Amino-substituted nitrogen-containing fused ring compound, pharmaceutical composition and application of amino-substituted nitrogen-containing fused ring compound

Abstract

The invention discloses an amino-substituted nitrogen-containing fused ring compound as well as a preparation method and application thereof. In particular to an amino-substituted nitrogen-containing fused ring compound shown as a general formula I '-1, I'-2 or I '-3, or pharmaceutically acceptable salts thereof, or enantiomers, diastereoisomers, tautomers, twist isomers, solvates, polymorphic substances or prodrugs thereof, a preparation method thereof and a pharmaceutical application thereof,

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and specifically, relates to a class of amino-substituted nitrogen-containing fused ring compounds, which have the activity of inhibiting EGFR cell proliferation and can be used to prepare drugs for the treatment and prevention of diseases related to the activity or expression of EGFR or ErbB. Background Art

[0002] Mutations affecting the intracellular catalytic domain or extracellular ligand-binding domain of the ErbB receptor may produce oncogenic activity (the ErbB protein family consists of 4 members, including ErbB-1, also known as epidermal growth factor receptor (EGFR) and Erb-2, also known as HER2 in humans). ErbB inhibitors are known treatments for various cancers. However, not every patient responds satisfactorily to this treatment. Therefore, there has long been a need in the art for new therapies that can address the variable responsiveness of cancer patients to known therapies. The present invention provides compositions and methods for preventing or treating cancer in patients with these oncogenic mutations, in the absence of observed variable responsiveness when treating patients with these ErbB mutants using existing standard of care treatments. Summary of the Invention

[0003] One of the technical problems to be solved by the present invention is to provide a novel EGFR inhibitor for preparing anti-tumor drugs. Through long-term and in-depth research, the inventors have prepared a class of structurally novel amino-substituted nitrogen-containing fused ring compounds represented by Formula I'-1, I'-2 or I'-3, and found that they have good inhibitory activity against EGFR enzyme, and the compounds can inhibit the EGFR protein at very low concentrations, and have excellent inhibitory activity against the cell proliferation of EGFR Del19-C797S / BaF3 and EGFR L858R-C797S / BaF3. Based on the above findings, the inventors have completed the present invention.

[0004] The present invention solves the above technical problems through the following technical solutions.

[0005] The present invention provides an amino-substituted nitrogen-containing fused ring compound represented by Formula I'-1, I'-2 or I'-3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof,

[0006]

[0007] Wherein:

[0008] U is selected from CR u or N, R uSelected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy;

[0009] M is selected from CR m or N, and R m is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano;

[0010] Z is selected from 3- to 12-membered heterocycloalkyl optionally substituted with one or more (preferably 1, 2 or 3) R Z (preferably 3-8 membered, more preferably 4-membered, 5-membered, 6-membered, 7-membered, 8-membered);

[0011] Each R Z is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl is optionally substituted with one or more R Za ;

[0012] Each R Za is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0013] T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more R T ;

[0014] Each R TIndependently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocycloalkyl or the 5- to 10-membered heteroaryl is optionally substituted by one or more R Ta substituents;

[0015] Each R Ta independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0016] Ar1 is optionally substituted by one or more R A1 substituted C6-C 10 aryl or C5-C 10 heteroaryl;

[0017] Each R A1 independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -O-(6-10 membered aryl), -O-(5-10 membered heteroaryl), -O-(C1-C6 alkyl)-(6-10 membered aryl), -O-(C1-C6 alkyl)-(5-10 membered heteroaryl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10An aryl, 3- to 10-membered heteroalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), -O-(6-10-membered aryl), -O-(5-10-membered heteroaryl), -O-(C1-C6 alkyl)-(6-10-membered aryl), -O-(C1-C6 alkyl)-(5-10-membered heteroaryl),, the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heteroalkyl, or the 5- to 10-membered heteroaryl is optionally substituted by one or more R A1a ; and

[0018] each R A1a independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heteroalkyl, or 5- to 10-membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heteroalkyl, or the 5- to 10-membered heteroaryl is optionally substituted by one or more R A1b ; and

[0019] each R A1b independently is halogen, CN, -OH, or -NH2;

[0020] Ar2 is

[0021] wherein ring E 1 is an optionally substituted C6-C g aryl or heteroaryl by one or more R 10 ;

[0022] wherein ring E 2 is an optionally substituted C5-C f aryl or heteroaryl by one or more R 10 ;

[0023] each R gIndependently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0024] Each R f Independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0025] Ring C is selected from substituted or unsubstituted 5- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, and the "substituted" means optionally substituted by one or more R b substituted;

[0026] Ring C1 is selected from substituted or unsubstituted 6- to 10-membered aryl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocycloalkyl; the "substituted" means optionally substituted by one or more R b substituted;

[0027] Each of said R b Independently is selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0028] The above-mentioned heteroaryl contains 1-3 heteroatoms independently selected from the group consisting of N, O, P, S or Se, and the above-mentioned heterocycloalkyl contains 1-3 heteroatoms independently selected from the group consisting of N, O, P or S.

[0029] In certain preferred embodiments of the present invention, some groups in the amino-substituted nitrogen-containing fused ring compounds represented by Formula I'-1, I'-2 or I'-3, or their pharmaceutically acceptable salts or enantiomers, diastereomers, tautomers, atropisomers, solvates, polymorphs or prodrugs are defined as follows, and the groups not mentioned are the same as those described in any embodiment of the present invention (abbreviation "in some preferred embodiments"),

[0030] In some preferred embodiments,

[0031] wherein

[0032] wherein

[0033] R 1 is H or a halogen, and the halogen is preferably F;

[0034] R e is hydrogen, a halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-NH(C1-C6 alkyl), -(C1-C3 alkyl)-N(C1-C6 alkyl)2; the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocycloalkyl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R e1 substituents;

[0035] each R e1 is independently a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0036] The range of Z is defined elsewhere in the text.

[0037] In some preferred embodiments,

[0038] wherein

[0039] wherein

[0040] X 1 is selected from -O-, -S- or -NR 3 -;

[0041] R a and R b are independently hydrogen, C 1-4 alkyl, and R c and R d are independently selected from hydrogen, a halogen or C 1-4 alkyl;

[0042] R 2 is hydrogen, a halogen, C 1-4 alkyl, C 1-4 alkoxy;

[0043] R 3 is hydrogen or C 1-4 alkyl, 3- to 6-membered cycloalkyl or heterocycloalkyl, preferably hydrogen or methyl;

[0044] Or R a together with R 2 and the atoms to which they are attached forms a 3- to 6-membered saturated carbocyclic ring, or R 2 together with R 3 and the atoms to which they are attached forms a 3- to 6-membered saturated ring, or R c together with R 2 and the atoms to which they are attached forms a 3- to 6-membered saturated carbocyclic ring, or R a together with R c and the atoms to which they are attached forms a 3- to 6-membered saturated ring;

[0045] R 1 is H or a halogen, said halogen being preferably F;

[0046] R e is hydrogen, a halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-NH(C1-C6 alkyl), -(C1-C3 alkyl)-N(C1-C6 alkyl)2,; said C1-C6 alkyl, said C2-C6 alkenyl, said C2-C6 alkynyl, said C3-C 10 cycloalkyl, said C6-C 10 aryl, said 3- to 10-membered heterocycloalkyl or said 5- to 10-membered heteroaryl is optionally substituted by one or more R e1 substituents;

[0047] Each R e1 is independently a halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0048] m is 1, 2 or 3;

[0049] n is 0, 1 or 2.

[0050] In some preferred embodiments, Ar 1 is a substituted 6-membered aryl or a substituted 6-membered heteroaryl.

[0051] In some preferred embodiments, R A1 is independently selected from: halogen, -CF3, C 1-6 alkyl, C2-C6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyaminocarbonyl, aryl C 1-6 alkoxy or C6 aryl.

[0052] In some preferred embodiments, X 1 is -NR 3 - or O.

[0053] In some preferred embodiments, R 2 is C 1-4 alkyl.

[0054] In some preferred embodiments, R a together with R 2 and the atoms to which they are attached form a 3-6 membered saturated carbocycle, preferably a 3-membered, 4-membered, 5-membered, 6-membered carbocycle, and R b , R c , R d are hydrogen.

[0055] In some preferred embodiments, R 2 together with R 3 and the atoms to which they are attached form a 3-6 membered saturated ring, preferably a 3-membered, 4-membered, 5-membered, 6-membered ring, and R a , R b , R c , R d are hydrogen.

[0056] In some preferred embodiments, R c together with R 2and the atoms to which they are attached form a 3-6 membered saturated carbon ring, preferably a 3-membered, 4-membered, 5-membered, 6-membered carbon ring, R a 、R b 、R d is hydrogen.

[0057] In some preferred embodiments, R a and R c and the atoms to which they are attached form a 3-6 membered saturated ring, preferably a 3-membered, 4-membered, 5-membered, 6-membered ring, R b 、R d is hydrogen.

[0058] In some preferred embodiments, R2 is hydrogen, and R a and R c and the atoms to which they are attached form a 3-6 membered saturated ring, preferably a 3-membered, 4-membered, 5-membered, 6-membered ring, R b 、R d is hydrogen.

[0059] In some preferred embodiments, R 3 is methyl, ethyl, n-propyl or n-butyl.

[0060] In some embodiments, X 1 is -NR 3 -, and R 2 is not hydrogen.

[0061] In some preferred embodiments, R 1 is hydrogen.

[0062] In some preferred embodiments, R 2 is methyl, ethyl, n-propyl or n-butyl, preferably methyl.

[0063] In some preferred embodiments,

[0064] Ar2 is

[0065] wherein G 1 、G 2 can each independently be C or N,

[0066] wherein ring E 2 is an optionally substituted C5-C f aryl with one or more R 10 ;

[0067] Each R gIndependently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl;

[0068] Each R f Independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl.

[0069] In some preferred embodiments, Ar1 is wherein B is selected from N or CR 4 , wherein R 4 is hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 6- to 10-membered aryl, 5- to 10-membered heteroaryl, -O-(6- to 10-membered aryl), -O-(5- to 10-membered heteroaryl), -O-(C1-C6 alkyl)-(6- to 10-membered aryl), -O-(C1-C6 alkyl)-(5- to 10-membered heteroaryl), -NH2-(C1-C4 alkyl), -NH2-(C1-C4 alkyl)-6-membered aryl, -NH2-(C1-C4 alkyl)-(5- to 6-membered heteroaryl), -COO(C1-C6 alkyl), C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkoxy-C6 aryl, C 1-6 alkoxy-C 5-6 heteroaryl, amino C 1-4 alkyl, C 1-6 alkylamino, C 1-6 aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl, C 1-6 alkoxyamino-carbonyl, aryl C 1-6 alkoxy or C6 aryl; said R4 is optionally substituted by one or more (preferably 1, 2 or 3) groups independently selected from the group consisting of halogen, amino, C1-C3 alkyl, C1-C3 alkoxy;

[0070] R 5 、R 5 '、R 6 、R 6 ' are each independently hydrogen, C1-C6 alkyl, -CF3, halogen, C2-C4 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl; said C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl may be substituted by one or more (1, 2 or 3) R B1 substituents, and R B1 is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl.

[0071] In some preferred embodiments, R 4 is selected from hydrogen, F, Cl, -O-6-membered aryl, 6- to 10-membered heteroaryl, -O-(C1-C6 alkyl)-(6- to 10-membered aryl) or -O-(C1-C6 alkyl)-(6- to 10-membered heteroaryl);

[0072] In some preferred embodiments, R 5 、R 5 '、R 6 、R 6 ' are each independently selected from hydrogen, halogen, C6-C 10 aryl, C2-C4 alkynyl;

[0073] In some preferred embodiments, R B1 is independently selected from halogen, C1-C6 alkyl.

[0074] In some preferred embodiments, R 5 、R 5 '、R 6 、R 6 ' are each independently preferably H, F, Cl, ethynyl,

[0075] In some preferred embodiments, at least two of R 5 、R 5 '、R 6 、R 6 ' are hydrogen.

[0076] In some preferred embodiments, B is N, and R 6 's are independently C6-C 10 aryl, 5- to 10-membered heteroaryl; the C6-C 10 aryl, 5- to 10-membered heteroaryl may be substituted by one or more R B1 's; each R B1 is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl.

