CN105884695B

CN105884695B - Heterocyclic derivatives species tyrosine kinase inhibitor

Info

Publication number: CN105884695B
Application number: CN201610059987.3A
Authority: CN
Inventors: 吴永谦
Original assignee: Shandong Xuanzhu Pharma Co Ltd
Current assignee: BEIJING TIANXINYUAN PHARMACEUTICAL SCIENCE AND TECHNOLOGY DEVELOPMENT Co Ltd; Beijing Sihuan Pharmaceutical Co Ltd; Beijing Ao He Research Institute Co Ltd; Jilin Shengtong Chemical Co Ltd
Priority date: 2015-02-13
Filing date: 2016-01-28
Publication date: 2019-02-26
Anticipated expiration: 2036-01-28
Also published as: CN105884695A

Abstract

The invention belongs to pharmaceutical technology fields, and in particular to heterocyclic derivatives species tyrosine kinase inhibitor, its pharmaceutically acceptable salt, its ester and their stereoisomer shown in general formula (I), wherein Y, W, Q, m, L, R₁、R₂、R₃、R₄、R₅、R₆、R₇、R₇′、R₈、R₈' be defined as in the description.The invention further relates to the preparation methods of these compounds, pharmaceutical preparation and pharmaceutical composition and these compounds containing these compounds are used to prepare prevention as tyrosine kinase inhibitor and/or treat the application in the drug of drug resistance disease caused by the Cancerous disease and EGFR T790M mutation that EGFR mutation causes.

Description

Heterocyclic derivative tyrosine kinase inhibitor

1. Field of the invention

The invention belongs to the technical field of medicines, and particularly relates to pyrimidine heterocyclic derivative tyrosine kinase inhibitors, pharmaceutically acceptable salts, esters and stereoisomers thereof, preparation methods, pharmaceutical preparations and pharmaceutical compositions of the compounds, and applications of the compounds as tyrosine kinase inhibitors in preparation of medicines for preventing and/or treating cancer diseases caused by EGFR mutation and drug-resistant diseases caused by EGFR T790M mutation.

2. Background of the invention

Cancer, also known as malignant tumor, has been a serious threat to human health and life. In 2004, 740 million people died of cancer worldwide. In 2008, the third national cause of death survey in china shows that the cancer death rate in china has increased by about eight years in the past 30 years, and nearly 200 million people dying from cancer every year have very severe situation.

Lung cancer is one of the clinically common malignant tumors, and the morbidity and mortality of lung cancer are the first of the malignant tumors. From a histopathological perspective, lung cancer is divided into two types: small cell lung cancer (small cell lung cancer SCLC) and non-small cell lung cancer (non-small cell lung cancer, NSCLC). NSCLC includes lung cancer except SCLC such as squamous carcinoma, adenocarcinoma, and large cell carcinoma, and accounts for 80-85% of the total lung cancer. 70% of NSCLC are diagnosed in advanced stage and are difficult to be cured radically by operation or radiotherapy. In addition, over 50% of early stage patients experience local recurrence or distant metastasis despite active treatment such as surgery, radiation therapy, and adjuvant chemotherapy. Therefore, chemotherapy-based systemic treatment is of great significance in the treatment of NSCLC.

In recent years, with the intensive research on tumor cell signaling pathways, a small molecule Tyrosine Kinase Inhibitor (TKI) molecular targeted drug targeting an Epidermal Growth Factor Receptor (EGFR) has achieved a good result in the treatment of NSCLC. EGFR is a transmembrane protein belonging to the receptor tyrosine kinase (ERBB) family, which has four subtypes: EGFR (ERBB1 or HER-1), HER-2(ERBB2), HER-3(ERBB3) and HER-4(ERBB4) play a major role in the transformation and growth of tumors. The FDA has rapidly approved two reversible single-target small molecule EGFR TKIs, i.e., gefitinib (efitinib, Iressa) and Erlotinib (Erlotinib, Tarcewa), for the treatment of advanced NSCLC with first-line treatment failure. In 2013, the FDA approved the first irreversible multi-target EGFR TKI, Afatinib, for better treatment of NSCLC.

EGFR TKI is marketed as being only therapeutically sensitive to NSCLC populations with EGFR mutations, more than 90% of which are exon 19 deletions and exon 21L 858R mutations, common in asia, non-smoking, female patients. In the initial stage of applying the EGFR TKI, the curative effect of the patient is obvious, the progressive-free survival (PFS) period is prolonged, the Objective Response Rate (ORR) is improved, and the life quality is greatly improved, but most of the patients can have drug resistance to the drugs after being treated for 10 months on average. In addition, because the existing EGFR TKI simultaneously acts on wild EGFR, side effects such as rash, diarrhea and the like are generated, the clinic is restricted, EGFR TKI with stronger selectivity and drug resistance can be developed, and NSCLC can be better treated.

Of the patients who developed resistance, 50% contained the T790M mutation encoded by exon 20, with less than 5% of the other mutations (e.g., D761Y, L747S, T845A); in addition, 20% of the tumor cells contained the resistance caused by amplification of the MET tumor gene, and half of them also had the T790M mutation. The T790M mutation is shown to be the main reason for the drug resistance of EGFR TKI. The T790M mutation, in which the threonine at position 790 of EGFR is replaced with methionine, is not fully understood as the mechanism by which resistance is caused. The possible mechanism is that methionine occupies more space than threonine to form steric hindrance, so that the affinity of ATP in an EGFR kinase region is changed, and EGFR-TKI small molecule drugs cannot effectively block EGFR activation signals, thereby losing the killing effect on tumor cells and generating drug resistance.

To date, no EGFR TKI drug directed against the T790M mutation has been marketed. WO2012061299A1 (published as 2012.05.10) discloses a drug CO-1686 developed by Avila Therapeutics in the second stage of clinical trial, which is directed against the T790M mutation, treats EGFR TKI-resistant NSCLC, selectively inhibits mutant EGFR, and has high safety. This technique has been validated clinically. The specific structure of CO-1686 is as follows:

therefore, the EGFR TKI with different structures aiming at the T790M mutation is developed, so that the EGFR TKI has higher selectivity, stronger pharmacological activity, higher safety or better physicochemical properties, is of great significance for treating NSCLC, and has a huge market.

3. Summary of the invention

The technical problem to be solved by the invention is to provide a pyrimidine heterocyclic derivative tyrosine kinase inhibitor which is applied to preparing medicines for preventing and/or treating cancer diseases caused by EGFR mutation and drug-resistant diseases caused by EGFR T790M mutation.

The technical scheme of the invention is as follows:

scheme 1. Compounds represented by the following formula (I), pharmaceutically acceptable salts thereof, esters thereof, and stereoisomers thereof,

wherein,

y is selected from C or N;

w, Q are each independently selected from C (R)₇R₇′)、NR₈', O, S, S (O) or S (O)₂；

m is an integer from 0 to 5;

l is selected from absent O, NR₈', S, S (O) or S (O)₂；

R₃Selected from hydrogen atom, halogen atom, cyano group, nitro group, hydroxyl group, carboxyl group, amino group, C_1-6Alkyl radical, C_1-6Alkylamino, di-C_1-6Alkylamino, halogeno C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonyloxy, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylamino sulfonamido, C_1-6Alkylamido, 3-14 membered cyclic groupGroup, 3-14 membered cyclic group-C_1-6Alkyl, a 3-14 membered cyclic group-O-, a 3-14 membered cyclic group-NH-, or a 3-14 membered cyclic group-S-;

R₄selected from hydrogen atoms, C optionally substituted by substituents_1-6Alkyl, 3-10 membered heterocyclic group, 6-8 membered aryl or 5-8 membered heteroaryl, said substituents being selected from halogen atom, hydroxy, amino, nitro, C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6An alkylsulfonylamino group or a 3-14 membered cyclic group;

R₁、R₂、R₅、R₆、R₇、R₇′、R₈、R₈' are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a cyano group, a nitro group, a hydroxyl group, a carboxyl group, an amino group, and C_1-6Alkyl radical, C_1-6Alkylamino radical, C_2-6Alkenyl radical, C_2-6Alkynyl, di-C_1-6Alkylamino, halogeno C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonyloxy, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylamido, 3-14 membered cyclic group or 3-14 membered cyclic group-C_1-6An alkyl group.

Scheme 2. the compounds described in the above scheme 1, pharmaceutically acceptable salts thereof, esters thereof, and stereoisomers thereof, wherein,

y is selected from C or N;

x, V are each independently selected from C, N or O;

w, Q are each independently selected from C (R)₇R_7′)、NR₈', O or S;

m is an integer from 0 to 4;

l is selected from absent, O or NR₈′；

R₃Selected from hydrogenAtom, halogen atom, hydroxyl group, amino group, C_1-6Alkyl radical, C_1-6Alkylamino, halogeno C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonyloxy, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylamido, 3-10 membered cyclic group-C_1-6Alkyl, a 3-10 membered cyclic group-O-, a 3-10 membered cyclic group-NH-, or a 3-10 membered cyclic group-S-;

R₄selected from hydrogen atoms, C optionally substituted by substituents_1-6Alkyl, 3-8 membered heterocyclyl or 5-8 membered heteroaryl, said substituents being selected from the group consisting of halogen atoms, hydroxy, amino, C_1-6Alkyl radical, C_1-6Alkylcarbonyl group, C_1-6Alkylamido radical, C_1-6Alkylsulfonyl radical, C_1-6An alkylsulfonylamino group or a 3-to 10-membered heterocyclic group;

R₁、R₂、R₅、R₆、R₇、R₇′、R₈、R₈' are each independently selected from the group consisting of a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, and C_1-6Alkyl radical, C_1-6Alkylamino, di-C_1-6Alkylamino, halogeno C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonyloxy, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylamido, 3-8 membered heterocyclyl or 3-8 membered heterocyclyl-C_1-6An alkyl group.

Scheme 3. the compounds described in the above scheme 2, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof, wherein,

y is selected from C or N;

w, Q are each independently selected from NH or O;

m is selected from 2 or 3;

l is selected from absent;

R₃selected from hydrogen atom, halogen atom, hydroxyl, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonylamino group, C_1-4Alkylamido, 5-6 membered heterocyclyl-C_1-4Alkyl or 5-6 membered heterocyclyl-O-;

R₄selected from hydrogen atoms, C optionally substituted by substituents_1-4Alkyl or 5-6 membered heterocyclic group, said substituent being selected from the group consisting of halogen atom, hydroxy, amino, C_1-4Alkyl radical, C_1-4Alkylcarbonyl group, C_1-4Alkylsulfonyl or C_1-4An alkylsulfonylamino group;

R₁、R₂、R₅、R₆each independently selected from hydrogen atom, halogen atom, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy or halo C_1-4An alkoxy group;

R₇、R₇' is selected from a hydrogen atom, a methyl group or an ethyl group;

R₈selected from a hydrogen atom, a methyl group or an ethyl group.

Scheme 4. the compounds described in the above scheme 3, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof, wherein,

R₃selected from hydrogen atom, chlorine atom, hydroxyl group, amino group, methyl group, trifluoromethyl group, methoxy group, trifluoromethoxy group, methylsulfonyl group, propylsulfonyl group or isopropylsulfonyl group;

R₄selected from a hydrogen atom, a pyrrolidinyl group, a tetrahydrofuryl group, a tetrahydropyranyl group, a tetrahydropyridonyl group, a dihydropyridinonyl group, a piperidino group, a piperidinyl group, a piperazinyl group or a morpholinyl group, optionally substituted by a substituent selected from a chlorine atom, a fluorine atom, a methyl group, an ethyl group, an acetyl group, a methanesulfonyl group, a propanesulfonyl group or a methanesulfonylamino group；

R₁、R₂、R₅、R₆Each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, a trifluoromethyl group, a methoxy group or a trifluoromethoxy group;

R₈selected from a hydrogen atom, a methyl group or an ethyl group.

Scheme 5. the compounds described in the above scheme 2, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof, wherein,

y is selected from C or N;

w, Q are each independently selected from NH or O;

m is selected from 2 or 3;

l is selected from O or NH;

R₃selected from hydrogen atoms, halogen atoms, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy radical, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl or 5-6 membered heterocyclyl-O-;

R₄selected from C optionally substituted by substituents_1-4Alkyl or 5-6 membered heterocyclic group, said substituent being selected from halogen atom, C_1-4Alkylcarbonyl group, C_1-4Alkylamido radical, C_1-4Alkylsulfonyl radical, C_1-4An alkylsulfonylamino group or a 5-6 membered heterocyclic group;

R₈selected from a hydrogen atom, a methyl group or an ethyl group.

Scheme 6. the compounds described in the above scheme 5, pharmaceutically acceptable salts thereof, esters thereof and stereoisomers thereof, wherein,

R₃selected from hydrogen atom, fluorine atom, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methylsulfonyl or tetrahydrofuranyl-O-;

R₄selected from methyl, ethyl, propyl, isopropyl, butyl, pyrrolidinyl, tetrahydrofuryl, tetrahydrothienyl, tetrahydropyridonyl, piperidinonyl, piperidinyl, piperazinyl or morpholinyl, optionally substituted with a substituent selected from a chlorine atom, a fluorine atom, acetyl, acetylamino, methanesulfonyl, propanesulfonyl, methanesulfonylamino, tetrahydrofuryl, pyrrolidinyl, piperidinyl or piperazinyl;

R₁、R₂、R₅、R₆each independently selected from a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group, an ethyl group, a trifluoromethyl group, a methoxy group or a trifluoromethoxy group;

R₈selected from a hydrogen atom, a methyl group or an ethyl group.

The invention also provides a pharmaceutical composition containing the compound of the general formula (I), pharmaceutically acceptable salts, esters or stereoisomers thereof.

The invention also provides a pharmaceutical preparation containing the compound of the general formula (I), pharmaceutically acceptable salt, ester or stereoisomer thereof and a pharmaceutical carrier and/or diluent.

The invention also provides the compound of the general formula (I), pharmaceutically acceptable salts, esters or stereoisomers thereof and a pharmaceutical composition containing the compound of the general formula (I), the pharmaceutically acceptable salts or the stereoisomers thereof, which are used as medicines for treating cancer diseases caused by EGFR mutation and drug-resistant diseases caused by EGFR T790M mutation.

The invention also provides application of the compound of the general formula (I), pharmaceutically acceptable salts, esters or stereoisomers thereof and a pharmaceutical composition containing the compound of the general formula (I), the pharmaceutically acceptable salts or stereoisomers thereof in preparing medicines for treating cancer diseases caused by EGFR mutation and drug-resistant diseases caused by EGFR T790M mutation.

The present invention also provides a method for treating cancer diseases caused by EGFR mutation and drug-resistant diseases caused by EGFR t790M mutation, comprising the step of administering to a subject in need thereof an effective amount of the compound of the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof, or a pharmaceutical composition containing the compound of the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof or a stereoisomer thereof.

The compound is selected from:

the term "halo" as used herein means substituted with a "halogen atom" which means a fluorine atom, chlorine atom, bromine atom, iodine atom or the like.

The invention isThe above-mentioned "C_1-6Alkyl "denotes straight or branched alkyl having 1 to 6 carbon atoms, including for example" C_1-4Alkyl group "," C_1-3Alkyl "and the like, specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3-dimethylbutyl, 2-dimethylbutyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 1, 2-dimethylpropyl, and the like. "C" according to the invention_1-4The alkyl group "means a specific example containing 1 to 4 carbon atoms among the above examples.

The "halo C" of the present invention_1-6Alkyl "means one or more" halogen atoms "substituted" C_1-6A group derived from one or more hydrogen atoms on an alkyl group, said "halogen atom" and "C_1-6Alkyl "is as defined above. The "halo C" of the present invention_1-4The alkyl group "means a specific example containing 1 to 4 carbon atoms among the above examples.

"C" according to the invention_2-6Alkenyl "means a straight or branched chain or cyclic alkenyl group of 2 to 6 carbon atoms containing at least one double bond, including, for example," C_2-4Alkenyl groups "and the like. Examples include, but are not limited to: vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1, 3-butadiene, 1-pentenyl, 2-pentenyl, 3-pentenyl, 1, 3-pentadiene, 1, 4-pentadiene, 1-hexenyl, 2-hexenyl, 3-hexenyl, 1, 4-hexadiene, cyclopentenyl, 1, 3-cyclopentadienyl, cyclohexenyl, 1, 4-cyclohexadienyl and the like.

