WO2022166741A1

WO2022166741A1 - Macrocyclic compound containing benzoheterocycle and acting as egfr kinase inhibitor, and pharmaceutical composition and use thereof

Info

Publication number: WO2022166741A1
Application number: PCT/CN2022/074255
Authority: WO
Inventors: 刘飞; 彭岩; 徐宏江; 任成�; 严正磊
Original assignee: 正大天晴药业集团股份有限公司
Priority date: 2021-02-06
Filing date: 2022-01-27
Publication date: 2022-08-11
Also published as: CN116761603A

Abstract

A macrocyclic compound containing a benzoheterocycle and acting as an EGFR kinase inhibitor. Specifically disclosed is a compound as represented by formula I or a pharmaceutically acceptable salt, a stereoisomer and a tautomer thereof, a preparation method therefor, a pharmaceutical composition containing the compound, and the medical use thereof.

Description

Macrocyclic compound containing benzoheterocycle as EGFR kinase inhibitor, pharmaceutical composition and use thereof

CROSS-REFERENCE TO RELATED APPLICATIONS

This disclosure claims the rights and priority of Chinese Invention Patent Application No. 202110176252.X, filed with the State Intellectual Property Office of the People's Republic of China on February 6, 2021, and filed with the State Intellectual Property Office of the People's Republic of China on April 9, 2021 The rights and priority of the Chinese invention patent application No. 202110384260.3, the rights and priority of the Chinese invention patent application No. 202110631753.2 submitted to the State Intellectual Property Office of the People's Republic of China on June 7, 2021, and the The rights and priority of Chinese Invention Patent Application No. 202110929601.0 filed by the State Intellectual Property Office of the People's Republic of China, the entire contents of which are hereby incorporated by reference in their entirety.

technical field

The present application relates to a macrocyclic compound containing a benzoheterocycle as an EGFR kinase inhibitor, and specifically discloses a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, and tautomer thereof, and a preparation method thereof , a pharmaceutical composition containing the compound, and its medical use.

Background technique

EGFR (epidermal growth factor receptor)-TKI (tyrosine kinase inhibitor, tyrosine kinase inhibitor) as a small molecule inhibitor, competes with EGFR through endogenous ligands, inhibits tyrosine kinase Activation of EGFR, thereby blocking the EGFR signaling pathway, ultimately produces a series of biological effects such as inhibiting tumor cell proliferation, metastasis, and promoting tumor cell apoptosis. It is one of the main targets of lung cancer therapy.

Osimertinib (Osimertinib, AZD9291) is a third-generation EGFR-TKI targeted drug. Although it has a high response rate for drug resistance caused by T790M mutation, patients will also develop drug resistance (Clin Cancer Res; 21 (17), 2015). In 2015, "Nature Medicine, 21, 560–562, 2015" reported the resistance analysis of AZD9291 in 15 patients for the first time, in which the third mutation, the EGFR C797S mutation, was one of the main mechanisms leading to drug resistance to Osimertinib, accounting for about 40%. %. It is of great research significance to provide patients with safer and more effective fourth-generation EGFR C797S/T790M inhibitors.

SUMMARY OF THE INVENTION

The present application relates to compounds of formula I or pharmaceutically acceptable salts, stereoisomers, tautomers thereof,

Wherein, L is selected from O, -C(O)O-, -C(O)N(R ^a )- or -N(R ^b )-;

R ^a and R ^b are each independently selected from hydrogen, C _1-8 alkyl or C _3-6 cycloalkyl;

R ¹ is selected from hydrogen, C _1-8 alkyl, C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;

The C _1-8 alkyl is optionally substituted with one or more R ^c selected from hydroxy, halogen, ^C _1-8 alkoxy, -NH ₂ , -N(C _1-8 alkyl ) ₂ , -NH(C _1-8 alkyl), or optionally substituted with one or more groups selected from hydroxy, halogen or C _1-6 alkyl, containing 1, 2 or 3 groups selected from N , O or S heteroatom 3-8 membered heterocycloalkyl;

The C _3-10 cycloalkyl or 3-10 membered heterocycloalkyl is optionally substituted with one or more R selected from C _1-8 alkyl, C substituted with one or more deuterium _1-8 alkyl, C _1-8 alkyl substituted with one or more halogens, C _1-8 alkyl substituted with one C _3-8 cycloalkyl, C _3-8 cycloalkyl, halogen, cyano group, amino group or hydroxyl group;

Or R ^b and R ¹ are connected to each other to form a 5-membered heterocycloalkyl group; the 5-membered heterocycloalkyl group is optionally substituted by C _1-8 alkyl, halogen, cyano, amino, hydroxyl or oxygen;

R ² is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C _1-8 alkyl or C _1-8 alkoxy, wherein C _1-8 alkyl or C _1-8 alkoxy is optional is replaced by one or more R';

Each R ³ is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C _1-8 alkyl or C _1-8 alkoxy, wherein C _1-8 alkyl or C _1-8 alkoxy is optionally substituted with one or more R";

Each R' and R" is independently selected from halogen, hydroxy, cyano, amino or nitro;

n is selected from 0, 1, 2 or 3.

In some embodiments, the L is selected from O, -C(O)N(R ^a )- or -N(R ^b )-.

In some embodiments, the L is selected from -C(O)N(R ^a )- or -N(R ^b )-.

In some embodiments, the R ^a and R ^b are each independently selected from hydrogen, C _1-6 alkyl, or C _3-6 cycloalkyl.

In some embodiments, the R ^a and R ^b are each independently selected from hydrogen, C _1-5 alkyl, or C _3-6 cycloalkyl.

In some embodiments, the R ^a and R ^b are each independently selected from hydrogen, C _1-4 alkyl, or C _3-5 cycloalkyl.

In some embodiments, the R ^a and R ^b are each independently selected from hydrogen, C _1-3 alkyl, or C _3-4 cycloalkyl.

In some embodiments, the R ^a and R ^b are each independently selected from hydrogen or C _1-3 alkyl. In some embodiments, the R ^a and R ^b are each independently selected from hydrogen, methyl, ethyl, or n-propyl.

In some embodiments, the R ^a and R ^b are each independently selected from hydrogen.

In some embodiments, the R ¹ is selected from hydrogen, C _1-6 alkyl, C _3-8 cycloalkyl or 3-8 containing 1, 2 or 3 heteroatoms selected from N, O or S membered heterocycloalkyl; the C _1-6 alkyl is optionally substituted by one or more R ^c , and the C _3-8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted by one or more an R substitution.

In some embodiments, the R ¹ is selected from hydrogen, C _1-4 alkyl, C _3-6 cycloalkyl or 3-6 containing 1, 2 or 3 heteroatoms selected from N, O or S membered heterocycloalkyl; the C _1-4 alkyl is optionally substituted by one or more R ^c , and the C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more an R substitution.

In some embodiments, the R ¹ is selected from hydrogen, C _1-3 alkyl, C _3-6 cycloalkyl or 3-6 containing 1, 2 or 3 heteroatoms selected from N, O or S membered heterocycloalkyl; the C _1-3 alkyl is optionally substituted by one or more R ^c , and the C _3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted by one or more an R substitution.

In some embodiments, the R ¹ is selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, oxetanyl, azetidine, thietanyl, tetrahydrofuranyl, tetrahydro pyranyl, piperidinyl or tetrahydropyrrolyl, the methyl, ethyl or propyl optionally substituted with one or more R ^c , the cyclopropyl, oxetanyl, azetidine , thietanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, or tetrahydropyrrolyl optionally substituted with one or more Rs.

In some other embodiments, the R ¹ is selected from hydrogen, methyl, ethyl, propyl, cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl, the methyl, ethyl or propyl is optionally substituted with one or more R ^c , the cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl is optionally substituted with one or more R.

In other embodiments, the R ¹ is selected from hydrogen, methyl, ethyl, cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl, the methyl or ethyl optionally being Substituted with one or more R ^c , the cyclopropyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl is optionally substituted with one or more R.

In other embodiments, the R ¹ is selected from hydrogen, C _1-6 alkyl optionally substituted by hydroxy or halogen, C _3-8 cycloalkyl or contains 1, 2 or 3 selected from N, O or a 3-8 membered heterocycloalkyl of a heteroatom of S; the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs. In other embodiments, the R ¹ is selected from hydrogen, C _1-4 alkyl optionally substituted by hydroxy or halogen, C _3-6 cycloalkyl or contains 1, 2 or 3 selected from N, O or a 3-6 membered heterocycloalkyl of a heteroatom of S; the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs. In other embodiments, the R ¹ is selected from hydrogen, C _1-3 alkyl optionally substituted by hydroxy or halogen, C _3-6 cycloalkyl or contains 1, 2 or 3 selected from N, O or a 3-6 membered heterocycloalkyl of a heteroatom of S; the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs.

In other embodiments, the R ¹ is selected from C _3-6 cycloalkyl or a 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, the Cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs.

In some embodiments, the heterocycloalkyl of R ¹ is selected from 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, containing 1, 2 or 3 heteroatoms selected from N, O or S. 8-, 9- or 10-membered heterocycloalkyl optionally substituted with one or more Rs.

In some embodiments, the heterocycloalkyl group of R ¹ is selected from 3-9 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.

In some embodiments, the heterocycloalkyl group of R ¹ is selected from 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.

In some embodiments, the heterocycloalkyl group of R ¹ is selected from 3-7 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.

In some embodiments, the heterocycloalkyl group of R ¹ is selected from 3-6 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.

In some embodiments, the heterocycloalkyl group of R ¹ is selected from 4-6 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.

In some embodiments, the heterocycloalkyl group of R ¹ is selected from 5-6 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl group optionally substituted with one or more R.

In some embodiments, the heterocycloalkyl for R is selected from 5-membered heterocycloalkyl containing ¹ , 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl optionally is substituted with one or more Rs.

In some embodiments, the heterocycloalkyl of R ¹ is selected from 6-membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, the heterocycloalkyl optionally is substituted with one or more Rs.

In some embodiments, the R ^b and R ¹ are linked to each other to form a tetrahydropyrrole, the tetrahydropyrrole is optionally surrounded by one or more selected from the group consisting of C _1-6 alkyl, halogen, cyano, amino, hydroxyl or oxygen group substitution.

In some embodiments, the R ^b and R ¹ are connected to each other to form

said

Optionally substituted with one or more groups selected from _C1-3 alkyl, fluoro, chloro, cyano, amino, hydroxy or oxygen. In some embodiments, the R ^b and R ¹ are interconnected to form a substituted with one or more oxygens

In some embodiments, the R ^c is selected from hydroxy, halogen, C _1-6 alkoxy, -NH ₂ , -N(C _1-6 alkyl) ₂ , -NH(C _1-6 alkyl) , or a 3-8 membered heteroatom containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally substituted by one or more groups selected from hydroxy, halogen or C _1-6 alkyl Cycloalkyl.

In some embodiments, the R ^c is selected from hydroxy, halogen, C _1-4 alkoxy, -NH ₂ , -N(C _1-4 alkyl) ₂ , -NH(C _1-4 alkyl) , or a 4-6 membered heteroatom containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally substituted with one or more groups selected from hydroxy, halogen or C _1-4 alkyl Cycloalkyl.

In some embodiments, the R ^c is selected from the group consisting of hydroxy, fluoro, chloro, C _1-3 alkoxy, -NH ₂ , -N(C _1-3 alkyl) ₂ , -NH(C _1-3 alkane group), or 5-6 containing 1, 2 or 3 heteroatoms selected from N, O or S optionally substituted with one or more groups selected from hydroxy, halogen or C _1-3 alkyl Membered heterocycloalkyl.

In some embodiments, the R ^c is selected from hydroxy, fluoro, methoxy, -N(CH ₃ ) ₂ , tetrahydropyranyl, tetrahydropyrrolyl, morpholinyl, or 1,4-dioxane ring base.

In some embodiments, the R is selected from C _1-6 alkyl, C 1-6 alkyl substituted with one or more deuteriums, C _1-6 alkyl substituted with one or more halogens, C _1-6 alkyl substituted with one or more halo C _3-6 cycloalkyl substituted C _1-6 alkyl, C _3-6 cycloalkyl, halogen, cyano, amino or hydroxy.

In some embodiments, the R is selected from C _1-4 alkyl, per-deuterated C _1-4 alkyl, C ₁ substituted with one or more groups selected from fluorine, chlorine, bromine or iodine _-4 alkyl, C _1-4 alkyl substituted with one C _3-6 cycloalkyl, C _3-6 cycloalkyl, fluorine, chlorine, bromine, iodine, cyano, amino or hydroxy.

In some embodiments, the R is selected from C _1-3 alkyl, per-deuterated C _1-3 alkyl, C ₁ substituted with one or more groups selected from fluorine, chlorine, bromine or iodine _-3 alkyl, C _1-3 alkyl substituted with one C _3-5 cycloalkyl, C _3-5 cycloalkyl, fluoro, chloro, bromo, cyano, amino or hydroxy.

_In some embodiments, the R is selected from methyl, ethyl, n _- _propyl , isopropyl, _-CD3 , _-C2D5 , _-C3D7 , _-CF3 , _-CH2CH2 F, -CH ₂ CHF ₂ , -CH ₂ CF ₃ , -C ₂ F ₅ , -C ₃ F ₇ , methyl substituted with one C _3-5 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentane group, fluorine, chlorine, bromine, cyano, amino or hydroxyl.

_In some embodiments, the _R is selected from methyl, _ethyl , _-CD3 , _-C2D5 , _-CF3 , _-CH2CH2F , _-CH2CHF2 , _-CH2CF3 _, -C ₂ F ₅ , cyclopropylmethyl, cyclopropyl, fluoro, chloro, bromo, cyano, amino or hydroxy.

In some embodiments, the R is selected from methyl, ethyl, _-CD3 , _-CF3 , cyclopropyl, cyclopropylmethyl, cyano, amino, or hydroxy.

In some embodiments, the R is selected from methyl.

In some embodiments, the heterocycloalkyl group of R ¹ is selected from azetidine, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, azacyclo Heptyl, imidazolinyl, pyrazolinyl, piperazinyl, hexahydropyrimidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, morpholinyl or tetrahydropyranyl , the heterocycloalkyl is optionally substituted with one or more Rs.

