WO2023125989A1

WO2023125989A1 - Quinazoline compound and application thereof

Info

Publication number: WO2023125989A1
Application number: PCT/CN2022/144234
Authority: WO
Inventors: 张朝欣; 夏广新; 霍国永; 李志龙; 柯樱; 马星; 王雪松; 毛海斌; 付玉红
Original assignee: 上海医药集团股份有限公司
Priority date: 2021-12-31
Filing date: 2022-12-30
Publication date: 2023-07-06
Also published as: CN118434740A

Abstract

A quinazoline compound and an application thereof. The quinazoline compound is shown as a formula 1, it has a good inhibiting effect on KRAS G12D mutant protein and has a good patent medicine prospect.

Description

A kind of quinazoline compound and application thereof

This application requires Chinese patent application 202111667946X with filing date on December 31, 2021, Chinese patent application 2022101950735 on March 1, 2022, Chinese patent application 2022103345291 on March 30, 2022, Chinese patent application on June 16, 2022 Priority of patent application 2022106876377 and Chinese patent application 2022112051102 dated September 29, 2022. This application cites the full text of the above-mentioned Chinese patent application.

technical field

The invention relates to a quinazoline compound and its application.

Background technique

RAS represent a group of closely related monomeric globular proteins (21 kDa molecular weight) of 189 amino acids that associate with the plasma membrane and bind GDP or GTP. RAS acts as a molecular switch. When RAS contains bound GDP, it is in a resting or off position and "inactive". In response to exposure of cells to certain growth-promoting stimuli, RAS is induced to exchange its bound GDP for GTP. In the case of binding GTP, RAS is "turned on" and is able to interact with and activate other proteins (its "downstream targets"). The RAS protein itself has a very low intrinsic ability to hydrolyze GTP back to GDP, thereby turning itself off. Shutting down RAS requires an exogenous protein called GTPase Activating Protein (GAP), which interacts with RAS and greatly accelerates the conversion of GTP to GDP. Any mutation in RAS that affects its ability to interact with GAP or convert GTP back to GDP will result in prolonged activation of the protein and thus the signals sent to the cell telling it to continue growing and dividing. As these signals cause cells to grow and divide, overactivated RAS signaling can ultimately lead to cancer.

Structurally, RAS proteins contain a G domain responsible for the enzymatic activity of RAS—guanine nucleotide binding and hydrolysis (GTPase reaction). It also contains a C-terminal extension called the CAAX box, which can be modified post-translationally and is responsible for targeting the protein to the membrane. The G domain is approximately 21-25 kDa in size and contains a phosphate binding loop (P-loop). The P-loop represents the pocket in the protein that binds nucleotides, and this is the rigid part of the domain with conserved amino acid residues necessary for nucleotide binding and hydrolysis (glycine 12, threo amino acid 26 and lysine 16). The G domain also contains the so-called switch I region (residues 30-40) and switch II region (residues 60-76), both of which are the dynamic part of the protein, since the dynamic part switches between the resting and loaded states This capability is often expressed as a "spring-loaded" mechanism. The main interaction is the hydrogen bond formed by threonine-35 and glycine-60 with the γ-phosphate of GTP, which maintains the switch 1 and switch 2 regions in their active conformations, respectively. Following hydrolysis of GTP and release of phosphate, both relax into the inactive GDP conformation.

The most notable members of the RAS subfamily are HRAS, KRAS and NRAS, which are primarily implicated in many types of cancer. However, many other members exist, including DIRAS1; DIRAS2; DIRAS3; ERAS; GEM; MRAS; NKIRAS1; NKIRAS2; NRAS; RALA; RALB; RAP1A; RAP1B; RAP2A; RAP2B; RAP2C; RASL11B; RASL12; REM1; REM2; RERG; RERGL; RRAD; RRAS and RRAS2.

Mutations in any of the three major isoforms of the RAS gene (HRAS, NRAS or KRAS) are one of the most common events in human tumorigenesis. About 30% of all human tumors are found to carry some mutation in the RAS gene. Notably, KRAS mutations are detected in 25%-30% of tumors. In contrast, the rates of oncogenic mutations in NRAS and HRAS family members were much lower (8% and 3%, respectively). The most common KRAS mutations are found at residues G12 and G13 and at residue Q61 in the P-loop. Among tumor-associated KRAS G12 mutations, KRAS G12D mutations accounted for the highest probability, about 40%.

Based on the importance of aberrant activation of KRAS in cancer progression and the prevalence of KRAS gene mutations in human cancers, KRAS has been a target of interest for drug developers. Despite the progress made in this field, there remains a need in the art for improved KRAS G12D mutein inhibitors.

Contents of the invention

The technical problem to be solved by the present invention is to overcome the deficiency of KRAS G12D mutant protein inhibitors in the prior art, and therefore, a quinazoline compound and its application are provided. The quinazoline compounds provided by the invention have good inhibitory effect on KRAS G12D mutant protein.

The present invention solves the above-mentioned technical problems through the following technical solutions.

The present invention provides a compound as shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotope Compound:

Among them, R ¹ is C ₆ -C ₁₈ aryl, "C ₆ -C ₁₈ aryl substituted by 1 or more R ^1-1 ", 5-10 heteroaryl or "by 1 or more R ^1-2 substituted 5-10 heteroaryl", said 5-10 heteroaryl and said "5-10 heteroaryl substituted by 1 or more R ^1-2 " heteroatoms independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R ^1-1 is independently hydroxyl, halogen, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by 1 or more R ^1-1-1 , C ₂ -C ₆ alkynyl,

C ₃ -C ₆ cycloalkyl or "3-membered or 4-10-membered cycloalkyl substituted by 1 or more R ^1-1-2 ", or any two adjacent R ^1-1 are connected to it The carbon atoms together form a 4-10-membered cycloalkyl group, "4-10-membered cycloalkyl group substituted by 1 or more R ^1-1-3 ", 4-10-membered heterocycloalkyl group, "by 1 or more R ^1-1-4 substituted 4-10 membered heterocycloalkyl", 5-10 heteroaryl and "5-10 heteroaryl substituted by 1 or more R ^1-1-5 The heteroatoms in the "group" are independently one or more of N, O or S; the 4-10 membered heterocycloalkyl and "4 substituted by 1 or more R ^1-1-4 The heteroatoms in -10-membered heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R ^1-1-1 is independently halogen, deuterium, hydroxyl or -OC ₁ -C ₆ alkyl;

R ^1-1-2a and R ^1-1-2b are independently C ₁ -C ₆ alkyl;

R ^1-1-2 are independently halogen or hydroxyl;

R ^1-1-3 is independently halogen or C ₁ -C ₆ alkyl; R ^1-1-4 is independently halogen or C ₁ -C ₆ alkyl;

R ^1-2 is independently amino, C ₃ -C ₆ cycloalkyl, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by 1 or more halogens;

R ² is H or halogen;

Y is -OR ³ , C ₁ -C ₆ alkyl substituted by 1 or more Y ^1-1 , C ₂ -C ₆ alkenyl substituted by 1 or more Y ^1-2 , substituted by 1 or C ₂ -C ₆ alkynyl substituted by multiple Y ^1-3 , C ₃ -C ₆ cycloalkyl substituted by one or more Y ^1-4 or -N=S(O)Y ^1-5 Y ^{1 -6} ;

R ³ is C ₁ -C ₆ alkyl substituted by 1 or more R ^3-1 ;

R ^3-1 is defined as follows:

When R ¹ is C ₆ -C ₁₈ aryl or "C ₆ -C ₁₈ aryl substituted by 1 or more R ^1-1 ", R ^3-1 is defined as case 1 or case 2:

Scenario 1:

R ^3-1 is independently -OC ₁ -C ₆ alkyl, 4-10 membered heterocycloalkyl, "4-10 membered heterocycloalkyl substituted by 1 or more R ^3-1-1 " or deuterium; and the number of R ^3-1 is at least 2, wherein one R ^3-1 is -OC ₁ -C ₆ alkyl, and the other R ^3-1 is 4-10 membered heterocycloalkyl or replaced by one Or a 4-10 membered heterocycloalkyl group substituted by multiple R ^3-1-1 ;

The heteroatoms in the 4-10 membered heterocycloalkyl and the "4-10 membered heterocycloalkyl substituted by 1 or more R ^3-1-1 " are independently N, O or One or more of S, the number of heteroatoms is 1-3;

R ^3-1-1 is independently -OC ₁ -C ₆ alkyl;

Scenario 2:

R ^3-1 is independently deuterium, hydroxyl, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R ^3-1-2 " or "substituted by 1 or more R ^3- ^{1- 3-} substituted 8-membered heterocycloalkyl";

And at least one R ^3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R ^3-1-2 " or "substituted by one or more R ^3-1-3 8-membered heterocycloalkyl";

When at least one of R ^3-1 is a 5-6 membered monocyclic heterocycloalkyl group substituted by 1 or more R ^3-1-2 , at least one R ^3-1-2 and said "is 1 or more R ^3-1-2 substituted 5-6 membered monocyclic heterocycloalkyl "heteroatoms of the 5-6 membered monocyclic heterocycloalkyl are connected;

The "5-6-membered monocyclic heterocycloalkyl substituted by 1 or more R ^3-1-2 " and the "8-membered substituted by 1 or more R ^3-1-3 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R ^3-1-2 and R ^3-1-3 are independently 3-6 membered heterocycloalkyl, C ₁ -C ₆ alkyl, C substituted by 1 or more R ^3-1-1-1 ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, halogen, deuterium or 3-6 membered cycloalkyl, or any two R ^3-1-3 connected to the same atom The atoms together form a 3-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group, and the heteroatoms of the 4-10 membered heterocycloalkyl group are independently one or more of N, O or S species, the number of heteroatoms is 1-3;

The heteroatoms in the 3-6 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R ^3-1-1-1 is independently 3-6 membered cycloalkyl, halogen, 3-8 membered heterocycloalkyl or 3-substituted by one or more R ^3-1-1-1-1 8-membered heterocycloalkyl; heteroatoms in the 3-8-membered heterocycloalkyl and 3-8-membered heterocycloalkyl substituted by one or more R ^3-1-1-1-1 independently one or more of P, N, O or S, and the number of heteroatoms is 1-3;

R ^3-1-1-1-1 is independently oxo (=O), =NH, hydroxyl, C ₁ -C ₆ alkyl or replaced by 1 or more R ^{3-1-1-1-1- 1} substituted C ₁ -C ₆ alkyl;

R ^3-1-1-1-1-1 is independently hydroxyl;

When R ¹ is 5-10 heteroaryl or "5-10 heteroaryl substituted by 1 or more R ^1-2 ", R ^3-1 is independently 4-10 membered heterocycloalkyl or " 4-10 membered heterocycloalkyl substituted by 1 or more R ^3-1-4 "; said 5-10 heteroaryl and "5-10 substituted by 1 or more R ^1-2 The heteroatoms in "heteroaryl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R ^3-1-4 are independently halogen;

Y ^1-1 , Y ^1-2 , Y ^1-3 and Y ^1-4 are independently -OC ₁ -C ₆ alkyl, 4-10 membered heterocycloalkyl, "substituted by 1 or more halogens 4-10 membered heterocycloalkyl", hydroxyl, halogen or deuterium; the heteroatoms in the 4-10 membered heterocycloalkyl substituted by 1 or more halogens are independently N, O or S One or more, the number of heteroatoms is 1-3;

Y ^1-5 and Y ^1-6 are independently C ₁ -C ₆ alkyl, C ₁ -C ₆ alkyl substituted by 1 or more Y ^1-5-1 (X2 compound) or "by 1 or multiple halogen substituted 4-10 membered heterocycloalkyl”; the heteroatoms in the 4-10 membered heterocycloalkyl substituted by one or more halogens are independently N, O or S One or more, the number of heteroatoms is 1-3;

Y ^1-5-1 is a 4-10 membered heterocycloalkyl group substituted by one or more halogens, and the heteroatoms in the 4-10 membered heterocycloalkyl group substituted by one or more halogens are independently Ground is one or more of N, O or S, and the number of heteroatoms is 1-3

^R4 is a bridged ring heterocycloalkyl group with 7-12 members, the heteroatoms in the bridged ring heterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1 -3;

R ⁴ is a 7-12-membered bridged ring heterocycloalkyl or "7-12-membered bridged ring heterocycloalkyl substituted by 1 or more R ^4-1 ", the 7-12-membered bridge The heteroatoms in the cycloheterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R ^4-1 is C ₁ -C ₆ alkyl;

A is CR ⁵ or N;

R ⁵ is H, C ₁ -C ₆ alkyl, cyano, halogen or C ₁ -C ₆ alkyl substituted by one or more halogens;

Described compound as shown in formula I is not following compound:

In a preferred embodiment, the compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolic Products or their isotopic compounds:

C ₃ -C ₆ cycloalkyl or "4-10 membered cycloalkyl substituted by 1 or more R ^1-1-2 ", or any two adjacent carbon atoms connected by R ^1-1 Together form a 4-10 membered cycloalkyl, "4-10 membered cycloalkyl substituted by 1 or more R ^1-1-3 ", 4-10 membered heterocycloalkyl, "by 1 or In the 4-10 membered heterocycloalkyl group substituted by multiple R ^1-1-4 ", the 5-10 heteroaryl group and the "5-10 heteroaryl group substituted by 1 or more R ^1-1-5 " The heteroatoms in are independently one or more of N, O or S; the 4-10-membered heterocycloalkyl and "4-10-membered substituted by 1 or more R ^1-1-4 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-4; R ^1-1-1 is independently halogen or deuterium;

R ^1-1-2a , R ^1-1-2b and R ^1-1-3 are independently C ₁ -C ₆ alkyl;

R ^1-1-2 are independently halogen or hydroxyl;

R ^1-2 is independently amino, C ₁ -C ₆ alkyl or C ₁ -C ₆ alkyl substituted by one or more halogens;

R ² is H or halogen;

R ³ is C ₁ -C ₆ alkyl substituted by 1 or more R ^3-1 ;

R ^3-1 is defined as follows:

Scenario 1:

R ^3-1-1 is independently -OC ₁ -C ₆ alkyl;

Scenario 2:

R ^3-1 is independently deuterium, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R ^3-1-2 " or "substituted by 1 or more R ^3-1-3 8-membered heterocycloalkyl";

R ^3-1-2 and R ^3-1-3 are independently 3-6 membered heterocycloalkyl, C ₁ -C ₆ alkyl, C substituted by 1 or more R ^3-1-1-1 ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, halogen, deuterium or 3-6 membered cycloalkyl;

R ^3-1-1-1 is independently 3-6 membered cycloalkyl, halogen, 3-8 membered heterocycloalkyl or 3-substituted by one or more R ^3-1-1-1-1 8-membered heterocycloalkyl; heteroatoms in the 3-8-membered heterocycloalkyl and 3-8-membered heterocycloalkyl substituted by one or more R ^3-1-1-1-1 independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R ^3-1-1-1-1 is independently oxo (=O), =NH, C ₁ -C ₆ alkyl or substituted by 1 or more R ^3-1-1-1-1-1 C ₁ -C ₆ alkyl;

R ^3-1-1-1-1-1 is independently hydroxyl;

R ^3-1-4 are independently halogen;

Y ^1-1 , Y ^1-2 , Y ^1-3 and Y ^1-4 are independently -OC ₁ -C ₆ alkyl, 4-10 membered heterocycloalkyl, "substituted by 1 or more halogens 4-10 membered heterocycloalkyl", hydroxyl or deuterium; the heteroatom in the 4-10 membered heterocycloalkyl substituted by 1 or more halogens is independently one of N, O or S or more, the number of heteroatoms is 1-3;

Y ^1-5 and Y ^1-6 are independently C ₁ -C ₆ alkyl or "4-10 membered heterocycloalkyl substituted by 1 or more halogens"; said 1 or more halogens The heteroatoms in the substituted 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R ^4-1 is C ₁ -C ₆ alkyl;

A is CR ⁵ or N;

R ⁵ is H, C ₁ -C ₆ alkyl, cyano, halogen or C ₁ -C ₆ alkyl substituted by one or more halogens.

