CN112574224A

CN112574224A - KRAS G12C inhibitor and application thereof

Info

Publication number: CN112574224A
Application number: CN202011050829.4A
Authority: CN
Inventors: 郭洪利; 陈涛; 周峰; 高大新; 陈大为
Original assignee: Shanghai de Novo Pharmatech Co Ltd
Current assignee: Shanghai de Novo Pharmatech Co Ltd
Priority date: 2019-09-30
Filing date: 2020-09-29
Publication date: 2021-03-30
Also published as: WO2021063346A1

Abstract

The invention discloses a novel KRAS G12C inhibitor. The compound shown as the formula I, the isomer or the pharmaceutically acceptable salt thereof has the following structure. Book (I)The compound shown in the formula I and the composition thereof disclosed by the invention can effectively treat diseases related to KRAS G12C, such as: cancer.

Description

KRAS G12C inhibitor and application thereof

Technical Field

The invention relates to a novel compound for inhibiting KRAS G12C activity. In particular, the present invention relates to compounds that irreversibly inhibit KRAS G12C activity, pharmaceutical compositions comprising the same, and their use as cancer therapeutics.

Background

The RAS gene family mainly includes three genes, KRAS, NRAS and HRAS. The RAS gene is a proto-oncogene, which becomes an oncogene having oncogenic activity when activated. RAS encodes a group of monomeric globular proteins (21kD) consisting of 188-. RAS proteins are GDP/GTP-binding proteins that can cycle between an inactive GDP-bound state and an active GTP-bound state, acting as a "molecular switch". The GDP/GTP cycle of RAS is activated by guanine nucleotide exchange factors (e.g., SOS or RASGRP) and by GTPase activating proteins (GAPs, e.g., p120GAP or neurofibromin). GAPs interact with RAS to greatly accelerate conversion of GTP to GDP, turning off the switch inactivates RAS, and any mutation that affects the ability of RAS to interact with GAP or convert GTP back to GDP will cause the continuous activation of RAS and thus produce a prolonged signal to the cell. Since RAS can regulate cellular proliferation, differentiation and senescence through a variety of important signaling pathways, prolonged activation of downstream signaling pathways (e.g., PI3K-AKT-mTOR, RAF-MEK-ERK, RALGDS-RAL) ultimately leads to the development of cancer.

The RAS protein includes a highly conserved N-terminal G binding domain that also contains a p-loop of binding nucleotides and switch I (residues 30-40) and switch II (residues 60-76). Wherein the p-loop is a rigid portion of the binding domain with conserved amino acid residues (glycine 12, threonine 26 and lysine 16) necessary for amino acid binding and hydrolysis. Threonine-35 and glycine-60 in switch I and switch II can form hydrogen bonds with the gamma-phosphate of GTP, maintaining the active conformation of the regions of switches I and II, respectively. After GTP hydrolysis and phosphate release, both can relax into the inactive GDP conformation. In addition, RAS proteins also include a C-terminal extension called the CAAX cassette, which can be post-translationally modified and is responsible for targeting the protein to the cell membrane (Jonathan et al Nature Reviews,2016,15: 771-.

RAS genes can be continuously activated by point mutation, overexpression, and gene insertion and translocation, the most common of which is point mutation, and about 30% of human malignancies have point mutation of RAS gene. The most common are the point mutations of KRAS, the common mutation sites are codons 12, 13, 61, and the most common mutation is at codon 12. These activating mutations increase RAS protein content in the GTP-bound state by inactivating endogenous gtpase activity and causing gtpase-activated protein resistance (Zenker et al.j Med Genet,2007,44: 131-.

Abnormal expression of KRAS accounts for 20% of all malignancies, with the G12C mutation being one of the most frequent mutations found in approximately 13% of malignancies. Wherein the incidence of the G12C mutation in non-small Cell lung cancer is about 11%, and the incidence of the G12C mutation in colorectal, pancreatic and endometrial cancers is about 1% -4% (Hobbs et al.J. Cell Sci,2016,129: 1287-1292; Prior et al.cancer Res,2012,72: 2457-67).

An increasing number of studies have shown that KRAS, particularly mutants including KRAS G12C, have a key role in malignancies, making KRAS an important target in the pharmaceutical industry, but to date there are no relevant drugs on the market, and therefore, there is an urgent need to develop novel inhibitors of KRAS mutants including KRAS G12C.

Disclosure of Invention

The technical problem to be solved by the present invention is to provide a novel compound inhibiting KRAS G12C activity, which is effective in treating various diseases related to KRAS G12C, such as cancer.

The invention provides a compound shown as a formula I, an isomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof;

wherein the content of the first and second substances,

the alpha and beta bonds are single or double bonds, respectively;

x is N or CR₂；

When the beta bond is a single bond, Y is C (O) and Z is NR₃(ii) a When the beta bond is a double bond, Y and Z are each independently N or CR₂；

When the alpha bond is a single bond, W is N and V is CH₂Or C (O); when the alpha bond is a double bond, W is C and V is CR₄Or N;

u and M are each independently N, C or CH;

ring A is phenyl, 3-8 membered cycloalkyl, 5-6 membered heteroaryl or 4-8 membered heterocycloalkyl; the A ring is unsubstituted or selectively substituted by 1 to 3R₅The group is substituted at any position;

ring B is 5-10 membered heterocycloalkyl; the B ring is unsubstituted or selectively substituted by 1-3R₆The group is substituted at any position;

r is C_6-10Aryl, 5-10 membered heteroaryl, or 9-14 membered fused heterocycloalkyl; the R is unsubstituted or optionally substituted by 1 or more R₇The group is substituted at any position;

R₁is C_2-4Alkenyl radical, C_2-4Alkynyl or partially unsaturated C_4-6A cycloalkyl group; the R is₁Is unsubstituted or selected fromIs coated with 1 to 3R₈The group is substituted at any position;

R₂is hydrogen, hydroxy, halogen, cyano, amino, -R_A、-NR_AR_B、-OR_Aor-SR_A；

R₃Is C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl or 5-10 heteroaryl-C_1-4An alkyl group; the R is₃Is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, cyano, amino, oxo, halogeno C_1-6Alkyl radical, C_1-6Alkyl radical, C_3-6Cycloalkyl radical, C_3-6cycloalkyl-C_1-4Alkyl, 4-6 membered heterocycloalkyl or 4-6 membered heterocycloalkyl-C_1-4The substituent of the alkyl group is substituted at any position;

R₄is hydrogen, hydroxy, halogen, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy-C_1-6Alkyl radical, C_1-6alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl or C_3-8A cycloalkyl group;

R₅is hydrogen, hydroxy, halogen, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy-C_1-6Alkyl radical, C_1-6alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl, acyl, C_3-8Cycloalkyl having a ring system of_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl OR-B (OR')₂；

R₆Is hydrogen, oxo, hydroxy, cyano, amino, C_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O) OR 'OR-C (O) NR'₂；R₆In (A), the C_1-6The alkyl is unsubstituted or optionally substituted by 1 to 3 groups selected from halogen, hydroxy, amino, carboxyl, cyano, C_1-4Alkoxy, halo C_1-4Alkoxy and C_1-6The substituent of the alkylamino group is substituted at any position;

R₇is hydrogen, hydroxy, halogen, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy-C_1-4Alkyl radical, C_1-6alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl, -NH-C_3-6Cycloalkyl, - (CH)₂)_nOR’、-NHC(O)R”、-C(O)R”、-C(O)N(R”)₂、-OC(O)R”、-OC(O)N(R”)₂OR-B (OR')₂；R₇In (A), the C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl or 5-10 membered heteroaryl-C_1-4The alkyl is unsubstituted or optionally substituted by 1 to 3 groups selected from halogen, hydroxy, amino, carboxyl, cyano, C_1-4Alkyl, halo C_1-4Alkyl radical, C_1-4Alkoxy, halo C_1-4Alkoxy and C_1-6The substituent of the alkylamino group is substituted at any position;

R₈is hydrogen, deuterium, halogen, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy-C_1-4Alkyl radical, C_1-6alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C_1-4Alkyl or 3-10 heterocycloalkyl-C_1-4An alkyl group; wherein, the C_1-6alkylamino-C_1-4The alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl group is unsubstituted or optionally substituted with 1 to 3 substituents selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy, oxo and C_1-4The substituent of the alkyl group is substituted at any position;

R_Ais hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl, 5-10 membered heteroaryl, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, C_3-10cycloalkyl-C_1-6Alkyl, 3-10 membered heterocycloalkyl-C_1-6Alkyl radical, C_6-10aryl-C_1-6Alkyl or 5-10 membered heteroaryl-C_1-6An alkyl group; the R is_AIs unsubstituted or optionally substituted by one or more R_cSubstitution at any position;

R_Bis hydrogen, cyano, hydroxy or C_1-6An alkyl group;

or, R_AAnd R_BAre linked to each other to form a 4-8 heterocycloalkyl group; the heterocycloalkyl is unsubstituted or optionally substituted by 1 to 3 substituents selected from the group consisting of hydroxy, cyano, amino, oxo, halogen, C_1-4Alkyl, acyl, C_1-4Alkoxy radical, C_1-6Alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, hydroxy-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl and 5-10 membered heteroaryl-C_1-4The substituent of the alkyl group is substituted at any position;

R_cis a hydroxyl group,Cyano, amino, oxo, halogen, C_1-4Alkyl radical, C_1-4Alkylene radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, hydroxy-C_1-6Alkyl radical, C_1-4alkoxy-C_1-6Alkyl, amino-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl, - (CH)₂)_n-N(CN)R’、-(CH₂)_n-C(O)R’、-(CH₂)_n-C(O)N(R’)₂、-(CH₂)_n-S(O)₂N(R’)₂、-(CH₂)_n-NR”C(O)R’、-(CH₂)_n-NR”S(O)₂R' or- (CH)₂)_n-B(OR”)₂；R_cIn (A), the C_1-4Alkylene radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4The alkyl is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy radical, C_1-4Alkylamino and C_1-4The substituent of the alkyl group is substituted at any position;

r' is hydrogen, C_1-4Alkyl, halo C_1-4Alkyl, hydroxy-C_1-4Alkyl radical, C_1-4alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl radical, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10Aryl, 6-to 10-membered heteroaryl, C_6-10aryl-C_1-4Alkyl or 6-10 membered heteroaryl-C_1-4An alkyl group;

r' is hydrogen or C_1-6An alkyl group;

n is an integer of 0 to 4;

and, the following is excluded: when ring A is phenyl or 1, 3-dioxolyl, R₂Is hydrogen.

All embodiments and combinations of variables described below for formula I are included within the scope of the structural formula of the present invention as shown in formula I.

In some embodiments, certain groups of the compounds of formula I, isomers, stable isotopic derivatives, or pharmaceutically acceptable salts thereof, are defined as follows, and non-described groups are as described in any one of the above embodiments:

wherein, the alpha bond and the beta bond are respectively a single bond or a double bond;

x is N or CH;

when the beta bond is a single bond, Y is C (O) and Z is NR₃(ii) a When the beta bond is a double bond, Y and Z are each N or CR₂；

u and M are each independently N, C or CH;

R₁is C_2-4Alkenyl radical, C_2-4Alkynyl or partially unsaturated C_4-6A cycloalkyl group; the R is₁Is unsubstituted or optionally substituted by 1 to 3R₈The group being substituted at randomA location;

R₂is-R_A、-NR_AR_B、-OR_Aor-SR_A；

R₆Is hydrogen, oxo, hydroxy, cyano, amino, C_1-6Alkyl radical, C_1-6Alkylamino radical, C_1-6Alkoxy, halo C_1-6Alkoxy, -C (O)) OR 'OR-C (O) NR'₂；R₆In (A), the C_1-6The alkyl is unsubstituted or optionally substituted by 1 to 3 groups selected from halogen, hydroxy, amino, carboxyl, cyano, C_1-4Alkoxy, halo C_1-4Alkoxy and C_1-6The substituent of the alkylamino group is substituted at any position;

R₈is hydrogen, deuterium, halogen, cyano, C_1-6Alkyl, halo C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkoxy, hydroxy-C_1-4Alkyl radical, C_1-6alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6Alkyl ammoniaradical-C_1-4Alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C_1-4Alkyl or 3-10 heterocycloalkyl-C_1-4An alkyl group; wherein, the C_1-6alkylamino-C_1-4The alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl group is unsubstituted or optionally substituted with 1 to 3 substituents selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy, oxo and C_1-4The substituent of the alkyl group is substituted at any position;

R_Ais C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_6-10Aryl, 5-10 membered heteroaryl, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, C_3-10cycloalkyl-C_1-6Alkyl, 3-10 heterocycloalkyl-C_1-6Alkyl radical, C_6-10aryl-C_1-6Alkyl or 5-10 membered heteroaryl-C_1-6An alkyl group; the R is_AIs unsubstituted or optionally substituted by one or more R_cSubstitution at any position;

R_Bis hydrogen, cyano, hydroxy or C_1-6An alkyl group;

R_cis hydroxy, cyano, amino, oxo, halogen, C_1-4Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, hydroxy-C_1-6Alkyl radical, C_1-4alkoxy-C_1-6Alkyl, amino-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl, - (CH)₂)_n-N(CN)R’、-(CH₂)_n-C(O)R’、-(CH₂)_n-C(O)N(R’)₂、-(CH₂)_n-S(O)₂N(R’)₂、-(CH₂)_n-NR”C(O)R’、-(CH₂)_n-NR”S(O)₂R' or- (CH)₂)_n-B(OR”)₂；R_cIn (A), the C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4The alkyl is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy radical, C_1-4Alkylamino and C_1-4The substituent of the alkyl group is substituted at any position;

r' is hydrogen or C_1-6An alkyl group;

n is an integer of 0 to 4.

wherein the α and β bonds are double bonds, respectively;

x is N; w is C, V is CH or N; y is CR₂(ii) a Z is N;

u and M are each independently N, C;

ring A is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl;

ring B is

The B ring is unsubstituted or selectively substituted by 1-3R₆The group is substituted at any position;

r is C_6-10Aryl or 5-10 membered heteroaryl; r is unsubstituted or 1-4R₇The group is substituted at any position;

R₁is C_2-4An alkenyl group; the R is₁Is unsubstituted or optionally substituted by 1 to 3R₈The group is substituted at any position;

R₂is-OR_A；

R₆Is hydrogen, C_1-6Alkyl or C_1-6An alkoxy group; r₆In (A), the C_1-6The alkyl is unsubstituted or optionally substituted by 1 to 3 groups selected from halogen, hydroxy, cyano and C_1-4The substituent of the alkoxy is substituted at any position;

R₇is hydrogen, hydroxy, halogen, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy radical, C_3-8Cycloalkyl or 3-8 membered heterocycloalkyl;

R₈is hydrogen, deuterium, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy-C_1-4Alkyl radical, C_1-6alkoxy-C_1-4Alkyl radicalamino-C_1-4Alkyl or C_1-6alkylamino-C_1-4An alkyl group;

R_Ais C_1-6Alkyl radical, C_3-10Cycloalkyl, 3-10 membered heterocycloalkyl, C_3-10cycloalkyl-C_1-6Alkyl or 3-10 heterocycloalkyl-C_1-6An alkyl group; the R is_AIs unsubstituted or optionally substituted by one or more R_cSubstitution at any position;

R_cis hydroxy, cyano, amino, oxo, halogen, C_1-4Alkyl radical, C_1-4Alkylene radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-4Alkyl or halo C_1-4An alkoxy group.

wherein R is₃Is C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, C_6-10Aryl, 5-10 heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl or 5-10 heteroaryl-C_1-4An alkyl group; the R is₃Is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, cyano, amino, C_1-6Alkyl or C_3-6The substituents of the cycloalkyl group are substituted at any position;

R₇is hydrogen, hydroxy, halogen, C_2-6Alkenyl radical, C_2-6Alkynyl, cyano, amino, C_1-6Alkyl radical, C_1-6Alkoxy, halo C_1-6Alkyl, halo C_1-6Alkoxy, hydroxy-C_1-4Alkyl radical, C_1-6alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl radical, C_3-8Cycloalkyl radical, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10Aryl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl, -NH-C_3-6Cycloalkyl, - (CH)₂)_nOR’、-NHC(O)R”、-C(O)R”、-C(O)N(R”)₂、-OC(O)R”、-OC(O)N(R”)₂OR-B (OR')₂；

R_cIs hydroxy, cyano, amino, oxo, halogen, C_1-4Alkyl radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, hydroxy-C_1-6Alkyl radical, C_1-4alkoxy-C_1-6Alkyl, amino-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl, - (CH)₂)_n-N(CN)R’、-(CH₂)_n-C(O)R’、-(CH₂)_n-C(O)N(R’)₂、-(CH₂)_n-S(O)₂N(R’)₂、-(CH₂)_n-NR”C(O)R’、-(CH₂)_n-NR”S(O)₂R' or- (CH)₂)_n-B(OR”)₂；R_cIn (A), the C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4The alkyl is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy radical, C_1-4Alkylamino and C_1-4The substituent of the alkyl group is substituted at an arbitrary position.

In some embodiments, the alpha bond is a double bond; the beta bond is a single bond or a double bond.

In some embodiments, the α and β bonds are double bonds, respectively; x is N; w isC and V are CR₄Or N; y is CR₂(ii) a Z is N.

In some embodiments, the alpha bond is a double bond; the beta bond is a single bond; x is N; w is C and V is CR₄Or N; y is C (O), Z is NR₃；

In some embodiments, the A ring is a 5-6 membered heteroaryl or a 5-6 membered heterocycloalkyl.

In some embodiments, the a ring is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furanyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, or tetrazolyl.

In some embodiments, the a ring is furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, or tetrazolyl.

In some embodiments, the a ring is 2, 3-dihydrofuranyl.

In some embodiments, the a ring is of any of the following structures:

the A ring is unsubstituted or selectively substituted by 1-3R₅Substituted in any position, R₅The definition is as described above.

In some embodiments, the a ring is of any of the following structures:

In some embodiments, the B ring is of any one of the following structures:

the B ring is unsubstituted or R of 1-3 is selected₆Substituted in any position, R₆The definition is as described above.

In some embodiments, the R is₆Is H, -CH₃、-CF₃、-CHF₂、-CH₂CN、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂OCH₃or-CH₂OCH₃。

In some embodiments, the B ring is

In some embodiments, the B ring is

In some embodiments, the 9-14 membered fused heterocycloalkyl in said R is a monocyclic heterocycloalkyl fused with a phenyl, naphthyl, pyridinyl, pyrimidinyl, pyrazinyl group, preferably a 9-or 13-membered fused heterocycloalkyl, such as: indolinyl, 2, 3-dihydrobenzofuranyl, 1, 3-dihydrobenzo [ c ] [1,2] oxaboronyl, 1, 3-dihydronaphtho [2,1-c ] [1,2] oxaboronyl, 1, 3-dihydronaphtho [2,3-c ] [1,2] oxaboronyl, and the like.

In some embodiments, R is phenyl, naphthyl, pyridyl, quinolyl, isoquinolyl, 2, 3-dihydrobenzofuranyl, 1H-benzo [ d ]]Imidazole-2 (3H) -keto, 1H-indazolyl, phthalazinyl, 1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaboronyl, 3-hydroxy-1, 3-dihydronaphtho [2,1-c ]][1,2]Oxaboronyl or 1-hydroxy-1, 3-dihydronaphtho [2,3-c ]][1,2]Oxaboronyl; r is unsubstituted or 1-5, 1-4 or 1-3R₇Substituted in any position, R₇The definition is as described above.

In some embodiments, the R is₇Is hydrogen, halogen, hydroxy, amino, cyano, C_1-4Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy radical, C_1-6Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl or-B (OH)₂。

In some embodiments, the R is₇In (A), the C_3-6The cycloalkyl group or the 3-6 membered heterocycloalkyl group is unsubstituted or optionally substituted at any position with 1 to 3 substituents selected from the group consisting of hydroxy, amino, fluoro, chloro, methyl, trifluoromethyl and trifluoromethoxy.

In some embodiments, the R is any of the following structures:

in some embodiments, the R is any of the following structures:

in some embodiments, the R is any of the following structures:

in some embodiments, the R is₁Is composed of

Wherein R is_8aIs H, D, halogen or C_1-3alkoxy-C_1-4An alkyl group; r_8bAnd R_8cEach independently is H, D, halogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy-C_1-4Alkyl radical, C_1-3alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C_1-4Alkyl or 3-10 heterocycloalkyl-C_1-4An alkyl group; wherein, the C_1-6alkylamino-C_1-4Alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C_1-4Alkyl or 3-10 heterocycloalkyl-C_1-4The alkyl is unsubstituted or optionally substituted by 1 to 3 groups selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy, oxo and C_1-4The substituent of the alkyl group is substituted at an arbitrary position.

In some embodiments, the R is₁Is composed of

Wherein R is_8aH, D or halogen; r_8bAnd R_8cAs defined above.

In some embodiments, the R is₁Is composed of

In some embodiments, the R is_AIs C_1-6Alkyl, 5-6 membered heteroaryl, C_3-8Cycloalkyl, 3-8 membered heterocycloalkyl, 5-6 membered heteroaryl-C_1-4Alkyl radical, C_3-8cycloalkyl-C_1-4Alkyl or 3-8 membered heterocycloalkyl-C_1-4An alkyl group; the R is_AIs unsubstituted or optionally substituted by 1 to 5R_cSubstitution at any position; r_cAs defined above.

In some embodiments, the R is₂is-OR_A；R_AAs defined above.

In some embodiments, the R is₂Is any one of the following structures:

in some embodiments, the R is₂Is any one of the following structures:

in some embodiments, the R is₂is-NR_AR_B；R_AAnd R_BAs defined above.

In some embodiments, the R is₂Is any one of the following structures:

in some embodiments, the R is₂Is 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl; said 5-to 10-membered heteroaryl or 3-to 10-membered heterocycloalkyl is unsubstituted orIs selectively substituted by one or more R_cThe substitution is in any position.

In some embodiments, the R is₂Is 5-6 membered heteroaryl or 4-8 membered heterocycloalkyl; said 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with one or more R_cThe substitution is in any position.

In some embodiments, the R is₂Is any one of the following structures:

in some embodiments, the R is₂Is H or CN.

In some embodiments, the R is₃Is cyclohexyl, cyclopropylmethyl, phenyl, pyridyl, pyrimidinyl, thiazole or 1H-pyrazolyl; the R is₃Is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, cyano, amino, C_1-6Alkyl or C_3-6The substituents of the cycloalkyl group are substituted at arbitrary positions.

In some embodiments, the R is₃Is any one of the following structures:

in some embodiments, the R is₄Is hydrogen, halogen, C_2-4Alkenyl radical, C_1-4Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, halo C_1-3Alkoxy or C_3-6A cycloalkyl group.

In some embodiments, the compound of formula I, isomer, stable isotopic derivative, or pharmaceutically acceptable salt thereof is a compound of formula II, isomer, stable isotopic derivative, or pharmaceutically acceptable salt thereof:

wherein, ring A, ring B, X, U, M, R, R₁、R₂And R₄As defined above.

In some embodiments, the compound of formula I, isomer, stable isotopic derivative or pharmaceutically acceptable salt thereof is a compound of formula IIA, IIB, IIC or IID, isomer, stable isotopic derivative or pharmaceutically acceptable salt thereof:

wherein, ring B, R, R_A、R₁And R₅As defined above.

The compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof has any structure as follows:

the invention also provides a preparation method of the compound shown in the formula I, which is any one of the following methods:

the method comprises the following steps: in a solvent, the compound shown as the formula II-1 and R-L are subjected to coupling reaction to obtain the compound shown as the formula II,

1) suzuki coupling reaction: wherein Lev is Cl, Br or I, and L is boric acid or a borate group; or Lev is boric acid or a borate group, and L is Cl, Br or I; the Suzuki coupling reaction condition is a common reaction condition in the field, the solvent is preferably 1, 4-dioxane, the catalytic system is preferably a [1,1' -bis (diphenylphosphino) ferrocene ] palladium dichloride/sodium carbonate aqueous solution system or a tetratriphenylphosphine palladium/sodium carbonate aqueous solution system, the reaction temperature is preferably 80-120 ℃, and the reaction time is preferably 0.5-16 hours.