"C" according to the invention_2-6Alkynyl "refers to a straight or branched chain alkynyl group of 2-6 carbon atoms containing a triple bond, including, for example," C_2-4Alkynyl "and the like. Examples include, but are not limited to: ethynyl, propynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 4-methyl-2-pentynyl, 2-hexynyl, 3-hexynyl, 5-methylThe radical-2-hexynyl, and the like.

"C" according to the invention_1-6Alkoxy radical, C_1-6Alkylamino, di-C_1-6Alkylamino radical, C_1-6Alkylcarbonyl group, C_1-6Alkylcarbonyloxy, C_1-6Alkylsulfonyl radical, C_1-6Alkylsulfonylamino group, C_1-6Alkylamino sulfonamido, C_1-6"Alkylamido" means an alkyl group represented by formula C_1-6alkyl-O-, C_1-6alkyl-NH-, (C)_1-6Alkyl radical)₂N-、C_1-6alkyl-C (O) -, C_1-6alkyl-C (O) -O-, C_1-6alkyl-SO₂-、C_1-6alkyl-SO₂-NH-、C_1-6alkyl-NH-SO₂-NH-、C_1-6alkyl-C (O) -NH-linked groups in which "C" is_1-6Alkyl "is as defined above. "C" according to the invention_1-4Alkoxy radical, C_1-4Alkylamino, di-C_1-4Alkylamino radical, C_1-4Alkylcarbonyl group, C_1-4Alkylcarbonyloxy, C_1-4Alkylsulfonyl radical, C_1-4Alkylsulfonylamino group, C_1-4Alkylamino sulfonamido, C_1-4"Alkylamido" refers to a specific example of the above examples that contains 1 to 4 carbon atoms.

The "halo C" of the present invention_1-6Alkoxy "means one or more" halogen atoms "substituted for" C_1-6A group derived from one or more hydrogen atoms on an alkoxy group, said "halogen atom" and "C_1-6Alkoxy "is as defined above. The "halo C" of the present invention_1-4The "alkoxy group" refers to a specific example containing 1 to 4 carbon atoms among the above examples.

The "3-to 14-membered cyclic group" of the present invention means a cyclic group having 3 to 14 ring atoms, and includes 3-to 14-membered heterocyclic group, 3-to 14-membered cycloalkyl group, 3-to 14-membered aryl group, 3-to 14-membered heteroaryl group, 3-to 14-membered fused cyclic group, 3-to 14-membered bridged cyclic group, 3-to 14-membered spiro cyclic group, 3-to 14-membered fused heterocyclic group, 3-to 14-membered bridged heterocyclic group, 6-to 8-membered aryl group, 6-to 14-membered fused aryl group, 3-to 8-membered cycloalkyl group, 3-to 10-membered heterocyclic group, 3-to 8-membered heterocyclic group, 5-to 8-membered heteroaryl group, and 5-to 14-membered fused heteroaryl group. The term "3-to 10-membered cyclic group" as used herein refers to a specific example of the "3-to 14-membered cyclic group" having 3 to 10 ring atoms.

The 6-8 membered aryl group means a monocyclic aryl group having 6 to 8 carbon atoms, and examples thereof include, but are not limited to: phenyl, cyclooctatetraenyl, and the like.

The 6-to 14-membered fused aryl group means an unsaturated aromatic-having fused ring group containing 6 to 14 ring carbon atoms, formed by two or more ring structures sharing two adjacent carbon atoms with each other, and specific examples include, but are not limited to: naphthalene, anthracene, phenanthrene, and the like. The "6-to 10-membered aryl" means a cyclic structure having 6 to 10 ring atoms in the above examples.

The 3-to 8-membered cycloalkyl group means a cyclic alkyl group derived from an alkane moiety having 3 to 8 carbon atoms by removing one hydrogen atom, and includes, for example, "3-to 6-membered cycloalkyl group", "4-to 6-membered cycloalkyl group", and the like. Examples include, but are not limited to: cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, etc.

The 3-to 14-membered fused ring group means a cyclic structure containing 3 to 14 carbon atoms or/and hetero atoms formed by two or more cyclic structures sharing two adjacent atoms with each other, and includes, for example, "4-to 11-membered fused ring alkyl", "6-to 11-membered fused ring alkyl", "5-to 10-membered fused ring alkyl", "7-to 10-membered fused ring alkyl", "3-to 12-membered fused ring alkyl", "9-to 10-membered fused ring alkyl", and the like. Examples include, but are not limited to: and the like.

The 3-14-membered spirocyclic group means a spirocyclic structure containing 3 to 14 carbon atoms and formed by two or more cyclic structures sharing one carbon atom with each other while including a carbon atom which may be oxidized, and includes, for example, "4-11-membered spirocyclic group", "6-11-membered spirocyclic group""5-10 membered spirocyclic group", "7-9 membered spirocyclic group", "7-8 membered spirocyclic group", "9-10 membered spirocyclic group" and the like. Specific examples include, but are not limited to: and the like.

The 3-14-membered bridged ring group means a bridged ring structure containing 3 to 14 carbon atoms formed by two or more cyclic structures sharing two non-adjacent carbon atoms with each other and including that the carbon atoms may be oxo-substituted, and includes, for example, "5-11-membered bridged ring group", "6-11-membered bridged ring group", "5-10-membered bridged ring group", "7-9-membered bridged ring group", "7-8-membered bridged ring group", "9-10-membered bridged ring group" and the like. Specific examples include, but are not limited to: and the like.

The 3-to 10-membered heterocyclic group means a cyclic group containing 3 to 8 ring atoms (wherein at least one hetero atom is contained) and including carbon atom, nitrogen atom and sulfur atom which may be oxo-substituted, and includes, for example, "3-to 8-membered heterocyclic group", "3-to 7-membered heterocyclic group", "3-to 6-membered heterocyclic group", "4-to 7-membered heterocyclic group", "4-to 6-membered heterocyclic group", "5-to 7-membered heterocyclic group", "5-to 6-membered nitrogen-containing heterocyclic group", "6-to 8-membered heterocyclic group" and the like. Specific examples include, but are not limited to: aziridinyl, 2H-aziridinyl, diazacyclopropenyl, 3H-diazacyclopropenyl, azetidinyl, 1, 4-dioxanyl, 1, 3-dioxolanyl, 1, 4-dioxadienyl, tetrahydrofuryl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4, 5-dihydroimidazolyl, pyrazolidinyl, 4, 5-dihydropyrazolyl, 2, 5-dihydrothienyl, tetrahydrothienyl, 4, 5-dihydrothiazolyl, thiazolidinyl, piperidinyl, tetrahydropyridinyl, piperidonyl, tetrahydropyridinonyl, dihydropyridinonyl, piperazinyl, morpholinyl, 4, 5-dihydrooxazolyl, 4, 5-dihydroisoxazolyl, 2, 3-dihydroisoxazolyl, Oxazolidinyl, 2H-1, 2-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 3-thiazinyl, 6H-1, 3-thiazinyl, 2H-pyranyl, 2H-pyran-2-onyl, 3, 4-dihydro-2H-pyranyl and the like, with "5-to 6-membered heterocyclic group" being preferred.

The 3-14-membered fused heterocyclic group means a fused ring structure having 3 to 14 ring atoms (wherein at least one hetero atom is contained) and being connected by two or more ring structures sharing two adjacent atoms with each other, and includes carbon atoms, nitrogen atoms and sulfur atoms which may be oxo, and includes, for example, "4-12-membered fused heterocyclic group", "6-11-membered fused heterocyclic group", "5-10-membered fused heterocyclic group", "7-10-membered fused heterocyclic group", "9-10-membered fused heterocyclic group", "3-10-membered nitrogen-containing fused heterocyclic group", "9-10-membered nitrogen-containing fused heterocyclic group" and the like. Specific examples include, but are not limited to: tetrahydroimidazo [4,5-c ] pyridyl, 3, 4-dihydroquinazolinyl, 1, 2-dihydroquinoxalinyl, benzo [ d ] [1,3] dioxolyl, 1, 3-dihydroisobenzofuranyl, 2H-chromenyl, 2H-chromen-2-one, 4H-chromenyl, 4H-chromen-4-one, chromanyl, 4H-1, 3-benzoxazinyl, 4, 6-dihydro-1H-furo [3,4-d ] imidazolyl, 3a,4,6,6 a-tetrahydro-1H-furo [3,4-d ] imidazolyl, 4, 6-dihydro-1H-thieno [3,4-d ] imidazolyl, 4, 6-dihydro-1H-pyrrolo [3,4-d ] imidazolyl, benzimidazolyl, octahydro-benzo [ d ] imidazolyl, decahydroquinolinyl, hexahydrothienoimidazole, hexahydrofuroimidazole, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazolyl, octahydrocyclopenta [ c ] pyrrolyl, indolinyl, isoindolyl, benzoxazolinyl, benzothiazolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 1,2,3, 4-tetrahydroquinolinyl, 4H-1, 3-benzoxazine and the like.

3-14 membered spiroheterocyclyl means a compound containing 3-14 ring atoms (wherein at least one heteroatom is present)And (b) a spiro ring structure formed by two or more cyclic structures sharing one ring atom with each other while including a carbon atom, a nitrogen atom and a sulfur atom which may be oxo, and include, for example, "5-11-membered spiroheterocyclic group", "6-11-membered spiroheterocyclic group", "5-10-membered spiroheterocyclic group", "7-11-membered spiroheterocyclic group", "7-10-membered spiroheterocyclic group", "7-9-membered spiroheterocyclic group", "7-8-membered spiroheterocyclic group", "9-10-membered spiroheterocyclic group" and the like. Specific examples include, but are not limited to: and the like.

The 3-14-membered bridged heterocyclic group means a bridged ring structure containing 3 to 14 ring atoms (wherein at least one hetero atom is contained) and formed by two or more ring structures sharing two non-adjacent ring atoms and being bonded to each other, while including carbon atoms, nitrogen atoms and sulfur atoms which may be oxo-substituted, and includes, for example, "5-10-membered bridged heterocyclic group", "6-11-membered bridged heterocyclic group", "6-9-membered bridged heterocyclic group", "6-10-membered bridged heterocyclic group", "7-9-membered bridged heterocyclic group", "7-8-membered bridged heterocyclic group", "9-10-membered bridged heterocyclic group" and the like. Specific examples include, but are not limited to: and the like.

The 5-to 8-membered heteroaryl group means a cyclic group having an aromatic group containing 5 to 8 ring atoms (of which at least one heteroatom is contained), and including carbon atoms, nitrogen atoms and sulfur atoms, which may be oxo-substituted, and includes, for example, "5-to 7-membered heteroaryl group", "5-to 6-membered heteroaryl group" and the like. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2, 3-triazolyl, 1,2, 4-triazolyl, 1,2, 3-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,3, 4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, 1, 4-dioxadienyl, 2H-1, 2-oxazinyl, 4H-1, 2-oxazinyl, 6H-1, 2-oxazinyl, 4H-1, 3-oxazinyl, 6H-1, 3-oxazinyl, 4H-1, 4-oxazinyl, Pyridazinyl, pyrazinyl, 1,2, 3-triazinyl, 1,3, 5-triazinyl, 1,2,4, 5-tetrazinyl, azepinyl, 1, 3-diazacycloheptenyl, and azepinyl, etc., preferably "5-to 6-membered heteroaryl".

The 5-to 14-membered thick heteroaryl group means an unsaturated aromatic fused ring structure having 5 to 14 ring atoms (wherein at least one hetero atom is contained) and being connected by two or more ring structures sharing two adjacent atoms with each other, and includes carbon atoms, nitrogen atoms and sulfur atoms which may be oxo groups, and includes, for example, "5-to 10-membered thick heteroaryl group", "7-to 10-membered thick heteroaryl group", "9-to 10-membered thick heteroaryl group" and the like. Specific examples include, but are not limited to: benzofuranyl, benzoisoturanyl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, pyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, and the like.

In the present invention, L is a bond when not present, and phenyl is directly bonded with a substituent R₄And (4) connecting.

The "EGFR" of the present invention refers to an epidermal growth factor receptor (epidermal growth factor receptor), which is a transmembrane protein belonging to the receptor tyrosine kinase (ERBB) family and plays a major role in the transformation and growth of tumors. The amino acid sequence of EGFR is known to those skilled in the art and can be found in various public databases, such as the NCBI database.

The wild-type EGFR in the invention refers to the EGFR which is carried by individuals obtained from nature (namely individuals which are not artificially mutagenized) or is wild-type.

The mutant EGFR of the present invention refers to a mutant EGFR that is directly or indirectly produced from a wild-type gene by mutation.

The T790M mutation of EGFR in the present invention means that the 790 th amino acid residue of EGFR is changed from T to M, i.e., threonine at 790 th position of EGFR is replaced by methionine.

The present invention also provides a process for the preparation of compounds of formula (I), but is not limited to the following:

the abbreviations used in the present invention have the following meanings:

DCE is 1, 2-dichloroethane, TEA is triethylamine, THF is tetrahydrofuran, DCM is dichloromethane, DMF is N, N-dimethylformamide, DIPEA is N, N-diisopropylethylamine, EA is ethyl acetate.

The reaction equation is as follows:

wherein Y, W, Q, m, L, R in the above reaction equation₁、R₂、R₃、R₄、R₅、R₆、R₇、R_7′、R₈As described previously.

The reaction steps are as follows:

1. preparation of intermediate 1, intermediate 3 and intermediate 5

Intermediate 1, intermediate 3 and intermediate 5 were purchased or prepared separately.

2. Preparation of intermediate 2

Raw material 1 is dissolved in a suitable organic solvent, a suitable lewis acid solution (preferably zinc chloride in ether) is added under ice-bath, and after stirring for 1 hour, intermediate 1 is added. An appropriate organic base (preferably TEA) is dissolved in an appropriate organic solvent, added dropwise to the reaction solution, and allowed to warm to room temperature to complete the reaction. The reaction solution is concentrated and the crude product is separated by a suitable method (such as column chromatography) to obtain an intermediate 2. The organic solvent is preferably a mixed solvent of DCE and tert-butyl alcohol.

3. Preparation of intermediate 4

Dissolving intermediate 2 and intermediate 3 in appropriate organic solvent (such as 1, 4-dioxane), adding appropriate amount of acid (such as hydrochloric acid), heating to react, concentrating, and separating the crude product by appropriate method (such as column chromatography) to obtain intermediate 4.

4. Preparation of intermediate 6

Dissolving intermediate 4, intermediate 5 and appropriate base (preferably DIPEA) in appropriate organic solvent (such as DMF), heating to reaction completion, adding water and appropriate organic solvent (such as DCM), separating, washing organic phase with saturated saline, drying, concentrating, and separating crude product by appropriate method (such as column chromatography) to obtain intermediate 6.

5. Preparation of intermediate 7

Dissolving the intermediate 6 in a proper organic solvent (such as methanol), adding a proper catalyst (such as palladium carbon), introducing hydrogen, and reacting at room temperature. After the reaction, the catalyst was filtered off, and the filtrate was concentrated to give intermediate 7.

6. Preparation of intermediate 8

Dissolving the intermediate 7 in a mixed solvent of a proper organic solvent (such as THF) and water, adding 3-chloropropionyl chloride, reacting at room temperature to obtain a solution of an intermediate 8 after the reaction is finished, and directly using the solution in the next reaction without treatment.

7. Preparation of compounds of formula (I)

Adding appropriate base (such as NaOH solution) into the solution of intermediate 8, heating to reaction completion, cooling to room temperature, adding water, extracting with appropriate organic solvent (such as EA), combining organic phases, washing with saturated saline solution, drying, concentrating, and separating the crude product by appropriate method (such as column chromatography) to obtain the compound shown in formula (I).

"pharmaceutically acceptable salts" of the compounds of formula (I) according to the invention refer to the acidic functions (e.g. -COOH, -OH, -SO) present in the compounds of formula (I)₃H, etc.) with a suitable inorganic or organic cation (base), including salts with alkali or alkaline earth metals, ammonium salts, and salts with nitrogen-containing organic bases; and basic functional groups present in the compounds of formula (I) (e.g. -NH)₂Etc.) with suitable inorganic or organic anions (acids), including with inorganic acids, with organic carboxylic acids.