Wherein, R ¹ is C ₆ -C ₁₈ aryl, "C ₆ -C ₁₈ aryl substituted by 1 or more R ^1-1 " or 5-10 heteroaryl, said 5-10 heteroaryl The heteroatoms in the group are independently one or more of N, O or S, and the number of heteroatoms is 1-4;

C ₃ -C ₆ cycloalkyl or "4-10 membered cycloalkyl substituted by 1 or more R ^1-1-2 ", or any two adjacent carbon atoms connected by R ^1-1 together form a 4-10 membered cycloalkyl group or "4-10 membered cycloalkyl group substituted by 1 or more R ^1-1-3 ";

R ^1-1-1 is independently halogen or deuterium;

R ^1-1-2a , R ^1-1-2b and R ^1-1-3 are independently C ₁ -C ₆ alkyl;

R ^1-1-2 are independently halogen or hydroxyl;

R ^1-1-3 are independently halogen or C ₁ -C ₆ alkyl;

R ² is H or halogen;

R ³ is C ₁ -C ₆ alkyl substituted by 1 or more R ^3-1 ;

R ^3-1 is defined as Case 1 or Case 2:

Scenario 1:

The heteroatoms in the 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R ^3-1-1 is independently -OC ₁ -C ₆ alkyl;

Scenario 2:

And at least one R ^3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R ^3-1-2 " or "substituted by one or more R ^3-1-3 8-membered heterocycloalkyl", at least 1 R ^3-1-2 and said "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R ^3-1-2 " The heteroatom connection of 5-6 membered monocyclic heterocycloalkyl;

R ^3-1-1-1 is independently 3-6 membered cycloalkyl or halogen;

R ^4-1 is C ₁ -C ₆ alkyl;

A is CR ⁵ or N;

Described compound as shown in formula I is not following compound:

In a preferred embodiment, the compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolic In product or its isotope compound, described compound shown in formula I is the compound shown in formula Ia:

Or C ₃ -C ₆ cycloalkyl, or any two adjacent R ^1-1 together with the carbon atom to which they are connected form a 4-10 membered cycloalkyl;

R ^1-1-1 is independently halogen or deuterium;

R ^1-1-2a , R ^1-1-2b and R ^1-1-3 are independently C ₁ -C ₆ alkyl;

R ² is H or halogen;

R ³ is C ₁ -C ₆ alkyl substituted by 1 or more R ^3-1 ;

R ^3-1 is defined as Case 1 or Case 2:

Scenario 1:

R ^3-1-1 is independently -OC ₁ -C ₆ alkyl;

Scenario 2:

R ^3-1-2 and R ^3-1-3 are independently 3-6 membered heterocycloalkyl, C ₁ -C ₆ alkyl, C substituted by 1 or more R ^3-1-1-1 ₁ -C ₆ alkyl, -OC ₁ -C ₆ alkyl, halogen or deuterium;

R ^3-1-1-1 is independently a 3-6 membered cycloalkyl group;

R ^4-1 is C ₁ -C ₆ alkyl;

A is CR ⁵ or N; R ⁵ is H, C ₁ -C ₆ alkyl, cyano or halogen;

Described compound as shown in formula I is not following compound:

R ^1-1-1 is independently halogen or deuterium;

R ^1-1-2a , R ^1-1-2b and R ^1-1-3 are independently C ₁ -C ₆ alkyl;

R ² is H or halogen;

R ³ is C ₁ -C ₆ alkyl substituted by 1 or more R ^3-1 ;

R ^3-1 is defined as Case 1 or Case 2:

Scenario 1:

R ^3-1-1 is independently -OC ₁ -C ₆ alkyl;

Scenario 2:

R ^3-1-1-1 is independently a 3-6 membered cycloalkyl group;

R ⁴ is a 7-12 membered bridged ring heterocycloalkyl group, and the heteroatoms in the 7-12 membered bridged ring heterocycloalkyl group are independently one or more of N, O or S, and hetero The number of atoms is 1-3;

A is CR ⁵ or N; R ⁵ is H, C ₁ -C ₆ alkyl, cyano or halogen;

Described compound as shown in formula I is not following compound:

In a preferred embodiment, the compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compounds:

R ^1-1-2a , R ^1-1-2b and R ^1-1-3 are independently C ₁ -C ₆ alkyl;

R ^1-1-2 are independently halogen or hydroxyl;

R ² is H or halogen;

R ³ is C ₁ -C ₆ alkyl substituted by 1 or more R ^3-1 ;

R ^3-1 is defined as follows:

Scenario 1:

R ^3-1-1 is independently -OC ₁ -C ₆ alkyl;

Scenario 2:

R ^3-1-1-1 is independently 3-6 membered cycloalkyl or halogen;

R ^3-1-4 are independently halogen;

R ^4-1 is C ₁ -C ₆ alkyl;

A is CR ⁵ or N;

In a preferred embodiment, in R ¹ , the C ₆ -C ₁₈ aryl group and the C ₆ in the "C ₆ -C ₁₈ aryl group substituted by 1 or more R ^1-1 " -C ₁₈ aryl is independently C ₆ -C ₁₄ aryl, such as phenyl or naphthyl.

In a preferred embodiment, in R ¹ , the 5-10 heteroaryl group in the 5-10 heteroaryl group or "the 5-10 heteroaryl group substituted by 1 or more R ^1-2 " is independently is a 5- or 6-membered heteroaryl.

In a preferred embodiment, in R ¹ , the heteroatoms in the 5-10 heteroaryl group or "5-10 heteroaryl group substituted by 1 or more R ^1-2 " are independently N, The number is 1.

In a preferred embodiment, in R ¹ , the 5-10 heteroaryl group in the 5-10 heteroaryl group or "the 5-10 heteroaryl group substituted by 1 or more R ^1-2 " is independently is pyridyl.

In a preferred embodiment, in R ^1-1 , said halogen is independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ^1-1 , the C ₁ -C ₆ alkyl and "the C ₁ -C ₆ alkyl substituted by 1 or more R ^1-1-1 " The C ₁ -C ₆ alkyl in is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as ethyl.

In a preferred embodiment, in R ^1-1 , the C ₂ -C ₆ alkynyl is a C ₂ -C ₄ alkynyl, such as ethynyl.

In a preferred embodiment, in R ^1-1 , the C ₃ -C ₆ cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane, such as cyclopropane or cyclobutane.

In a preferred embodiment, in R ^1-1 , any two adjacent R ^1-1 and the carbon atoms connected together form a 4-10-membered cycloalkane in a 4-10-membered cycloalkyl group. 8-membered spirocycloalkyl, such as spiro[3,4]octyl (spiro[3,4]octyl forms with C ₆ -C ₁₈ aryl

).

In a preferred embodiment, in R ^1-1 , said any adjacent two R ^1-1 together with the carbon atoms they are connected to form a 4-10 membered cycloalkyl group and said "by 1 or The 4-10-membered cycloalkyl groups in the multiple R ^1-1-3 substituted 4-10-membered cycloalkyl groups are independently 8-membered spirocycloalkyl groups, such as spiro[3.4]octyl.

In a preferred embodiment, in R ^1-1-1 , the halogens are independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ^1-1-1 , the -OC ₁ -C ₆ alkyl is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , sec-butoxy, isobutoxy or tert-butoxy, such as methoxy.

In a preferred embodiment, in R ^1-1 , the C ₁ -C ₆ alkyl substituted by 1 or more R ^1-1-1 is

In a preferred embodiment, among R ^1-1-2a , R ^1-1-2b and R ^1-1-3 , the C ₁ -C ₆ alkyl groups are independently methyl, ethyl, n-propyl , isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl.

In a preferred embodiment, among R ^1-1-2 and R ^1-1-3 , said halogen is independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ^1-1-3 , the C ₁ -C ₆ alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, Isobutyl or tert-butyl, eg methyl or ethyl.

In a preferred embodiment, in R ^1-1 , the 4-10 membered cycloalkyl group substituted by 1 or more R ^1-1-2 is

In a preferred embodiment, in R ^1-1 , the 3-membered cycloalkyl group substituted by 1 or more R ^1-1-4 is

In a preferred embodiment, in R ^1-1 , any two adjacent R ^1-1s together with ^the carbon atoms connected to them form 4-10 substituted by one or more R ^1-1-3 The 4-10 membered cycloalkyl group substituted by 1 or more R ^1-1-3 in the membered cycloalkyl group is

(pass

Form a parallel ring with the C ₆ -C ₁₈ aryl where R ^1-1 is located, namely

).

In a preferred embodiment, in R ¹ , the C ₆ -C ₁₈ aryl group substituted by 1 or more R ^1-1 is

(For example

),

(For example

),

(For example

),

(For example

),

(For example

),

(For example

),

(For example

),

(For example

),

(For example

),

(For example

)or

(For example

).

(For example

)or

(For example

).

In a preferred embodiment, in R ^1-2 , the C ₁ -C ₆ alkyl _and the C 1 -C ₆ alkyl in the C ₁ -C ₆ alkyl substituted by 1 or more halogens are independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.

In a preferred embodiment, in R ^1-2 , the halogen in the C ₁ -C ₆ alkyl substituted by 1 or more halogens is independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ^1-2 , the C ₁ -C ₆ alkyl substituted by one or more halogens is trifluoromethyl.

In a preferred embodiment, in R ^1-2 , the C ₃ -C ₆ cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl.

In a preferred embodiment, in R ¹ , the 5-10 membered heteroaryl group substituted by 1 or more R ^1-2 is

(For example

),

(For example

)or

(For example

).

In a preferred embodiment, in R ² , said halogen is independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ³ , _the C ₁ -C ₆ alkyl in the C 1 -C ₆ alkyl substituted by 1 or more R ^3-1 is methyl, ethyl, n- Propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl or n-propyl.

In a preferred embodiment, in R ^3-1 and R ^3-1-1 , the -OC ₁ -C ₆ alkyl is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, isobutoxy or tert-butoxy, eg methoxy. Preferably, R ^3-1 here is defined as R ^3-1 in case 1.

In a preferred embodiment, in R ^3-1 in case 1, the 4-10 membered heterocycloalkyl and "4-10 membered heterocycle substituted by 1 or more R ^3-1-1 The heterocycloalkyl in "alkyl" is independently bicyclic heterocycloalkyl.

In a preferred embodiment, in R ^3-1 , the 4-10 membered heterocycloalkyl and "4-10 membered heterocycloalkyl substituted by 1 or more R ^3-1-1 " The 4-10-membered heterocycloalkyl group is independently an 8-membered heterocycloalkyl group, and can also be a bicyclo[3.2.1]octaheterocycloalkyl group. Preferably, R ^3-1 here is defined as R ^3-1 in case 1.

In a preferred embodiment, in R ^3-1 , the 4-10 membered heterocycloalkyl and "4-10 membered heterocycloalkyl substituted by 1 or more R ^3-1-1 " The heteroatoms in the 4-10 membered heterocycloalkyl are independently N and/or O, and the number of heteroatoms is 1 or 2. Preferably, R ^3-1 here is defined as R ^3-1 in case 1.

In a preferred embodiment, in R ^3-1 , the 4-10 membered heterocycloalkyl and "4-10 membered heterocycloalkyl substituted by 1 or more R ^3-1-1 " The 4-10 membered heterocycloalkyl groups are independently

Preferably, R ^3-1 here is defined as R ^3-1 in case 1.

In a preferred embodiment, in R ^3-1 , the 4-10 membered heterocycloalkyl substituted by 1 or more R ^3-1-1 is

Preferably, R ^3-1 here is defined as R ^3-1 in case 1. In a preferred embodiment, in R ^3-1 , the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R ^3-1-2 are independently N and/ or O, and the number of heteroatoms is 1 or 2. Preferably, R ^3-1 here is defined as R ^3-1 in case 2.

In a preferred embodiment, in R ^3-1 , the 5-6 membered monocyclic heterocycloalkyl substituted by one or more R ^3-1-2 is tetrahydropyrrolyl or morpholinyl. Preferably, R ^3-1 here is defined as R ^3-1 in case 2.

In a preferred embodiment, in R ^3-1 in case 2, the heterocycloalkyl in the 8-membered heterocycloalkyl substituted by 1 or more R ^3-1-3 is bicyclic Heterocycloalkyl. In a preferred embodiment, in R ^3-1 , the 8-membered heterocycloalkyl group substituted by 1 or more R ^3-1-3 is bicyclo[3.2.1]octane base or bicyclo[3.3.0]octacycloalkyl. Preferably, R ^3-1 here is defined as R ^3-1 in case 2.

In a preferred embodiment, in R ^3-1 , the heteroatom in the 8-membered heterocycloalkyl substituted by one or more R ^3-1-3 is N, and the number is 1. Preferably, R ^3-1 here is defined as R ^3-1 in case 2.

In a preferred embodiment, among R ^3-1 in case 2, the 8-membered heterocycloalkyl group substituted by 1 or more R ^3-1-3 is bicyclic [3.2.1] An octaheterocycloalkyl group or a bicyclo[3.3.0] octaheterocycloalkyl group, wherein the heteroatom in the heterocycloalkyl group is N and the number is one.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , the 3-6 membered heterocycloalkyl is 4 membered heterocycloalkyl.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , the heterocycloalkyl in the 3-6 membered heterocycloalkyl is a monocyclic heterocycloalkyl.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , the heteroatom in the 3-6 membered heterocycloalkyl is O, and the number is 1.

In a preferred embodiment, in R ^3-1-2 and R ^3-1-3 , the 3-6 membered heterocycloalkyl is oxetane, for example

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , said C ₁ -C ₆ alkyl, " said one or more R ^{3-1-1- 1} The C ₁ -C ₆ alkyl in "substituted C ₁ -C ₆ alkyl" and the C ₁ -C ₆ alkyl in the -OC ₁ -C ₆ alkyl are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl or isopropyl.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , said halogen is independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ^3-1-2 and R ^3-1-3 _, the C _3-6 cycloalkyl is independently cyclopropyl, cyclobutyl, cyclopentyl or cyclobutyl Alkyl, such as cyclopropanyl.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , any two adjacent R ^3-1-3 and the carbon atoms connected to them together form a 3-10-membered ring Alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, eg cyclopropyl.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , any two R ^3-1-3 connected to the same atom together form 3- The 10-membered cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, eg cyclopropyl or cyclobutyl.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , any two R ^3-1-3 connected to the same atom together form 4- The 10-membered heterocycloalkyl group is a 4-6-membered heterocycloalkyl group.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , any two R ^3-1-3 connected to the same atom together form 4- The heteroatoms in the 10-membered heterocycloalkyl are independently N and/or O, and the number of heteroatoms is 1 or 2.

In a preferred embodiment, in R ^3-1-1-1 , the 3-6 membered cycloalkyl group is cyclopropanyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropane base.

In a preferred embodiment, in R ^3-1-1-1 , said halogen is independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ^3-1-1-1 , the 3-8 membered heterocycloalkyl and the substituted by one or more R ^3-1-1-1-1 The 3-8 membered heterocycloalkyl in the 3-8 membered heterocycloalkyl is independently a 5-6 membered monocyclic heterocycloalkyl or cyclopropyl and a 5-membered heterocycloalkyl, and the heteroatom is N and/or S, the number is 1 or 2, for example

In a preferred embodiment, in R ^3-1-1-1-1 , the C ₁ -C ₆ alkyl and substituted by one or more R ^3-1-1-1-1-1 C ₁ -C ₆ alkyl in C ₁ -C ₆ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, For example methyl.

In a preferred embodiment, among R ^3-1-2 and R ^3-1-3 , the C ₁ -C ₆ alkyl substituted by one or more R ^3-1-1-1 is

In a preferred embodiment, in R ^3-1 , the 5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R ^3-1-2 is

In a preferred embodiment, in R ^3-1 , the 8-membered heterocycloalkyl group substituted by one or more R ^3-1-3 is

In a preferred embodiment, in R ³ , the C ₁ -C ₆ alkyl substituted by one or more R ^3-1 is

In a preferred embodiment, in Y, the C ₁ -C ₆ alkyl in the C ₁ -C ₆ alkyl substituted by one or more Y ^1-1 is methyl, ethyl, n-propyl radical, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as ethyl.

In a preferred embodiment, in Y, the C ₂ -C ₆ alkenyl in the C 2 -C ₆ alkenyl substituted by 1 or more Y ^1-2 is C ₂ _-C ₄ alkenyl, For example vinyl.

In a preferred embodiment, in Y, the C ₂ _-C 6 alkynyl in the C 2 -C ₆ alkynyl substituted by 1 or more Y ^1-3 is a _{C 2} _-C ₄ alkynyl, For example ethynyl.

In a preferred embodiment, in Y, the C ₃ -C ₆ cycloalkyl in the C ₃ -C ₆ cycloalkyl substituted by 1 or more Y ^1-4 is cyclopropyl, cyclobutyl , cyclopentyl or cyclohexyl, such as cyclopropyl.

In a preferred embodiment, among Y ^1-1 , Y ^1-2 , Y ^1-3 and Y ^1-4 , said 4-10 membered heterocycloalkyl and said "are replaced by 1 or more The heterocycloalkyl group in Y ^1-1-1 substituted 4-10 membered heterocycloalkyl group is independently bicyclic heterocycloalkyl group. In a preferred embodiment, among Y ^1-1 , Y ^1-2 , Y ^1-3 and Y ^1-4 , said 4-10 membered heterocycloalkyl and said "are replaced by 1 or more The 4-10 membered heterocycloalkyl group in Y ^1-1-1 substituted 4-10 membered heterocycloalkyl group is independently an 8-membered heterocycloalkyl group, and can also be a bicyclo[3.3.0]octane heterocycloalkane base.

In a preferred embodiment, among Y ^1-1 , Y ^1-2 , Y ^1-3 and Y ^1-4 , said 4-10 membered heterocycloalkyl and said "are replaced by 1 or more The heteroatom in Y ^1-1-1 substituted 4-10 membered heterocycloalkyl" is N, and the number is 1.

In a preferred embodiment, among Y ^1-1 , Y ^1-2 , Y ^1-3 , Y ^1-4 and Y ^1-1-1 , the C ₁ -C ₆ alkyl group and the - The C ₁ -C ₆ alkyl in the OC ₁ -C ₆ alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a preferred embodiment, in Y ^1-1-1 , the halogen is F, Cl, Br or I, such as Cl or F.

In a preferred embodiment, in Y, the C ₁ -C ₆ alkyl substituted by one or more Y ^1-1 is

In a preferred embodiment, in Y, the C ₂ -C ₆ alkenyl substituted by one or more Y ^1-2 is

In a preferred embodiment, in Y, the C ₂ -C ₆ alkynyl substituted by one or more Y ^1-3 is

In a preferred embodiment, in Y, the C ₃ -C ₆ cycloalkyl group substituted by one or more Y ^1-4 is

In a preferred embodiment, among Y ^1-5 and Y ^1-6 , the C ₁ -C ₆ alkane is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl group, isobutyl or tert-butyl, such as methyl.

In a preferred embodiment, among Y ^1-5 and Y ^1-6 , the 4-10 membered heterocycloalkyl group substituted by 1 or more halogens is an 8-membered heterocycloalkyl group, and the heteroatom is N , the number is 1, and it can also be bicyclic [3.3.0] octaheterocycloalkyl.

