32 to 38 were synthesized using the appropriate reactants with reference to the procedures of Examples 9 to 20.

Test case: 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:

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

The experimental method in which the specific conditions are not indicated in the test examples of the present invention is usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer of the product. Reagents without specific source are routine reagents purchased from the market.

Test Example 1, Determination of Inhibition of Activity of EGFR Mutant Kinase by Compounds of the 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 the Invitrogen kit Z ^-- LYTE® Kinase Assay Kit-Tyrosine 4 Peptide (Invitrogen, PV3193). According to the kit instructions, configure the appropriate concentration of enzyme buffer (50mM HEPES PH7.5, 0.01% BRIJ-35, 10mM MgCl ₂ , 4mM MnCl ₂ , 1mM EGTA, 2mMDTT), enzyme/matrix peptide solution, ATP solution and The peptide peptides were completely phosphorylated and gently mixed uniformly; a 4× concentration of the test compound solution was prepared with distilled water and mixed well.

The configured enzyme/matrix peptide solution and fully phosphorylated matrix 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 enzyme buffer was added to the completely inhibited control group. 2.5uL of ATP solution and 2.5uL of the corresponding concentration of DMSO solution were added to the non-inhibited control group, and 2.5 uL of enzyme buffer and 2.5 uL of the corresponding concentration of DMSO solution were added to the completely phosphorylated matrix control group; The plate was attached and shaken on a shaker for 30 seconds to uniformly mix the solutions, and incubated at room temperature for 1 hour.

According to the instructions, the developing solution was prepared according to the corresponding ratio. After mixing, the reaction wells were added to 5 uL of the reaction wells, and the sealing plates were attached to the shaker and shaken for 30 seconds to uniformly mix the solutions, and incubated at room temperature for 1 hour. 5 uL of stop solution was added to each well, and after mixing uniformly, fluorescence was read at 445 nm and 520 nm by excitation at 400 nm.

The biochemical activity of the compounds of the present invention was determined by the above test, and the IC ₅₀ values at which the inhibition of EGFR and EGFR mutant enzyme activities were measured are shown in Tables 1 to 3 below.

Conclusion: The compounds of the examples of the present invention have a significant inhibitory effect on the proliferation of EGFR kinase.

Conclusion: The compounds of the examples of the present invention have significant inhibitory effects on the proliferation of EGFR T790M, L858R and T790M/L858R kinases.

Conclusion: The compounds of the examples 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 Inhibition of Activity of EGFR Mutant Cells by Compounds of the Invention

The following method was used to determine the inhibitory effect of the compounds 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 Covering 80 to 90%, digested with 0.25% trypsin (EDTA) and then planted in 96-well plates, 2000 cells per well (100 μl IMDM (2% FBS, P/S) medium), placed at 37 ° C, 5 Incubate for 24 hours in a % CO ₂ incubator. The drug was configured as a 20 mM stock solution, diluted to a 200× concentration gradient with a 100% DMSO gradient, and diluted 20-fold with IMDM (2% FBS, 100 units/ml P/S) to ensure DMSO concentration in each culture system. Both are 0.5%). After 24 hours, the medium was removed, 90 μl (IMDM, 10% FBS, 100 units/ml P/S, 5 ng/ml VEGF) and 10 μl of drug were added to each well, and gently mixed by shaking. The control group and the blank group contained only 100 μl (IMDM). , 10% FBS, P/S, 5 ng/ml VEGF), placed in a 37 ° C, 5% CO ₂ incubator, 72 hours after adding 10 μl of CCK-8 per well, and then placed at 37 ° C, 5% CO ₂ culture Incubate for 4 hours in the chamber and measure 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 ₅₀ values are shown in Table 4 below.

Conclusion: The compounds of the examples of the present invention have significant inhibitory effects on the proliferation of NCI-H-1975 and PC-9 GR cells.