2) Stille coupling reaction: wherein Lev is Cl, Br or I, L is-Sn (CH)₃)₃or-Sn (n-Bu)₃(ii) a Or Lev is-Sn (CH)₃)₃or-Sn (n-Bu)₃L is Cl, Br or I; the Stille coupling reaction condition is a common reaction condition in the field, the solvent is preferably 1, 4-dioxane, the catalytic system is preferably tetratriphenylphosphine palladium/cuprous iodide, tetratriphenylphosphine palladium/tris (2-furyl) phosphonium or bis-triphenylphosphine palladium dichloride/tris (2-furyl) phosphonium, and the reaction condition is preferably that the reaction is carried out in a microwave or sealed tube at 80-160 ℃ for 0.5-4 hours.

The method 2 comprises the following steps: in a solvent, a compound of formula II-2 and R₁(CO) Cl or (R)₁(CO))₂Reacting O under alkaline condition to obtain a compound shown as a formula II,

wherein the solvent is preferably dichloromethane; the base is preferably triethylamine or N, N-diisopropylethylamine; the reaction temperature is preferably 0-35 ℃; the reaction time is preferably 0.5 to 6 hours.

The method 3 comprises the following steps: in a solvent, a compound of formula II-2 and R₁(CO) OH is subjected to condensation reaction to obtain a compound shown as a formula II,

wherein, the solvent is preferably dichloromethane and/or ethyl acetate; the base is preferably triethylamine or N, N-diisopropylethylamine; the reaction temperature is preferably 0-35 ℃; the condensing agent is preferably HATU or 1-propylphosphoric anhydride; the reaction time is preferably 0.5 to 6 hours.

The compound shown in the formula I and the pharmaceutically acceptable salt thereof can be synthesized by a general chemical method.

In general, salts can be prepared by reacting the free base or acid with equal chemical equivalents or an excess of acid (inorganic or organic) or base (inorganic or organic) in a suitable solvent or solvent composition.

The invention also provides a pharmaceutical composition, which comprises a therapeutically effective amount of active components and pharmaceutically acceptable auxiliary materials; the active component comprises one or more of a compound shown as a formula I, an isomer and a pharmaceutically acceptable salt thereof.

In the pharmaceutical composition, the active ingredient may also include other therapeutic agents for cancer.

In the pharmaceutical composition, the pharmaceutically acceptable adjuvant may include a pharmaceutically acceptable carrier, diluent and/or excipient.

The pharmaceutical composition may be formulated into various types of administration unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, injections (solutions and suspensions), and the like, preferably liquids, suspensions, emulsions, suppositories, injections (solutions and suspensions), and the like, according to the therapeutic purpose.

For shaping the pharmaceutical composition in the form of tablets, any excipient known and widely used in the art may be used. For example, carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, and the like; binders such as water, ethanol, propanol, common syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc.; disintegrators such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, calcium carbonate, fatty acid esters of polyethylene sorbitan, sodium lauryl sulfate, monoglyceride stearate, starch, lactose and the like; disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil and hydrogenated oil; adsorption promoters such as quaternary ammonium bases and sodium lauryl sulfate, etc.; humectants such as glycerin, starch, and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, and the like; and lubricants such as pure talc, stearates, boric acid powder, polyethylene glycol, and the like. Optionally, conventional coating materials can be selected to make into sugar-coated tablet, gelatin film-coated tablet, enteric coated tablet, film-coated tablet, double-layer film tablet and multilayer tablet.

For shaping the pharmaceutical composition in the form of pellets, any of the excipients known and widely used in the art may be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin, talc and the like; binders such as gum arabic powder, tragacanth powder, gelatin, ethanol and the like; disintegrating agents, such as agar and kelp powder.

For shaping the pharmaceutical composition in the form of suppositories, any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides and the like.

For preparing the pharmaceutical composition in the form of injection, the solution or suspension may be sterilized (preferably by adding appropriate amount of sodium chloride, glucose or glycerol) and made into injection with blood isotonic pressure. In the preparation of injection, any carrier commonly used in the art may also be used. For example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and fatty acid esters of polyethylene sorbitan, and the like. In addition, conventional lytic agents, buffers, analgesics, and the like may be added.

In the present invention, the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected from a wide range, and generally ranges from 5 to 95% by mass, preferably from 30 to 80% by mass.

In the present invention, the method of administration of the pharmaceutical composition is not particularly limited. The formulation of various dosage forms can be selected for administration according to the age, sex and other conditions and symptoms of the patient. For example, tablets, pills, solutions, suspensions, emulsions, granules or capsules are administered orally; the injection can be administered alone or mixed with infusion solution (such as glucose solution and amino acid solution) for intravenous injection; the suppository is administered to the rectum.

The invention also provides an application of the compound shown in the formula I, an isomer or pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparation of KRAS G12C inhibitor.

The invention also provides application of the compound shown in the formula I, an isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparation of medicines for treating related diseases mediated by KRAS G12C. The related disease is cancer. Further, the cancer is a cancer containing KRAS gene with G12C mutation in tumor cell DNA.

The invention also provides the compound shown in the formula I, an isomer or pharmaceutically acceptable salt thereof, or application of the pharmaceutical composition in preparing a medicament for treating and/or relieving cancer.

The invention also provides application of the compound shown in the formula I, an isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in preparing medicines for treating and/or relieving non-small cell lung cancer, pancreatic cancer and/or colorectal cancer.

The invention also provides the compound shown in the formula I, an isomer or pharmaceutically acceptable salt thereof, or application of the pharmaceutical composition in treating cancer.

The invention also provides application of the compound shown in the formula I, an isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in treating and/or relieving non-small cell lung cancer, pancreatic cancer, endometrial cancer and/or colorectal cancer.

The invention further provides a method for treating cancer by using the compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof, or the pharmaceutical composition, which comprises the following steps: administering to a mammal a therapeutically desired dose of a compound according to formula (I), an isomer, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

The mammal, preferably a human.

The invention further provides the compound shown in the formula I, an isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition can be combined with one or more other kinds of therapeutic agents and/or therapeutic methods to treat and/or alleviate related diseases mediated by KRAS G12C. The KRAS G12C-mediated related diseases are cancers. Further, the cancer is a cancer containing KRAS gene with G12C mutation in tumor cell DNA.

The compound shown in the formula I, the isomer or the pharmaceutically acceptable salt thereof can be preferably used for treating and/or alleviating the cancer mediated by KRAS G12C by combining the pharmaceutical composition with one or more other kinds of therapeutic agents and/or therapeutic methods. Further, the KRAS G12C-mediated cancer is a cancer containing a G12C mutated KRAS gene in tumor cell DNA.

The other therapeutic agent (e.g. other therapeutic agents useful in the treatment of cancer) may be administered in a single therapeutic form or in separate therapeutic forms in succession with the compound of formula (I).

The invention further provides a combined preparation which comprises the compound shown in the formula I, an isomer or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition and other types of therapeutic agents and/or therapeutic methods for treating cancers.

In the present invention, the cancer includes metastatic and non-metastatic cancers, also includes familial hereditary and sporadic cancers, and also includes solid tumors and non-solid tumors.

Specific examples of such cancers may include, but are not limited to: eye cancer, bone cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), stomach cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including glioblastoma, medulloblastoma), ovarian cancer, bladder cancer, cervical cancer, endometrial cancer, fallopian tube cancer, peritoneal cancer, testicular cancer, kidney cancer (including adenocarcinoma and nephrocyte carcinoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck cancer, colon cancer, small intestine cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, bile duct cancer, liver cancer, sarcoma, skin cancer, lymphoid leukemia (including acute lymphoblastic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia, hodgkin lymphoma, non-hodgkin lymphoma, T-cell chronic lymphocytic leukemia, B-cell chronic lymphocytic leukemia), One or more of myeloid related leukemia (including acute myeloid leukemia, chronic myeloid leukemia) and AIDs related leukemia.

Unless otherwise indicated, the following terms appearing in the specification and claims of the invention have the following meanings:

the term "C_t-q"refers to a range from a start point to an end point, where t and q, and each point in the range, are integers representing the number of carbon atoms, e.g., C_1-4Represents a carbon number of 1,2,3 or 4; c_1-6Represents a number of carbon atoms of 1,2,3,4, 5 or 6; c_3-8Represents a number of carbon atoms of 3,4, 5, 6,7 or 8; c_t-qCan be used in combination with any group containing carbon atoms for limiting the number of carbon atoms, e.g. C_1-6Alkyl radical, C_1-4Alkylene radical, C_3-8Cycloalkyl radical, C_6-10Aryl radical, C_1-4Alkoxy radical, C_3-8Cycloalkyl radical C_1-4Alkyl groups, and the like.

The term "alkyl" refers to a saturated straight or branched chain hydrocarbon group containing 1 to 20 carbon atoms, preferably 1 to 10 carbon atoms, more preferably 1 to 8, 1 to 6,1 to 4 or 1 to 3 carbon atoms, representative examples of alkyl groups including but not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, octyl, nonyl, decyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-dimethylpentyl, 2-methylhexyl, n-pentyl, n-hexyl, n-heptyl, octyl, nonyl, decyl, 1-dimethylpropyl, 1, 2-dimethylbutyl, 1,2, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2, 3-dimethylpentyl, 2, 4-dimethylpentyl, 2-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 2, 4-trimethylpentyl, undecyl, dodecyl, and their various isomers, and the like.

The term "alkylene" refers to a saturated straight or branched non-bridged divalent alkyl group containing 1 to 20 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1 to 4 or 1 to 3 carbon atoms, for example methylene (═ CH)₂) Ethylene (═ CHCH)₃) 2-isopropylidene (═ CH (CH)₃)₂) And the like.

The term "cycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or polycyclic group containing 3 to 20 carbon atoms. "cycloalkyl" is preferably 3-10 membered monocycloalkyl or partially unsaturated 4-6 membered cycloalkyl, more preferably 3-8 or 3-6 membered monocycloalkyl, for example: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclobutenyl, cyclopentenyl, cyclohexenyl. "polycyclic cycloalkyl" includes "bridged cyclic groups", "fused cycloalkyl" and "spirocycloalkyl". The monocyclic cycloalkyl or polycyclic cycloalkyl groups can be linked to the parent molecule through any carbon atom in the ring.

The term "heterocycloalkyl" refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) nonaromatic cyclic group consisting of carbon atoms and heteroatoms selected from nitrogen, oxygen, sulfur and boron, the cyclic group beingThe group may be monocyclic or polycyclic, preferably monocyclic, bicyclic or tricyclic, in the present invention the number of heteroatoms in the heterocycloalkyl group is preferably 1,2,3 or 4, and the nitrogen, carbon, sulfur or boron atom in the heterocycloalkyl group may optionally be oxidized. The nitrogen atom may optionally be further substituted with other groups to form tertiary amines or quaternary ammonium salts. "monocyclic heterocycloalkyl" is preferably 3-10 membered monocyclic heterocycloalkyl, more preferably 3-8 or 4-8 membered monocyclic heterocycloalkyl. Representative examples include, but are not limited to: aziridinyl, tetrahydrofuranyl-2-yl, morpholinyl, thiomorpholinyl, thiomorpholin-S-oxide-4-yl, piperidinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, 1, 4-dioxane, pyranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, 2, 3-dihydrofuranyl, 2, 5-dihydrofuranyl, dihydropyrazolyl, 2, 3-dihydro-1H-pyrrolidinyl, 2, 5-dihydro-1H-pyrrolidinyl, 1-tetrahydro-2H-thiopyranyl, 1-imino-1-tetrahydro-2H-thiopyranyl, 1-tetrahydrothienyl, 1-imino-1-tetrahydrothienyl, thiomorpholinyl-S-oxide-4-yl, piperidinyl, pyrrolidinyl, piperazinyl, homopiperazinyl, 1, 4-dioxane, pyranyl, tetrahydropyranyl, 2, 5-dihydro-1H-pyrrolidinyl, 1, 1-dioxido-3, 4-dihydro-2H-thiopyranyl, 1-imino-1-oxido-3, 4-dihydro-2H-thiopyranyl, 1-dioxido-2, 3-dihydrothienyl, 1-imino-1-oxido-2, 3-dihydrothienyl, 1, 3-dioxolanyl, 1, 3-dioxolyl, 1, 3-oxathiolanyl, 1, 4-dioxa-2-hexenyl, 3, 4-dihydro-2H-pyranyl, 3, 6-dihydro-2H-pyranyl, 1,2,3, 4-tetrahydropyrazinyl, 1,2,3, 4-tetrahydropyridinyl, 1,2,3, 6-tetrahydropyridinyl and the like. "polycyclic heterocycloalkyl" includes "fused heterocycloalkyl", "spiroheterocyclyl" and "bridged heterocyclyl", "fused heterocycloalkyl" includes monocyclic heterocycloalkyl rings fused to aryl, cycloalkyl, heterocycloalkyl or heteroaryl groups, fused heterocycloalkyl groups include, but are not limited to: indolinyl, 2, 3-dihydrobenzofuranyl, 1, 3-dihydroisobenzofuranyl, 2, 3-dihydrobenzo [ b ]]Thienyl, dihydrobenzopyranyl, 1,2,3, 4-tetrahydroquinolyl, benzo [ d][1,3]Dioxolanyl, 1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaborolan radical

3-hydroxy-1, 3-dihydronaphtho [2,1-c ]][1,2]Oxaborolan radical

1-hydroxy-1, 3-dihydronaphtho [2,3-c ]][1,2]Oxaborolan radical

And the like. "spiroheterocyclyl" refers to a bicyclic group formed by two heterocycloalkyl groups or a cycloalkyl group and a heterocycloalkyl group sharing a carbon atom, including, but not limited to:

and the like. "bridged heterocyclyl" means a monocyclic heterocycloalkyl group in which any two unlinked ring atoms are bridged by a straight chain radical of 1 to 3 additional carbon or heteroatoms (said straight chain radical being selected from, but not limited to: -CH:)₂-、-O-、-NH-、-S-、-CH₂CH₂-、-CH₂O-、-CH₂S-、-CH₂NH-、-CH₂CH₂CH₂-、-CH₂OCH₂-、-CH₂CH₂O-、-CH₂CH₂NH-、-CH₂NHCH₂-, bridged heterocyclic groups include, but are not limited to:

the bicyclic heterocycloalkyl group is preferably a 7-to 12-membered bicyclic heterocycloalkyl group. Monocyclic heterocycloalkyl and bicyclic heterocycloalkyl can be linked to the parent molecule through any ring atom in the ring. The above ring atoms particularly denote carbon atoms and/or nitrogen atoms constituting the ring skeleton.

The term "cycloalkylalkyl" refers to a cycloalkyl group attached to the parent nuclear structure through an alkyl group. Thus, "cycloalkylalkyl" encompasses the definitions of alkyl and cycloalkyl above.

The term "heterocycloalkylalkyl" refers to a linkage between a heterocycloalkyi and the parent nuclear structure through an alkyl group. Thus, "heterocycloalkylalkyl" embraces the definitions of alkyl and heterocycloalkyl described above.

The term "alkenyl" refers to a straight, branched, or cyclic non-aromatic hydrocarbon group containing at least 1 carbon-carbon double bond. Wherein 1-3 carbon-carbon double bonds, preferably 1 carbon-carbon double bond, may be present. The term "C_2-4Alkenyl "means an alkenyl group having 2 to 4 carbon atoms, the term" C_2-6Alkenyl "means alkenyl having 2 to 6 carbon atoms and includes ethenyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted.

The term "alkynyl" refers to a straight, branched, or cyclic hydrocarbon group containing at least 1 carbon-carbon triple bond. Wherein 1-3 carbon-carbon triple bonds, preferably 1 carbon-carbon triple bond, may be present. The term "C_2-6Alkynyl "refers to alkynyl groups having 2 to 6 carbon atoms and includes ethynyl, propynyl, butynyl, and 3-methylbutynyl.

The term "alkoxy" refers to a cyclic or acyclic alkyl group having the indicated number of carbon atoms attached through an oxygen bridge, including alkyloxy, cycloalkyloxy, and heterocycloalkyloxy. Thus, "alkoxy" encompasses the above definitions of alkyl, heterocycloalkyl, and cycloalkyl.

The term "aryl" refers to any stable 6-14 membered all-carbon monocyclic or fused bicyclic aromatic group having a conjugated pi-electron system, at least one ring of which is aromatic, preferably 6-10 membered, for example: phenyl, naphthyl, tetrahydronaphthyl, 2, 3-indanyl, biphenyl, or the like.

The term "heteroaryl" refers to an aromatic ring group formed by replacement of at least 1 ring carbon atom with a heteroatom selected from nitrogen, oxygen or sulfur, which may be a 5-6 membered monocyclic ring structure or a 7-12 membered bicyclic ring structure, preferably a 5-10 membered heteroaryl. In the present invention, the number of hetero atoms is preferably 1,2 or 3, and includes pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyridazin-3 (2H) -onyl, 1H-benzo [ d ] imidazol-2 (3H) -onyl, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, tetrazolyl, 1H-indazolyl, isoindolyl, indolyl, isoindolyl, benzofuryl, benzothienyl, benzothiazolyl, benzoxazolyl, quinolyl, isoquinolyl, quinazolinyl and the like.

The term "arylalkyl" refers to an alkyl linkage between an aryl group and the parent nucleus structure. Thus, "arylalkyl" encompasses the above definitions of alkyl and aryl groups.

The term "heteroarylalkyl" refers to a heterocycloalkyl group attached to the parent nucleus structure through an alkyl group. Thus, "heteroarylalkyl" embraces the definitions of alkyl and heteroaryl as described above.

The term "halogen" denotes fluorine, chlorine, bromine or iodine.

The term "haloalkyl" refers to an alkyl group optionally substituted with a halogen. Thus, "haloalkyl" encompasses the above definitions of halogen and alkyl.

The term "haloalkoxy" refers to an alkoxy group optionally substituted with a halogen. Thus, "haloalkoxy" encompasses the above definitions of halogen and alkoxy.

The term "amino" refers to the group-NH₂. The term "alkylamino" refers to an amino group wherein at least one hydrogen atom is replaced with an alkyl group, and includes "monoalkylamino" and "dialkylamino," examples of which include, but are not limited to: -NHCH₃、-N(CH₃)₂、-NHCH₂CH₃、-N(CH₂CH₃)₂、-N(CH₂CH₂CH₃)₂、-N(CH₃)(CH₂CH₃)、-N(CH₃)(CH₂CH₂CH₃). The term "aminoalkyl" refers to an alkyl group wherein any one of the hydrogen atoms is replaced by an amino group, examples include, but are not limited to: -CH₂NH₂、-CH₂CH₂NH₂. Thus, "aminoalkyl" and "alkylaminoThe group "includes the definitions of alkyl and amino as described above.

The term "alkylaminoalkyl" refers to an alkyl group wherein any one of the hydrogen atoms is replaced with an alkylamino group, examples include, but are not limited to: -CH₂N(CH₃)₂、-CH₂CH₂N(CH₃)₂、-CH₂CH₂CH₂N(CH₃)₂、-CH₂NHCH₃. Thus, "alkylaminoalkyl" embraces the definitions of alkylamino and alkyl as described above.

The term "hydroxy" refers to-OH. The term "hydroxyalkyl" means that any one of the hydrogen atoms on the alkyl group is replaced by a hydroxyl group, examples include, but are not limited to: -CH₂OH、-CH₂CH₂OH、-CH₂CH₂C(CH₃)₂OH、-CH(CH₃)₂And (5) OH. Thus, "hydroxyalkyl" encompasses the above definitions of hydroxy and alkyl.

The term "alkoxyalkyl" means an alkyl group in which any one of the hydrogen atoms is replaced with an alkoxy group, examples include, but are not limited to: -CH₂OCH₃、-CH₂CH₂OCH₃. Thus, "alkoxyalkyl" encompasses the definitions of alkoxy and alkyl as described above.

The term "acyl" refers to-C (O) R ".

The term "oxo" refers to ═ O, for example, carbonyl (-CO-), nitroso (-N ═ O), sulfinyl (-SO-) or sulfonyl (-SO-)₂-, moiety.

The term "cyano" refers to — CN.

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

The "room temperature" of the invention means 15-30 ℃.

In the present invention, unless otherwise specified, the term "optionally substituted at any position by 1 to 3 groups" means that any 1,2 or 3 hydrogen atoms of the 1,2 or 3 atoms specified on the group are substituted with the specified group, provided that the normal valency of the specified atom is not exceeded, said substitutions being those reasonable substitutions common in the art, for example ═ O cannot be substituted on an aryl group.

In the present invention, when the bond to a substituent exhibits an intersection with a bond linking two atoms in the ring, then such substituent may be bonded to any bondable ring atom on the ring.

In the present invention, any combination of variables is permitted only if such combination would result in a stable compound.

In the present invention, when any variable occurs more than one time in the composition or structure of a compound, its definition in each case is independent. For example, the A ring is substituted with 1-3R₅When substituted by radicals, each R₅The substituents are independent substituents and may be the same or different.

The compound of formula (I) in any of the embodiments described herein includes isotopic derivatives thereof. The isotopically substituted derivatives include: isotopically substituted derivatives of formula (I) wherein any hydrogen atom (1 to 5) is substituted with 1 to 5 deuterium atoms; having 1 to 3C atoms of any carbon atom (1 to 3) in formula (I)₁₄Isotopically substituted derivatives by substitution of atoms or by 1 to 3O atoms of any oxygen atom of formula (I)₁₈Isotopically substituted derivatives by atomic substitution.

The "Pharmaceutically acceptable salts" described herein are discussed in Berge, et al, "pharmaceutical acceptable salts", j.pharm.sci.,66,1-19(1977), and are apparent to the pharmaceutical chemist, as being substantially non-toxic and providing the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism, excretion, etc. The compounds of the present invention may have an acidic group, a basic group or an amphoteric group, and typical pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with an acid, for example: hydrochloride, hydrobromide, sulphate, pyrosulphate, hydrogen sulphate, sulphite, bisulphite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, propionate, decanoate, octanoate, formate, acrylate, isobutyrate, hexanoate, heptanoate, oxalate, malonate, succinate, suberate, benzoate, methylbenzoate, phthalate, maleate, methanesulfonate, p-toluenesulfonate, (D, L) -tartaric acid, citric acid, maleic acid, (D, L) -malic acid, fumaric acid, succinic acid, succinate, lactate, trifluoromethanesulfonate, naphthalene-1-sulfonate, mandelate, pyruvate, stearate, ascorbate, salicylate. When the compound of the present invention contains an acidic group, pharmaceutically acceptable salts thereof may further include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; examples of the organic base salt include salts with ammonia, alkylamines, hydroxyalkylamines, amino acids (lysine and arginine), and N-methylglucamine.

The term "isomers" as used herein means that the compounds of formula I of the present invention may have asymmetric centers and racemates, racemic mixtures and individual diastereomers, and all such isomers, including stereoisomers and geometric isomers, are encompassed by the present invention. In the present invention, when a compound of formula I or a salt thereof exists in stereoisomeric forms (e.g., which contain one or more asymmetric carbon atoms), individual stereoisomers (enantiomers and diastereomers) and mixtures thereof are included within the scope of the invention. The invention also includes individual isomers of the compounds or salts represented by formula I, as well as mixtures of isomers with one or more chiral centers reversed therein. The scope of the invention includes: mixtures of stereoisomers, and purified enantiomerically or enantiomerically/diastereomerically enriched mixtures. The present invention includes mixtures of stereoisomers in all possible different combinations of all enantiomers and diastereomers. The present invention includes all combinations and subsets of stereoisomers of all specific groups defined above.

The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.

The reagents and starting materials used in the present invention are commercially available.

Detailed Description

The structures of all compounds of the invention can be determined by nuclear magnetic resonance¹H NMR) and/or mass spectrometric detection (MS).

¹H NMR chemical shifts (. delta.) are recorded by PPM (10)^-6). NMR was performed on a Bruker AVANCE-400 spectrometer. A suitable solvent is deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), deuterated dimethyl sulfoxide (DMSO-d)₆) Tetramethylsilane was used as internal standard (TMS).