In some other embodiments, the heterocycloalkyl of R ¹ is selected from azetidinyl, tetrahydropyrrolyl, piperidinyl, azepanyl, imidazolinyl, pyrazolinyl, piperazine , hexahydropyrimidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, morpholinyl or tetrahydropyranyl, said heterocycloalkyl optionally being replaced by one or more an R substitution.

In other embodiments, the heterocycloalkyl of R ¹ is selected from

The heterocycloalkyl is optionally substituted with one or more Rs.

In some embodiments, the R ¹ is selected from hydrogen, cyclopropyl,

methyl, ethyl, propyl,

The methyl, ethyl or propyl is ^optionally substituted with one or more R; the cyclopropyl,

optionally substituted with one or more R.

In some embodiments, the R ^b and R ¹ are connected to each other to form

In other embodiments, the R ¹ is selected from hydrogen, cyclopropyl,

methyl, ethyl, propyl, or

optionally substituted with one or more R.

In other embodiments, the R ¹ is selected from hydrogen, cyclopropyl,

methyl, ethyl, or

The methyl or ethyl is ^optionally substituted with one or more R; the cyclopropyl,

optionally substituted with one or more R. In other embodiments, the R ¹ is selected from hydrogen, cyclopropyl,

The cyclopropyl,

optionally substituted with one or more R. In other embodiments, the R1 is selected from cyclopropyl optionally substituted with ^one or more Rs. In other embodiments, the R ¹ is selected from optionally substituted with one or more R

In other embodiments, the R ¹ is selected from optionally substituted with one or more R

In some embodiments, the R ² is selected from hydrogen, halogen, hydroxy, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy, wherein C _1-6 alkyl or C _1-6 Alkoxy is optionally substituted with one or more R'.

In some embodiments, the R ² is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxy, cyano, amino, nitro, C _1-4 alkyl or C _1-4 alkoxy, wherein C _{1 -4Alkyl} or _C1-4alkoxy is optionally substituted with one or more R'.

In some embodiments, the R ² is selected from hydrogen, fluorine, chlorine, bromine, hydroxy, cyano, amino, nitro, C _1-3 alkyl or C _1-3 alkoxy, wherein C _1-3 Alkyl or _C1-3alkoxy is optionally substituted with one or more R'.

In some embodiments, the R ² is selected from hydrogen, fluorine, chlorine, bromine, or C _1-3 alkyl, wherein the C _1-3 alkyl is optionally substituted with one or more R'.

In some embodiments, the R ² is selected from hydrogen, fluoro, chloro, or C _1-3 alkyl, wherein the C _1-3 alkyl is optionally substituted with one or more R'.

In some embodiments, the R ² is selected from fluoro or C _1-3 alkyl, wherein the C _1-3 alkyl is optionally substituted with one or more fluoro.

In some embodiments, the R ² is selected from fluoro or methyl optionally substituted with one or more fluoro. In some embodiments, the R ² is selected from fluoro, methyl or trifluoromethyl.

In some embodiments, the R' is selected from fluoro, chloro, bromo, hydroxy, cyano, amino, or nitro.

In some embodiments, the R' is selected from fluoro, chloro or bromo.

In some embodiments, the R' is selected from fluoro or chloro.

In some embodiments, the R' is selected from fluoro.

In some embodiments, each of said R ³ is independently selected from halogen, hydroxy, cyano, amino, nitro, C _1-6 alkyl or C _1-6 alkoxy, wherein C _1-6 alkoxy or C _1-6 alkoxy optionally substituted with one or more R".

In some embodiments, each of said R ³ is independently selected from halogen, hydroxy, cyano, amino, nitro, C _1-4 alkyl or C _1-4 alkoxy, wherein C _1-4 alkoxy or C _1-4 alkoxy optionally substituted with one or more R".

In some embodiments, each of said R ³ is independently selected from fluoro, chloro, hydroxy, cyano, amino, C _1-3 alkyl or C _1-3 alkoxy, wherein C _1-3 alkyl or C _1-3 alkoxy optionally substituted with one or more R".

In some embodiments, the R" is selected from fluoro, chloro, bromo, or hydroxy.

In some embodiments, the R" is selected from fluoro, chloro or bromo.

In some embodiments, the R" is selected from fluoro or chloro.

In some embodiments, the R" is selected from fluoro.

In some embodiments, the n is selected from 0, 1 or 2.

In some embodiments, the n is selected from 0 or 1.

In some embodiments, the n is zero.

In some embodiments, the n is 1.

In other embodiments, the R ³ is selected from hydrogen, fluorine, chlorine, bromine, or C _1-6 alkyl optionally substituted with one or more halogens. In some embodiments, the R ³ is selected from hydrogen, fluorine, chlorine, bromine, or C _1-4 alkyl optionally substituted with one or more atoms selected from fluorine or chlorine. In other embodiments, the R ³ is selected from hydrogen, fluorine, chlorine, or C _1-3 alkyl optionally substituted with one or more fluorine atoms. In other embodiments, the ^R3 is selected from hydrogen, fluorine, chlorine, or methyl optionally substituted with one or more fluorine atoms. In other embodiments, the ^R3 is selected from hydrogen, fluoro, chloro or trifluoromethyl.

In other embodiments, the L is selected from -C(O)N(R ^a )-, and R ¹ is selected from cyclopropyl optionally substituted with one or more R; alternatively, the R ¹ is selected from from optionally substituted with one or more R

or R ¹ is selected from optionally substituted with one or more R

In other embodiments, the L is selected from -N(R ^b )-, and R ¹ is selected from cyclopropyl optionally substituted with one or more R; or, the R ¹ is selected from optionally substituted by one or more R

or R ¹ is selected from optionally substituted with one or more R

In some embodiments, structural fragments

selected from

In some embodiments, structural fragments

selected from

In other embodiments, structural fragments

selected from

In other embodiments, structural fragments

selected from

In other embodiments, structural fragments

selected from

In other embodiments, structural fragments

selected from

In other embodiments, structural fragments

selected from

In some embodiments, the heteroatom of the heterocycloalkyl described herein is N; in some embodiments, the heteroatom of the heterocycloalkyl described herein is O.

In some embodiments, the present application encompasses the above-defined variables and embodiments thereof, as well as any combination thereof.

In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, is selected from the compound of formula I', or a pharmaceutically acceptable salt, stereoisomer thereof , tautomers,

The definitions of L, R ¹ , R ² and R ³ are as described above.

In some embodiments, the R ¹ is selected from hydrogen, C _1-8 alkyl optionally substituted with hydroxy or halo, C _3-10 cycloalkyl or contains 1, 2 or 3 selected from N, O or A 3-10 membered heterocycloalkyl of a heteroatom of S, the cycloalkyl or heterocycloalkyl is optionally substituted with one or more Rs selected from C _1-8 alkyl, substituted by one or Multiple deuterium substituted C _1-8 alkyl, C _1-8 alkyl substituted with one or more halogens, C _1-8 alkyl substituted with one C _3-8 cycloalkyl, C _3-8 ring Alkyl, halogen, cyano, amino or hydroxyl;

The R ² is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C _1-8 alkyl or C _1-8 alkoxy, wherein C _1-8 alkyl or C _1-8 alkoxy optionally substituted with one or more R' selected from halogen, hydroxy, cyano, amino or nitro;

Said ^R3 is selected from hydrogen, halogen or _C1-8 alkyl optionally substituted with one or more halogens.

In some embodiments, the compound of formula I of the present application, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, is selected from the group consisting of formula II, formula III, formula IV, formula V, formula VI, formula VII or a compound of formula VIII or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,

Wherein, the definitions of R ¹ , R ² , R ³ or n are the same as those defined above in this application.

In some embodiments, the application provides the following compounds or pharmaceutically acceptable salts, stereoisomers, tautomers thereof:

In another aspect, the present application relates to a pharmaceutical composition comprising a compound of formula I of the present application or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof. In some embodiments, the pharmaceutical compositions of the present application further include pharmaceutically acceptable excipients.

In another aspect, the present application relates to a method of treating an EGFR-mediated disease in an individual, comprising administering to an individual in need of such treatment, preferably a mammal, more preferably a human, a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable amount thereof The salts, stereoisomers, tautomers, or pharmaceutical compositions thereof.

In another aspect, the present application relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof in the manufacture of a medicament for the prevention or treatment of EGFR-mediated diseases the use of.

In another aspect, the present application relates to the use of a compound of formula I, or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof, in the prevention or treatment of EGFR-mediated diseases.

In another aspect, the present application relates to a compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer, or pharmaceutical composition thereof for the prevention or treatment of EGFR-mediated diseases.

In some embodiments, the EGFR-mediated diseases described herein are selected from EGFR mutant-mediated diseases. wherein the mutant is selected from one, two, three, or four of L858R, T790M, d19 (eg, d746-750, which is one of exon 19 deletion mutations), C797S; in some embodiments , wherein the mutant is selected from two mutants of L858R and T790M; in some embodiments, wherein the mutant is selected from two mutants of d19 and T790M. Further, in some embodiments, wherein the mutant comprises a C797S mutant; further, wherein the mutant is selected from three mutants of L858R, T790M and C797S; or wherein the mutant is selected from three mutants of d19, T790M and C797S.

In some embodiments, the EGFR-mediated disease described herein is selected from cancer.

In some embodiments, the EGFR-mediated disease described herein is selected from lung cancer.

In some embodiments, the EGFR-mediated disease described herein is selected from non-small cell lung cancer.

The compounds of the present application have good kinase and cellular activities (including wild-type and mutant types such as d19, T790M, C797S and L858R). It has stable metabolism in vitro and in vivo, and has excellent efficacy in vivo.

definition

Unless otherwise specified, the following terms used in this application have the following meanings. A particular term should not be considered indeterminate or unclear unless specifically defined, but should be understood according to its ordinary meaning in the art. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.

The term "substituted" means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, so long as the valence of the specified atom is normal and the compound after substitution is stable. When the substituent is oxo (ie =O), it means that two hydrogen atoms are substituted and oxo does not occur on an aromatic group.

As used herein, "one or more" refers to an integer from one to ten. For example, "one or more" means one, two, three, four, five, six, seven, eight, nine or ten; alternatively, "one or more" means one, two , three, four, five or six; alternatively, "one or more" means one, two or three.

The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes both the occurrence and the non-occurrence of said event or circumstance. For example, an ethyl group "optionally" substituted with halogen means that the ethyl group can be unsubstituted ( _CH2CH3 ₎ , monosubstituted (eg CH2CH2F ₎ , polysubstituted (eg _CHFCH2F , _CH ₂ CHF ₂ etc.) or fully substituted (CF ₂ CF ₃ ). It will be understood by those skilled in the art that for any group containing one or more substituents, no substitution or substitution pattern is introduced that is sterically impossible and/or cannot be synthesized.

_Cmn in this context, is that the moiety has an integer number of carbon atoms in the given range. For example " _C1-6 " means that the group may have 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms.

When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. So, for example, if a group is substituted with 2 Rs, each R has independent options.

When the number of a linking group is 0, such as -(CH ₂ ) ₀ -, it means that the linking group is a covalent single bond.

When one of the variables is selected from a single bond, it means that the two groups to which it is attached are directly connected.

When a substituent's bond is cross-linked to two atoms on a ring, the substituent can bond to any atom on the ring. For example, structural unit

Indicates that it can be substituted at any position on cyclohexyl or cyclohexadiene.

Indicates that substituents are attached to other structures. For example, when the heterocycloalkyl of R ¹ is selected from

when, indicating

Connect to L:

The term "halo" or "halogen" refers to fluorine, chlorine, bromine and iodine.

The term "hydroxyl" refers to the -OH group.

The term "cyano" refers to the -CN group.

The term "amino" refers to the _-NH2 group.

The term "nitro" refers to the -NO ₂ group.

The term "alkyl" refers to a hydrocarbon group of the general formula _CnH2n+1 _. The alkyl group can be straight or branched. For example, the term "C1-6 alkyl" refers to an alkyl group containing ₁ to ₆ carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, neopentyl, hexyl, 2-methylpentyl, etc.). Similarly, the alkyl portion of alkoxy, alkylamino, dialkylamino, alkylsulfonyl, and alkylthio (ie, alkyl) have the same definitions above.

The term "alkoxy" refers to -O-alkyl.

The term "alkylamino" refers to -NH-alkyl.

The term "dialkylamino" refers to -N(alkyl) ₂ .

The term "alkylsulfonyl" refers to _-SO2 -alkyl.

The term "cycloalkyl" refers to a carbocyclic ring that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the carbocycle is typically a 3- to 10-membered ring (eg, 3, 4, 5, 6, 7, 8, 9, 10 membered rings). Non-limiting examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, norbornyl (bicyclo[2.2.1]heptyl), bicyclo[2.2.2]octyl, diamond Alkyl etc.

The term "heterocycloalkyl" refers to a cyclic group that is fully saturated and may exist as a monocyclic, bridged or spirocyclic ring. Unless otherwise indicated, the heterocycle is typically a ring containing 1 to 3 heteroatoms (preferably 1 or 2 heteroatoms) independently selected from sulfur, oxygen and/or nitrogen. Examples of 3-membered heterocycloalkyl groups include, but are not limited to, oxiranyl, oxiranyl, ethylene oxide, and non-limiting examples of 4-membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetine Examples of cyclyl, thibutanyl, 5-membered heterocycloalkyl include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, pyrrolidinyl, isoxazolidinyl, oxazolidinyl, isothiazolidinyl, thiazolidine Examples of yl, imidazolidinyl, tetrahydropyrazolyl, 6-membered heterocycloalkyl include, but are not limited to, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, morpholinyl, piperazinyl, 1, Examples of 4-thioxanyl, 1,4-dioxanyl, thiomorpholinyl, 1,3-dithianyl, 1,4-dithianyl, 7-membered heterocycloalkyl include But not limited to azepanyl, oxepanyl, thiepanyl. Preferred are monocyclic heterocycloalkyl groups having 5 or 6 ring atoms.

The term "treating" means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:

(i) inhibiting the disease or disease state, i.e. arresting its development;

(ii) Alleviation of the disease or disease state, even if the disease or disease state resolves.

The term "prevention" means administering a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, especially when such When a mammal is predisposed to the disease state, but has not been diagnosed with the disease state.