Claims (42)

a compound, tautomer, meso, racemate, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt of the formula (I) In the preparation of a medicament for treating cancer, Wherein: 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; and when A is a carbon atom R ² is a cyano group; when A is a nitrogen atom, R ² is unsubstituted; and 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 a- CH ₂ )r-Ar or -O(CH ₂ )r-Ar; Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl are each independently optionally further one or more halogen, alkyl Or substituted with a substituent of a trifluoromethyl group; R is selected from aryl, pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl or -NR ⁸ R ⁹ wherein the aryl group, pyridine The base, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholyl is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, pendant oxy, hydroxy or hydroxyalkyl Substituting; or the pyrrolidinyl group is an N-oxide; 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 bridged heterocyclic group, wherein the monospiroheterocycle Base, double ring Or a bicyclic bridge heterocyclyl optionally further substituted with one or more substituents selected from alkyl, alkoxy, halo, haloalkyl, hydroxy or hydroxyalkyl; r is 0, 1 or 2; Is 0 or 1. The use of claim 1, wherein the cancer is a cancer resistant. The use of claim 2, wherein the cancer is a cancer resistant to a reversible inhibitor of EGFR. The use of claim 3, wherein the cancer is a cancer resistant to gefitinib, erlotinib or lapatinib. The use of claim 1 or 2, wherein the cancer is a solid tumor. The use according to claim 5, wherein the cancer is head and neck cancer, 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 6, wherein the cancer is non-small cell lung cancer. The use of any one of claims 1 to 7 wherein the cancer carries an EGFR mutation. The use of claim 8, 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 of any one of claims 1 to 7 wherein the cancer carries a HER2 mutation. The use according to any one of claims 1 to 10, wherein R is pyridinyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl; the pyridyl group, tetrahydropyran The benzyl, piperidinyl, pyrrolidinyl, morpholinyl group is optionally further substituted with one or more alkyl or pendant oxy groups; or the pyrrolidinyl group is an N-oxide. The use of claim 11, wherein the R is a pyrrolidinyl group. The use according to any one of claims 1 to 11, 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, 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. The use of claim 13, wherein the monospiroheterocyclyl, bicyclic fused heterocyclyl or bicyclic bridge heterocyclyl is selected from the group consisting of: The use according to any one of claims 1 to 14, wherein the compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof The steroids, diastereomers, mixtures thereof, and pharmaceutically acceptable salts are selected from the group consisting of: A method of treating cancer comprising 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, a diastereomer Isomers, mixtures thereof, and pharmaceutically acceptable salts: Wherein: R ¹ to R ⁷ , R, A, n are as defined in the first item of the patent application. The method of claim 16, wherein the cancer is a cancer resistant. The method of claim 17, wherein the cancer is a cancer resistant to a reversible inhibitor of EGFR. The method of claim 18, wherein the cancer is a cancer resistant to gefitinib, erlotinib or lapatinib. The method of claim 16 or 17, wherein the cancer is a solid tumor. The method of claim 20, wherein the cancer is head and neck cancer, 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 method of claim 21, wherein the cancer is non-small cell lung cancer. The method of any one of claims 16 to 20, wherein the cancer carries an EGFR mutation and/or carries a HER2 mutation. The method of claim 23, 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. a compound, tautomer, meso, racemate, enantiomer, diastereomer, and mixtures thereof of the formula (I) as a medicament for treating cancer, And pharmaceutically acceptable salts: Wherein: R ¹ to R ⁷ , R, A, n are as defined in the first item of the patent application. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound represented by the formula (I) as described in claim 25 of the patent application. In the form of a mixture, and a pharmaceutically acceptable salt, wherein the cancer is a cancer resistant. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 26 of the patent application. In the form of a mixture, and a pharmaceutically acceptable salt, wherein the cancer is a cancer that is resistant to a reversible inhibitor of EGFR. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 27 of the patent application. In the form of a mixture, and a pharmaceutically acceptable salt, wherein the cancer is cancer resistant to gefitinib, erlotinib or lapatinib. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a compound represented by the formula (I) as described in claim 25 or 26 of the patent application. And a mixture thereof, and a pharmaceutically acceptable salt, wherein the cancer is a solid tumor. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound represented by the formula (I) as described in claim 29 of the patent application. a mixture thereof, and a pharmaceutically acceptable salt, wherein the cancer is head and neck cancer, colorectal cancer, bladder cancer, lung cancer, pancreatic cancer, breast cancer, prostate cancer, stomach cancer, oral cancer, liver cancer, glioblastoma, ovary Cancer or non-small cell lung cancer. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 30 of the patent application. In the form of a mixture, and a pharmaceutically acceptable salt, wherein the cancer is non-small cell lung cancer. The compound, tautomer, meso, racemate, enantiomer, diastereomer, and diastereomer of the formula (I) as described in any one of claims 25 to 29; Isomers, and mixtures thereof, and pharmaceutically acceptable salts, wherein the cancer carries an EGFR mutation, and/or carries a HER2 mutation. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 32 of the patent application. a mixture form, and a pharmaceutically acceptable salt, wherein the EGFR mutation comprises a deletion mutation EGFR del 746-750 on the ELREA sequence, a T790M point mutation in exon 20, an EGFR del 746-750/T790M double mutation or L858R/T790M Double mutation. a compound, tautomer, meso, racemate, enantiomer, diastereomer, mixture thereof, and pharmaceutically acceptable salt of the formula (I) : Wherein: 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; and when A is a carbon atom R ² is a cyano group; when A is a nitrogen atom, R ² is unsubstituted; and 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 a- CH ₂ )r-Ar or -O(CH ₂ )r-Ar; Ar is selected from aryl or heteroaryl, wherein the aryl or heteroaryl are each independently optionally further one or more halogen, alkyl Or substituted with a substituent of a trifluoromethyl group; R is selected from aryl, pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl or -NR ⁸ R ⁹ wherein the aryl group, pyridine The base, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholyl is optionally further substituted with one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, pendant oxy, hydroxy or hydroxyalkyl Substituting; or the pyrrolidinyl group is an N-oxide; 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 bridged heterocyclic group, wherein the monospiroheterocycle Base, double ring Or a bicyclic bridge heterocyclyl optionally further substituted with one or more substituents selected from alkyl, alkoxy, halo, haloalkyl, hydroxy or hydroxyalkyl; r is 0, 1 or 2; Is 0 or 1. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 34 of the patent application. a mixture form, and a pharmaceutically acceptable salt, wherein R is pyridyl, tetrahydropyranyl, piperidinyl, pyrrolidinyl, morpholinyl; the pyridyl, tetrahydropyranyl, piperidine The pyridine, pyrrolidinyl, morpholinyl group is optionally further substituted with one or more alkyl or pendant oxy substituents; or the pyrrolidinyl group is an N-oxide. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound represented by the formula (I) as described in claim 35 of the patent application. In the form of a mixture, and a pharmaceutically acceptable salt, wherein R is pyrrolidinyl. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 36 of the patent application. In the form of a mixture, and a pharmaceutically acceptable salt, wherein R is a chiral pyrrolidine tetrahydro group. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 34 of the patent application. a mixture form, and a pharmaceutically acceptable salt, 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, the monospiroheterocyclic group, the bicyclic ring The fused heterocyclic group or the bicyclic bridged heterocyclic group is optionally further substituted with one or more substituents selected from the group consisting of an alkyl group, an alkoxy group, a hydroxyl group, and a hydroxyalkyl group. a compound, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, and the compound of the formula (I) as described in claim 38 of the patent application. a mixture form, and a pharmaceutically acceptable salt, wherein the monospiroheterocyclyl, bicyclic fused heterocyclyl or bicyclic bridged heterocyclic group is selected from the group consisting of: A compound of the formula (I) or a tautomer, a racemate, an enantiomer or a diastereomer thereof, as described in any one of claims 34 to 39, And mixtures thereof, and pharmaceutically acceptable salts selected from the group consisting of: A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 34 to 40, or a tautomer, racemate, enantiomer or diastereomer thereof. And mixtures thereof, and pharmaceutically acceptable salts and pharmaceutically acceptable carriers. A method of preparing a pharmaceutical composition according to claim 41, which comprises the compound according to any one of claims 34 to 40, or a tautomer, a racemate thereof, and an antipode The isomers, diastereomers, mixtures thereof, and pharmaceutically acceptable salts are combined with a pharmaceutically acceptable carrier or diluent.