Liquid mass spectrometry (LCMS) was determined by an Agilent 1200HPLC/6120 mass spectrometer using a chromatographic column: xtimate C18,3.0 × 50mm, 3 μm, column temperature 40 ℃; or by Thermo UltiMate 3000HPLC/MSQ PLUS mass spectrometer using column Xbridge C18, 3.0X 50mm, 3.5 μm, column temperature 30 ℃. Agilent gradient elution conditions one: 95-5% of solvent A₁And 5-95% of solvent B₁(0-2.0 min), then 95% solvent B₁And 5% of solvent A₁(hold for 1.1 minutes) percent is the volume percent of a solvent based on the total solvent volume. Solvent A₁: 0.01% trifluoroacetic acid (TFA) in water; solvent B₁: 0.01% trifluoroacetic acid in acetonitrile; the percentages are the volume percent of solute in solution. Thermo gradient elution condition two: 95-5% of solvent A₂And 5-95% of solvent B₂(0-2 min) and then 95% solvent B₂And 5% of solvent A₂(hold for 1.8 minutes) percent is the volume percent of a solvent based on the total solvent volume. Solvent A₂: 10mM ammonium bicarbonate in water; solvent B₂: and (3) acetonitrile.

All compounds of the invention can be separated by preparative high performance liquid chromatography or flash column chromatography.

Preparative high performance liquid chromatograph (prep-HPLC) preparative liquid chromatography using shimadzu LC-20, column: xtimate 21.2 x 250mm, 10 um. Mobile phase A: 10mmol/L aqueous ammonium bicarbonate, mobile phase B: acetonitrile, gradient elution conditions 1: the mobile phase B is 10 to 30 percent, and the elution time is 5 minutes; the mobile phase B is 30-60%, and the elution time is 15 minutes; condition 2: mobile phase B from 15% to 25%, elution time: 5 minutes, eluting the mobile phase B from 25 to 55 percent, and the elution time is 15 minutes; condition 3: mobile phase B from 15% to 30%, elution time: 5 minutes, eluting mobile phase B from 30% to 65%, and eluting for 15 minutes; condition 4: mobile phase B from 0% to 35%, elution time: 5 minutes, eluting the mobile phase B from 35 to 60 percent, and the elution time is 15 minutes; condition 5: mobile phase B from 10% to 40%, elution time: 5 minutes, elution mobile phase B from 40% to 80%, elution time 15 minutes. Mobile phase A: 0.1% aqueous trifluoroacetic acid, mobile phase B: acetonitrile, gradient elution conditions 6: the mobile phase B is 15-25%, the elution time is 5 minutes, 25-55%, and the elution time is 15 minutes; condition 7: the mobile phase B is 15 to 30 percent, the elution time is 5 minutes, 30 to 60 percent, and the elution time is 15 minutes; condition 8: mobile phase B from 15% to 45%, elution time 5 min, 45% to 80%, elution time 15 min. Detection wavelength: 214nm &254 nm; flow rate: 15.0 mL/min.

Flash column chromatography (Flash system/CheetahTM) uses Agela Technologies MP200, the matched normal phase separation column uses Flash column Silica-CS (25g, 40g, 80g, 120g or 330g), Tianjin Bonneaijie, the elution system is ethyl acetate/petroleum ether or dichloromethane/methanol; the reversed phase separation column is C18 reversed phase column (12g, 20g, or 40g), and the elution system is acetonitrile/0.1% trifluoroacetic acid water solution or acetonitrile/10 mmol/L ammonium bicarbonate water solution.

The thin-layer silica gel plate (prep-TLC) is a tobacco-stage yellow sea HSGF254 or Qingdao GF254 silica gel plate.

The microwave reaction described in the examples of the present invention was used

Initiator + microwaveSystem EU (356006) type Microwave reactor. The reactions in all the examples were carried out under nitrogen or argon atmosphere, unless otherwise specified in the present invention.

The hydrogen atmosphere refers to a reaction system with a hydrogen balloon attached in a volume of about 1L.

The abbreviations used in the examples of the present invention have the following meanings:

PdCl₂dppf·CH₂Cl₂: [1,1' -bis (diphenylphosphino) ferrocene]A palladium dichloride dichloromethane complex; HATU: o- (7-azabenzeneBenzotriazol-1-yl) -N, N' -tetramethylurea; TBSCl: tert-butyldimethylsilyl chloride; DMF: n, N-dimethylformamide; DMSO, DMSO: dimethyl sulfoxide; the DIAD: diisopropyl azodicarboxylate; (Boc)₂O: di-tert-butyl dicarbonate; DIPEA: n, N-diisopropylethylamine; NCS: n-chlorosuccinimide; LiHMDS: lithium bis (trimethylsilyl) amide; t-BuONa: sodium tert-butoxide; BINAP: 1,1 '-binaphthyl-2, 2' -bis-diphenylphosphine; pd₂(dba)₃: tris (dibenzylideneacetone) dipalladium; pd (PPh)₃)₄: tetrakis (triphenylphosphine) palladium.

And (3) synthesis of an intermediate:

(S) - (1- (2, 2-difluoroethyl) pyrrolidin-2-yl) methanol

To a solution of L-prolinol (505mg, 5mmol) in acetonitrile (10mL) were added 2, 2-difluoroethyl trifluoromethanesulfonate (1.1g, 5.04mmol) and potassium carbonate (760mg, 5.5mmol), and the reaction was stirred at 0 ℃ for 1 hour, then warmed to room temperature and stirred for 3 hours. The reaction was quenched by the addition of water (100mL), the aqueous phase was extracted 3 times with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate ═ 3/1) to give (S) - (1- (2, 2-difluoroethyl) pyrrolidin-2-yl) methanol (600mg) as a yellow oil. M/z [ M + H ]]⁺166.2。

(S) - (1- (2-fluoroethyl) pyrrolidin-2-yl) methanol

To a solution of L-prolinol (2.07g, 0.02mol) and potassium carbonate (3g, 0.02mol) in acetonitrile (40mL) under an ice-water bath was added fluoroethyl p-toluenesulfonate (4.91g, 0.02 mol). The reaction was stirred at room temperature for 12 hours. Filtering the reaction solution with diatomite, concentrating the filtrate under reduced pressure, and purifying the residue by Flash column chromatography (dichloromethane/methanol-9/1) to obtain (S) - (1- (2-fluoroethyl) pyrrolidine-2-Mesityl) methanol (0.5g) was a yellow oil. M/z [ M + H ]]⁺148.2。

N-ethyl-N- (2-fluoroethyl) azetidin-3-amine

Step 1: a mixture of 3-amino-1-benzhydrylazetidine (5g, 21mmol), 1-bromo-2-fluoroethane (3.2g, 25.2mmol) and potassium carbonate (7.2g, 52.5mmol) in acetonitrile (50mL) was stirred in a sealed tube at 80 ℃ for 48 hours. The reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 20/1) to give 1-benzhydryl-N- (2-fluoroethyl) azetidin-3-amine (4.5g) as a white solid. M/z [ M + H ]]⁺285.2。

Step 2: a mixture of 1-benzhydryl-N- (2-fluoroethyl) azetidin-3-amine (4g, 14.1mmol), iodoethane (3.3g, 21.1mmol) and potassium carbonate (5.8g, 42.2mmol) in acetonitrile (50mL) was stirred in a sealed tube at 40 ℃ for 20 h. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 2/1) to give 1-benzhydryl-N-ethyl-N- (2-fluoroethyl) azetidin-3-amine (3g) as a yellow oil. M/z [ M + H ]]⁺313.2。

And step 3: 1-Diphenylmethyl-N-ethyl-N- (2-fluoroethyl) azetidin-3-amine (1g, 3.19mmol), ammonium formate (4g, 63.8mmol), palladium hydroxide on carbon (1g) were added to methanol (20mL), the reaction was replaced 3 times with nitrogen, and then stirred at 60 ℃ for 6 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give N-ethyl-N- (2-fluoroethyl) azetidin-3-amine (466mg) as a yellow oil. M/z [ M + H ]]⁺147.2。

3-fluoro-4-chloro-5-bromoaniline

To a solution of 3-fluoro-5-bromoaniline (600mg, 3.16mmol) in DMF (15mL) was added NCS (506mg, 3.79mmol) in portions. The reaction solution was stirred at room temperatureAfter 3 hours, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 3/1) to give 3-fluoro-4-chloro-5-bromoaniline (310mg) as a yellow solid. M/z [ M + H ]]⁺224.0；¹H NMR(400MHz,DMSO-d₆):δ6.77(dd,J＝2.4,1.6Hz,1H),6.52(dd,J＝2.4,11.6Hz,1H),5.84(s,2H).

3-bromo-2-chloro-5-fluoroaniline

Step 1: 1-chloro-2, 6-dibromo-4-fluorobenzene (1.0g, 3.47mmol), benzophenone imine (754mg, 4.16mmol), t-BuONa (500mg, 5.21mmol), BINAP (324mg, 0.52mmol) and Pd₂(dba)₃A solution of (156mg, 0.17mmol) in dry toluene (30mL) was purged with nitrogen and stirred at 80 ℃ for 16 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 15/1) to give 3-bromo-2-chloro-N- (diphenylmethylene) -5-fluoroaniline (1.1g) as a white solid. M/z [ M + H ]]⁺388.0。

Step 2: hydrochloric acid (2M, 1.4mL) was added to a solution of 3-bromo-2-chloro-N- (diphenylmethylene) -5-fluoroaniline (1.1g, 2.84mmol) in tetrahydrofuran (20mL) under ice-bath conditions, and the reaction was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 10/1) to give 3-bromo-2-chloro-5-fluoroaniline (600mg) as a yellow oil. M/z [ M + H ]]⁺224.0。

4-bromo-1-fluoronaphthalen-2-ol

To a solution of 4-bromonaphthalen-2-ol (200mg, 0.9mmol) in dichloromethane (3mL) under an ice-water bath were added N-fluorobisbenzenesulfonamide (347mg, 1.1mmol) and zirconium tetrachloride (12mg, 0.05mmol), respectivelyl), the reaction solution was stirred overnight at room temperature. Then, the mixture was washed with a saturated aqueous sodium bicarbonate solution, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 4/1) to give 4-bromo-1-fluoronaphthalen-2-ol (75mg) as a white solid.¹H NMR(400MHz,DMSO-d₆):δ8.13-8.11(m,1H),7.91-7.81(m,1H),7.52-7.47(m,3H),5.43(br.s,1H)。

3-bromo-5-fluoro-4-isopropylaniline

Step 1: to a solution of 3-fluoro-5-bromoaniline (1.8g, 9.5mmol) in N, N-dimethylformamide (36mL) under ice-bath conditions was added N-iodosuccinimide (2.3g, 10.4mmol), and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water (10mL), the aqueous phase was extracted with ethyl acetate, the organic phases were combined and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate ═ 10/1) to give 3-bromo-5-fluoro-4-iodoaniline (2.7g) as a white solid. M/z [ M + H ]]⁺316.0。

Step 2: isopropenylboronic acid pinacol ester (293mg, 1.74mmol), 3-bromo-5-fluoro-4-iodoaniline (500mg, 1.58mmol), potassium phosphate (1.01g, 4.75mmol) and PdCl under nitrogen₂dppf·CH₂Cl₂(130mg, 0.16mmol) of the mixture in 1, 4-dioxane (25mL) was stirred at 80 ℃ for 16 h. Filtration, concentration of the filtrate under reduced pressure and Flash column chromatography (petroleum ether/ethyl acetate 4/1) of the residue afforded 3-bromo-5-fluoro-4- (prop-1-en-2-yl) aniline (272mg) as a yellow oil. M/z [ M + H ]]⁺230.2。

And step 3: 3-bromo-5-fluoro-4- (prop-1-en-2-yl) aniline (272mg, 1.18mmol) and platinum carbon (30mg) were added to ethyl acetate (20mL) and methanol (25mL), and the mixture was stirred at room temperature for 16 hours under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to give 3-bromo-5-fluoro-4-isopropylaniline (250mg) as a yellow oil. M/z [ M + H ]]⁺232.0。

3-bromo-4-cyclopropyl-5-fluoroaniline

Replacing isopropenyl boronic acid pinacol ester in the step 2 with cyclopropylboronic acid to react by using the synthesis method of the steps 1 and 2 of 3-bromo-5-fluoro-4-isopropylaniline to obtain 3-bromo-4-cyclopropyl-5-fluoroaniline as colorless oily matter. M/z [ M + H ]]⁺232.0。

N, N-di-Boc-2-amino-4-bromo-5-chloropyridine

Will (Boc)₂O (1.04g, 4.77mmol), triethylamine (483mg, 4.77mmol) and 4-dimethylaminopyridine (58.3mg, 0.48mmol) were added to a solution of 2-amino-4-bromo-5-chloropyridine (330mg, 1.59mmol) in tetrahydrofuran (5mL) and stirred at room temperature under nitrogen for 4 hours. Adding water to quench the reaction, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and purifying the residue by Flash column chromatography (petroleum ether/ethyl acetate ═ 0-10%) to obtain N, N-di-Boc-2-amino-4-bromo-5-chloropyridine (400mg) as a white solid. M/z [ M + Na]⁺429.3。

6-chloro-N, N-bis (4-methoxybenzyl) -5- (trifluoromethyl) pyrazin-2-amine

Step 1: to a solution of 6-chloro-5-iodopyrazin-2-amine (9.56g, 37.4mmol) in DMF (58mL) under ice-bath conditions was added sodium hydrogen (60%, 3.74g, 93.5mmol), the reaction mixture was stirred for 40 min, p-methoxybenzyl chloride (14.6g, 93.5mmol) was slowly added to the reaction mixture and stirring continued for 2 h. The reaction was quenched with ice water, the pH was adjusted to 7 to 8 with aqueous potassium hydrogen sulfate (1M), the aqueous phase was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 5/1) to give 6-chloro-5-iodo-N, N-bis (4-methoxybenzyl) pyrazin-2-amine (10.6g) as a pale yellow solid. M/z [ M + H ]]⁺495.9。

Step 2: 6-chloro-5-iodo-N, N-bis (4-methoxybenzyl) pyrazin-2-amine (2.5g, 5.10mmol), methyl 2, 2-difluoro-2- (fluorosulfonyl) acetate (2.9g, 15.0mmol) and cuprous iodide (2.86g, 15.0mmol) were suspended in a solution of anhydrous DMF (70mL) and the reaction was stirred at 100 ℃ for 4 hours under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (50mL) and ice water (30mL), filtered, the filtrate was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate ═ 6/1) to give 6-chloro-N, N-bis (4-methoxybenzyl) -5- (trifluoromethyl) pyrazin-2-amine (2.0g) as a pale yellow solid. M/z [ M + H ]]⁺438.0。

6- (bis (4-methoxybenzyl) amino) -2-chloro-3- (trifluoromethyl) isonicotinonitrile

Step 1: 2, 6-dichloro-4-cyanopyridine (5.0g, 28.9mmol), p-methoxybenzyl chloride (8.92g, 34.7mmol) and DIPEA (26mL,145mmol) were dissolved in anhydrous 1, 4-dioxane (55mL) and the reaction mixture was stirred at 120 ℃ overnight. Concentrated under reduced pressure and the residue purified by Flash column chromatography (petroleum ether/ethyl acetate 5/1) to give 2- (bis (4-methoxybenzyl) amino) -6-chloroisonicotinonitrile (9.8g) as a yellow solid. M/z [ M + H ]]⁺394.0。

Step 2: 2- (bis (4-methoxybenzyl) amino) -6-chloroisonicotinic acid nitrile (8.7g, 37.4mmol), N-iodosuccinimide (5.73g, 25.5mmol) were dissolved in anhydrous DMF (70mL), the reaction mixture was stirred overnight at 100 deg.C, ethyl acetate (500mL) was diluted, the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 10/1) to give 6- (bis (4-methoxybenzyl) amino) -2-chloro-3-iodoisonicotinic acid nitrile (9g) as a yellow solid. M/z [ M + H ]]⁺522.0。

And step 3: 6- (bis (4-methoxybenzyl) amino) -2-chloro-3-iodoisonicotinic acid nitrile (8.0g, 15.4mmol), 2, 2-difluoro-2- (fluorosulfonyl) was added at room temperature) Methyl acetate (8.9g, 46.2mmol) and cuprous iodide (8.8g, 46.2mmol) were suspended in anhydrous DMF (120mL) and the reaction was stirred at 100 ℃ for 4 h under nitrogen. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (500mL), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate ═ 10/1) to give 6- (bis (4-methoxybenzyl) amino) -2-chloro-3- (trifluoromethyl) isonicotinonitrile (8.0g) as a yellow solid. M/z [ M + H ]]⁺463.0。

4-bromo-5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole

Step 1: under nitrogen protection, NCS (3.5g, 25.9mmol) was added to a solution of 3-bromo-5-fluoro-2-methylaniline (4.8g, 23.5mmol) in isopropanol (35mL), the reaction system was stirred at 80 ℃ for 2 hours and then directly concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 2/1) to give 3-bromo-4-chloro-5-fluoro-2-methylaniline (2.6g) as a yellow solid.

Step 2: to a solution of 3-bromo-4-chloro-5-fluoro-2-methylaniline (1.5g, 6.12mmol) in acetic acid (25mL) was added sodium nitrite (549mg, 7.96mmol), and the reaction solution was stirred overnight at room temperature and then directly concentrated. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 5/1) to give 4-bromo-5-chloro-6-fluoro-1H-indazole (628mg) as a yellow solid.

And step 3: to a solution of 4-bromo-5-chloro-6-fluoro-1H-indazole (575mg, 2.3mmol) in dichloromethane (10mL) were added 3, 4-dihydropyran (387mg, 4.6mmol) and p-toluenesulfonic acid (44mg, 0.23mmol), respectively, the reaction solution was stirred at room temperature for 2 hours and directly concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate ═ 10/1) to give 4-bromo-5-chloro-6-fluoro-1- (tetrahydro-2H-pyran-2-yl) -1H-indazole (821mg) as a yellow solid.

2-chloro-3-methoxynaphthalen-1-yl trifluoromethanesulfonate

Step 1: chloromethyl methyl ether (1.1g, 13.8mmol) was added to a solution of 3-methoxynaphthalen-1-ol (2.0, 11.5mmol) and DIPEA (1.97g, 23.0mmol) in dichloromethane (20 mL). The reaction solution is stirred for 4 hours at room temperature, then is directly decompressed and concentrated, and the residue is purified by Flash column chromatography (0 percent to 20 percent of ethyl acetate/petroleum ether) to obtain 3-methoxy-1- (2-methoxyethoxy) naphthalene (2g) which is colorless oily matter. M/z [ M + H ]]⁺219.2。

Step 2: n-butyllithium (2.5M in tetrahydrofuran, 1.2mL, 2.8mmol) was slowly added to a solution of 3-methoxy-1- (2-methoxyethoxy) naphthalene (0.5g, 2.34mmol), tetramethylethylenediamine (0.35mL, 3.0mmol) in tetrahydrofuran (5mL) at-10 ℃ under nitrogen, and the reaction was stirred at-10 ℃ for 1.5 hours. Then, hexachloroethane solid (0.87g, 3.66mmol) was added in portions to the above reaction solution. The reaction solution is warmed to room temperature, water is added for quenching reaction, ethyl acetate is used for extraction, an organic phase is dried by anhydrous sodium sulfate, filtration and decompression concentration are carried out on a filtrate, and a residue is purified by Flash column chromatography (ethyl acetate/petroleum ether is 0-16 percent) to obtain 2-chloro-3-methoxy-1- (2-methoxyethoxy) naphthalene (0.5g) which is colorless oily matter. M/z [ M + H ]]⁺253.2；¹H NMR(400MHz,DMSO-d₆):δ8.02(d,J＝8.2Hz,1H),7.88(d,J＝8.2Hz,1H),7.60-7.49(m,1H),7.49-7.42(m,1H),7.37(s,1H),5.26(s,2H),3.97(s,3H),3.61(s,3H)。

And step 3: a solution of 2-chloro-3-methoxy-1- (2-methoxyethoxy) naphthalene (0.5g, 1.98mmol) and hydrogen chloride (4.0M in 1, 4-dioxane, 4.0mL) in dichloromethane (10mL) was stirred at room temperature for 1.5 hours, then saturated aqueous sodium bicarbonate was added to adjust the pH to 7.0, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 2-chloro-3-methoxynaphthalene-1-ol (0.41g) as a yellow solid. M/z [ M + H ]]⁺209.0。

And 4, step 4: trifluoromethanesulfonic anhydride (0.7g, 2.5mmol) was added to a solution of 2-chloro-3-methoxynaphthalen-1-ol (0.4g, 1.92mmol) and triethylamine (0.8mL, 5.76mmol) in dichloromethane (5mL) under ice-bath conditions. The reaction solution was stirred at 0 ℃ for 2 hours. Adding water for quenchingReaction, the aqueous phase is extracted with ethyl acetate, the organic phase is separated and dried with anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, and the residue is purified by Flash column chromatography (ethyl acetate/petroleum ether is 0% -20%) to obtain 2-chloro-3-methoxynaphthalene-1-yl trifluoromethanesulfonate (0.17g) as a white solid. M/z [ M + H ]]⁺341.0。

Synthesis of boronic acids and boronic esters

The general synthesis method of the boric acid comprises the following steps: in a dry ice acetone bath, a tetrahydrofuran (5-15 mL/mmol bromide) solution of aryl or heteroaryl bromide (1 equivalent) is replaced by nitrogen, n-butyllithium (2.5M n-hexane solution, 0.9-1 equivalent) is added dropwise to the solution, the reaction solution is stirred at-78 ℃ for 1 hour, trimethyl borate (1.5-2.5 equivalents) is added, the reaction solution is stirred at-78 ℃ for 4 hours, and water is added to quench the reaction. The mixture was diluted with ethyl acetate and washed with saturated brine, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate) to give the corresponding boronic acid.

The general synthesis method of the borate comprises the following steps: bromide or triflate (1 equivalent) of aryl or heteroaryl, pinacol diboron (2-3 equivalents), potassium acetate (3-5 equivalents) and PdCl₂dppf·CH₂Cl₂(0.1 to 0.15 equivalent) of 1, 4-dioxane (5 to 15mL/mmol of bromide) solution is replaced with nitrogen, and the reaction system is stirred at 80 to 120 ℃ under nitrogen for 4 to 16 hours. Quenching the reaction with water, extracting the water phase with ethyl acetate, separating the organic phase, concentrating under reduced pressure, and purifying the residue with Flash column chromatography (petroleum ether/ethyl acetate) to obtain the corresponding borate.

TABLE 1

Intermediate 5 was synthesized using a borate ester synthesis procedure to give the corresponding boronic acid product.

Intermediate 32: synthesis of (2-amino-3, 5-dichloro-6-fluorophenyl) boronic acid

Step 1: trifluoroacetic anhydride (3.78g, 18mmol) was added to a solution of 2, 4-dichloro-5-fluoroaniline (2.62g, 14.6mmol) and sodium carbonate (2.65g, 25mmol) in methyl tert-butyl ether (60mL) under ice-bath conditions, the reaction solution was stirred at room temperature for 12 hours, diluted with n-hexane and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 19/1) to give N- (2, 4-dichloro-5-fluorophenyl) -2,2, 2-trifluoroacetamide (3g) as a grey solid.