The term "effective amount" means (i) treatment or prevention of a particular disease, condition or disorder, (ii) alleviation, amelioration or elimination of one or more symptoms of a particular disease, condition or disorder, or (iii) prevention or delay herein The amount of a compound of the present application to be used for the onset of one or more symptoms of a particular disease, condition or disorder described in . The amount of a compound of the present application that constitutes an "effective amount" will vary depending on the compound, the disease state and its severity, the mode of administration, and the age of the mammal to be treated, but can be routinely determined by those skilled in the art according to their own knowledge and this disclosure.

The term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue without more toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.

As the pharmaceutically acceptable salts, for example, metal salts, ammonium salts, salts with organic bases, salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids and the like can be mentioned .

The term "pharmaceutical composition" refers to a mixture of one or more compounds of the present application or salts thereof and pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate administration of a compound of the present application to an organism.

The term "pharmaceutically acceptable excipients" refers to those excipients which are not significantly irritating to the organism and which do not impair the biological activity and properties of the active compound. Suitable excipients are well known to those skilled in the art, such as carbohydrates, waxes, water-soluble and/or water-swellable polymers, hydrophilic or hydrophobic materials, gelatin, oils, solvents, water, and the like.

The term "individual" includes mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the class Mammalia: humans, non-human primates (eg, chimpanzees and other apes and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domestic animals , such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs. Examples of non-human mammals include, but are not limited to, birds, fish, and the like. In one embodiment of the related methods and compositions provided herein, the mammal is a human. The word "comprise" or "comprise" and its English variants such as comprises or comprising should be understood in an open, non-exclusive sense, ie, "including but not limited to".

The compounds and intermediates of the present application may also exist in different tautomeric forms, and all such forms are included within the scope of the present application. The term "tautomer" or "tautomeric form" refers to structural isomers of different energies that are interconvertible via a low energy barrier. For example, proton tautomers (also known as proton tautomers) include interconversions via migration of protons, such as keto-enol and imine-enamine isomerizations. A specific example of a proton tautomer is an imidazole moiety in which a proton can move between two ring nitrogens. Valence tautomers include interconversions through recombination of some of the bonding electrons. For example, non-limiting examples of tautomers include, but are not limited to

The present application also includes isotopically-labeled compounds of the present application that are the same as those described herein, but wherein one or more atoms have been replaced by an atom having an atomic weight or mass number different from that normally found in nature. Examples of isotopes that may be incorporated into the compounds of the present application include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine, and chlorine, such as 2H, ^3H , ^11C , ^13C , ^14C , ¹³ , ^respectively N, ¹⁵ N, ¹⁵ O, ¹⁷ O, ¹⁸ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I, ¹²⁵ I and ³⁶ Cl and the like.

Certain isotopically-labeled compounds of the present application (eg, those labeled ^with3H ^and14C ) are useful in compound and/or substrate tissue distribution assays. Tritiated (ie ³ H) and carbon-14 (ie ¹⁴ C) isotopes are especially preferred for their ease of preparation and detectability. Positron emitting isotopes such ^as15O , ^13N , ^11C ^and18F can be used in positron emission tomography (PET) studies to determine substrate occupancy. Isotopically labeled compounds of the present application can generally be prepared by the following procedures analogous to those disclosed in the Schemes and/or Examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.

In addition, substitution with heavier isotopes such as deuterium (ie 2H ⁾ may provide certain therapeutic advantages resulting from greater metabolic stability (eg increased in vivo half-life or reduced dosage requirements), and thus in some cases The following may be preferred, where the deuterium substitution may be partial or complete, and partial deuterium substitution means that at least one hydrogen is replaced by at least one deuterium.

The compounds of the present application may be asymmetric, eg, have one or more stereoisomers. Unless otherwise specified, all stereoisomers include, such as enantiomers and diastereomers. The compounds of the present application containing asymmetric carbon atoms can be isolated in optically pure or racemic forms. Optically pure forms can be resolved from racemic mixtures or synthesized by using chiral starting materials or chiral reagents.

The pharmaceutical composition of the present application can be prepared by combining the compound of the present application with suitable pharmaceutically acceptable excipients, for example, it can be formulated into solid, semi-solid, liquid or gaseous preparations, such as tablets, pills, capsules, powders , granules, ointments, emulsions, suspensions, suppositories, injections, inhalants, gels, microspheres and aerosols, etc.

Typical routes of administration of a compound of the present application, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof include, but are not limited to, oral, rectal, topical, inhalation, parenteral, sublingual, intravaginal, intranasal, intraocular, intraperitoneal, Intramuscular, subcutaneous, intravenous administration.

The pharmaceutical composition of the present application can be manufactured by methods well known in the art, such as conventional mixing method, dissolving method, granulation method, sugar-coated pill method, grinding method, emulsification method, freeze-drying method and the like.

In some embodiments, the pharmaceutical composition is in oral form. For oral administration, the pharmaceutical compositions can be formulated by admixing the active compound with pharmaceutically acceptable excipients well known in the art. These excipients enable the compounds of the present application to be formulated into tablets, pills, lozenges, dragees, capsules, liquids, gels, slurries, suspensions, etc., for oral administration to patients.

Solid oral compositions can be prepared by conventional mixing, filling or tabletting methods. It can be obtained, for example, by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if desired, and processing the mixture into granules to obtain tablets or icing core. Suitable adjuvants include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners or flavoring agents, and the like.

The pharmaceutical compositions may also be suitable for parenteral administration as sterile solutions, suspensions or lyophilized products in suitable unit dosage forms.

In all methods of administration of the compounds described herein, the daily dose is from 0.01 to 200 mg/kg body weight, in single or divided doses.

The compounds of the present application can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by their combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include but are not limited to the examples of the present application.

The chemical reactions of the specific embodiments of the present application are carried out in suitable solvents suitable for the chemical changes of the present application and the required reagents and materials. In order to obtain the compounds of the present application, it is sometimes necessary for those skilled in the art to modify or select the synthesis steps or reaction schemes on the basis of the existing embodiments.

An important consideration in the planning of synthetic routes in the art is the selection of suitable protecting groups for reactive functional groups, for example, reference can be made to Greene's Protective Groups in Organic Synthesis (4th Ed). Hoboken, New Jersey: John Wiley & Sons, Inc. cited in this application All references to are incorporated into this application in their entirety.

This application uses the following acronyms:

Pd(dppf) _CH2Cl2 is [1,1' _- bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex; TBTU stands for O-benzotriazole-N,N ,N',N'-tetramethylurea tetrafluoroboric acid; Pd ₂ (dba) ₃ represents tris(dibenzylidene-BASE acetone) dipalladium; Pd(OAc) ₂ represents palladium acetate; Xantphos represents 4,5-bis (diphenylphosphine)-9,9-dimethylxanthene; DMF stands for N,N-dimethylformamide; SEM-Cl stands for 2-(trimethylsilyl)ethoxymethyl chloride.

Detailed ways

For the sake of clarity, the present application is further illustrated with examples, but the examples do not limit the scope of the present application. All reagents used in this application were commercially available and used without further purification.

Embodiment 1:

(1) the preparation method of compound A:

Methyl 2-chloro-6-methylisonicotinate (20.0 g), 1-methyl-5-hydroxypyrazole (21.4 g), Pd(dppf)Cl ₂ CH ₂ Cl ₂ (2.64 g), carbonic acid Sodium (25.125 g) was dissolved in anisole (400 mL). The reaction solution was purged with argon for 3 times, and the reaction was stirred at 130 °C for about 10 h. After the reaction was completed, it was lowered to room temperature, filtered with suction, and the filter cake was rinsed with 80 mL of toluene. 60 mL of methanol was added to the filtrate, and 40 mL of 4M hydrogen chloride dioxane solution was slowly added dropwise. After the dropping was completed, it was stirred at room temperature for 2 h. After the stirring was completed, suction filtration was performed, and the filter cake was rinsed with 40 mL of toluene. The target compound was obtained, which was dried under vacuum at 50°C for 8h. Compound A was obtained, ESI-MS: m/z=248.26 [M+H] ⁺ .

(2) the preparation method of compound B:

(R)-5-Amino-4-methyl-1-pentanol (4.65 g), 2-fluoro-5-bromonitrobenzene (8.32 g), and potassium carbonate (11.50 g) were added to N,N - Dimethylformamide (85mL), react at 50°C for 4h; after the reaction is complete, pour the reaction solution into 500mL water, extract with ethyl acetate (400mL*2), combine the ethyl acetate phases, and dry over anhydrous sodium sulfate , concentrated until there is no liquid outflow to obtain the target product B, which is directly used in the next reaction without further purification. ESI-MS: m/z=317.10 [M+H] ⁺ .

(3) the preparation method of compound C:

Compound B (4.31 g) was dissolved in dichloromethane (80 mL), triethylamine (2.75 g) was slowly added and the temperature was lowered to 0-5 °C, and p-toluenesulfonyl chloride (2.86 g) was slowly added dropwise, and the dropwise addition was completed. The reaction was carried out at 20-25 °C for 3 h, and the reaction was complete; the reaction solution was washed with sodium bicarbonate solution (1M, 100 mL*2), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated until no liquid was released, to obtain compound C without further Purified and used directly in the next reaction. ESI-MS: m/z=471.10 [M+H] ⁺ .

(4) the preparation method of compound D:

Compound C (13.6 mmol), compound A (4.26 g) and potassium carbonate (4.70 g) were added to N,N-dimethylformamide (80 mL) and reacted at 70°C for 6 h, the reaction was complete; the reaction solution was poured into Pour into 800 mL of water, extract with ethyl acetate (500 mL*2), combine the ethyl acetate phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound D by column chromatography. ESI-MS: m/z=546.22 [M+H] ⁺ .

(5) the preparation method of compound E:

Compound D (4.00 g) was dissolved in methanol (80 mL) and tetrahydrofuran (10 mL), Raney Ni (0.4 g) was slowly added, the reaction solution was replaced with nitrogen for 2 times, and then with hydrogen for 3 times, and the reaction was carried out at 25°C for 8.5 h , the reaction was complete; the reaction solution was filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound E, which was directly used in the next reaction without further purification. ESI-MS: m/z=516.17 [M+H] ⁺ .

(6) the preparation method of compound F:

Compound E (3.70 g) was dissolved in tert-butanol (15 mL) and dichloromethane (80 mL), a solution of cyanogen bromide (0.91 g) in dichloromethane (5 mL) was added dropwise, and the reaction was performed at 25°C for 6 h, and the reaction was complete; Add sodium bicarbonate solution (1M, 100mL) to the reaction solution, separate the layers, keep the dichloromethane phase, wash with sodium bicarbonate solution (1M, 100mL*2), dry over anhydrous sodium sulfate, concentrate until no liquid flows out, column Chromatography gave compound F. ESI-MS: m/z=541.19 [M+H] ⁺ .

(7) preparation method of compound G:

Compound F (3.00 g) was dissolved in tetrahydrofuran (60 mL), sodium hydroxide (0.89 g) water (40 mL) solution was added dropwise, and the reaction was carried out at 20-25°C for 45 min. The reaction was complete; pH=5-6 was adjusted with 6M hydrochloric acid, The tetrahydrofuran and water were evaporated under reduced pressure, dichloromethane (100 mL) and triethylamine (2.25 g, 22.2 mmol, 4 eq) were added, and the solution was stirred and dissolved. After drying and filtration, a solution of compound G in dichloromethane was obtained. ESI-MS: m/z=527.20 [M+H] ⁺ .

(8) the preparation method of compound H:

TBTU (2.12g) was added to the dichloromethane solution of compound G (5.54mmol), and the reaction was completed at 20-25°C for 16h; the reaction solution was washed with water (50mL*3), the organic phase was dried over anhydrous sodium sulfate, and concentrated When no liquid flows out, compound H is obtained by column chromatography. ESI-MS: m/z=509.25 [M+H] ⁺ .

(9) the preparation method of embodiment 1:

Compound H (150 mg), cyclopropanecarboxamide (37 mg), Pd ₂ (dba) ₃ (67 mg), 2-(di-tert-butylphosphine)biphenyl (45 mg), potassium tert-butoxide (200 mg) were added to tert-amyl In alcohol (10 mL), nitrogen was replaced 3 times, and the reaction was carried out at 105 ° C for 3.5 h. The reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. When there is no liquid out, Example 1 (70 mg) is obtained by preparative liquid phase purification. ESI-MS: m/z=514.41 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ )δ12.79(s,1H), 10.30(s,1H), 8.58(s,1H), 8.14(s,1H), 8.00–7.93(m,1H), 7.79(s, 1H), 7.53(d, J=8.8Hz, 1H), 7.46(dd, J=8.7, 2.0Hz, 1H), 4.39(td, J=9.2, 8.7, 4.2Hz, 1H), 4.19 (dd,J=13.8,3.3Hz,1H),4.08(q,J=7.4,6.0Hz,1H),3.90(dd,J=13.7,10.0Hz,1H),3.76(s,3H),2.74( s, 1H), 2.68 (s, 3H), 2.22 (dd, J=14.1, 6.8Hz, 1H), 2.01–1.88 (m, 2H), 1.80 (tt, J=7.8, 4.8Hz, 1H), 1.51 -1.42(m, 1H), 0.81(t, J=7.6Hz, 7H).

Embodiment 2:

Compound H (100 mg), (R)-3-aminotetrahydropyran hydrochloride (40 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), Potassium tert-butoxide (130 mg) was added to tert-amyl alcohol (10 mL), replaced with nitrogen three times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and combined The organic phase was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 2 (29 mg). ESI-MS: m/z=530.42 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ )δ12.59(s,1H), 8.60(s,1H), 8.18(s,1H), 7.82(s,1H), 7.41(d, J=8.7Hz, 1H), 6.99(s, 1H), 6.80(d, J=8.2Hz, 1H), 4.39(td, J=9.3, 4.0Hz, 1H), 4.16(dd, J=13.8, 3.3Hz, 1H), 4.09 (p, J=4.6Hz, 1H), 3.92–3.82 (m, 2H), 3.77 (s, 3H), 3.74 (dd, J=10.1, 5.3Hz, 1H), 3.43–3.30 (m, 2H) ,3.19(dd,J＝11.1,8.2Hz,1H),2.71(s,4H),2.29–2.13(m,1H),2.00(dt,J＝10.0,4.3Hz,1H),1.93(q,J = 6.4, 5.8 Hz, 2H), 1.75 (dt, J=12.7, 4.9 Hz, 1H), 1.63–1.41 (m, 3H), 0.82 (d, J=6.5 Hz, 3H).