In a preferred embodiment, among Y ^1-5 and Y ^1-6 , the 4-10 membered heterocycloalkyl substituted by 1 or more halogens is

In a preferred embodiment, in R ⁴ , the 7-12-membered bridged ring heterocycloalkyl is an 8-membered bridged ring heterocycloalkyl group, the heteroatom is N, the number is 2, and it can also be a bicyclic ring [3.2.1] Octyl, eg

In a preferred embodiment, in R ⁴ , the 7-12 membered bridged ring heterocyclyl in the "7-12 membered bridged ring heterocycloalkyl substituted by 1 or more R ^4-1 " The alkyl group is an 8-membered bridged ring heterocycloalkyl group, the heteroatom is N, and the number is 2, and it can also be a bicyclo[3.2.1]octyl group.

In a preferred embodiment, in R ^4-1 , the C ₁ -C ₆ alkyl is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl.

In a preferred embodiment, in R ⁴ , the "7-12 membered bridged ring heterocycloalkyl substituted by 1 or more R ^4-1 " is

In a preferred embodiment, in R ⁵ , the C ₁ -C ₆ alkyl group is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl base.

In a preferred embodiment, in R ⁵ , said halogen is preferably F, Cl, Br or I, such as F.

In a preferred embodiment, in R ⁵ , the halogen in the C ₁ -C ₆ alkyl substituted by one or more halogens is independently F, Cl, Br or I, such as F.

In a preferred embodiment, in R ⁵ , the C ₁ -C ₆ alkyl in the C ₁ -C ₆ alkyl substituted by one or more halogens is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, eg methyl.

In a preferred embodiment, in R ⁵ , the C ₁ -C ₆ alkyl substituted by one or more halogens is difluoromethyl.

In a preferred embodiment, ^R is

The 4-10 membered heterocycloalkyl group substituted by 1 or more R ^3-1-1 is

The 5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R ^3-1-2 is

The 8-membered heterocycloalkyl group substituted by 1 or more R ^3-1-3 is

In a preferred embodiment, the compound shown in formula I is any one of the following compounds:

; used in the structure

Refers to, the chemical bond that expresses the three-dimensional configuration

or a mix thereof.

In a preferred embodiment, the pharmaceutically acceptable salt of the compound shown in formula I is any of the following compounds:

used in the structure

Refers to, the chemical bond that expresses the three-dimensional configuration

or a mix thereof.

pass

The deprotection group was obtained, and the retention time of compound 297-4a under the following chiral conditions was 8.91 minutes: chiral column CHIRALPAK IC, 2x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol/L ammonia methanol) , mobile phase B: ethanol; flow rate: 20 ml/min; elution with 10% phase B in 21 minutes, detector UV 230/210 nm;

pass

The deprotection group was obtained, and the retention time of compound 297-4b was 13.2 minutes under the following chiral conditions: chiral column CHIRALPAK IC, 2x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol/L ammonia methanol) , mobile phase B: ethanol; flow rate: 20 ml/min; elution with 10% phase B in 21 minutes, detector UV 230/210 nm;

pass

The deprotection group was obtained, and the retention time of compound 298-5a under the following chiral conditions was 1.363 minutes: chiral column CHIRALPAK IF, 2x 25 cm, 5 microns; mobile phase A: n-hexane (0.1%, 10 mol/liter ammonia Methanol), mobile phase B: methanol/ethanol (1/1); flow rate: 20 ml/min; elution with 20% mobile phase B; detector UV222 nanometers;

pass

The deprotection group was obtained, and the retention time of compound 298-5b under the following chiral conditions was 1.958 minutes: chiral column CHIRALPAK IF, 2x 25 cm, 5 microns; mobile phase A: n-hexane (0.1%, 10 mol/liter ammonia Methanol), mobile phase B: methanol/ethanol (1/1); flow rate: 20 ml/min; elution with 20% mobile phase B; detector UV222 nanometers;

pass

The deprotection group was obtained, and the retention time of compound 303-7a under the following chiral conditions was 4.665 minutes: chiral column CHIRAL ART Cellulose-SC, 2x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol/L Ammonia methanol), mobile phase B: ethanol; flow rate: 20 ml/min; within 12 minutes with 50% phase B for elution; detector UV224/211 nanometers;

pass

The deprotection group was obtained, and the retention time of compound 303-7b under the following chiral conditions was 7.115 minutes: chiral column CHIRAL ART Cellulose-SC, 2x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol/L Ammonia methanol), mobile phase B: ethanol; flow rate: 20 ml/min; within 12 minutes with 50% phase B for elution; detector UV224/211 nanometers;

pass

The retention time of compound 305-10a was 21.3 minutes under the following chiral resolution conditions: chiral column (R,R)-WHELK-O1-Kromasil, 2.11x 25 cm, 5 μm; mobile phase A : n-hexane (0.1% 2 mol/L ammonia methanol); mobile phase B: isopropanol; flow rate: 20 ml/min; eluted with 50% mobile phase for 48 minutes; detector: 206/234 nanometers;

pass

The retention time of compound 305-10b was 31.2 minutes under the following chiral resolution conditions: chiral column (R,R)-WHELK-O1-Kromasil, 2.11x 25 cm, 5 μm; mobile phase A : n-hexane (0.1% 2 mol/L ammonia methanol); mobile phase B: isopropanol; flow rate: 20 ml/min; eluted with 50% mobile phase for 48 minutes; detector: 206/234 nm.

According to the present invention, the compound represented by formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound It can be synthesized by methods including methods similar to those known in the chemical field, and its steps and conditions can refer to the steps and conditions of similar reactions in the art, especially according to the description herein. Starting materials are generally from commercial sources such as Aldrich or can be readily prepared using methods well known to those skilled in the art (available through SciFinder, Reaxys online database).

The present invention provides a pharmaceutical composition, which comprises the above-mentioned compound as shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its Prodrugs, their metabolites or their isotope compounds and pharmaceutical excipients.

In the pharmaceutical composition, the compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, The dosage of its metabolites or its isotopic compounds can be therapeutically effective.

The present invention also provides the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite , its isotope compound or the application of the above-mentioned pharmaceutical composition in the preparation of KRAS mutant protein inhibitors.

In the application, the KRAS mutein can be a KRAS G12D mutein; the KRAS mutein inhibitor is used in vitro, mainly for experimental purposes, for example: as a standard sample or a control sample to provide comparison, Or make a kit according to conventional methods in the art to provide rapid detection for the effect of KRAS G12D mutant protein inhibitors.

The present invention also provides the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite , its isotope compound or the above-mentioned pharmaceutical composition in the preparation of medicines, and the medicines are used to prevent or treat cancers mediated by KRAS mutations.

The KRAS mutein is preferably a KRAS G12D mutein.

The cancer mediated by the KRAS mutant protein can be blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer.

The present invention also provides the above-mentioned compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite , its isotope compound or the above-mentioned pharmaceutical composition in the preparation of medicine, and the medicine is used for preventing or treating cancer.

The cancers are, for example, hematological cancers, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer.

The cancer is a cancer mediated by KRAS mutation. The KRAS mutein can be a KRAS G12D mutein.

The present invention also provides a method for treating, preventing or treating cancer mediated by KRAS mutation, which comprises administering to a patient

A therapeutically effective amount of the above-mentioned compound represented by formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite, its isotope Compound or the above-mentioned pharmaceutical composition.

The KRAS mutein can be a KRAS G12D mutein.

The present invention also provides a method for treating, preventing or treating cancer, which comprises administering to a patient a therapeutically effective amount of the above-mentioned compound represented by formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer isomer, its tautomer, its prodrug, its metabolite, its isotopic compound or the above-mentioned pharmaceutical composition.

The present disclosure also relates to a method of treating a hyperproliferative disease in a mammal, the method comprising administering to said mammal a therapeutically effective amount of a compound of the present disclosure or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or its derivatives.

Ras mutations, including but not limited to K-Ras, H-Ras or N-Ras mutations that have been identified in hematological cancers or malignancies such as cancers affecting the blood, bone marrow and/or lymph nodes. Accordingly, certain embodiments relate to administering a disclosed compound (eg, in the form of a pharmaceutical composition) to a patient in need of treatment for a hematological cancer or malignancy.

In certain specific embodiments, the present disclosure is directed to a method for treating lung cancer comprising administering an effective amount of any of the compounds described above (or a pharmaceutical composition comprising the compound) to a subject in need thereof.

In the present invention, the cancer or malignant tumor includes but not limited to leukemia and lymphoma. In some embodiments, the blood diseases are such as acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), chronic Myelogenous leukemia (CML), acute monocytic leukemia (AMoL), and/or other leukemias. In certain embodiments, the lymphoma is, for example, all subtypes of Hodgkin's lymphoma or non-Hodgkin's lymphoma.

In the present invention, in some embodiments, the lung cancer is non-small cell lung cancer (NSCLC), such as adenocarcinoma, squamous cell lung cancer or large cell lung cancer. In other embodiments, the lung cancer is small cell lung cancer. Other lung cancers include, but are not limited to, adenomas, carcinoids, and undifferentiated carcinomas.

In the present invention, in some embodiments, the cancer, such as acute myeloid leukemia, juvenile cancer, childhood adrenocortical carcinoma, AIDS-related cancer (such as lymphoma and Kaposi's sarcoma), anal cancer, appendix Carcinoma, Astrocytoma, Atypical Dysmorphoid, Basal Cell Carcinoma, Cholangiocarcinoma, Bladder Cancer, Bone Cancer, Brain Stem Glioma, Brain Tumor, Breast Cancer, Bronchial Tumor, Burkitt Lymphoma, Carcinoid, Atypical malformations, embryonal tumors, germ cell tumors, primary lymphomas, cervical cancer, childhood cancers, chordomas, cardiac tumors, chronic lymphocytic leukemia (CLL), chronic myelogenous leukemia (CML), chronic Myeloproliferative disorders, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, extrahepatic ductal carcinoma in situ (DCIS), embryonal tumors, central nervous system cancer, endometrial cancer, ependymoma, Esophageal cancer, granulomatous neuroblastoma, Ewing's sarcoma, extracranial germ cell tumor, extragonadal germ cell tumor, eye cancer, fibrous histiocytoma of bone, gallbladder cancer, gastric cancer, gastrointestinal carcinoid, gastrointestinal Stromal tumor (GIST), germ cell tumor, gestational trophoblastic tumor, hairy cell leukemia, head and neck cancer, heart disease, liver cancer, Hodgkin lymphoma, hypopharyngeal cancer, intraocular melanoma, islet cell tumor, pancreatic neuroendocrine Tumors, Kidney Cancer, Laryngeal Cancer, Lip and Mouth Cancer, Liver Cancer, Lobular Carcinoma in Situ (LCIS), Lung Cancer, Lymphoma, Metastatic Squamous Cell Carcinoma, Occult Primary, Midline Cancer, Oral Cancer, Multiple Endocrine Oncological syndromes, multiple myeloma/plasmacytoma, mycoses, mycosis fungoides, myelodysplastic syndromes, myelodysplastic/myeloproliferative neoplasms, multiple myeloma, Merkel cell carcinoma, malignant mesothelium Malignant fibrous histiocytoma of bone and osteosarcoma, nasal cavity and paranasal sinuses, nasal cavity and sinus neuroblastoma, non-Hodgkin lymphoma, non-small cell lung cancer (NSCLC), oral cavity cancer, lip and oral cavity cancer, mouth Pharyngeal cancer, ovarian cancer, pancreatic cancer, papillomatosis, paraganglioma, paranasal sinus and nasal cavity cancer, parathyroid cancer, penile cancer, throat cancer, pleuropulmonary blastoma, primary central nervous system ( CNS) lymphoma, prostate cancer, rectal cancer, transitional cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, skin cancer, gastric (stomach) cancer, small cell lung cancer, small bowel cancer, soft tissue sarcoma, T-cell lymphoma, Cancer of the testis, larynx, thymoma and thymic carcinoma, thyroid, transitional cell carcinoma of the renal pelvis and ureter, trophoblastic tumors, uncommon childhood carcinomas, urethra, uterine sarcoma, vaginal, vulvar, or viral . In some embodiments, the non-cancerous hyperproliferative disease, eg, benign hyperplasia of the skin (eg, psoriasis), restenosis, or the prostate (eg, benign prostatic hypertrophy (BPH)).

Definition of Terms

The term "pharmaceutically acceptable" means that salts, solvents, auxiliary materials, etc. are generally non-toxic, safe and suitable for use by patients. The "patient" is preferably a mammal, more preferably a human.

The term "pharmaceutically acceptable salt" refers to a pharmaceutically acceptable salt as defined herein and possesses all the effects of the parent compound. Pharmaceutically acceptable salts A pharmaceutically acceptable salt can be prepared by adding a corresponding acid to an appropriate organic solvent of an organic base and treating it according to a conventional method.

Examples of salt formation include: For base addition salts, it is possible by using alkali metal or alkaline earth metal hydroxides or alkoxides (e.g. ethanolate or methoxide) or suitable basic organic amines (e.g. diethanolamine, cholate) in aqueous media. alkali or meglumine) to prepare alkali metal (such as sodium, potassium or lithium) or alkaline earth metal (such as aluminum, magnesium, calcium, zinc or bismuth) salts.

Alternatively, for acid addition salts, salts with inorganic acids, such as hydrochloric, hydrobromic, sulfuric, nitric, phosphoric; and organic acids, such as acetic, benzenesulfonic, benzoic, camphorsulfonic, Citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, oxalic acid, pyruvic acid, propanediol acid, mandelic acid, methanesulfonic acid, mucofuric acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, tartaric acid, citric acid, cinnamic acid, p-toluenesulfonic acid, or trimethylacetic acid.

The term "solvate" refers to a compound of the present invention in combination with a stoichiometric or non-stoichiometric amount of solvent. The solvent molecules in a solvate may exist in an ordered or non-ordered arrangement. The solvent includes but not limited to: water, methanol, ethanol and the like.

The term "prodrug" refers to a compound that is inactive or less active in vitro after the chemical structure of the drug is modified, and releases the active drug through enzymatic or non-enzymatic conversion in vivo to exert its medicinal effect.

The term "metabolite" refers to intermediate metabolites and final metabolites in metabolism.

The term "isotopic compound" means that one or more atoms in a compound may be present in non-natural abundance. Take the hydrogen atom, for example, in the form of its unnatural abundance meaning that about 95% of it is deuterium.

The term "pharmaceutical excipients" may be those excipients widely used in the field of pharmaceutical production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide a method for the subject to dissolve the active ingredient at a desired rate after administration, or to promote the activity of the subject after administration of the composition. The ingredients are effectively absorbed. The pharmaceutical excipients can be inert fillers, or provide certain functions, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredients of the composition. Described pharmaceutical adjuvant can comprise one or more in the following adjuvant: binding agent, suspending agent, emulsifying agent, diluent, filler, granulating agent, adhesive, disintegrating agent, lubricant, antiadhesive Glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, coloring agents, flavoring agents, and sweeteners.

The pharmaceutical compositions of the present invention may be prepared according to the disclosure using any method known to those skilled in the art. For example, conventional mixing, dissolving, granulating, emulsifying, milling, encapsulating, entrapping or freeze-drying processes.

The pharmaceutical compositions of the present invention may be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical or parenteral (infusion, injection, implant). Intravenous, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the invention may also be in controlled or delayed release dosage forms (eg liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, gelcaps, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry preparations that can be dissolved or suspended in pharmaceutically acceptable carriers, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges agent.

"Treatment" means any treatment of a disease in a mammal, including: (1) preventing the disease, that is, causing the symptoms of the clinical disease to not develop; (2) inhibiting the disease, that is, preventing the development of clinical symptoms; (3) alleviating the disease, That is to cause the subsidence of clinical symptoms.

"Effective amount" means that, when administered to a patient in need of treatment, the compound is in an amount sufficient to (i) treat the associated disease, (ii) attenuate, ameliorate, or eliminate one or more symptoms of a particular disease or condition, or (iii) Delaying the onset of one or more symptoms of a particular disease or condition described herein. The amount corresponding to the amount of the carbonyl heterocyclic compound represented by formula II or a pharmaceutically acceptable salt thereof or the above-mentioned pharmaceutical composition will be based on, for example, the specific compound, the disease condition and its severity, The characteristics of the patient in need of treatment (eg weight) will vary, but can nonetheless be routinely determined by those skilled in the art.

"Prevention" in the present invention refers to the reduction of the risk of acquiring or developing a disease or disorder.

The term "alkyl" refers to a straight or branched chain alkyl group having the indicated number of carbon atoms. Examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl and It resembles an alkyl group. Unless a substituent is specifically indicated, an alkyl group is unsubstituted.

The term "heterocycloalkyl" means a stable 3- to 10-membered saturated cyclic group consisting of 2-9 carbon atoms and 1-3 heteroatoms selected from nitrogen, oxygen and sulfur. Unless specifically stated otherwise in this specification, a heterocycloalkyl group may be monocyclic ("monocyclic heterocycloalkyl"), or a bicyclic, tricyclic or multicyclic ring system, which may include fused (fused ring), bridged (bridged ring) or spiro (spiro) ring system (e.g. a bicyclic ring system (“bicyclic heterocycloalkyl”). A heterocycloalkyl bicyclic ring system can be in a or both rings include one or more heteroatoms; and are saturated. Unless a substituent is specified, a heterocycloalkyl is unsubstituted.

The term "aryl" refers to phenyl or naphthyl.

The term "heteroaryl" refers to an aromatic group containing heteroatoms, preferably containing 1, 2 or 3 aromatic 4-10 membered monocyclic or 5-10 membered bicyclic rings independently selected from nitrogen, oxygen and sulfur, For example, furyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, isoxazolyl, oxazolyl, diazolyl, imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl , thiazolyl, isothiazolyl, thiadiazolyl, benzimidazolyl, indolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, quinoline base, isoquinolinyl, etc.

The description of the invention used in the structural formula

Refers to, the chemical bond that expresses the three-dimensional configuration

or mixtures thereof, such as compounds

means

Mix in any proportion.