Step 2: n-butyllithium (2.5M in N-hexane, 8.7mL, 22.7mmol) was added dropwise to a solution of N- (2, 4-dichloro-5-fluorophenyl) -2,2, 2-trifluoroacetamide (3g, 10.9mmol) in tetrahydrofuran (47mL) at 78 ℃ under nitrogen protection, the reaction was stirred at this temperature for 2 hours, then the reaction was quenched with trimethyl borate (2.47g, 23.9mmol), the resulting mixture was diluted with ethyl acetate, the organic phase was washed with saturated brine, the organic phase was separated and concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 3/1) to give intermediate 32(850mg) as a yellow oil. M/z [ M + H ]]⁺224.0。

Intermediate 33: synthesis of 3, 4-dimethyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) phenol

To a solution of intermediate 13(50mg, 0.17mmol) in 1, 4-dioxane (2mL) was added hydrogen chloride (4M in 1, 4-dioxane, 0.5mL) and the resulting mixture was stirred at room temperature for 3 hours. Then directly concentrated under reduced pressure to give intermediate 33(42mg) as a yellow oil. M/z [ M + H ]]⁺249.2。

Intermediates 1 to 6: synthesis of 4- (4-bromofuro [2,3-f ] quinazolin-9-yl) piperazine-1-carboxylic acid tert-butyl ester

Step 1: 4-bromo-2, 6-difluorobenzonitrile (25g, 0.11mol), aqueous ammonia (100mL) and isopropanol (60mL) were added to the tube, and the reaction was stirred at 90 ℃ for 16 hours. The reaction solution was cooled to room temperature and poured into water, a large amount of solid precipitated, filtered and the filter cake vacuum dried to give intermediate 1-1(23.2g) as a grey solid. M/z [ M + H ]]⁺215.0。

Step 2: to a solution of 2, 2-diethoxyethanol (3.7g, 27.9mmol) in DMF (60mL) under ice-bath conditions was added sodium hydrogen (60%, 1.1g, 27.9mmol) in portions and the resulting mixture was stirred at 0 ℃ for 1 h. Then, intermediate 1-1(5g, 23.3mmol) was added to the above reaction solution, and stirred at 50 ℃ for 1 hour. The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 4/1) to give intermediate 1-2(4.8g, yield: 63%) as a gray solid. M/z [ M + Na]⁺350.8。

And step 3: a suspension of polyphosphoric acid (16.9g, 50.1mmol) in toluene (150mL) was warmed to 50 ℃. Intermediate 1-2(5.5g, 16.7mmol) was added to the above solution and the resulting mixture was stirred at 50 ℃ for 2 hours. The reaction solution was diluted with ethyl acetate in an ice-water bath, the organic phase was washed with a saturated aqueous solution of sodium bicarbonate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 6/1) to give intermediate 1-3(1.1g) as a gray solid. M/z [ M + H ]]⁺237.0。

And 4, step 4: a mixed solution of intermediates 1 to 3(0.33g, 1.39mmol) in formic acid (12mL) and concentrated sulfuric acid (0.3mL) was stirred at 100 ℃ for 0.5 hour. The reaction solution is cooled to room temperature and poured into water, a large amount of solid is separated out, the filtration is carried out, and the intermediate 1-4(0.21g) is obtained as yellow solid after the filter cake is dried in vacuum. M/z [ M + H ]]⁺264.8。

And 5: to a solution of intermediate 1-4(350mg, 1.32mmol) and N, N-dimethylaniline (1.78g, 14.7mmol) in 1, 4-dioxane (16mL) was added phosphorus oxychloride (1.6mL), and the reaction mixture was stirred at 110 ℃ for 1 hour. The reaction was quenched with water, the aqueous phase extracted with ethyl acetate, the organic phase separated and concentrated under reduced pressure to give intermediates 1-5 (crude) as yellow solids. M/z [ M + H ]]⁺282.8。

Step 6: DIPEA (1.7g, 13.2mmol) was added to a solution of intermediate 1-5 (crude) and 1-tert-butoxycarbonylpiperazine (0.37g, 1.98mmol) in 1, 4-dioxane (30mL), and the reaction was stirred at 50 ℃ for 21 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 1/1) to give intermediates 1-6(650mg) as a yellow solid. M/z [ M + H ]]⁺433.0。

Intermediates 2 to 4: synthesis of tert-butyl 4- (4-bromo-7-chlorofuro [2,3-f ] quinazolin-9-yl) piperazine-1-carboxylate

Step 1: to a solution of intermediate 1-3(0.43g, 1.81mmol) in ethanol (15mL) was added a solution of potassium hydroxide (0.41g, 7.3mmol) in water (3mL), and the resulting mixture was stirred at 90 ℃ for 4 hours. The reaction was cooled to room temperature and diluted with water, the aqueous phase was extracted with dichloromethane, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 2/3) to give intermediate 2-1(406mg) as a grey solid. M/z [ M + H ]]⁺254.8。

Step 2: to a solution of intermediate 2-1(406mg, 1.59mmol) in tetrahydrofuran (60mL) was added a solution of triphosgene (467mg, 1.5mmol) in tetrahydrofuran (20mL), and the resulting mixture was stirred at 60 ℃ for 2 hours. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 4/1) to give intermediate 2-2(325mg) as a grey solid. M/z [ M + H ]]⁺280.8。

And step 3: to intermediate 2-2(100mg, 0.36mmol) and N, N-To a solution of dimethylaniline (0.2mL) in 1, 4-dioxane (5mL) was added phosphorus oxychloride (2mL), and the reaction mixture was stirred at 110 ℃ for 2 hours. The reaction was quenched with water, the aqueous phase extracted with ethyl acetate, the organic phase separated and concentrated under reduced pressure to give intermediate 2-3 (crude) as a yellow solid. M/z [ M + H ]]⁺316.8。

And 4, step 4: to a solution of intermediate 2-3 (crude) and DIPEA (0.78g, 6.03mmol) in 1, 4-dioxane (5mL) was added 1-tert-butoxycarbonylpiperazine (100mg, 0.53mmol), the reaction was stirred at 50 ℃ for 2 hours, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure. The residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 3/2) to give intermediate 2-4(100mg) as a white solid. M/z [ M + H ]]⁺466.6。

Synthesis of intermediates 2-5 to 2-6

Replacing 1-tert-butoxycarbonylpiperazine in step 4 with 2-tert-butoxycarbonyl-2, 7-diazaspiro [3.5] nonane or (S) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester by using a synthesis method of an intermediate 2-4 to obtain an intermediate 2-5-2-6:

TABLE 2

Intermediates 3 to 9: synthesis of tert-butyl 4- (4-bromo-7-chloro-1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazolo [3,4-f ] quinazolin-9-yl) piperazine-1-carboxylate

Step 1: 4-bromo-6-nitro-1H-indazole (9g, 37.2mmol), iron powder (10.4g, 186mmol) and ammonium chloride (10g, 186mmol) were added to a mixed solution of water (30mL) and ethanol (130mL), respectively, and the resulting mixture was stirred at 80 ℃ for 2 hours. Filtering, concentrating the filtrate under reduced pressureThe residue was purified by Flash column chromatography (dichloromethane/methanol ═ 1/1) to give intermediate 3-1(7.0g) as a yellow solid. M/z [ M + H ]]⁺213.8。

Step 2: to a solution of chloral hydrate (3.9g, 23.6mmol), concentrated hydrochloric acid (5mL), anhydrous sodium sulfate (13.4g, 94.3mmol) in water (50mL) was added a solution of intermediate 3-1(2.5g, 11.8mmol) in DMF (25 mL). After stirring the resulting mixture at 90 ℃ for 30 minutes, hydroxylamine hydrochloride (4.9g, 70.7mmol) was added and stirring was continued at 90 ℃ overnight. The reaction was quenched by the addition of ice water and the resulting mixture was stirred for a further 15 minutes, filtered and the filter cake washed with water and dried under vacuum to give intermediate 3-2(2.9g) as a yellow solid. M/z [ M + H ]]⁺284.5。

And step 3: a solution of intermediate 3-2(2.9g, 10.2mmol) in concentrated sulfuric acid (20mL) was stirred at 60 ℃ for 1.5 h, then added carefully to ice water, the reaction mixture was filtered, and the filter cake was washed with water and dried under vacuum to give intermediate 3-3(2.7g) as a brown solid. M/z [ M + H ]]⁺267.8。

And 4, step 4: to a solution of intermediate 3-3(2.7g, 10.2mmol) in 1, 4-dioxane (40mL) under ice-bath conditions was added a solution of sodium hydroxide (4.1g, 102mmol) in water (5mL) followed by dropwise addition of 30% hydrogen peroxide (5.8g, 50.7 mmol). After the addition, the reaction solution was warmed to room temperature and stirred for 1.5 hours, the reaction was quenched with a saturated aqueous solution of sodium thiosulfate (2mL), and the mixture was concentrated under reduced pressure and purified by Flash column chromatography (acetonitrile/10 mmol/L aqueous ammonium bicarbonate solution ═ 20%) to give intermediate 3-4(2.0g) as a yellow solid. M/z [ M + H ]]⁺257.8。

And 5: HATU (1.6g, 6.3mmol) was added to a solution of intermediate 3-4(1.6g, 6.3mmol), ammonium chloride (3.3g, 62.5mmol) and DIPEA (2.4g, 18.8mmol) in DMF (50mL) under ice-bath conditions, the resulting mixture was stirred at room temperature for 2 days, water (10mL) was added to quench the reaction, and the reaction was purified by Flash column chromatography (30% acetonitrile in aqueous ammonium bicarbonate) to give intermediate 3-5(630mg) as a pale yellow solid. M/z [ M + H ]]⁺256.8。

Step 6: stirring intermediate 3-5(300mg, 1.2mmol) and urea (3.5g, 58.8mmol) at 180 deg.C for 2 hr, cooling to 80 deg.C, adding water (15mL), stirring for 5 min, filtering the reaction mixtureThe filter cake was washed with water and dried in vacuo to give intermediate 3-6(330mg) as a pale yellow solid. M/z [ M + H ]]⁺280.8。

And 7: to a solution of intermediate 3-6(330mg, 1.2mmol) in phosphorus oxychloride (35mL) under ice-bath conditions was added N, N-dimethylaniline (3mL) and the resulting mixture was stirred at 100 ℃ overnight. The reaction mixture was concentrated under reduced pressure, the residue was diluted with ethyl acetate and washed with ice water, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether: 15/1) to give intermediate 3-7(196mg) as a pale yellow solid. M/z [ M + H ]]⁺319.0。

And 8: a solution of intermediate 3-7(196mg, 0.6mmol), DIPEA (239mg, 1.9mmol), 1-tert-butoxycarbonylpiperazine (138mg, 0.7mmol) in tetrahydrofuran (15mL) was stirred at room temperature for 30 minutes, then the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether ═ 1/3) to give intermediate 3-8(226mg) as a pale yellow solid. M/z [ M + H ]]⁺467.0。

And step 9: to a solution of intermediate 3-8(226mg, 0.5mmol) and p-toluenesulfonic acid (9mg, 0.05mmol) in tetrahydrofuran (5mL) was added 3, 4-dihydro-2H-pyran (61mg, 0.7 mmol). The reaction mixture was stirred at room temperature for 2 hours, then ethyl acetate was added to dilute the mixture, the organic phase was washed with water, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether: 13/1) to give intermediate 3-9(230mg) as a pale yellow solid. M/z [ M + H ]]⁺551.2。

Intermediates 4 to 5: synthesis of 2- ((S) -1-acryloyl-4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile

Step 1: to a solution of intermediate 2-3(1.1g, 3.56mmol) and DIPEA (14.1g, 109mmol) in 1, 4-dioxane (60mL) was added a solution of (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (0.86g, 4.43mmol) in acetonitrile (10 mL). The reaction solution was stirred at 50 deg.CAfter stirring for 2 hours, the reaction was quenched with water, the aqueous phase was extracted with dichloromethane, the organic phase was separated and concentrated under reduced pressure to give intermediate 4-1 (crude) as a yellow oil. M/z [ M + H ]]⁺406.0。

Step 2: to a solution of intermediate 4-1 (crude) in 1, 4-dioxane (50mL) was added (Boc)₂O (3.9g, 17.8 mmol). The reaction solution was stirred at room temperature for 12 hours, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 1/1) to give intermediate 4-2(810mg) as a yellow solid. M/z [ M + H ]]⁺506.0。

And step 3: a mixture of intermediate 4-2(800mg, 1.58mmol), N-methyl-L-prolinol (1.63g, 14.2mmol), cesium carbonate (2.32g, 7.11mmol) and DIPEA (3.68g, 28.5mmol) in 1, 4-dioxane (15mL) was placed in a sealed tube, bubbled with nitrogen for 2-3 minutes, and the resulting mixture was heated to 130 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, extracted with ethyl acetate, the organic phase was separated, and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 9/1) to give intermediate 4-3(360mg) as a yellow oil. M/z [ M + H ]]⁺585.2。

And 4, step 4: a mixed solution of intermediate 4-3(110mg, 0.19mmol) in dichloromethane (5mL) and trifluoroacetic acid (0.5mL) was stirred at room temperature for 3 hours, and then concentrated under reduced pressure to give intermediate 4-4 (crude) as a yellow oil. M/z [ M + H ]]⁺485.2。

And 5: a solution of acrylic anhydride (39mg, 0.31mmol) in dry dichloromethane (1mL) was added dropwise to a solution of intermediate 4-4 (crude) and DIPEA (0.5mL) in dry dichloromethane (6mL) under ice-bath conditions. The reaction mixture was stirred at room temperature for 6 hours, quenched with water, the aqueous phase extracted with ethyl acetate, the organic phase separated and concentrated under reduced pressure, and the residue purified by Flash column chromatography (dichloromethane/methanol-8/1) to give intermediate 4-5(70mg) as a yellow oil. M/z [ M + H ]]⁺539.2。

Intermediates 4 to 7: synthesis of 1- ((S) -4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one

Step 1: to a solution of intermediate 2-3(0.35g, 1.06mmol) and tert-butyl (S) -3-methylpiperazine-1-carboxylate (0.32g, 1.59mmol) in 1, 4-dioxane (15mL) was added DIPEA (2.35g, 18.2 mmol). The reaction solution was stirred at 50 ℃ for 3 hours, quenched with water, the aqueous phase extracted with ethyl acetate, the organic phase separated and concentrated under reduced pressure, and the residue purified by Flash column chromatography (petroleum ether/ethyl acetate 3/1) to give intermediate 4-6(290mg) as a yellow solid. M/z [ M + H ]]⁺481.0。

Step 2-4: by using the synthesis method of the step 3-5 of the intermediate 4-5, the intermediate 4-6 is used for reaction to obtain 4-7 which is yellow oily matter. M/z [ M + H ]]⁺514.2。

Synthesis of intermediate 4-8-4-15

Replacing N-methyl-L-prolinol in the step 3 with (R) -1-morpholinopropan-2-ol, (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol, ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol, (S) - (1- (2, 2-difluoroethyl) pyrrolidin-2-yl) methanol, (S) - (1- (2-fluoroethyl) pyrrolidin-2-yl) methanol, and 6-methylpyridin-3-ol to obtain intermediates 4-8 to 4-13 by using a synthesis method of an intermediate 4-5; replacing acrylic anhydride in the step 5 with methacrylic anhydride to obtain an intermediate 4-14; replacing tert-butyl (S) -3-methylpiperazine-1-carboxylate in step 1 with tert-butyl (3S,5S) -3, 5-dimethylpiperazine-1-carboxylate gives intermediates 4 to 15:

TABLE 3

Intermediate 5-3: synthesis of (S) -2- (1-acryloyl-4- (4-bromo-7- (3- (diethylamino) azetidin-1-yl) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile

Step 1: to a solution of intermediate 4-2(173mg, 0.34mmol) in 1, 4-dioxane (10mL) was added N, N-diethylazetidin-3-amine hydrochloride (137mg, 0.68mmol) and DIPEA (0.2mL, 1.02mmol), the reaction solution was microwave-reacted at 120 ℃ for 1.5 hours, then the reaction solution was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 10/1) to give intermediate 5-1(142mg) as a pale yellow solid. M/z [ M + H ]]⁺598.2。

Step 2&3: and (3) reacting the intermediate 5-1 by using the intermediate 4-5 and the synthesis method of the step 4-5 to obtain 5-3 brown oily matter. M/z [ M + H ]]⁺552.2。

Intermediate 6-1: synthesis of 2- ((S) -4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile

Step 1& 2: same as intermediate 4-5, step 3& 4.

And step 3: triethylamine (0.23mL, 1.6mmol), 2-fluoroacrylic acid (36mg, 0.4mmol), and 1-propylphosphoric anhydride (50% ethyl acetate solution, 0.6mmol) were added to a solution of intermediate 4-4(100mg, 0.2mmol) in anhydrous ethyl acetate (3mL), respectively, under ice-bath conditions. After the reaction mixture was stirred at 0 ℃ for 0.5 hour, the reaction was quenched by the addition of saturated aqueous sodium bicarbonate (20mL), the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 20/1) to give intermediate 6-1(90mg) as a yellow solid. M/z [ M + H ]]⁺557.2。

Synthesis of intermediates 6-2 to 6-16

Synthesis method utilizing intermediate 6-1, wherein N-methyl-L-prolinol in step 1 is replaced by (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol, (S) - (1- (2-fluoroethyl) pyrrolidin-2-yl) methanol, ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol, ((2S,4S) -4-fluoro-1-methylpyrrolidin-2-yl) methanol or (3R,5S) -5- (hydroxymethyl) -1-methylpyrrolidin-3-carbonitrile to give 6-2, 6-4, 6-5, N-methylcyrrolidin-2-yl, 6-10 or 6-12; using the intermediate 9-10 as an initial raw material to react to obtain 6-3; replacing the 2-fluoroacrylic acid in the step (3) with 2-chloroacrylic acid, 2- (methoxymethyl) acrylic acid, 4-methoxycrotonic acid or crotonic acid to react to obtain 6-9; using intermediate 9-10 and ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol, (R) - (4-methylmorpholin-3-yl) methanol or (4-methylmorpholin-2-yl) methanol as starting materials to obtain 6-11, 6-13 or 6-14; replacing 2-fluoroacrylic acid in step 3 with 4-methoxycrotonic acid to obtain 6-15 using intermediate 9-10 as starting material; starting with intermediate 9-10 and ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol, the 2-fluoroacrylic acid in step 3 was replaced with 4-methoxycrotonic acid to give 6-16:

TABLE 4

Intermediates 6 to 18: synthesis of 2- ((S) -4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2, 3-dihydrofuro [2,3-f ] quinazolin-9-yl) -1- ((E) -4-morpholinylbut-2-enoyl) piperazin-2-yl) acetonitrile

Step 1: oxalyl chloride (1.5mL) was added to a solution of (E) -4-bromobut-2-enoic acid (170mg, 1.03mmol) in dichloromethane (5mL), and the reaction mixture was stirred at 70 ℃ for 3 hours and then directly concentrated under reduced pressure. The residue was dissolved in dichloromethane (1mL), and the above solution was added dropwise to intermediate 9-12(210mg, 0.43mmol) and pyridine (34)0mg, 4.31mmol) in dichloromethane (10mL), stirring the resulting mixture at room temperature for 1 hour, quenching the reaction by adding ice water (20mL), extracting the aqueous phase with dichloromethane, washing the organic phase with saturated brine, separating the organic phase and drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to give intermediate 6-17 (crude) as a brown oil. M/z [ M + H ]]⁺633.0。

Step 2: morpholine (183mg, 2.10mmol) was added to a solution of intermediate 6-17 (crude) in dichloromethane (10mL) under ice-bath conditions, and the reaction was stirred at room temperature for 0.5 h. The reaction mixture was directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol-4/1) to give intermediate 6-18(130mg) as a yellow oil. M/z [ M + H ]]⁺640.2。

Intermediate 7-3: synthesis of (S) -2- (4- (4-bromo-7- (3- (ethyl (2-fluoroethyl) amino) azetidin-1-yl) furo [2,3-f ] quinazolin-9-yl) -1- (2-fluoropropenyl) piperazin-2-yl) acetonitrile

Step 1: by utilizing the synthesis method of the intermediate 5-1, the intermediate 4-2 reacts with N-ethyl-N- (2-fluoroethyl) azetidin-3-amine to obtain an intermediate 7-1. M/z [ M + H ]]⁺616.2。

Step 2: hydrogen chloride (4M solution in 1, 4-dioxane, 2mL) was added dropwise to a solution of intermediate 7-1(150mg, 0.24mmol) in anhydrous 1, 4-dioxane (4mL) under ice-bath conditions, and the reaction mixture was stirred at room temperature for 2 hours after completion of the addition. The reaction solution is directly decompressed and concentrated to obtain an intermediate 7-2 (crude product) which is a light yellow solid. M/z [ M + H ]]⁺516.2。

And step 3: to a solution of intermediate 7-2 (crude) and triethylamine (0.7mL, 5.43mmol) in anhydrous ethyl acetate (10mL) was added 2-fluoroacrylic acid (97.7mg, 1.1mmol) and 1-propylphosphoric anhydride (50% in ethyl acetate, 1.63mmol) in an ice-water bath, and after the addition, the reaction was allowed to warm to room temperature and stirring was continued for 3 hours. The reaction was directly concentrated under reduced pressure, and the residue was purified by prep-TLC (100% ethyl acetate) to give intermediate 7-3(80mg) as a pale yellow solid。m/z:[M+H]⁺588.2。

Intermediate 7-5: synthesis of (S) -2- (4- (4-bromo-7- (3- (diethylamino) azetidin-1-yl) furo [2,3-f ] quinazolin-9-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile

Step 1: to a mixed solution of intermediate 4-1(397mg, 0.98mmol) in anhydrous ethyl acetate (20mL) and triethylamine (1.35mL) under ice-bath conditions were added 2-fluoroacrylic acid (353mg, 3.92mmol) and 1-propylphosphoric anhydride (50% in ethyl acetate, 6.0mmol), respectively. The reaction mixture was stirred at room temperature for 1.5 hours, the reaction was quenched with ice-water, the aqueous phase was extracted with ethyl acetate (30mL), the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 50/1) to give intermediate 7-4(332mg) as a yellow solid. M/z [ M + H ]]⁺478.2。

Step 2: a solution of intermediate 7-4(70mg, 0.146mmol), N-diethylaminoazetidine dihydrochloride (59mg, 0.292mmol) and DIPEA (189mg, 1.46mmol) in acetonitrile (20mL) was stirred at 80 ℃ for 2 hours, the reaction solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 40/1) to give intermediate 7-5(65mg) as a white solid. M/z [ M + H ]]⁺570.2。

Synthesis of intermediates 7-6

Replacing N-ethyl-N- (2-fluoroethyl) azetidin-3-amine in the step 1 with N, N-bis (2-fluoroethyl) azetidin-3-amine by using a synthesis method of an intermediate 7-4 to obtain an intermediate 7-6:

TABLE 5

Intermediate 8-5: synthesis of 2- ((S) -1-acryloyl-4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) -1H-pyrazolo [3,4-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile

Step 1&2: after a solution of intermediate 3-7(350mg, 1.09mmol), DIPEA (427mg, 3.3mmol), (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (261mg, 1.32mmol) in DMSO (15.0mL) was stirred at room temperature for 30 minutes, (Boc)₂O (478mg, 2.19mmol), the reaction was stirred at room temperature for 30 minutes, then quenched with water (50mL), the aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether ═ 1/3) to give intermediate 8-2(380mg) as a yellow solid. M/z [ M + H ]]⁺606.2。

And step 3: a mixture of intermediate 8-2(180mg, 297. mu. mol), N-methyl-L-prolinol (171mg, 1.48mmol), DIPEA (192mg, 1.48mmol) and cesium carbonate (557mg, 1.48mmol) in 1,4 dioxane (5mL) was stirred in a sealed tube at 165 ℃ for 3 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane ═ 1/3) to give intermediate 8-3(330mg) as a pale yellow solid. M/z [ M + H ]]⁺587.2。

And 4, step 4: trifluoroacetic acid (0.5mL) was slowly added dropwise to a solution of intermediate 8-3(230mg, 393. mu. mol) in dichloromethane (2.5 mL). After the reaction solution was stirred at room temperature for 2 hours, it was concentrated under reduced pressure to give intermediate 8-4 (crude product) as a brown solid. M/z [ M + H ]]⁺487.2。

And 5: to a solution of intermediate 8-4 (crude) in dichloromethane (10mL) under ice-bath conditions was added DIPEA (151mg, 1.17mmol) and acrylic anhydride (50mg, 392. mu. mol), respectively. After the reaction solution was stirred at room temperature for 5 minutes, 1 drop of ammonia was added to quench the reaction, which was then directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 1:1) to give intermediate 8-5(200mg) as a yellow solid. M/z [ M + H ]]⁺539.2。

Intermediates 9 to 13: synthesis of 2- ((S) -1-acryloyl-4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2, 3-dihydrofuro [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile

Step 1: to a solution of allyl alcohol (6.36mL, 93mmol) in anhydrous DMF (15mL) under ice-bath conditions was added sodium hydrogen (60%, 2.23g, 93mmol) and the reaction was warmed to room temperature and stirred for 1.5 h. A solution of 2-amino-4-bromo-6-fluorobenzonitrile (10g, 46.5mmol) in anhydrous DMF (5mL) was added dropwise to the reaction mixture, the resulting mixture was stirred at room temperature for 10 hours, water (500mL) was added to quench the reaction, the reaction was filtered, and the filter cake was dried under vacuum to give intermediate 9-1(11.7g) as a yellow solid. M/z [ M + H ]]⁺253.0。