Embodiment 3:

Compound H (50 mg), Pd(OAc) ₂ (2.2 mg), Xantphos (11.4 mg), potassium fluoride (14.3 mg) and N-formylsaccharin (24.9 mg) were dispersed in DMF (3 mL) and replaced with nitrogen 3 times, react at 85°C for 6h, the raw materials react completely, then drop to room temperature and add ammonia water (1mL) to quench, and stir at 20-25°C for 16h; the reaction solution is filtered and purified by preparative liquid phase to obtain Example 3 (8mg). ESI-MS: m/z=474.36 [M+H] ⁺ .

¹ H NMR (500 MHz, methanol-d ₄ ) δ 8.88 (s, 1H), 8.24 (s, 1H), 8.03 (d, J=1.6 Hz, 2H), 7.88 (dd, J=8.4, 1.6 Hz, 1H), 7.60 (d, J=8.5Hz, 1H), 4.53 (td, J=9.2, 4.4Hz, 1H), 4.40–4.35 (m, 1H), 4.18–4.11 (m, 1H), 4.02–3.93 (m, 1H), 3.84(s, 3H), 2.85(d, J=9.2Hz, 1H), 2.80(s, 3H), 2.38–2.30(m, 1H), 2.14–2.00(m, 2H), 1.59 (q, J=10.7, 8.8 Hz, 1H), 0.91 (d, J=6.6 Hz, 3H).

Example 4:

Compound H (100 mg), hydroxyacetamide (18 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and potassium tert-butoxide (130 mg) were added In amyl alcohol (10 mL), nitrogen was replaced 3 times, and the reaction was carried out at 105 °C for 5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. Until no liquid flows out, Example 4 (10 mg) was obtained by preparative liquid phase purification. ESI-MS: m/z=504.40 [M+H] ⁺ .

¹ H NMR (500 MHz, methanol-d ₄ ) δ 8.86(s, 1H), 8.25(s, 1H), 8.02(d, J=4.1Hz, 2H), 7.78(s, 1H), 7.60-7.54( m, 1H), 7.44 (s, 2H), 4.53 (dt, J=11.9, 6.0Hz, 1H), 4.38–4.32 (m, 1H), 4.17 (s, 2H), 4.13 (dd, J=9.8, 5.4Hz, 1H), 3.91–3.87 (m, 1H), 3.85 (s, 3H), 2.81 (s, 3H), 2.38–2.30 (m, 1H), 2.09–2.02 (m, 2H), 1.65–1.55 (m, 2H), 0.92 (d, J=6.5Hz, 3H).

Example 5:

Compound H (100 mg), 4-aminomethyltetrahydropyran (27 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and tert-butanol Potassium (130 mg) was added to tert-amyl alcohol (10 mL), replaced by nitrogen three times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined. , dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 5 (44.5 mg). ESI-MS: m/z=544.37 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.62(s, 1H), 8.61(s, 1H), 8.19(s, 1H), 7.83(s, 1H), 7.43(d, J=8.7Hz, 1H), 6.98(s, 1H), 6.82(d, J=8.2Hz, 1H), 4.38(dt, J=9.1, 4.3Hz, 1H), 4.17(dd, J=13.8, 3.3Hz, 1H), 4.09(ddd,J=9.4,5.9,3.6Hz,1H),3.88(ddt,J=11.0,6.4,3.0Hz,3H),3.77(s,3H),3.29(td,J=11.7,2.1Hz, 2H), 3.00(d, J＝6.7Hz, 2H), 2.71(s, 3H), 2.26–2.17(m, 1H), 1.94(dtd, J＝12.8, 7.1, 6.1, 3.8Hz, 2H), 1.86 (ddd, J=11.2, 7.4, 4.1Hz, 1H), 1.74–1.67 (m, 2H), 1.50–1.41 (m, 1H), 1.29–1.22 (m, 3H), 0.81 (d, J=6.5Hz , 3H).

Example 6:

Compound H (100 mg), 2-methoxyethylamine (22 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and potassium tert-butoxide (130 mg) ), added tert-amyl alcohol (10 mL), replaced with nitrogen for 3 times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined and anhydrous It was dried over sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 6 (29 mg). ESI-MS: m/z=504.40 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ )δ 12.65(s, 1H), 8.58(s, 1H), 8.15(s, 1H), 7.79(s, 1H), 7.46(d, J=8.7Hz, 1H), 7.04(s, 1H), 6.89–6.83(m, 1H), 4.39(td, J=9.3, 4.2Hz, 1H), 4.17(dd, J=13.9, 3.3Hz, 1H), 4.08(dd ,J=9.7,4.9Hz,1H),3.87(dd,J=13.7,10.1Hz,1H),3.77(s,3H),3.54(t,J=5.6Hz,2H),3.32(s,3H) ,3.29(t,J＝5.6Hz,2H),2.74(d,J＝10.9Hz,1H),2.69(s,3H),2.20(d,J＝11.5Hz,1H),1.50–1.41(m, 1H), 1.24 (d, J=4.0 Hz, 2H), 0.81 (d, J=6.5 Hz, 3H).

Example 7:

Compound H (100 mg), N,N-dimethylethylenediamine (26 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and tert-butanol Potassium (130 mg) was added to tert-amyl alcohol (10 mL), replaced by nitrogen three times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined. , dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 7 (49 mg). ESI-MS: m/z=517.37 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.51(s, 1H), 8.50(s, 1H), 8.04(s, 1H), 7.67(s, 1H), 7.39(d, J=8.7Hz, 1H), 6.84 (d, J=2.2Hz, 1H), 6.66 (dd, J=8.6, 2.2Hz, 1H), 4.39–4.36 (m, 1H), 4.17 (dd, J=10.6Hz, 1H), 4.05–4.03(m, 1H), 3.84(dd, J=3.5Hz, 1H), 3.75(s, 3H), 3.41(t, J=6.3Hz, 2H), 3.28(t, J=6.2Hz, 2H) ), 2.86(s, 6H), 2.75(m, 1H), 2.62(s, 3H), 2.21(m, 1H), 1.99–1.92(m, 2H), 1.46(m, J=9.1Hz, 1H) , 0.81 (d, J=6.5Hz, 3H).

Example 8:

Compound H (100 mg), 1-(2-aminoethyl)pyrrolidine (34 mg), Pd2(dba ₎₃ ₍ 45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and tert-butyl Potassium alkoxide (130 mg) was added to tert-amyl alcohol (10 mL), nitrogen was replaced 3 times, and the reaction was completed at 105 ° C for 3.5 h; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic The phase was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 8 (60 mg). ESI-MS: m/z=543.37 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.53(s, 1H), 8.55(s, 1H), 8.10(s, 1H), 7.74(s, 1H), 7.40(d, J=8.7Hz, 1H), 6.85 (d, J=2.2Hz, 1H), 6.66 (dd, J=8.7, 2.2Hz, 1H), 4.38 (td, J=9.3, 4.3Hz, 1H), 4.17 (dd, J=13.8 ,3.2Hz,1H),4.06(dt,J＝9.4,5.1Hz,1H),3.85(dd,J＝13.7,10.1Hz,1H),3.76(s,3H),3.62(d,J＝4.5Hz ,1H),3.41(t,J＝6.4Hz,2H),3.36(t,J＝5.6Hz,2H),3.10(m,1H),2.74(m,1H),2.66(s,3H),2.21 (t, J=9.9Hz, 1H), 2.04-1.86 (m, 8H), 1.50-1.41 (m, 1H), 0.81 (d, J=6.5Hz, 3H).

Example 9:

Compound H (100mg), N-(2-aminoethyl)morpholine (38mg), Pd2(dba ₎₃ ₍ 45mg), 2-(di-tert-butylphosphine)biphenyl (29mg), tert-butanol Potassium (130 mg) was added to tert-amyl alcohol (10 mL), replaced by nitrogen three times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined. , dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 9 (28 mg). ESI-MS: m/z=559.38 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.52(s, 1H), 8.53(s, 1H), 8.07(s, 1H), 7.70(s, 1H), 7.40(d, J=8.7Hz, 1H), 6.84(d, J＝2.2Hz, 1H), 6.66(dd, J＝8.7, 2.2Hz, 1H), 4.38(d, J＝4.4Hz, 1H), 4.15(d, J＝3.2Hz, 1H), 4.05(t, J＝5.5Hz, 1H), 3.86(d, J＝10.2Hz, 4H), 3.75(s, 3H), 3.46(t, J＝6.3Hz, 2H), 3.41–3.19( m, 6H), 2.79–2.70 (m, 1H), 2.64 (s, 3H), 2.21 (t, J=8.7Hz, 1H), 1.95 (q, J=13.2, 10.7Hz, 2H), 1.50–1.40 (m, 1H), 1.26–1.21 (m, 1H), 0.81 (d, J=6.5Hz, 3H).

Example 10:

Compound H (100 mg), 2-pyrrolidone (20 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and potassium tert-butoxide (130 mg) were added In amyl alcohol (10 mL), nitrogen was replaced 3 times, and the reaction was carried out at 105 ° C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, Concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 10 (25 mg). ESI-MS: m/z=514.43 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.79(s, 1H), 8.55(s, 1H), 8.11(s, 1H), 7.95(d, J=2.1Hz, 1H), 7.76(s, 1H), 7.60(d, J＝8.8Hz, 1H), 7.50(dd, J＝8.7, 2.1Hz, 1H), 4.38(td, J＝9.4, 4.3Hz, 1H), 4.20(dd, J＝13.9 ,3.2Hz,1H),4.07(dd,J＝9.8,5.1Hz,1H),3.94(dd,J＝13.7,10.2Hz,1H),3.87(t,J＝7.0Hz,2H),3.76(s ,3H),2.76(d,J＝9.1Hz,1H),2.66(s,3H),2.54(d,J＝3.4Hz,2H),2.20(d,J＝10.1Hz,1H),2.09(p , J=7.5Hz, 2H), 1.95 (qt, J=7.8, 4.6Hz, 2H), 1.47 (dt, J=15.9, 5.9Hz, 1H), 0.81 (d, J=6.5Hz, 3H).

Example 11:

Compound H (100 mg), S-(tetrahydro-2H-pyran-3-yl)methanamine hydrochloride (36 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine) Biphenyl (29mg) and potassium tert-butoxide (130mg) were added to tert-amyl alcohol (10mL), replaced with nitrogen for 3 times, and reacted at 105°C for 3.5h, the reaction was complete; 20mL of water was added to the reaction solution, ethyl acetate (20mL*2) extraction, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 11 (73 mg). ESI-MS: m/z=544.42 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ )δ12.60(s,1H), 8.62(s,1H), 8.20(s,1H), 7.84(s,1H), 7.41(d, J=8.7Hz, 1H), 6.92(s, 1H), 6.77(d, J=8.7Hz, 1H), 4.39(dt, J=9.4, 4.5Hz, 1H), 4.17(dd, J=13.8, 3.3Hz, 1H), 4.10 (d, J=7.9Hz, 1H), 3.91–3.81 (m, 2H), 3.77 (s, 3H), 3.74 (dt, J=11.4, 3.9Hz, 1H), 3.34 (td, J=10.8, 2.8Hz, 1H), 3.17 (dd, J=11.2, 8.9Hz, 1H), 2.95 (q, J=6.9Hz, 2H), 2.72 (s, 4H), 2.20 (d, J=11.2Hz, 1H) ,1.97–1.84(m,4H),1.61(dt,J=13.0,3.8Hz,1H),1.52–1.40(m,2H),1.36–1.27(m,1H),0.81(d,J=6.5Hz , 3H).

Example 12:

Compound H (100 mg), (R)-1,4-dioxane-2-methylamine hydrochloride (45 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine) ) biphenyl (29mg) and potassium tert-butoxide (130mg) were added to tert-amyl alcohol (10mL), replaced by nitrogen for 3 times, and reacted at 105°C for 3.5h, the reaction was complete; 20mL of water was added to the reaction solution, ethyl acetate Ester (20 mL*2) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 12 (29 mg). ESI-MS: m/z=546.38 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.37(s, 1H), 8.41(s, 1H), 7.92(s, 1H), 7.55(d, J=1.2Hz, 1H), 7.29(d, J=8.7Hz,1H),6.78(d,J=2.2Hz,1H),6.62(dd,J=8.6,2.2Hz,1H),5.66(s,1H),4.35(td,J=8.9,4.2 Hz, 1H), 4.15 (dd, J=13.8, 3.2Hz, 1H), 3.99 (dq, J=9.7, 5.2, 4.7Hz, 1H), 3.85–3.75 (m, 3H), 3.73 (s, 3H) ,3.66(dd,J＝11.3,2.4Hz,1H),3.59(td,J＝11.2,2.5Hz,1H),3.49(td,J＝11.1,2.7Hz,1H),3.30(dd,J＝11.4 ,9.8Hz,2H),3.04(d,J=5.8Hz,2H),2.76(s,1H),2.55(s,3H),2.20(m,1H),2.01–1.87(m,2H),1.43 (q, J=9.3, 8.4 Hz, 1H), 0.81 (d, J=6.5 Hz, 3H).

Example 13:

Compound H (100 mg), (S)-3-aminotetrahydrofuran (36 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and potassium tert-butoxide ( 130 mg), added to tert-amyl alcohol (10 mL), replaced with nitrogen for 3 times, and reacted at 105 ° C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined. It was dried over sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 13 (40 mg). ESI-MS: m/z=516.42 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ )δ12.56(s,1H), 8.60(s,1H), 8.17(s,1H), 7.82(s,1H), 7.39(d, J=8.7Hz, 1H), 6.87(d, J＝2.2Hz, 1H), 6.70(dd, J＝8.7, 2.2Hz, 1H), 4.39(q, J＝5.3Hz, 1H), 4.16(dd, J＝13.8, 3.2 Hz, 1H), 4.10 (d, J=9.8Hz, 1H), 3.97 (dd, J=6.5, 3.4Hz, 1H), 3.90 (dd, J=8.8, 5.7Hz, 1H), 3.88–3.81 (m ,2H),3.77(s,3H),3.76–3.72(m,1H),3.58(dd,J=8.9,3.6Hz,1H),2.70(s,4H),2.26–2.15(m,2H), 1.98–1.89 (m, 2H), 1.85–1.78 (m, 1H), 1.50–1.42 (m, 1H), 0.82 (d, J=6.5Hz, 3H).