The "ester" of the compound represented by the general formula (I) of the present invention means an ester which can be formed by esterification with an alcohol when a carboxyl group is present in the compound represented by the formula (I), and an ester which can be formed by esterification with an organic acid, an inorganic acid, an organic acid salt or the like when a hydroxyl group is present in the compound represented by the formula (I). The ester can be hydrolyzed in the presence of acid or alkali to generate corresponding acid or alcohol.

The "stereoisomers" of the compounds of the general formula (I) of the present invention are classified into conformational isomers and configurational isomers, and configurational isomers are also classified into cis-trans isomers and optical isomers. "stereoisomers" refers to compounds of the invention when they contain one or more asymmetric centers, each of which independently produces two optical isomers, and the scope of the invention includes all possible optical isomers and diastereomeric mixtures and pure or partially pure compounds. The compounds of the present invention, if they contain an olefinic double bond, include both cis-and trans-isomers, unless otherwise specified. The compounds of the present invention may exist in tautomeric forms having different points of attachment of hydrogen through one or more double bond shifts. For example, a ketone and its enol form are keto-enol tautomers. Each tautomer and mixtures thereof are included in the compounds of the invention.

The invention further claims a pharmaceutical composition comprising the compound shown in the formula (I), pharmaceutically acceptable salts and esters thereof, and stereoisomers thereof and one or more pharmaceutically acceptable carriers and/or diluents, and the pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. Administered to a patient in need of such treatment by oral, parenteral, rectal, or pulmonary administration. For oral administration, it can be made into conventional solid preparations such as tablet, capsule, pill, granule, etc.; it can also be made into oral liquid, such as oral solution, oral suspension, syrup, etc. When the composition is formulated into oral preparations, appropriate filler, binder, disintegrating agent, lubricant, etc. can be added. For parenteral administration, it can be made into injection, including injection solution, sterile powder for injection and concentrated solution for injection. The injection can be prepared by conventional method in the existing pharmaceutical field, and can be prepared without adding additives or adding appropriate additives according to the properties of the medicine. For rectal administration, it can be made into suppository, etc. For pulmonary administration, it can be made into inhalant or spray.

The compounds represented by the general formula (I), pharmaceutically acceptable salts, esters and stereoisomers thereof can be administered to mammals, such as humans, by oral, parenteral (intravenous, intramuscular, subcutaneous or rectal), pulmonary, topical, etc. administration. The amount of the compound of the present invention in the pharmaceutical formulation is from 0.01 to about 100% by weight relative to the individual formulation. The dose varies depending on the administration subject, administration route, disease, disorder and the like, and for example, the compound of the present invention (as an active ingredient) can be orally administered to a diabetic patient (body weight: about 60kg) in the following doses: about 0.01-30mg per day, preferably about 0.1-20mg per day, more preferably about 1-20mg per day. The dose may be administered once a day or divided into several administrations.

The compounds of formula (I) or a pharmaceutically acceptable salt, ester or stereoisomer thereof, of the present invention may be administered alone or in combination with other therapeutic agents, particularly in combination with a second therapeutic agent selected from an anti-neoplastic agent and/or an immunosuppressive agent, said second therapeutic agent being selected from: antimetabolites including, but not limited to, for example, capecitabine, gemcitabine, and the like; growth factor inhibitors including, but not limited to, for example, pazopanib, imatinib, and the like; antibodies including, but not limited to, for example, herceptin, bevacizumab, and the like; mitotic inhibitors including, but not limited to, for example, paclitaxel, vinorelbine, docetaxel, doxorubicin, and the like; antineoplastic hormones including, but not limited to, letrozole, tamoxifen, fulvestrant, and the like; alkylating agents including, but not limited to, for example, cyclophosphamide, carmustine, and the like; platinoids including, but not limited to, for example, carboplatin, cisplatin, oxaliplatin, and the like; topoisomerase inhibitors, including but not limited to, for example, topotecan and the like; immunosuppressive species, including but not limited to, for example everolimus and the like. The components to be combined can be administered simultaneously or separately in sequential order, in the same formulation or in combination in separate and distinct formulations.

The compounds of formula (I), their pharmaceutically acceptable salts, their esters or their stereoisomers of the present invention are useful in the treatment of hyperproliferative diseases, including cancer and non-cancerous diseases, selected from: brain tumor, lung cancer, non-small cell lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, pancreatic cancer, breast cancer, head and neck cancer, cervical cancer, endometrial cancer, colorectal cancer, liver cancer, kidney cancer, esophageal adenocarcinoma, esophageal squamous cell carcinoma, solid tumor, non-hodgkin's lymphoma, central nervous system tumor (glioma, glioblastoma multiforme, gliosarcoma), prostate cancer, or thyroid cancer; non-cancerous diseases are, for example, benign hyperplasia of the skin or prostate.

The present invention also provides a pharmaceutical composition comprising a compound of the general formula (I) or a pharmaceutically acceptable salt, ester or stereoisomer thereof as described above in accordance with the present invention together with one or more pharmaceutically acceptable carriers and/or diluents. The compositions may be prepared by mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, of the present invention with one or more conventional pharmaceutical carriers and/or diluents. The composition can be prepared into any clinically or pharmaceutically acceptable dosage form, and is applied to a patient needing the treatment in a mode of oral administration, parenteral administration, pulmonary administration, local administration and the like.

Experiments prove that the compound has excellent anti-tumor effect and is expected to have excellent treatment effect on hyperproliferative diseases and chronic obstructive pulmonary diseases; and reduces the generation of drug resistance; in addition, the compound of the invention has simple preparation process and stable quality, and is easy to carry out large-scale industrial production.

The advantageous effects of the compounds of the present invention are further illustrated below by experiments, but this should not be understood as the compounds of the present invention have only the following advantageous effects.

Experimental example 1 in vitro enzymatic Activity test of the Compound of the present invention

And (3) testing the sample: the chemical names and preparation methods of some compounds of the invention are shown in the preparation examples of each compound.

Control drug: CO-1686, prepared according to the method of WO2012061299A1 (published as 2012.05.10).

The abbreviations used in the following experiments have the following meanings:

EDTA: ethylenediaminetetraacetic acid

DMSO, DMSO: dimethyl sulfoxide

SD: standard deviation of

The experimental method comprises the following steps: compounds were screened on the kinases EGFR and EGFR _ T790M using the method of Mobility Shift Assay in the presence of Km ATP.

1 preparation of reagents

(1) 1-fold kinase buffer (For EGFR and EGFR _ d746-750and EGFR (d746-750/T790M))

50mM HEPES(pH 7.5)、0.0015％Brij-35、10mM MgCl₂、10mM MnCl₂、10mM MnCl₂、2mM DTT；

(2) 1-fold kinase buffer (For EGFR T790M and EGFR _ L858R and EGFR _ T790M/L858R)

50mM HEPES(pH 7.5)、0.0015％Brij-35、5mM MgCl₂、2mM DTT

(3) Stopping liquid

100mM HEPES(pH 7.5)、0.015％Brij-35、0.2％Coating Reagent#3、50mM EDTA

(4)2.5 fold polypeptide solution

1-fold kinase buffer FAM-labeled peptide and ATP

(5)2.5 times enzyme solution

1-fold addition of enzyme to kinase buffer

2 preparation of the Compound

Compounds were made up into 50-fold stock solutions in DMSO, then 100. mu.L of stock solution was added to a new 96-well plate and diluted 1: 4-fold in DMSO with a total of 10 gradients. Then 10. mu.L of each concentration was placed in a new 96-well plate, and 90. mu.L of 1-fold kinase buffer was added to each well and mixed well.

3 Experimental methods

(1) The prepared compound solution in the above 96-well plate was transferred to a 384-well plate, and 5. mu.L of the compound solution was added to each well. I.e., a1 for 96-well plates to a1 and a2 for 384-well plates, a2 for 96-well plates to A3 and a4 for 384-well plates, and so on;

(2) preparing 2.5 times of enzyme solution, and adding the kinase into 1 time of kinase buffer solution;

(3) preparing 2.5 times polypeptide solution, adding FAM-labeled peptide and ATP into 1 time kinase buffer solution r;

(4) adding 2.5 times of enzyme solution into a prepared 384-well plate containing 5 μ L of compound solution, 10 μ L per well;

(5) incubating at room temperature for 10 min;

(6) adding 2.5 times of polypeptide solution into the 384-well plate, wherein each well is 10 mu L;

(7) incubating at 28 ℃ for a period of time;

(8) adding 25 mu L of stop solution to terminate the reaction;

(9) the Caliper takes the readings.

4 data processing

5 inhibition Rate calculation

1) Copying data of enzyme activity change from the Caliper program;

2) converting the data of the change of the enzyme activity into the data of the inhibition rate of the enzyme activity, wherein the formula is as follows:

the inhibition ratio (%) ═ (maximum-measured value)/(maximum-minimum) × 100. "maximum value": DMSO control; "minimum value": blank control.

3) Outputting the data into XLFit excel, and then obtaining IC₅₀The value is obtained. The formula is as follows:

Y＝Bottom+(Top-Bottom)/(1+(IC₅₀/X)^HillSlope)

6 results and conclusions of the experiment:

TABLE 1 IC of the Compounds of the invention against EGFR and EGFR T790M₅₀Value of

TABLE 2 IC of the compounds of the invention against EGFR and EGFR T790M₅₀Value of

TABLE 3 IC of the compounds of the invention against EGFR and EGFR T790M₅₀Value of

Table 4 IC of compounds of the invention against EGFR and EGFR T790M₅₀Value of

And (4) experimental conclusion:

the compounds of the invention selectively inhibited EGFR _ T790M better than the control.

Experimental example 2 in vitro cytological Activity assay of Compounds of the invention

PBS: phosphate buffer

DMSO, DMSO: dimethyl sulfoxide

1. Cell culture

1.1 preparation of cell suspension

① removing the culture medium from the flask;

② adding PBS to rinse the cells;

③ digesting with pancreatin, centrifuging, and collecting;

④ resuspended in medium containing 10% fetal bovine serum, counted and adjusted to 2X 10⁴Perml (H1975) or 3X 10⁴mL (a431) concentration (cell viability must be greater than 90%);

⑤ adding cell suspension into 96-well plate, each well has 100 μ L, i.e. 2000/well of H1975 cells and 3000/well of A431 cells;

⑥37℃,5％CO₂the culture was carried out overnight in an incubator.

2. Preparation of the Compounds

Compounds were made in 10mM (XZP-3613) or 5mM (XZP-3778) stock solutions in DMSO. Before use, the stock solution was first diluted to 4mM with DMSO and then diluted 1:4 times with DMSO in a gradient for a total of 10 gradients. Finally, 100-fold dilutions were made in the corresponding medium (i.e., 2. mu.L of diluted compound plus 198. mu.L of medium).

3. Contrast group setting

Vehicle control: 0.25% DMSO;

blank control: medium without cells.

4. Compound treatment of cells (24 hours after cell plating with compound)

Fill 50 μ L of growth medium containing 10% FBS per well, and then add 50 μ L of diluted compound to the well. The final concentration of test compound was:

test compound concentration: 10000,2500,625,156.25,39.06,9.76,2.44,0.61,0.15,0.04[ nM ]

II, placing the cell plate in an incubator for 72 hours, and detecting by a CTG method

The plate to be tested was allowed to equilibrate at room temperature for 30 minutes and 80. mu.L of medium was discarded. Add 60. mu.L of CTG reagent (CelltiterGlo kit), place on a rapid shaker for 2min and then 10min at room temperature. Values were read using Envision instruments.

5. Data analysis

IC₅₀And (3) calculating: inhibition (%) (vehicle control well read-test compound well read)/(vehicle control well read-blank) x 100, curve-fitted using GraphPad Prism 5 software to obtain IC₅₀The value is obtained.

Vehicle control well readings: value of 0.25% DMSO alone without compound addition, blank value: blank control values.

Inhibition of 100 × (HC-test compound pore reading)/(HC-LC)

6. Results of the experiment

TABLE 5 IC of the Compounds of the invention on H1975, A431 cells₅₀Value of

TABLE 6 IC of the Compounds of the invention on H1975, A431 cells₅₀Value of

And (4) experimental conclusion:

the compound of the invention has the characteristics of better inhibiting effect on cells with EGFR mutase (H1975) and cells with wild type EGFR (A431), and the inhibiting effect is obviously better than that of a contrast agent CO-1686.

4. Detailed description of the preferred embodiments

The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.

Preparation example 1 preparation of tert-butyl (4-bromo-3-nitrophenyl) carbamate

3-Nitro-4-bromoaniline (5.0g,23mmol), di-tert-butyl dicarbonate (7.6g,35mmol) and triethylamine (2.32g,23mmol) were dissolved in tetrahydrofuran (50mL) and the reaction was heated at 60 ℃ for 2 hours. The solvent was dried, water (50mL) was added, extraction was performed with ethyl acetate, the organic phase was separated, dried, concentrated, and column chromatography was performed (petroleum ether: ethyl acetate ═ 10:1) to obtain a product (5.8g, yield 79%).

Preparation example 2 preparation of tert-butyl 4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) carbamate

Tert-butyl (4-bromo-3-nitrophenyl) carbamate (5.8g,18.3mmol), N¹,N¹,N²-trimethylethyl-1, 2-diamine (3.73g,36.6mmol), potassium carbonate (5.05g,36.6mmol) were added to N, N-dimethylacetamide (75mL) and an oil bath at 100 ℃ for 8 hours. Ethyl acetate (500mL) was added, and the mixture was washed with saturated brine (500mL), separated, the organic phase was dried, concentrated, and subjected to column chromatography (dichloromethane: methanol 10:1) to obtain the product (1.87g, yield 30%).

Preparation example 3 preparation of tert-butyl (3-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -phenyl) carbamate

Tert-butyl 4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) carbamate (1.87g,5.5mmol) was dissolved in methanol (25mL), palladium on carbon catalyst (187mg) was added, hydrogen was replaced, and the mixture was stirred at room temperature for 2 hours. Suction filtration, washing with a small amount of methanol, concentration of the organic phase and column chromatography (dichloromethane: methanol ═ 10:1) gave the product (1.4g, 82% yield).

Preparation example 4 preparation of tert-butyl (3-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) carbamate

Tert-butyl (3-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -phenyl) carbamate (1.4g,4.54mmol) was dissolved in dichloromethane (30mL), triethylamine (459mg,4.54mmol) was added, acryloyl chloride (493mg,5.45mmol) was added under ice bath, the mixture was warmed to room temperature and stirred for 30 minutes, a saturated solution of sodium hydrogencarbonate (50mL) was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentration was performed, and column chromatography (dichloromethane: methanol ═ 10:1) gave the product (1.19g, yield 72%).

Preparation example 5 preparation of N- (5-amino-2- (2- (dimethylamino) ethyl) (meth) amino) phenyl) acrylamide

Tert-butyl (3-acrylamido-4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) carbamate (1.19g,3.28mmol) was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (25mL, V/V ═ 1:1), stirred at room temperature for 30 minutes, the solvent was dried, a saturated solution of sodium hydrogencarbonate (10mL) was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated, and column chromatography (dichloromethane: methanol ═ 10:1) was performed to obtain a product (803mg, yield 93%).

PREPARATION EXAMPLE 64 preparation of fluoro-2-methoxyaniline

4-fluoro-2-methoxy-1-nitrobenzene (15.00g,87.67mmol) was added to methanol (200mL), palladium on carbon (200mg) was added under nitrogen, and the mixture was reacted under hydrogen atmosphere for 16 hours, followed by suction filtration and concentration of the filtrate to obtain the title compound (11.67g, yield 94.3%).

PREPARATION EXAMPLE 74 preparation of fluoro-2-methoxy-5-nitroaniline

4-fluoro-2-methoxyaniline (6.5g,46mmol) was dissolved in portions in concentrated sulfuric acid (50mL) under ice bath, and after stirring for 30 minutes under ice bath, potassium nitrate (5.2g,51mmol) was added in portions, and after the addition, the temperature was raised to room temperature, and the reaction was stirred for 12 hours. After the reaction was completed, the reaction solution was poured into ice cubes, aqueous ammonia was added dropwise to adjust the pH to 8, ethyl acetate (200mL × 3) was extracted, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (petroleum ether: ethyl acetate ═ 3:1) to obtain the title compound (6.9g, yield 80%).