Step 2: intermediate 9-1(11.7g, 46.2mmol) was added to o-dichlorobenzene (80mL), and the reaction solution was stirred at 180 ℃ for 2.5 hours and then directly purified by Flash column chromatography (petroleum ether/ethyl acetate-5/1) to give intermediate 9-2(10g) as a yellow solid. M/z [ M + H ]]⁺253.0；¹H NMR(400MHz,DMSO-d₆):δ6.63(s,1H),5.98-5.88(m,2H),5.20-5.14(m,2H),4.37(s,2H),3.53(d,J＝4.0Hz,2H)。

And step 3: pivaloyl chloride (8.0mL, 65.2mmol) was added to a solution of intermediate 9-2(6.6g, 26.1mmol), 4-dimethylaminopyridine (318mg, 2.6mmol) and pyridine (20mL) in dichloromethane (100mL) under ice-bath conditions, and the reaction was allowed to warm to room temperature slowly and stirred for 2 h. The reaction was quenched with water (100mL), the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 4/1) to give intermediate 9-3(10g) as a yellow solid. M/z [ M + H ]]⁺423.2。

And 4, step 4: after introducing ozone into a mixed solution of intermediate 9-3(10g, 23.7mmol) in dichloromethane (50mL) and methanol (50mL) at-78 ℃ for 15 minutes, residual ozone in the reaction solution was removed, sodium borohydride (13.5g, 356mmol) was added, and the reaction solution was warmed to room temperature and stirred for 30 minutes. The reaction was quenched with water (100mL), the organic phase separated, washed with dilute hydrochloric acid (1M, 20mL) and concentrated under reduced pressure to give intermediate 9-4(8.0g) as a yellow solid. m/z [ 2]M+H]⁺343.0。

And 5: to a solution of intermediate 9-4(8.0g, 23.4mmol), triphenylphosphine (7.4g, 28.1mmol) in tetrahydrofuran (150mL) was slowly added DIAD (5.54mL, 28.1mmol) under ice-bath conditions. The reaction solution was stirred at 0 ℃ for 15 minutes. Then concentrated directly under reduced pressure and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 3/1) to give intermediate 9-5(5g) as a yellow solid. M/z [ M + H ]]⁺323.0。

Step 6: intermediate 9-5(4.5g, 13.9mmol) was added to concentrated sulfuric acid (50mL) and the reaction was stirred at 50 ℃ for 24 h. The reaction mixture was slowly poured into ice water under ice bath conditions to precipitate a large amount of solid, the solid was dispersed in ethyl acetate (100mL) after filtration, an aqueous sodium hydroxide solution (10M, 10mL) was added and stirring was continued for 10 minutes, and the solid was purified by Flash column chromatography (ethyl acetate/petroleum ether/dichloromethane/═ 3/1/1) to give intermediate 9-6(2.1g) as a pale yellow solid. M/z [ M + H ]]⁺257.0。

And 7: heating intermediate 9-6(300mg, 1.17mmol) and urea (3.5g, 58.5mmol) to 180 ℃, stirring in a molten state for 2 hours, cooling to 100 ℃, adding water (15mL), stirring for 1 hour, cooling to 0 ℃, filtering, washing a filter cake with water, and drying in vacuum to obtain intermediate 9-7(330mg) as a light yellow solid. M/z [ M + H ]]⁺283.0。

And 8: intermediate 9-7(330mg, 1.17mmol) and N, N-dimethylaniline (0.5mL) were added to phosphorus oxychloride (10mL) and the reaction was stirred at 110 ℃ for 2 hours. Then directly concentrating under reduced pressure, diluting the residue with ethyl acetate, washing with ice water, separating the organic phase and concentrating under reduced pressure to obtain intermediate 9-8 (crude product) as yellow solid. M/z [ M + H ]]⁺319.0。

Step 9-13: by using the synthesis method of the intermediate 4-5, the intermediate 9-8 is used for reaction to obtain the intermediate 9-13 as yellow solid. M/z [ M + H ]]⁺541.0。

Synthesis of intermediates 9 to 14

Using the synthesis method of intermediate 9-11, replacing (S) -2- (piperazin-2-yl) acetonitrile in step 9 with (S) -2-methylpiperazine and replacing N-methyl-L-prolinol in step 11 with ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol gave intermediate 9-14:

TABLE 6

Intermediates 10 to 13: (9- (4-Acryloylpiperazin-1-yl) -4-bromo-7- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2, 3-dihydrofuro [2,3-f ] quinazolin-2-methyl) acetic acid methyl ester

Step 1: to intermediate 9-3(9.2g, 21.8mmol) in dichloromethane (160mL) under ice-bath conditions was added m-chloroperoxybenzoic acid (13.4g, 65.5mmol) in portions, and the reaction was slowly warmed to 25 ℃ and stirred for 24 hours. The reaction solution was diluted with dichloromethane, the organic phase was washed with saturated aqueous sodium carbonate solution and water, the organic phase was separated and concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 20/1) to give intermediate 10-1(8.1g) as a pale yellow solid. M/z [ M + H ]]⁺437.2。

Step 2: to a solution of intermediate 10-1(8.1g, 18.5mmol) in methanol (150mL) was added potassium carbonate solid (51.2g, 370mmol) and the reaction was stirred at 70 ℃ for 20 h. The reaction solution was cooled to room temperature, diluted with dichloromethane, filtered, the filtrate was concentrated, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 1/1) to give intermediate 10-2(4g) as a white solid. M/z [ M + H ]]⁺269.0；¹H NMR(400MHz,DMSO-d₆):δ6.41(s,1H),6.12(br.s,2H),5.09(br.s,1H),5.01-4.95(m,1H),3.66(dd,J＝3.6,12.0Hz,1H),3.54(dd,J＝3.6,12.0Hz,1H),3.05(dd,J＝7.2,15.2Hz,1H),2.87(dd,J＝7.2,15.2Hz,1H)。

And step 3: intermediate 10-2(1.2g, 4.5mmol) and aqueous potassium hydroxide (2M, 22mL) were added to ethanol (30mL) and the reaction was stirred at 90 ℃ under reflux for 12 h. Cooling the reaction liquid to 0 ℃, adjusting the pH to 5-6 by using 1M hydrochloric acid, extracting the water phase by using dichloromethane, separating the organic phase, concentrating under reduced pressure, and using a Flash column to obtain residuesPurification by chromatography (dichloromethane/methanol ═ 10/1) afforded intermediate 10-3(1.1g) as a white solid. M/z [ M + H ]]⁺287.0。

And 4, step 4: intermediate 10-3(800mg, 2.8mmol) and urea (8.4g, 140mmol) were mixed well and heated to 180 ℃ with stirring for 1.5 hours. The reaction solution was cooled to room temperature, water (15mL) was then added, followed by stirring at 100 ℃ for 1 hour, suction filtration under reduced pressure, the filtrate was extracted with an ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 5/1) to give intermediate 10-4(350mg) as a white solid. M/z [ M + H ]]⁺313.0。

And 5: acetic anhydride (0.3mL, 2.88mmol) was added to a solution of intermediate 10-4(300mg, 0.96mmol) in anhydrous pyridine (5mL), the reaction was stirred at room temperature for 5 hours and then directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 20/1) to give intermediate 10-5(310mg) as a white solid. M/z [ M + H ]]⁺355.0。

Step 6&7: a solution of intermediate 10-5(310mg, 0.87mmol) and phosphorus oxychloride (10mL) in N, N-dimethylaniline (0.5mL) was stirred at 110 ℃ for 2 h. Concentrating under reduced pressure. Ethyl acetate (50mL) was added to the residue under ice-bath conditions, followed by washing with ice water, separating the organic phase, drying over anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to give intermediate 10-6. DIPEA (2mL) was added to a solution of intermediate 10-6 and 1-tert-butoxycarbonylpiperazine (810mg, 4.35mmol) in anhydrous tetrahydrofuran (10mL) under ice-bath conditions, and the reaction was stirred at this temperature for 10 minutes. The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 3/1) to give intermediate 10-7(430mg) as a yellow solid. M/z [ M + H ]]⁺541.0。

And 8: to a solution of intermediate 10-7(420mg, 0.78mmol) in acetonitrile (10mL) under ice-bath conditions was added an aqueous solution of lithium hydroxide (1M, 7.8mL) and the reaction was stirred at this temperature for 2 hours. The aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 3/1) to give intermediate 10-8(330mg) as a yellow solid. M/z [ M + H ]]⁺499.0。

And step 9: intermediate 10-8(330mg, 0.66mmol) and imidazole (449mg, 6.60mmol) were dissolved in anhydrous pyridine (10mL), concentrated under reduced pressure, and repeated twice. After redissolving in anhydrous pyridine (10mL) under ice-bath conditions, TBSCl in anhydrous pyridine (298mg, 2mmol, 2mL) was added dropwise and the reaction was allowed to warm slowly to room temperature and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 5/1) to give intermediate 10-9(380mg) as a yellow solid. M/z [ M + H ]]⁺613.2。

Step 10&11: sodium hydrogen (26mg, 0.65mmol) was dispersed in anhydrous DMF (5mL) under ice bath conditions, a DMF solution of ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol (87mg, 0.65mmol, 0.5mL) was added dropwise under nitrogen protection, the reaction was stirred at this temperature for 0.5 h, then a DMF solution of intermediate 10-9 (80mg, 0.13mmol, 0.5mL) was added dropwise to the above reaction, and stirring was continued for 0.5 h under ice bath to give a reaction containing intermediate 10-10. The reaction solution was then diluted with ethyl acetate, the reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol-20/1) to give intermediate 10-11(83mg) as a yellow solid. M/z [ M + H ]]⁺638.2。

Step 12&13: to intermediate 10-11(83mg, 0.13mmol) in dichloromethane (5mL) was added trifluoroacetic acid (2mL) dropwise. The reaction solution is stirred for 2 hours and then decompressed and concentrated to obtain an intermediate 10-12. To a solution of intermediate 10-12 and DIPEA (0.2mL) in dry dichloromethane (2mL) under ice-bath conditions was slowly added a solution of acrylic anhydride in dichloromethane (0.5M, 0.3 mL). The reaction solution was stirred at this temperature for 10 minutes. The reaction was quenched with 1 drop of ammonia water, the mixture was directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol-30/1) to give intermediate 10-13(50mg) as a yellow solid. M/z [ M + H ]]⁺592.0。

Intermediate 11-1: 2- ((S) -4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) -1- ((E) -4- (dimethylamino) but-2-enoyl) piperazin-2-yl) acetonitrile

Step 1& 2: same as intermediate 4-7, steps 3& 4.

And step 3: to a solution of intermediate 4-4(50mg, 0.1mmol) in dry dichloromethane (5mL) was added DIPEA (90. mu.L, 0.5mmol), trans-4-dimethylaminocrotonate (33mg, 0.2mmol), and HATU (57mg, 0.15mmol), respectively. The reaction mixture was stirred at room temperature overnight, the reaction was quenched by addition of saturated aqueous sodium bicarbonate (20mL), the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 20/1) to give intermediate 11-1(40mg) as a yellow oil. M/z [ M + H ]]⁺596.2。

Synthesis of intermediates 11-2 to 11-3

Replacing N-methyl-L-prolinol in the step 1 with (S) - (4, 4-difluoro-1-methylpyrrolidin-2-yl) methanol or ((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methanol by using a synthesis method of an intermediate 11-1 to obtain intermediates 11-2-11-3;

TABLE 7

Intermediate 12-1: synthesis of 2- ((S) -4- (7- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborane-2-yl) -2, 3-dihydrofuro [2,3-f ] quinazolin-9-yl) -1- (2-fluoropropy-loyl) piperazin-2-yl) acetonitrile

Under the protection of nitrogen, addingIntermediate 6-11(100mg, 0.17mmol), pinacol diboron (86mg, 0.34mmol), potassium acetate (50mg, 0.51mmol) and PdCl₂dppf·CH₂Cl₂(14mg, 0.017mmol) of a mixture of 1, 4-dioxane (10mL) was stirred at 90 ℃ for 15 h. The reaction system was diluted with ethyl acetate, washed with water, and the organic phase was separated and concentrated under reduced pressure to give intermediate 12-1(106mg) as a yellow solid. M/z [ M + H ]]⁺625.4。

Synthesis of intermediates 12-2 to 12-3

By utilizing the synthesis method of the intermediate 12-1, the intermediate 9-11 or 9-14 is used for reaction to obtain a product 12-2-12-3:

TABLE 8

Intermediates 13 to 13: synthesis of 2- ((S) -4- (4-bromo-7- (((S) -1-methylpyrrolidin-2-yl) methoxy) isoxazolo [5,4-f ] quinazolin-9-yl) -1- (2-fluoropropoyl) piperazin-2-yl) acetonitrile

Step 1: to a solution of 2-amino-4-bromo-6-fluorobenzonitrile (23.6g, 110mmol) in anhydrous acetonitrile (370mL) were added N-iodosuccinimide (27.2g, 121mmol) and trifluoroacetic acid (25g, 220mmol) in this order, and the reaction was stirred at room temperature for 1.5 hours in the dark and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed successively with a saturated aqueous sodium hydrogen sulfite solution, a saturated aqueous sodium hydrogen carbonate solution and a saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was slurried with dichloromethane at 0 ℃ and filtered, and the filter cake was dried under vacuum to give intermediate 13-1(22.3g) as an off-white solid. M/z [ M + H ]]⁺340.8。

Step 2: bis (triphenylphosphine) palladium dichloride (4.59g, 6.54mmol) was added to a mixed solution of intermediate 13-1(22.3g, 65.4mmol), (E) -styrylboronic acid (14.5g, 98.1mmol) and potassium carbonate (18.1g, 131mmol) in toluene (200mL) and ethanol (50mL), the reaction was replaced with nitrogen 3 times, stirred at 80 ℃ overnight, cooled and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, washed with water and saturated brine, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was slurried with dichloromethane under ice bath conditions, filtered, and the filter cake was dried under vacuum to give intermediate 13-2(6.92g) as a yellow solid. M/z [ M + H ]]⁺317.0。

And step 3: hydrogen peroxide (30%, 9mL) was added dropwise to a DMSO (90mL) solution of intermediate 13-2(6.92g, 21.8mmol) and potassium carbonate (6.03g, 43.6mmol), and the reaction was stirred at room temperature for 1.5 h. Then pouring the reaction liquid into ice water, precipitating a large amount of solid, carrying out suction filtration, and carrying out vacuum drying on a filter cake to obtain an intermediate 13-3(7.03g) which is a yellow solid. M/z [ M + H ]]⁺335.0。

And 4, step 4: to a solution of intermediate 13-3(7.03g, 21mmol) in tetrahydrofuran (212mL) was added triphosgene (6.22g, 21mmol), and the reaction was stirred at room temperature overnight. Concentrating under reduced pressure, adding into ice water, adjusting pH to 8 with saturated sodium bicarbonate water solution, vacuum filtering, washing filter cake with petroleum ether, and vacuum drying to obtain intermediate 13-4(7.1g) as yellow solid. M/z [ M + H ]]⁺361.0。

And 5: intermediate 13-4(10.7g, 29.5mmol) was added to phosphorus oxychloride (106mL), followed by N, N-dimethylaniline (10.6mL) and the reaction stirred at 110 ℃ for 2 hours. The phosphorus oxychloride was removed by concentration under reduced pressure, the residue was poured into ice water, and the pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The aqueous phase was extracted with ethyl acetate/tetrahydrofuran, the combined organic phases were washed with water and saturated brine, the separated organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 13-5(11.7g) as a yellow solid. M/z [ M + H ]]⁺397.0。

Step 6: a solution of (S) -2- (piperazin-2-yl) acetonitrile dihydrochloride (5.88g, 29.7mmol) and DIPEA (10.5g, 80.9mmol) in DMF (60mL) was replaced with nitrogen under ice-bath conditions, and the medium was replaced with nitrogenA solution of intermediate 13-5(10.7g, 27.0mmol) in DMF (100mL) was added dropwise to the above reaction solution, followed by addition of (Boc)₂O (29.4g, 135mmol) and DIPEA (25.6g, 198mmol), and the reaction was stirred at room temperature overnight. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 1/1) to give intermediate 13-6(15.4g) as a yellow solid. M/z [ M + H ]]⁺586.0。

And 7: intermediate 13-6(4.72g, 8.04mmol), N-methyl-L-prolinol (2.78g, 24.1mmol), cesium carbonate (7.86g, 24.1mmol), DIPEA (5.2g, 40.2mmol) and 1, 4-dioxane (60mL) were added to a sealed tube, bubbled with nitrogen for 2-3 min, and the resulting mixture was stirred at 150 ℃ for 3 h. The reaction solution was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 10/1) to give intermediate 13-7(3.23g) as a yellow solid. M/z [ M + H ]]⁺665.2。

And 8: to a mixed solution of intermediate 13-7(2.63g, 3.95mmol) in dichloromethane (36mL) and water (6mL) were added N-methyl-N-morpholine oxide (0.93g, 7.9mmol) and potassium osmate dihydrate (0.15g, 0.4mmol), and the reaction was stirred at room temperature overnight. The reaction was quenched with 10% aqueous sodium thiosulfate (6mL), stirred for 0.5 h, the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 13-8(2.76g) as a yellow solid. M/z [ M + H ]]⁺699.2。

And step 9: to a mixed solution of intermediate 13-8(2.76g, 3.95mmol) in tetrahydrofuran (28mL) and water (21mL) was added sodium periodate (2.03g, 9.47 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was quenched with water (14mL), the aqueous phase was extracted with dichloromethane, the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 10/1) to give intermediate 13-9(2.07g) as a yellow solid. M/z [ M + H ]]⁺591.0。

Step 10: intermediate 13-9(2.07g, 3.5mmol) and hydroxylamine hydrochloride (0.49g, 7.0mmol) were mixed with ethanol (20mL) and water (10mL) under ice-bath conditionsTo the solution was added dropwise an aqueous solution (10mL) of sodium carbonate (0.37g, 3.5mmol), and the reaction system was stirred at room temperature overnight. Concentrated under reduced pressure to remove ethanol, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give intermediate 13-10(2.02g) as a yellow solid. M/z [ M + H ]]⁺606.2。

Step 11: to a solution of intermediate 13-10(2.02g, 3.3mmol) in tetrahydrofuran (100mL) under ice-bath conditions was added potassium tert-butoxide (0.56g, 5.0mmol), and the reaction was stirred at 0 ℃ for 15 minutes, then warmed to room temperature and stirred for 1.5 hours. The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 10/1) to give intermediate 13-11(0.95g) as a yellow solid. M/z [ M + H ]]⁺586.2；¹H NMR(400MHz,DMSO-d₆):δ6.25(s,1H),5.75(s,1H),4.63-4.35(m,4H),4.20-4.09(m,1H),3.92-3.65(m,4H),3.11-3.05(m,2H),2.88(s,3H),2.86-2.81(m,2H),2.24-2.14(m,1H),2.06-1.76(m,4H),1.43(s,9H)。

Step 12: a solution of hydrogen chloride in 1, 4-dioxane (4M, 2.5mL) was added dropwise to a solution of intermediate 13-11(170mg, 290. mu. mol) in dichloromethane (5mL) under ice-bath conditions, and the reaction was stirred at 0 ℃ for 1 hour. Quenching with ice water, extracting the water phase with ethyl acetate, mixing the organic phases, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain intermediate 13-12(200mg) as off-white solid. M/z [ M + H ]]⁺486.2。

Step 13: to a solution of intermediate 13-12(200mg, crude) in anhydrous DMF (5mL) was added DIPEA (0.5mL), 2-fluoroacrylic acid (99mg, 0.6mmol) and HATU (171mg, 0.45mmol), respectively. The reaction mixture was stirred at room temperature overnight, the reaction was quenched by addition of saturated aqueous sodium bicarbonate, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol-10/1) to give intermediate 13-13(120mg) as a yellow solid. M/z [ M + H ]]⁺558.0。

Intermediate 15-7: synthesis of tert-butyl (S) -4- (4-bromo-6- (2-isopropylphenyl) -7-oxo-6, 7-dihydrofuro [2,3-f ] quinazolin-9-yl) -3-methylpiperazine-1-carboxylate

Step 1: to a solution of 2, 2-ethoxyethanol (2.8g, 0.021mmol) in anhydrous tetrahydrofuran (50mL) was added sodium hydride (60%, 0.88g, 0.022mol) in portions under ice-bath conditions, and the reaction mixture was stirred at 10 ℃ for 1 hour. A solution of methyl 4-bromo-2, 6-difluorobenzoate (5g, 0.02mol) in tetrahydrofuran (10mL) was then added slowly dropwise to the reaction mixture. After the reaction system was stirred at room temperature for 2 hours, the reaction was quenched with ice water (20mL), the aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 20/1) to give intermediate 15-1(4.1g) as a colorless oil. M/z [ M + Na]⁺387.0。

Step 2: a suspension of polyphosphoric acid (11.4g, 33.7mmol) in toluene (80mL) was stirred at 60 ℃ for 30 minutes. Then, a toluene solution (20mL) of intermediate 15-1(4.1g, 11.2mmol) was added to the above suspension, the reaction was stirred at 60 ℃ for 1 hour and then concentrated under reduced pressure, the residue was diluted with ethyl acetate (50mL), the organic phase was washed with water and a saturated aqueous sodium bicarbonate solution, respectively, the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 10/1) to give intermediate 15-2(2g) as a yellow solid. M/z [ M + H ]]⁺273.0。

And step 3: a solution of intermediate 15-2(2.0g, 7.32mmol) in methanolic ammonia (7M, 10mL) was heated to 100 ℃ in a sealed tube and stirred overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 1/3) to give intermediate 15-3(1.15g) as a white solid. M/z [ M + H ]]⁺258.0。

And 4, step 4: to a solution of intermediate 15-3(630mg, 2.44mmol) in anhydrous 1, 2-dichloroethane (20mL) was added oxalyl chloride (372mg, 2.93 m) dropwisemol), the reaction solution was stirred at 80 ℃ for 2 hours. The reaction solution was then cooled in an ice-water bath, and a solution of 2-isopropylaniline (660mg, 4.88mmol) in anhydrous 1, 2-dichloroethane (5mL) was slowly added dropwise to the reaction solution. The reaction mixture was stirred at room temperature for 1 hour, the reaction was quenched with ice water (20mL), the organic phase was separated, the aqueous phase was extracted with dichloromethane (30mL), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 3/1) to give intermediate 15-4(820mg) as a white solid. M/z [ M + H ]]⁺419.0。

And 5: LiHMDS (1M in tetrahydrofuran, 4.3mL) was slowly added dropwise to a solution of intermediate 15-4(0.82g, 1.96mmol) in dry tetrahydrofuran (30mL) at-20 deg.C, the resulting mixture was slowly warmed to room temperature and stirred for 1 hour, then quenched with saturated aqueous ammonium chloride (20mL), the aqueous phase was extracted with ethyl acetate, the organic phase was separated, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, the residue was slurried with a petroleum ether/ethyl acetate solvent mixture (1/1, 30mL), filtered, and the filter cake was dried under vacuum to give intermediate 15-5(680mg) as a white solid. M/z [ M + H ]]⁺399.0。

Step 6: to a solution of intermediate 15-5(0.3g, 0.75mmol) in dry acetonitrile (30mL) was added triethylamine (455mg, 4.5mmol) and phosphorus oxychloride (691mg, 4.5mmol) in that order. The reaction mixture was stirred at 80 ℃ for 2 hours and then directly concentrated under reduced pressure to give intermediate 15-6 (crude) as a yellow solid.