Example 14:

(1) preparation method of compound I:

Compound H (300 mg), sodium iodide (177 mg), cuprous iodide (11.4 mg), and N,N-dimethylethylenediamine (10.6 mg) were added to 2-pentanol (7 mL) under nitrogen Replace 3 times, microwave reaction at 140°C for 10h, the reaction is complete; add 50mL of water to the reaction solution, extract with ethyl acetate (20mL*2), combine the organic phases, dry over anhydrous sodium sulfate, and concentrate until no liquid flows out to obtain the compound I, without further purification, was directly used in the next reaction. ESI-MS: m/z=557.23 [M+H] ⁺ .

(2) the preparation method of embodiment 14:

Compound I (100 mg), copper hydroxide (25 mg), and potassium tert-butoxide (50 mg) were added to (S)-3-hydroxytetrahydrofuran (5 mL), replaced by nitrogen three times, and reacted at 140°C for 8 h by microwave. Complete; 50 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 14 (5 mg). ESI-MS: m/z=517.35 [M+H] ⁺ .

¹ H NMR (500MHz, methanol-d ₄ ) δ 8.52(s, 1H), 8.15(s, 1H), 7.84(s, 1H), 7.36(d, J=8.7Hz, 1H), 6.80(s, 1H), 6.65 (d, J=8.7, 2.2Hz, 1H), 4.46 (q, J=5.3Hz, 1H), 4.18 (dd, J=13.8, 3.2Hz, 1H), 4.10 (d, J=9.8 Hz,1H),3.99(dd,J=6.5,3.4Hz,1H),3.96(dd,J=8.8,5.7Hz,1H),3.92–3.85(m,2H),3.80(s,3H),3.78 –3.74(m,1H),3.61(dd,J=8.9,3.6Hz,1H),2.71(s,4H),2.26–2.15(m,2H),1.99–1.90(m,2H),1.83–1.78 (m, 1H), 1.54–1.48 (m, 1H), 0.84 (d, J=6.5Hz, 3H).

Example 15:

Compound H (100 mg), 4-amino-1-methylpiperidine (34 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and tert-butanol Potassium (130 mg) was added to tert-amyl alcohol (10 mL), replaced by nitrogen three times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined. , dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 15 (71 mg). ESI-MS: m/z=543.47 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ )δ12.65-12.41(m,1H), 9.50(s,1H), 8.57(s,1H), 8.12(s,1H), 7.76(s,1H), 7.39(d,J＝8.8Hz,1H),6.87(dd,J＝7.6,2.1Hz,1H),6.71–6.66(m,1H),4.39(dt,J＝10.9,5.7Hz,1H),4.16 (dd,J＝13.9,3.3Hz,1H),4.08(dd,J＝9.9,5.6Hz,1H),3.84(dd,J＝13.5,10.2Hz,1H),3.76(s,3H),3.50( d, J=12.2Hz, 2H), 3.35–3.18 (m, 1H), 3.11–3.04 (m, 1H), 2.80 (d, J=4.5Hz, 3H), 2.74 (d, J=9.3Hz, 1H) ), 2.67(s, 3H), 2.54(s, 1H), 2.27–2.11(m, 3H), 1.95(h, J=8.5, 6.7Hz, 3H), 1.59(d, J=13.0Hz, 1H) , 1.49–1.42 (m, 1H), 0.82 (d, J=6.5Hz, 3H).

Example 16:

Compound H (100 mg), trifluoroethylamine hydrochloride (66 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), and potassium tert-butoxide (130 mg) were combined ), added tert-amyl alcohol (10 mL), replaced with nitrogen for 3 times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined and anhydrous It was dried over sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 16 (13 mg). ESI-MS: m/z=528.37 [M+H] ⁺ .

¹ H NMR (500MHz, methanol-d ₄ )δ8.47(s,1H), 8.05(s,1H), 7.62(s,1H), 7.21(s,1H), 6.83(s,1H), 6.73( d, J=7.3Hz, 1H), 4.43 (td, J=9.4, 4.3Hz, 1H), 4.24 (dd, J=13.9, 3.2Hz, 1H), 3.97 (dd, J=9.8, 5.1Hz, 1H) ), 3.84(dd, J=13.7, 10.2Hz, 1H), 3.75(s, 3H), 2.77(s, 1H), 2.57(s, 3H), 2.25(s, 1H), 1.95(d, J= 21.1 Hz, 2H), 1.49 (d, J=15.0 Hz, 1H), 1.34–1.27 (m, 2H), 0.85 (d, J=6.2 Hz, 3H).

Example 17:

(1) preparation method of compound B-1:

(R)-5-amino-4-methyl-1-pentanol (520mg), 5-bromo-1,2-difluoro-3-nitrobenzene (1g), and potassium carbonate (1.28g), Add N,N-dimethylformamide (10mL), react at 55°C for 4h, the reaction is complete; pour the reaction solution into 100mL water, extract with ethyl acetate (20mL*2), combine the organic phases, anhydrous sodium sulfate Dry and concentrate until no liquid flows out to obtain compound B-1, which is directly used in the next reaction without further purification. ESI-MS: m/z=337.16 [M+H] ⁺ .

(2) the preparation method of compound C-1:

Compound B-1 (1.4 g) was dissolved in dichloromethane (15 mL), triethylamine (0.85 g) was slowly added dropwise, and the temperature was lowered to 0-5 °C, and a solution of toluenesulfonyl chloride (1.59 g) in dichloromethane was slowly added dropwise. Chloromethane (5mL) solution was added dropwise and reacted at 20-25°C for 16h. After the reaction was completed, the reaction solution was washed with aqueous sodium bicarbonate solution (1M, 50mL*2), and the layers were separated. The organic phase was dried over anhydrous sodium sulfate and concentrated to nothing. The liquid flows out to obtain compound C-1, which is directly used in the next reaction without further purification. ESI-MS: m/z=489.12 [M+H] ⁺ .

(3) the preparation method of compound D-1:

Compound C-1 (4.1 mmol), compound A (1.2 g) and potassium carbonate (1.2 g) were added to N,N-dimethylformamide (20 mL) and reacted at 60°C for 6.5 h, the reaction was complete; The liquid was poured into 400 mL of water, extracted with ethyl acetate (200 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated until no liquid flowed out. Compound D-1 was obtained by column chromatography. ESI-MS: m/z=566.12 [M+H] ⁺ .

(4) preparation method of compound E-1:

Compound D-1 (1.7 g) was dissolved in methanol (6 mL) and tetrahydrofuran (6 mL), Raney Ni (0.1 g) was slowly added, the reaction solution was replaced with nitrogen for 2 times and then with hydrogen for 3 times, and the reaction was carried out at 25°C After 2 h, the reaction was complete; the reaction solution was filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound E-1, which was directly used in the next reaction without further purification. ESI-MS: m/z=536.14 [M+H] ⁺ .

(5) preparation method of compound F-1:

Compound E-1 (1.4 g) was dissolved in tert-butanol (2 mL) and dichloromethane (10 mL), and a solution of cyanogen bromide (0.39 g, 3.68 mmol, 1.2 eq) in dichloromethane (5 mL) was added dropwise, After the dropwise addition was completed, the reaction was carried out at 25°C for 30h, and the reaction was complete; sodium bicarbonate aqueous solution (1M, 100mL) was added to the reaction solution, and the layers were separated, the dichloromethane phase was retained, and the sodium bicarbonate solution (1M, 50mL*2) was washed, and no Dry with aqueous sodium sulfate, concentrate until no liquid flows out, and obtain compound F-1 by column chromatography. ESI-MS: m/z=561.17 [M+H] ⁺ .

(6) preparation method of compound G-1:

Compound F-1 (0.54g) was dissolved in tetrahydrofuran (10mL), sodium hydroxide (143mg) water (10mL) solution was added dropwise, and the reaction was performed at 20-25°C for 30min, and the reaction was complete; adjust pH=5-6 with 6M hydrochloric acid , tetrahydrofuran and water were evaporated under reduced pressure, dichloromethane (20 mL) and triethylamine (362 mg) were added, the solution was stirred, and the solution was dried and filtered to obtain a dichloromethane solution of compound G-1.

(7) preparation method of compound H-1:

To the dichloromethane solution of compound G-1 (0.89 mmol), TBTU (344 mg) was added, and the reaction was completed at 20-25 °C for 5 h; the reaction solution was washed with water (50 mL*3), and the organic phase was dried with anhydrous sodium sulfate, Concentrate until no liquid flows out, and obtain compound H-1 by column chromatography. ESI-MS: m/z=527.20 [M+H] ⁺ .

(8) the preparation method of embodiment 17:

Compound H-1 (150 mg), cyclopropanecarboxamide (29 mg), Pd ₂ (dba) ₃ (52 mg), 2-(di-tert-butylphosphine)biphenyl (34 mg), potassium tert-butoxide (170 mg), Add tert-amyl alcohol (5 mL), replace with nitrogen for 3 times, react at 100°C for 6 h, the reaction is complete; add 20 mL of water to the reaction solution, extract with ethyl acetate (20 mL*2), combine the organic phases, and dry over anhydrous sodium sulfate , concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 17 (14 mg). ESI-MS: m/z=532.38 [M+H] ⁺ .

¹ H NMR (500MHz, chloroform-d)δ11.98(s,1H), 9.75(s,1H), 8.51(s,1H), 8.40(s,1H), 7.91(s,1H), 7.64(s ,1H),6.68(d,J＝12.7Hz,1H),4.42–4.34(m,1H),4.30(d,J＝13.6Hz,1H),4.08(dt,J＝9.9,5.4Hz,1H) ,3.95(t,J=11.5Hz,1H),3.85(s,3H),2.84(s,3H),2.51(s,1H),2.33–2.26(m,1H),2.13(d,J=5.1 Hz, 1H), 2.03(d, J＝14.9Hz, 1H), 1.58(dd, J＝14.8, 7.7Hz, 1H), 1.26(m, 1H), 1.02(d, J＝6.5Hz, 3H), 0.81 (t, J=6.9 Hz, 4H).

Example 18:

(1) The preparation method of compound A-1-1:

1-Methyl-5-hydroxypyrazole (30 g) and potassium carbonate (90 g) were added to acetonitrile (900 mL), SEM-Cl (90 mL) was added dropwise at 25°C, and the addition was completed and the reaction was carried out at 20-25°C for 16 h. The reaction was complete; the reaction solution was filtered, the filtrate was evaporated to dryness, methyl tert-butyl ether (300 mL) was added to the residue, heated to 65° C. to dissolve, then n-heptane (120 mL) was added, the temperature was naturally cooled for crystallization, and suction filtered, The filter cake is dried to obtain compound A-1-1. ESI-MS: m/z=229.30 [M+H] ⁺ .

(2) the preparation method of compound A-1-2:

Compound A-1-1 (26g), NIS (30.7g) and benzoic acid (2.8g) were added to dichloromethane (260mL) and reacted at 20-25°C for 3h, the reaction was complete; the reaction solution was water (500mL*2 ) washing, separating the layers, drying the organic phase with anhydrous sodium sulfate, concentrating until no liquid flows out, and obtaining compound A-1-2 by column chromatography. ESI-MS: m/z=355.20 [M+H] ⁺ .

(3) the preparation method of compound A-1-3:

2-Fluoroisonicotinic acid (20 g), methyl iodide (40.2 g) and potassium carbonate (39 g) were added to N,N-dimethylformamide (200 mL), and reacted at 40°C for 16 h, the reaction was complete; Pour into 1500 mL of water, extract with ethyl acetate (500 mL*2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound A-1-3 by column chromatography. ESI-MS: m/z=156.08 [M+H] ⁺ .

(4) preparation method of compound A-1-4:

Biboron pinacol ester (14.8g), methoxy(cyclooctadiene)iridium dimer (570mg), 4,4-di-tert-butylbipyridine (468mg) were added to cyclohexane (150mL) ), nitrogen was replaced 3 times, and stirred at 25 °C for 1 h; the solution of compound A-1-3 (9 g) in cyclohexane (30 mL) was added dropwise, and the dropwise addition was completed and the reaction was carried out at 75 °C for 4 h, and the reaction was complete; Evaporate to dryness to obtain compound A-1-4, which is directly used in the next reaction without further purification. ESI-MS: m/z=199.99 [M+H] ⁺ .

(5) preparation method of compound A-1-5:

Compound A-1-2 (5.9g), compound A-1-4 (5.0g), Pd(dppf)Cl ₂ (1.3g), cesium carbonate (8.2g) were added to N,N-dimethylformamide (50mL), nitrogen was replaced 3 times, stirred at 100°C for 4h, the reaction was complete; the reaction solution was poured into 300mL of water, extracted with dichloromethane (100mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to no Liquid flowed out, and column chromatography gave compound A-1-5. ESI-MS: m/z=382.34 [M+H] ⁺ .

(6) preparation method of compound A-1:

Compound A-1-5 (5.9 g) was added to hydrogen chloride/1,4-dioxane (4M, 20 mL), stirred at 25°C for 3 h, the reaction was complete; the reaction solution was evaporated to dryness to obtain compound A-1, It was directly used in the next reaction without further purification. ESI-MS: m/z=252.17 [M+H] ⁺ .

(7) preparation method of compound D-2:

Compound C (1.2 g), compound A-1 (1.1 g), potassium carbonate (1.1 g) were added to N,N-dimethylformamide (10 mL), and reacted at 60°C for 6.5 h, the reaction was complete; The liquid was poured into 50 mL of water, extracted with ethyl acetate (20 mL*2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated until no liquid was eluted, and the compound D-2 was obtained by column chromatography. ESI-MS: m/z=550.16 [M+H] ⁺ .

(8) the preparation method of compound E-2:

Compound D-2 (600 mg) was dissolved in methanol (10 mL) and tetrahydrofuran (2 mL), Raney Ni (0.1 g) was slowly added, the reaction solution was replaced with nitrogen for 2 times and then with hydrogen for 3 times, and the reaction was carried out at 25°C for 16 h. , the reaction was complete; the reaction solution was filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound E-2, which was directly used in the next reaction without further purification. ESI-MS: m/z=520.20 [M+H] ⁺ .