Preparation example 8 preparation of tert-butyl 4- (3-methoxy-4-nitrophenyl) -3, 6-dihydropyridine-1 (2H) -carboxylate

4-chloro-2-methoxy-1-nitrobenzene (8.0g,42.6mmol) and tert-butyl 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acidThe ester (13.2g,42.6mmol) was dissolved in a mixed solvent of DMF (50mL) and water (10mL), and potassium carbonate (11.8g,85.3mmol) and Pd (PPh) were added to the system₃)₄(986mg,0.85mmol), the reaction was stirred at 90 ℃ for 16 h under nitrogen. After the reaction was completed, water (100mL) was added, extraction was performed with ethyl acetate (100mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to obtain the title compound (10.0g, yield 70.0%).

PREPARATION EXAMPLE 94 preparation of (3-methoxy-4-nitrophenyl) -1,2,3, 6-tetrahydropyridine

Tert-butyl 4- (3-methoxy-4-nitrophenyl) -3, 6-dihydropyridine-1 (2H-formate (1.08g,3.23mmol) was dissolved in a mixed solution of dichloromethane and trifluoroacetic acid (15mL, V/V ═ 1:1), stirred at room temperature for 30 minutes, the solvent was dried, a saturated solution of sodium hydrogencarbonate (10mL) was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, and concentration was performed to obtain the product (728mg, 96% yield).

PREPARATION EXAMPLE 101 preparation of 4- (3-methoxy-4-nitrophenyl) -3, 6-dihydropyridin-1 (2H) -yl) ethyl-1-one

4- (3-methoxy-4-nitrophenyl) -1,2,3, 6-tetrahydropyridine (6.8g,29.0mmol) was dissolved in dichloromethane (100mL), triethylamine (5.87g,58.1mmol) was added slowly under ice bath, followed by acetyl chloride (4.56g,58.1mmol), stirring at 0 ℃ for 1 hour, and stirring at room temperature for 2 hours. After the reaction was completed, it was washed with water (50 mL. times.2), dried, filtered, and concentrated to obtain the title compound (7.7g, yield 96.0%).

Preparation example preparation of 111- (4- (4-amino-3-methoxyphenyl) piperidin-1-yl) ethyl-1-one

1- (4- (3-methoxy-4-nitrophenyl) -3, 6-dihydropyridin-1 (2H) -yl) ethyl-1-one (7.7g,27.9mmol) was dissolved in methanol (100mL), Pd/C (200mg) was added to the system under a nitrogen blanket, and the system was stirred at room temperature under a hydrogen atmosphere for 16 hours. After completion of the reaction, filtration and concentration of the filtrate gave the title compound (6.5g, yield 94.0%).

PREPARATION 124-chloro-N- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidin-2-amine

A zinc chloride ether solution (22mL,20mmol,1M) was added dropwise to a solution of 2, 4-chloro-5- (trifluoromethyl) pyrimidine (2.0g,9.22mmol) in t-butanol and 1, 2-dichloroethane (80mL,1:1) at 0 ℃ and stirred at 0 ℃ for 1 hour. Then, 2-methoxyaniline (1.14g,9.22mmol) and triethylamine (1.03g,10.14mmol) were added to the reaction system in this order, and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated under reduced pressure and the solid was recrystallized from methanol to give the title compound (2.1g, yield 75.0%).

Preparation example 13N⁴- (4-bromo-3-nitrophenyl) -N²Preparation of- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-chloro-N- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidin-2-amine (2.2g,7.24mmol) and 4-bromo-3-nitroaniline (2.36g,10.87mmol) were added to dioxane (60mL), and concentrated hydrochloric acid (2mL) was added dropwise. The reaction solution was then heated to 100 ℃ for 2 hours. After completion of the reaction, the reaction mixture was evaporated to dryness, and the residue was washed with ethyl acetate and dried to give the title compound (3.2g, yield 91.2%).

Preparation of 141- (4- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one

1- (4- (4-amino-3-methoxyphenyl) piperidin-1-yl) ethyl-1-one (560mg,2.26mmol) was dissolved in dichloromethane (10mL), triethylamine (228mg,2.26mmol) was added, 2, 4-dichloro-5-trifluoromethylpyrimidine (588mg,2.71 mmol) was slowly added, stirring was performed at room temperature for 2 hours, a saturated solution of sodium hydrogencarbonate (20mL) was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentration was performed, and reverse phase chromatography was performed (water: acetonitrile 10:1-3:2) to obtain a product (212mg, yield 22%).

Preparation example 154 preparation of- (3-methoxy-4-nitrophenyl) -1- (methylsulfonyl) -1,2,3, 6-tetrahydropyridine

4- (3-methoxy-4-nitrophenyl) -1,2,3, 6-tetrahydropyridine (2.3g,9.8mmol) and triethylamine (2.47g,24.5mmol) were added to dichloromethane (50mL), methanesulfonyl chloride (1.68g,14.7mmol) was added dropwise in an ice bath, and after completion of the addition, the mixture was allowed to warm to room temperature for 12 hours. Concentration and purification of the crude product by silica gel column chromatography (petroleum ether: ethyl acetate 4:1) gave the title compound (2.5g, 81.7% yield).

Preparation of 162-methoxy-4- (1- (methylsulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) aniline

4- (3-methoxy-4-nitrophenyl) -1- (methylsulfonyl) -1,2,3, 6-tetrahydropyridine (2.5g,8.0mmol) was dissolved in methanol (100mL), palladium on charcoal (400mg) was added, the mixture was stirred at room temperature under hydrogen for 16 hours, and the filtrate was filtered with suction and concentrated to give the title compound (2.1g, 92.3% yield).

Preparation 174-chloro-N- (2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine

2-methoxy-4- (1- (methylsulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) aniline (753mg,2.65mmol) was added to a mixed solvent of 1, 2-dichloroethane (20mL) and t-butanol (20mL), a zinc chloride diethyl ether solution (1mol/L,5.83mL,5.83mmol) was added under ice-bath, and after stirring for 1 hour, 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (575mg,2.65mmol) was added. Triethylamine (293mg,2.9mmol) was dissolved in a mixed solvent of 1, 2-dichloroethane (10mL) and t-butanol (10mL), and the solution was slowly dropped into the solution, allowed to warm to room temperature, and stirred for 16 hours. The reaction was concentrated directly, and the crude product was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (700mg, yield 56.8%).

PREPARATION EXAMPLE 183 preparation of methoxy-4-nitrophenol

A sodium hydroxide solution (39mL,117mmol,3M) was added to a solution of 4-fluoro-2-methoxy-1-nitrobenzene (10.0g,58.4mmol) in thionyl chloride (100mL) and reacted in an oil bath at 80 ℃ for 20 hours. After completion of the reaction, the pH was adjusted to 5 with concentrated hydrochloric acid, followed by extraction with ethyl acetate (100mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (9.0g, yield 90.1%).

Preparation example 194 preparation of fluoro-2-methoxyaniline

4-fluoro-2-methoxy-1-nitrobenzene (5.13g,30mmol) was dissolved in methanol (50mL), palladium on carbon catalyst (513mg) was added to displace the hydrogen, stirred at room temperature for 30 min, filtered with suction, and the organic phase was spin dried to give the product (3.60g, 85% yield).

Example 1 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 1)

(1) Preparation of 4-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine

2- (isopropylsulfonyl) aniline (1.99g,10mmol), 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (2.6g,12mmol) and a catalytic amount of trifluoroacetic acid (80mg) were added to tetrahydrofuran (30mL) and heated at 60 ℃ for 1.5 hours. The solvent was dried, ethyl acetate (50mL) was added, washed with saturated sodium bicarbonate (50mL), the organic phase was dried, concentrated, and separated by column chromatography (petroleum ether: ethyl acetate ═ 10:1-5:1) to give the product (188mg, yield 5%).

(2) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2- (isopropylsulfonyl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

4-chloro-N- (2- (isopropylsulfonyl) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine (188mg,0.495mmol), N- (5-amino- (2- ((dimethylamino) ethyl) (meth) amino) phenyl) acrylamide (196mg,0.75mmol), potassium carbonate (138mg,1.0mmol), Pd₂(dba)₃(18mg) and X-Phos (36mg) were added to 1, 4-dioxane (10mL) and heated at 100 ℃ for 5 hours under nitrogen. The solvent was dried, a saturated solution of sodium chloride (50mL) was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentration and reverse phase chromatography (water: acetonitrile 10:1-1:1) gave the product (12mg, yield 4%).

Molecular formula C₂₈H₃₄F₃N₇O₃S molecular weight 606LC-MS (M/z):303(M + H)⁺)/2

¹H-NMR(400MHz,CDCl₃)δ:9.80(s,1H),9.35(s,1H),8.49(d,1H,J＝2.4Hz),8.42(d,1H,J＝8.0Hz),8.35(s,1H),7.82(dd,1H,J₁＝1.6Hz,J₂＝8.0Hz),7.50-7.53(m,2H),7.11-7.16(m,2H),6.94(s,1H),6.39-6.44(m,1H),5.90-6.20(m,1H),5.74-5.77(m,1H),3.64-3.66(m,1H),3.00-3.30(m,4H),2.74(s,6H),2.70(s,3H),1.31(d,6H,J＝8.8Hz).

Example 2 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 2)

(1)N⁴- (4-bromo-3-nitrophenyl) -N²Preparation of- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

(2)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) -N²Preparation of (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-bromo-3-nitrophenyl) -N²- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (3.0g,6.2mmol) and N¹,N¹,N²-trimethylethane-1, 2-diamine (6.33g,62.0mmol) was added to DMA (50mL), and then the reaction solution was heated to 115 ℃ for 16 hours. After the reaction was completed, the reaction solution was diluted with water (100mL), extracted with ethyl acetate (100mL), and the ethyl acetate layer was evaporated under reduced pressure to dryness, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1-3:1) to obtain the title compound (2.5g, yield 7.98%).

(3)N¹- (2- (dimethylamino) ethyl) -N⁴- (2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -methylphenyl-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) -N²- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (0.4g,0.79mmol) and Pd/C (100mg, 10%) were added to methanol (30mL), and the system was stirred at room temperature under a hydrogen atmosphere for 1 hour. After the reaction was complete, it was filtered and concentrated to give the title compound (300mg, 79.7% yield).

(4) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

Acryloyl chloride (114mg,1.26mmol) was added dropwise to N at room temperature¹- (2- (dimethylamino) ethyl) -N⁴- (2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹A solution of (E) -methylphenyl-1, 2, 4-triamine (300mg,0.63mmol) in tetrahydrofuran (5mL) was stirred at 25 ℃ for 1 hour. After completion of the reaction, the reaction mixture was concentrated, dichloromethane (20mL) was added and washed successively with sodium hydrogencarbonate solution and brine, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was evaporated to dryness, and the residue was separated by TLC (dichloromethane: methanol ═ 20:1) to give the title compound (98mg, yield 29.3%).

Molecular formula C₂₆H₃₀F₃N₇O₂Molecular weight 529.6LC-MS (M/z) 530.1(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:10.19(s,1H),8.55(s,1H),8.27(s,1H),8.21(d,J＝7.6Hz,1H),8.43(dd,J＝2.0Hz,J＝8.4Hz,1H),7.18(d,J＝8.4Hz,1H),6.89–6.94(m,2H),6.82(d,J＝7.6Hz,1H),6.72(s,1H),6.43(s,1H),6.37–6.42(m,1H),5.90(s.,1H),5.70(d,J＝5.2Hz,2H),2.94(t,J＝4.8Hz,2H),2.71–2.75(m,7H),2.47(s.,2H),2.34(s.,6H),1.93(s,3H).

EXAMPLE 3 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 3)

(1)N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Dissolving 4-fluoro-2-methoxy-5-nitroaniline (149mg,0.8mmol) and 4-chloro-N- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidin-2-amine (250mg,0.8mmol) in dioxane (10mL), dropwise adding concentrated hydrochloric acid (0.1mL), reacting at 100 ℃ for 4 hours, cooling to room temperature, evaporating to remove solvent, adding saturated NaHCO₃The solution was adjusted to pH 8, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 30:1) to give the title compound (240mg, yield 66%).

(2)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²-(2-Methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (200mg,0.4mmol) and N¹,N¹,N²-trimethylethane-1, 2-diamine (61mg,0.6mmol) was dissolved in DMF (10mL), DIEA (78mg,0.6mmol) was added dropwise, and the reaction was heated to 85 ℃ for 8 hours. After cooling to room temperature, water (20mL) and ethyl acetate (50mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (150mL × 2), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol ═ 10:1) to give the title compound (160mg, yield 68%).

(3)N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of methylbenzene-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxyphenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (150mg,0.3mmol) was dissolved in methanol (50mL), and palladium on carbon (10%, 15mg) was added to replace hydrogen gas, followed by reaction at room temperature for 4 hours. After the reaction was complete, filtration and concentration of the filtrate gave the title compound (120.0mg, 85% yield).

(4) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide

Under ice bath, N is added¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Methylbenzene-1, 2, 4-triamine (120.0mg,0.2mmol) was dissolved in tetra-amineTo a mixed solution of tetrahydrofuran (5mL) and water (0.5mL), 3-chloropropionyl chloride (38.0mg,0.3mmol) was slowly added dropwise, allowed to warm to room temperature for reaction for 2 hours, extracted with ethyl acetate (150mL × 2), combined organic phases, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (130mg, 92% yield).

(5) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propionamide (130mg,0.2mmol) was dissolved in tetrahydrofuran (5mL), and a sodium hydroxide solution (1mL, 50%) was added dropwise to 65 ℃ to react for 10 hours, after completion of the reaction, water (10mL) was added, ethyl acetate was extracted (30mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 10:1) to obtain the title compound (94mg, yield 77%).

Molecular formula C₂₇H₃₂F₃N₇O₃Molecular weight 559.6LC-MS (M/z) 560.3(M + H)⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:10.00(s,1H),8.37(s,1H),8.31(s,1H),8.26(s,1H),8.01(s,1H),7.76(d,1H,J＝7.6Hz),7.03(s,1H),6.87-6.94(m,2H),6.62-6.63(m,1H),6.45(brs,1H),6.21(dd,1H,J₁＝16.8Hz,J₂＝14.8Hz),5.71-5.74(m,1H),3.79(s,3H),3.73(s,3H),2.95(brs,2H),2.72(s,3H),2.26-2.43(m,8H).

Example 4 preparation of N- (5- ((2- ((4- (1-acetylpiperidin-4-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acrylamide (Compound 5)

(1) Preparation of 1- (4- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one

(2) Preparation of N- (5- ((2- ((4- (1-acetylpiperidin-4-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide

1- (4- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one (212mg,0.49mmol), N- (5-amino-2 ((2- (dimethylamino) ethyl (methyl)) amino) phenyl) acrylamide (196mg,0.75mmol), potassium carbonate (138mg,1.0mmol), Pd₂(dba)₃(21mg) and X-Phos (42mg) were added to 1, 4-dioxane (10mL), nitrogen blanketed, and heated in an oil bath at 100 ℃ for 5 hours. Spin-drying the solvent, adding sodium chloride to saturateThe solution (50mL) was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, concentrated and separated by reverse phase chromatography (water: acetonitrile 10:1-3:2) to give the product (40mg, 12% yield).

The molecular formula is as follows: c₃₃H₄₁F₃N₈O₃Molecular weight: 654LC-MS (m/z): 655(M + H)⁺)

¹H-NMR(400MHz,MeOD)δ:8.40(s,1H),8.24(s,1H),8.10(s,1H),7.34(dd,1H,J₁＝2.4Hz,J₂＝8.8Hz),7.11(d,1H,J＝8.8Hz),6.89(d,1H,J＝1.6Hz),6.71(d,1H,J＝8.0Hz),6.55(dd,1H,J₁＝10.0Hz,J₂＝16.8Hz),6.35(dd,1H,J₁＝1.6Hz,J₂＝16.8Hz),5.78(dd,1H,J₁＝1.6Hz,J₂＝10.0Hz),4.64-4.68(m,2H),3.98-4.08(m,1H),3.87(s,3H),3.15-3.25(m,1H),2.95(t,2H,J＝10.0Hz),2.63-2.67(m,2H),2.63(s,3H),2.40(t,2H,J＝10.0Hz),2.25(s,6H),2.13(s,3H),1.93-1.87(m,2H),1.57-1.70(m,2H).