[0077] In some preferred embodiments, Ar 1 has the structures shown in Formula ii-2, ii-3, or ii-4,

[0078]

[0079] wherein

[0080] X2 is O, NH, or N-Me;

[0081] X3 is CH or N;

[0082] t is 0 or 1;

[0083] R 5 's, R 5 's, R 6 's, R 6 's are independently hydrogen, C1-C6 alkyl, -CF3, or halogen, and the halogen is preferably F or Cl;

[0084] R 7 is halogen, preferably F, and the number of R 7 's is 1, 2, or 3.

[0085] In some preferred embodiments, the above-mentioned halogen is independently fluorine or chlorine;

[0086] In some preferred embodiments, the above-mentioned 3- to 10-membered cycloalkyl is independently 3- to 8-membered cycloalkyl, preferably 3- to 6-membered cycloalkyl;

[0087] In some preferred embodiments, the above-mentioned 3- to 12-membered heterocycloalkyl is independently 3- to 8-membered heterocycloalkyl, preferably 4-, 5-, 6-, 7-, or 8-membered heterocycloalkyl;

[0088] In some preferred embodiments, one or more of the above are independently 1, 2, 3 or 4;

[0089] In some preferred embodiments, the above 3- to 10-membered heterocycloalkyl is independently 3- to 8-membered heterocycloalkyl, preferably 4- to 6-membered heterocycloalkyl;

[0090] In some preferred embodiments, the above 5- to 10-membered heteroaryl is independently 6- to 10-membered heteroaryl, preferably 6- to 9-membered heteroaryl;

[0091] In some preferred embodiments, the above 3- to 6-membered saturated ring is a 3- to 6-membered saturated carbocyclic ring or a 3- to 6-membered saturated heterocyclic ring; preferably a 3-, 4-, 5- or 6-membered saturated ring;

[0092] In some preferred embodiments, the above 3- to 6-membered saturated carbocyclic ring is a 3-, 4-, 5- or 6-membered saturated carbocyclic ring.

[0093] In some preferred embodiments, R 5 is H or F.

[0094] In some preferred embodiments, R 6 is H, F, Cl or ethynyl.

[0095] In some preferred embodiments, R 1 is hydrogen.

[0096] In some preferred embodiments, R c and R d are hydrogen.

[0097] In some preferred embodiments, R b , R c and R d are hydrogen.

[0098] In some preferred embodiments, Z is selected from

[0099]

[0100] In some preferred embodiments, R e is selected from hydrogen, methyl,

[0101]

[0102] In some preferred embodiments, Ar1 is any of the following structures:

[0103]

[0104] In some preferred embodiments, Ar2 is any of the following structures:

[0105]

[0106] In some preferred embodiments, ring C is a substituted or unsubstituted pyrrolidine ring, piperidine ring, piperazine ring, benzene ring, or pyridine ring; the "substituted" means optionally substituted by one or more R b substituents.

[0107] In some preferred embodiments, ring C1 is a substituted or unsubstituted pyrrole ring, benzene ring, pyridine ring, or pyrimidine ring; the "substituted" means optionally substituted by one or more R b substituents.

[0108] In some preferred embodiments, each R b is independently selected from halogen, CN, -OH, -NH2, -O-(C1-C3 alkyl), -NH(C1-C3 alkyl), -N(C1-C3 alkyl)2, C1-C3 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C7 cycloalkyl, C6-C 10 aryl, 4-8 membered heteroalkyl, or 5-10 membered heteroaryl.

[0109] In some preferred embodiments, is selected from any one of the following structures:

[0110]

[0111] In some preferred embodiments, Z, T, U, M, Ar1, Ar2, B, ring C, ring C1, ring E1, ring E2, R1, Re, R 5 , R 5 ', R 6 , R 6 ', X2, X3, R a , R b , R c , R d , R 2 , R 3 , R 4 , R 7 each independently has the corresponding structure in any one of Compounds 1-71 of the Examples.

[0112] In some preferred embodiments, the nitrogen-containing fused ring compounds represented by Formulae I'-1, I'-2, or I'-3 are any one of the following structures:

[0113]

[0114]

[0115] Another object of the present invention is to provide a drug and its composition for treating or preventing tumors or autoimmune diseases. The technical solutions for achieving the above object are as follows:

[0116] On the one hand, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a nitrogen-containing fused ring compound represented by formula I'-1, I'-2 or I'-3, its or its pharmaceutically acceptable salt or enantiomer, diastereomer, geometric isomer, tautomer, torsional isomer, solvate, polymorph or prodrug, and a pharmaceutically acceptable carrier. In certain embodiments of the pharmaceutical composition, the pharmaceutical composition is formulated for intravenous administration, intramuscular administration, oral administration, rectal administration, inhalation administration, nasal administration, topical administration, ocular administration or otic administration. In other embodiments of the pharmaceutical composition, the pharmaceutical composition is a tablet, pill, capsule, liquid, inhalant, nasal spray solution, suppository, solution, emulsion, ointment, eye drop or ear drop. In other embodiments of the pharmaceutical composition, it further comprises one or more additional therapeutic agents.

[0117] On the other hand, the present invention provides the use of a nitrogen-containing fused ring compound represented by formula I'-1, I'-2 or I'-3, its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, or prodrug in the preparation of a drug for preventing, treating, or alleviating disorders or diseases mediated by abnormal EGFR activity.

[0118] On the other hand, the present invention provides the use of substance Z in the preparation of a drug for preventing, treating, or alleviating disorders or diseases mediated by abnormal EGFR activity;

[0119] The substance Z is a nitrogen-containing fused ring compound represented by formula I'-1, I'-2 or I'-3, its stereoisomer, geometric isomer, tautomer, pharmaceutically acceptable salt, or prodrug, or the pharmaceutical composition as described above.

[0120] On the other hand, the nitrogen-containing fused ring compounds represented by the general formula I'-1, I'-2 or I'-3 provided by the present invention, or pharmaceutically acceptable salts thereof, or their enantiomers, diastereomers, geometric isomers, tautomers, atropisomers, solvates, polymorphs or prodrugs, or the pharmaceutical compositions as described above are used for preparing a method involving the compound or composition for treating or preventing proliferative diseases (e.g., cancer (e.g., leukemia, melanoma, multiple myeloma), benign neoplasm, angiogenesis, inflammatory diseases, autoinflammatory diseases and autoimmune diseases) in a subject. The tumors are independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer, pancreatic cancer, etc.; the autoimmune diseases are independently selected from rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia or psoriasis; the inflammatory diseases are independently selected from osteoarthritis, gouty arthritis, ulcerative colitis and / or inflammatory bowel disease, etc.; the infectious diseases are independently selected from sepsis, septic shock, endotoxin shock, gram-negative sepsis and / or toxic shock syndrome.

[0121] On the other hand, the present invention provides the use of a substance Z in the preparation of a drug for treating or preventing proliferative diseases; the proliferative diseases can be cancer (e.g., leukemia, melanoma, multiple myeloma), benign neoplasm, angiogenesis, inflammatory diseases, infectious diseases, autoinflammatory diseases or autoimmune diseases; the cancers are independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer or pancreatic cancer; the autoimmune diseases are independently selected from rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia or psoriasis; the inflammatory diseases are independently selected from osteoarthritis, gouty arthritis, ulcerative colitis and / or inflammatory bowel disease; the infectious diseases are independently selected from sepsis, septic shock, endotoxin shock, gram-negative sepsis and / or toxic shock syndrome;

[0122] The substance Z is a nitrogen-containing fused ring compound represented by the general formula I'-1, I'-2 or I'-3, or a pharmaceutically acceptable salt thereof, or its enantiomers, diastereomers, tautomers, atropisomers, solvates, polymorphs or prodrugs, or the pharmaceutical composition as described above.

[0123] On the other hand, the present invention provides a method for treating or preventing disorders or diseases mediated by abnormal EGFR kinase activity, which comprises administering to a patient in need thereof a therapeutically effective amount of substance Z as described above;

[0124] The substance Z is a nitrogen-containing fused ring compound represented by general formula I'-1, I'-2 or I'-3, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, or the pharmaceutical composition as described above.

[0125] The term

[0126] Unless otherwise defined, all technical terms used herein have the same meaning as commonly understood by those skilled in the art to which the claimed subject matter pertains. Unless otherwise stated, all patents, patent applications, and published materials cited herein in their entirety are incorporated herein by reference.

[0127] It should be understood that the foregoing summary and the following detailed description are exemplary and explanatory only and do not limit the subject matter of the present invention in any way. In this application, unless otherwise specifically stated, the singular also includes the plural. It must be noted that, unless clearly stated otherwise in the text, the singular forms used in this specification and the claims include the plural forms of the indicated items. It should also be noted that, unless otherwise stated, the terms "or" or "or" mean "and / or". In addition, the term "comprising" and other forms, such as "including", "containing" and "having" are not restrictive.

[0128] Definitions of standard chemical terms can be found in reference works (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York). Unless otherwise stated, conventional methods within the skill of the art are employed, such as mass spectrometry, NMR, IR, and UV / VIS spectroscopy and pharmacological methods. Unless a specific definition is provided, the terms used herein in the descriptions related to analytical chemistry, organic synthetic chemistry, and pharmaceutical and medicinal chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, drug preparation, formulation and delivery, and the treatment of patients. For example, the instructions provided by the manufacturer for the kits can be utilized, or the reactions can be carried out and purification can be performed in a manner known in the art or as described in the present invention. Generally, the above-mentioned techniques and methods can be implemented according to the descriptions in various general and more specific documents cited and discussed in this specification, in a conventional manner well-known in the art. In this specification, groups and their substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.

[0129] When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes chemically equivalent substituents obtained when the structural formula is written from right to left. For example, -CH2O- is equivalent to -OCH2-.

[0130] The section headings used herein are for the purpose of organizing the article only and should not be construed as limiting the subject matter described. All documents or portions of documents cited in this application, including but not limited to patents, patent applications, articles, books, manuals of operations, and theses, are hereby incorporated by reference in their entirety.

[0131] In front of certain chemical groups defined herein, the total number of carbon atoms present in the group is represented by a simplified symbol. For example: C1-6 alkyl or C1-C6 alkyl refers to an alkyl group having a total of 1 to 6 (1, 2, 3, 4, 5, or 6) carbon atoms as defined below; C2-C6 alkenyl refers to an alkenyl group having 2 to 6 (2, 3, 4, 5, or 6) carbon atoms as defined below; C2-C6 alkynyl refers to an alkynyl group having 2 to 6 (2, 3, 4, 5, or 6) carbon atoms as defined below; C3-C8 cycloalkyl or 3-8 membered cycloalkyl refers to a cycloalkyl group having a total of 3 to 8 (1, 2, 3, 4, 5, 6, 7, or 8) carbon atoms as defined below; C6-C10 aryl or 6-10 membered aryl refers to an aryl group having a total of 6 to 10 (6, 7, 8, 9, or 10) carbon atoms as defined below. The total number of carbon atoms in the simplified symbol does not include the carbon present in the substituents that may be present in the group.

[0132] In front of certain chemical groups defined herein, the total number of carbon atoms and heteroatoms present in the group is represented by a simplified symbol. For example: C3-8 heterocycloalkyl, C3-C8 heterocycloalkyl, or 3-8 membered heterocycloalkyl refers to a heterocycloalkyl group having a total of 3 to 8 (3, 4, 5, 6, 7, or 8) carbon atoms and heteroatoms as defined below; C5-10 heteroaryl, C5-C10 heteroaryl, or 5-10 membered heteroaryl refers to a heteroaryl group having a total of 5 to 10 (5, 6, 7, 8, 9, or 10) carbon atoms and heteroatoms as defined below. The total number of carbon atoms and heteroatoms in the simplified symbol does not include the carbon atoms and heteroatoms present in the substituents that may be present in the group.

[0133] Except as otherwise provided above, when used in the specification and claims of this application, unless otherwise specifically indicated, the following terms have the meanings set forth below.

[0134] In the present application, the term "halogen" refers to fluorine, chlorine, bromine or iodine; "hydroxyl" refers to the -OH group; "hydroxyalkyl" refers to an alkyl group as defined below substituted by a hydroxyl group (-OH); "carbonyl" refers to the -C(=O)- group; "nitro" refers to -NO2; "cyano" refers to -CN; "amino" refers to -NH2; "substituted amino" refers to an amino group substituted by one or two alkyl groups, alkylcarbonyl groups, aralkyl groups, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino, alkylcarbonylamino, aralkylamino, heteroaralkylamino; "carboxyl" refers to -COOH.

[0135] In the present application, as a group or as part of another group (for example, used in groups such as halogen-substituted alkyl), the term "alkyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing no unsaturated bonds, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6) carbon atoms and connected to the rest of the molecule by a single bond. Examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, decyl, and the like.