(9) preparation method of compound F-2:

Compound E-2 (570 mg) was dissolved in tert-butanol (1.5 mL) and dichloromethane (6 mL), and a solution of cyanogen bromide (140 mg) in dichloromethane (2 mL) was added dropwise, and the reaction was carried out at 25 °C after the dropwise addition. 30h, the reaction was complete; sodium bicarbonate solution (1M, 100mL) was added to the reaction solution, the liquid was separated, the dichloromethane phase was retained, washed with sodium bicarbonate solution (1M, 50mL*2), dried over anhydrous sodium sulfate, and concentrated to No liquid flowed out, and the compound F-2 was obtained by column chromatography. ESI-MS: m/z=545.19 [M+H] ⁺ .

(10) preparation method of compound G-2:

Compound F-2 (0.59g) was dissolved in tetrahydrofuran (10mL), sodium hydroxide (170mg) water (10mL) solution was added dropwise, and the reaction was performed at 20-25°C for 30min, and the reaction was complete; adjust pH=5-6 with 6M hydrochloric acid , tetrahydrofuran and water were evaporated under reduced pressure, dichloromethane (20 mL) and triethylamine (450 mg) were added, the solution was stirred, dried and filtered to obtain a dichloromethane solution of compound G-2.

(11) preparation method of compound H-2:

TBTU (420 mg) was added to the dichloromethane solution of compound G-2 (1.09 mmol), and the reaction was completed at 20-25 °C for 5 h; the reaction solution was washed with water (50 mL*3), and the organic phase was dried with anhydrous sodium sulfate, Concentrate until no liquid flows out, and obtain compound H-2 by column chromatography. ESI-MS: m/z=513.17 [M+H] ⁺ .

(12) the preparation method of embodiment 18:

Compound H-2 (100 mg), trifluoroethylamine hydrochloride (66 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), potassium tert-butoxide ( 130 mg) was added to tert-amyl alcohol (10 mL), replaced with nitrogen for 3 times, and reacted at 105 ° C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phases were combined and anhydrous It was dried over sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 18 (25 mg). ESI-MS: m/z=532.05 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.56 (s, 1H), 8.52 (dd, J=2.3, 1.0 Hz, 1H), 7.90 (s, 1H), 7.40 (d, J=8.7 Hz, 1H), 7.32(dd, J＝2.1, 1.0Hz, 1H), 6.96(d, J＝2.2Hz, 1H), 6.77(dd, J＝8.7, 2.3Hz, 1H), 6.33(t, J＝6.9 Hz,1H),4.39(td,J=9.1,8.6,4.3Hz,1H),4.18(dd,J=13.8,3.3Hz,1H),4.05(dd,J=9.6,5.0Hz,1H),3.92 (d, J=2.9Hz, 1H), 3.76(s, 3H), 2.77(s, 1H), 2.23(s, 1H), 2.00(dd, J=20.4, 10.6Hz, 2H), 1.47(s, 2H), 1.25 (t, J=6.8Hz, 1H), 0.83 (d, J=6.6Hz, 3H).

Example 19:

Compound H-2 (100 mg), 1-(2-aminoethyl) pyrrolidine (34 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), tertiary Potassium butoxide (130 mg) was added to tert-amyl alcohol (10 mL), nitrogen was replaced 3 times, and the reaction was completed at 105 ° C for 3.5 h; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic The phase was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 19 (20 mg). ESI-MS: m/z=547.42 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.49(s, 1H), 8.49(d, J=2.2Hz, 1H), 7.88(s, 1H), 7.33(d, J=8.7Hz, 1H) ,7.29(d,J＝2.0Hz,1H),6.77(d,J＝2.1Hz,1H),6.63(dd,J＝8.7,2.1Hz,1H),4.37(d,J＝4.3Hz,1H) ,4.15(dd,J=13.7,3.2Hz,1H),4.02(s,1H),3.84–3.80(m,1H),3.74(s,3H),3.19(t,J=6.7Hz,2H), 2.77(t, J=6.7Hz, 3H), 2.67(d, J=6.1Hz, 4H), 2.21(s, 1H), 1.96(q, J=14.5, 13.2Hz, 2H), 1.76(q, J = 3.4 Hz, 4H), 1.44 (d, J=9.1 Hz, 1H), 0.81 (d, J=6.5 Hz, 3H).

Example 20:

Compound H (100 mg), 1-(3-aminopropyl) pyrrolidine (38 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), tert-butanol Potassium (130 mg) was added to tert-amyl alcohol (10 mL), replaced by nitrogen three times, and reacted at 105°C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic phases were combined, Dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 20 (77 mg). ESI-MS: m/z=557.66 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.57(s, 1H), 8.58(s, 1H), 8.14(s, 1H), 7.78(s, 1H), 7.41(d, J=8.7Hz, 1H), 6.86 (d, J=2.1Hz, 1H), 6.69 (dd, J=8.7, 2.2Hz, 1H), 4.39 (td, J=9.3, 4.1Hz, 1H), 4.17 (dd, J=13.8 ,3.3Hz,1H),4.11–4.04(m,1H),3.85(dd,J=13.6,10.1Hz,1H),3.77(s,3H),3.56(s,1H),3.29–3.22(m, 2H), 3.13(t, J=6.7Hz, 2H), 3.03(s, 1H), 2.74(d, J=6.7Hz, 1H), 2.68(s, 3H), 2.21(d, J=11.7Hz, 1H), 2.04–1.84 (m, 8H), 1.50–1.41 (m, 1H), 1.18 (d, J=6.2Hz, 2H), 0.81 (d, J=6.5Hz, 3H).

Example 21:

Compound H-2 (100 mg), 1-(3-aminopropyl) pyrrolidine (38 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), tertiary Potassium butoxide (130 mg) was added to tert-amyl alcohol (10 mL), nitrogen was replaced 3 times, and the reaction was completed at 105 ° C for 3.5 h; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), and the organic The phase was dried over anhydrous sodium sulfate, concentrated until no liquid flowed out, and purified by preparative liquid phase to obtain Example 21 (30 mg). ESI-MS: m/z=561.61 [M+H] ⁺ .

¹ H NMR (500MHz, chloroform-d) δ 8.53(d, J=1.9Hz, 1H), 8.10(s, 1H), 7.42(s, 1H), 7.06(d, J=8.7Hz, 1H), 6.61(dd,J=8.7,2.1Hz,1H),6.52(d,J=2.1Hz,1H),4.47(td,J=9.1,5.1Hz,1H),4.31(dd,J=13.8,3.4Hz ,1H),3.93–3.88(m,1H),3.78(s,3H),3.63(dd,J=13.7,9.6Hz,1H),3.15(t,J=6.3Hz,2H),2.98(m, 4H), 2.85–2.82 (m, 4H), 2.26 (q, J=7.5, 6.3Hz, 1H), 2.10 (td, J=9.7, 4.9Hz, 1H), 1.97–1.91 (m, 6H), 1.51 (dh, J=11.8, 3.3 Hz, 1H), 0.91 (d, J=6.6 Hz, 3H).

The following compounds were prepared with reference to the preparation process of Example 1:

Example 22:

Compound H-2 (100 mg), (S)-1,1,1-trifluoroisopropylamine hydrochloride (44 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine) were combined Benzene (29 mg) and potassium tert-butoxide (130 mg) were added to tert-amyl alcohol (10 mL), replaced by nitrogen for 3 times, and reacted at 100 ° C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, ethyl acetate (20 mL) *2) Extraction, combining the organic phases, drying over anhydrous sodium sulfate, concentrating until no liquid flows out, and purifying by preparative liquid phase to obtain Example 22 (10 mg). ESI-MS: m/z=546.35 [M+H] ⁺ .

¹ H NMR (500MHz, chloroform-d)δ8.50(s,1H),8.12(s,1H),7.38(s,1H),7.11(d,J=8.4Hz,1H),6.73-6.62(m ,2H),4.46(td,J＝9.1,5.0Hz,1H),4.32(dd,J＝13.8,3.2Hz,1H),4.04–3.96(m,1H),3.91(dt,J＝9.9,5.2 Hz, 1H), 3.80(s, 3H), 3.65(dd, J=13.8, 9.5Hz, 1H), 2.78(s, 1H), 2.26(s, 1H), 2.10(td, J=9.7, 4.9Hz , 1H), 2.04–1.92 (m, 1H), 1.52 (d, J=8.3 Hz, 1H), 1.44 (d, J=6.7 Hz, 3H), 0.92 (d, J=6.4 Hz, 3H).

Example 23:

Compound H (100 mg), 3-oxetanamine (21 mg), Pd ₂ (dba) ₃ (45 mg), 2-(di-tert-butylphosphine)biphenyl (29 mg), potassium tert-butoxide (132 mg) , added tert-amyl alcohol (10 mL), replaced with nitrogen for 3 times, reacted at 105 ° C for 3.5 h, the reaction was complete; 20 mL of water was added to the reaction solution, extracted with ethyl acetate (20 mL*2), the organic phases were combined, anhydrous sulfuric acid Dry over sodium, concentrate until no liquid flows out, and purify by preparative liquid phase to give Example 23 (34 mg). ESI-MS: m/z=502.40 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ )δ12.20(s,1H),8.40(d,J=1.3Hz,1H),7.92(s,1H),7.55(d,J=1.3Hz,1H) ,7.32(d,J＝8.7Hz,1H),6.66(d,J＝2.3Hz,1H),6.49(dd,J＝8.7,2.2Hz,1H),6.40(d,J＝6.1Hz,1H) ,4.85(t,J＝6.1Hz,2H),4.50(q,J＝6.2Hz,1H),4.45–4.42(m,2H),4.35(q,J＝4.6Hz,1H),4.14(dd, J=13.8, 3.2Hz, 1H), 4.02–3.96(m, 1H), 3.78(dd, J=13.6, 10.1Hz, 1H), 3.72(s, 3H), 2.75(s, 1H), 2.55(d , J＝3.2Hz, 3H), 2.19(d, J＝10.9Hz, 1H), 1.95(d, J＝14.6Hz, 1H), 1.90(s, 1H), 1.48–1.39(m, 1H), 0.80 (d, J=6.5 Hz, 3H).

Example 24:

(1) preparation method of compound D-3:

Compound C-1 (1.6 g), compound A-1 (1.0 g), potassium carbonate (1.6 g) were added to N,N-dimethylformamide (16 mL), and reacted at 60°C for 4.5 h, the reaction was complete ; Pour the reaction solution into 200 mL of water, extract with ethyl acetate (100 mL*2), combine the organic phases, dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and obtain compound D-3 by column chromatography. ESI-MS: m/z=568.07 [M+H] ⁺ .

(2) the preparation method of compound E-3:

Compound D-3 (1.5 g) was dissolved in methanol (8 mL) and tetrahydrofuran (8 mL), Raney Ni (0.15 g) was slowly added, the reaction solution was replaced with nitrogen for 2 times and then with hydrogen for 3 times, and the reaction was carried out at 25°C 4h, the reaction was complete; the reaction solution was filtered, and the filtrate was concentrated until no liquid flowed out to obtain compound E-3, which was directly used in the next reaction without further purification. ESI-MS: m/z=538.20 [M+H] ⁺ .

(3) the preparation method of compound F-3:

Compound E-3 (1.4 g) was dissolved in tert-butanol (3 mL) and dichloromethane (12 mL), and a solution of cyanogen bromide (360 mg) in dichloromethane (2 mL) was added dropwise, and the reaction was carried out at 25 °C after the dropwise addition. 30h, the reaction was complete; sodium bicarbonate solution (1M, 100mL) was added to the reaction solution, the liquid was separated, the dichloromethane phase was retained, washed with sodium bicarbonate solution (1M, 50mL*2), dried over anhydrous sodium sulfate, and concentrated to No liquid flowed out, and column chromatography gave compound F-3. ESI-MS: m/z=563.20 [M+H] ⁺ .

(4) preparation method of compound G-3:

Compound F-3 (1.2 g) was dissolved in tetrahydrofuran (20 mL), sodium hydroxide (340 mg) water (10 mL) solution was added dropwise, and the reaction was performed at 20-25°C for 30 min, and the reaction was complete; adjust pH=5-6 with 6M hydrochloric acid , tetrahydrofuran and water were evaporated under reduced pressure, dichloromethane (20 mL) and triethylamine (0.86 g) were added, the solution was stirred and dissolved, dried and filtered to obtain a dichloromethane solution of compound G-3. ESI-MS: m/z=549.16 [M+H] ⁺ .

(5) the preparation method of compound H-3:

TBTU (820 mg) was added to the dichloromethane solution of compound G-3 (2.13 mmol), and the reaction was completed at 20-25 °C for 5 h; the reaction solution was washed with water (50 mL*3), and the organic phase was dried with anhydrous sodium sulfate, Concentrate until no liquid flows out, and obtain compound H-3 by column chromatography. ESI-MS: m/z=531.15 [M+H] ⁺ .

(6) the preparation method of embodiment 24:

Compound H-3 (100 mg), (R)-3-aminotetrahydrofuran (35 mg), Pd ₂ (dba) ₃ (43 mg), 2-(di-tert-butylphosphine)biphenyl (28 mg), potassium tert-butoxide (127mg), was added to tert-amyl alcohol (5mL), nitrogen was replaced 3 times, the reaction was carried out at 105°C for 3.5h, the reaction was complete; 20mL of water was added to the reaction solution, extracted with ethyl acetate (20mL*2), and the organic phases were combined, Dry over anhydrous sodium sulfate, concentrate until no liquid flows out, and purify by preparative liquid phase to obtain Example 24 (13 mg). ESI-MS: m/z=538.37 [M+H] ⁺ .

¹ H NMR (500MHz, DMSO-d ₆ ) δ 12.64(s, 1H), 8.46(d, J=2.2Hz, 1H), 7.89(s, 1H), 7.30(d, J=1.9Hz, 1H) ,6.69–6.60(m,1H),6.45(dd,J＝14.4,1.7Hz,1H),6.20(d,J＝5.8Hz,1H),4.36(td,J＝9.4,3.6Hz,1H), 4.31–4.25 (m, 1H), 4.02 (t, J=5.8Hz, 1H), 3.93 (ddd, J=14.1, 7.6, 4.3Hz, 2H), 3.84 (t, J=7.5Hz, 1H), 3.80 –3.76(m,1H),3.75(s,3H),3.56(dd,J=8.4,3.1Hz,1H),2.73(s,1H),2.26–2.15(m,2H),1.92(t,J = 12.7Hz, 2H), 1.84–1.76 (m, 1H), 1.49–1.40 (m, 1H), 1.25 (d, J=5.6Hz, 1H), 0.87 (d, J=6.5Hz, 3H).