EXAMPLE 5 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 6)

(1) Preparation of 4- (3-methoxy-4-nitrophenyl) morpholine

4-fluoro-2-methoxy-1-nitrobenzene (8.55g,49.97mmol), N-diisopropylethylamine (12.90g,100.00mmol) and morpholine (4.79g,54.99mmol) were dissolved in N, N-dimethylformamide (80mL) and the temperature was raised to 85 ℃ for 6 hours. Cooling to room temperature, pouring into water (400mL), filtering, washing the filter cake with water, drying to obtain a crude product, adding the crude product into ethyl acetate (250mL), heating to 85 ℃ to dissolve the crude product completely, cooling to room temperature to precipitate a large amount of solid, performing suction filtration, washing the filter cake with ethyl acetate, and performing vacuum drying to obtain the title compound (7.83g, yield 65.8%).

(2) Preparation of 2-methoxy-4-morpholinoaniline

4- (3-methoxy-4-nitrophenyl) morpholine (7.78g,32.66mmol) was dissolved in methanol (250mL), palladium on carbon (300mg) was added, the reaction was carried out at room temperature for 6 hours, suction filtration was carried out, and the filtrate was concentrated to give the title compound (6.51g, yield 95.7%).

(3) Preparation of 4-chloro-N- (2-methoxy-4-morpholinophenyl) -5- (trifluoromethyl) pyrimidin-2-amine

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (2.17g,10.00mmol) was added to a mixed solution of 1, 2-dichloroethane (20mL) and t-butanol (20mL), a zinc chloride diethyl ether solution (1mol/L,22mL) was added under ice-cooling, after stirring for 1 hour, 2-methoxy-4-morpholinoaniline (2.08g,9.99mmol) was added, triethylamine (1.11g,11.00mmol) was dissolved in a solution of 1, 2-dichloroethane (10mL) and t-butanol (10mL), and the solution was slowly dropped into the above solution, allowed to naturally warm to room temperature, and stirred for 16 hours. The reaction was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (1.53g, yield 39.4%).

(4)N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4-morpholinophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-chloro-N- (2-methoxy-4-morpholinophenyl) -5- (trifluoromethyl) pyrimidin-2-amine (760mg,1.95mmol) and 4-fluoro-2-methoxy-5-nitroaniline (363mg,1.95mmol) were added to 1, 4-dioxane (20mL), hydrochloric acid (0.3mL) was added dropwise, and the mixture was heated to 100 ℃ for reaction for 16 hours. The reaction was directly concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 50:1) to give the title compound (700mg, yield 66.7%).

(5)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4-morpholinophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4-morpholinophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (677mg,1.26mmol), N¹,N¹,N²-trimethylethane-1, 2-diamine (142mg,1.39mmol) and N, N-diisopropylethylamine (325mg,2.52mmol) were dissolved in N, N-dimethylformamide (10mL), warmed to 85 ℃ for 6 hours, dichloromethane (90mL) and water (50mL) were added, extracted, the organic phase was washed with saturated brine (80mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (660mg, 84.1% yield).

(6)N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -methylbenzene-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4-morpholinophenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (660mg,1.06mmol) was dissolved in methanol (40mL), palladium on carbon (100mg) was added, the reaction was carried out at room temperature for 6 hours under a hydrogen atmosphere, suction filtration was carried out, and the filtrate was concentrated to give the title compound (570mg, yield 91.05%).

(7) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹-methylbenzene-1, 2, 4-triamine (376mg,0.64mmol) was dissolved in tetrahydrofuran (10mL) and water (1mL), 3-chloropropionyl chloride (81mg,0.64mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction mixture was concentrated to give a crude product (436mg) which was used directly in the next reaction.

(8) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4-morpholinophenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide (436mg crude) was dissolved in tetrahydrofuran (10mL), and a sodium hydroxide solution (6mol/L,2mL) was added, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, water (20mL) was added, ethyl acetate (30mL × 2) was extracted, the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 20:1) to obtain the title compound (180mg, two-step total yield 43.8%).

Molecular formula C₃₁H₃₉F₃N₈O₄Molecular weight 644.7LC-MS (m/z): 645.4(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:10.50(brs,1H),9.40(brs,1H),8.30(s,1H),8.16(d,J＝8.4Hz,1H),7.90-7.70(m,1H),7.60-7.40(m,1H),6.74(s,1H),6.50-6.41(m,4H),5.70(d,J＝12.0Hz,1H),3.89-3.85(m,11H),3.10(s,6H),2.70(s,3H),2.68-2.10(m,7H).

EXAMPLE 6 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (1-methyl-2-oxopiperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 8)

(1) Preparation of 4-bromo-1-methylpyridin-2 (1H) -one

Dissolving 4-bromopyridin-2 (1H) -one (3.0g,17.2mmol) in tetrahydrofuran (100mL), cooling to 0 ℃ under nitrogen, adding sodium hydride (mass fraction 60%, 0.69g,17.2mmol), heating to room temperature, stirring for 15 minutes, slowly adding methyl iodide (3.30mL,53.0mmol) dropwise, stirring for 16 hours at room temperature after the addition, adding water (80mL) and ethyl acetate (80mL), separating, washing the organic phase with saturated brine, drying over anhydrous sodium sulfate, and concentrating to obtain the title compound (2.85g, 88.2% yield).

(2) Preparation of tert-butyl (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate

Tert-butyl (4-bromo-2-methoxyphenyl) carbamate (2.5g,8.3mmol), pinacol diboron diborate (2.32g,9.1mmol) and potassium acetate (1.63g,16.6mmol) were added to N, N-dimethylformamide (100mL), 1' -bis (diphenylphosphino) ferrocene palladium dichloride dichloromethane complex (410mg,0.50mmol) was added under nitrogen protection, the temperature was raised to 80 ℃ for reaction for 16 hours, water and dichloromethane were added after cooling to room temperature, liquid separation was performed, the organic phase was washed 3 times with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate 100:1) to give the title compound (1.75g, yield 60.3%).

(3) Preparation of tert-butyl (2-methoxy-4- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) carbamate

Tert-butyl (2-methoxy-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenyl) carbamate (1.2g,3.4mmol), 4-bromo-1-methylpyridin-2 (1H) -one (0.64g,3.4mmol) and potassium carbonate (0.94g,6.8mmol) were added to 1, 4-dioxane (100mL) and water (20mL), 1' -bis (diphenylphosphino) ferrocene palladium dichloride (249mg,0.34mmol) was added under nitrogen protection, the temperature was raised to 90 ℃ for 6 hours, filtration was performed, the filtrate was concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (1.1g, yield 98.2%).

(4) Preparation of tert-butyl (2-methoxy-4- (1-methyl-2-oxopiperidin-4-yl) phenyl) carbamate

Tert-butyl (2-methoxy-4- (1-methyl-2-oxo-1, 2-dihydropyridin-4-yl) phenyl) carbamate (1.1g,3.3mmol) was dissolved in methanol (50mL), platinum dioxide (0.55g, mass ratio 50%) was added, stirring was performed at room temperature under a hydrogen atmosphere for 16 hours, suction filtration was performed, and the filtrate was concentrated to obtain the title compound (1.1g, yield 99.8%).

(5) Preparation of 4- (4-amino-3-methoxyphenyl) -1-methylpiperidin-2-one

Tert-butyl (2-methoxy-4- (1-methyl-2-oxopiperidin-4-yl) phenyl) carbamate (1.1g,3.3mmol) was dissolved in dichloromethane (10mL) and trifluoroacetic acid (10mL), stirred at room temperature for 0.5 h, and concentrated under reduced pressure to give the product (750mg, 97.3% yield).

(6) Preparation of 4- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one

A zinc chloride diethyl ether solution (1mol/L,4.0mL,4.0mmol) was added dropwise to a mixed solution (40mL,1:1) of tert-butanol and 1, 2-dichloroethane of 2, 4-chloro-5- (trifluoromethyl) pyrimidine (868mg,4.0mmol) at 0 ℃ and stirred at 0 ℃ for 1 hour, and then 4- (4-amino-3-methoxyphenyl) -1-methylpiperidin-2-one (750mg,3.2mmol) and triethylamine (404mg,4.0mmol) were added successively to the reaction system and stirred at 25 ℃ for 16 hours. The solvent was evaporated under reduced pressure and the crude product was purified by reverse phase column chromatography (methanol/water, 0-70%, plus 0.4% trifluoroacetic acid) to give the title compound (190mg, 14.3% yield).

(7) Preparation of 4- (4- ((4- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one

4- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one (190mg,0.46mmol) and 4-fluoro-2-methoxy-5-nitroaniline (85.6mg,0.46mmol) were added to 1, 4-dioxane (20mL), concentrated hydrochloric acid (0.5mL) was added dropwise, and the reaction mixture was heated to 100 ℃ for reaction for 2 hours. After the reaction was completed, the reaction solution was evaporated to dryness, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to obtain the title compound (240mg, yield 92.4%).

(8) Preparation of 4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one

Mixing 4- (4- ((4- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one (240mg,0.43mmol), N¹,N¹,N²-trimethylethane-1, 2-diamine (66mg,0.65mmol) and N, N-diisopropylethylamine (166mg,1.29mmol) were added to N, N-dimethylformamide (5mL), and the mixture was heated to 85 ℃ for reaction for 16 hours. After the reaction was completed, the reaction solution was diluted with water (20mL), extracted with ethyl acetate (50mL × 3), the organic phases were combined, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1-1:1) to give the title compound (235mg, yield 84.5%).

(9) Preparation of 4- (4- ((4- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one

4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one (235mg,0.36mmol) and palladium on charcoal (24mg, 10% by mass) were added to methanol (30mL) and reacted at 25 ℃ for 1.5 hours under a hydrogen atmosphere. After the reaction was completed, filtration was carried out, and the filtrate was concentrated to give the title compound (210mg, yield 94.6%).

(10) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (1-methyl-2-oxopiperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propionamide

3-Chloroacrylchloride (43mg,0.34mmol) was added dropwise to a mixed solution of 4- (4- ((4- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenyl) -1-methylpiperidin-2-one (210mg,0.34mmol) in tetrahydrofuran (5mL) and water (0.5mL) at 25 ℃ to react at 25 ℃ for 2 hours. The reaction solution was used directly in the next reaction.

(11) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (1-methyl-2-oxopiperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

To the reaction solution obtained in the above step, sodium hydroxide solution (33% by mass, 0.2mL,1.65mmol) was added, and the mixture was stirred at 65 ℃ for 7 hours, concentrated, and the crude product was purified by reverse phase column chromatography (methanol/water, 0-60%, 0.4% trifluoroacetic acid added) to give the title compound (45mg, 19.7% yield in two steps).

Molecular formula C₃₃H₄₁F₃N₈O₄Molecular weight 670.7LC-MS (M/z):671.4(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:10.02(s,1H),8.92(s,1H),8.30(s,2H),8.00(s,1H),7.68(s,1H),7.01(s,1H),6.95(s,1H),6.57(s,1H),6.48-6.32(m,1H),6.17(d,J＝16.8Hz,1H),5.71(d,J＝10.0Hz,1H),3.84(s,3H),3.72(s,3H),2.96-2.85(m,4H),2.84(s,3H),2.73(s,3H),2.39-2.29(m,4H),2.20(s,6H),1.99-1.86(m,2H).

EXAMPLE 7 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (1-methyl-2-oxopiperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 9)

(1) Preparation of 4- (3-methoxy-4-nitrophenyl) -1- (methylsulfonyl) -1,2,3, 6-tetrahydropyridine

(2) Preparation of 2-methoxy-4- (1- (methylsulfonyl) -1,2,3, 6-tetrahydropyridin-4-yl) aniline

(3) Preparation of 4-chloro-N- (2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine

(4)N⁴- (4-fluoro-3-nitrophenyl) -N²Preparation of (2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-chloro-N- (2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine (700mg,1.50mmol) and 4-fluoro-3-nitroaniline (234mg,1.50mmol) were added to 1, 4-dioxane (20mL), hydrochloric acid (0.3mL) was added dropwise, and the mixture was heated to 100 ℃ for reaction for 12 hours. The reaction mixture was suction-filtered under reduced pressure, and the obtained filter cake was the title compound (658mg, yield 75.0%).

(5)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) -N²Preparation of (2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-3-nitrophenyl) -N²- (2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (320mg,0.55mmol), N¹,N¹,N²-trimethylethane-1, 2-diamine (67mg,0.66mmol) and N, N-diisopropylethylamine (177mg,1.38mmol) were dissolved in N, N-dimethylformamide (10mL), heated to 85 ℃ for reaction for 6 hours, dichloromethane (90mL) and water (50mL) were added, the mixture was separated, washed with an organic phase saturated saline (80mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was subjected to silica gel column chromatography (dichloromethane: methanol ═ 40:1) to give the title compound as a brown solid (620mg, yield 82.6%).

(6)N¹- (2- (dimethylamino) ethyl) -N⁴- (2- ((2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -methylbenzene-1, 2, 4-triamine

N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) -N²- (2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (620mg,0.93mmol) was dissolved in methanol (40mL), palladium on charcoal (100mg) was added, the reaction was stirred at room temperature under hydrogen atmosphere for 6 hours, and the filtrate was concentrated by suction filtration to give the title compound (504mg, yield 85.1%).

(7) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- (2- ((2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide

Will N¹- (2- (dimethylamino) ethyl) -N⁴- (2- ((2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹-methylbenzene-1, 2, 4-triamine (230mg,0.36mmol) was dissolved in tetrahydrofuran (10mL) and water (1mL), 3-chloropropionyl chloride (137mg,1.08mmol) was added, and the reaction was stirred at room temperature for 2 hours. The reaction solution was used directly in the next step.

(8) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -5- ((2- ((2-methoxy-4- (1- (methylsulfonyl) piperidin-4-yl) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

Sodium hydroxide solution (6mol/L,2mL) was added to the reaction mixture obtained in the previous step, and the temperature was raised to 70 ℃ for reaction for 2 hours. The reaction solution was cooled to room temperature, water (20mL) was added, ethyl acetate (30mL × 2) was extracted, the organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 1:40) to give the title compound (100mg, two-step total yield 40.2%).

Molecular formula C₃₂H₄₁F₃N₈O₄Molecular weight of S690.8 LC-MS (m/z): 691.8(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:10.32(s,1H),8.64(s,1H),8.30(s,1H),8.23-8.16(m,2H),7.71(s,1H),7.46-7.44(m,1H),6.86(s,1H),6.69(s,1H),6.68-6.60(m,1H),6.49-6.31(m,2H),5.75-5.73(m,1H),3.95-3.93(m,2H),3.88(s,3H),2.91-2.73(m,10H),2.60-2.50(m,1H),2.36-2.29(m,8H),1.97-1.91(m,2H),1.87-1.72(m,2H).

Example 8 preparation of N- (5- ((2- ((4- (1-acetylpiperidin-4-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (meth) amino) phenyl) acrylamide (Compound 11)

(1) Preparation of 2-chloro-N- (4-fluoro-3-nitrophenyl) -5- (trifluoromethyl) pyridin-4-amine

4-fluoro-3-nitroaniline (1.0g,6.41mmol) and 2-chloro-4-iodo-5- (trifluoromethyl) pyridine (2.36g,7.69mmol) and cesium carbonate (4.17g,12.81mmol) were dissolved in 1, 4-dioxane (40mL) under N₂Adding Pd into the system under protection₂(dba)₃(283mg,0.31mmol) and Xantphos (359mg,0.62mmol), were reacted for 16 h with heating in an oil bath at 110 ℃. After the reaction, the mixture was concentrated, and the residue was subjected to silica gel column chromatography (PE: EA ═5:1) to yield the title compound (1.0g, 46.5% yield).

(2) Preparation of 1- (4- (4- ((4- ((4-fluoro-3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one

1- (4- (4-amino-3-methoxyphenyl) piperidin-1-yl) ethyl-1-one (0.75g,3.02mmol), 2-chloro-N- (4-fluoro-3-nitrophenyl) -5- (trifluoromethyl) pyridin-4-amine (0.85g,2.53mmol) and cesium carbonate (1.65g,5.06mmol) were dissolved in 1, 4-dioxane (20mL) under N₂Adding Pd into the system under protection₂(dba)₃(283mg,0.31mmol) and 4, 5-bis diphenylphosphino-9, 9-dimethylxanthene (359mg,0.62mmol), reacted in an oil bath at 110 ℃ for 16 hours. After the reaction was completed, it was concentrated, and the residue was purified by silica gel column chromatography (PE: EA ═ 5:1) to obtain the title compound (0.6g, yield 43.3%).