Those skilled in the art can understand that, according to the practice used in this field, the present invention describes the structural formula used in the group

means that the corresponding group is connected with other fragments and groups in the compound through this site.

On the basis of not violating common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present invention.

The positive and progressive effect of the present invention is that the compound of the present invention has a good inhibitory effect on the KRAS G12D mutant protein.

Detailed ways

The present invention is further illustrated below by means of examples, but the present invention is not limited to the scope of the examples.

Example 1

4-((S or R)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( R)-2-methoxy-3-((1R,3S,5S)-3-methoxy-8-azabicyclo[3.2.1]octyl-8-yl)propoxy)quinazoline -7-yl)-5-ethylnaphthalene-2-ol dihydrochloride 288a; 4-((R or S)-4-((1R,5S)-3,8-diazacyclo[3.2. 1] Octyl-3-yl)-6,8-difluoro-2-((R)-2-methoxy-3-((1R,3S,5S)-3-methoxy-8-nitrogen Heterobicyclo[3.2.1]octyl-8-yl)propoxy)quinazolin-7-yl)-5-ethylnaphthalene-2-ol dihydrochloride 288b

The synthetic route is as follows:

step 1:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, to compound 2,4-difluoro-3-bromoaniline (100 g, 456.718 mmol, 1.0 equivalent) in acetonitrile (1000 ml) was added N-iodosuccinyl Amine (129.8 g, 548.062 mmol, 1.2 equiv) and p-toluenesulfonic acid monohydrate (9.14 g, 45.672 mmol, 0.1 equiv). The mixture was stirred at 70°C under nitrogen protection for 16 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and 1000 ml of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (1000 mL x 3), and the organic phases were combined. The organic phase was washed successively with saturated sodium carbonate solution (1000 ml x 2), saturated sodium sulfite (1000 ml) and saturated brine (500 ml), then dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain the crude product . The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 288-10 (yellow solid, 152 g, Yield 94%). MS (ESI, m/z): 333.8/335.8 [M+H] ⁺ .

Step 2:

Under the condition of stirring at 25 degrees Celsius, bistriphenylphosphine palladium dichloride (31.96 g, 43.24 mmol, 0.1 equiv) and triethylamine (165.84 g, 1556.86 mmol, 3.6 equiv). Air is replaced by carbon monoxide by gas displacement operation. The mixture was stirred at 80° C. for 16 hours under 1 atmosphere of carbon monoxide, and the reaction progress was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and the mixture was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 288-11 (yellow solid, 95 g, Yield 74%). MS (ESI, m/z): 280.0/282.0 [M+H] ⁺ .

Step 3:

To a solution of compound 288-11 (93.5 g, 317.154 mmol, 1.0 eq) in THF (250 mL) was slowly added trichloroacetyl isocyanate (94.34 g, 475.731 mmol, 1.5 eq) under stirring at 25°C. The mixture was stirred at 25°C for 0.5 h, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was slurried by 500 ml of methyl tert-butyl ether to obtain compound 288-12 (white solid, 132 g, yield 84%). MS (ESI, m/z): 466.9/468.9/470.9 [M+H] ⁺ .

Step 4:

To a solution of compound 288-12 (132 g, 267.686 mmol, 1.0 eq) in methanol (1300 mL) was slowly added ammonia methanol solution (7 mol/L, 130 mL) under stirring at 25°C. The mixture was stirred at 25°C for 1 hour, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was slurried by methyl tert-butyl ether (1000 mL) to obtain compound 288-13 (white solid, 80 g, yield 97%). MS (ESI, m/z): 276.9/278.9 [M+H] ⁺ .

Step 5:

Under the condition of stirring under nitrogen protection at 0 degrees Celsius, compound 288-13 (40 g, 137.172 mmol, 1.0 equivalent), phosphorus oxychloride (600 ml) and N,N-diisopropylethyl were added successively to a 1000 ml flask. Amine (60 mL). The resulting mixture was stirred at 90°C for 16 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 288-14 (pale yellow solid, 27 g , yield 59%). MS (ESI, m/z): 312.9/314.9/316.9 [M+H] ⁺ .

Step 6:

Under the condition of nitrogen protection and stirring at 0 degrees Celsius, compound 288-14 (27 g, 81.711 mmol, 1.0 equivalent) and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (18.26 g, 81.711 mmol, 1.0 eq) in dichloromethane (300 mL) was slowly added triethylamine (26.11 g, 245.133 mmol, 3 eq). The mixture was stirred at 25°C for 1 hour, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 279-1 (pale yellow solid, 41 g , yield 97%). MS(ESI,m/z):488.9/490.8[M+H] ⁺ ; ¹ H NMR(300MHz, CDCl ₃ )δ7.43–7.37(m,1H),4.55–4.31(m,4H),3.79– 3.54(m,2H),2.03–1.91(m,2H),1.82–1.70(m,2H),1.54(s,9H); ¹⁹ F NMR(282MHz,CDCl ₃ )δ-106.78,-106.79,-111.04 ,-111.04.

Step 7:

Under stirring condition at 25 degrees centigrade, (3-external)-3-methoxy-8-azabicyclo[3.2.1]octane hydrochloride (900 mg, 4.812 mmol, 1.0 eq.) and potassium carbonate ( 2.1 g, 14.43 mmol, 3 eq) in ethanol (9 ml) solution was slowly added tert-butyldimethylsilyl (R)-(-)-glycidyl ether (2.1 g, 10.586 mmol, 2.2 eq ). The mixture was stirred at 25°C for 2 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the insoluble matter was removed by filtration, the filter cake was washed with ethanol (10 ml x 3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 288-15 (colorless oil, 987 mg , yield 59%). MS (ESI, m/z): 330.2 [M+H] ⁺ .

Step 8:

Under the condition of nitrogen protection and stirring at 0 degrees Celsius, to the solution of compound 288-15 (860 mg, 2.479 mmol, 1.0 eq) in anhydrous THF (9 mL) was slowly added a solution of potassium tert-butoxide in THF (1 mol/L, 5.7 mL, 5.7 mmol, 2.3 equiv). After the mixture was stirred at 0°C for 0.5 hours, methyl iodide (851.92 mg, 5.702 mmol, 2.3 eq) was slowly added to the reaction solution. The mixture was stirred at 25°C for 2 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, water (20 mL) was added to the reaction solution, the mixture was extracted with ethyl acetate (10 mL) and dichloromethane (10 mL×2), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 288-16 (pale yellow oil, 687 mg , yield 76%). MS (ESI, m/z): 344.5 [M+H] ⁺ .

Step 9:

To a solution of compound 288-16 (320 mg, 0.885 mmol, 1.0 eq) in dichloromethane (4 mL) was slowly added trifluoroacetic acid (4 mL) under stirring at 0 °C. The mixture was stirred at 25°C for 8 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% methanol (10% 7 mol/liter ammonia methanol)/dichloromethane, and the obtained fraction was obtained by removing the solvent by rotary evaporation under reduced pressure. Compound 288-17 (pale yellow oil, 152 mg, yield 71%). MS (ESI, m/z): 230.2 [M+H] ⁺ .

Step 10:

Compound 282-2 was synthesized with reference to the patent (WO2021041671).

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, compound 279-1 (2.4 g, 4.655 mmol, 1.0 equivalent), compound 282-2 (1.51 g, 4.190 mmol, 0.9 equivalent), potassium phosphate (2.08 g, 9.310 mmol, 2.0 equiv), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxy , phosphapentyl conjugate (0.24 g, 0.698 mmol, 0.15 eq), tris(dibenzylideneacetone) dipalladium (0) (0.31 g, 0.326 mmol, 0.07 eq), toluene (20 ml) and water (4 ml). The mixture was reacted at 80°C for 3 hours under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature. 50 mL of water was added to the reaction solution for dilution, the resulting mixture was extracted with ethyl acetate (50 mL x 2) and dichloromethane (50 mL x 1), and the organic phases were combined. The organic phase was dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 15% ethyl acetate/(petroleum ether/dichloromethane=7:3), and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain the compound 288-18 (pale yellow solid, 2.02 g, 67%). MS (ESI, m/z): 625.0/627.0 [M+H] ⁺ .

Step 11:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, compound 288-18 (190 mg, 0.283 mmol, 1 equivalent), triethylenediamine (6.68 mg, 0.057 mmol, 0.2 equivalent), cesium carbonate ( 187.96 mg, 0.566 mmol, 2 eq), 288-17 (81.88 mg, 0.340 mmol, 1.2 eq) and N,N-dimethylformamide (2.5 mL). The mixture was reacted at 100° C. for 2 hours under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature. The mixture was concentrated under reduced pressure to obtain crude product. The resulting crude product was purified by a reverse-phase chromatography column (C18 column), eluting with 50% → 95% methanol/water (0.1% ammonia) within 20 minutes; detector, UV 254 nm; The solvent was removed by rotary evaporation to obtain compound 288-2 (off-white solid, 161 mg, yield 66%). MS (ESI, m/z): 818.1 [M+H] ⁺ .

Step 12:

Compound 288-2 (146 mg) obtained in step 11 was subjected to chiral resolution by preparative liquid chromatography: chiral column CHIRALPAK IC, 3 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol/L Ammonia methanol), mobile phase B: ethanol; flow rate: 18 ml/min; within 20 minutes with 50% phase B for elution, detector UV 224/210 nanometers, to obtain two products. The product with shorter retention time (7.535 minutes) is compound 288-2a (off-white solid, 68 mg, recovery rate 46%), MS (ESI, m/z): 818.1[M+H] ⁺ ; longer retention time (13.075 minutes) The product was compound 288-2b (off-white solid, 64 mg, recovery 45%), MS (ESI, m/z): 818.1[M+H] ⁺ .

In the chiral resolution method of some similar chiral compounds in the present invention, the respective retention times and ee/dr values are shown in the following table 1:

Table 1

Step 13:

Under the condition of stirring at room temperature, a solution of hydrochloric acid in 1,4-dioxane (4 mol/L, 2 ml). The reaction solution was reacted at room temperature for 1 hour, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product is purified by a reverse phase chromatographic column (C18 column): reverse phase column Xselect CSH C18 OBD Column, 30x 150 mm, 5 microns, mobile phase A: water (0.05% hydrochloric acid), mobile phase B: acetonitrile, flow rate: 60 ml/min, eluted with 20% to 26% mobile phase B for 10 minutes; detector: 220 nm, gave compound 288a (yellow solid, 34.2 mg, 55%) MS (ESI, m/z): 674.3[ M+H] ⁺ , ¹ H NMR (400MHz,DMSO-d ₆ )δ10.59–10.51(m,1H),10.33–10.23(m,1H),10.08–9.95(m,1H),9.85–9.72( m,1H),7.79–7.73(m,1H),7.72–7.66(m,1H),7.43–7.36(m,1H),7.33(d,J＝2.6Hz,1H),7.18–7.11(m, 1H),7.00(d,J＝2.6Hz,1H),4.66–4.58(m,1H),4.55–4.37(m,3H),4.35–4.28(m,1H),4.23–4.10(m,3H) ,4.07–4.02(m,1H),4.00–3.92(m,1H),3.89–3.82(m,1H),3.70–3.59(m,1H),3.50–3.43(m,3H),3.33–3.06( m,5H),2.44–2.29(m,2H),2.24–1.67(m,12H),0.93–0.80(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-116.68,-116.70, -123.69, -123.70. The chiral analysis conditions for compound 288a were: N-Lux 3 μm Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol/L ammonia ); flow rate: 2 ml/min; gradient elution with 50% phase B in 8 min; detector UV 254 nm; retention time: 4.560 min; dr>40:1.

Step 13':

Compound 288b (yellow solid) can be obtained by the same method as step 13 of this example. MS(ESI,m/z):674.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ10.52–10.43(m,1H),10.27–10.17(m,1H),10.04– 9.91(m,1H),9.81–9.70(m,1H),7.80–7.73(m,1H),7.72–7.66(m,1H),7.41–7.35(m,1H),7.33(d,J=2.6 Hz,1H),7.20–7.11(m,1H),7.00(d,J＝2.6Hz,1H),4.65–4.59(m,1H),4.52–4.37(m,3H),4.34–4.26(m, 1H),4.22–4.09(m,3H),4.06–3.91(m,2H),3.87–3.80(m,1H),3.71–3.59(m,1H),3.49–3.43(m,3H),3.32– 3.12(m,5H),2.41–2.32(m,2H),2.20–1.88(m,12H),0.88–0.82(m,3H); ¹⁹ F NMR(377MHz,DMSO- d ₆ )δ-116.71,- 116.73, -123.71, -123.72. The chiral analysis conditions for compound 288b were: N-Lux 3 μm Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol/L ammonia ); flow rate: 2 ml/min; gradient elution with 50% phase B in 8 min; detector UV 254 nm; retention time: 5.750 min; dr>40:1.

Other similar compounds of the present invention can be prepared by the synthesis method shown in Example 1 above. Table 2 below shows some compounds and their characterization data prepared by referring to the above synthesis method.

Table 2

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol disalt Salt 312a; (R or S)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro- 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalene-2 -phenol dihydrochloride 312b

312a: Mass spectrum [M+H] ⁺ 622.3:

¹ H NMR (300MHz, DMSO-d ₆ +D ₂ O) δ7.85–7.74(m,2H),7.43–7.34(m,2H),7.04(d,J=2.6Hz,1H),5.71–5.44 (m,1H),4.65–4.40(m,4H),4.25–4.12(m,2H),3.98–3.71(m,5H),3.37–3.22(m,1H),2.73–2.54(m,1H) ,2.45–1.83(m,11H),0.85–0.67(m,3H);

¹⁹ F NMR (282MHz, DMSO-d ₆ )δ-116.33, -116.34, -119.18, -123.13, -123.14, -172.71;

Chiral analysis conditions: N-Lux 3m Cellulose-4 (H18-063498), 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol/L ammonia); flow rate: 3.5 ml/min; gradient elution with 35% phase B in 7 min; detector UV 220 nm; retention time: 3.966 min; dr>40:1;

312b: Mass spectrum [M+H] ⁺ 622.3:

¹ H NMR (400MHz,DMSO-d ₆ )δ10.03–9.90(m,1H),7.83–7.74(m,1H),7.72–7.63(m,1H),7.41–7.32(m,2H),7.03 –6.99(m,1H),5.39–5.16(m,1H),4.34–4.23(m,2H),4.14–4.05(m,1H),4.04–3.95(m,1H),3.59–3.43(m, 4H),3.13–2.98(m,3H),2.86–2.77(m,1H),2.48–2.41(m,1H),2.39–2.28(m,1H),2.19–1.94(m,3H),1.89– 1.73(m,3H),1.66(s,4H),0.79–0.69(m,3H);

¹⁹ F NMR (377MHz, DMSO) δ-118.62, -119.20, -123.87, -172.13;

Chiral analysis conditions: N-Lux 3m Cellulose-4 (H18-063498), 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (20 mmol/L ammonia); flow rate: 3.5 mL/min; gradient elution with 35% phase B in 7 min; detector UV 220 nm; retention time: 4.840 min; dr>40:1.

4-((S or R)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-(( R)-2-Hydroxy-3-((1R,3S,5S)-3-methoxy-8-azabicyclo[3.2.1]octane-8-yl)propoxy)quinazoline-7 -yl)-5-ethylnaphthalene-2-ol dihydrochloride 323a4-((R or S)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octane -3-yl)-6,8-difluoro-2-((R)-2-hydroxyl-3-((1R,3S,5S)-3-methoxy-8-azabicyclo[3.2.1 ]octane-8-yl)propoxy)quinazolin-7-yl)-5-ethylnaphthalene-2-ol dihydrochloride 323b

323a: Mass spectrum [M+H] ⁺ 660.3:

¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O) δ7.80–7.65(m,2H),7.45–7.30(m,2H),7.17(d,J=7.1Hz,1H),6.99(d ,J=2.5Hz,1H),4.57–4.34(m,5H),4.29–4.13(m,3H),4.12–4.04(m,1H),3.93(d,J=13.6Hz,1H),3.82( d,J＝13.8Hz,1H),3.53–3.34(m,1H),3.28–3.15(m,4H),3.14–3.00(m,1H),2.45–2.29(m,2H),2.25–2.10( m,4H),2.06–1.84(m,8H),0.93–0.72(m,3H);

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-116.79, -123.68;

Chiral analysis conditions: N-Lux Cellulose-4, 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 3 ml/min; at 6.5 Gradient elution with 50% phase B in minutes; detector UV220 nm; retention time: 3.549 minutes; dr>32:1;

323b: Mass spectrum [M+H] ⁺ 660.3:

¹ H NMR (400MHz,DMSO-d ₆ )δ10.76–9.44(m,4H),7.80–7.65(m,2H),7.43–7.29(m,2H),7.15(d,J=7.1Hz,1H ),6.98(d,J＝2.6Hz,1H),4.85–4.74(m,2H),4.49–4.44(m,2H),4.23–4.11(m,4H),3.98–3.76(m,2H), 3.73–3.58(m,1H),3.46–3.34(m,2H),3.22(s,3H),2.42–2.29(m,2H),2.22–2.08(m,4H),2.05–1.85(m,8H ),0.87–0.83(m,3H);

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-116.543, -116.607, -123.467, -123.606;

Chiral analysis conditions: N—Lux Cellulose-4, 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 3 ml/min; at 6.5 Gradient elution with 50% phase B within minutes; detector UV 220 nm; retention time: 4.935 minutes; dr>40:1.