Test Example 1: In vitro kinase activity

1.1 EGFR (WT) inhibitory activity screening

Dilute 50 ng/μL of EGFR (WT, Carna) stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20) and add 6 μL of 1.67× 0.005 ng/μL to each well The working solution (final concentration is 0.003ng/μL), different compounds dissolved in DMSO were added to the wells with a nanoliter sampler, so that the final concentration of the compounds was 100nM-0.0244nM, 4-fold gradient, a total of 7 concentrations, while A blank control well (without enzyme) and a negative control well (with enzyme, with DMSO as a solvent) were set, and two duplicate wells were set. After the enzyme reacted with the compound or vehicle for 30 min, 5× of 25 μM ATP (final concentration of 5 μM, Sigma) prepared in kinase buffer and 5× of 0.5 μM substrate (final concentration of 0.1 μM, ULight-poly GT, PerkinElmer), mix 1:1 and add 4 μL per well to the wells; after sealing the plate with a sealing membrane, after 2 hours of reaction at room temperature, add 5 μL of 4× 40 mM EDTA (final concentration 10 mM) to each well for 5 min at room temperature, and then per Add 5 μL of 4× 8nM detection reagent (final concentration of 2nM, Eu-anti-phospho-tyrosine antibody, PerkinElmer) to the wells, incubate for 1 hour at room temperature, and read the plate with a PerkinElmer Envision multi-function microplate reader (excitation 320nm, emission 665nm), Using a four parameter fit, _IC50 was calculated.

1.2 EGFR (L858R/T790M) inhibitory activity screening

50 ng/μL of EGFR (L858R/T790M, Carna) stock solution was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 μL of 1.67× 0.004175 ng was added to each well. /μL of working solution (final concentration is 0.0025ng/μL), different compounds dissolved in DMSO were added to the wells with a nanoliter dispenser, so that the final concentration of the compounds was 10nM-0.0024nM, 4-fold gradient, a total of 7 concentrations , and set up blank control wells (without enzyme) and negative control wells (containing enzyme, plus solvent DMSO), and set up 2 duplicate wells. After the enzyme reacted with the compound or vehicle for 30 min, 5× of 25 μM ATP (final concentration of 5 μM, Sigma) prepared in kinase buffer and 5× of 0.5 μM substrate (final concentration of 0.1 μM, ULight-poly GT, PerkinElmer), mix 1:1 and add 4 μL per well to the wells; after sealing the plate with a sealing membrane, after 2 hours of reaction at room temperature, add 5 μL of 4× 40 mM EDTA (final concentration 10 mM) to each well for 5 min at room temperature, and then per Add 5 μL of 4× 8nM detection reagent (final concentration of 2nM, Eu-anti-phospho-tyrosine antibody, PerkinElmer) to the wells, incubate for 1 hour at room temperature, and read the plate with a PerkinElmer Envision multifunctional microplate reader (excitation 320nm, emission 665nm), using Four parameter fit, _IC50 was calculated.

1.3 EGFR (d746-750/T790M) inhibitory activity screening

50 ng/μL of EGFR (d746-750/T790M, Carna) stock solution was diluted with kinase buffer (50 mM HEPES, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and 6 μL of 1.67× EGFR was added to each well. 0.005ng/μL of working solution (final concentration of 0.003ng/μL), different compounds dissolved in DMSO were added to the wells with a nanoliter dispenser, so that the final concentration of the compounds was 10nM-0.0024nM, 4-fold gradient, a total of 7 At the same time, a blank control well (without enzyme) and a negative control well (with enzyme, plus DMSO as a solvent) were set, and two duplicate wells were set. After the enzyme reacted with the compound or vehicle for 30 min, 5× of 25 μM ATP (final concentration of 5 μM, Sigma) prepared in kinase buffer and 5× of 0.5 μM substrate (final concentration of 0.1 μM, ULight-poly GT, PerkinElmer), mix 1:1 and add 4 μL per well to the wells; after sealing the plate with a sealing membrane, after 2 hours of reaction at room temperature, add 5 μL of 4× 40 mM EDTA (final concentration 10 mM) to each well for 5 min at room temperature, and then per Add 5 μL of 4× 8nM detection reagent (final concentration of 2nM, Eu-anti-phospho-tyrosine antibody, PerkinElmer) to the wells, incubate for 1 hour at room temperature, and read the plate with a PerkinElmer Envision multifunctional microplate reader (excitation 320nm, emission 665nm), using Four parameter fit, _IC50 was calculated.

1.4 EGFR (L858R/T790M/C797S) inhibitory activity screening

Dilute 50 ng/μL of EGFR (L858R/T790M/C797S, BPS) stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20), and add 6 μL of 1.67× EGFR to each well. 0.00167ng/μL of working solution (final concentration of 0.001ng/μL), different compounds dissolved in DMSO were added to the wells with a nanoliter sampler, so that the final concentration of the compounds was 10nM-0.0024nM, 4-fold gradient, a total of 7 At the same time, a blank control well (without enzyme) and a negative control well (with enzyme, plus DMSO as a solvent) were set, and two duplicate wells were set. After the enzyme reacted with the compound or vehicle for 30 min, 5× of 25 μM ATP (final concentration of 5 μM, Sigma) prepared in kinase buffer and 5× of 0.5 μM substrate (final concentration of 0.1 μM, ULight-poly GT, PerkinElmer), mix 1:1 and add 4 μL per well to the wells; after sealing the plate with a sealing membrane, after 2 hours of reaction at room temperature, add 5 μL of 4× 40 mM EDTA (final concentration 10 mM) to each well for 5 min at room temperature, and then per Add 5 μL of 4× 8nM detection reagent (final concentration of 2nM, Eu-anti-phospho-tyrosine antibody, PerkinElmer) to the wells, incubate for 1 hour at room temperature, and read the plate with a PerkinElmer Envision multifunctional microplate reader (excitation 320nm, emission 665nm), using Four parameter fit, _IC50 was calculated.

1.5 EGFR (d746-750/T790M/C797S) inhibitory activity screening

Dilute 50 ng/μL of EGFR (d746-750/T790M/C797S, BPS) stock solution with kinase buffer (50 mM HEPES, 10 mM MgCl ₂ , 2 mM DTT, 1 mM EGTA, 0.01% Tween 20) and add 6 μL of 1.67 to each well 0.05ng/μL working solution of × (final concentration is 0.03ng/μL), different compounds dissolved in DMSO were added to the wells with a nanoliter dispenser, so that the final compound concentration was 10nM-0.0024nM, 4-fold gradient, A total of 7 concentrations were set, and blank control wells (without enzyme) and negative control wells (with enzyme and DMSO added) were set simultaneously, and 2 duplicate wells were set. After the enzyme reacted with the compound or vehicle for 30 min, 5× of 25 μM ATP (final concentration of 5 μM, Sigma) prepared in kinase buffer and 5× of 0.5 μM substrate (final concentration of 0.1 μM, ULight-poly GT, PerkinElmer), mix 1:1 and add 4 μL per well to the wells; after sealing the plate with a sealing membrane, after 2 hours of reaction at room temperature, add 5 μL of 4× 40 mM EDTA (final concentration 10 mM) to each well for 5 min at room temperature, and then per Add 5 μL of 4× 8nM detection reagent (final concentration of 2nM, Eu-anti-phospho-tyrosine antibody, PerkinElmer) to the wells, incubate for 1 hour at room temperature, and read the plate with a PerkinElmer Envision multifunctional microplate reader (excitation 320nm, emission 665nm), using Four-parameter fitting was used to calculate IC ₅₀ , and the results are shown in Table 1.

Table 1 In vitro kinase activity results

Note: NA means not detected

Test Example 2 In vitro stability evaluation of liver microsomes

The 300 μL final incubation system contains 30 μL liver microsomes (protein concentration: 0.15 mg/mL), 30 μL NADPH+MgCl ₂ , 3 μL test compound (prepared in acetonitrile), and 237 μL PBS buffer (pH 7.4). The proportion of organic solvent (acetonitrile) is 1%. Make 2 servings of each species, 0.3 mL each. Pre-incubate with NADPH for 5 min at 37°C, add 30 μL NADPH + MgCl ₂ to mix, and take out 50 μL at 0, 15, 30, and 60 min. The reaction was stopped with 300 μL of ice acetonitrile containing internal standard.

The samples were incubated with 50 μL, 300 μL of ice acetonitrile containing the internal standard (diazepam 20 ng/mL) was added for precipitation, vortexed for 5 min, and centrifuged (12000 rpm, 4° C.) for 10 min. Aspirate 75 μL of the supernatant, add 75 μL of ultrapure water to dilute and mix, and inject 0.5 μL for analysis.

Test Example 3 In vivo pharmacokinetic evaluation

ICR mice, weighing 18-20 g, were randomly divided into groups after 3-5 days of adaptation, 9 mice in each group, and the corresponding compounds were administered by gavage at a dose of 10 mg/kg.

The test animals (ICR mice) were fasted for 12 hours before administration, given food for 4 hours after administration, and had free access to water before and after the experiment and during the experiment.

After intragastric administration, about 0.1 mL of blood was collected from the orbit at 0min, 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 24h. After anticoagulation with EDTA-K2, within 30min at 4°C and 4000rpm. Plasma was separated by centrifugation for 10 min. All plasma was stored at -20°C immediately after collection for testing.

Aspirate 20 μL of plasma samples to be tested and standard samples, add 300 μL of acetonitrile solution containing internal standard (diazepam 20 mg/mL), shake and mix for 5 min, centrifuge at 12000 rpm for 10 min, take 70 μL of supernatant, add 70 μL of ultrapure water to dilute, and mix. Homogenize, pipette 2 μL for LC/MS/MS determination, and record the chromatogram.

Experiments show that the compounds of the present application have good pharmacokinetic properties in vivo, and have higher oral exposure.

Table 2 Pharmacokinetic parameters

PK参数PK parameter	实施例23IG 10mg/kgEmbodiment 23IG 10mg/kg	实施例24IG 10mg/kgEmbodiment 24IG 10mg/kg
Tmax(h)Tmax(h)	2.002.00	6.006.00
Cmax(ng/mL)Cmax(ng/mL)	653653	172172
AUC(0-t)(ngh/mL)AUC(0-t)(ngh/mL)	85268526	17071707
AUC(0-∞)(ngh/mL)AUC(0-∞)(ngh/mL)	85518551	17171717
t1/2(h)t1/2(h)	2.442.44	2.772.77
MRT(0-t)(h)MRT(0-t)(h)	7.427.42	7.247.24

Claims

A compound of formula I or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof,

Wherein, L is selected from O, -C(O)O-, -C(O)N(R a )- or -N(R b )-;

R a and R b are each independently selected from hydrogen, C 1-8 alkyl or C 3-6 cycloalkyl;

R 1 is selected from hydrogen, C 1-8 alkyl, C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S; the C 1-8 alkyl is optionally substituted with one or more R c selected from hydroxy, halogen, C 1-8 alkoxy, -NH 2 , -N(C 1-8 alkyl) 2 , -NH(C 1-8 alkyl), or optionally substituted with one or more groups selected from hydroxy, halogen or C 1-6 alkyl, containing 1, 2 or 3 groups selected from N, O or a 3-8-membered heterocycloalkyl of a heteroatom of S; the C 3-10 -membered cycloalkyl or 3-10-membered heterocycloalkyl is optionally substituted with one or more Rs selected from C 1-8 alkyl, C 1-8 alkyl substituted with one or more deuterium, C 1-8 alkyl substituted with one or more halogens, C 1-8 substituted with one C 3-8 cycloalkyl 8 alkyl, C 3-8 cycloalkyl, halogen, cyano, amino or hydroxyl;

Or R b and R 1 are connected to each other to form a 5-membered heterocycloalkyl group; the 5-membered heterocycloalkyl group is optionally substituted by C 1-8 alkyl, halogen, cyano, amino, hydroxyl or oxygen;

R 2 is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy is optional is replaced by one or more R';

Each R 3 is independently selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy is optionally substituted with one or more R";

Each R' and R" is independently selected from halogen, hydroxy, cyano, amino or nitro;

n is selected from 0, 1, 2 or 3.
The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein L is selected from O, -C(O)N(R a )- or -N( R b )-;

Alternatively, the L is selected from -C(O)N(R a )- or -N(R b )-.
The compound of claim 1 or 2 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R a and R b are independently selected from hydrogen, C 1-6 alkyl or C 3-6 cycloalkyl;

Alternatively, the R a and R b are independently selected from hydrogen, C 1-5 alkyl or C 3-6 cycloalkyl;

Alternatively, the R a and R b are independently selected from hydrogen, C 1-4 alkyl or C 3-5 cycloalkyl;

Alternatively, the R a and R b are independently selected from hydrogen, C 1-3 alkyl or C 3-4 cycloalkyl;

Alternatively, said R a and R b are each independently selected from hydrogen or C 1-3 alkyl;

Alternatively, the R a and R b are each independently selected from hydrogen, methyl, ethyl or n-propyl;

Alternatively, the R a and R b are each independently selected from hydrogen.
The compound of any one of claims 1-3 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R 1 is selected from hydrogen, C 1-6 alkyl, C 3 -8 cycloalkyl or 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, said C 1-6 alkyl optionally surrounded by one or more R c substituted, the C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl is optionally substituted with one or more R;

Alternatively, the R 1 is selected from hydrogen, C 1-4 alkyl, C 3-6 cycloalkyl or a 3-6 membered heterocycloalkane containing 1, 2 or 3 heteroatoms selected from N, O or S base, the C 1-4 alkyl is optionally substituted with one or more R c , the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more R;

Alternatively, the R 1 is selected from hydrogen, C 1-3 alkyl, C 3-6 cycloalkyl or 3-6 membered heterocycloalkane containing 1, 2 or 3 heteroatoms selected from N, O or S base, the C 1-3 alkyl is optionally substituted with one or more R c , the C 3-6 cycloalkyl or 3-6 membered heterocycloalkyl is optionally substituted with one or more R;