(3) Preparation of 1- (4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one

1- (4- (4- ((4- ((4-fluoro-3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one (0.6g,1.1mmol) and N¹,N¹,N²-trimethylethane-1, 2-diamine (0.35g,3.43mmol) was added to acetonitrile (20mL) and reacted at 85 ℃ in an oil bath for 16 hours. After completion of the reaction, the reaction solution was diluted with water (100mL), extracted with ethyl acetate (100 mL. times.3), and the organic phases were combined and concentrated under reduced pressure to give the title compound (0.59g, 85.5% yield).

(4) Preparation of 1- (4- (4- ((4- ((3-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one

1- (4- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one (0.59g,0.94mmol) and palladium on charcoal (100mg, 10%) were added to methanol (20mL), and the reaction was stirred at 25 ℃ for 1 hour under a hydrogen atmosphere. After the reaction was completed, filtration was performed, and the filtrate was concentrated to obtain the title compound (400mg, yield 71.2%).

(5) Preparation of N- (5- ((2- ((4- (1-acetylpiperidin-4-yl) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyridin-4-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide

Acryloyl chloride (60mg,0.66mmol) was added dropwise to a solution of 1- (4- (4- ((4- ((3-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperidin-1-yl) ethyl-1-one (100mg,0.17mmol) in tetrahydrofuran (5mL) at 25 ℃ and reacted for 1 hour at 25 ℃. After completion of the reaction, the reaction mixture was concentrated, followed by addition of dichloromethane (20mL), and washing with saturated sodium bicarbonate solution (20mL) and saturated brine (20mL) in this order, the organic phase was concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (DCM: MeOH ═ 20:1) to give the title compound (50mg, yield 45.9%).

The molecular formula is as follows: c₃₄H₄₂F₃N₇O₃Molecular weight: 653.8LC-MS (m/z): 654.4(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:10.38(s,1H),8.54(s,1H),8.23(s,1H),7.83(d,J＝7.6Hz,1H),7.21(d,J＝8.0Hz,1H),6.88-6.91(m,2H),6.66(s,2H),6.44-6.52(m,2H),6.29-6.36(m,2H),5.74(d,J＝9.6Hz,1H),4.75(d,J＝12.0Hz,1H),3.90(d,J＝12.8Hz,1H),3.82(s,3H),3.14(t,J＝12.8Hz,1H),2.84(s,1H),2.72(s,3H),2.56–2.64(m,2H),2.28–2.32(m,6H),2.13(s,3H),2.00(s,2H),1.80–1.88(m,2H),1.54–1.57(m,2H).

Example 9 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 12)

(1) Preparation of 3-methoxy-4-nitrophenol

4-fluoro-2-methoxy-1-nitrobenzene (5g,29.22mmol) was dissolved in dimethyl sulfoxide (30mL), aqueous sodium hydroxide (30mL,60mmol,2M) was added, and the reaction was heated to 80 ℃ and stirred for 16 hours. The reaction solution was adjusted to pH 6 with 1M dilute hydrochloric acid, ethyl acetate (50mL × 3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and dried by spinning, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to obtain the title compound (3.9g, yield 79.6%) as a pale yellow solid.

(2) Preparation of 4- (2-bromoethoxy) -2-methoxy-1-nitrobenzene

3-methoxy-4-nitrophenol (1.9g,11.24mmol) was dissolved in acetonitrile (30mL), potassium carbonate (3g,21.71mmol) and 1, 2-dibromoethane (2.5g,13.3mmol) were added, and the reaction was heated to 80 ℃ and stirred for 16 hours. The reaction solution was spin-dried, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 20:1) to give the title compound (1.8g, yield 58.1%) as a pale yellow solid.

(3) Preparation of (2- (3-methoxy-4-nitrophenoxy) ethyl) (methyl) sulfane

4- (2-Bromoethoxy) -2-methoxy-1-nitrobenzene (1.5g,5.43mmol) was dissolved in ethanol (20mL), aqueous sodium thiomethoxide (3.5mL,7mmol,2M) was added, and the reaction was stirred at 25 ℃ for 3 hours. The reaction solution was spun dry and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the title compound (1g, yield 76.9%) as a yellow solid.

(4) Preparation of 2-methoxy-4- (2- (methylsulfonyl) ethoxy) -1-nitrobenzene

(2- (3-methoxy-4-nitrophenoxy) ethyl) (methyl) sulfane (0.9g,3.7mmol) was dissolved in dichloromethane (10mL), cooled to 0 ℃ in an ice-water bath, m-chloroperoxybenzoic acid (85%, 2g,9.85mmol) was added, and the reaction was stirred at 25 ℃ for 16 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate (5mL), separated, the organic phase was washed with saturated aqueous sodium carbonate (5mL), dried over anhydrous sodium sulfate, filtered, the filtrate was dried by spinning, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to obtain the title compound (0.8g, yield 78.4%) as a pale yellow solid.

(5) Preparation of 2-methoxy-4- (2- (methylsulfonyl) ethoxy) aniline

2-methoxy-4- (2- (methylsulfonyl) ethoxy) -1-nitrobenzene (0.8g,2.9mmol) was dissolved in methanol (10mL), palladium on carbon (0.1g) was added, and the reaction was stirred under hydrogen pressure at 25 ℃ for 16 hours. The reaction mixture was filtered, and the filtrate was spin-dried to give the title compound (0.65g, yield 91.5%) as a pale yellow solid.

(6) Preparation of 4-chloro-N- (2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine

2, 4-chloro-5- (trifluoromethyl) pyrimidine (0.53g,2.44mmol) was dissolved in a mixed solvent of t-butanol and 1, 2-dichloroethane (5mL,1:1), cooled to 0 ℃ and added with a zinc chloride ether solution (2.9mL,2.9mmol,1M), and the reaction was stirred for 1 hour. A mixed solution of 2-methoxy-4- (2- (methylsulfonyl) ethoxy) aniline (0.6g,2.44mmol) in t-butanol and 1, 2-dichloroethane (5mL,1:1) was added, triethylamine (0.28g,2.77mmol) was added, and the reaction was stirred at 25 ℃ for 16 hours. The reaction solution was spin-dried, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (0.7g, yield 67.3%) as a yellow solid.

(7)N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-chloro-N- (2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine (0.5g,1.17 mmol) and 4-fluoro-2-methoxy-5-nitroaniline (0.22g,1.18mmol) were dissolved in dioxane (5mL), diluted hydrochloric acid (5mL,4M) was added, and the reaction was heated to 100 ℃ and stirred for 2 hours. The reaction solution was spin-dried, saturated aqueous sodium bicarbonate was added to adjust pH to 8, extraction was performed with ethyl acetate (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was spin-dried, and the resulting crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to obtain the title compound (0.53g, yield 77.9%) as a pale yellow solid.

(8)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (0.42g,0.73mmol) was dissolved in N, N-dimethylformamide (5mL), N, N, N' -trimethylethylenediamine (0.1g,0.98mmol) and diisopropylethylamine (0.18g,1.39mmol) were added, and the reaction was heated to 80 ℃ and stirred for 16 hours. The reaction solution was spin-dried, and the resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to obtain the title compound (0.36g, yield 75.0%) as a brown-yellow solid.

(9)N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -toluene-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (0.36g,0.55mmol) was dissolved in methanol (10mL), palladium on carbon (50mg) was added, and the reaction was stirred under hydrogen pressure at 25 ℃ for 2 hours. The reaction was filtered, and the filtrate was spin-dried to give the title compound (0.3g, yield 88.2%) as a pale yellow solid.

(10) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹-toluene-1, 2, 4-triamine (0.2g,0.32mmol) was dissolved in a mixed solvent of tetrahydrofuran (5mL) and water (1mL), cooled to 0 deg.C, 3-chloropropionyl chloride (60mg,0.47mmol) was added, and the reaction was stirred at 25 deg.C for 3 hours. Ethyl acetate (20mL) and a saturated aqueous solution of sodium chloride (20mL) were added to the solution, the solution was separated, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry, and the resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give the title compound (0.19g, yield 82.6%) as a pale yellow solid.

(11) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (2- (methylsulfonyl) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propionamide (0.13g,0.18mmol) was dissolved in tetrahydrofuran (5mL), an aqueous sodium hydroxide solution (0.2mL,0.2mmol,1M) was added, and the reaction was stirred at 60 ℃ for 1 hour. Ethyl acetate (20mL) and a saturated aqueous solution of sodium chloride (20mL) were added to the solution, the solution was separated, the aqueous phase was extracted with ethyl acetate (20mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was spun dry, and the resulting crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to obtain the title compound (56mg, yield 46.7%) as a pale yellow solid.

Molecular formula C₃₀H₃₈F₃N₇O₆Molecular weight of S681.7 LC-MS (M/z) 682.3(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:9.92(brs,1H),8.28(s,1H),8.18-8.19(m,1H),7.73(brs,1H),7.38(brs,1H),6.69(s,1H),6.35-6.49(m,3H),5.69(d,J＝11.6Hz,1H)4.43-4.44(m,2H),3.85(s,6H),3.40-3.49(m,2H),3.18-3.03(m,5H),2.41-2.82(m,11H).

Example 10 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 13)

(1) Preparation of 3-methoxy-N- (2- (methylthio) ethyl) -4-nitroaniline

2-aminoethanethiol hydrochloride (4.5g,40mmol) and iodomethane (5.7g,40mmol) were dissolved in water (20mL), a solution of sodium hydroxide (1.6g,40mmol) in water (20mL) was slowly added at 30 deg.C, after dropwise addition was complete, after stirring at 30 deg.C for 1 hour, 4-fluoro-2-methoxy-1-nitrobenzene (3.0g,17.5mmol) and triethylamine (5mL) were added, reaction was completed at 100 deg.C for 4 hours, extraction was performed with dichloromethane (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (petroleum ether: ethyl acetate 10:1) was performed to obtain the title compound (3.0g, yield 70.8%).

(2) Preparation of 3-methoxy-N- (2- (methylsulfonyl) ethyl) -4-nitroaniline

3-methoxy-N- (2- (methylthio) ethyl) -4-nitroaniline (3.0g,12.4mmol) was dissolved in dichloromethane (100mL), and m-chloroperoxybenzoic acid (4.3g,24.9mmol) was slowly added and reacted at 25 ℃ for 1 hour. After the reaction was completed, a sodium thiosulfate solution (150mL) was added, dichloromethane (100mL × 3) was extracted, organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and column chromatography (petroleum ether: ethyl acetate ═ 3:1) was performed to obtain the title compound (2.7g, yield 79.4%).

(3) 3-methoxy-N¹Preparation of (2- (methylsulfonyl) ethyl) benzene-1, 4-diamine

3-methoxy-N- (2- (methylsulfonyl) ethyl) -4-nitroaniline (2.7g,9.8mmol) was dissolved in methanol (50mL), palladium on carbon (270mg) was added, and the reaction was carried out under a hydrogen atmosphere at 25 ℃ for 12 hours. After the reaction was completed, filtration and concentration of the filtrate gave the title compound (2.0g, yield 83.3%).

(4)N¹- (4-chloro-5- (trifluoro)Methyl) pyrimidin-2-yl) -2-methoxy-N⁴Preparation of (2- (methylsulfonyl) ethyl) benzene-1, 4-diamine

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (890mg,4.1mmol) was dissolved in a mixed solution of tert-butanol and 1, 2-dichloroethane (30mL, V/V ═ 1:1) under ice-cooling, a 1M zinc chloride diethyl ether solution (8.2mL) was added dropwise thereto, and after completion of the addition, stirring was continued for 1 hour under ice-cooling, 3-methoxy-N was added dropwise¹A mixed solution of tert-butanol and 1, 2-dichloroethane (20mL, V/V ═ 1:1) of- (2- (methylsulfonyl) ethyl) benzene-1, 4-diamine (1.0g,4.1mmol) was added dropwise, and the reaction was carried out at 25 ℃ for 12 hours, after which the solvent was evaporated to dryness to give the title compound (700mg, 40.2% yield).

(5)N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-fluoro-2-methoxy-5-nitroaniline (307mg,1.65mmol) and N¹- (4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) -2-methoxy-N⁴- (2- (methylsulfonyl) ethyl) benzene-1, 4-diamine (700mg,1.65mmol) was dissolved in dioxane (20mL), concentrated hydrochloric acid (0.1mL) was added dropwise, the reaction was carried out at 100 ℃ for 4 hours, the reaction was completed, the reaction mixture was cooled to room temperature, the solvent was evaporated, a saturated sodium bicarbonate solution was added to adjust the pH to 8, the aqueous phase was extracted with ethyl acetate (30mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 30:1) to obtain the title compound (400mg, yield 42.2%).

(6)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxy)Preparation of the radical-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (400mg,0.7mmol) and N¹,N¹,N²-trimethylethane-1, 2-diamine (100mg,1.0mmol) was dissolved in DMF (10mL), N-diisopropylethylamine (130mg,1.0mmol) was added dropwise, and the reaction was heated to 85 ℃ for 8 hours. Cooling to room temperature, water (50mL) and ethyl acetate (50mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (50mL × 2), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by column chromatography (dichloromethane: methanol ═ 10:1) to give the title compound (280mg, yield 60.9%).

(7)N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -methylbenzene-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (280mg,0.43mmol) was dissolved in methanol (50mL), palladium on carbon (30mg) was added, and the reaction was carried out under hydrogen atmosphere at 25 ℃ for 4 hours. After the reaction was complete, filtration and concentration of the filtrate gave the title compound (200mg, 74.3% yield).

(8) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propionamide

Under ice bath, N is added¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹-methylbenzene-1, 2, 4-triamine (200mg,0.32mmol) was dissolved in a mixed solution of tetrahydrofuran (10mL) and water (1mL), 3-chloropropionyl chloride (51mg,0.4mmol) was slowly added dropwise, the mixture was raised to 25 ℃ to react for 2 hours, extracted with ethyl acetate (50mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (60mg, yield 26.2%).

(9) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((2- (methylsulfonyl) ethyl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propionamide (60mg,0.08mmol) was dissolved in tetrahydrofuran (5mL), sodium hydroxide solution (1mL, 50%) was added dropwise, allowed to rise to 65 ℃ for 10 hours, after the reaction was completed, water (20mL) was added, and extraction was performed with ethyl acetate (30mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane: methanol ═ 10:1) to obtain the title compound (25mg, yield 43.9%).

Molecular formula C₃₀H₃₉F₃N₈O₅Molecular weight of S680.7 LC-MS (M/z) 681.3(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:8.49(d,J＝8.4Hz,1H),8.32(s,1H),7.75(s,2H),7.58(s,1H),6.83(d,J＝8.0Hz,1H),6.76(s,1H),6.69(s,1H),6.35-6.39(m,1H),6.05-6.12(m,1H),5.57(d,J＝10.4Hz,1H),4.20-4.24(m,2H),3.91(s,3H),3.84(s,3H),3.40-3.48(m,2H),3.19(m,2H),3.07(s,3H),2.85(m,2H),2.70(s,3H),2.59(s,6H).

EXAMPLE 11 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (2- (methylsulfonylamino) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 14)

(1) Preparation of tert-butyl (2- (3-methoxy-4-nitrophenoxy) ethyl) carbamate

4-fluoro-2-methoxy-1-nitrobenzene (5g,29.2mmol) and tert-butyl (2-hydroxyethyl) carbamate (4.71g,29.2mmol) were dissolved in toluene (250mL), potassium hydroxide (3.28g,58.4mmol), water (50mL) and tetrabutylammonium bromide (0.94g,2.92mmol) were added, and the reaction was heated to reflux for 16 hours. Cooled to room temperature, water (200mL) was added, extracted with ethyl acetate (200mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the title compound (4.2g, 46% yield).

(2) Preparation of 2- (3-methoxy-4-nitrophenoxy) ethylamine

Tert-butyl (2- (3-methoxy-4-nitrophenoxy) ethyl) carbamate (4g,12.8mmol) was dissolved in dichloromethane (100mL), trifluoroacetic acid (10mL) was added, stirred at 25 ℃ for 16 hours, water (100mL) was added, dichloromethane was extracted (100 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to give the title compound (2.5g, 92% yield).