4-((S or R)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(2 -((1R,3R,5S)-3-methoxy-8-azabicyclo[3.2.1]octyl-8-ethoxy)quinazolin-7-yl)-5-ethylnaphthalene- 2-Phenol dihydrochloride 324a 4-((S or R)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8 -Difluoro-2-(2-((1R,3R,5S)-3-methoxy-8-azabicyclo[3.2.1]octyl-8-ethoxy)quinazolin-7-yl )-5-ethylnaphthalene-2-ol dihydrochloride 324b

324a: Mass spectrum [M+H] ⁺ 630.3:

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-116.543, -116.607, -123.467, -123.606;

Chiral analysis conditions: N-Lux Cellulose-4, 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 2 ml/min; at 8 Gradient elution with 50% phase B within minutes; detector UV220 nm; retention time: 4.957 minutes; dr>40:1;

324b: Mass spectrum [M+H] ⁺ 630.3:

¹ H NMR (400MHz,DMSO-d ₆ )δ10.83–9.49(m,4H),7.81–7.65(m,2H),7.41–7.30(m,2H),7.15(d,J=7.1Hz,1H ),6.99(d,J＝2.5Hz,1H),4.86–4.73(m,2H),4.53–4.39(m,2H),4.18–4.12(m,4H),4.00–3.79(m,2H), 3.75–3.59(m,1H),3.46–3.36(m,2H),3.22(s,3H),2.42–2.31(m,2H),2.25–2.08(m,4H),2.06–1.86(m,8H ),0.87–0.83(m,3H);

¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-116.543, -116.607, -123.594, -123.604;

Chiral Analysis Conditions N-Lux Cellulose-4, 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; mobile phase B: methanol (0.1% diethylamine); flow rate: 2 ml/min; at 8 min Gradient elution with 50% phase B; detector UV 220 nm; retention time: 6.085 minutes; dr>40:1.

Example 2

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-2-((S)-1-(cyclo Propylmethyl)pyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol dihydrochloride 297a ; (R or S)-4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-2-((S)-1-( Cyclopropylmethyl)pyrrolidin-2-yl)methoxy)-6,8-difluoroquinazolin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol dihydrochloride 297b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, toluene ( 140 ml) and water (28 ml) were added successively tris(dibenzylideneacetone) dipalladium (1.31 g, 1.36 mmol, 0.1 equiv), 3-(tert-butyl)-4-(2,6 -dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxophosphapentyl (0.47 g, 1.36 mmol, 0.1 eq) and potassium phosphate (6.07 g, 27.2 mM moles, 2.0 equivalents). The resulting mixture was reacted at 80° C. under nitrogen protection and stirring for 4 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was cooled to room temperature, and concentrated under reduced pressure to remove the solvent to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 297-2 (white solid, 5.9 g, Yield 64%). MS(ESI,m/z):643.2/645.2[M+H] ⁺ ; ¹ H NMR(400MHz, CDCl ₃ )δ7.72–7.66(m,1H),7.56–7.52(m,1H),7.44– 7.38(m,1H),7.31–7.27(m,1H),7.09(d,J＝2.7Hz,1H),5.29(s,2H),4.53–4.29(m,4H),3.75-3.58(m, 2H), 3.52(s, 3H), 2.67–2.51(m, 1H), 2.47–2.31(m, 1H), 2.00(d, J=6.2Hz, 2H), 1.91–1.76(m, 2H), 1.53 (s, 9H), 0.83 (t, J=7.5Hz, 3H); ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ -111.03, -117.16, -118.65.

Step 2:

Under the condition of stirring at 25 degrees Celsius, potassium carbonate (2.73 g, 18.78 mmol, 2.0 equiv) and methyl bromide were successively added to a solution of L-prolinol (1 g, 9.40 mmol, 1.0 equiv) in acetonitrile (10 ml). Cyclopropane (1.33 g, 9.40 mmol, 1.0 equiv). The resulting mixture was reacted at 60° C. for 3 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was cooled to room temperature, excess potassium carbonate was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 12% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 297-3 (pale yellow oil, 1.35 g , yield 88%). MS (ESI, m/z): 156.1[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ3.64–3.59(m,1H),3.42–3.38(m,1H),3.36–3.25( m,1H),3.13(s,1H),2.69–2.63(m,1H),2.64–2.51(m,1H),2.39–2.23(m,1H),2.10–2.04(m,1H),1.99– 1.65(m,4H),0.99–0.79(m,1H),0.60–0.38(m,2H),0.17–0.06(m,2H).

Step 3:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, the N,N-dimethylformaldehyde of compound 297-2 (250 mg, 0.369 mmol, 1.0 equivalent) and compound 297-3 (72.4 mg, 0.433 mmol, 1.2 equivalent) To a solution of the amide (5 mL) was added triethylenediamine (8.7 mg, 0.08 mmol, 0.2 eq) and cesium carbonate (253 mg, 0.738 mmol, 2.0 eq) sequentially. The mixture was reacted at 100°C for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was cooled to room temperature, diluted with 50 ml of water, then extracted with ethyl acetate (50 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (100 ml x 3), and then washed with Dry over sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 297-4 (white solid, 182.6 mg, yield rate of 61%). MS (ESI, m/z): 762.3 [M+H] ⁺ .

Step 4:

Compound 297-4 (180 mg) obtained in step 3 was subjected to chiral resolution by high performance liquid chromatography: chiral column CHIRALPAK IC, 2 x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol/L ammonia Methanol), mobile phase B: ethanol; flow rate: 20 ml/min; eluted with 10% phase B in 21 minutes, detector UV 230/210 nanometers, two products were obtained. The product with shorter retention time (8.91 minutes) is compound 297-4a (white solid, 88 mg, recovery rate 48%), MS (ESI, m/z): 762.3[M+H] ⁺ ; longer retention time ( 13.2 minutes) was compound 297-4b (white solid, 89 mg, recovery 49%), MS (ESI, m/z): 762.3[M+H] ⁺ .

Step 5:

Under stirring conditions at zero degrees Celsius, 4 mol/L hydrochloric acid 1,4-dioxane solution (2 mL ). The mixture was reacted at 25° C. for 2 hours with stirring, and the reaction process was monitored by liquid quality. After the reaction, concentrated under reduced pressure to remove excess solvent to obtain crude product. The obtained crude product was purified by a reverse phase chromatographic column (C18 column), and eluted with 5%→95% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 25 minutes; detector, UV254/220 nm; to obtain the compound 297a (yellow solid, 37.8 mg, 49% yield). MS(ESI,m/z):618.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.84–7.76(m,2H),7.43–7.35(m,2H ),7.05(d,J＝2.7Hz,1H),4.78–4.69(m,2H),4.56–4.39(m,2H),4.24–4.15(m,2H),4.02–3.90(m,2H), 3.86–3.79(m,1H),3.73–3.65(m,1H),3.42–3.33(m,1H),3.31–3.22(m,1H),3.09–3.00(m,1H),2.50–2.41(m ,1H),2.38–2.22(m,2H),2.11–1.88(m,7H),1.24–1.11(m,1H),0.80–0.72(m,3H),0.68–0.55(m,2H),0.45 -0.34 (m, 2H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -116.33, -119.02, -123.30.

Step 5':

Under stirring conditions at zero degrees Celsius, 4 mol/L hydrochloric acid 1,4-dioxane solution (2 mL ). The mixture was reacted at 25°C for 2 hours with stirring, and the reaction process was monitored by liquid quality. After the reaction, concentrated under reduced pressure to remove excess solvent to obtain crude product. The obtained crude product was purified by a reverse phase chromatographic column (C18 column), and eluted with 5%→95% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 25 minutes; detector, UV254/220 nm; to obtain the compound 297b (yellow solid, 33.9 mg, 43% yield). MS(ESI,m/z):618.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.84–7.77(m,2H),7.43–7.35(m,2H ),7.05(d,J＝2.6Hz,1H),4.75–4.69(m,2H),4.53–4.40(m,2H),4.24–4.14(m,2H),4.00–3.80(m,3H), 3.73–3.65(m,1H),3.40–3.33(m,1H),3.31–3.21(m,1H),3.08–2.99(m,1H),2.50–2.44(m,1H),2.40–2.21(m ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -116.36, -119.06, -123.24.

Example 3

(R or S)-4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8-fluoro-2-( (2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol Formate salt 298a; (S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6-chloro-8- Fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoro Naphthalene-2-ol dicarboxylate 298b

synthetic route:

step 1:

2-Amino-4-bromo-5-chloro-3-fluorobenzoic acid (20.0 g, 70.771 mmol, 1.0 equiv) and urea (44.74 g, 707.710 mmol, 10.0 equiv). The mixture was warmed to 150°C and stirred at this temperature for 16 hours. After the reaction was completed, the temperature was lowered to 25 degrees Celsius, diluted with 500 ml of water, stirred for 30 minutes and then filtered. The filter cake was washed with water (50 ml x 3), and the solid was collected and dried under reduced pressure to obtain the crude product of compound 298-1 (yellow solid, 25 gram), the compound was directly used in the next step of synthesis without further purification. MS(ESI,m/z):290.9/292.9/294.8[MH] ^- ; ¹ H NMR(400MHz,DMSO-d ₆ )δ7.79(d,J＝1.8Hz,1H),6.86(s,1H) ,5.41(s,1H).

Step 2:

At 25 degrees Celsius, under the condition of nitrogen protection and stirring, compound 1-5 (25 g, 68.148 mmol, 1.0 equivalent), N,N-diisopropylethylamine (40.0 ml) and oxychloride were added successively to the reaction flask. Phosphorus (400.0 mL). The resulting mixture was stirred and reacted at 90°C for 16 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, and concentrated under reduced pressure to remove excess reagents. Then 400 mL of water was added to the obtained crude product, extracted with ethyl acetate (400 mL x 3). The organic phases were combined, washed with 300 ml of saturated brine, dried over anhydrous sodium sulfate, and filtered to remove the desiccant; the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0%→10% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 298-2 (yellow solid, 16.93 g, Yield 75%). MS (ESI, m/z): 328.8/330.8/332.8 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ8.21 (d, J=2.0 Hz, 1H).

Step 3:

Triethylamine (15.56 g, 146.055 mmol, 15.56 g, 146.055 mmol, 3.0 equivalents), followed by dropwise addition of tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (10.88 g, 48.685 mmol, 1.0 equivalents) in ultra-dry dichloromethane (20.0 mL ) solution. The mixture was reacted at 25°C for 1 hour, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction is complete, cool to room temperature. The mixture was concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0%→20% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 298-3 (yellow solid, 24 g, Yield 92%). MS (ESI, m/z): 505.0/507.1/509.1 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.75 (d, J=2.0Hz, 1H), 4.52–4.29 (m, 4H), 3.79–3.50(m,2H), 2.04–1.89(m,2H), 1.80–1.66(m,2H), 1.52(s,9H).

Step 4:

Under nitrogen protection conditions at 25 degrees Celsius, compound 298-3 (800 mg, 1.501 mmol, 1.0 equivalents), compound 255-1 (obtained by referring to patent WO2021041671, 972.02 mg, 1.801 mmoles, 1.2 equivalents) were sequentially added to the reaction flask ), tris(dibenzylideneacetone)dipalladium (138.87 mg, 0.15 mmol, 0.1 equiv), 4-(9-anthracenyl)-3-(tert-butyl)-2,3-dihydrobenzo[ D][1,3]oxo, phosphapentyl conjugate (112.36 mg, 0.30 mmol, 0.2 equiv), cesium carbonate (988.24 mg, 3.002 mmol, 2.0 equiv), toluene (7.0 mL) and water (1.4 mL). The mixture was stirred at 60°C for 24 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the temperature was lowered to 25 degrees Celsius, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 20% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 298-4 (white solid, 590 mg , yield 46%). MS (ESI, m/z): 811.1/813.1 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.82–7.76 (m, 1H), 7.72 (d, J＝1.6Hz, 1H) ,7.53(d,J＝2.4Hz,1H),7.33–7.27(m,1H),7.11–7.07(m,1H),5.30(s,2H),4.83–4.70(m,1H),4.48–4.35 (m,2H),4.09–4.02(m,1H),3.84(brs,1H),3.53(brs,3H),3.45–3.36(m,1H),2.09–1.95(m,3H),1.68-1.61 (m,1H), 1.56(s,9H), 0.94–0.83(m,18H), 0.59–0.46(m,3H).

Step 5:

At 25 degrees Celsius, under the condition of nitrogen protection and stirring, compound 298-4 (510 mg, 0.597 mmol, 1 equivalent), triethylenediamine (14.09 mg, 0.119 mmol, 0.2 equivalent) and cesium carbonate (409.35 mg, 1.194 Millimoles, 2 equivalents) in N,N-dimethylformamide (6 ml) solution was added compound (2R,7aS)-2-fluorotetrahydro-1H-pyrrolizine-7a(5H)-methanol (12.01 g , 0.716 mmol, 1.2 equivalents). The mixture was stirred and reacted at 100°C for 1.5 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, 200 ml of water was added to dilute the reaction solution, the resulting mixture was extracted with ethyl acetate (300 ml x 3), the combined organic layers were washed with saturated brine (100 ml x 3), and dried over anhydrous sodium sulfate. The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative thin-layer chromatography, eluted with a gradient of 0%→6% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 298-5 (yellow solid, 210 mg, Yield 44%). MS (ESI, m/z): 778.3/780.3 [M+H] ⁺ .

Step 6:

Compound 298-5 (210 mg) obtained in step 5 was subjected to chiral resolution by supercritical liquid chromatography: chiral column CHIRALPAK IF, 2x 25 cm, 5 microns; mobile phase A: n-hexane (0.1%, 10 mol/ Liter ammonia methanol), mobile phase B: methyl alcohol/ethanol (1/1); Flow velocity: 20 milliliters/minute; With 20% mobile phase B elution; Detector UV222 nanometers, obtain two products. The product with shorter retention time (1.363 minutes) is compound 298-5a (white solid, 92.2 mg, recovery 44%), MS (ESI, m/z): 778.3/780.3[M+H] ⁺ ; longer retention The product at time (1.958 minutes) was compound 298-5b (white solid, 92.6 mg, yield 44%), MS (ESI, m/z): 778.3/780.3 [M+H] ⁺ .

Step 7:

Under stirring conditions at 0°C, to a solution of compound 298-5a (92.2 mg, 0.117 mmol, 1.00 eq) in methanol (3 mL) was added dropwise a solution of hydrochloric acid in 1,4-dioxane (4 mol/L, 3 ml). The mixture was reacted at room temperature for 1.5 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was purified by a reverse-phase flash chromatography column (C18 column), eluted with 5%→95% (acetonitrile/methanol (1/1))/water mobile phase (0.1% formic acid) within 25 minutes, and detected UV 254 nm afforded compound 298a (white solid, 44.3 mg, yield 54%). MS(ESI,m/z):634.2/636.2[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ8.30–8.19(m,1H),8.01–7.94(m,1H), 7.82–7.77(m,1H),7.50–7.43(m,1H),7.41–7.37(m,1H),7.10–7.00(m,1H),5.40–5.15(m,1H),4.38–4.24(m ,2H),4.12–4.04(m,1H),4.02–3.95(m,1H),3.94–3.91(m,1H),3.82–3.49(m,5H),3.16–3.00(m,3H),2.89 -2.78 (m, 1H), 2.16 - 1.98 (m, 3H), 1.93 - 1.65 (m, 7H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -110.40, -122.63, -172.09.

Step 7':

Under stirring conditions at 0°C, to a solution of compound 298-5b (92.6 mg, 0.117 mmol, 1.00 eq) in methanol (3 mL) was added dropwise a solution of hydrochloric acid in 1,4-dioxane (4 mol/L, 3 ml). The mixture was reacted at room temperature for 1.5 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated to obtain a crude product. The crude product was purified by a reverse-phase flash chromatography column (C18 column), eluted with 5%→95% (acetonitrile/methanol (1/1))/water mobile phase (0.1% formic acid) within 25 minutes, and detected Using UV 254 nm, compound 298b was obtained (white solid, 31.2 mg, yield 36%). MS(ESI,m/z):634.2/636.2[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ8.27(s,2H),8.01–7.95(m,1H),7.81– 7.78(m,1H),7.50–7.44(m,1H),7.41(d,J=2.6Hz,1H),7.07(d,J=2.5Hz,1H),5.39–5.19(m,1H),4.40 –4.25(m,2H),4.13–4.07(m,1H),4.03–3.97(m,1H),3.93–3.89(m,1H),3.84–3.75(m,2H),3.71–3.60(m, 3H), 3.16–3.06(m,2H), 3.04–2.99(m,1H), 2.88–2.78(m,1H), 2.18–1.97(m,3H), 1.91–1.70(m,7H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -110.38, -122.60, -172.17.

Example 4

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 2R,7aS)-2-Fluorotetrahydro-1H-pyrroline-7a(5H)-ylmethoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-oldimethyl Salt 299a; (R or S)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro- 2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-ylmethoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2 -Phenol dicarboxylate 299b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 279-1 (500 mg, 0.97 mmol, 1.0 equivalent), compound 255-1 (627.9 mg, 1.16 mmol, 1.2 equivalent), potassium phosphate ( 415.90 mg, 1.94 mmol, 2.0 equiv), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3] Oxyphosphine (67.46 mg, 0.19 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (89.71 mg, 0.09 mmol, 0.1 equiv), toluene (5.0 mL) and water (1 mL) . The resulting mixture was reacted at 80°C for 8 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, 50 ml of water was added to the reaction liquid for dilution, then extracted with ethyl acetate (50 ml x 3), and the organic phases were combined. The organic phase was washed with 50 ml of saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and eluted with a gradient of 0%→10% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 299-1 (white solid, 370 mg, Yield 46%). MS (ESI, m/z): 795.3/797.3 [M+H] ⁺ .