[0136] In the present application, as a group or as part of another group, the term "alkenyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one double bond, having, for example, 2 to 10 (preferably 2 to 8, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as, but not limited to, vinyl, propenyl, allyl, but-1-enyl, but-2-enyl, pent-1-enyl, penta-1,4-dienyl, and the like.

[0137] In the present application, as a group or as part of another group, the term "alkynyl" means a straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, containing at least one triple bond and optionally one or more double bonds, having, for example, 2 to 10 (preferably 2 to 8, more preferably 2 to 6) carbon atoms and connected to the rest of the molecule by a single bond, such as, but not limited to, ethynyl, prop-1-ynyl, but-1-ynyl, pent-1-en-4-ynyl, and the like.

[0138] In the present application, as a group or as part of another group, the term "cycloalkyl" means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting only of carbon and hydrogen atoms, which may include fused ring systems, bridged ring systems or spiro ring systems, having for example 3 to 12 carbon atoms, preferably 3 to 8 carbon atoms, more preferably 3 to 6 carbon atoms, and which is saturated or unsaturated and may be attached to the remainder of the molecule via any suitable carbon atom by a single bond. Unless specifically indicated otherwise in this specification, the carbon atoms in the cycloalkyl may optionally be oxidized. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indenyl, 2,3-dihydroindenyl, 1,2,3,4-tetrahydro-naphthalenyl, 5,6,7,8-tetrahydro-naphthalenyl, 8,9-dihydro-7H-benzocyclohepten-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, fluorenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl, bicyclo[3.1.1]heptyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octenyl, bicyclo[3.2.1]octenyl, adamantyl, octahydro-4,7-methano-1H-indenyl and octahydro-2,5-methano-s-indacenyl, etc.

[0139] As a group or as part of another group, the term "heterocyclic group" or "heterocycloalkyl group" in the present application means a stable 3- to 20-membered non-aromatic cyclic group composed of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from nitrogen, phosphorus, oxygen, sulfur, and selenium. Unless otherwise specifically indicated in this specification, the heterocyclic group can be a monocyclic, bicyclic, tricyclic, or more-ringed ring system, which can include a fused ring system, a bridged ring system, or a spiro ring system; the nitrogen, carbon, or sulfur atoms in the heterocyclic group can be optionally oxidized; the nitrogen atoms can be optionally quaternized; and the heterocyclic group can be partially or fully saturated. The heterocyclic group can be connected to the rest of the molecule via a carbon atom or a heteroatom by a single bond. In a heterocyclic group containing fused rings, one or more rings can be an aryl group or a heteroaryl group as defined below, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a 4- to 10-membered heterocycle, more preferably a 4- to 8-membered heterocycle, and even more preferably a 4- to 6-membered heterocycle; the heteroatoms in the heterocyclic group are preferably 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur. Examples of the heterocyclic group include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]nonan-7-yl, 2-oxa-6-aza-spiro[3.3]heptan-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, azetidinyl, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuryl, oxazinyl, dioxolanyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, imidazolidinyl, quinuclidinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, dihydroindolyl, octahydroindolyl, octahydroisoindolyl, pyrrolidinyl, pyrazolidinyl, phthalimido, etc.

[0140] In the present application, as a group or as part of another group, the term "aryl group" means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably having 6 to 10 carbon atoms). For the purposes of the present invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or more-ringed ring system, and can also be fused with a cycloalkyl group or a heterocyclic group as defined above, provided that the aryl group is connected to the rest of the molecule via an atom on the aromatic ring by a single bond. Examples of the aryl group include, but are not limited to, phenyl, naphthyl, anthracenyl, phenanthryl, fluorenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1,4-benzoxazin-3(4H)-one-7-yl, etc.

[0141] In the present application, the term "arylalkyl" means an alkyl group as defined above substituted by an aryl group as defined above.

[0142] In the present application, as a group or as part of another group, the term "heteroaryl" means a 5- to 16-membered conjugated ring system group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, phosphorus, and sulfur within the ring. Unless otherwise specifically indicated in the present specification, the heteroaryl can be a monocyclic, bicyclic, tricyclic, or more ring system, and can also be fused with the cycloalkyl or heterocyclic group defined above, provided that the heteroaryl is connected to the rest of the molecule through a single bond via an atom on the aromatic ring. The nitrogen, carbon, or sulfur atoms in the heteroaryl can be optionally oxidized; the nitrogen atoms can be optionally quaternized. For the purposes of the present invention, the heteroaryl is preferably a 5- to 12-membered aromatic group, more preferably a 5- to 10-membered aromatic group, and even more preferably a 5- to 6-membered aromatic group; the heteroatoms in the heteroaryl preferably include 1 to 4 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur, and more preferably include 1, 2, or 3 heteroatoms independently selected from nitrogen, oxygen, phosphorus, and sulfur in a 5- to 6-membered aromatic group. Examples of heteroaryl include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indolyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, indolizinyl, isoindolyl, indazolyl, isoindazolyl, purinyl, quinolinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, pteridinyl, carbazolyl, carbolinyl, phenanthridinyl, phenanthrolinyl, acridinyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazolyl, cinnolinyl, quinazolinyl, phenylthio, indolizinyl, phenanthroline, isoxazolyl, phenoxazinyl, phenothiazinyl, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthyridine, [1,2,4]triazolo[4,3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1,2,4]triazolo[4,3-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine, etc.

[0143] In the present application, the term "heteroarylalkyl" means an alkyl group as defined above substituted by a heteroaryl group as defined above.

[0144] In the present application, "optional" or "optionally" means that the subsequent described event or condition may or may not occur, and this description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl is substituted or unsubstituted, and this description includes both the substituted aryl and the unsubstituted aryl.

[0145] In the present application, "one or more" means 1, 2, 3, 4, 5, or 6.

[0146] As used herein, the terms "moiety", "structural moiety", "chemical moiety", "group", and "chemical group" refer to specific fragments or functional groups in a molecule. A chemical moiety is generally considered a chemical entity that is incorporated into or attached to a molecule.

[0147] "Stereoisomers" refer to compounds that are composed of the same atoms, bonded by the same bonds, but have different three-dimensional structures, including enantiomers, diastereoisomers (geometric isomers, conformational isomers). The present invention will cover various stereoisomers and their mixtures.

[0148] When the compounds of the present invention contain an olefinic double bond, unless otherwise specified, the compounds of the present invention are intended to include E- and Z-geometric isomers.

[0149] "Tautomers" refer to isomers formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the present invention will also be included within the scope of the present invention.

[0150] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral carbon atoms and may thus give rise to enantiomers, diastereoisomers, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The present invention is intended to include all possible isomers, as well as their racemic and optically pure forms. The compounds of the present invention can be prepared by selecting racemates, diastereoisomers, or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as crystallization and chiral chromatography.

[0151] Conventional techniques for the preparation / isolation of individual isomers include chiral synthesis from suitable optically pure precursors or the resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high-performance liquid chromatography. See, for example, Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; A. M. Stalcup, Chiral Separations, Annu. Rev. Anal. Chem. 3:341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIA OF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Chem. Res. 1990, 23, 128.

[0152] In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0153] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that are able to retain the biological effectiveness of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, etc.; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate, trifluoroacetate, propionate, hexanoate, octanoate, decanoate, undecenoate, glycolate, gluconate, lactate, sebacate, adipate, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate, cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, benzenesulfonate, p-toluenesulfonate, alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalenedisulfonate, etc. These salts can be prepared by methods known in the art.

[0154] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that can maintain the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, etc. Preferred inorganic salts are ammonium salts, sodium salts, potassium salts, calcium salts and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, polyamine resins, etc. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. These salts can be prepared by methods known in the art.

[0155] "Polymorphs" refer to different solid crystalline phases of certain compounds of the present invention in the solid state due to the presence of two or more different molecular arrangements. Some compounds of the present invention can exist in more than one crystal form, and the present invention aims to include all crystal forms and their mixtures.

[0156] Generally, crystallization will produce solvates of the compounds of the present invention. The term "solvate" as used in the present invention refers to an aggregate containing one or more molecules of the compounds of the present invention and one or more solvent molecules. The solvent can be water, in which case the solvate is a hydrate. Alternatively, the solvent can be an organic solvent. Thus, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., as well as the corresponding solvated forms. The compounds of the present invention can form true solvates, but in some cases, they can also retain only indeterminate water or a mixture of water plus some indeterminate solvent. The compounds of the present invention can react in a solvent or precipitate or crystallize out from a solvent. The solvates of the compounds of the present invention are also included within the scope of the present invention.

[0157] The present invention also includes prodrugs of the above compounds. In the present application, the term "prodrug" refers to a compound that can be converted into the bioactive compound of the present invention under physiological conditions or by solvolysis. Therefore, the term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of the compound of the present invention. When administered to an individual in need, the prodrug may be inactive, but is converted into the active compound of the present invention in vivo. Prodrugs are generally rapidly converted in vivo to produce the parent compound of the present invention, for example, by hydrolysis in the blood. Prodrugs generally provide the advantages of solubility, tissue compatibility, or slow release in mammalian organisms. Prodrugs include known amino protecting groups and carboxyl protecting groups. Specific methods for preparing prodrugs can be referred to Saulnier, M.G., et al., Bioorg. Med. Chem. Lett. 1994, 4, 1985-1990; Greenwald, R.B., et al., J. Med. Chem. 2000, 43, 475.

[0158] In the present application, "pharmaceutical composition" refers to a preparation of the compound of the present invention and a medium generally accepted in the art for delivering a bioactive compound to a mammal (such as a human). This medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to facilitate the administration to an organism, facilitate the absorption of the active ingredient, and thus exert its biological activity.

[0159] As used herein, the term "pharmaceutically acceptable" refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the present invention and is relatively non-toxic, that is, the substance can be administered to an individual without causing adverse biological reactions or interacting with any component contained in the composition in an adverse manner.

[0160] In the present application, "pharmaceutically acceptable carrier" includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been permitted by the relevant government regulatory authorities for use in humans or livestock.

[0161] The "tumors", "diseases related to abnormal cell proliferation", etc. described in the present invention include, but are not limited to, diseases such as leukemia, gastrointestinal stromal tumor, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, squamous cell carcinoma of the lung, adenocarcinoma of the lung, breast cancer, prostate cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, intestinal cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, etc.

[0162] As used herein, the terms "preventive", "prevent", and "prevention" include reducing the likelihood of the occurrence or exacerbation of a disease or disorder in a patient.

[0163] As used herein, the terms "treat" and other similar synonyms include the following meanings:

[0164] (i) Preventing the occurrence of a disease or disorder in a mammal, particularly when such mammal is predisposed to the disease or disorder but has not been diagnosed as having the disease or disorder;

[0165] (ii) Inhibiting a disease or disorder, i.e., arresting its development;

[0166] (iii) Alleviating a disease or disorder, i.e., causing the state of the disease or disorder to regress; or

[0167] (iv) Relieving the symptoms caused by the disease or disorder.

[0168] As used herein, the terms "effective amount", "therapeutically effective amount" or "pharmaceutically effective amount" refer to the amount of at least one agent or compound that, when administered, is sufficient to alleviate to some extent one or more symptoms of the disease or disorder being treated. The result can be the reduction and / or alleviation of signs, symptoms or causes, or any other desired change in a biological system. For example, an "effective amount" for treatment is the amount of a compound disclosed herein that is required to provide a clinically significant alleviation of the disorder. Techniques such as dose escalation trials can be used to determine the effective amount suitable for any individual case.

[0169] As used herein, the terms "administer", "administering", "administration" and the like refer to methods capable of delivering a compound or composition to the desired site for biological action. These methods include, but are not limited to, oral route, duodenal route, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration and rectal administration. Techniques for the administration of the compounds and methods described herein are well known to those of skill in the art, such as those discussed in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.

[0170] As used herein, the terms "drug combination", "drug combination therapy", "combination therapy", "administering other treatment", "administering other therapeutic agent", etc. refer to a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, which includes fixed and non-fixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration to a patient of at least one compound described herein and at least one synergistic agent in the form of a single entity or a single dosage form. The term "non-fixed combination" refers to the simultaneous administration, co-administration or sequential administration at variable intervals to a patient of at least one compound described herein and at least one synergistic agent in the form of separate entities. These also apply to cocktail therapies, such as the administration of three or more active ingredients.