(3) Preparation of N- (2- (3-methoxy-4-nitrophenoxy) ethyl) methanesulfonamide

2- (3-methoxy-4-nitrophenoxy) ethylamine (2.5g,11.8mmol) was dissolved in dichloromethane (100mL), triethylamine (3.58g,35.4 mmol) was added, methanesulfonyl chloride (1.63g,14.2mmol) was added dropwise under ice bath, reaction was carried out at 25 ℃ for 16 hours, water (100mL) was added, dichloromethane was extracted (100 mL. times.2), dried over anhydrous sodium sulfate, and concentrated to obtain the objective compound (3.3g, yield 96.5%).

(4) Preparation of N- (2- (4-amino-3-methoxyphenoxy) ethyl) methanesulfonamide

N- (2- (3-methoxy-4-nitrophenoxy) ethyl) methanesulfonamide (3g,10.3mmol) was dissolved in methanol (50mL), palladium on carbon (300mg) was added, the reaction was allowed to proceed with hydrogen for 16 hours, the palladium on carbon was filtered off, and the filtrate was concentrated to give the objective compound (2.5g, yield 93%).

(5) Preparation of N- (2- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenoxy) ethyl) methanesulfonamide

Dissolving 2, 4-dichloro-5- (trifluoromethyl) pyrimidine (0.83g,3.84mmol) in a mixed solvent of 1, 2-dichloroethane/tert-butanol (1:1,20mL), adding a zinc chloride diethyl ether solution (1mol/L,7.68mL,7.68mmol) under ice bath, stirring for 1 hour, adding N- (2- (4-amino-3-methoxyphenoxy) ethyl) methanesulfonamide (1.0g,3.84mmol), dropwise adding triethylamine (1.16g,11.52mmol), stirring for 16 hours at a temperature of 25 ℃, concentrating, and subjecting the crude product to silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to obtain the target compound (600mg, yield 35.5%).

(6) Preparation of N- (2- (4- ((4- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenoxy) ethyl) methanesulfonamide

N- (2- (4- ((4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenoxy) ethyl) methanesulfonamide (200mg,0.454mmol) was dissolved in 1, 4-dioxane (20mL), 4-fluoro-2-methoxy-5-nitroaniline (84.6mg,0.454mmol) and concentrated hydrochloric acid (0.05mL) were added, the mixture was stirred at 100 ℃ for 16 hours, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 1:1) to give the objective compound (150mg, yield 56%).

(7) Preparation of N- (2- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenoxy) ethyl) methanesulfonamide

Reacting N- (2- (4- ((4- ((4-fluoro-2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyPhenoxy) ethyl) methanesulfonamide (150mg,0.254mmol) was dissolved in N, N-dimethylformamide (10mL), and N, N-diisopropylethylamine (98.5mg,0.762mmol) and N were added¹,N¹,N²-trimethylethane-1, 2-diamine (26mg,0.254mmol), heating to 100 ℃ for 16 hours reaction, adding water, precipitating a solid, and filtering by suction to obtain the target compound (85mg, yield 49.7%).

(8) Preparation of N- (2- (4- ((4- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenoxy) ethyl) methanesulfonamide

N- (2- (4- ((4- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenoxy) ethyl) methanesulfonamide (85mg,0.126mmol) was dissolved in methanol (5mL), palladium on carbon (8.5mg) was added, the reaction was carried out at room temperature under a hydrogen atmosphere for 16 hours, filtration was carried out by suction, and the filtrate was concentrated to give the title compound (77mg, yield 95%).

(9) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (2- (methylsulfonylamino) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide

N- (2- (4- ((4- ((5-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxyphenyl) amino) -5- (trifluoromethyl) pyrimidin-2-yl) amino) -3-methoxyphenoxy) ethyl) methanesulfonamide (77mg,0.12mmol) was dissolved in tetrahydrofuran/water (10:1,10mL), 3-chloropropionyl chloride (45.7mg,0.36mmol) was added, stirring was carried out at 25 ℃ for 1 hour, and the reaction was used directly in the next step.

(10) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (2- (methylsulfonylamino) ethoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

To the reaction solution in the previous step was added sodium hydroxide solution (5mol/L,10mL), stirred at 65 ℃ for 1 hour, concentrated, and the crude product was purified by silica gel column chromatography (methanol: dichloromethane ═ 1:50) to give the objective compound (35mg, two-step yield 41.9%).

Molecular formula C₃₀H₃₉F₃N₈O₆Molecular weight of S696.7 LC-MS (m/z): 349.2(M/2+ H)⁺)

¹H-NMR(400MHz,DMSO-d₆)δ:10.1(brs,1H),8.27(s,2H),8.08-8.01(m,2H),7.56(d,J＝8.0Hz,1H),7.27(t,J＝5.8Hz，1H),6.99(s,1H),6.55(s,1H),6.22(d,J＝16.8Hz,1H),5.73(d,J＝12.0Hz,1H),4.02-3.94(m,2H),3.76(s,7H),3.30-3.25(m,2H),3.18-3.06(m,2H),2.91(s,4H),2.67(s,4H),2.60-2.30(m,5H).

EXAMPLE 12 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 15)

(1) Preparation of (3- (3-methoxy-4-nitrophenoxy) propyl) (methyl) sulfane

3-methoxy-4-nitrophenol (1.7g,10.05mmol) was dissolved in tetrahydrofuran (30mL), 3- (methylthio) propan-1-ol (1.07g,10.08mmol) and 3-n-butylphosphine (3.25g,16.06mmol) and azobisformyldipiperidine (4.06g,16.09mmol) were added and reacted at 25 ℃ for 12 h. The reaction was completed, filtered, the filtrate was concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 2:1) to give the title compound (2.1g, yield 81.2%).

(2) Preparation of 2-methoxy-4- (3- (methylsulfonyl) propoxy) -1-nitrobenzene

(3- (3-methoxy-4-nitrophenoxy) propyl) (methyl) sulfane (2.0g,7.77mmol) was dissolved in methylene chloride (30mL), and perbenzoic acid (2.0g,11.59mmol) was added to react at 25 ℃ for 3 hours. The reaction was completed, water (100mL) was added, and extraction was performed with dichloromethane (3 × 50mL), the organic phases were combined and concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether: ethyl acetate ═ 3:1) to give the title compound (1.5g, yield 66.7%).

(3) Preparation of 2-methoxy-4- (3- (methylsulfonyl) propoxy) aniline

2-methoxy-4- (3- (methylsulfonyl) propoxy) -1-nitrobenzene (1.5g,5.18mmol) was dissolved in methanol (30mL), Raney's nickel was added, hydrogen was added, and the reaction was allowed to proceed overnight at 25 ℃. The reaction was complete, filtered, the filtrate concentrated and the residue was used directly in the next step (1.0g, 74.6% yield).

(4) Preparation of 4-chloro-N- (2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine

2, 4-dichloro-5- (trifluoromethyl) pyrimidine (0.84g,3.87mmol) was dissolved in a mixed solution of t-butanol (10mL) and 1, 2-dichloroethane (10mL), a zinc chloride diethyl ether solution (1N,8.5mL,8.50mmol) was added under ice-water bath, and stirred for 1h, and triethylamine (0.43g,4.26mmol) was added dropwise to the reaction mixture and stirring was continued for 20 min. 2-methoxy-4- (3- (methylsulfonyl) propoxy) aniline (1.0g,3.86mmol) was dissolved in tert-butanol (2mL) and 1, 2-dichloroethane (2mL), and the mixture was slowly added dropwise to the reaction mixture and reacted at 25 ℃ for 12 hours. The solution was spin dried, ethyl acetate (50mL) and water (30mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (2X 20mL), the organic layers were combined and concentrated, and the residue was recrystallized from ethyl acetate to give the title compound (500mg, 29.5% yield).

(5)N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-chloro-N- (2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine (170.0mg,0.386mmol) and 4-fluoro-2-methoxy-5-nitroaniline (72.0mg,0.387mmol) were dissolved in 1, 4-dioxane (5mL), 3 drops of concentrated HCl were added, heated to 100 ℃ and reacted for 12 h. The solution was spin dried, ethyl acetate (50mL) and water (20mL) were added, the layers were separated, the aqueous layer was extracted with ethyl acetate (2X 30mL), the organic layers were combined and concentrated, and the residue was recrystallized from ethyl acetate to give the title compound (180mg, 79.1% yield).

(6)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- (3)Preparation of- (methylsulfonyl) propoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (180.0mg,0.305mmol) was dissolved in N, N-dimethylformamide (5mL), and N was added¹，N¹，N²Trimethylethane-1, 2-diamine (47.0mg,0.460mmol) and N, N-diisopropylethylamine (118.0mg,0.913mmol), heated to 85 ℃ and reacted for 3 h. Ethyl acetate (20mL) and water (40mL) were added to separate the layers, the aqueous layer was extracted with ethyl acetate (2 × 10mL), the organic layers were combined and concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol ═ 30:1) to give the title compound (140mg, yield 68.4%).

(7)N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -methylbenzene-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (140mg,0.208mmol) was dissolved in methanol (10mL), palladium on carbon (50mg) was added, hydrogen was bubbled through, reaction was carried out at 25 ℃ for 12h, filtration, and the filtrate was concentrated to give the title compound (110mg, 82.4% yield).

(8) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹-methylbenzene-1, 2, 4-triamine (110.0mg,0.171mmol) was dissolved in a mixed solution of tetrahydrofuran (10mL) and water (2mL), and 3-chloropropionyl chloride (47.0mg,0.37mmol) was added to react at 25 ℃ for 2 hours. The solution was spun dry, ethyl acetate (20mL) was added, washed with saturated sodium bicarbonate (10mL), the aqueous phase was extracted with ethyl acetate (2X 10mL), the organic phases were combined and concentrated, and the residue was directly subjected to the next reaction (125.2mg, 100% yield).

(9) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- (3- (methylsulfonyl) propoxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propionamide (125.2mg,0.171mmol) was dissolved in tetrahydrofuran (10mL), sodium hydroxide solution (5N,1.0mL) was added, and the mixture was heated to 60 ℃ for 12 h. Ethyl acetate (20mL) and water (10mL) were added to separate the layers, the aqueous layer was extracted with ethyl acetate (2 × 10mL), the organic layers were combined and concentrated, and the residue was subjected to silica gel column chromatography (dichloromethane: methanol ═ 20:1) to give the title compound (65mg, yield 57.1%).

Molecular formula C₃₁H₄₀F₃N₇O₆Molecular weight of S695.8 LC-MS (M/z) 696.4(M + H)⁺)

¹H-NMR(400MHz,CDCl₃)δ:10.10(s,1H),8.30(s,1H),8.19(d,J＝7.6Hz,1H),7.77(brs,1H),7.55(brs,1H),6.80(s,1H),6.29-6.47(m,4H),5.69(d,J＝10.0Hz,1H),4.06(s,2H),3.89(s,3H),3.86(s,3H),3.25(t,J＝6.8Hz,2H),2.95(s,3H),2.89(s,2H),2.73(s,3H),2.28-2.32(m,10H).

Example 13 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 16)

(1) Preparation of 3- (3-methoxy-4-nitrophenoxy) tetrahydrofuran

3-methoxy-4-nitrophenol (1.0g,5.91mmol), 3-hydroxytetrahydrofuran (0.52g,5.91mmol) and triphenylphosphine (1.86g,7.09mmol) were dissolved in anhydrous THF (40mL), the reaction liquid nitrogen was cooled to 0 ℃ under protection, diethyl azodicarboxylate (1.5g,8.8mmol) was slowly added dropwise, and after completion of addition, the reaction solution was moved to 25 ℃ for reaction for 16 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was purified by column chromatography (PE: EA ═ 8:1) to give the title compound (1.2g, yield 84.8%).

(2) Preparation of 2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) aniline

3- (3-methoxy-4-nitrophenoxy) tetrahydrofuran (1.2g,5.02mmol) was dissolved in MeOH (20mL), followed by addition of palladium on carbon (0.2g, 10%) and hydrogen sparge for 2 hours at room temperature. After completion of the reaction, filtration and concentration of the filtrate gave the title compound (0.9g, 85.8% yield).

(3) Preparation of 4-chloro-N- (2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine

A zinc chloride diethyl ether solution (8.6mL,8.6mmol,1M) was added dropwise to a mixed solution of tBuOH and DCE (40mL, tBuOH: DCE ═ 1:1) of 2, 4-chloro-5- (trifluoromethyl) pyrimidine (0.94g,4.33mmol) at 0 ℃ and stirred at 0 ℃ for 1 hour, and then 2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) aniline (0.9g,4.3mmol) and triethylamine (0.53g,5.24mmol) were sequentially added to the reaction system and stirred at 25 ℃ for 16 hours. Concentrated under reduced pressure and the solid recrystallized from methanol (50mL) to give the title compound (1.0g, 59.6% yield).

(4)N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²Preparation of- (2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-chloro-N- (2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) -5- (trifluoromethyl) pyrimidin-2-amine (1.0g, 2.57mmol) and 4-fluoro-2-methoxy-5-nitroaniline (0.57g,3.06mmol) were added to dioxane (30mL), concentrated hydrochloric acid (1mL, 36%) was added dropwise, and the reaction was heated to 100 ℃ for 2 hours. After completion of the reaction, the reaction mixture was concentrated, and the residue was washed with ethyl acetate (50mL) and dried to give the title compound (0.9g, yield 65.0%).

(5)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (0.9g,1.67mmol) and N¹,N¹,N²-trimethylethane-1, 2-diamine (0.52g,5.09mmol) was added to acetonitrile (20mL) and heated to 85 ℃ for 2 hours. After completion of the reaction, the reaction solution was diluted with water (100mL), extracted with ethyl acetate (100 mL. times.3), and the organic phases were combined and concentrated under reduced pressure to give the title compound (0.7g, 67.5% yield).

(6)N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -methylphenyl-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (0.6g,0.96mmol) and palladium on carbon (100mg, 10%) were added to methanol (30mL), and the reaction was stirred at 25 ℃ for 1 hour under a hydrogen atmosphere. After the reaction was completed, filtration was carried out, and the filtrate was concentrated to obtain the title compound (500mg, yield 87.6%).

(7) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

Acryloyl chloride (30.6mg,0.34mmol) was added dropwise to N at 25 deg.C¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) oxy) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹A solution of (E) -methylphenyl-1, 2, 4-triamine (100mg,0.17mmol) in tetrahydrofuran (5mL) was reacted at 25 ℃ for 1 hour. After completion of the reaction, the reaction mixture was concentrated, dichloromethane (10mL) was added and the mixture was washed successively with saturated sodium bicarbonate solution (20mL) and saturated brine (20mL), the organic phase was concentrated under reduced pressure, and the residue was separated by thin layer chromatography (DCM: MeOH ═ 20:1) to give the title compound (50mg, yield 45.8%).

The molecular formula is as follows: c₃₁H₃₈F₃N₇O₅Molecular weight: 645.7LC-MS (m/z): 646.4(M + H)⁺)

¹H-NMR(400MHz,MeOD)δ:8.22(s,1H),7.74(d,J＝8.8Hz,1H),6.97(s,1H),6.54–6.60(m,2H),6.30–6.40(m,2H),5.81(d,J＝10.0Hz,1H),4.97(s,1H),3.87–3.98(m,7H),3.83(s,3H),3.25(s,2H),2.84(s,2H),2.71(s.,3H),2.55(s,6H),2.19–2.25(m,1H),2.06–2.10(m,1H).

Example 14 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 17)

(1) Preparation of N- (3-methoxy-4-nitrophenyl) tetrahydrofuran-3-amine

4-fluoro-2-methoxy-1-nitrobenzene (3.93g,23.0mmol), 3-aminotetrahydrofuran (2.0g,23.0mmol), triethylamine (2.32g,23.0mmol) were added to N, N-dimethylformamide (50 mL). Heating at 100 deg.C for 8 hr. Ethyl acetate (200mL) was added, washed with saturated brine, the organic phase was dried, spun-dried, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 5:1) to give the product (3.89g, yield 71.1%).