And 7: to a suspension of intermediate 15-6 (crude) in acetonitrile (20mL) were added DIPEA (485mg, 3.75mmol) and tert-butyl (S) -3-methylpiperazine-1-carboxylate (180mg, 0.9mmol), respectively. The reaction mixture was stirred at 60 ℃ for 2 hours, then directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 1/1) to give intermediate 15-7(380mg) as a pale yellow solid. M/z [ M + H ]]⁺581.2。

Synthesis of intermediate 15-8-15-10

Replacing (S) -3-methylpiperazine-1-carboxylic acid tert-butyl ester with (S) -2- (cyanomethyl) piperazine-1-carboxylic acid benzyl ester or 2, 7-diazaspiro [3.5] nonane-2-carboxylic acid tert-butyl ester in step 7 by using the synthesis method of the intermediate 15-7 to obtain an intermediate 15-8 or 15-10;

replacing 2-isopropyl aniline with 2-isopropyl-4-methylpyridin-3-amine in step 4 by using a synthesis method of an intermediate 15-7 to obtain an intermediate 15-9;

TABLE 9

Synthesis of the Compounds:

example 1: synthesis of 1- (4- (4- (5-methyl-1H-indazol-4-yl) furo [2,3-f ] quinazolin-9-yl) piperazin-1-yl) prop-2-en-1-one (Compound 1-1-1)

Step 1: intermediate 1-6(120mg, 0.28mmol), (5-methyl-1H-indazol-4-yl) boronic acid (80mg, 0.45mmol), cesium carbonate (92mg, 0.28mmol) and PdCl₂dppf·CH₂Cl₂A mixture of 1, 4-dioxane (12mL) (15mg, 0.02mmol) and water (1mL) was replaced with nitrogen 3 times and the reaction was stirred at 90 ℃ for 12 h. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (100% ethyl acetate) to give compound 1A (110mg, yield: 56%) as a yellow oil. M/z [ M + H ]]⁺485.0。

Step 2: a mixture of compound 1A (110mg, 0.23mmol) in dichloromethane (10mL) and trifluoroacetic acid (1mL) was stirred at room temperature for 1 hour and concentrated under reduced pressure to give compound 1B (crude) as a yellow oil. M/z [ M + H ]]⁺385.0。

And step 3: to a solution of compound 1B (crude) and DIPEA (1mL) in dichloromethane (20mL) was added dropwise a solution of acryloyl chloride in dichloromethane (1M, 25mg, 0.28mL), and the reaction was stirred at room temperature for 30 minutes. After quenching the reaction with water and concentrating under reduced pressure, the residue was purified by prep-HPLC (condition 1) to give compound 1-1-1(33.1mg, two-step yield: 32%) as a yellow solid. M/z [ M + H ]]⁺439.0；¹H NMR(400MHz,DMSO-d₆):δ13.17(s,1H),8.77(s,1H),8.28(d,J＝2.0Hz,1H),7.70(s,1H),7.60(d,J＝8.4Hz,1H),7.51(s,1H),7.42(d,J＝8.4Hz,1H),6.94(d,J＝16.4,10.4Hz,1H),6.62(d,J＝2.0Hz,1H),6.21(d,J＝16.4,2.0Hz,1H),5.77(d,J＝10.4,2.4Hz,1H),3.90-3.85(m,4H),3.73-3.66(m,4H),2.23(s,3H)。

Example 2: synthesis of (S) -2- (1-acryloyl-4- (4- (5-amino-2-chloro-3-fluorophenyl) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 1-1-2)

Step 1: to a solution of intermediate 1-5(425mg, 1.5mmol) and triethylamine (0.62mL, 4.5mmol) in dichloromethane (10mL) was added (S) -2- (1-acryloylpiperazin-2-yl) acetonitrile hydrochloride (480mg, 2.7mmol), and the reaction solution was stirred at room temperature for 16 hours. Adding water to quench the reaction, extracting the aqueous phase with dichloromethane, combining the organic phases and drying over anhydrous sodium sulfate, filtering and concentrating. The residue was purified by Flash column chromatography (ethyl acetate/petroleum ether ═ 0% to 70%) to give compound 3A (160mg, yield: 26%) as a pale yellow solid. m/z: [ M + H ]]⁺426.0。

Step 2: under the protection of nitrogen, compound 3A (0.11g, 0.26mmol), intermediate 2(0.11g, 0.38mmol), PdCl₂dppf·CH₂Cl₂A mixed solution of water (0.8mL) (32mg, 0.04mmol) and sodium carbonate (1.0M, 0.78mL) in water (0.8mL) and 1, 4-dioxane (7mL) was reacted at 100 ℃ for 1 hour, then the reaction system was cooled to room temperature, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure and purified by prep-HPLC (condition 2) to give compound 1-1-2(36mg, yield: 28%) as an off-white solid. M/z [ M + H ]]⁺491.2；¹H NMR(400MHz,DMSO-d₆):δ8.78(s,1H),8.37(s,1H),7.66(s,1H),7.00-6.80(m,2H),6.69-6.63(m,1H),6.57(s,1H),6.23(d,J＝16.6Hz,1H),5.86-5.76(m,3H),5.60-5.120(m,1H),4.90-4.00(m,4H),3.80-3.52(m,1H),3.22-2.99(m,3H)。

Example 3: synthesis of 1- (4- (4- (5-methyl-1H-indazol-4-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methyl) furo [2,3-f ] quinazolin-9-yl) piperazin-1-yl) prop-2-en-1-one (Compound 1-2-1)

Step 1: to a solution of N-methyl-L-prolinol (159mg, 1.38mmol) in DMF (12mL) under ice-bath conditions was added sodium hydrogen (60%, 56mg, 1.38mmol) in portions, the reaction was stirred at 0 ℃ for 1 hour, then intermediate 2-4(63.5mg, 0.13mmol) was added to the above reaction solution, and the resulting mixture was stirred at room temperature for 2 hours. The reaction was quenched with ice water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 4/1) to give compound 4A (29mg, yield: 40%) as a yellow oil. M/z [ M + H ]]⁺545.8。

Step 2: compound 4A (29mg, 53.1. mu. mol), (5-methyl-1H-indazol-4-yl) boronic acid (19mg, 106. mu. mol), aqueous sodium carbonate (0.26mL, 1M) and PdCl₂dppf·CH₂Cl₂(4.5mg, 5.31. mu. mol) of a 1, 4-dioxane (4mL) mixture was placed in a microwave tube, and the reaction system was replaced with nitrogen and then subjected to a microwave reaction at 100 ℃ for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 1/1) to give compound 4B (17mg, yield: 59%) as a yellow oil.

And step 3: a solution of compound 4B (17mg, 28.5. mu. mol) in dichloromethane (5mL) and trifluoroacetic acid (0.5mL) was stirred at room temperature for 2 hours and then concentrated under reduced pressure to give compound 4C (crude) as a yellow oil. M/z [ M + H ]]⁺497.8。

And 4, step 4: to a solution of compound 4C (crude) and DIPEA (0.5mL) in dichloromethane (5mL) was added a solution of acryloyl chloride (2.8mg, 31.3. mu. mol) in dichloromethane (5mL) dropwise and the reaction was stirred at room temperature for 10 minutes. After quenching the reaction with water, it was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 4) to give compound 1-2-1(3.56mg, two-step yield: 23%) as a white solid. M/z [ M + H ]]⁺551.8；¹H NMR(400MHz,DMSO-d₆):δ13.14(s,1H),8.17(d,J＝2.0Hz,1H),7.58(d,J＝8.4Hz,1H),7.49(s,1H),7.46(s,1H),7.41(d,J＝8.4Hz,1H),6.92(dd,J＝16.4,10.4Hz,1H),6.53(d,J＝2.0Hz,1H),6.21(dd,J＝16.4,2.0Hz,1H),5.76(dd,J＝10.4,2.0Hz,1H),4.44-4.39(m,1H),4.24-4.19(m,1H),3.89-3.86(m,4H),3.61-3.72(m,4H),2.96-2.97(m,1H),2.57-2.65(m,1H),2.38(s,3H),2.23(s,3H),2.16-2.00(m,2H),1.66-1.72(m,3H)。

Example 4: synthesis of 2- ((2S) -1-acryloyl-4- (4- (5-methyl-1H-indazol-4-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 1-2-2)

Step 1: a mixture of intermediate 2-6(100mg, 0.18mmol), N-methyl-L-prolinol (238mg, 2.06mmol), cesium carbonate (268mg, 0.82mmol) and DIPEA (505mg, 3.91mmol) in 1, 4-dioxane (15mL) was placed in a sealed tube, displaced with nitrogen and stirred at 150 ℃ for 3 hours. The reaction solution was cooled to room temperature, diluted with ethyl acetate, the organic phase was washed with water, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 4/1) to give compound 6A (40mg, yield: 36%) as a yellow oil. M/z [ M + H ]]⁺619.2。

Step 2: compound 6A (40mg, 64.6. mu. mol), (5-methyl-1H-indazol-4-yl) boronic acid (57mg, 323. mu. mol), aqueous sodium carbonate (0.30mL, 1M) and PdCl₂dppf·CH₂Cl₂(5.2mg, 6.45. mu. mol) of a mixture of 1, 4-dioxane (3mL) was placed in a microwave tube, and after nitrogen substitution, the reaction was carried out by microwave at 110 ℃ for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 4/1) to give compound 6B (35mg, yield: 80%) as a yellow solid. M/z [ M + H ]]⁺671.3。

And step 3: a mixture of Compound 6B (45mg, 67.1. mu. mol) and 10% palladium on carbon (45mg) in methanol (20mL) was replaced with hydrogen gasStirred at room temperature for 2.5 hours under hydrogen atmosphere. The reaction solution was filtered through celite, and the filtrate was concentrated under reduced pressure to give compound 6C (crude) as a yellow solid. M/z [ M + H ]]⁺537.4。

And 4, step 4: to a solution of compound 6C (crude) and DIPEA (0.5mL) in dichloromethane (8mL) was added dropwise a solution of acrylic acid chloride (6.1mg, 67.1. mu. mol) in dichloromethane (2mL) and the reaction was stirred at room temperature for 3 hours. After quenching the reaction with water and concentrating under reduced pressure, the residue was purified by prep-HPLC (condition 2) to give compound 1-2-2(6mg, two-step yield: 13%) as a white solid. M/z [ M + H ]]⁺591.2；¹H NMR(400MHz,DMSO-d₆):δ13.17(s,1H),8.23(s,1H),7.59(d,J＝8.8Hz,1H),7.48-7.51(m,2H),7.41(d,J＝8.8Hz,1H),6.93-6.90(m,1H),6.55(t,J＝2.0Hz,1H),6.25(d,J＝16.8,2.0Hz,1H),5.82(d,J＝10.8Hz,1H),5.19-4.93(m,1H),4.59-4.10(m,6H),3.22-2.96(m,6H),2.42(s,3H),2.30-2.20(m,4H),1.95-2.00(m,1H),1.62-1.78(m,3H)。

Example 5: synthesis of 2- ((2S) -1-acryloyl-4- (4- (5-chloro-6-fluoro-1H-indazol-4-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile trifluoroacetate (Compound 1-2-3)

Step 1: intermediate 4-3(100mg, 0.17mmol), intermediate 3(57mg, 0.19mmol), aqueous sodium carbonate (0.85mL, 0.85mmol) and PdCl₂dppf.CH₂Cl₂(14mg, 0.017mmol) of a mixture of 1, 4-dioxane (5mL) was replaced with nitrogen gas 3 times, and the reaction system was microwave-reacted at 110 ℃ for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol-9/1) to give compound 9A (crude) as a yellow solid. M/z [ M + H ]]⁺759.4。

Step 2: the mixed solution of the compound 9A (crude product) in dichloromethane (2mL) and trifluoroacetic acid (0.5mL) is stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to obtain a compound 9B (crude product)Product) was a yellow oil. M/z [ M + H ]]⁺575.4。

And step 3: to a solution of compound 9B (crude) and DIPEA (0.5mL) in dichloromethane (3mL) was added dropwise a solution of acrylic anhydride in dichloromethane (0.1mL, 0.25M) and the reaction was stirred at room temperature for 2 hours. The reaction was quenched with water, the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 6) to give compound 1-2-3(1.65mg, three-step yield: 13%) as a yellow solid. M/z [ M + H ]]⁺629.2；¹H NMR(400MHz,DMSO-d₆):δ13.13(s,1H),8.24-8.14(m,3H),7.75(s,1H),6.71(s,1H),6.17(dd,J＝2.0,16.4Hz,1H),5.75(d,J＝10.8Hz,1H),5.25(t,J＝4.8Hz,1H),4.79-4.44(m,3H),4.25-3.68(m,5H),3.14-2.94(m,4H),2.94-2.85(m,4H),2.05-1.77(m,5H)。

Example 6: synthesis of 2- ((2S) -1-acryloyl-4- (4- (2-chloro-3-hydroxynaphthalen-1-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 1-2-4)

Step 1: under the protection of nitrogen, intermediate 4-3(26.6mg, 0.08mmol), intermediate 17(30mg, 0.06mmol), Pd (PPh)₃)₄A solution of (6.5mg, 0.006mmol) and aqueous sodium carbonate (1.0M, 0.17mL) in 1, 4-dioxane (2.0mL) was replaced with nitrogen and then reacted at 120 ℃ for 0.5 hour with a microwave. Then, the reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane 0% to 10%) to give compound 12A (24mg, yield: 67%) as a yellow solid. M/z [ M + H ]]⁺697.2。

Step 2: boron tribromide (0.2mL) was slowly added dropwise to a solution of compound 12A (5mg, 7.2. mu. mol) in tetrahydrofuran (2mL) at-40 deg.C, the reaction was slowly warmed to room temperature and stirred for 1 hour, the reaction was cooled to 0 deg.CThe reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 12B (crude) as a yellow solid. M/z [ M + H ]]⁺583.2。

And step 3: to a solution of compound 12B (crude) and triethylamine (0.05mL, 0.36mmol) in dichloromethane (1mL) under ice-bath conditions was added a solution of acryloyl chloride in dichloromethane (0.85M, 0.016mL), the reaction was stirred at room temperature for 0.5 h, the solvent was removed by concentration under reduced pressure, the residue was dissolved in acetonitrile (2mL), aqueous ammonia (1mL) was added, and the resulting mixture was stirred at room temperature for 0.5 h. The mixture was directly purified by prep-HPLC (condition 2) to give compounds 1-2-4(0.42mg, two-step yield: 9%) as a white solid. M/z [ M + H ]]⁺637.3。

Example 7: synthesis of 2- ((2S) -1-acryloyl-4- (4- (2-fluoro-6-hydroxyphenyl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 1-2-5)

By using the synthesis method of the compound 1-2-2, the (5-methyl-1H-indazol-4-yl) boronic acid in the step 2 is replaced by (2-fluoro-6-hydroxyphenyl) boronic acid, and the compound 1-2-5 is obtained by reaction. M/z [ M + H ]]⁺571.2；¹H NMR(400MHz,DMSO-d₆):δ10.17(s,1H),9.81(br.s,1H),8.26(s,1H),7.54(s,1H),7.36(dd,J＝8.4,15.2Hz,1H),6.92(d,J＝8.4Hz,1H),6.85(t,J＝9.2Hz,1H),6.77(s,1H),6.24(dd,J＝2.0,16.4Hz,1H),5.83(d,J＝10.0Hz,1H),5.20-4.95(m,1H),4.82-4.53(m,2H),4.28-4.03(m,2H),3.94-3.57(m,2H),3.41-3.23(m,2H),3.23-3.02(m,4H),3.00(s,3H),2.36-2.26(m,1H),2.16-1.87(m,4H)。

Example 8: synthesis of 2- ((2S) -1-acryloyl-4- (4- (2, 3-dichloro-5-hydroxyphenyl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile trifluoroacetate (Compound 1-2-6)

By using the synthesis method of the compound 1-2-4, the intermediate 4-3 and the intermediate 19 react to obtain the compound 1-2-6. M/z [ M + H ]]⁺621.2；¹H NMR(400MHz,DMSO-d₆):δ10.52(t,J＝5.2Hz,1H),9.83(s,1H),8.29(s,1H),7.49(s,1H),7.18-6.17(d,J＝2.8Hz,1H),6.87-6.83(m,2H),6.25-6.20(m,1H),5.83-5.80(d,J＝10.4Hz,1H),5.18(s,1H),4.93(s,1H),4.78-4.71(m,1H),4.64-4.55(m,2H),4.22-4.05(m,3H),3.89-3.85(m,4H),3.64-3.60(m,1H),3.39-3.36(m,1H),3.20-3.01(m,3H),2.38-1.88(m,4H)。

Example 9: synthesis of 2- ((S) -1-acryloyl-4- (4- (3-hydroxynaphthalen-1-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 1-3-1)

Step 1: intermediate 4-5(100mg, 0.18mmol), intermediate 1(70mg, 0.22mmol), aqueous sodium carbonate (0.90mL, 0.90mmol) and PdCl₂dppf·CH₂Cl₂(14.6mg, 0.02mmol) of a mixture of 1, 4-dioxane (9mL) was replaced with nitrogen 3 times and the reaction system was reacted with a microwave at 110 ℃ for 1 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 9/1) to give compound 8A (30mg, yield: 51%) as a yellow solid. M/z [ M + H ]]⁺647.2。

Step 2: to a solution of compound 8A (30mg, 46.4. mu. mol) in 1, 4-dioxane (2mL) was added a solution of hydrogen chloride in 1, 4-dioxane (0.2mL, 4M), the reaction solution was stirred at room temperature for 1 hour and then concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 3) to give compound 1-3-1(12.0mg, yield: 43%) as a yellow solid. M/z [ M + H ]]⁺603.4；¹H NMR(400MHz,DMSO-d₆):δ10.00(s,1H),8.22(s,1H),7.84(d,J＝8.4Hz,1H),7.52-7.43(m,3H),7.29(d,J＝2.0Hz,1H),7.22-7.17(m,2H),6.96(br.s,1H),6.55(d,J＝2.0Hz,1H),6.25(dd,J＝2.0,2.4Hz,1H),5.82(d,J＝10.8Hz,1H),5.19-4.95(m,1H),4.58-4.40(m,2H),4.26-4.11(m,4H),3.86-3.81(m,1H),3.22-2.98(m,4H),2.69-2.61(m,1H),2.39(s,3H),2.22-2.18(m,1H),2.01-1.96(m,1H),1.73-1.65(m,3H)。

Example 10: synthesis of 2- ((S) -1-acryloyl-4- (4- (2-chloro-3-fluoro-5-hydroxyphenyl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 1-3-2)

By utilizing the synthesis method of the compound 1-3-1, the intermediate 1 in the step 1 is replaced by the intermediate 16 to react to obtain the compound 1-3-2. M/z [ M + H ]]⁺605.2；¹H NMR(400MHz,DMSO-d₆):δ10.45(s,1H),8.26(s,1H),7.46(s,1H),6.94-6.91(m,2H),6.83-6.82(m,1H),6.78-6.75(m,1H),6.24-6.19(m,1H),5.81-5.78(m,1H),4.42-4.38(m,1H),4.24-4.19(m,2H),4.17-4.12(m,1H),4.05-3.99(m,1H),3.03-2.94(m,3H),2.62-2.56(m,2H),2.38(s,3H),2.21-2.15(m,2H),2.02-1.92(m,2H),1.73-1.63(m,4H)。

Example 11: synthesis of 2- ((2S) -1-acryloyl-4- (4- (2-amino-3, 5-dichloro-6-fluorophenyl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 1-4-1)

Intermediate 4-5(70mg, 0.13mmol), intermediate 32(58mg, 0.26mmol), aqueous sodium carbonate (1M, 0.65mL, 0.5mmol) and PdCl₂dppf·CH₂Cl₂(11mg, 0.013mmol) of a mixture of 1, 4-dioxane (5mL) was replaced 3 times with nitrogen and the reaction system was microwaved at 110 ℃ for 1 hour. Quenching the reaction with water, extracting the aqueous phase with ethyl acetate, separating the organic phase and washing with saturated brine, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, subjecting the residue to prep-HPLCIsolation condition 5) to give compound 1-4-1(7.71mg, yield: 10%) as an off-white solid. M/z [ M + H ]]⁺638.2；¹H NMR(400MHz,DMSO-d₆):δ8.29(d,J＝14.4Hz,1H),7.66(d,J＝8.4Hz,1H),7.57-7.49(m,1H),7.00(br.s,1H),6.77(s,1H),6.25(dd,J＝2.0,16.8Hz,1H),5.82(d,J＝11.2Hz,1H),5.36-5.31(m,2H),5.21-4.39(m,1H),4.26-4.03(m,4H),3.13-2.93(m,5H),2.68-2.61(m,1H),2.39-2.31(m,4H),2.21-2.19(m,1H),2.03-1.91(m,2H),1.76-1.61(m,3H)。

Example 12: synthesis of (S) -2- (1-acryloyl-4- (4- (5-amino-2-chloro-3-fluorophenyl) -7- (3- (diethylamino) azetidin-1-yl) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile trifluoroacetate (Compound 1-4-2)

Intermediate 5-3(28mg, 0.05mmol), intermediate 2(27mg, 0.10mmol), aqueous sodium carbonate (1M, 0.15mL) and Pd (PPh)₃)₄(5.8mg, 0.005mmol) of a mixture of 1, 4-dioxane (5mL) was bubbled with nitrogen for 1-2 minutes and the reaction system was microwaved at 120 ℃ for 0.5 hour. The reaction was quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (separation condition 6) to give compound 1-4-2(7.08mg, yield: 24%) as an off-white solid. M/z [ M + H ]]⁺617.2；¹H NMR(400MHz,DMSO-d₆):δ8.22(s,1H),7.36(s,1H),7.24-6.98(m,1H),6.98-6.91(m,1H),6.81(s,1H),6.66-6.62(s,1H),6.51(s,1H),6.24-6.60(d,J＝16.0Hz,1H),5.82-5.79(d,J＝12.0Hz,1H),4.47-4.38(m,4H),3.75(m,10H),3.21(m,5H),1.23-1.20(m,6H)。.

Example 13: synthesis of compound 1-4-3-1-4-90

Using the synthesis method of the compound 1-4-1 or 1-4-2, a compound obtained by reacting an intermediate 2, (3-fluoro-5-hydroxyphenyl) boronic acid, an intermediate 4, 5-amino-2-methylphenylboronic acid pinacol ester, an intermediate 5, 10, 6,7, 11, 5-amino-2-fluorophenylboronic acid pinacol ester, a 4-amino-2-chlorophenylboronic acid pinacol ester, an intermediate 8, 9, (2-fluoro-4-hydroxyphenyl) boronic acid, (2-chloro-5-hydroxyphenyl) boronic acid, 2-fluoro-4-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxolan-2-yl) aniline, (2, 3-difluoro-4-hydroxyphenyl) boronic acid, (3-chloro-4-hydroxyphenyl) boronic acid, (2-chloro-4-hydroxyphenyl) boronic acid, intermediate 12, (5-amino-2, 3-difluorophenyl) boronic acid, intermediate 33, 14, (2-chloro-5-methoxyphenyl) boronic acid, (2,3, 5-trichlorophenyl) boronic acid, intermediate 23, (5-amino-2-chlorophenyl) boronic acid, (3-chloro-5- (trifluoromethyl) phenyl) boronic acid, (5-chloro-2-methylphenyl) boronic acid, (5-fluoro-2-methylphenyl) boronic acid, intermediate 20, (2-chloro-5- (trifluoromethyl) phenyl) boronic acid, p, Reacting the intermediate 21, (2, 5-dichlorophenyl) boric acid, the intermediate 22, 24, 25 or 26 and 4-5 to obtain a compound 1-4-3-1-4-40; reacting the intermediate 27 with 4-10 to obtain a compound 1-4-41; reacting the intermediate 6-5 with (2,3, 5-trichlorophenyl) boric acid and the intermediate 15 or 4-hydroxy-2-trifluoromethyl phenylboronic acid pinacol ester to obtain a compound 1-4-42-1-4-44; respectively reacting the intermediate 7-6, 6-7, 4-11, 4-12, 6-1, 6-2, 4-7, 7-3, 6-4, 4-8, 6-5, 4-9, 11-1, 4-10, 4-14, 6-6 or 6-9 with the intermediate 2 to obtain a compound 1-4-45-1-4-61; respectively reacting (2-chloro-5-hydroxyphenyl) boric acid, intermediates 6, 33, 8, 15 and 20 and an intermediate 6-4 to obtain a compound 1-4-62-1-4-67; respectively reacting the intermediate 11-1, 4-15, 6-5, 6-7, 6-1, 6-2, 6-8, 6-6, 11-2, 6-10, 11-3, 6-12, 4-9 or 4-10 with the intermediate 20 to obtain a compound 1-4-68-1-4-81; reacting the intermediate 7-5, 6-5 or 6-1 and 6 to obtain a compound 1-4-82-1-4-84; reacting the intermediate 6-5 with 27 or 28 to obtain a compound 1-4-85-1-4-86; reacting the intermediate 28 with 6-1 or 6-8 to obtain a compound 1-4-87-1-4-88; respectively reacting the intermediate 4-12 or 4-13 with the intermediate 15 to obtain a compound 1-4-89-1-4-90:

watch 10

Example 14: synthesis of 2- ((S) -1-acryloyl-4- (4- (2-amino-5-chloropyridin-4-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile trifluoroacetate (Compound 1-5-1)

Using the synthetic method of compound 1-4-2, intermediate 4-5 and 18 are reacted to give compound 13A.