[0171] Those skilled in the art should also understand that in the methods described below, the functional groups of intermediate compounds may need to be protected by appropriate protecting groups. Such functional groups include hydroxyl, amino, mercapto and carboxylic acid. Suitable hydroxyl protecting groups include trialkylsilyl or diarylalkylsilyl (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl), tetrahydropyranyl, benzyl, etc. Suitable protecting groups for amino, amidino and guanidino groups include tert-butoxycarbonyl, benzyloxycarbonyl, etc. Suitable mercapto protecting groups include -C(O)-R" (where R" is alkyl, aryl or aralkyl), p-methoxybenzyl, triphenylmethyl, etc. Suitable carboxyl protecting groups include alkyl, aryl or aralkyl esters.

[0172] The protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T.W. and P.G.M. Wuts, Protective Groups in Organic Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymer resin.

[0173] Based on the common general knowledge in the art, the above preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0174] The reagents and raw materials used in the present invention are all commercially available.

[0175] The positive and progressive effects of the present invention are as follows: The present invention relates to novel compounds having the structural features of general formula I' (I'-1, I'-2 and I'-3), which selectively inhibit the enzymatic activity of EGFR and significantly inhibit the growth of various tumor cells, and are a class of therapeutic drugs with a completely new mechanism of action. Detailed Description of the Invention

[0176] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the described examples. For the experimental methods without specific conditions indicated in the following examples, they are carried out according to conventional methods and conditions, or selected according to the product specifications. Unless otherwise stated, percentages and parts are by weight percentage and weight parts.

[0177] Among them, the Chinese names of the reagents represented by chemical formulas or English letter abbreviations are listed as follows:

[0178] iPrOH: isopropanol; EtOH: ethanol; DCM: dichloromethane; TFA: trifluoroacetic acid; MeOH: methanol; NaOH: sodium hydroxide; HCl: hydrogen chloride; TEA: triethylamine; Raney Ni: Raney nickel; 1,4 - dioxane: 1,4 - dioxane; NaH: sodium hydride; H2O: water; Pd / C: palladium on carbon; H2: hydrogen; HATU: 2-(7 - azabenzotriazol - 1 - yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DMF: N,N - dimethylformamide; THF: tetrahydrofuran; Boc2O: di - tert - butyl dicarbonate; NBS: N - bromosuccinimide; NCS: N - chlorosuccinimide; NIS: N - iodosuccinimide; MeCN: acetonitrile; DIPEA / DIEA: N,N - diisopropylethylamine; NaBH4: sodium borohydride; AcOH: acetic acid; ethyl acetate: ethyl acetate; NaBH3CN: sodium cyanoborohydride; K2CO3: potassium carbonate; Cs2CO3: cesium carbonate; nBuLi: n - butyllithium; LiAlH4: lithium aluminum hydride; Pd(dppf)Cl2: [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium; KOAc: potassium acetate. Fumaronitrile: fumaronitrile; P(nBu)3: tri - n - butylphosphine; LDA: lithium diisopropylamide; LiOH: lithium hydroxide; MeI: methyl iodide; EtI: ethyl iodide; (CH2O) n : paraformaldehyde; HCO2H: formic acid; CH3COCl: acetyl chloride; LCMS: liquid chromatography - mass spectrometry; Xantphos: 4,5 - bis(diphenylphosphino)-9,9 - dimethyloxanthrene; TLC: thin - layer chromatography; eq.: equivalent; DCE: 1,2 - dichloroethane; HEPES: 4 - (2 - hydroxyethyl)-1 - piperazineethanesulfonic acid; EGTA: ethylene glycol - bis(2 - aminoethyl ether)-N,N,N',N'-tetraacetic acid; DTT: dithiothreitol Synthesis of Intermediate A1

[0179]

[0180] Conditions and reagents: (a) EtOH, formamidine acetate, 80 °C, 8 h; (b) H2SO4, KNO3, -5 °C, 12 h; (c) MeOH, NH4Cl, Fe, 80 °C, 8 h; (e) SOCl2, DMF, reflux for 3 h; (e) DCM, 50 °C;

[0181] Step a:

[0182] Synthesis of 7-bromo-5-methylquinazolin-4(3H)-one (A1-2)

[0183] Add 2-amino-4-bromo-6-methylbenzoic acid (9.2 g, 40 mmol) and formamidine acetate (4.16 g, 40.00 mmol) to ethanol (60 mL), heat to 80 °C and reflux for 8 h. Monitor by LCMS. After the reaction is completed, cool to room temperature and a large amount of solid precipitates. Filter, and wash the filter cake with a small amount of petroleum ether. Collect and dry to obtain the product 7-bromo-5-methylquinazolin-4(3H)-one (6.72 g, yield 70%); MS: 240 [M+H] + .

[0184] Step b:

[0185] Synthesis of 7-bromo-5-methyl-6-nitroquinazolin-4(3H)-one (A1-3)

[0186] Under normal temperature conditions, slowly add 7-bromo-5-methylquinazolin-4(3H)-one (6.72 g, 28 mmol) to H2SO4 (50 mL), cool to about -20 °C with an ice-salt bath, add KNO3 (3.02 g, 30 mmol) in batches (about 20 min), and control the system temperature below -10 °C. Slowly raise the temperature of the reaction system to 10 °C and react for 2 h. Monitor by HPLC. After the reaction is completed, slowly pour the reaction system into crushed ice, and a large amount of solid precipitates. Filter, wash the filter cake 3 times with water, collect and dry to obtain the product 7-bromo-5-methyl-6-nitroquinazolin-4(3H)-one (4.77 g, yield 60%).

[0187] Step c: Synthesis of 6-amino-7-bromo-5-methylquinazolin-4(3H)-one (A1-4)

[0188] Add isopropanol (50 mL), water (25 mL), iron powder (6 g) and ammonium chloride (700 mg) to the reaction flask, heat the reaction solution to 75 °C, and add 7-bromo-5-methyl-6-nitroquinazolin-4(3H)-one (4.77 g, 16.8 mmol) and react for 2 h. Cool the reaction solution to 50 °C. Filter with a Buchner funnel, and distill the filtrate under reduced pressure to 40 mL. Filter to obtain 4 g of the solid 6-amino-7-bromo-5-methylquinazolin-4(3H)-one (yield 93.7%).

[0189] Step d:

[0190] 4 g of 6-amino-7-bromo-5-methylquinazolin-4(3H)-one was suspended in thionyl chloride (50 mL). Under stirring at room temperature, 5 drops of DMF were added, and then the temperature of the system was raised to 100 °C for reaction. After the system became clear (about 3 h), the reaction was continued under reflux for 2 h. The reaction was monitored by LCMS (quenching the system with MeOH). After the reaction was completed, the system was directly concentrated under reduced pressure to obtain 4.1 g of a brown solid;

[0191] Step e:

[0192] The above-obtained solid (1 g, 3.7 mmol) was suspended in 1,2-dichloromethane (20 mL), and ultrasonic treatment was used to make it disperse evenly. Under ice bath conditions, 3-chloro-2-fluoroaniline (2.1 g, 14.8 mmol) was slowly added dropwise. After the addition was completed, the ice bath was removed, and the mixture was heated to 50 °C for reaction for 1 h. The reaction was monitored by LCMS. After the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The residue was added with MeOH, and ultrasonic treatment was used to make it disperse evenly. Then, it was filtered, and the filter cake was collected to obtain product A1 (705 mg, yield 50%).

[0193] Using appropriate raw materials, referring to the preparation method of A1 above, A2 - A7 were synthesized

[0194]

[0195]

[0196] Compound 1

[0197]

[0198] Synthesis of Compound 1-1: In a reaction flask, 7-bromo-N4-(3-chloro-2-fluorophenyl)-5-methylquinazoline-4,6-diamine (381 mg, 1 mmol), 3-ethynyl-1,3-dimethylpyrrolidine (184 mg, 1.5 mmol), Pd(PPh3)2Cl2 (140 mg, 0.2 mmol), CuI (38 mg, 0.2 mmol), Cs2CO3 (1.3 g, 4 mmol), and DMF (6 mL) were added. The mixture was evacuated and replaced with nitrogen three times. The reaction was heated to 80 °C for 2 h. After the reaction was completed, 20 mL of water and 50 mL of EA were added, and the organic phase was separated by extraction. The organic phase was dried over sodium sulfate and then evaporated to dryness. The crude product was purified by reverse-phase preparation to obtain N4-(3-chloro-2-fluorophenyl)-7-((1,3-dimethylpyrrolidin-3-yl)ethynyl)-5-methylquinazoline-4,6-diamine (140 mg, yield 33%)

[0199] Synthesis of Compound 1

[0200] To N4-(3-chloro-2-fluorophenyl)-7-((1,3-dimethylpyrrolidin-3-yl)ethynyl)-5-methylquinazoline-4,6-diamine (140 mg, 0.33 mmol) and acrylic acid (47 mg, 0.66 mmol) in DMF (3 mL) solution, pyridine (78 mg, 0.99 mmol) and EDCI (157 mg, 0.82 mmol) were added, and the mixture was stirred at room temperature for 2 h. After concentration, reverse-phase preparation gave the yellow solid N-(4-((3-chloro-2-fluorophenyl)amino)-7-

[0201] ((1,3-dimethylpyrrolidin-3-yl)ethynyl)-5-methylquinazolin-6-yl)acrylamide (33 mg, yield 21%);

[0202] 1 H NMR (400 MHz, d-DMSO δ=9.15 (s, 1H), 8.67 - 8.63 (m, 1H), 8.61 - 8.55 (m, 1H), 8.27 (dt, J=2.2, 7.4 Hz, 1H), 7.75 (br, s, 1H), 7.18 - 7.05 (m, 2H), 6.54 - 6.44 (m, 1H), 6.41 - 6.28 (m, 1H), 5.83 (dd, J=1.2, 10.0 Hz, 1H),

[0203] 5.01 (d, J=8.8 Hz, 1H), 2.92 (dt, J=5.8, 8.8 Hz, 1H), 2.72 (S, 3H), 2.55 - 2.46 (m, 1H), 2.41 - 2.35 (m, 4H), 2.34 - 2.26 (m, 1H), 1.91 (ddd, J=5.8, 8.8, 12.8 Hz, 1H), 1.47 (s, 3H). MS (ESI) m / z 478 [M+H]+.

[0204] Using appropriate intermediates, alkynyl compounds and acrylic compounds as raw materials, the following compounds were obtained according to the preparation method of Example 1:

[0205] Compound 2

[0206]

[0207] Using 5-ethynyl-2-methyl-2-azabicyclo[3.1.0]hexane instead of 3-ethynyl-1,3-dimethylpyrrolidine as the raw material

[0208] H 1NMR (400 MHz, DMSO-d6) δ 10.24 - 10.01 (m, 1H), 9.88 (s, 1H), 8.66 (s, 1H), 8.56 - 8.36 (m, 1H), 7.78 (d, J = 1.6 Hz, 1H), 7.56 (s, 2H), 6.62 (dd, J = 10.0, 16.8 Hz, 1H), 6.35 (dd, J = 1.6, 17.2 Hz, 1H), 5.87 (dd, J = 1.6, 10.2 Hz, 1H),

[0209] 3.14 (d, J = 8.4 Hz, 1H), 2.95 (d, J = 9.2 Hz, 1H), 2.72 (s, 3H), 2.38 (dd, J = 3.6, 9.2 Hz, 2H), 2.27 (s, 3H),

[0210] 1.94 (td, J = 4.4, 8.0 Hz, 1H), 1.37 (t, J = 4.4 Hz, 1H), 1.02 (dd, J = 3.6, 8.0 Hz, 1H).

[0211] Compound 3

[0212] A7 is replaced by A1

[0213]

[0214] 1H NMR (400 MHz, DMSO-d6) δ 9.24 (d, J = 8.0 Hz, 1H), 8.84 (s, 1H), 8.70 (d, J = 5.7 Hz, 1H), 8.22 (s, 1H), 8.06 (br s, 1H), 8.04 - 7.98 (m, 2H), 7.67 (d, J = 11.9 Hz, 1H), 7.43 - 7.37 (m, 1H), 7.29 (td, J = 7.5, 1.1 Hz, 1H), 7.23 - 7.15 (m, 1H),

[0215] 6.56 (dd, J = 16.8, 1.0 Hz, 1H), 6.37 (dd, J = 16.8, 10.2 Hz, 1H), 5.95 (dd, J = 10.1, 1.1 Hz, 1H), 2.92 (dt, J = 5.8, 8.8 Hz, 1H), 2.72 (S, 3H), 2.55 - 2.46 (m, 1H), 2.41 - 2.35 (m, 4H), 2.34 - 2.26 (m, 1H), 1.91 (ddd, J = 5.8, 8.8, 12.8 Hz, 1H), 1.47 (s, 3H).