Alternatively, the R 1 is selected from the group consisting of hydrogen, methyl, ethyl, propyl, cyclopropyl, oxetanyl, azetidinyl, thietanyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl, the methyl, ethyl or propyl optionally substituted with one or more R c , the cyclopropyl, oxetanyl, azetidinyl, thia cyclobutyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl or tetrahydropyrrolyl optionally substituted with one or more R;

Alternatively, the R 1 is selected from hydrogen, cyclopropyl,
methyl, ethyl, propyl,
The methyl, ethyl or propyl is optionally substituted with one or more R; the cyclopropyl,
optionally substituted with one or more R;

Alternatively, the R b and R 1 are interconnected to form a tetrahydropyrrole, which is optionally substituted by one or more groups selected from C 1-6 alkyl, halogen, cyano, amino, hydroxyl or oxygen group replacement;

Alternatively, the R b and R 1 are connected to each other to form
said
optionally substituted with one or more groups selected from C 1-3 alkyl, fluoro, chloro, cyano, amino, hydroxy or oxygen;

Alternatively, the R b and R 1 are connected to each other to form a

Alternatively, the R b and R 1 are connected to each other to form

Alternatively, said R 1 is selected from hydrogen, C 1-6 alkyl optionally substituted with hydroxy or halogen, C 3-8 cycloalkyl or containing 1, 2 or 3 heteroatoms selected from N, O or S 3-8 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R;

Alternatively, said R 1 is selected from hydrogen, C 1-4 alkyl optionally substituted with hydroxy or halogen, C 3-6 cycloalkyl or containing 1, 2 or 3 heteroatoms selected from N, O or S 3-6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R;

Alternatively, said R 1 is selected from hydrogen, C 1-3 alkyl optionally substituted with hydroxy or halogen, C 3-6 cycloalkyl or containing 1, 2 or 3 heteroatoms selected from N, O or S 3-6 membered heterocycloalkyl, the cycloalkyl or heterocycloalkyl is optionally substituted with one or more R;

Alternatively, the R 1 is selected from C 3-6 cycloalkyl or a 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, the cycloalkyl or hetero cycloalkyl is optionally substituted with one or more R;

in:

Optionally, the heterocycloalkyl of R 1 is selected from 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered containing 1, 2 or 3 heteroatoms selected from N, O or S , 9- or 10-membered heterocycloalkyl optionally substituted with one or more R;

Alternatively, the heterocycloalkyl group of R 1 is selected from 3-9 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally by one or more R substitutions;

Alternatively, the heterocycloalkyl group of said R 1 is selected from 3-8 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, said heterocycloalkyl group optionally being one or more R substitutions;

Alternatively, the heterocycloalkyl group of R 1 is selected from 3-7 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally by one or more R substitutions;

Alternatively, the heterocycloalkyl of said R1 is selected from 3-6 membered heterocycloalkyl containing 1 , 2 or 3 heteroatoms selected from N, O or S, said heterocycloalkyl optionally being one or more R substitutions;

Alternatively, the heterocycloalkyl group for R 1 is selected from 4-6 membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally by one or more R substitutions;

Alternatively, the heterocycloalkyl of said R1 is selected from 5-6 membered heterocycloalkyl containing 1 , 2 or 3 heteroatoms selected from N, O or S, said heterocycloalkyl optionally being one or more R substitutions;

Alternatively, the heterocycloalkyl group of said R 1 is selected from 5-membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally by one or Multiple R substitutions;

Alternatively, the heterocycloalkyl group of R 1 is selected from 6-membered heterocycloalkyl groups containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally by one or Multiple R substitutions;

Alternatively, the heterocycloalkyl of the R 1 is selected from azetidinyl, oxetanyl, thietanyl, tetrahydropyrrolyl, tetrahydrofuranyl, piperidinyl, azepanyl, imidazole oxazolinyl, pyrazolinyl, piperazinyl, hexahydropyrimidinyl, oxazolinyl, isoxazolinyl, thiazolinyl, isothiazolinyl, morpholinyl or tetrahydropyranyl, the hetero cycloalkyl is optionally substituted with one or more R;

Alternatively, the heterocycloalkyl of R 1 is selected from

The heterocycloalkyl is optionally substituted with one or more R;

Alternatively, the R 1 is selected from hydrogen, cyclopropyl,
The cyclopropyl,
optionally substituted with one or more R;

Alternatively, the R 1 is selected from cyclopropyl optionally substituted with one or more R;

Alternatively, the R 1 is selected from optionally substituted with one or more R

Alternatively, the R 1 is selected from optionally substituted with one or more R
The compound of any one of claims 1-4 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R c is selected from hydroxyl, halogen, C 1-6 alkoxy , -NH 2 , -N(C 1-6 alkyl) 2 , -NH(C 1-6 alkyl), or optionally by one or more selected from hydroxyl, halogen or C 1-6 alkyl group-substituted 3-8 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S;

Alternatively, the R c is selected from hydroxy, halogen, C 1-4 alkoxy, -NH 2 , -N(C 1-4 alkyl) 2 , -NH(C 1-4 alkyl), or optionally 4-6 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, substituted by one or more groups selected from hydroxy, halogen or C1-4 alkyl;

Alternatively, the R c is selected from hydroxy, fluoro, chloro, C 1-3 alkoxy, -NH 2 , -N(C 1-3 alkyl) 2 , -NH(C 1-3 alkyl), or 5-6 membered heterocycloalkane containing 1, 2 or 3 heteroatoms selected from N, O or S, optionally substituted with one or more groups selected from hydroxy, halogen or C1-3 alkyl base;

Alternatively, the R c is selected from hydroxy, fluoro, methoxy, -N(CH 3 ) 2 , tetrahydropyranyl, tetrahydropyrrolyl, morpholinyl, or 1,4-dioxanyl.
The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R is selected from C 1-6 alkyl, by one or more Deuterium substituted C 1-6 alkyl, C 1-6 alkyl substituted with one or more halogens, C 1-6 alkyl substituted with one C 3-6 cycloalkyl, C 3-6 cycloalkyl , halogen, cyano, amino or hydroxyl;

Alternatively, said R is selected from C 1-4 alkyl, per-deuterated C 1-4 alkyl, C 1-4 alkyl substituted with one or more groups selected from fluorine, chlorine, bromine or iodine , C 1-4 alkyl substituted by one C 3-6 cycloalkyl, C 3-6 cycloalkyl, fluorine, chlorine, bromine, iodine, cyano, amino or hydroxyl;

Alternatively, said R is selected from C 1-3 alkyl, per-deuterated C 1-3 alkyl, C 1-3 alkyl substituted with one or more groups selected from fluorine, chlorine, bromine or iodine , C 1-3 alkyl substituted by one C 3-5 cycloalkyl, C 3-5 cycloalkyl, fluorine, chlorine, bromine, cyano, amino or hydroxyl;

Alternatively, the R is selected from methyl, ethyl, n - propyl , isopropyl, -CD3 , -C2D5 , -C3D7 , -CF3 , -CH2CH2F , -CH 2 CHF 2 , -CH 2 CF 3 , -C 2 F 5 , -C 3 F 7 , methyl substituted with a C 3-5 cycloalkyl, cyclopropyl, cyclobutyl, cyclopentyl, fluoro, chlorine, bromine, cyano, amino or hydroxyl;

Alternatively, the R is selected from methyl, ethyl , -CD3 , -C2D5 , -CF3 , -CH2CH2F , -CH2CHF2 , -CH2CF3 , -C2F 5. Cyclopropylmethyl, cyclopropyl, fluorine, chlorine, bromine, cyano, amino or hydroxyl;

Alternatively, the R is selected from methyl, ethyl, -CD3 , -CF3 , cyclopropyl, cyclopropylmethyl, cyano, amino or hydroxy;

Alternatively, the R is selected from methyl.
The compound of any one of claims 1-6 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R 2 is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C 1-6 alkyl or C 1-6 alkoxy, wherein C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more R';

Alternatively, the R 2 is selected from hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, cyano, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy, wherein C 1-4 alkyl or C 1-4 alkoxy optionally substituted with one or more R';

Alternatively, the R 2 is selected from hydrogen, fluorine, chlorine, bromine, hydroxyl, cyano, amino, nitro, C 1-3 alkyl or C 1-3 alkoxy, wherein C 1-3 alkyl or C 1-3 alkoxy is optionally substituted with one or more R';

Alternatively, the R 2 is selected from hydrogen, fluorine, chlorine, bromine or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more R';

Alternatively, the R 2 is selected from hydrogen, fluorine, chlorine or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more R';

Alternatively, the R 2 is selected from fluoro or C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with one or more fluoro;

Alternatively, the R 2 is selected from fluorine or methyl optionally substituted with one or more fluorines;

Alternatively, the R 2 is selected from fluoro, methyl or trifluoromethyl.
The compound of any one of claims 1-7 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R' is selected from fluorine, chlorine, bromine, hydroxyl, cyano, amino or nitro;

Alternatively, the R' is selected from fluorine, chlorine or bromine;

Alternatively, the R' is selected from fluorine or chlorine;

Alternatively, the R' is selected from fluorine.
The compound of any one of claims 1-8 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein each R is independently selected from halogen, hydroxyl, cyano , amino, nitro, C 1-6 alkyl or C 1-6 alkoxy, wherein C 1-6 alkyl or C 1-6 alkoxy is optionally substituted with one or more R";

Alternatively, each of said R 3 is independently selected from halogen, hydroxyl, cyano, amino, nitro, C 1-4 alkyl or C 1-4 alkoxy, wherein C 1-4 alkyl or C 1 -4 alkoxy is optionally substituted with one or more R";

Alternatively, each of said R 3 is independently selected from fluorine, chlorine, hydroxyl, cyano, amino, C 1-3 alkyl or C 1-3 alkoxy, wherein C 1-3 alkyl or C 1- 3 alkoxy is optionally substituted by one or more R";

Alternatively, said R3 is selected from hydrogen, fluorine, chlorine, bromine or C1-6 alkyl optionally substituted with one or more halogens;

Alternatively, said R3 is selected from hydrogen, fluorine, chlorine, bromine or C1-4 alkyl optionally substituted with one or more atoms selected from fluorine or chlorine;

Alternatively, said R3 is selected from hydrogen, fluorine, chlorine or C1-3 alkyl optionally substituted with one or more fluorine atoms;

Alternatively, said R is selected from hydrogen, fluorine, chlorine or methyl optionally substituted with one or more fluorine atoms;

Alternatively, the R3 is selected from hydrogen, fluorine, chlorine or trifluoromethyl.
The compound of any one of claims 1-9 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R" is selected from fluorine, chlorine, bromine or hydroxyl;

Alternatively, the R" is selected from fluoro, chloro or bromo;

Alternatively, the R" is selected from fluorine or chlorine;

Alternatively, the R" is selected from fluoro.
The compound of any one of claims 1-10 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein n is selected from 0, 1 or 2;

Alternatively, the n is selected from 0 or 1;

Or, the n is 0;

Alternatively, the n is 1.
The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein L is selected from -C(O)N(R a )-, and R 1 is selected from any cyclopropyl optionally substituted with one or more R; alternatively, the R is selected from optionally substituted with one or more R
or R 1 is selected from optionally substituted with one or more R

Alternatively, the L is selected from -N(R b )-, and R 1 is selected from cyclopropyl optionally substituted by one or more R; or, the R 1 is selected from optionally substituted by one or more R R substituted
or R 1 is selected from optionally substituted with one or more R
The compound of any one of claims 1-12 or a pharmaceutically acceptable salt, stereoisomer, tautomer, structural fragment thereof
selected from

Or, Structural Fragments
selected from

Or, Structural Fragments
selected from
The compound of claim 1 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof is selected from the compound of formula I' or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof Construct,
The compound of claim 14 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof, wherein R 1 is selected from hydrogen, C 1-8 alkyl optionally substituted by hydroxy or halogen , C 3-10 cycloalkyl or 3-10 membered heterocycloalkyl containing 1, 2 or 3 heteroatoms selected from N, O or S, said cycloalkyl or heterocycloalkyl optionally being substituted with one or more R selected from C 1-8 alkyl, C 1-8 alkyl substituted with one or more deuteriums, C 1-8 alkyl substituted with one or more halogens, C 1-8 alkyl substituted with one or more halo a C 3-8 cycloalkyl substituted C 1-8 alkyl, C 3-8 cycloalkyl, halogen, cyano, amino or hydroxy;

The R 2 is selected from hydrogen, halogen, hydroxyl, cyano, amino, nitro, C 1-8 alkyl or C 1-8 alkoxy, wherein C 1-8 alkyl or C 1-8 alkoxy optionally substituted with one or more R' selected from halogen, hydroxy, cyano, amino or nitro;

Said R3 is selected from hydrogen, halogen or C1-8 alkyl optionally substituted with one or more halogens.
The compound of any one of claims 1-15 or a pharmaceutically acceptable salt, stereoisomer, tautomer thereof selected from formula II, formula III, formula IV, formula V, formula VI, formula VII or a compound of formula VIII or a pharmaceutically acceptable salt, stereoisomer thereof,
The following compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers:

Alternatively, the following compounds or their pharmaceutically acceptable salts, stereoisomers, tautomers:
A pharmaceutical composition comprising the compound of any one of claims 1-17 or a pharmaceutically acceptable salt, stereoisomer, or tautomer thereof.
The compound of any one of claims 1-17 or a pharmaceutically acceptable salt, stereoisomer, tautomer, or the pharmaceutical composition of claim 18 is prepared to prevent or treat EGFR-mediated use in medicines for diseases;

Optionally, the EGFR-mediated disease is selected from EGFR mutant-mediated diseases;

Optionally, the above mutants are selected from one, two, three or four of L858R, T790M, d19, and C797S;

Optionally, the above-mentioned mutants are selected from two mutants of L858R and T790M;

Optionally, the above-mentioned mutant is selected from two mutants of d19 and T790M;

Optionally, the above-mentioned mutant comprises the C797S mutant;

Optionally, the above-mentioned mutant type is selected from three mutant types of L858R, T790M and C797S; or the above-mentioned mutant type is selected from three mutant types of d19, T790M and C797S;

Optionally, the EGFR-mediated disease is selected from cancer;

Optionally, the EGFR-mediated disease is selected from lung cancer;

Optionally, the EGFR-mediated disease is selected from non-small cell lung cancer.