To a solution of compound 13A (40mg, 0.05mmol) in dichloromethane (3mL) was added trifluoroacetic acid (1mL), and the reaction was stirred at room temperature for 1 hour. Then, the mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 8) to give compound 1-5-1(5.95mg, yield: 14%) as a pale yellow solid. M/z [ M + H ]]⁺587.2。

Example 15: synthesis of 2- ((S) -1-acryloyl-4- (4- (5-amino-2-chloro-3-fluorophenyl) -7- (((S) -4, 4-difluoropyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) piperazin-2-yl) ethyl trifluoroacetate (Compound 1-5-2)

Step 1: a solution of intermediate 4-6(0.1g, 0.2mmol) and trifluoroacetic acid (1mL) in dichloromethane (1mL) was stirred at 40 ℃ for 1 hour. The reaction was then concentrated, and the residue was dissolved in dichloromethane (5mL) and adjusted to neutral pH with triethylamine. Acryloyl chloride (0.8M in methylene chloride, 0.5mL) was added to the above solution, and the resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether ═ 0 to 60%) to give compound 16A (80mg, yield: 91%) as a pale yellow solid. M/z [ M + H ]]⁺460.0。

Step 2: a solution of compound 16A (50.0mg, 0.11mmol), (S) -4, 4-difluoro-2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester (116mg, 0.50mmol), DIPEA (40.7mg, 0.33mmol) and cesium carbonate (0.64g, 1.98mmol) in 1, 4-dioxane (1mL) was stirred at 110 deg.C for 2 hours. The reaction solution was then concentrated, and the residue was purified by Flash column chromatography (ethyl acetate/petroleum ether ═ 0 to 70%) to give compound 16B (30mg, yield: 42%) as a yellow oil. M/z [ M + H ]]⁺661.4。

And step 3: compound 16B (30mg, 4.5. mu. mol), intermediate 2(18mg, 0.06mmol), Pd (PPh)₃)₄(5.2mg, 4.5. mu. mol) and a 1, 4-dioxane (1.5mL) solution of aqueous sodium carbonate (1.0M, 0.14mL) were reacted at 120 ℃ for 0.5 hour with a microwave. The reaction solution was cooled to room temperature, directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane ═ 0 to 10%) to give compound 16C (15mg, yield: 45%) as a yellow solid. M/z [ M + H ]]⁺726.4。

Step 2: to a solution of compound 16C (15mg, 0.02mmol) in dichloromethane (1mL) was added trifluoroacetic acid (1mL), and the reaction was stirred at room temperature for 1 hour. Then, the mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to give compound 1-5-2(0.72mg, yield: 6%) as a pale yellow solid. M/z [ M + H ]]⁺626.2。

Example 16: synthesis of Compound 1-5-3-1-5-4

Replacing (S) -4, 4-difluoro-2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester in step 2 with (2S,4R) -4-fluoro-2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester or (S) -4- (difluoromethylene) -2- (hydroxymethyl) pyrrolidine-1-carboxylic acid tert-butyl ester by using a synthesis method of a compound 1-5-2 to obtain a compound 1-5-3-1-5-4:

TABLE 11

Example 17: synthesis of 1- (7- (4- (5-methyl-1H-indazol-4-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) -2, 7-diazaspiro [3.5] nonan-2-yl) prop-2-en-1-one (Compound 1-6-1)

By using the synthesis method of the compound 1-2-4, the compound 1-6-1 is obtained by reacting the intermediate 2-5. M/z [ M + H ]]⁺592.4；¹H NMR(400MHz,DMSO-d₆):δ13.16(s,1H),8.15(s,1H),7.58(d,J＝8.4Hz,1H),7.51(s,1H),7.44(s,1H),7.40(d,J＝15.6Hz,1H),6.52(s,1H),6.39(dd,J＝17.2,10.4Hz,1H),6.15(d,J＝16.8Hz,1H),5.70(d,J＝10.8Hz,1H),4.43-4.38(m,1H),4.22-4.17(m,1H),4.06(s,2H),3.77(s,2H),3.52-3.65(m,4H),2.95-2.97(m,1H),2.57-2.60(m,1H),2.37(s,3H),2.23(s,3H),2.15-2.19(m,1H),1.92-1.99(m,5H),1.63-1.70(m,3H).

Example 18: synthesis of 1- (4- (4- (3-hydroxynaphthalen-1-yl) -7- (6-methylpyridin-3-yl) furo [2,3-f ] quinazolin-9-yl) piperazin-1-yl) prop-2-en-1-one (Compound 1-7-1)

Step 1: intermediate 4-2(200mg, 0.39mmol), intermediate 1(118mg, 0.37mmol), aqueous sodium carbonate (1.95mL, 1M) and Pd (PPh)₃)₄(45mg, 0.04mmol) of a mixture of 1, 4-dioxane (20mL) was placed in a microwave tube, and after the reaction system was replaced with nitrogen, the reaction system was reacted with a microwave at 90 ℃ for 5 hours. The reaction solution was then cooled to room temperature and quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phases were combined and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 3/2) to give compound 17A (240mg, yield: 100%) as a yellow solid. M/z [ M + H ]]⁺614.2。

Step 2: compound 17A (220mg, 0.36mmol), (6-methylpyridin-3-yl) boronic acid (128mg, 0.93mmol), aqueous sodium carbonate (1.8mL, 1M) and Pd (PPh)₃)₄(86mg, 0.09mmol) of a 1, 4-dioxane (20mL) mixture was placed in a microwave tube, and the reaction system was replaced with nitrogen and then subjected to a microwave reaction at 90 ℃ for 5 hours. The reaction solution was then cooled to room temperature and quenched with water, the aqueous phase was extracted with ethyl acetate, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate 4/1) to give compound 17B (230mg, yield: 87%) as a yellow solid. M/z [ M + H ]]⁺671.2。

And step 3: a mixture of compound 17B (120mg, 0.18mmol) in methanol (10mL) and hydrochloric acid (1mL, 1M) was stirred at 50 ℃ for 3 hours and then directly concentrated under reduced pressure to give compound 17C (75mg, yield: 79%) as a yellow solid. M/z [ M + H ]]⁺527.2。

And 4, step 4: to a solution of compound 17C (75mg, 0.14mmol) and DIPEA (0.5mL) in dichloromethane (5mL) was added dropwise acrylic anhydride (0.6mL, 0.5M in dichloromethane) and the reaction was stirred at room temperature for 3 hours. The reaction was quenched with aqueous ammonia (5mL), the resulting mixture was stirred at room temperature for 2 hours, then directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 5) to give compound 1-7-1(7.12mg, yield: 9%) as a white solid. M/z [ M + H ]]⁺581.2；¹H NMR(400MHz,DMSO-d₆):δ10.07(br.s,1H),9.54(d,J＝1.2Hz,1H),8.71(dd,J＝1.6,8.0Hz,1H),8.33(s,1H),7.86-7.82(m,2H),7.55-7.42(m,3H),7.31(d,J＝2.0Hz,1H),7.22-7.20(m,2H),6.96(dd,J＝2.4,14.0Hz,1H),6.63(d,J＝2.0Hz,1H),6.25(dd,J＝2.0,16.4Hz,1H),5.83(d,J＝10.4,1H),5.30-5.00(m,1H),4.62-4.18(m,3H),3.90-3.51(m,2H),3.29-3.06(m,3H),2.57(s,3H).

Example 19: synthesis of 2- ((S) -4- (4- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) furo [2,3-f ] quinazolin-9-yl) -1- (2-fluoroacryloyl) piperazin-2-yl) acetonitrile trifluoroacetate (Compound 1-8-1)

Step 1: under the protection of nitrogen, intermediate 6-1(130mg, 0.23mmol), pinacol diboron (120mg, 0.47mmol) and PdCl₂dppf·CH₂Cl₂A solution of (38mg, 0.05mmol) and potassium acetate (68mg, 0.69mmol) in 1, 4-dioxane (5mL) was stirred at 100 ℃ for 16 h. The reaction was cooled to room temperature and diluted with ethyl acetate (50mL), washed with brine, the organic phase was separated and concentrated under reduced pressure to give compound 18A (crude) as a yellow solid. M/z [ M + H ]]⁺605.2。

Step 2: to a solution of compound 18A (crude) in 1, 4-dioxane (7mL) was added 6-chloro-4-methyl-5- (trifluoromethyl) pyridin-2-amine (70mg, 0.33mmol), Pd (PPh) in that order₃)₄(53mg, 0.046mmol) and aqueous sodium carbonate (1.0M, 0.7 mL). The reaction system was purged with nitrogen for 2 minutes and subjected to microwave reaction at 120 ℃ for 0.5 hour. The reaction system was cooled to room temperature, diluted with ethyl acetate (50mL), washed with brine, the organic phase was separated and concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 6) to give compound 1-8-1(4.3mg, yield: 3%) as a white solid. M/z [ M + H ]]⁺653.2；¹H NMR(400MHz,DMSO-d₆):δ8.22(d,J＝2.4Hz,1H),7.31(s,1H),6.77(s,2H),6.75(d,J＝2.0Hz,1H),6.49(s,1H),5.45-4.52(m,4H),4.41-4.37(m,1H),4.23-4.13(m,3H),4.02-3.99(m,1H),3.13-3.06(m,2H),3.02-2.96(m,1H),2.65-2.56(m,1H),2.39(s,3H),2.39(s,3H),2.25-2.15(m,1H),2.03-1.93(m,1H),1.71-1.62(m,3H),1.28-1.23(m,2H)。

Example 20: synthesis of Compound 1-8-2-1-8-5

By utilizing a compound 1-8-1 synthesis method, reacting an intermediate 6-1, 6-10 or 6-8 with corresponding amine respectively to obtain a compound 1-8-2-1-8-5:

TABLE 12

Example 21: synthesis of 1- (4- (4- (5-methyl-1H-indazol-4-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) -1H-pyrazolo [3,4-f ] quinazolin-9-yl) piperazin-1-yl) prop-2-en-1-one (Compound 2-1-1)

Step 1: a solution of intermediate 3-9(106mg, 0.2mmol), N-methyl-L-prolinol (111mg, 0.8mmol), DIPEA (250mg, 0.4mmol) and cesium carbonate (188mg, 0.5mmol) in 1,4 dioxane (2.5mL) was stirred in a sealed tube at 170 ℃ for 3 hours. The reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane ═ 1/3) to give compound 7A (115mg, yield: 95%) as a pale yellow solid. M/z [ M + H ]]⁺632.3。

Step 2: compound 7A (46.8mg, 74.2. mu. mol), 5-methyl-1- (tetrahydro-2H-pyran-2-yl) -4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-indazole (30.5mg, 89.1. mu. mol), PdCl₂dppf·CH₂Cl₂(6mg, 7.3. mu. mol), 1,4 dioxane (25mL) mixture of aqueous sodium carbonate (1M, 222. mu. mol) was replaced with nitrogen 3 times. The reaction system was stirred at 100 ℃ for 3 hours, then cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (methanol/dichloromethane ═ 1/6) to give compound 7B (40.3mg, yield: 71%) as a pale yellow solid.

And step 3: to a solution of compound 7B (40.3mg, 52.6. mu. mol) in dichloromethane (5mL) was added trifluoroacetic acid (1mL) dropwise. Stirring the reaction solution at room temperature for 5 hours, and then concentrating the reaction solution under reduced pressure to obtain the productCompound 7C (crude) was a brown solid. M/z [ M + H ]]⁺498.3。

And 4, step 4: to a solution of compound 7C (crude) in dichloromethane (3mL) was added DIPEA (17.1mg, 133. mu. mol) and acrylic anhydride (5.6mg, 44.2. mu. mol), respectively, under an ice-water bath. After the reaction solution was stirred at room temperature for 5 minutes, 1 drop of ammonia was added to quench the reaction, and the resulting mixture was concentrated under reduced pressure and purified by prep-HPLC (condition 2) to give compound 2-1-1(3.01mg, two-step yield: 12%) as a white solid. M/z [ M + H ]]⁺552.3；¹H NMR(400MHz,DMSO-d₆):δ13.28(s,1H),13.16(s,1H),7.64(s,1H),7.58(d,J＝8.8Hz,1H),7.51(s,1H),7.41(d,J＝8.8Hz,1H),7.26(s,1H),6.91-6.85(m,1H),6.19(dd,J＝16.4,2.0Hz,1H),5.77-5.73(m,1H),4.47-4.44(m,2H),3.89-3.84(m,4H),3.69-3.59(m,4H),3.31(s,3H),2.26(s,3H),1.74-1.65(m,4H),1.26-1.22(m,3H)。

Example 22: synthesis of 2- ((S) -1-acryloyl-4- (4- (5-amino-2-chloro-3-fluorophenyl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) -1H-pyrazolo [3,4-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (compound 2-1-2)

Intermediate 8-5(30mg, 55.6. mu. mol), intermediate 2(30mg, 111. mu. mol), Pd (PPh)₃)₄(5mg, 5.5. mu. mol), aqueous sodium carbonate (1M, 17.7mg, 167. mu. mol) was added to 1,4 dioxane (25mL), respectively. The reaction mixture was subjected to a microwave reaction at 130 ℃ for 0.5 hour after displacement with nitrogen, the reaction mixture was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 2) to give compound 2-1-2(1.18mg, yield: 3%) as a white solid. M/z [ M + H ]]⁺604.3；¹H NMR(400MHz,DMSO-d₆):δ9.73(s,1H),7.84-7.77(m,2H),7.63-7.56(m,1H),7.22-7.20(m,1H),6.89(s,2H),6.65-6.58(m,2H),6.24-6.20(m,1H),5.81-5.73(m,1H),4.25-4.20(m,4H),3.30(s,3H),3.31(s,3H),2.13-2.09(m,4H),2.03-1.91(m,4H),1.26-1.22(m,2H)。

Example 23: synthesis of 2- ((S) -1-acryloyl-4- (4- (5-amino-2-chloro-3-fluorophenyl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2, 3-dihydrofuro [3,4-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile (Compound 3-1-1)

Intermediate 9-9(40mg, 74.2. mu. mol), intermediate 2(25mg, 89. mu. mol), PdCl₂dppf·CH₂Cl₂(6mg, 7.4. mu. mol), aqueous sodium carbonate (1M, 0.5mL) was added to 1,4 dioxane (4mL), respectively. The reaction mixture was subjected to a microwave reaction at 120 ℃ for 1 hour after displacement with nitrogen, the reaction mixture was cooled to room temperature and then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 5) to give compound 3-1-1(3mg, yield: 12%) as a pale yellow solid. M/z [ M + H ]]⁺606.3；¹H NMR(400MHz,DMSO-d₆):δ6.95(s,1H),6.93-6.83(m,2H),6.58(dd,J＝2.0,12.0Hz,1H),6.43(s,1H),6.21(dd,J＝2.0,12.0Hz,1H),5.80(d,J＝10.8Hz,1H),5.74(s,1H),4.81(t,J＝8.4Hz,2H),4.39-4.33(m,1H),4.30-4.06(m,2H),4.01-3.90(m,1H),3.13-3.02(m,3H),2.98-2.92(m,1H),2.45-2.37(m,3H),2.06-1.95(m,2H),1.80-1.59(m,3H),1.55-0.82(m,7H)。

Example 24: synthesis of Compound 3-1-2-3-1-16

By utilizing the synthesis method of the compound 3-1-1 or 1-4-2, reacting an intermediate 2, 20, 28, 27 or (5-chloroisoquinolin-4-yl) boric acid with the intermediate 6-3 to obtain a compound 3-1-2-3-1-6; reacting the intermediate 6-11 with the intermediate 20, 28 or 625 to obtain a compound 3-1-7-3-1-9; reacting the intermediate 6-13, 6-14, 6-15, 6-16 or 6-18 with the intermediate 20 to obtain a compound 3-1-10-3-1-14; reacting the intermediate 6-15 with the intermediate 28 or 27 to obtain a compound 3-1-15-3-1-16:

watch 13

Example 25: synthesis of 1- (4- (4- (5-amino-2- (trifluoromethyl) phenyl) -7- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2- (hydroxymethyl) -2, 3-dihydrofuro [2,3-f ] quinazolin-9-yl) piperazin-1-yl) prop-2-en-1-one (Compound 3-2-1)

Step 1: intermediate 10-13(50mg, 0.09mmol), intermediate 20(22mg, 0.09mmol), Pd (PPh)₃)₄(9mg, 0.0,1mmol), aqueous sodium carbonate (0.3mL, 1M) was added to 1,4 dioxane (4 mL). The reaction system was stirred at 110 ℃ for 1 hour under nitrogen protection, then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol: 20/1) to give compound 20A (40mg, yield: 70%) as a yellow solid. M/z [ M + H ]]⁺673.2。

Step 2: compound 20A (40mg, 0.06mmol) was dissolved in acetonitrile (5mL) under ice-bath conditions, aqueous lithium hydroxide (1M, 0.6mL) was added, and the reaction was stirred at this temperature for 1 hour. Then, the mixture was extracted with an ethyl acetate/tetrahydrofuran mixed solvent (10/1), the organic phase was separated and concentrated, and the residue was purified by prep-HPLC (condition 5) to give compound 3-2-1(3.9mg, yield: 11%) as a white solid. M/z [ M + H ]]⁺631.3；¹H NMR(400MHz,DMSO-d₆):δ7.44(d,J＝8.8Hz,1H),6.88-6.82(m,2H),6.67(d,J＝8.4Hz,1H),6.45(d,J＝8.4Hz,1H),6.16(dd,J＝2.0,16.4Hz,1H),5.94(br.s,2H),5.73(dd,J＝2.0,10.4Hz,1H),5.26(br.s,1H),5.11-5.00(m,2H),4.39-4.21(m,2H),3.84-3.75(m,3H),3.64-3.42(m,4H),3.04-2.86(m,3H),2.77-2.70(m,1H),2.39(s,3H),2.18-1.24(m,6H)。

Example 26: synthesis of 2- ((S) -4- (4- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -7- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2, 3-dihydrofuro [2,3-f ] quinazolin-9-yl) -1- (2-fluoropropy l) piperazin-2-yl) acetonitrile trifluoroacetate (Compound 3-3-1)

Compound 12-1(106mg, 0.17mmol), 6-chloro-4-methyl-5- (trifluoromethyl) pyridin-2-amine (36mg, 0.17mmol), aqueous sodium carbonate (1.0M, 0.5mL) and Pd (PPh)₃)₄(20mg, 0.017mmol) was added to 1, 4-dioxane (2mL), the reaction mixture was purged with nitrogen, then subjected to microwave reaction at 120 ℃ for 1 hour, and then directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 6) to give compound 3-3-1(22mg, yield: 19%) as a yellow solid. M/z [ M + H ]]⁺673.2；1H NMR(400MHz,DMSO-d₆):δ10.30(br.s,2H),6.91(s,1H),6.87-6.67(m,2H),6.45(s,1H),5.57-5.52(m,1H),5.45-5.37(m,2H),5.27-5.22(m,1H),4.84-4.75(m,3H),4.63-4.58(m,1H),4.28-4.19(m,2H),4.16-4.08(m,2H),4.05-3.94(m,2H),3.38-3.28(m,2H),3.24-3.10(m,3H),3.04(s,3H),2.36-2.35(m,3H),2.33-2.32(m,2H)。

Example 27: synthesis of 6-amino-2- (9- ((S) -3- (cyanomethyl) -4- (2-fluoropropenyl) piperazin-1-yl) -7- (((S) -1-methylpyrrolidin-2-yl) methoxy) -2, 3-dihydrofuro [2,3-f ] quinazolin-4-yl) -3- (trifluoromethyl) isonicotinonitrile trifluoroacetate (Compound 3-3-2)

Step 1: under the protection of nitrogen, 6- (di (a), (b), (c) and (d)4-methoxybenzyl) amino) -2-chloro-3- (trifluoromethyl) isonicotinic acid nitrile (130mg, 0.28mmol), 12-2(120mg, 0.19mmol), PdCl₂dppf·CH₂Cl₂A mixed solution of 1, 4-dioxane (30mg, 0.04mmol) and potassium fluoride (120mg, 2.07mmol) and water (6.6mL/3.0mL) was reacted at 120 ℃ for 0.5 hour by microwave. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol: 10/1) to give compound 19A (100mg, yield: 56%) as a yellow solid. M/z [ M + H ]]⁺934.7。

Step 2: a solution of compound 19A (90mg, 0.09mmol) in trifluoroacetic acid (5.0mL) was stirred at 50 ℃ for 4 hours under nitrogen. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, the residue was adjusted to pH 8 with saturated aqueous sodium bicarbonate, the aqueous phase was extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 10/1) to give compound 19B (80mg, crude) as a black oil. M/z [ M + H ]]⁺594.0。

And step 3: to a solution of compound 19B (70mg, 0.12mmol), 1-propylphosphoric anhydride (50% in ethyl acetate, 2.40mmol) and DIPEA (774mg, 6.0mmol) in anhydrous ethyl acetate/dichloromethane (10.0mL/2.0mL) under ice-bath conditions was added 2-fluoroacrylic acid (53mg, 0.59mmol), and the reaction was stirred at room temperature for 1 hour. The extract was diluted with dichloromethane (100mL), the organic phase was washed with saturated brine, the organic phase was separated and dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol ═ 10/1) to give compound 3-3-2(10.1mg, two-step yield: 13%) as a white solid. M/z [ M + H ]]⁺666.3；¹H NMR(400MHz,DMSO-d₆):δ9.71(s,1H),7.55(s,1H),7.05(s,1H),5.45-5.24(m,2H),4.84-4.80(m,1H),4.69-4.51(m,1H),4.21-4.17(m,1H),3.98-3.95(m,1H),3.84-3.76(m,1H),3.60-3.57(m,2H),3.54-3.46(m,4H),3.31-3.27(m,3H),3.13-3.08(m,4H),2.96(s,3H),2.34-2.33(m,1H),2.28-2.24(m,1H),2.07-1.87(m,3H)。

Example 28: synthesis of Compound 3-3-3 to 3-3-9

By utilizing the synthesis method of the compound 3-3-1, 6-chloro-5- (trifluoromethyl) pyridine-2-amine and an intermediate 6-11 react to obtain a compound 3-3-3; by utilizing the synthesis method of the compound 3-3-2, the intermediate 12-2 and 6-chloro-N, N-bis (4-methoxybenzyl) -5- (trifluoromethyl) pyrazine-2-amine, 6-chloro-4-methoxy-5- (trifluoromethyl) pyridine-2-amine, 6-chloro-4-methyl-5- (trifluoromethyl) pyridine-2-amine or 6-chloro-5- (trifluoromethyl) pyridine-2-amine are respectively reacted to obtain the compound 3-3-4-3-7; using the intermediates 9-11 and 20 as starting materials, replacing 2-fluoroacrylic acid in the step 3 with (E) -4-fluorobut-2-enoic acid to obtain a compound 3-3-8; using the intermediate 12-2 and 6-chloro-4-methyl-5- (trifluoromethyl) pyridine-2-amine as starting materials, replacing 2-fluoroacrylic acid in the step 3 with (E) -4-methoxybut-2-enoic acid to obtain a compound 3-3-9:

TABLE 14

Example 29: synthesis of 1- ((S) -4- (4- (6-amino-4-methyl-3- (trifluoromethyl) pyridin-2-yl) -7- (((2S,4R) -4-fluoro-1-methylpyrrolidin-2-yl) methoxy) -2, 3-dihydrofuro [2,3-f ] quinazolin-9-yl) -3-methylpiperazin-1-yl) prop-2-en-1-one (Compound 3-3-10)