[0216]

[0217] 1H NMR (400 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.76 (s, 1H), 8.66 (s, 1H), 8.45 (s, 1H), 7.55 (s, 2H),

[0218] 7.25 (t, J = 7.6 Hz, 1H), 6.83 (td, J = 5.6, 15.6 Hz, 1H), 6.45 (d, J = 15.6 Hz, 1H), 3.66 - 3.60 (m, 4H), 3.18 (d, J = 2 Hz, 2H), 3.13 (d, J = 8.4 Hz, 1H), 2.95 (d, J = 9.0 Hz, 1H), 2.73 (S, 3H), 2.48 - 2.38 (m, 6H), 2.24 (s, 3H), 1.98 - 1.90 (m, 1H),

[0219] 1.37 (t, J = 4.4 Hz, 1H), 1.04 (dd, J = 4.0, 8.0 Hz, 1H).

[0220] Compound 5

[0221]

[0222] 1 1H NMR (400 MHz, DMSO-d6) δ 10.15 (s, 1H), 10.08 (s, 1H), 8.64 (s, 1H), 8.54 (s, 1H), 7.53 (s, 2H),

[0223] 7.26 (t, J = 8.0 Hz, 1H), 6.56 (dd, J = 17.2, 10.0 Hz, 1H), 6.38 - 6.32 (m, 1H), 5.83 (d, J = 10.4 Hz, 1H),

[0224] 3.15 (dd, J = 21.2, 11.6 Hz, 1H), 2.93 - 2.82 (m, 2H), 2.73 (S, 3H), 2.48 - 2.45 (m, 3H), 2.32 (s, 3H).

[0225] Compound 6

[0226]

[0227] 11H NMR (400 MHz, d6-DMSO) δ 10.05 (s, 1H), 10.01 (s, 1H), 8.70 (s, 1H), 8.36 (s, 1H), 8.14 (br d, J = 7.2 Hz, 1H), 8.13 - 7.94 (m, 1H), 7.92 - 7.85 (m, 1H), 7.22 - 7.05 (m, 2H), 6.56 (d, J = 6.0 Hz, 2H), 5.84 - 5.79 (m, 1H), 3.27 (br d, J = 7.2 Hz, 1H), 3.16 (br d, J = 11.6 Hz, 1H), 2.72 (S, 3H), 2.51 (s, 3H), 2.16 - 2.08 (m, 3H), 2.04 (br d, J = 14.8 Hz, 1H), 1.86 - 1.75 (m, 1H), 1.45 (s, 3H), 1.38 - 1.31 (m, 1H).

[0228] Compound 7

[0229]

[0230] 1 1H NMR (400 MHz, DMSO-d6) δ 9.85 (s, 2H), 8.65 (s, 1H), 8.53 (s, 1H), 8.03 (d, J = 2.4 Hz, 1H),

[0231] 7.70 (dd, J = 2.5, 9.0 Hz, 1H), 7.45 (dt, J = 6.1, 8.0 Hz, 1H), 7.34 - 7.25 (m, 2H), 7.25 (d, J = 9.2 Hz, 1H),

[0232] 7.16 (dt, J = 1.9, 8.6 Hz, 1H), 6.56 (br dd, J = 10.2, 17.1 Hz, 1H), 6.33 (dd, J = 1.8, 17.1 Hz, 1H), 5.83 (dd, J = 1.8, 10.2 Hz, 1H), 5.24 (s, 2H), 3.94 - 3.82 (m, 3H), 3.57 (d, J = 8.1 Hz, 1H), 2.74 (S, 3H), 2.35 - 2.23 (m, 1H), 1.94 (td, J = 7.3, 12.2 Hz, 1H), 1.43 (s, 3H).

[0233] Compound 8

[0234]

[0235] 11H NMR (400 MHz, DMSO-d6) δ 11.5 (brs, 1H), 8.6 - 8.3 (m, 2H), 8.2 (s, 1H), 8.1 (s, 1H), 7.8 (td, J = 7.6, 1.6 Hz, 1H), 7.6 (d, J = 7.6 Hz, 1H), 7.4 (dd, J = 6.8, 5.2 Hz, 1H), 7.3 (d, J = 2.2 Hz, 1H), 7.1 (d, J = 8.8 Hz, 1H), 7.1 - 7.0 (m, 1H), 6.5 (dd, J = 16.8, 10.2 Hz, 1H), 6.3 (dd, J = 16.8, 2.0 Hz, 1H), 6.1 (s, 1H), 5.8 - 5.7 (m, 1H), 5.2 (s, 2H), 3.6 (s, 3H), 2.9 - 2.6 (m, 4H), 2.74 (S, 3H), 2.0 – 1.9 (m, 1H), 1.9 - 1.8 (m, 2H).

[0236] Using appropriate intermediates, alkynes and acrylic acids as raw materials, compound 9 - 28 was prepared with reference to the preparation method of Example 1:

[0237]

[0238]

[0239]

[0240] Synthesis of Intermediate B1

[0241]

[0242] Step b: Synthesis of 7 - bromo - 5 - fluoro - 6 - nitroquinazolin - 4(3H) - one (B1 - 2)

[0243] At room temperature, 7 - bromo - 5 - fluoroquinazolin - 4(3H) - one (7.29 g, 30 mmol) was slowly added to H2S04 (50 mL), and the mixture was cooled to about - 20 °C in an ice - salt bath. KNO3 (3.3 g, 33 mmol) was added in portions (for about 20 min), and the temperature of the reaction system was controlled below - 10 °C. The reaction system was slowly warmed to 10 °C and reacted for 2 h. Monitored by HPLC, after the reaction was completed, the reaction system was slowly poured into crushed ice, a large amount of solid was precipitated, filtered, the filter cake was washed with water 3 times, collected, and dried to obtain the product 7 - bromo - 5 - fluoro - 6 - nitroquinazolin - 4(3H) - one (4.3 g, yield 50%).

[0244] Step c: Synthesis of 6 - amino - 7 - bromo - 5 - fluoroquinazolin - 4(3H) - one (B1 - 3)

[0245] Add isopropyl alcohol (50 mL), water (25 mL), iron powder (7 g) and ammonium chloride (800 mg) to a reaction flask. Heat the reaction solution to 75 °C, and add 7-bromo-5-fluoro-6-nitroquinazolin-4(3H)-one (4.3 g, 1.5 mmol) and react for 2 h. Cool the reaction solution to 50 °C. Filter it through a Buchner funnel, and distill the filtrate under reduced pressure to 40 mL. Filter to obtain 3.4 g of solid 6-amino-7-bromo-5-fluoroquinazolin-4(3H)-one (yield 89%). Step d:

[0246] Suspend 3.4 g of 6-amino-7-bromo-5-fluoroquinazolin-4(3H)-one in thionyl chloride (50 mL). Under stirring at room temperature, add DMF (6 drops), then heat the system to 100 °C for reaction. After the system becomes clear (about 3 h), reflux for another 2 h. Monitor by LCMS (quenching the system with MeOH). After the reaction is completed, directly concentrate the system under reduced pressure to obtain 3.4 g of brown solid;

[0247] Step e:

[0248] Suspend the above-obtained solid (1 g, 3.6 mmol) in 1,2-dichloromethane (20 mL), and ultrasonically disperse it evenly. Under ice bath conditions, slowly add 3-chloro-2-fluoroaniline (1.57 g, 10.8 mmol). After adding, remove the ice bath and heat to 50 °C for reaction for 1 h. Monitor the reaction by LCMS. After the reaction is completed, rotary evaporate the solvent under reduced pressure. Add MeOH to the residue and ultrasonically disperse it evenly. Filter, and collect the filter cake to obtain product B1 (600 mg, yield 43%).

[0249] Using appropriate raw materials, refer to the preparation method of B1 above to synthesize B2 - B7

[0250]

[0251]

[0252] Using appropriate intermediates, alkynes and acrylic compounds as raw materials, refer to the preparation method of Example 1 to prepare compounds 29 - 37

[0253] Compound 29

[0254]

[0255] 11H NMR (400 MHz, CDCl3) δ 9.26 (br s, 1H), 9.15 (s, 1H), 8.77 (s, 1H), 8.46 (br s, 1H), 8.35 - 8.30 (m, 1H), 7.79 (br s, 1H), 7.27 - 7.15 (m, 2H), 6.66 - 6.54 (m, 2H), 5.85 (dd, J = 2.4, 9.2 Hz, 1H), 3.52 (d, J = 10.0 Hz, 1H), 3.53 - 3.40 (m, 1H), 2.96 - 2.82 (m, 1H), 2.74 - 2.63 (m, 4H), 2.52 (ddd, J = 5.6, 7.8, 13.2 Hz, 1H), 2.14 (ddd, J = 7.0, 8.6, 13.1 Hz, 1H), 1.63 s, 3H). Compound 30

[0256]

[0257] 1 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 8.76 - 8.58 (m, 3H), 7.95 - 7.89 (m, 2H), 7.83 - 7.76 (m, 1H), 7.69 (br d, J = 7.8 Hz, 1H), 7.54 (dd, J = 2.4, 8.8 Hz, 1H), 7.24 (br d, J = 6.6 Hz, 1H), 7.05 (d, J = 8.8 Hz, 1H), 6.54 - 6.37 (m, 2H), 5.88 (d, J = 9.8 Hz, 1H), 5.34 (s, 2H), 3.06 (d, J = 8.8 Hz, 1H), 3.05 - 2.95 (m, 1H), 2.63 - 2.55 (m, 1H), 2.47 - 2.41 (m, 4H), 2.44 - 2.35 (m, 1H), 2.04 - 1.96 (m, 1H), 1.54 (s, 3H).

[0258] Compound 31

[0259]

[0260] 1H NMR (400 MHz, DMSO - d6) δ 9.27 (d, J = 8.0 Hz, 1H), 8.86 (s, 1H), 8.73 (d, J = 5.7 Hz, 1H), 8.21 (s, 1H), 8.05 (br s, 1H), 8.07 - 7.97 (m, 2H), 7.64 (d, J = 11.9 Hz, 1H), 7.41 - 7.37 (m, 1H), 7.26 (td, J = 7.5, 1.1 Hz, 1H), 7.24 - 7.15 (m, 1H),

[0261] 6.55 (dd, J = 16.8, 1.0 Hz, 1H), 6.35 (dd, J = 16.8, 10.2 Hz, 1H), 5.97 (dd, J = 10.1, 1.1 Hz, 1H), 2.94 (dt, J = 5.8, 8.8 Hz, 1H), 2.53 - 2.43 (m, 1H), 2.43 - 2.36 (m, 4H), 2.33 - 2.28 (m, 1H), 1.96 - 1.86 (m, 1H), 1.46 (s, 3H).

[0262] Compound 32

[0263]

[0264] 1H NMR (400 MHz, DMSO-d6,): δ 10.25 (d, J = 8.3 Hz, 1H), 9.66 (s, 1H), 8.53 (s, 1H), 7.76 - 7.70 (m, 3H),

[0265] 7.42 (t, J = 7.9 Hz, 2H), 7.14 (d, J = 7.4 Hz, 1H), 7.05 (d, J = 8.9 Hz, 2H), 7.06 - 6.98 (m, 2H), 6.94 - 6.86 (m, 1H), 6.68 (d, J = 14.9 Hz, 1H), 2.94 (dt, J = 5.8, 8.8 Hz, 1H), 2.53 - 2.43 (m, 1H), 2.43 - 2.36 (m, 4H), 2.33 - 2.28 (m, 1H), 1.91 - 1.96 (m, 1H), 1.46 (s, 3H).

[0266]

[0267]

[0268] Synthesis of Intermediate C1

[0269]

[0270] Step b: Synthesis of 7-bromo-5-chloro-6-nitroquinazolin-4(3H)-one (C1-2)

[0271] Under normal temperature conditions, 7-bromo-5-chloroquinazolin-4(3H)-one (5.2 g, 20 mmol) was slowly added to H2S04 (50 mL). The mixture was cooled to about -20 °C in an ice-salt bath, and KNO3 (2.3 g, 22 mmol) was added in portions over about 20 min while controlling the system temperature below -10 °C. The reaction system was slowly warmed to 10 °C and reacted for 2 h. Monitored by HPLC, after the reaction was completed, the reaction system was slowly poured into crushed ice, a large amount of solid was precipitated, filtered, the filter cake was washed with water 3 times, collected, and dried to obtain the product 7-bromo-5-chloro-6-nitroquinazolin-4(3H)-one (3.7 g, yield 60%).