Step 2:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, compound 299-1 (260 mg, 0.311 mmol, 1.0 equivalent), triethylenediamine (7.33 mg, 0.06 mmol, 0.2 equivalent), and cesium carbonate were sequentially added to the Shrek tube. (204.4 mg, 0.62 mmol, 2.0 equiv), (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol (67.65 mg, 0.40 mmol, 1.2 equiv) and N,N - Dimethylformamide (3.0 ml). The resulting mixture was reacted at 100°C for 4 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, 20 ml of water was added to the reaction liquid for dilution, then extracted with ethyl acetate (20 ml x 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 ml x 2), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 299-2 (white solid, 200 mg, Yield 80%). MS (ESI, m/z): 762.3 [M+H] ⁺ .

Step 3:

Compound 299-2 (200 mg) obtained in step 2 was subjected to chiral resolution by preparative high-performance liquid chromatography: chiral column CHIRALPAK IA, 3 x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol/ liter ammonia methanol), mobile phase B: isopropanol; flow rate: 25 ml/min; within 18 minutes with 20% phase B for elution, detector: UV 218/233 nanometers, two products were obtained. The product with shorter retention time (7.4 minutes) is compound 299-2a (white solid, 70 mg, recovery rate 37%), MS (ESI, m/z): 762.3[M+H] ⁺ ; longer retention time ( 11.5 minutes) was compound 299-2b (white solid, 70 mg, recovery 37%), MS (ESI, m/z): 762.3[M+H] ⁺ .

Step 4:

Under stirring conditions at zero degrees Celsius, compound 299-2a (70 mg, 0.87 mmol, 1.0 eq), methanol (1.0 ml) and hydrochloric acid in 1,4-dioxane (4 mol/ml , 1.0 ml). The obtained mixture was reacted for 1 hour under the condition of stirring at zero degree Celsius, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by reverse-phase chromatography column (C18 column), and eluted with 5%→95% acetonitrile/water mobile phase (0.1% formic acid) within 25 minutes; detector: UV254/220 nm; compound 299a was obtained (White solid, 60 mg, 92% yield). MS(ESI,m/z):618.0[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ8.27–8.22(m,2H),8.02–7.95(m,1H),7.59– 7.53(m,1H),7.51–7.45(m,1H),7.41(d,J=2.5Hz,1H),7.15(d,J=2.5Hz,1H),5.38–5.18(m,1H),4.32 –4.24(m,2H),4.12–4.06(m,1H),4.03–3.95(m,2H),3.79–3.69(m,2H),3.63–3.50(m,2H),3.15–3.00(m, 3H), 2.88–2.79(m,1H), 2.17–2.10(m,1H), 2.08–1.98(m,2H), 1.92–1.71(m,7H); ¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-110.21, -118.75, -124.67, -172.08. The chiral analysis conditions of compound 299a are: N-Lux 3 μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethylamine ); flow rate: 3 ml/min; isocratic elution with 40% phase B in 8 min; detector UV 220 nm; retention time: 4.457 min; dr>40:1.

Step 5:

Compound 299b (white solid, 60 mg, yield 92%) could be obtained by the same method as step 4. MS(ESI,m/z):618.0[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ8.27–8.22(m,2H),8.02–7.95(m,1H),7.59– 7.52(m,1H),7.51–7.45(m,1H),7.42(d,J＝2.6Hz,1H),7.16–7.11(m,1H),5.38–5.19(m,1H),4.33–4.24( m,2H),4.11–4.06(m,1H),4.01–3.94(m,2H),3.79–3.69(m,2H),3.63–3.49(m,2H),3.15–2.99(m,3H), 2.88–2.79(m,1H),2.16–2.11(m,1H),2.08–1.97(m,2H),1.90–1.70(m,7H); ¹⁹ F NMR(377MHz, DMSO-d ₆ )δ-110.21 , -118.70, -124.62, -172.16. The chiral analysis conditions of compound 299b are: N-Lux 3 μm Cellulose-2 (H18-089501), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethylamine ); flow rate: 3 ml/min; isocratic elution with 40% phase B in 8 minutes; detector UV 220 nm; retention time: 6.04 minutes; dr>40:1.

Example 5

1-((S or R)-8-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-6,8-difluoro-2 -(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-6-hydroxynaphthalen-1-yl)ethyl Alkan-1-one dihydrochloride 300a; 1-((R or S)-8-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3- Base)-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)- 6-Hydroxynaphthalen-1-yl)ethan-1-one dihydrochloride 300b

The synthetic route is as follows:

step 1:

Under nitrogen protection at 25 degrees Celsius, triethylenediamine (0.37 grams, 3.104 mmoles, 0.2 equivalents), compound 279-1 (8.0 grams, 15.518 mmoles, 1.0 equivalents) and cesium carbonate (10.64 grams, 31.036 mmoles, 2.0 eq) was added to the mixture of (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol (3.12 g, 18.622 mmol, 1.2 eq) N,N-dimethyl Formamide (60 mL) solution. After the addition, the resulting mixture was stirred and reacted for 2 hours at 60°C under nitrogen protection, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature and diluted with 500 ml of water, the resulting mixture was extracted with ethyl acetate (400 ml x 3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→7% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 300-10 (white solid, 6.8 g, yield rate of 68%). MS(ESI,m/z):611.7/613.7[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ7.34–7.30(m,1H),5.38–5.20(m,1H),4.39– 4.15(m,6H),3.54(brs,2H),3.39–3.16(m,3H),3.03–2.95(m,1H),2.35–2.13(m,3H),2.00–1.89(m,5H), 1.82–1.72 (m, 2H), 1.51 (s, 9H).

Step 2:

Compound 300-1 was synthesized with reference to the patent (WO2021041671).

Under nitrogen protection stirring condition at 25 degrees centigrade, to compound 300-10 (450 mg, 0.73 mmol, 1.0 equivalent), compound 300-1 (508.6 mg, 1.028 mmol, 1.4 equivalent), three (dibenzylidene acetone) Dipalladium (62 mg, 0.07 mmol, 0.1 equiv) and 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1 ,3] Potassium phosphate (190.6 mg, 0.89 mmol, 2 eq) was added to a mixed solution of oxo,phosphapentyl conjugate (48.5 mg, 0.15 mmol, 0.2 eq) in toluene (4 mL) and water (1 mL). The resulting mixture was reacted at 80° C. for 5 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was cooled to room temperature, diluted with 20 ml of water, the resulting mixture was extracted with ethyl acetate (20 ml x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 300-2 (yellow solid, 600 mg, Yield 91%). MS (ESI, m/z): 990.3 [M+H] ⁺ .

Step 3:

To a solution of compound 300-2 (600 mg, 0.667 mmol, 1 eq) in N,N-dimethylformamide (6 mL) was added cesium fluoride (507 mg, 3.33 mmol) under stirring at 0°C. , 5 equivalents). The mixture was stirred at 25°C for 4 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction was over, 60 milliliters of water was added to the reaction solution. The resulting mixture was extracted with ethyl acetate (60 mL x 3), and the organic phases were combined. The organic phase was washed with 60 ml of saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 300-3 (yellow solid, 380 mg, Yield 95%). MS (ESI, m/z): 744.4 [M+H] ⁺ .

Step 4:

Compound 300-3 (380 mg) obtained in step 3 of this example was subjected to chiral resolution by preparative high-performance liquid chromatography: chiral column CHIRALPAK IA, 3 x 25 cm, 5 microns; mobile phase A: n-hexane: dichloro Methane=5:1 (0.5% 2 mol/L ammonia methanol), mobile phase B: isopropanol; flow rate: 40 ml/min; elution with 5% phase B in 10 minutes, detector UV 234/ 220 nm, two products were obtained. The product with shorter retention time (5.7 minutes) was compound 300-3a (white solid, 120 mg, recovery 31.5%), compound 300-3a: MS (ESI, m/z): 744.4[M+H] ⁺ ; The product with longer retention time (7.7 minutes) was compound 300-3b (white solid, 170 mg, recovery rate 44.7%), compound 300-3b: MS (ESI, m/z): 744.4[M+H] ⁺ .

Step 5:

Under the condition of stirring at zero degrees Celsius, triethylsilane (56.8 mg, 0.459 mmol, 3 equivalents). The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5%→95% methanol/water mobile phase (0.1% hydrochloric acid) within 25 minutes; detector: UV254/220 nanometers; compound 300a was obtained (yellow solid, 48 mg, 44% yield). MS(ESI,m/z):618.0[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.61–11.45(m,1H),10.67–9.96(m,2H),9.87– 9.74(m,1H),7.99–7.94(m,1H),7.78–7.70(m,1H),7.53–7.46(m,2H),7.42(d,J=2.5Hz,1H),7.21(d, J＝2.5Hz,1H),5.70–5.45(m,1H),4.55–4.43(m,4H),4.41–4.32(m,1H),4.22–4.11(m,2H),4.04–3.96(m, 1H),3.90–3.73(m,4H),3.33–3.23(m,1H),2.70–2.60(m,1H),2.38–2.29(m,1H),2.23–2.15(m,5H),2.09– 1.92 (m, 5H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -116.33, -123.35, -172.65. The chiral analysis conditions of compound 300a are: N-CHIRALART Cellulose-SB (Ser.No.105CA80166), 4.6x100 mm, 3 microns; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol/L Ammonia); flow rate: 2 ml/min; isocratic elution with 10% phase B in 6.5 min; detector UV 220 nm; retention time: 4.119 min; dr>40:1.

Step 5':

Compound 300b (yellow solid) can also be obtained according to the method in step 5 of this example. MS(ESI,m/z):618.0[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.51–11.40(m,1H),10.57–9.95(m,2H),9.83– 9.68(m,1H),7.99–7.93(m,1H),7.77–7.70(m,1H),7.53–7.46(m,2H),7.43–7.40(m,1H),7.20(d,J=2.6 Hz,1H),5.68–5.45(m,1H),4.66–4.59(m,2H),4.56–4.49(m,1H),4.45–4.36(m,2H),4.20–4.11(m,2H), 4.06–3.95(m,1H),3.89–3.68(m,4H),3.34–3.21(m,1H),2.69–2.53(m,1H),2.38–2.29(m,1H),2.24–2.11(m , 5H), 2.08–1.88 (m, 5H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-116.36, -116.37, -123.33, -123.34, -172.70. The chiral analysis conditions of compound 300a are: N-CHIRALART Cellulose-SB (Ser.No.105CA80166), 4.6 x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol/ liter ammonia); flow rate: 2 ml/min; isocratic elution with 10% phase B in 6.5 minutes; detector UV 220 nm; retention time: 4.492 minutes; dr>40:1.

Example 6

(S or R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( (2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalene-2-ol 301a; (R or S)-4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynylnaphthalene-2-ol 301b

The synthetic route is as follows:

step 1:

Compound 300-2 (710.0 mg) was chirally resolved by preparative supercritical liquid chromatography: chiral column CHIRAL ART Cellulose-SC, 3 x 25 mm, 5 microns; mobile phase A: supercritical carbon dioxide fluid, mobile Phase B: ethanol/dichloromethane=1/1; flow rate: 70 ml/min; elution with 35% phase B, detector UV 234 nm, two products were obtained. The product with shorter retention time (4.87 minutes) is compound 300-2a (yellow solid, 262 mg, recovery 37%), MS (ESI, m/z): 900.4[M+H] ⁺ ; longer retention time ( 6.90 minutes) was compound 300-2b (yellow solid, 285 mg, recovery 40%), compound 300-2b: MS (ESI, m/z): 900.4[M+H] ⁺ .

Step 2:

Under nitrogen protection at 0°C, to a solution of compound 300-2a (150 mg, 0.167 mmol, 1.0 eq) in acetonitrile (2.5 ml), slowly dropwise add a solution of hydrochloric acid in 1,4-dioxane (4 mol/ liter, 0.5 ml). The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was re-dissolved with a mixed solution of isopropanol/dichloromethane (volume ratio 1/9, 25 ml), and saturated sodium bicarbonate (10 ml) and saturated sodium carbonate (10 ml) were added thereto to adjust the aqueous phase When the pH was above 7, the organic phase was separated and the aqueous phase was extracted with dichloromethane (25 ml x 2), and all the organic phases were combined. Dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, using 0%→10% (methanol/7 moles per liter of ammonia methanol=8/2)/dichloromethane gradient elution, and the obtained fraction was obtained by removing the solvent by rotary evaporation under reduced pressure to obtain Compound 301-1a (pale yellow solid, 115 mg, yield 91%). MS (ESI, m/z): 756.4 [M+H] ⁺ .

step 3

To a solution of compound 301-1a (115 mg, 0.152 mmol, 1 equiv) in N,N-dimethylformamide (1 mL) was added cesium fluoride (115.6 mg, 0.760 mmol) under stirring at zero degrees Celsius , 5 equivalents). The mixture was stirred at 25°C for 4 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction was over, 25 milliliters of water was added to the system to dilute the reaction solution, and the resulting mixture was extracted with isopropanol/chloroform (1/3, 25 milliliters x 3), and the organic phases were combined; the organic phase was washed with 25 milliliters of saturated brine, without Dry over sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product obtained is purified by high performance liquid chromatography: chromatographic column YMC-Actus Triart C18, 30x 150 mm, 5 microns; mobile phase A: water (10 mmol/L ammonium bicarbonate and 0.1% ammonia water), mobile phase B: Acetonitrile; flow rate: 60 ml/min, elution with 35% → 65% phase B, detector UV 220/254 nm. Compound 301a was obtained (white solid, 35.7 mg, 39% yield). MS(ESI,m/z):600.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ10.22(s,1H),7.92–7.86(m,1H),7.55–7.40( m,3H),7.36(d,J=2.6Hz,1H),7.08(d,J=2.5Hz,1H),5.38–5.18(m,1H),4.31–4.19(m,2H),4.10–4.02 (m,1H),4.00–3.93(m,1H),3.64–3.60(m,1H),3.54–3.41(m,4H),3.15–3.06(m,2H),3.05–2.99(m,1H) ,2.88–2.78(m,1H),2.16–2.10(m,1H),2.08–1.98(m,2H),1.89–1.59(m,7H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ- 119.05, -119.06, -124.89, -124.91, -172.07. The conditions for chiral analysis of compound 301a are: N-CHIRALPAK IG-3, 3.0 x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; mobile phase B: ethanol (20 mmol/L ammonia); flow rate: 2 mL /min; isocratic elution with 50% phase B in 3 minutes; detector UV 230 nm; retention time: 1.317 minutes; dr>40:1.

step 4

Compound 300b (white solid) can also be obtained according to the method of step 2 and step 3 of this example. MS(ESI,m/z):600.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ10.19(s,1H),7.92–7.87(m,1H),7.55–7.40( m,3H),7.36(d,J=2.6Hz,1H),7.08(d,J=2.6Hz,1H),5.36–5.19(m,1H),4.28–4.20(m,2H),4.09–4.05 (m,1H),4.00–3.95(m,1H),3.62–3.60(m,1H),3.56–3.42(m,4H),3.11–3.06(m,2H),3.03–3.00(m,1H) ,2.87–2.77(m,1H),2.16–2.09(m,1H),2.07–1.97(m,2H),1.88–1.63(m,7H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ- 119.00, -124.85, -172.15. The chiral analysis conditions of compound 301b are: N-CHIRALPAK IG-3, 3.0x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: ethanol (20 mmol/L ammonia); flow rate: 2 mL/min; isocratic elution with 50% phase B in 3 min; detector UV 230 nm; retention time: 0.645 min; dr>40:1.

Example 7

(S or R)-7'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-( (2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-2',3'-dihydrospiro[cyclobutane -1,1'-indene]-5'-phenol dihydrochloride 302a; (S or R)-7'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1 ]octane-3-yl)-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazoline -7-yl)-2',3'-dihydrospiro[cyclobutane-1,1'-indene]-5'-phenol dihydrochloride 302b

The synthetic route is as follows

step 1:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, sodium hydride (60%, 4.78 g, 121.760 mmol, 5.0 equivalents), the mixture was reacted at 50 degrees Celsius for 1 hour. 1,3-dibromopropane (5.18 g, 24.352 mmol, 1.0 equivalent) was added dropwise to the above mixed system at 50°C. After the addition was complete, the reaction was continued for 16 hours, and the reaction process was monitored by air quality. After the reaction, the reaction solution was cooled to room temperature. Then slowly pour ammonium chloride aqueous solution (200 milliliters) into the reaction solution to quench the reaction, the resulting mixture was extracted with ethyl acetate (200 milliliters x 3), the organic phases were combined, and the organic phase was washed with 500 milliliters of saturated brine, anhydrous Dry over sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, eluting with petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 302-1 (colorless oil, 1.38 g, yield 23%). ¹ H NMR (400MHz, CDCl ₃ )δ7.32–7.30(m,1H),7.19–7.17(m,1H),7.06–7.02(m,1H),6.91(d,J=5.5Hz,1H), 6.53 (d, J=5.5Hz, 1H), 3.41–3.33 (m, 2H), 2.40–2.28 (m, 1H), 2.25–2.15 (m, 1H), 2.08–2.01 (m, 2H).

Step 2:

To a solution of compound 302-1 (1.3 g, 5.253 mmol, 1.0 eq) in ethanol (26 mL) was added platinum/carbon (10%, 130 mg) under stirring at 25 °C. The mixture was reacted for 4 hours in a hydrogen atmosphere of 1 atmosphere, and the reaction process was monitored by thin layer chromatography. After the reaction, the platinum/carbon was removed by filtration, the filter cake was washed with ethanol (50 ml x 3), the combined filtrates were concentrated under reduced pressure to obtain the crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with petroleum ether. The obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 302-2 (colorless oil, 1.28 g, yield 99%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.34–7.31(m,1H),7.11–7.09(m,1H),6.98–6.94(m,1H),3.13–3.02(m,2H),2.85–2.81 (m,2H), 2.35–2.32(m,2H), 2.15–2.04(m,2H), 2.01–1.90(m,2H).