(2) 3-methoxy-N¹Preparation of (tetrahydrofuran-3-yl) benzene-1, 4-diamine

N- (3-methoxy-4-nitrophenyl) tetrahydrofuran-3-amine (3.89g,16.3mmol) was dissolved in methanol (25mL), a palladium-on-carbon catalyst (389mg) was added, hydrogen was replaced, the mixture was stirred at room temperature for 2 hours, filtered with suction, washed with a small amount of methanol, the solvent was spun off, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give a product (2.78g, yield 82.0%).

(3)N¹- (4-chloro-5- (trifluoromethyl) pyrimidin-2-yl) -2-methoxy-N⁴Preparation of (tetrahydrofuran-3-yl) benzene-1, 4-diamine

Reacting 3-methoxy-N¹- (tetrahydrofuran-3-yl) benzene-1, 4-diamine (2.78g,13.4mmol) was dissolved in a mixed solution (1:1,30mL) of t-butanol and 1, 2-dichloroethane, a solution (1.0mol/L,13.4mL,3.4mmol) of zinc chloride in diethyl ether was added, and after stirring for 30 minutes, 2, 4-dichloro-5-trifluoromethylpyrimidine (2.9)1g,13.4mmol) and triethylamine (1.35g,13.4mmol) were stirred at room temperature for 2 hours, the reaction was quenched by addition of water (200mL), extracted with dichloromethane, the solvent was dried by spinning off and recrystallized from methanol to give the product (2.72g, 52.1% yield).

(4) Preparation of 4-fluoro-2-methoxyaniline

(5) Preparation of 4-fluoro-2-methoxy-5-nitroaniline

4-fluoro-2-methoxyaniline (3.60g,25.5mmol) was dissolved in concentrated sulfuric acid (25mL), concentrated nitric acid (65%, 1.77mL,25.5mmol) was slowly added under ice bath, stirred at room temperature for 30 min, water (150mL) was slowly added, suction filtered, the solid was dissolved with dichloromethane, washed with saturated sodium bicarbonate solution, the organic phase was dried over anhydrous sodium sulfate, spun dry, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 10:1) to give the product (1.94g, 41% yield).

(6)N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²Preparation of (2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

4-fluoro-2-methoxy-5-nitroaniline (372mg,2.0m mol), N¹- (4-chloro-5)- (trifluoromethyl) pyrimidin-2-yl) -2-methoxy-N⁴- (tetrahydrofuran-3-yl) benzene-1, 4-diamine (778mg,2.0m mol), hydrochloric acid (74mg) were added to 1, 4-dioxane (10mL), and oil-bathed at 100 ℃ for 2 hours under nitrogen. The solvent was dried, a saturated solution of sodium bicarbonate (10mL) was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, dried, and the crude product was purified by silica gel column chromatography (petroleum ether: ethyl acetate ═ 4:1) to give the product (699mg, yield 65%).

(7)N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrophenyl) -N²Preparation of- (2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine

Will N⁴- (4-fluoro-2-methoxy-5-nitrophenyl) -N²- (2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (699mg,1.30mmol), N-trimethylethylenediamine (133mg,1.30mmol), diisopropylethylamine (168mg,1.30mmol) was dissolved in N, N-dimethylformamide (15mL), stirred at 100 ℃ for 2 hours, cooled to room temperature, ethyl acetate (200mL) was added, washed with saturated saline (200mL), the organic phase was dried, spun dried, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give a product (371mg, yield 46%).

(8)N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹Preparation of (E) -methylbenzene-1, 2, 4-triamine

Will N⁴- (4- ((2- (dimethylamino) ethyl) (methyl) amino) -2-methoxy-5-nitrobenzeneRadical) -N²- (2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) -5- (trifluoromethyl) pyrimidine-2, 4-diamine (371mg,0.60mmol) was dissolved in methanol (10mL), palladium on carbon catalyst (37mg) was added to replace hydrogen, and stirring was carried out at room temperature for 30 minutes, followed by suction filtration, and the organic phase was spin-dried to give the product (323mg, yield 91.5%).

(9) Preparation of 3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propanamide

Will N¹- (2- (dimethylamino) ethyl) -5-methoxy-N⁴- (2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) -N¹-methylbenzene-1, 2, 4-triamine (323mg,0.546mmol) was added to dichloromethane (5 mL). 3-chloropropionyl chloride (69.3mg,0.546mmol) was slowly added dropwise in an ice bath, after the addition was completed, the mixture was warmed to room temperature and stirred for 2 hours, saturated sodium bicarbonate (5mL) was added, extraction was performed with ethyl acetate (30mL), the organic phase was dried over anhydrous sodium sulfate, spin-dried, and the crude product was purified by silica gel column chromatography (dichloromethane: methanol ═ 10:1) to give a product (200mg, yield 53.8%).

(10) Preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide

3-chloro-N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) propionamide (200mg,0.294mmol) was dissolved in tetrahydrofuran (10mL), an aqueous sodium hydroxide solution (1.0mol/L,0.29mL,0.29mol) was added, and the mixture was stirred at 60 ℃ for 1 hour. After cooling to room temperature, a saturated solution of sodium chloride (20mL) was added, extraction was performed with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, spin-dried, and subjected to reverse phase chromatography (water: acetonitrile ═ 10:1-3:2) to obtain a product (41mg, yield 21.7%).

Molecular formula C₃₁H₃₉F₃N₈O₄Molecular weight 644.7LC-MS (M/z):645.3(M + H)⁺)

¹H-NMR(400MHz,MeOD)δ:8.15(s,1H),7.50(s,1H),6.94(s,1H),6.81-6.86(m,1H),6.25-6.45(m,3H),6.13(s,1H),5.80(d,1H,J＝9.2Hz),4.01-4.10(m,1H),3.92-3.95(m,2H),3.92(s,3H),3.80-3.83(m,1H),3.78(s,3H),3.63-3.65(m,1H),3.33-3.40(m,2H),3.07-3.15(m,2H),2.68-2.80(m,9H),2.20-2.30(m,1H),1.82-1.92(m,1H).

Example 15 preparation of N- (2- ((2- (dimethylamino) ethyl) (methyl) amino) -4-methoxy-5- ((2- ((2-methoxy-4- ((tetrahydrofuran-3-yl) amino) phenyl) amino) -5- (trifluoromethyl) pyrimidin-4-yl) amino) phenyl) acrylamide (Compound 23)

(1) Preparation of tert-butyl 4-acetylpiperazine-1-carboxylic acid ester

N-Boc-piperazine (3.70g, 20mmol) was dissolved in dichloromethane (50mL), triethylamine (2.02g, 20mmol) was added, acetyl chloride (1.57g, 20mmol) was added under ice bath, stirred at 25 ℃ for 30 minutes, saturated solution of sodium bicarbonate (50mL) was added, extracted with dichloromethane (100mL), the organic phase was dried over anhydrous sodium sulfate, spun dry, and column chromatographed (dichloromethane: methanol ═ 10:1) to give the product as a white solid (3.82g, 83.8% yield).

(2) Preparation of N-acetylpiperazine

Tert-butyl 4-acetylpiperazine-1-carboxylate (3.82g,16.8mmol) was dissolved in a mixed solution of dichloromethane (10mL) and trifluoroacetic acid (10mL), stirred at 25 ℃ for 30 minutes, the solvent was dried by spinning under reduced pressure, and column chromatography (dichloromethane: methanol ═ 10:1) gave a yellow oil (1.91g, yield 88.8%).

(3) Preparation of N-acetyl-N- (3-methoxy-4-nitrophenyl) piperazine

4-fluoro-2-methoxy-1-nitrobenzene (2.55g, 14.9mmol), N-acetylpiperazine (1.91g, 14.9mmol), potassium carbonate (2.47g, 17.9mmol) were added to N, N-dimethylacetamide (25 mL). The reaction was heated to 120 ℃ for 5 hours. Ethyl acetate (50mL) was added, and the mixture was washed with saturated brine (50mL), dried, and subjected to spin-drying to obtain a product by column chromatography (petroleum ether: ethyl acetate: 5:1) as a white solid (1.87g, yield 45.0%).

(4) Preparation of 1- (4- (4-amino-3-methoxyphenyl) piperazin-1-yl) ethanone

N-acetyl-N- (3-methoxy-4-nitrophenyl) piperazine (1.87g, 6.7mmol) was dissolved in methanol (25mL), palladium on carbon catalyst (187mg) was added, hydrogen was replaced, the mixture was stirred at 25 ℃ for 2 hours, filtered with suction, washed with a small amount of methanol (5mL), the solvent was dried by spinning, and separated by column chromatography (dichloromethane: methanol ═ 10:1) to give a brown solid (1.4g, yield 83.9%).

(5) Preparation of 2-chloro-N- (4-fluoro-3-nitrophenyl) -5- (trifluoromethyl) pyridin-4-amine

2-chloro-4-iodo-5- (trifluoromethyl) pyridine (2.36g, 7.68mmol), 4-fluoro-3-nitroaniline (1.0g,6.41mmol), cesium carbonate (4.2g, 12.9mmol), tris (dibenzylideneacetone) dipalladium (236mg), and 4, 5-bis diphenylphosphine-9, 9-dimethylxanthene (236mg) were added to 1, 4-dioxane (30 mL). Heating to 100 ℃ for 6 hours under the protection of nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether: ethyl acetate: 10:1) to give a pale yellow solid (1.0g, yield 46.5%).

(6) Preparation of 1- (4- (4- ((6- ((4-fluoro-3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone

2-chloro-N- (4-fluoro-3-nitrophenyl) -5- (trifluoromethyl) pyridin-4-amine (671mg, 2.0mmol), 1- (4- (4-amino-3-methoxyphenyl) piperazin-1-yl) ethanone (498mg, 2.0mmol), cesium carbonate (652mg, 2.0mmol), tris (dibenzylideneacetone) dipalladium (67mg), and 2-dicyclohexylphosphonium-2, 4, 6-triisopropylbiphenyl (67mg) were added to 1, 4-dioxane (30 mL). Heating to 100 ℃ for 6 hours under the protection of nitrogen. After completion of the reaction, the solvent was evaporated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate: 10:1-4:1) to give a pale yellow solid (275mg, yield 25.1%).

(7) Preparation of 1- (4- (4- ((6- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone

1- (4- (4- ((6- ((4-fluoro-3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (275mg, 0.50mmol), N, N, N-trimethylethylenediamine (51mg, 0.50mmol), N, N-diisopropylethylamine (65mg, 0.50mmol) was added to N, N-dimethylformamide (5mL), and heated to 100 ℃ for 5 hours. Saturated sodium chloride solution (30mL) was added, and the mixture was extracted with dichloromethane (50mL), and the organic phase was washed three times with water (50mL), dried over anhydrous sodium sulfate, dried, and subjected to column chromatography (dichloromethane: methanol ═ 10:1) to give the product as a pale yellow oily liquid (238mg, yield 75.4%).

(8) Preparation of 1- (4- (4- ((6- ((3-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone

1- (4- (4- ((6- ((4- ((2- (dimethylamino) ethyl) (methyl) amino) -3-nitrophenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (238mg, 0.38mmol) was dissolved in methanol (10mL), palladium on carbon catalyst (24mg) was added, hydrogen was replaced, stirring was carried out at 25 ℃ for 2 hours, suction filtration was carried out, washing was carried out with a small amount of methanol (5mL), and the solvent was spin-dried to give a pale yellow oily product (183mg, yield 80.7%).

(9) Preparation of N- (5- ((6- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -3- (trifluoromethyl) pyridin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -3-chloropropanamide

1- (4- (4- ((6- ((3-amino-4- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) amino) -5- (trifluoromethyl) pyridin-2-yl) amino) -3-methoxyphenyl) piperazin-1-yl) ethanone (183mg, 0.304mmol), triethylamine (31mg, 0.307mmol) were dissolved in dichloromethane (10mL), 3-chloropropionyl chloride (39mg, 0.307mmol) was added under ice bath, after completion of the addition, the temperature was raised to 25 ℃ and stirred for 30 minutes, the solvent was spin-dried, a saturated solution of sodium hydrogencarbonate (10mL) was added, extraction was performed with dichloromethane (30mL), the organic phase was dried over anhydrous sodium sulfate, spin-dried, and column chromatography (dichloromethane: methanol ═ 10:1) gave a pale yellow oily product (139mg, yield 66.2%).

(10) Preparation of N- (5- ((6- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -3- (trifluoromethyl) pyridin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) acrylamide

N- (5- ((6- ((4- (4-acetylpiperazin-1-yl) -2-methoxyphenyl) amino) -3- (trifluoromethyl) pyridin-2-yl) amino) -2- ((2- (dimethylamino) ethyl) (methyl) amino) phenyl) -3-chloropropanamide (139mg, 0.20mmol) was dissolved in tetrahydrofuran (10mL), an aqueous sodium hydroxide solution (1.0mol/L, 0.20mL, 0.20mol) was added, and the mixture was warmed to 60 ℃ and stirred for 1 hour. Cooled to 25 ℃, saturated sodium chloride solution (20mL) was added, extraction was performed with dichloromethane (30mL), the organic phase was dried over anhydrous sodium sulfate, spin-dried, and reverse phase chromatography was performed (water: acetonitrile ═ 10:1-3:2) to obtain the product as a white solid (85mg, yield 64.5%).

¹H-NMR(400MHz,CDCl3)δ:8.03(s,1H),7.81(s,1H),7.27-7.29(m,2H),7.07(dd,1H,J ₁＝8.4Hz,J₂＝2.0Hz),6.72-6.79(m,1H),6.60(d,1H,J＝1.6Hz),6.41-6.46(m,2H),6.15(s,1H),5.86(dd,1H,J ₁＝6.4Hz,J₂＝1.6Hz),3.80(s,3H),3.56-3.65(m,4H),3.25-3.28(m,2H),2.76(s,3H),3.12-3.15(m,2H),3.05-3.12(m,4H),2.74(s,6H),2.68(s,3H),2.16(s,3H)。

Claims

1. A compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

wherein,

y is selected from C or N;

w, Q are each independently selected from NH or O;

m is selected from 2;

l is selected from absent;

R₃selected from hydrogen atom, halogen atom, hydroxyl, amino, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy or C_1-4An alkylsulfonyl group;

R₄selected from a hydrogen atom, a 6-membered heterocyclic group optionally substituted by a substituent selected from a halogen atom, C_1-4Alkyl radical, C_1-4Alkylcarbonyl or C_1-4An alkylsulfonyl group;

R₇、R₇' is selected from a hydrogen atom;

R₈selected from a hydrogen atom, a methyl group or an ethyl group.

2. The compound of claim 1, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof:

wherein,

R₄selected from a hydrogen atom, a tetrahydropyranyl group, a tetrahydropyridonyl group, a dihydropyridinonyl group, a piperidino group, a piperidinyl group, a piperazinyl group or a morpholinyl group, optionally substituted by a substituent selected from a chlorine atom, a fluorine atom, a methyl group, an ethyl group, an acetyl group, a methanesulfonyl group or a propanesulfonyl group;

R₇、R₇' is selected from a hydrogen atom;

R₈selected from a hydrogen atom, a methyl group or an ethyl group.

3. The compound of claim 2, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from the group consisting of:

4. a compound represented by the general formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer thereof:

wherein,

y is selected from N;

w, Q are each independently selected from NH;

m is selected from 2;

l is selected from O or NH;

R₃selected from methyl, ethyl, trifluoromethyl, methoxy, ethoxy or trifluoromethoxy;

R₄selected from methyl, ethyl, propyl, isopropyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, piperazinyl or morpholinyl, optionally substituted with a substituent selected from acetyl, acetamido, methanesulfonyl or methanesulfonylamino;

R₇、R₇' is selected from a hydrogen atom;

R₈selected from a hydrogen atom, a methyl group or an ethyl group.

5. The compound of claim 4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, selected from:

6. a pharmaceutical composition comprising a compound of claim 1 or 4, or a pharmaceutically acceptable salt or stereoisomer thereof, in combination with one or more pharmaceutically acceptable carriers and/or diluents.

7. Use of a compound of claim 1 or 4, a pharmaceutically acceptable salt thereof, or a stereoisomer thereof, for the manufacture of a medicament for the treatment and/or prevention of EGFR mutation induced cancer diseases selected from non-small cell lung cancer, head and neck cancer, breast cancer, renal cancer, pancreatic cancer, esophageal cancer, prostate cancer, ovarian cancer, or any combination thereof, and EGFR T790M mutation induced drug resistant diseases.