[0272] Step c: Synthesis of 6-amino-7-bromo-5-chloroquinazolin-4(3H)-one (C1-3)

[0273] Isopropanol (50 mL), water (25 mL), iron powder (5 g) and ammonium chloride (600 mg) were added to a reaction flask. The reaction solution was heated to 75 °C, and 7-bromo-5-chloro-6-nitroquinazolin-4(3H)-one (3.7 g, 1.2 mmol) was added and reacted for 2 h. The reaction solution was cooled to 50 °C. Filtered through a Buchner funnel, and the filtrate was distilled under reduced pressure to 40 mL. The solid 6-amino-7-bromo-5-chloroquinazolin-4(3H)-one (2.9 g, yield 89%) was obtained by filtration. Step d:

[0274] 2.9 g of 6-amino-7-bromo-5-chloroquinazolin-4(3H)-one was suspended in thionyl chloride (50 mL). Under stirring at room temperature, DMF (5 drops) was added, then the system was heated to 100 °C and reacted. After the system became clear (about 3 h), it was refluxed for another 2 h. Monitored by LCMS (quenching the system with MeOH), after the reaction was completed, the system was directly concentrated under reduced pressure to obtain 3.0 g of a brown solid;

[0275] Step e:

[0276] The solid obtained above (1 g, 3.3 mmol) was suspended in 1,2-dichloromethane (20 mL), and ultrasonicated to disperse evenly. Under ice bath conditions, 3-chloro-2-fluoroaniline (1.5 g, 10 mmol) was slowly added dropwise. After the addition was complete, the ice bath was removed, and the mixture was heated to 50 °C and reacted for 1 h. Monitored by LCMS, after the reaction was completed, the solvent was removed by rotary evaporation under reduced pressure. The residue was added with MeOH, ultrasonicated to disperse evenly, filtered, and the filter cake was collected to obtain the product C1 (500 mg, yield 38%).

[0277] Using appropriate raw materials, referring to the preparation method of C1 above, C2-C8 were synthesized.

[0278]

[0279]

[0280] Using appropriate intermediates, alkynyl compounds, and acrylic compounds as raw materials, compound 38-47 was prepared according to the preparation method of Example 1. Compound 38

[0281]

[0282] 1 H NMR(400MHz,CDCl3)δ9.25(s,1H),8.76(s,1H),8.69(s,1H),8.36(dt,J=1.9,7.4Hz,1H),7.94(br s,1H),7.28-7.16(m,2H),6.63-6.54(m,1H),6.54-6.43(m,1H),5.94(dd,J=1.2,10.1Hz,1H),3.12(d,J=9.0Hz,1H),

[0283] 3.04(dt,J=5.6,8.8Hz,1H),2.56(dt,J=6.1,9.1Hz,1H),2.44(s,1H),2.42(s,3H),2.41-2.33(m,1H),2.02-1.94(m,1H),1.58(s,3H).

[0284] Compound 39

[0285]

[0286] 1 H NMR(400MHz,DMSO-d6):δ9.87(s,1H),8.95(d,J=7.5Hz,1H),8.66(s,2H),8.39(s,1H),7.89-7.84(m,4H),7.26-7.22(m,1H),7.06-7.03(m,1H),6.82(d,J=2.4Hz,1H),6.64-6.54(m,1H),6.54-6.46(m,1H),

[0287] 5.95(dd,J=1.2,10.1Hz,1H),3.13(d,J=9.0Hz,1H),3.06(dt,J=5.6,8.8Hz,1H),2.58(dt,J=6.1,9.1Hz,1H),2.47(s,1H),2.42(s,3H),2.41-2.36(m,1H),2.22(s,3H),2.02-1.95(m,1H),1.57(s,3H).

[0288] Compound 40

[0289]

[0290] 1 1H NMR (400 MHz, DMSO-d6) δ 10.06 (br s, 1H), 9.66 (s, 1H), 8.66 (s, 1H), 8.43 (s, 1H), 7.56–7.43 (m, 2H), 7.26 (t, J = 8.0 Hz, 1H), 6.86–6.74 (m, 1H), 6.37 (d, J = 15.6 Hz, 1H), 3.06 (br d, J = 5.6 Hz, 2H), 2.77 (d, J = 8.8 Hz, 1H), 2.57 (t, J = 7.2 Hz, 2H), 2.55 - 2.51 (m, 1H), 2.26 (s, 3H), 2.24 (dd, J = 6.4, 12.8 Hz, 1H), 2.15 (s, 6H),

[0291] 1.81 (td, J = 7.2, 12.8 Hz, 1H), 1.43 (s, 3H).

[0292]

[0293]

[0294] Synthesis of Compound 48

[0295]

[0296] Step a: A mixture of 4-chloro-7-fluoro-6-nitroquinazoline (5.00 g, 21.9 mmol) and 2-(2-fluorophenyl)pyridin-4-amine (4.12 g, 21.9 mmol) in isopropanol (80.0 mL) was stirred at 80 °C for 12 h under a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to afford 7-fluoro-N-(2-(2-fluorophenyl)pyridin-4-yl)-6-nitroquinazolin-4-amine (48-2) as a dark yellow solid (8.3 g, crude). m / z ES+ [M + H]+ 380;

[0297] Step b: A mixture of 7-fluoro-N-(2-(2-fluorophenyl)pyridin-4-yl)-6-nitroquinazolin-4-amine (7.58 g, 20 mmol), potassium acetate (9.8 g, 100 mmol) in dimethylformamide (90.0 mL) was stirred at 100 °C for 2 h under a nitrogen atmosphere. The reaction mixture was diluted with water (200 mL) and filtered. The filter cake was dried to afford 4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-6-nitroquinazolin-7-ol (48-3) as a yellow solid (7.20 g, crude). m / z ES+ [M + H]+ 379;

[0298] Step c: At 0 °C, trifluoromethanesulfonyl chloride (4.2 g, 22.5 mmol) was added to a solution of 4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-6-nitroquinazolin-7-ol (5.65 g, 15 mmol) and triethylamine (3.0 g, 30 mmol) in dichloromethane (80.0 mL). The mixture was stirred at 0 °C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in 200 mL of ethyl acetate, and the organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated by rotary evaporation to obtain 4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-6-nitroquinazolin-7-yl trifluoromethanesulfonate (48-4) as a yellow solid (6.1 g, 80%).

[0299] Step d: 4-((2-(2-fluorophenyl)pyridin-4-yl)amino)-6-nitroquinazolin-7-yl trifluoromethanesulfonate (2.6 g, 5 mmol), 3-ethynyl-1,3-dimethylpyrrolidine (800 mg, 6.5 mmol), tetrakis(triphenylphosphine)palladium (578 mg, 0.5 mmol), and copper(I) iodide (190 mg, 1 mmol) were added to a mixed solution of dimethylformamide (25.0 mL) and triethylamine (5.00 mL), degassed, and purged with nitrogen three times. Then the reaction solution was stirred at 25 °C for 6 hours under nitrogen protection. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure, and purified by flash silica gel column chromatography to obtain 7-((1,3-dimethylpyrrolidin-3-yl)ethynyl)-N-(2-(2-fluorophenyl)pyridin-4-yl)-6-nitroquinazolin-4-amine (48-5) as a yellow solid (2.00 g). m / z ES+ [M+H]+ 483;

[0300] 11H NMR (400 MHz, DMSO-d6) δ 11.04 - 10.64 (m, 1H), 9.53 (br d, J = 1.4 Hz, 1H), 8.82 - 8.58 (m, 1H), 8.26 - 8.09 (m, 1H), 8.06 - 7.97 (m, 2H), 7.95 (s, 1H), 7.65 (d, J = 11.9 Hz, 1H), 7.46 - 7.38 (m, 1H), 7.27 (td, J = 7.5, 1.1 Hz, 1H), 7.25 - 7.15 (m, 1H), 2.95 (dt, J = 5.8, 8.8 Hz, 1H), 2.55 - 2.43 (m, 1H), 2.41 - 2.35 (m, 4H), 2.33 - 2.24 (m, 1H), 1.94 - 1.87 (m, 1H), 1.45 (s, 3H).

[0301] Step e: A mixture of 7 - ((1,3 - dimethylpyrrolidin - 3 - yl)ethynyl)-N-(2-(2 - fluorophenyl)pyridin - 4 - yl)-6 - nitroquinazolin - 4 - amine (170 mg, 0.35 mmol), iron powder (95.6 mg, 1.71 mmol), and ammonium chloride (91.6 mg, 1.71 mmol) in methanol (10.0 mL) and water (10.0 mL) was stirred at 80 °C for 1 hour under nitrogen protection. The combined solution was degassed and purged with nitrogen three times, and then the reaction solution was stirred at 25 °C for 6 hours under nitrogen protection. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse - phase preparative HPLC to give the solid 7 - ((1,3 - dimethylpyrrolidin - 3 - yl)ethynyl)-N4-(2-(2 - fluorophenyl)pyridin - 4 - yl)quinazolin - 4,6 - diamine (48 - 6) (90 mg). m / z ES+ [M + H]+ 453;

[0302] Step f: To a solution of 7-((1,3-dimethylpyrrolidin-3-yl)ethynyl)-N4-(2-(2-fluorophenyl)pyridin-4-yl)quinazoline-4,6-diamine (45 mg, 0.1 mmol), pyridine (15 mg, 0.2 mmol) and acrylic acid (11 mg, 0.15 mmol) in dimethylformamide (3.00 mL) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.4 mmol) in portions. The mixture was stirred at 25 °C for 0.5 h. The reaction mixture was filtered. The residue was purified by preparative HPLC to give N-(7-((1,3-dimethylpyrrolidin-3-yl)ethynyl)-4-((2-(2-fluorophenyl)pyridin-4-yl)amino)quinazolin-6-yl)acrylamide (48) as a pale yellow solid (28 mg). m / z ES+ [M+H]+ 507; 1H NMR (400 MHz, DMSO-d6) δ 9.27 (d, J = 8.0 Hz, 1H), 8.86 (s, 1H),

[0303] 8.73 (d, J = 5.7 Hz, 1H), 8.22 (s, 1H), 8.07 (br s, 1H), 8.05 - 7.99 (m, 2H), 7.98 (s, 1H), 7.64 (d, J = 11.9 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.27 (td, J = 7.5, 1.1 Hz, 1H), 7.25 - 7.15 (m, 1H), 6.55 (dd, J = 16.8, 1.0 Hz, 1H), 6.36 (dd, J = 16.8, 10.2 Hz, 1H), 5.96 (dd, J = 10.1, 1.1 Hz, 1H), 2.93 (dt, J = 5.8, 8.8 Hz, 1H), 2.56 - 2.45 (m, 1H), 2.42 - 2.36 (m, 4H), 2.36 - 2.24 (m, 1H), 1.95 - 1.89 (m, 1H), 1.46 (s, 3H).

[0304] Select appropriate amine compounds and alkyne compounds as raw materials, and refer to the preparation method of compound 48 to synthesize compounds 49 - 56

[0305]

[0306]

[0307] Synthesis of compound 57

[0308]

[0309] Step a: A mixture of 4-chloro-7-fluoro-6-nitroquinazoline (2.2 g, 10 mmol) and 6-chloro-5-fluoroindoline (1.7 g, 10 mmol) in isopropanol (50.0 mL) was stirred at 80 °C for 12 h under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain 4-(6-chloro-5-fluoroindolin-1-yl)-7-fluoro-6-nitroquinazoline (57-2) (3.6 g, crude) as a dark yellow solid. m / z ES+ [M+H]+ 363.0;

[0310] Step b: A mixture of 57-2 (3.6 g, 10 mmol), potassium acetate (4.9 g, 50 mmol) in dimethylformamide (45.0 mL) was stirred at 100 °C for 2 h under nitrogen protection. The reaction mixture was diluted with water (200 mL) and filtered. The filter cake was dried to obtain 57-3 (3.2 g, crude) as a yellow solid. m / z ES+ [M+H]+ 631;

[0311] Step c: Trifluoromethanesulfonyl chloride (2.5 g, 13.35 mmol) was added to a solution of 57-3 (3.2 g, 8.9 mmol) and triethylamine (1.9 g, 19 mmol) in dichloromethane (50.0 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was dissolved in 200 mL of ethyl acetate, and the organic phase was washed twice with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 57-4 (3.4 g, 78%) as a yellow solid.