Step 3:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, compound 302-2 (1.25 g, 5.008 mmol, 1.0 equivalent) and double pinacol borate (4.02 g, 15.024 mmol, 3.0 equivalent) were successively added to the reaction flask , methoxy(cyclooctadiene) iridium dimer (349.41 mg, 0.501 mmol, 0.1 equiv), 4,4-di-tert-butyl-2,2-dipyridine (289.92 mg, 1.002 mg, 0.2 equivalent) and n-hexane (25 ml). The mixture was reacted at 60°C for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was cooled to room temperature, and the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product 302-3 was directly used in the next reaction without further purification.

Step 4:

Water (5 ml), acetic acid (15 ml) and hydrogen peroxide (7.5 ml) were successively added to a solution of the crude product of compound 302-3 in tetrahydrofuran (10 ml) under stirring at 0°C. The mixture was reacted at 0°C for 1 hour, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was finished, add 100 ml of water to the reaction solution for dilution, then extract with ethyl acetate (100 ml x 3), and combine the organic phases; the organic phase was washed with 300 ml of saturated sodium bicarbonate, dried over anhydrous sodium sulfate, and removed by filtration desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→20% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 302-4 (yellow solid, 1.1 g , 85% yield in two steps). MS(ESI,m/z):251.0/253.0[MH] ^- . ¹ H NMR(400MHz,DMSO-d ₆ )δ9.59(s,1H),6.76(d,J＝2.2Hz,1H),6.61 –6.57(m,1H),2.90-2.82(m,2H),2.74–2.70(m,2H),2.27–2.24(m,2H),2.07–1.89(m,4H).

Step 5:

Under the condition of stirring under nitrogen protection at 0 degrees Celsius, the dichloride solution of compound 302-4 (950 mg, 3.565 mmol, 1.0 eq) and N,N-diisopropylethylamine (970.10 mg, 7.130 mmol, 2.0 eq) Chloromethyl methyl ether (362.57 mg, 4.278 mmol, 1.2 equiv) was slowly added dropwise to the solution in methane (10 mL). The mixture was reacted at 25°C for 1 hour, and the reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was over, 20 ml of water was added to the reaction liquid to quench the reaction. The resulting mixture was extracted with dichloromethane (20 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (10 ml x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product . The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→20% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 302-5 (colorless oil, 810 mg, yield: 72%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.08–7.07(m,1H),6.84–6.83(m,1H),5.14(s,2H),3.49(s,3H),3.12–2.99(m,2H ), 2.85–2.80(m,2H), 2.40–2.33(m,2H), 2.13–2.03(m,2H), 2.00-1.91(m,2H).

Step 6:

Under nitrogen protection conditions at 25 degrees Celsius, compound 302-5, bis-pinacol borate (512.68 mg, 1.918 mmol, 1.5 equivalents), [1,1-bis(diphenylphosphine ) ferrocene] dichloropalladium dichloromethane complex (109.64 mg, 0.128 mmol, 0.1 equiv), potassium acetate (396.28 mg, 3.837 mmol, 3.0 equiv) and 1,4-dioxane ( 4 ml). The mixture was reacted at 100°C for 4 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 40% methyl tert-butyl ether/petroleum ether, and the obtained fractions were evaporated under reduced pressure. The solvent was removed to obtain compound 305-6 (colorless oil, 220 mg, yield 50%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.23 (d, J=2.5Hz, 1H), 6.94-6.92 (m, 1H), 5.15 (s, 2H), 3.46 (s, 3H), 2.86–2.75 ( m,4H), 2.30–2.26(m,2H), 2.14–1.99(m,1H), 1.95–1.89(m,3H), 1.38(s,12H).

Step 7:

Under the condition of nitrogen protection stirring at 25 degrees Celsius, compound 300-10 (300 mg, 0.465 mmol, 1.0 equivalent), compound 302-6 (202.34 mg, 0.588 mmol, 1.2 equivalent), 3-( tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxo,phosphapentyl conjugate (32.36 mg, 0.093 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (44.85 mg, 0.047 mmol, 0.1 equiv), potassium phosphate (207.94 mg, 0.930 mmol, 2.0 equiv), toluene (3 mL) and water (0.6 mL) . The resulting mixture was reacted at 100°C under nitrogen protection for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 302-7 (brown solid, 350 g, yield rate 95%). MS (ESI, m/z): 750.5[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ7.39–7.35 (m, 1H), 7.01 (d, J=2.3Hz, 1H), 6.67 (d,J=2.4Hz,1H),5.44–5.20(m,1H),5.16(s,2H),4.56–4.14(m,6H),3.66–3.52(m,2H),3.49(s,3H ),3.37–3.18(m,2H),3.08–2.95(m,1H),2.89–2.84(m,2H),2.41–2.17(m,5H),2.16–1.84(m,12H),1.82–1.73 (m,2H), 1.54(s,9H).

Step 8:

Chiral resolution of compound 302-7 (350 mg) obtained in step 7 was performed by preparative supercritical liquid chromatography: chiral column CHIRAL ART Cellulose-SC, 3 x 25 cm, 5 μm; mobile phase A: supercritical carbon dioxide Fluid, mobile phase B: methanol (0.1% 2 mol/liter ammonia methanol); flow rate: 60 ml/min; elution with 50% phase B in 15 minutes, detector UV206 nanometers, to obtain two products. The product with shorter retention time (9.03 minutes) is compound 302-7a (yellow oil, 119 mg, recovery rate 34%), MS (ESI, m/z): 750.5[M+H] ⁺ ; longer retention time (13.03 minutes) The product was compound 303-7b (yellow oil, 121 mg, recovery 34%), MS (ESI, m/z): 750.5[M+H] ⁺ .

Step 9:

Under stirring conditions at 0°C, to compound 302-7a (119 mg, 0.153 mmol, 1.0 eq) in methanol (2 ml) was added dropwise a 4 mol/L hydrochloric acid solution in 1,4-dioxane ( 2 ml). The mixture was reacted at 25°C for 1 hour, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5%→95% (methanol/acetonitrile=1/1)/water mobile phase (0.1% hydrochloric acid) within 25 minutes; : UV254/220 nm; compound 302a was obtained (white solid, 84.3 mg, yield 79%). MS (ESI, m/z): 606.5[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O) δ7.82–7.73 (m, 1H), 6.75 (d, J＝2.3 Hz,1H),6.40(d,J＝2.3Hz,1H),5.68–5.50(m,1H),4.64–4.57(m,2H),4.56–4.42(m,2H),4.23–4.14(m, 2H),3.94–3.75(m,5H),3.36–3.27(m,1H),2.81–2.73(m,2H),2.70–2.59(m,1H),2.51–2.43(m,1H),2.38– 2.30(m,1H),2.28–2.12(m,4H),2.10–1.79(m,9H),1.78–1.65(m,1H),1.18–1.03(m,1H); ¹⁹ F NMR(377MHz,DMSO -d ₆ ) δ-114.88, -121.62, -172.67. The conditions for chiral analysis of compound 302a are: Opti-Chiral C9-3, 3.0 x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol/L ammonia); flow rate: 2 mL/min; isocratic elution with 40% phase B in 3.4 min; detector UV 220 nm; retention time: 2.105 min; dr>40:1.

Step 10:

Compound 302b (white solid) can also be obtained according to the method in step 9 of this example. MS (ESI, m/z): 606.5[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O) δ7.83–7.71 (m, 1H), 6.75 (d, J＝2.3 Hz,1H),6.40(d,J=2.3Hz,1H),5.69–5.50(m,1H),4.64–4.51(m,3H),4.49–4.40(m,1H),4.23–4.14(m, 2H),3.96–3.73(m,5H),3.38–3.25(m,1H),2.81–2.72(m,2H),2.68–2.55(m,1H),2.51–2.46(m,1H),2.39– 2.30(m,1H),2.27–2.13(m,4H),2.11–1.80(m,9H),1.79–1.66(m,1H),1.16–1.03(m,1H); ¹⁹ F NMR(377MHz,DMSO -d ₆ ) δ-114.88, -121.63, -172.65. The conditions for chiral analysis of compound 302b are: Opti-Chiral C9-3, 3.0 x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol/L ammonia); flow rate: 2 mL/min; isocratic elution with 40% phase B in 2.0 min; detector UV 220 nm; retention time: 1.552 min; dr>40:1.

Example 8

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( (2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-(ethyl-d5)-naphthalene-2-ol Dihydrochloride 303a; (R or S)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-di Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-(ethyl-d5) - Naphthalene-2-ol dihydrochloride 303b

The synthetic route is as follows:

step 1:

Compound 303-1 was synthesized with reference to the patent (WO2021041671).

Under the condition of stirring in a nitrogen atmosphere at -78 degrees Celsius, to a solution of compound 303-1 (2.37 g, 7.208 mmol, 1.0 equivalent) in anhydrous THF (24 mL) was slowly added dropwise in tetrahydrofuran of lithium bistrimethylsilylamide solution (1 mol/L, 15.85 mL, 15.85 mmol, 2.2 equiv). The mixture was reacted at -78°C for 30 minutes under a nitrogen atmosphere with stirring. Deuterium water (4.7 ml) was added dropwise to the above solution, and the mixture was stirred at -78°C under a nitrogen atmosphere for 5 minutes. The reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction solution was added dropwise into saturated ammonium chloride solution (25 ml) to quench, the resulting mixture was extracted with ethyl acetate (20 ml x 3), and the organic phases were combined. The organic phase was washed with 25 ml of saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, eluted with a gradient of 0%→12% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 303-2 (pale yellow solid, 1.6 g, 50% yield). MS (ESI, m/z): 314.1[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ7.78–7.72(m,1H),7.67–7.61(m,1H),7.40–7.33( m, 1H), 7.32 (d, J = 2.5Hz, 1H), 6.82 (d, J = 2.5Hz, 1H), 5.28 (s, 2H), 3.51 (s, 3H), 1.45 (s, 9H).

Step 2:

Under nitrogen protection and stirring at 15 degrees Celsius, compound 303-2 (1.5 g, 3.351 mmol, 1.0 equivalent), tetrahydrofuran (30 ml) and anhydrous palladium/carbon (10%, 220 mg) were successively added to a two-necked flask . Nitrogen was replaced by deuterium by a gas replacement operation. The mixture was reacted under an atmosphere of deuterium at atmospheric pressure for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→12% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 303-3 (yellow oil, 1.525 g , yield 99%). MS (ESI, m/z): 322.2[M+H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.64–7.58 (m, 1H), 7.37–7.29 (m, 2H), 7.20–7.14 ( m, 1H), 6.75(d, J=2.6Hz, 1H), 5.28(s, 2H), 3.52(s, 3H), 1.45(s, 9H).

Step 3:

To a solution of compound 303-3 (1.52 g, 3.310 mmol, 1.0 eq) in methanol (16 mL) was slowly added potassium hydroxide (796 mg, 3.0 eq) under stirring at 15°C. The mixture was reacted at 15°C for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was finished, adjust the pH to 5 with hydrochloric acid solution (1 mol/L), extract with ethyl acetate (50 ml x 3), combine the organic phases, wash the organic phase with saturated brine (50 ml x 3), anhydrous Dry over sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→12% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain a crude product (yellow solid, 978 mg). The crude product was slurried with n-hexane/methyl tert-butyl ether (5/1, 15 mL), and filtered to obtain compound 303-4 (pink white solid, 620 mg, yield 78%). MS (ESI, m/z): 238.1[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ7.54–7.49(m,1H),7.34–7.27(m,1H),7.13–7.07( m, 1H), 6.99 (d, J = 2.4Hz, 1H), 6.53 (d, J = 2.4Hz, 1H), 5.26 (s, 2H), 3.52 (s, 3H).

Step 4:

Under the condition of nitrogen protection and stirring at -40 degrees Celsius, compound 303-4 (670 mg, 2.682 mmol, 1.0 equivalent) and N,N-diisopropylethylamine (1.5 ml, 8.046 mmol, 3.0 equivalent) Trifluoromethanesulfonic anhydride (1.19 g, 4.023 mmol, 1.5 equiv) was slowly added dropwise to a solution of methyl chloride (7 mL). The mixture was reacted at 15°C under a nitrogen atmosphere for 30 minutes with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, a saturated sodium bicarbonate solution (25 ml) was added to quench the reaction, extracted with dichloromethane (50 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (50 ml x 3), washed with anhydrous sulfuric acid Dry over sodium, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→6% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 303-5 (pale yellow oil, 1.02 grams, 98%). MS (ESI, m/z): 370.1[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ7.67–7.61(m,1H),7.46–7.38(m,2H),7.33–7.27( m,2H), 5.29(s,2H), 3.53(s,3H).

Step 5:

Under nitrogen protection stirring condition at 15 degrees centigrade, compound 303-5 (970 mg, 2.495 mmol, 1.0 eq), biboronic acid pinacol ester (1.28 g, 4.990 mmol, 2.0 eq) and potassium acetate (773.2 mg, 7.485 millimoles, 3.0 equivalents) in 1,4-dioxane (10 milliliters) solution, add [1,1-bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex ( 213.9 mg, 0.250 mmol, 0.1 equiv). The mixture was reacted at 90°C under a nitrogen atmosphere for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction liquid was cooled to 15 degrees Celsius, water (50 ml) was added to the reaction liquid, extracted with ethyl acetate (50 ml x 3), and the organic phases were combined. The organic phase was washed with saturated brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→6% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 303-6 (colorless oil, 662 mg, 73%). MS(ESI,m/z):348.2[M+H] ⁺ ; ¹ H NMR(300MHz,CDCl ₃ )δ7.64–7.59(m,1H),7.43–7.32(m,3H),7.26–7.22( m,1H), 5.29(s,2H), 3.51(s,3H), 1.44(s,12H).

Step 6:

Under nitrogen protection stirring condition at 15 degrees centigrade, compound 300-10 (250 mg, 0.388 mmol, 1.0 equivalent), compound 303-6 (170 mg, 0.466 mmol, 1.2 equivalent), 3-(tert-butyl)- 4-(2,6-Dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxophosphapentyl conjugate (26.9 mg, 0.078 mmol, 0.2 equiv) and potassium phosphate (173.2 mg, 0.776 mmol, 2.0 eq) in toluene (2.5 mL) and water (0.5 mL) was added tris(dibenzylideneacetone)dipalladium(0) (37.3 mg, 0.039 mmol, 0.1 eq ). The resulting mixture was reacted at 80° C. under nitrogen protection and stirring for 4 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to 15 degrees Celsius, and 25 milliliters of water was added to the reaction solution for dilution, extracted with ethyl acetate (25 milliliters x 2) and dichloromethane (25 milliliters x 1), and the organic phases were combined; Wash with saturated brine (25 ml x 3), dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→7% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 303-7 (yellow solid, 220 mg, yield rate of 72%). MS (ESI, m/z): 753.4 [M+H] ⁺ .

Step 7:

Compound 303-7 (220 mg) obtained in step 6 was subjected to chiral resolution by high performance liquid chromatography: chiral column CHIRAL ART Cellulose-SC, 2 x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol / liter of ammonia methanol), mobile phase B: ethanol; flow rate: 20 ml/min; within 12 minutes with 50% phase B for elution; detector UV224/211 nanometers, to obtain two products. The product with shorter retention time (4.665 minutes) is compound 303-7a (white solid, 89.5 mg, recovery 41%), MS (ESI, m/z): 753.4[M+H] ⁺ ; longer retention time ( 7.115 minutes) was compound 303-7b (white solid, 86.6 mg, recovery 39%), compound 303-7b: MS (ESI, m/z): 753.4[M+H] ⁺ .

Step 8:

Under the condition of stirring at 15 degrees Celsius, a solution of hydrochloric acid in 1,4-dioxane (4 mol/L, 2 ml). The mixture was reacted at 25°C for 1.5 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a reverse phase chromatographic column (C18 column), eluted with 5% → 95% water mobile phase (0.1% hydrochloric acid)/methanol within 20 minutes, and the detector UV254/220 nanometers; to obtain compound 303a ( Yellow solid, 58.1 mg, 78% yield). MS(ESI,m/z):609.3[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ )δ11.65–11.29(m,1H),10.40–9.56(m,3H),7.83– 7.75(m,1H),7.73–7.64(m,1H),7.43–7.31(m,2H),7.17–7.11(m,1H),7.05–6.97(m,1H),5.72–5.45(m,1H ),4.70–4.59(m,2H),4.57–4.37(m,2H),4.23–4.09(m,2H),4.06–3.66(m,5H),3.37–3.22(m,1H),2.74–2.59 (m, 1H), 2.49-2.26 (m, 2H), 2.25-1.89 (m, 7H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -116.42, -123.51, -172.63.

Step 9:

Compound 303b (yellow solid) can also be obtained according to the method in step 8 of this example. MS(ESI,m/z):609.3[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ )δ11.67–11.25(m,1H),10.29–9.54(m,3H),7.82– 7.75(m,1H),7.72–7.66(m,1H),7.43–7.30(m,2H),7.18–7.10(m,1H),7.05–6.97(m,1H),5.73–5.45(m,1H ),4.71–4.60(m,2H),4.57–4.47(m,1H),4.46–4.37(m,1H),4.18–4.12(m,2H),4.04–3.92(m,1H),3.91–3.65 (m,4H),3.36–3.22(m,1H),2.76–2.57(m,1H),2.48–2.28(m,2H),2.26–1.91(m,7H); ¹⁹ F NMR (282MHz,DMSO- d ₆ ) δ-116.43, -123.48, -172.74.