To a solution of compound 19C (obtained by reacting intermediate 12-3 with 6-chloro-4-methoxy-5- (trifluoromethyl) pyridin-2-amine using the synthetic method of compound 19B) (120mg, 0.2mmol) in dichloromethane (5mL) was added dropwise acryloyl chloride (0.8M in dichloromethane, 0.5mL) and the resulting mixture was stirred at room temperature for 1 hour. After concentration under reduced pressure, the residue was purified by prep-HPLC (condition 5) to obtain compound 3-3-10(42mg, yield: 32%) as a white solid. M/z [ M + H ]]⁺630.4；¹H NMR(400MHz,DMSO-d₆):δ6.98-6.80(m,2H),6.77-6.67(m,2H),6.42(s,1H),6.20-6.14(m,1H),5.75(dd,J＝2.0,10.4Hz,1H),5.25-5.11(m,1H),4.78(t,J＝8.8Hz,2H),4.50-4.29(m,3H),4.25-4.20(m,1H),4.15-3.95(m,1H),3.81-3.78(m,1H),3.55-3.45(m,1H),3.36-3.26(m,2H),3.14-2.86(m,4H),2.48-2.42(m,1H),2.39(s,3H),2.36(s,3H),2.18-1.11(m,5H)。

Example 30: synthesis of 9- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -6- (2-isopropylphenyl) -4- (5-methyl-1H-indazol-4-yl) furo [2,3-f ] quinazolin-7 (6H) -one (compound 4-1-1)

Step 1: to a solution of intermediate 15-7(95mg, 0.16mmol) in 1, 4-dioxane (5mL) was added (5-methyl-1H-indazol-4-yl) boronic acid (58mg, 0.33mmol), Pd (PPh) respectively₃)₄(19mg, 0.016mmol) and aqueous sodium carbonate (0.48mL, 0.48 mmol). After the reaction mixture was bubbled with nitrogen for 1 to 2 minutes, reacted at 160 ℃ for 0.5 hour under microwave conditions, then the reaction liquid was cooled to room temperature and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (petroleum ether/ethyl acetate: 1/4) to give compound 10A (79mg, yield: 76%) as a pale yellow solid. M/z [ M + H ]]⁺633.3。

Step 2: a mixed solution of compound 10A (79mg, 0.12mmol) in dichloromethane (10mL) and trifluoroacetic acid (1mL) was stirred at room temperature for 2 hours and then directly concentrated under reduced pressure to give compound 10B (crude) as a yellow solid. M/z [ M + H ]]⁺533.3。

And step 3: to a solution of compound 10B (crude) in dry dichloromethane (10mL) was added DIPEA (78mg, 0.60mmol) and a solution of acrylic anhydride in dichloromethane (0.25M, 0.59mL, 0.15mmol), respectively, under ice-water bath. After the reaction mixture was stirred at this temperature for 1 hour, ammonia (0.05mL) was added to quench the reaction, the resulting mixture was directly concentrated under reduced pressure, and the residue was subjected to prep-HPLC (bar)Item 2) to give compound 4-1-1(24.3mg, yield: 34%) as a white solid. M/z [ M + H ]]⁺587.2；¹H NMR(400MHz,DMSO-d₆):δ13.14(s,1H),8.20-8.17(m,1H),7.52-7.21(m,7H),6.99-6.83(m,1H),6.58-6.46(m,1H),6.28-6.17(m,2H),5.81-5.73(m,1H),4.74-4.06(m,3H),3.97-3.86(m,1H),3.76-3.44(m,2H),3.31-3.06(m,2H),2.12-2.02(m,3H),1.38-1.26(m,3H),1.16-1.06(m,3H),1.00-0.88(m,3H)。

Example 31: synthesis of 2- ((2S) -1-acryloyl-4- (6- (2-isopropylphenyl) -4- (5-methyl-1H-indazol-4-yl) -7-oxo-6, 7-dihydrofuro [2,3-f ] quinazolin-9-yl) piperazin-2-yl) acetonitrile trifluoroacetate (Compound 4-1-2)

Step 1: using the procedure for the synthesis of compound 10A, intermediate 15-8 was reacted with (5-methyl-1H-indazol-4-yl) boronic acid to provide compound 11A as a white solid. M/z [ M + H ]]⁺692.2。

Step 2: to a solution of compound 11A (100mg, 0.14mmol) in methanol (30mL) was added palladium on carbon (10%, 60mg), and the reaction system was replaced with hydrogen gas 3 times, followed by stirring at room temperature under a hydrogen atmosphere for 1.5 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give Compound 11B (75mg, yield: 92%) as a white solid. M/z [ M + H ]]⁺558.3。

And step 3: to a solution of compound 11B (75mg, 0.13mmol) in dry dichloromethane (15mL) under ice-bath conditions were added DIPEA (50mg, 0.39mmol) and a solution of acrylic anhydride in dichloromethane (0.3M, 0.54mL, 0.16mmol), respectively. After the reaction mixture was stirred at this temperature for 5 hours, the reaction was quenched by adding aqueous ammonia (0.05mL), the resulting mixture was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 7) to give compound 4-1-2(4.1mg, yield: 5%) as a white solid. M/z [ M + H ]]⁺612.3；¹H NMR(400MHz,DMSO-d₆):δ13.17(s,1H),8.23(s,1H),7.55-7.29(m,7H),7.24(s,0.57H),7.11(s,0.30H),6.98(s,0.42H),6.58(d,J＝2.0Hz,0.50H),6.54(d,J＝2.0Hz,0.25H),6.50(d,J＝2.0Hz,0.17H),6.31-6.21(m,2H),5.84(d,J＝11.2Hz,1H),5.28-4.95(m,1H),4.30-4.03(m,5H),3.54-3.34(m,2H),3.13-2.94(m,2H),2.12-2.04(m,3H),1.17-1.08(m,3H),1.07-0.90(m,3H)。

Example 32: synthesis of 9- ((S) -4-acryloyl-2-methylpiperazin-1-yl) -4- (2-fluoro-6-hydroxyphenyl) -6- (2-isopropylphenyl) -furo [2,3-f ] quinazolin-7 (6H) -one (Compound 4-1-3)

Step 1: by utilizing the synthesis method of the compound 10A, the intermediate 15-7 and 4-fluoro-6-methoxyphenylboronic acid are reacted to obtain the compound 15A which is a light yellow solid. M/z [ M + H ]]⁺627.4。

Step 2: compound 15A (100mg, 0.16mmol) was dissolved in dry dichloromethane (7.0mL) and a solution of boron tribromide in dichloromethane (0.30mol/L,3.2mL, 0.96mmol) was slowly added dropwise at-20 ℃. After the reaction mixture was stirred at room temperature overnight, methanol (5mL) was added thereto and the mixture was further stirred for 30 minutes, and then directly concentrated under reduced pressure, and the residue was purified by Flash column chromatography (acetonitrile/0.1% aqueous trifluoroacetic acid solution ═ 0% to 50%) to give compound 15B (97mg, yield: 100%) as a pale yellow solid. M/z [ M + H ]]⁺513.3。

And step 3: to a solution of compound 15B (130mg, 0.21mmol) in dry dichloromethane (10mL) under ice-bath conditions were added DIPEA (260mg, 2.10mmol) and a solution of acrylic anhydride in dichloromethane (0.30M, 0.85mL, 0.26mmol), respectively. After the reaction mixture was stirred at this temperature for 1 hour, the reaction was quenched by addition of aqueous ammonia (2.5mL), and then the mixture obtained after further stirring for 2 hours was directly concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 5) to give compound 4-1-3(30.9mg, yield: 26%) as a white solid. M/z [ M + H ]]⁺567.2；¹H NMR(400MHz,DMSO-d₆):δ10.06(s,1H),8.15(s,1H),7.57(d,J＝7.2Hz,1H),7.48(t,J＝7.2Hz,1H),7.36(t,J＝7.2Hz,1H),7.27-7.22(m,2H),6.99-6.82(m,1H),6.78-6.67(m,3H),6.30-6.18(m,2H),5.76(dd,J＝2.0,10.0Hz,1H),4.66-4.38(m,2H),4.24-4.09(m,1H),3.95-3.81(m,2H),3.23-3.03(m,2H),1.30-1.24(m,3H),1.11(d,J＝6.8Hz,3H),1.03-0.99(m,3H).

Example 33: synthesis of (S) -9- (-4-acryloyl-2-methylpiperazin-1-yl) -4- (5-amino-2-chloro-3-fluorophenyl) -6- (2-isopropyl-4-methylpyridin-3-yl) -furo [2,3-f ] quinazolin-7 (6H) -one trifluoroacetate (Compound 4-1-4)

Step 1: a mixture of 15-9(350mg, 0.59mmol) in dichloromethane (16mL) and trifluoroacetic acid (2mL) was stirred at room temperature for 2h and concentrated under reduced pressure to give compound 14A (crude) as a yellow oil. M/z [ M + H ]]⁺497.2。

Step 2: to a solution of compound 14A (crude) and DIPEA (381mg, 2.95mmol) in dichloromethane (20mL) was added dropwise a solution of acrylic anhydride in dichloromethane (0.5M, 1.3mL, 0.65mmol), and the reaction was stirred at room temperature for 1 hour. The reaction was quenched with aqueous ammonia and concentrated under reduced pressure, and the residue was purified by Flash column chromatography (dichloromethane/methanol 30/1) to give compound 14B (400mg, two-step yield: 100%) as a yellow solid.

And step 3: compound 14B (55mg, 0.10mmol), intermediate 2(54mg, 0.20mmol), aqueous sodium carbonate (1M, 0.30mL) and Pd (PPh)₃)₄(12mg, 0.01mmol) of a mixture of 1, 4-dioxane (2mL) was charged into a microwave tube, and after bubbling nitrogen gas for 1 to 2 minutes, the reaction system was subjected to microwave reaction at 130 ℃ for 0.5 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by prep-HPLC (condition 7) to give compound 4-1-4(16.6mg, yield: 27%) as a white solid. M/z [ M + H ]]⁺615.2；¹H NMR(400MHz,DMSO-d₆):δ8.61(d,J＝4.8Hz,1H),8.23(d,J＝2.0Hz,1H),7.48-7.47(m,1H),6.98-6.83(m,1H),6.80(t,J＝1.6Hz,1H),6.56(dd,J＝2.4,12.0Hz,1H),6.33(s,1H),6.23-6.16(m,2H),5.76(dd,J＝2.4,10.8Hz,1H),4.65-3.39(m,2H),4.26-3.89(m,2H),3.72-3.46(m,2H),3.30-3.06(m,1H),2.79-2.73(m,1H),2.02(s,1.5H),2.01(s,1.5H),1.33-1.21(m,3H),1.12(d,J＝6.0Hz,3H),1.03(d,J＝6.0Hz,3H).

Example 34: synthesis of compound 4-1-5-4-1-12

By utilizing the synthesis method of the compound 4-1-1, the intermediate 15-9 and (5-methyl-1H-indazol-4-yl) boric acid are reacted to obtain the compound 4-1-5;

by utilizing the synthesis method of the compound 4-1-3, the intermediate 15-9 or 15-10 reacts with 2-chloro-5-methoxyphenylboronic acid pinacol ester to obtain the compounds 4-1-9 and 4-1-12; by using the synthesis method of the compound 4-1-4, the intermediate 15-7 or 15-10 is used as an initial raw material to react to obtain the compound 4-1-6 and the compound 4-1-11; replacing the intermediate 2 in the step 3 with an intermediate 32 to react to obtain a compound 4-1-7; using the intermediate 15-7 as a starting material, replacing the intermediate 2 in the step 3 with an intermediate 32 and 2, 3-dichlorophenylboronic acid respectively, and reacting to obtain compounds 4-1-8 and 4-1-10;

watch 15

Example 35: synthesis of Compound 5-1-1

Reaction using general procedure 1 gave compound 5-1-1:

TABLE 16

Biological examples:

example 1: pERK cell level assay

In the experiment, the PHOSPHO-ERK1/2(THR202/TYR 204) (Cisibo, 64ERKPEH) kit is used for detecting the phosphorylation level of ERK1/2 in human pancreatic cancer cells Mia Paca-2, and the inhibition effect of the compound on KRAS is researched through the phosphorylation level of ERK 1/2.

The experiment was performed according to the manufacturer's protocol. The density of MIA PaCa-2 cell (ATCC) suspension was adjusted to 2.1X 10 on the first day⁵Cell/cell-mL, 95 ul/well in 96-well plate, 2X 10 cells per well⁴The cell culture plate was placed at 37 ℃ in 5% CO₂The culture box of (1) was cultured overnight. The next day, compounds were diluted with a 100% DMSO gradient, further diluted with complete medium (DMDM + 10% FBS + 1% P/S) to give compound working solution, added at 5 ul/well to a 96-well cell culture plate, and incubated at 37 deg.C with 5% CO₂Incubate in the incubator for 4 hours. At the end of the incubation, the medium was aspirated, 50 ul/well 1 × lysis buffer was added, and the mixture was shaken at room temperature for 30 minutes. 16ul of lysate was added to a white, shallow-well 384-well plate, 4ul of the pre-prepared antibody mixture was added, the plate was sealed with a sealing plate membrane, and incubated overnight at room temperature. On the third day, detection was performed on a TECAN M1000 Pro plate reader using HTRF settings and the IC of the resulting compound was calculated₅₀The value is obtained. The results are shown in Table 17 below:

TABLE 17

Example 2: cell proliferation assay

In the present invention, the biological activity of the compound is evaluated by a cell proliferation assay.

1) 3000 Miapaca-2 human pancreatic cancer cells (Nanjing Kebai) were planted in a 96-well plate, and the cells were cultured in Dulbecco's Modified Eagle's matrix and 10% fetal calf serum under a culture environment of 37 ℃ and 5% CO₂. The next day, stock solutions of test compounds were dissolved in DMSO and added to the indicated concentration of medium and incubated for 72 hours with test compound concentrations ranging from 1.5nM to 100 μ M. Negative control cells were treated with vehicle only. Using Cell timer under instruction of product specificationGlo assay kit (Cell Titer-Glo, Promega) to evaluate Cell activity. Analyzing the data by using Graphpad software and obtaining IC₅₀Values and compound fitted curves (results are shown in table 18).

2) 3000 NCI-H358 human non-small cell lung cancer cells (Nanjing Kebai) were plated in 96-well plates and cultured in RPMI-1640 and 10% fetal calf serum at 37 ℃ and 5% CO 2. The next day, stock solutions of test compounds were dissolved in 10% DMSO and added to 96-well plates to indicated concentrations, and incubated for 72 hours with test compound concentrations ranging from 4.5nM to 30 μ M. Negative control cells were treated with vehicle only. Cell Titer-Glo assay kit (Cell Titer-Glo, Promega) was used to evaluate Cell activity under the instructions of the product instructions. Analyzing the data by using Graphpad software and obtaining IC₅₀Values and compound fitted curves (results are shown in table 19).

Watch 18

Watch 19

Claims

1. A compound as shown in formula I, an isomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof;

wherein the content of the first and second substances,

the alpha and beta bonds are single or double bonds, respectively;

x is N or CR₂；

u and M are each independently N, C or CH;

R₁is C_2-4Alkenyl radical, C_2-4Alkynyl or partially unsaturated C_4-6A cycloalkyl group; the R is₁Is unsubstituted or optionally substituted by 1 to 3R₈The group is substituted at any position;

R_Bis hydrogen, cyano, hydroxy or C_1-6An alkyl group;

R_cis hydroxy, cyano, amino, oxo, halogen, C_1-4Alkyl radical, C_1-4Alkylene radical, C_1-6Alkoxy radical, C_1-6Alkylamino, halogeno C_1-4Alkyl, halo C_1-4Alkoxy, hydroxy-C_1-6Alkyl radical, C_1-4alkoxy-C_1-6Alkyl, amino-C_1-6Alkyl radical, C_1-6alkylamino-C_1-6Alkyl radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4Alkyl, - (CH)₂)_n-N(CN)R’、-(CH₂)_n-C(O)R’、-(CH₂)_n-C(O)N(R’)₂、-(CH₂)_n-S(O)₂N(R’)₂、-(CH₂)_n-NR”C(O)R’、-(CH₂)_n-NR”S(O)₂R' or- (CH)₂)_n-B(OR”)₂；R_cIn (A), the C_1-4Alkylene radical, C_1-6Alkoxy radical, C_1-6Alkylamino radical, C_3-8A cycloalkyl group, a 3-to 8-membered heterocycloalkyl group, C_6-10Aryl, 5-10 membered heteroaryl, C_3-8cycloalkyl-C_1-4Alkyl, 3-8 membered heterocycloalkyl-C_1-4Alkyl radical, C_6-10aryl-C_1-4Alkyl, 5-10 membered heteroaryl-C_1-4The alkyl is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy radical, C_1-4Alkylamino and C_1-4The substituent of the alkyl group is substituted at any position;

r' is hydrogen or C_1-6An alkyl group;

n is an integer of 0 to 4;

2. The compound of formula I, its isomer, stable isotopic derivative or pharmaceutically acceptable salt of claim 1, wherein a ring is

The A ring is unsubstituted or selectively substituted by 1-3R₅Substitution at any position;

and/or, ring B is

The B ring is unsubstituted or R of 1-3 is selected₆The substitution is in any position.

3. A compound of formula I, its isomer, stable isotopic derivative or pharmaceutically acceptable salt according to claim 2, wherein R is₅Is H or-CH₂OH；

And/or, R₆Is H, -CH₃、-CF₃、-CHF₂、-CH₂CN、-CH₂OH、-CH₂CH₂OH、-CH₂CH₂OCH₃or-CH₂OCH₃。

4. A compound of formula I, an isomer, a stable isotopic derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein ring a is pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, furyl, thienyl, thiazolyl, isothiazolyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-triazolyl, 1,2, 3-triazolyl, tetrazolyl or 2, 3-dihydrofuryl;

and/or, ring B is

5. A compound of formula I, its isomers, stable isotopic derivatives or pharmaceutically acceptable salts thereof as claimed in claim 1, wherein R is phenyl, naphthyl, pyridinyl, pyrazinyl, pyridazinyl, quinolinyl, isoquinolinyl, 2, 3-dihydrobenzofuranyl, 1H-benzo [ d ] f]Imidazole-2 (3H) -keto, 1H-indazolyl, phthalazinyl, 1-hydroxy-1, 3-dihydrobenzo [ c ]][1,2]Oxaboronyl, 3-hydroxy-1, 3-dihydronaphtho [2,1-c ]][1,2]Oxaboronyl or 1-hydroxy-1, 3-dihydronaphtho [2,3-c ]][1,2]Oxaboronyl; r is unsubstituted or 1-5R₇Substitution at any position;

and/or, R₇Is hydrogen, halogen, hydroxy, amino, cyano, C_1-4Alkyl, halo C_1-3Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkoxy radical, C_1-6Alkylamino radical, C_3-6Cycloalkyl, 3-6 membered heterocycloalkyl or-B (OH)₂(ii) a Said C is_3-6The cycloalkyl group or the 3-6 membered heterocycloalkyl group is unsubstituted or optionally substituted at any position with 1 to 3 substituents selected from the group consisting of hydroxy, amino, fluoro, chloro, methyl, trifluoromethyl and trifluoromethoxy.

6. The compound of formula I, its isomer, stable isotopic derivative or pharmaceutically acceptable salt thereof as claimed in claim 1, wherein R is

7. A compound of formula I, its isomer, stable isotopic derivative or pharmaceutically acceptable salt according to claim 1, wherein R is₁Is composed of

Wherein R is_8aIs H, D, halogen or C_1-3alkoxy-C_1-4An alkyl group; r_8bAnd R_8cEach independently is H, D, halogen, C_1-6Alkyl, halo C_1-6Alkyl, hydroxy-C_1-4Alkyl radical, C_1-3alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl radical, C_1-6alkylamino-C_1-4Alkyl, 5-10 membered heteroaryl, 3-10 membered heterocycloalkyl, 5-10 heteroaryl-C_1-4Alkyl or 3-10 heterocycloalkyl-C_1-4An alkyl group; wherein, the C_1-6alkylamino-C_1-4The alkyl, heteroaryl, heterocycloalkyl, heterocycloalkylalkyl or heteroarylalkyl group is unsubstituted or optionally substituted with 1 to 3 substituents selected from halogen, hydroxy, amino, cyano, C_1-4Alkoxy, oxo and C_1-4The substituent of the alkyl group is substituted at any position;

or, R₁Is composed of

8. The compound of formula I as claimed in any one of claims 1 to 7, an isomer, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the α and β bonds are double bonds, respectively; x is N; w is C and V is CR₄Or N; y is CR₂(ii) a Z is N.

9. A compound of formula I, its isomer, stable isotopic derivative or pharmaceutically acceptable salt according to claim 1, wherein R is₂is-OR_A、-NR_AR_B5-10 membered heteroaryl or 3-10 membered heterocycloalkyl; said 5-10 membered heteroaryl or 3-10 membered heterocycloalkyl is unsubstituted or optionally substituted with one or more R_cSubstitution at any position;

and/or, R₄Is hydrogen, halogen, C_2-4Alkenyl radical, C_1-4Alkyl radical, C_1-3Alkoxy, halo C_1-3Alkyl, halo C_1-3Alkoxy or C_3-6A cycloalkyl group.

10. A compound of formula I, its isomer, stable isotopic derivative or pharmaceutically acceptable salt according to claim 1, wherein R is₂Is composed of

And/or, R₄Is hydrogen.

11. The compound of formula I, its isomer, stable isotope derivative or pharmaceutically acceptable salt according to any of claims 1 to 10, wherein it is a compound of formula II, its isomer, stable isotope derivative or pharmaceutically acceptable salt,

wherein, ring A, ring B, X, U, M, R, R₁、R₂And R₄Is as defined in any one of claims 1 to 10.

12. The compound of formula I, an isomer, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, according to claim 11, wherein X is N; u and M are each independently N, C;

ring A is 5-6 membered heteroaryl or 5-6 membered heterocycloalkyl;

ring B is

R₂is-OR_A；

R₄Is H;

R₈is hydrogen, deuterium, halogen, C_1-6Alkyl radical, C_1-6Alkoxy, hydroxy-C_1-4Alkyl radical, C_1-6alkoxy-C_1-4Alkyl, amino-C_1-4Alkyl or C_1-6alkylamino-C_1-4An alkyl group;

13. The compound of formula I, its isomer, stable isotope derivative or pharmaceutically acceptable salt as claimed in any of claims 1 to 10, wherein it is a compound of formula IIA, IIB, IIC or IID, its isomer, stable isotope derivative or pharmaceutically acceptable salt,

wherein, ring B, R, R_A、R₁And R₅Is as defined in any one of claims 1 to 10.

14. The compound of formula I as claimed in any one of claims 1 to 7, an isomer, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, wherein the α bond is a double bond; the beta bond is a single bond; x is N; w is C and V is CR₄Or N; y is C (O), Z is NR₃；

And/or, R₃Is cyclohexyl, cyclopropylmethyl, phenyl, pyridineAryl, pyrimidinyl, thiazole or 1H-pyrazolyl; the R is₃Is unsubstituted or optionally substituted by 1 to 3 substituents selected from halogen, hydroxy, cyano, amino, C_1-6Alkyl or C_3-6The substituents of the cycloalkyl group are substituted at any position;

and/or, R₄Is hydrogen.

15. The compound of formula I, an isomer, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, according to claim 14, wherein R is₃Is composed of

16. The compound of formula I according to claim 1, having any one of the following structures:

17. a pharmaceutical composition comprising a therapeutically effective amount of an active ingredient and a pharmaceutically acceptable adjuvant; the active component comprises the compound shown in the formula I, an isomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof as claimed in any one of claims 1 to 16.

18. Use of a compound of formula I, an isomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition of claim 17 in the preparation of a KRAS G12C inhibitor.

19. Use of a compound of formula I, an isomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17 for the preparation of a medicament for the treatment and/or alleviation of diseases associated with KRAS G12C.

20. The use of claim 19, wherein: the KRAS G12C related diseases are cancers.

21. Use of a compound of formula I, an isomer, a stable isotope derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 16, or a pharmaceutical composition according to claim 17 for the manufacture of a medicament for the treatment of cancer.

22. A combined preparation comprising a compound of formula I as defined in any one of claims 1 to 16, an isomer, a stable isotopic derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 17 in combination with other therapeutic agents for the treatment of cancer.