[0312] Step d: 57-4 (980 mg, 2 mmol), 3-ethynyl-1,3-dimethylpyrrolidine (270 mg, 2.2 mmol), tetrakis(triphenylphosphine)palladium (231 mg, 0.2 mmol), and copper(I) iodide (80 mg, 0.4 mmol) were added to a mixed solution of dimethylformamide (15.0 mL) and triethylamine (2.00 mL), degassed, and purged with nitrogen three times, and then the reaction solution was stirred at 25 °C for 6 h under nitrogen protection. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (3 × 20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure, and purified by flash silica gel column chromatography to obtain 67-5 (500 mg). m / z ES+ [M+H]+ 466.1;

[0313] Step e: A mixture of 67-5 (465 mg, 1 mmol), iron powder (200 mmol), and ammonium chloride (300 mg) in methanol (10.0 mL) and water (5.0 mL) was stirred at 80 °C for 1 hour under nitrogen protection. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (3 × 40 mL). The combined organic layers were washed with brine (3 × 50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC to give solid 57-6 (210 mg). m / z ES+ [M+H]+ 436.2;

[0314] Step f: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (78 mg, 0.4 mmol) was added portionwise to a solution of 57-6 (43 mg, 0.1 mmol), pyridine (15 mg, 0.2 mmol), and acrylic acid (11 mg, 0.15 mmol) in dimethylformamide (3.00 mL) at 25 °C. The mixture was stirred at 25 °C for 0.5 hour. The reaction mixture was filtered. The residue was purified by preparative HPLC to give 57 (19 mg). m / z ES+ [M+H]+ 490.2; 1H NMR (400 MHz, DMSO-d6) δ 9.18 (d, J = 1.8 Hz, 1H), 8.79 (s, 1H), 8.68 (m, 1H), 8.18 (s, 1H), 8.11 (s, 1H), 8.05 - 7.96 (m, 3H), 7.69 - 7.65 (m, 1H), 7.53 - 7.48 (m, 1H), 7.27 - 7.14 (m, 2H), 6.48 (dd, J = 17.0, 10.4 Hz, 1H), 6.32 (dd, J = 17.0, 10.4 Hz, 1H), 5.98 - 5.94 (m, 1H), 4.40 - 4.29 (m, 2H), 3.38 - 3.21 (m, 2H), 2.98 - 2.94 (m, 1H), 2.56 - 2.36 (m, 5H), 2.31 - 2.22 (m, 1H), 1.92 - 1.84 (m, 1H), 1.51 (s, 3H).

[0315] Select appropriate amine compounds and alkyne compounds as raw materials, and synthesize the following synthetic compounds with reference to the preparation method of compound 57.

[0316]

[0317]

[0318]

[0319]

[0320] Biological Test Evaluation (Ba / F3 Cell Line Proliferation Assay)

[0321] I. Cell Lines and Culture Conditions

[0322] Cell Lines:

[0323] Suspension Cells: EGFR Del19-C797S / BaF3 cells; EGFR L858R-C797S / BaF3 cells Adherent Cells: A-431 cells

[0324] Culture Medium: RPMI-1640 + 10% FBS or MMEM + 10% FBS

[0325] II. Experimental Procedures:

[0326] 1. Cell Resuscitation

[0327] a) Preheat the medium in a 37°C water bath.

[0328] b) Take out the cryotube from the liquid nitrogen tank, quickly place it in a 37°C water bath, and completely melt it within 1 minute.

[0329] c) Transfer the cell suspension to a 15 mL centrifuge tube containing 8 mL of culture medium, and centrifuge at 1000 rpm for 5 minutes.

[0330] d) Discard the supernatant, resuspend the cells in 1 mL of culture medium, transfer them to a 75 cm2 culture flask containing 15 mL of culture medium, and culture them in an incubator at 37°C and 5% CO2.

[0331] 2. Cell Passage

[0332] a) Preheat the medium in a 37°C water bath.

[0333] b) Suspension Cells: Collect the cells into a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, count the cells, adjust the cell density to 1x104 cells / mL, and then place them in an incubator at 37°C and 5% CO2.

[0334] Adherent Cells: Discard the culture medium, wash the cells once with PBS, add 1 mL of trypsin for digestion. After the cells become round, add 5 mL of culture medium to pipette them into single cells, transfer them to a 15 mL centrifuge tube, and centrifuge at 1000 rpm for 5 minutes. Discard the supernatant, count the cells, adjust the cell density to 1x10 4 cells / mL, and then place them in an incubator at 37°C and 5% CO2.

[0335] 3. Compound Preparation

[0336] a) Dilute the test compound (20 mM stock solution) to 10 mM with 100% DMSO as the starting concentration, and then serially dilute it 3-fold with a “9 + 0” concentration. In a 96-well dilution plate;

[0337] b) Dilute the above compound solution 1:100 with the culture medium to prepare a 10-fold working solution;

[0338] 4. Cell planar culture

[0339] a) Suspended cells: Centrifuge the cells in the logarithmic growth phase at 1000 rpm for 5 minutes, then resuspend the cells with the culture medium, and then count the cells;

[0340] Adherent cells: After collecting the cells by trypsin digestion of the cells in the logarithmic growth phase, centrifuge them at 1000 rpm for 5 minutes, resuspend them with the culture medium, and then count the cells;

[0341] b) Seed the cells into a 96-well cell culture plate at a density of 2000 cells / well;

[0342] 5. Compound treatment

[0343] a) Add the compound prepared in step 2 to the cell plate at 15 μL per well. The final concentrations of EGFR Del19-C797S / BaF3 cells and EGFR L858R-C797S / BaF3 are 1111, 370, 123, 41, 14, 4.6, 1.5, 0.5, 0.2, and 0 nM, and the final concentration of A431 cells is 10000, 3333, 1111, 370, 123, 41, 14, 4.6, 1.5, and 0 nM. The final concentration of DMSO is 0.1%. The blank control wells are the culture medium (0.1% DMSO);

[0344] b) Incubate the cells in the incubator for another 72 hours.

[0345] 6. Fluorescence signal reading

[0346] (1) Thaw the CTG reagent and equilibrate the cell plate to room temperature for 30 minutes.

[0347] (2) Add an equal volume of CTG solution to each well.

[0348] (3) Vortex on an orbital shaker for 5 minutes to lyse the cells.

[0349] (4) Place the cell plate at room temperature for 20 minutes to stabilize the fluorescence signal.

[0350] (5) Read the fluorescence value.

[0351] 7. Data processing

[0352] Data were analyzed using GraphPad Prism 7.0 software, and the data were fitted with nonlinear S-curve regression to obtain the dose-response curve, and the IC50 value (unit: nM) was calculated accordingly.

[0353] Cell survival rate (%) = (Lum test drug - Lum culture medium control) / (Lum cell control - Lum culture medium control) × 100%.

[0354] Results: The IC 50 of the compounds in most of the examples of the present invention for the proliferation inhibition activity of EGFR Del19-C797S / BaF3 and EGFR L858R-C797S / BaF3 cells 50 is less than 100 nM, and the IC of the inhibitory activity in some examples

[0355]

[0356]

[0357] is even less than 50 nM; the compounds in most of the examples have good selectivity for A431. The specific IC50 values are shown in the following table (A indicates IC50 < 50 nM; B indicates 50 nM < IC50 < 100 nM; C indicates 500 nM > IC50 > 100 nM;).

[0358] (1) Metabolic stability test: Metabolic stability incubation was carried out using liver microsomes (final concentration 0.5 mg / mL) with a system volume of 150 μL. The system contained NADPH (final concentration 1 mM), 1 μM test compound and positive control midazolam or negative control atenolol. The reaction was terminated with acetonitrile containing tinidazole at 0 min, 5 min, 10 min, 20 min and 30 min, vortexed for 10 min, centrifuged at 15000 rmp for 10 min, and 50 μL of the supernatant was injected into a 96-well plate. The metabolic stability of the compound was calculated by measuring the relative decrease in the amount of the original drug.

[0359] Results: The compounds of the present invention have high stability in liver microsomes of various species (rats, mice, dogs, monkeys, humans), and the half-life is greater than 20 min, such as compounds 1, 2, 29, 41, 49, 72, 74, etc.

[0360] Test Example 3: Pharmacokinetic experiment of the compound in mice

[0361] Test method: 1) Weigh the compound and add it to the solvent of 50 mM pH 4.7 Acetate buffer containing 20% HP-B-CD, shake well and sonicate to obtain a clear solution. Three mice (ICR mice, male), after fasting overnight, are injected with the drug via the tail vein, and the dosing dose is 1 mg / kg. 2) Weigh the compound and add it to the solvent of 0.5% CMC + 1% Tween 80, shake well and sonicate to obtain a suspension. Three mice (ICR mice, male), after fasting overnight, are given the drug by gavage, and the dosing dose is 5 mg / kg. 3) Sample collection: Blood is taken from the orbital cavity, anticoagulated with sodium heparin, placed on ice after collection, and centrifuged to separate plasma within 1 hour (centrifugation conditions: 8000 revolutions per minute, 6 minutes, 2 - 8 °C). Take 40 μL of the plasma sample, add 160 μL of cold acetonitrile containing the internal standard, vortex for 1 minute, and centrifuge at 18000 revolutions per minute for 10 minutes. Transfer the supernatant to a 96-well plate and take 5 μL for injection and analysis. 4) The LC-MS / MS method is used to analyze the drug concentration, and the pharmacokinetic parameters are calculated using Phoenix WinNolin software. The compounds of the present invention have excellent PK properties in mice, such as compounds 1, 2, 3, 29, 72, etc.

[0362] Test Example 4. Pharmacokinetic Experiment of the Compound in Rats

[0363] 1) Weigh the compound and add it to the solvent of 50 mM pH 4.7 Acetate buffer containing 20% HP - B - CD. Shake well and sonicate to obtain a clear solution for injection. 2) Weigh an appropriate amount of the compound and dissolve it in the solvent of 0.5% MC (v / v, 400 mPa·s) + 0.2% Tween80 (v / v). Vortex for 1 min and sonicate for 20 min to obtain a suspension with a concentration of 10 mg / mL (pH ∼ 7) for oral administration. 3) Male SD rats are used for the experiment. Before dosing and at 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, and 24 h after dosing, approximately 0.25 mL of blood is collected from the jugular vein. At 1 h, 4 h, and 12 h, 0.50 mL of blood is collected by cardiac puncture. Then, the brain tissue is collected. The plasma is anticoagulated with sodium heparin. After the blood and brain tissue samples are collected, they are placed on ice and centrifuged to separate the plasma (centrifugation conditions: 8000 revolutions per minute, 6 minutes, 4°C). The collected plasma and brain tissue are stored at -80°C before analysis. 4) The LC - MS / MS method is used to analyze the drug concentration, and the Phoenix WinNolin software is used to calculate the pharmacokinetic parameters. The brain tissue / plasma ratio will be calculated by the following formula: tissue / plasma ratio = blood drug concentration in tissue / blood drug concentration in plasma. The compounds of the present invention have excellent PK properties in rats, such as compounds 1, 2, 3, 29, 72; the compounds of the present invention have excellent blood - brain distribution, such as compounds 1, 72, etc., revealing that the compounds of the present invention can cross the blood - brain barrier to inhibit tumor growth.

[0364] All documents mentioned in the present invention are cited herein as references, as if each document was individually cited as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. An amino-substituted nitrogen-containing fused ring compound represented by Formula I'-1, I'-2 or I'-3, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, wherein: U is selected from CR u or N, R u is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano, hydroxy; M is selected from CR m or N, R m is selected from halogen, C1-C6 alkyl, C1-C6 alkoxy, cyano; Z is selected from 3- to 12-membered heterocycloalkyl; the 3- to 12-membered heterocycloalkyl is optionally substituted with one or more R Z substituted; Each R Z is independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; wherein the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted by one or more (preferably 1, 2 or 3) R Za substituents; Each R Za is independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; T is -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl; wherein the -O-(C1-C6 alkyl), -NH-(C1-C6 alkyl), C1-C6 alkyl, C2-C6 alkenyl or C2-C6 alkynyl is optionally substituted with one or more R T substituted; Each R T is independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; wherein the -O-(C1-C6 alkyl), the -NH(C1-C6 alkyl), the -N(C1-C6 alkyl)2, the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3-10 membered heterocycloalkyl or the 5-10 membered heteroaryl is optionally substituted with one or more R Ta substituents; Each R Ta is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; Ar1 is a substituted C6-C 10 aryl or a substituted C5-C 10 heteroaryl, and the substituents are one or more R A1 ; Each R A1 is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -O-(6-10 aryl), -O-(5-10 heteroaryl), -O-(C1-C6 alkyl)-(6-10 aryl), -O-(C1-C6 alkyl)-(5-10 heteroaryl),, -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 heterocycloalkyl or 5-10 heteroaryl; the -O-(C1-C6 alkyl), -O-(6-10 aryl), -O-(5-10 heteroaryl), -O-(C1-C6 alkyl)-(6-10 aryl), -O-(C1-C6 alkyl)-(5-10 heteroaryl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 heterocycloalkyl or 5-10 heteroaryl is optionally substituted by one or more R A1a substituents; Each R A1a is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; the -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered hetero cycloalkyl or 5- to 10-membered heteroaryl optionally substituted by one or more R A1b ; each R A1b independently is halogen, CN, -OH or -NH2; Ar2 is Wherein: ring E 1 is optionally substituted by one or more R g substituted C6-C 10 aryl or heteroaryl; Ring E 2 is optionally substituted with one or more R f and is a C5-C 10 aryl or heteroaryl; Each R g independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; Each R f independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; Ring C is selected from substituted or unsubstituted 5- to 10-membered heteroalkyl or 5- to 10-membered heteroaryl, and the term "substituted" means optionally substituted by one or more R b substituents; Ring C1 is selected from substituted or unsubstituted 6-10 aryl, 5-10 heteroaryl or 5-10 heterocycloalkyl; said "substituted" means optionally substituted by one or more R b substituents; Each R b is independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; The above-mentioned heteroaryl contains 1-3 heteroatoms independently selected from the group consisting of N, O, P, S or Se, and the above-mentioned heterocycloalkyl contains 1-3 heteroatoms independently selected from the group consisting of N, O, P or S.

2. The amino-substituted nitrogen-containing fused ring compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, characterized in that: For wherein, R 1 is H or a halogen, preferably F; R e is hydrogen, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl, -(C1-C3 alkyl)-NH(C1-C6 alkyl), -(C1-C3 alkyl)-N(C1-C6 alkyl)2,; the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl is optionally substituted with one or more R e1 substituents; Each R e1 is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; The range of group Z is defined as in claim 1.

3. The amino-substituted nitrogen-containing fused ring compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, characterized in that: For wherein, X 1 selected from -O-, -S- or -NR 3 -; R 3 is hydrogen or C 1-4 alkyl, 3-6 membered cycloalkyl or heterocycloalkyl, preferably hydrogen or methyl; R a 、R b are each independently hydrogen, C 1-4 alkyl; R c 、R d are each independently selected from hydrogen, halogen or C 1-4 alkyl; R 2 is hydrogen, a halogen, C 1-4 alkyl, C 1-4 alkoxy; or R a and R 2 and the atoms to which they are attached form a 3-6 membered saturated carbon ring, or R 2 and R 3 and the atoms to which they are attached form a 3-6 membered saturated ring, or R c and R 2 and the atoms to which they are attached form a 3-6 membered saturated carbon ring, or R a and R c and the atoms to which they are attached form a 3-6 membered saturated ring; R 1 is H or a halogen, preferably F; R e is hydrogen, halogen, CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl, -(C1-C3 alkyl)-NH(C1-C6 alkyl), -(C1-C3 alkyl)-N(C1-C6 alkyl)2; the C1-C6 alkyl, the C2-C6 alkenyl, the C2-C6 alkynyl, the C3-C 10 cycloalkyl, the C6-C 10 aryl, the 3- to 10-membered heterocycloalkyl or the 5- to 10-membered heteroaryl is optionally substituted with one or more R e1 substituents; Each R e1 is independently selected from halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; m is 1, 2 or 3; n is 0, 1 or 2.

4. The amino-substituted nitrogen-containing fused ring compound as claimed in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, characterized in that, It satisfies one or more of the following conditions: (1) Ar1 is a substituted 6-membered aryl or a substituted 6-membered heteroaryl; (2)R A1 independently selected from the following groups: halogen, -O-(CH2) r -(6-10 membered aryl), -O--(CH2) s -(5-10 membered heteroaryl), -CF3, C 1-6 alkyl, C2-C6 alkynyl, C 1-6 alkoxy, C 3-7 cycloalkyl, -hydroxyC 1-5 alkyl, -C 1-6 alkoxy-C 1-6 alkyl, -C 1-6 alkoxy-C6 aryl, -C 1-6 alkoxy-C 5-6 heteroaryl, amino, aminoC 1-4 alkyl, C 1-6 alkylamino, -C 1-6 aminoalkyl-C6 aryl, C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl-, C 1-6 alkoxyaminocarbonyl-, arylC 1-6 alkoxy- or C6 aryl; (3)R z independently selected from halogen, -O-(C1-C6 alkyl), C1-C6 alkyl, 3-10 membered heterocycloalkyl; (4) Ar2 is wherein G 1 and G 2 are independently C or N; Ring E 2 is optionally substituted by one or more (preferably 1, 2, or 3) R f substituted C5-C 10 aryl; Each R g independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; Each R f independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; (5) Ring C is a substituted or unsubstituted pyrrolidine ring, piperidine ring, piperazine ring, benzene ring, pyridine ring; (6) Ring C1 is a substituted or unsubstituted pyrrole ring, benzene ring, pyridine ring, pyrimidine ring.

5. The amino-substituted nitrogen-containing fused ring compound as claimed in claim 3, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, characterized in that, It satisfies one or more of the following conditions: (1)X 1 is - NR 3 - or O; (2)R 2 is a C1-4 alkyl group; (3)R a with R 2 and the atoms to which they are attached form a 3- to 6-membered saturated carbon ring, and Rb, Rc, Rd are hydrogen; (4)R 2 With R 3 and the atoms to which they are attached form a 3- to 6-membered saturated ring, where Ra, Rb, Rc, and Rd are hydrogen; (5)R c With R 2 and the atoms to which they are attached form a 3- to 6-membered saturated carbon ring, Ra, Rb, Rd are hydrogen; (6)R a With R c and the atoms to which they are attached form a 3- to 6-membered saturated ring, and Rb and Rd are hydrogen; (7)R 3 is methyl, ethyl, n-propyl or n-butyl; (8)X 1 is -NR 3 -, R 2 is not hydrogen; (9)R 2 is methyl, ethyl, n-propyl or n-butyl.

6. The amino-substituted nitrogen-containing fused ring compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, characterized in that: Ar1 is Wherein: B is selected from N or CR 4 , said R 4 is selected from hydrogen, halogen, C 1-6 alkyl, C 1-6 alkoxy, 6-10-membered aryl, 5-6-membered heteroaryl, -O-(6-10-membered aryl), -O-(5-10-membered heteroaryl), -O-(C1-C6 alkyl)-(6-10-membered aryl), -O-(C1-C6 alkyl)-(5-6-membered heteroaryl), -NH2-(C1-C4 alkyl), -NH2-(C1-C4 alkyl)-6-membered aryl, -NH2-(C1-C4 alkyl)-(5-6-membered heteroaryl), -COO(C1-C6 alkyl), C 3-7 cycloalkyl, hydroxy C 1-5 alkyl, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkylamino, -C 1-6 aminoalkyl-C6 aryl, -C 1-6 aminoalkyl-C 5-6 heteroaryl, C 1-6 alkoxycarbonyl-, C 1-6 alkoxyamino-carbonyl; said R 4 is optionally substituted by one or more (preferably 1, 2 or 3) groups independently selected from the group consisting of halogen, amino, C1-C3 alkyl, C1-C3 alkoxy; R 5 and R 5 ', R 6 and R 6 ' are each independently selected from hydrogen, C1-C6 alkyl, -CF3, halogen, C2-C4 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; said C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl may be substituted by one or more (preferably 1, 2 or 3) R B1 substituents, and R B1 is independently halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3-10 membered heterocycloalkyl or 5-10 membered heteroaryl; Alternatively, Ar1 has the structures shown in Formula ii-2, ii-3, ii-4, wherein: X2 is O, NH or NMe; X3 is CH or N; t is 0 or 1; R 5 、R 5 ', R 6 、R 6 ' are each independently hydrogen, C1-C6 alkyl, C2-C4 alkynyl, -CF3 or halogen, and the halogen is preferably F or Cl; R 7 is a halogen, preferably F, and the number of R 7 is 1, 2 or 3; Alternatively, B is N, and R 6 'independently is C6-C 10 aryl, 5- to 10-membered heteroaryl, and the C6-C 10 aryl, 5- to 10-membered heteroaryl may be substituted by one or more (preferably 1, 2 or 3) R B1 substituents, and R B1 independently is halogen, CN, -OH, -NH2, -O-(C1-C6 alkyl), -NH(C1-C6 alkyl), -N(C1-C6 alkyl)2, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 cycloalkyl, C6-C 10 aryl, 3- to 10-membered heterocycloalkyl or 5- to 10-membered heteroaryl.

7. The amino-substituted nitrogen-containing fused ring compound as claimed in claim 6, or a pharmaceutically acceptable salt, enantiomer, diastereoisomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, characterized in that, It satisfies one or more of the following conditions: (1)R 4 selected from hydrogen, F, Cl, -O-(6-membered aryl), -O-(6-10-membered heteroaryl), -O-(C1-C6 alkyl)-(6-10-membered aryl) or -O-(C1-C6 alkyl)-(6-10-membered heteroaryl); (2)R B1 independently selected from halogen, C1-C6 alkyl; (3)R 5 、R 5 ', R 6 、R 6 ' are each independently selected from H, halogen, C6-C 10 aryl or C2-C4 alkynyl; (4)R 5 、R 5 ', R 6 、R 6 ' are each independently preferably H, F, Cl, ethynyl, (5)R 5 is H or F; (6)R 6 is H, F, Cl or ethynyl; (7)R 5 、R 5 ', R 6 、R 6 ' at least two of them are hydrogen; (8) The halogen is fluorine or chlorine; (9) The 3-10 membered cycloalkyl is a 3-8 membered cycloalkyl, preferably a 3-6 membered cycloalkyl; (10) The 3-12 membered heterocycloalkyl is a 3-8 membered heterocycloalkyl, preferably a 4-membered, 5-membered, 6-membered, 7-membered or 8-membered heterocycloalkyl; (11) The one or more is 1, 2, 3 or 4; (12) The 3-10 membered heterocycloalkyl is a 3-8 membered heterocycloalkyl, preferably a 4-6 membered heterocycloalkyl; (13) The 5-10 membered heteroaryl is a 6-10 membered heteroaryl, preferably a 6-9 membered heteroaryl; (14) The 3-6 membered saturated ring is a 3-6 membered saturated carbocyclic ring or a 3-6 membered saturated heterocyclic ring; preferably a 3-membered, 4-membered, 5-membered, 6-membered saturated ring; (15) The 3-6 membered saturated carbocyclic ring is a 3-membered, 4-membered, 5-membered, 6-membered saturated carbocyclic ring; (16)R e selected from hydrogen, methyl, (17) Z is selected from (18) Ar1 is selected from any of the following structures: (19) Ar2 is selected from any of the following structures: (20) selected from any of the following structures:

8. The amino-substituted nitrogen-containing fused ring compound as claimed in claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer, tautomer, atropisomer, solvate, polymorph or prodrug thereof, characterized in that, The said compound is any of the following compounds:

9. A pharmaceutical composition, characterized in that, The said pharmaceutical composition comprises: (i) An effective amount of a compound as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof; and (ii) A pharmaceutically acceptable carrier.

10. Use of a substance Z in the manufacture of a medicament for preventing, treating or alleviating a disorder or disease mediated by abnormal EGFR kinase activity; The substance Z is a compound as described in any one of claims 1-8, or a pharmaceutically acceptable salt thereof, or an enantiomer, diastereomer, tautomer, solvate, polymorph or prodrug thereof, or a pharmaceutical composition as described in claim 9; The disease is preferably cancer, benign neoplasm, angiogenesis, inflammatory disease, infectious disease, autoinflammatory disease or autoimmune disease; the cancer is independently selected from non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, prostate cancer, liver cancer, skin cancer, gastric cancer, intestinal cancer, cholangiocarcinoma, brain cancer, leukemia, lymphoma, fibroma, sarcoma, basal cell carcinoma, glioma, kidney cancer, melanoma, bone cancer, thyroid cancer, nasopharyngeal cancer or pancreatic cancer; the autoimmune disease is independently selected from rheumatoid arthritis, systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic anemia or psoriasis; the inflammatory disease is independently selected from osteoarthritis, gouty arthritis, ulcerative colitis and / or inflammatory bowel disease; the infectious disease is independently selected from sepsis, septic shock, endotoxic shock, Gram-negative sepsis and / or toxic shock syndrome.

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