Example 9

4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-8-fluoro-2-(((2R, 7aS)-2-fluoro Tetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethynyl-6-fluoronaphthalene-2-ol 304

The synthetic route is as follows:

step 1:

2-Amino-4-bromo-3-fluorobenzoic acid (3 g, 12.178 mmol, 1 equiv) and urea (7.70 g, 121.780 mmol, 10 equivalent). The mixture was reacted at 150 degrees Celsius for 16 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction system was cooled to room temperature. At 25 degrees Celsius, add 100 ml of water to the reaction flask, filter, wash the filter cake with water (50 ml x 3), and collect the filter cake. Pour the filter cake into a 250 ml round bottom flask, add 20 ml of toluene and evaporate under reduced pressure, repeat three times to obtain dry compound 304-1 (brown solid, 3.6 g, yield 97%). MS (ESI, m/z): 258.8/260.8 [M+H] ⁺ . ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 11.48 (s, 2H), 7.68-7.59 (m, 1H), 7.49-7.39 (m, 1H).

Step 2:

Under nitrogen protection at 0°C, N,N-diisopropylethylamine (4.5 ml , 24.543 mmol, 2.08 equivalents). The mixture was reacted at 90°C under nitrogen protection for 16 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction liquid was cooled to room temperature, and rotary evaporated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 304-2 (pale yellow solid, 2.55 g, yield 70%). MS (ESI, m/z): 294.8/296.7/298.8 [M+H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.99–7.92 (m, 1H), 7.90–7.83 (m, 1H); ¹⁹ F NMR (282 MHz, CDCl ₃ ) δ-114.25.

Step 3:

Under the condition of nitrogen protection and stirring at 0 degrees Celsius, compound 304-2 (1.2 g, 3.893 mmol, 1 eq) and triethylamine (1.24 g, 11.679 mmol, 3 eq) in dichloromethane (10 ml) were added A solution of 8-tert-butoxycarbonyl-3,8-diazabicyclo[3.2.1]octane (0.87 g, 3.893 mmol, 1 eq) in dichloromethane (5 mL) was slowly added dropwise. The mixture was stirred and reacted at 25° C. for 1 hour. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, the reaction solution was rotary evaporated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→20% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 304-3 (yellow solid, 1.8 g, Yield 96%). MS(ESI,m/z):471.0/473.0/474.7[M+H] ⁺ ; ¹ H NMR(300MHz, CDCl ₃ )δ7.51–7.47(m,2H),4.51–4.26(m,4H), 3.64–3.60(m,2H), 1.99–1.90(m,2H), 1.78–1.67(m,2H), 1.52(s,9H).

Step 4:

Under nitrogen protection at 25 degrees Celsius, compound 304-3 (600 mg, 1.252 mmol, 1.0 equivalent), cesium carbonate (858.43 mg, 2.504 mmol, 2 equivalents) and 1,4-diazidebicyclooctane (29.56 mg, 0.251 mmol, 0.2 eq) in N,N-dimethylformamide (5 ml) was added (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol ( 251.68 mg, 1.503 mmol, 1.2 eq) in N,N-dimethylformamide (1.5 mL). The mixture was reacted at 80°C for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, and the mixture was purified by a reverse-phase chromatographic column (C18 column), and eluted with methanol/water (0.1% ammonia water) within 20 minutes; detector UV254/220 nanometers; to obtain the compound 304-4 (pale yellow solid, 409 mg, 66% yield). MS (ESI, m/z): 594.2/596.0 [M+H] ⁺ .

Step 5:

Under nitrogen protection conditions at 25 degrees Celsius, to compound 304-4 (409 mg, 0.661 mmol, 1 eq), 255-1 (427.59 mg, 0.793 mmol, 1.2 eq), 3-(tert-butyl)-4- (2,6-dimethoxyphenyl)-2,3-dihydrobenzo[d][1,3]oxophosphine conjugate (45.93 mg, 0.132 mmol, 0.2 equiv) and potassium phosphate (295.13 mg, 1.322 mmol, 2 equiv) in toluene (5.5 mL) and water (1.1 mL) was added tris(dibenzylideneacetone)dipalladium(0) (63.67 mg, 0.067 mmol, 0.1 equiv). The resulting mixture was reacted at 80°C for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, diluted with 50 ml of water, extracted with ethyl acetate (50 ml) and dichloromethane (50 ml x 2), and the organic phases were combined. Dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The resulting crude product was purified with a reversed-phase chromatographic column (C18 column), and eluted with 60% → 95% methanol/water (0.1% ammonia) mobile phase within 20 minutes; detector: UV254/220 nanometers; to obtain the compound 304-5 (yellow solid, 300 mg, yield 50%). MS (ESI, m/z): 900.8 [M+H] ⁺ .

Step 6:

Under nitrogen protection at 0°C, to a solution of compound 304-5 (290 mg, 0.319 mmol, 1.0 eq) in acetonitrile (5 mL), slowly dropwise add a solution of hydrochloric acid in 1,4-dioxane (4 mol/ liter, 1 ml). The mixture was stirred at 25°C under nitrogen protection for 2 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction finished, the reaction solution was rotary evaporated under reduced pressure to obtain the crude product, and the crude product was re-dissolved with isopropanol/dichloromethane mixed solution (volume ratio 1/9, 25 milliliters), and then saturated sodium bicarbonate (10 ml) was added thereto. ml) and saturated sodium carbonate (10 ml), adjust the pH of the aqueous phase>7, separate the organic phase, extract the aqueous phase with dichloromethane (25 ml x 2), and combine the organic phases. Dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% (methanol/ammonia methanol=8/2)/dichloromethane, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 304- 6 (pale yellow solid, 186 mg, 76% yield). MS (ESI, m/z): 756.4 [M+H] ⁺ .

Step 7:

To a solution of compound 304-6 (100 mg, 0.131 mmol, 1 eq) in N,N-dimethylformamide (1 mL) was added cesium fluoride (104.70 mg, 0.655 , 5 equivalents). The mixture was stirred at 25°C for 16 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, it was filtered, and the filter cake was washed with N,N-dimethylformamide (0.5 ml x 2), and the filtrates were combined to obtain a crude product. The crude product was purified by HPLC: reversed phase column: XBridge Shield RP18 OBD, 19 x 150 mm, 5 micron; mobile phase A: water (0.05% ammonia), mobile phase B: acetonitrile; flow rate: 25 ml/min ; eluted with 34%→61% of phase B; detector UV 220 nm; yielded compound 304 (pale yellow solid, 41.5 mg, 52% yield). MS(ESI,m/z):600.5[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ )δ10.14(s,1H),8.01–7.92(m,1H),7.73(d, J=8.6Hz,1H),7.51–7.41(m,1H),7.36(d,J=2.6Hz,1H),7.21–7.13(m,1H),7.07(d,J=2.5Hz,1H), 5.40–5.16(m,1H),4.36–4.18(m,2H),4.12–4.03(m,1H),4.02–3.93(m,1H),3.88–3.84(m,1H),3.58–3.40(m ,4H),3.17–3.05(m,2H),3.04–2.98(m,1H),2.90–2.77(m,1H),2.18–2.13(m,1H),2.08–1.98(m,2H),1.91 -1.60 (m, 7H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ -110.55, -110.56, -128.45, -128.49, -172.03, -172.14.

Example 10

4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-7-((S or R)-8-ethynyl-7-fluoro-3- Hydroxynaphthalene-1-yl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-methoxy)quinazoline-6-carbonitrile 305a ; 4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-7-((R or S)-8-ethynyl-7-fluoro-3 -Hydroxynaphthalene-1-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-methoxy)quinazoline-6-carbonitrile 305b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, a solution of the compound 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 81.188 mmol, 1.0 equivalent) in N,N-dimethylformamide (200 ml) N-iodosuccinimide (28.84 g, 121.782 mmol, 1.5 equiv) was added to . The mixture was stirred at 70°C under nitrogen protection for 16 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and 1000 ml of water was added to dilute the reaction solution. The pH of the aqueous phase was adjusted to 5 with concentrated hydrochloric acid at 0 °C. The mixture was extracted with dichloromethane (800 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium carbonate solution (500 ml x 2), saturated sodium sulfite (500 ml) and saturated brine (500 ml), then dried over anhydrous sodium sulfate, filtered and concentrated to obtain the crude compound 305-1. The resulting crude product was used directly in the next step without further purification. (black like solid, 36 g). MS (ESI, m/z): 357.9/359.8 [MH] ^- .

Step 2:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, to the solution of the above crude compound 305-1 (20 g, 81.188 mmol, 1.0 eq) in N,N-dimethylformamide (200 ml) was added iodoethane (10.40 g , 63.347 mmol, 1.2 equiv) and cesium carbonate (36.21 g, 105.578 mmol, 2.0 equiv). The mixture was stirred at 25°C under nitrogen protection for 16 hours, and the reaction progress was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to 25 degrees Celsius, and 1000 ml of water was added to dilute the reaction solution. The aqueous phase was extracted with dichloromethane (800 ml x 3), the combined organic phase was washed with saturated brine (500 ml x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0→10% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 305-2 (white solid, 11.8 g, Yield 55%). MS (ESI, m/z): 387.9/389.9 [M+H] ⁺ . ¹ H NMR (300MHz, CDCl ₃ ) δ8.14(d, J=1.9Hz, 1H), 4.37(q, J=7.1Hz, 2H), 1.42(t, J=7.1Hz, 3H); ¹⁹ F NMR (282MHz, CDCl ₃ ) δ-117.76.

Step 3:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, to the solution of compound 305-2 (4.00 g, 9.794 mmol, 1.00 eq) in N,N-dimethylformamide (40 ml) was added in batches with cuprous cyanide (1.85 g, 19.588 mmol, 2.0 equiv). The mixture was reacted for 16 hours at 90°C under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to 25 degrees Celsius, 400 ml of water was added to dilute the reaction solution, and then extracted with ethyl acetate (400 ml x 3), the organic phases were combined, and the organic phase was washed with 400 ml of saturated brine, and dried over anhydrous sodium sulfate , filtered to remove the desiccant, and the filtrate was concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 305-3 (white solid, 1.4 g , yield 35%). MS (ESI, m/z): 288.9/286.9 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ8.03 (d, J = 1.8 Hz, 1 H), 4.37 (q, J = 7.1 Hz , 2H), 1.41 (t, J=7.1 Hz, 3H); ¹⁹ F NMR (377 MHz, CDCl ₃ ) δ-125.24.

Step 4:

To compound 305-3 (1.4 g, 4.633 mmol, 1.00 eq) in tetrahydrofuran (14 mL) was added dropwise trichloroacetyl isocyanate (1.38 g, 6.950 mmol, 1.5 eq) at 25°C with nitrogen stirring. The mixture was reacted at 25°C for 1 hour under nitrogen stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was slurried with methyl tert-butyl ether (20 ml) to obtain compound 305-4 (white solid, 3.25 g, yield 89%). MS (ESI, m/z): 475.9/477.9 [M+H] ⁺ .

Step 5:

To a solution of compound 305-4 (3.25 g, 6.493 mmol, 1.00 eq) in methanol (14 mL) was added ammonia in methanol (7 mol/L, 1.4 mL) dropwise at 25 °C. The mixture was reacted at 25°C for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated to obtain a crude product. The obtained crude product was slurried by methyl tert-butyl ether (30 mL) to obtain compound 305-5 (white solid, 1.8 g, yield 93%). MS(ESI,m/z): 283.9/281.9[MH] ^- ,

¹ H NMR (300 MHz, DMSO-d ₆ ) δ 7.93-7.87 (m, 1H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-118.53.

Step 6:

Under the condition of nitrogen protection and stirring at 0 degrees Celsius, N,N-diisopropylethylamine (2 ml). The mixture was stirred at 25°C for 10 minutes, and then refluxed at 90°C for 4 hours. The reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% ethyl acetate/(petroleum ether: dichloromethane=10:1), and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain Compound 305-6 (pale yellow solid, 970 mg, yield 61%). ¹ H NMR (300MHz, CDCl ₃ ) δ8.46 (d, J=1.8Hz, 1H); ¹⁹ F NMR (282MHz, CDCl ₃ ) δ-107.62.

Step 7:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, triethylamine (917.56 mg, 8.613 mmol, 3.00 eq. ) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (641.65 mg, 2.871 mmol, 1.00 equiv). The mixture was reacted at 25°C for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/(petroleum ether: dichloromethane=1:1), and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain Compound 305-7 (pale yellow solid, 1.0 g, yield 67%). MS (ESI, m/z): 496.1/498.1/500.1 [M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.98 (d, J=1.8Hz, 1H), 4.52–4.32 (m, 4H), 3.81–3.65(m,2H), 2.05–1.91(m,2H), 1.72–1.62(m,2H), 1.53(s,9H).

Step 8:

Under nitrogen protection conditions at 25 degrees Celsius, to compound 305-7 (575 mg, 1.157 mmol, 1 equivalent), 255-1 (533.93 mg, 1.041 mmol, 0.9 equivalent), n-butyl bis (1-adamantyl ) Phosphine (83mg, 0.231mmol, 0.2eq) and potassium phosphate (737.08mg, 3.471mmol, 3eq) in toluene (12ml) and water (2.4ml) mixed solution add tris(dibenzylidene acetone) Dipalladium(0) (105.99 mg, 0.116 mmol, 0.1 equiv). The mixture was reacted at 80°C for 2 hours under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, and 50 ml of water was added to the reaction solution to dilute the reaction solution. The mixture was extracted successively with ethyl acetate (50 mL) and dichloromethane (50 mL x 2), and the organic phases were combined. The organic phase was washed with saturated brine (50 ml x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/(petroleum ether: dichloromethane=1:1), and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain Compound 305-8 (yellow solid, 675 mg, yield 73%). MS (ESI, m/z): 802.4/804.4 [M+H] ⁺ .

Step 9:

Under nitrogen protection at 25 degrees Celsius, compound 305-8 (650 mg, 0.810 mmol, 1.0 equivalent), cesium carbonate (527.85 mg, 1.620 mmol, 2 equivalents) and 1,4-diazidebicyclooctane (18.17 mg, 0.162 mmol, 0.2 eq) in N,N-dimethylformamide (10 ml) was added (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol ( 154.75 mg, 0.972 mmol, 1.2 eq) in N,N-dimethylformamide (3 mL). The mixture was reacted at 60°C for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction liquid was cooled to room temperature, 90 ml of water was added to the reaction liquid for dilution, dichloromethane (90 ml x 4) was extracted, and the organic phases were combined. The organic phase was washed with saturated brine (90 ml x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by preparative thin-layer chromatography (methanol/dichloromethane=1/16) to obtain compound 305-9 (pale yellow solid, 400 mg, yield 53%). MS (ESI, m/z): 925.5 [M+H] ⁺ .

Step 10:

The compound 305-9 (400 mg) obtained in step 9 was subjected to chiral resolution by preparative high-performance liquid chromatography, and the resolution conditions were: chiral column (R, R)-WHELK-O1-Kromasil, 2.11 x 25 cm, 5 microns; mobile phase A: n-hexane (0.1% 2 mol/L ammonia methanol), mobile phase B: isopropanol; flow rate: 20 ml/min; elute with 50% mobile phase for 48 minutes; detector : 206/234 nm gave two products. The compound with shorter retention time (21.3 minutes) is 305-10a (white solid, 120 mg, recovery 30%), MS (ESI, m/z): 925.5[M+H] ⁺ ; longer retention time (31.2 minutes) was 305-10b (white solid, 160 mg, recovery 40%), MS (ESI, m/z): 925.5[M+H] ⁺ .

Step 11:

Under nitrogen protection at room temperature, a solution of 1,4-dioxane (4 mol/L , 3 ml). The reaction solution was reacted at room temperature under nitrogen protection for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product 305-11a was directly used in the next reaction without purification. MS (ESI, m/z): 781.4 [M+H] ⁺ .

Step 12:

To a solution of compound 305-11a in N,N-dimethylformamide (3 mL) was added cesium fluoride (190 mg) under stirring at 0°C. The mixture was reacted at room temperature for 4 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was purified by a reverse phase chromatography column (C18 column), reverse phase column: XBridge Shield RP18 OBD Column, 30x 150 mm, 5 microns; mobile phase A: water (10 mmol/L ammonium bicarbonate), Mobile phase B: acetonitrile; flow rate: 60 ml/min; elution with 30% to 52% of phase B, detector: 254/220 nm, to obtain compound 305a (off-white solid, 46.6 mg, yield 58%) . MS(ESI,m/z):625.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ10.28(s,1H),8.28(d,J=1.2Hz,1H),8.11 –7.94(m,1H),7.57–7.47(m,1H),7.44(d,J=2.6Hz,1H),7.16(d,J=2.5Hz,1H),5.52–5.02(m,1H), 4.47–4.25(m,2H),4.13–4.08(m,1H),4.05–3.93(m,2H),3.69–3.60(m,1H),3.61–3.49(m,3H),3.15–3.05(m ,2H),3.02–2.98(m,1H),2.86–2.76(m,1H),2.15–2.11(m,1H),2.10–1.92(m,2H),1.92–1.71(m,3H),1.71 -1.52 (m, 4H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -110.00, -124.82, -172.19.

Compound 305b (yellow solid, 46.6 mg, yield 58%) could be obtained by the same method as step 11 and step 12 of this example. MS(ESI,m/z):625.45[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ10.27(s,1H),8.28(s,1H),8.20–7.90(m, 1H),7.54–7.41(m,2H),7.16(d,J＝2.5Hz,1H),5.51–5.08(m,1H),4.44–4.23(m,2H),4.07–3.96(m,1H) ,4.04–3.94(m,2H),3.70–3.46(m,4H),3.17–2.94(m,3H),2.87–2.78(m,1H),2.74–2.59(m,1H),2.18–1.93( m, 3H), 1.90-1.52 (m, 7H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -110.02, -124.85, -172.11.

Example 11

(4S or 4R)-4-(4-(1,5-Dimethyl-3,8-diazacyclo[3.2.1]octane-3-yl)-6,8-difluoro-2- (((2R,7aS)-2-Fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalene-2-ol disalt Salt 306a; (4R or 4S)-4-(4-(1,5-dimethyl-3,8-diazacyclo[3.2.1]octane-3-yl)-6,8-di Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalene-2 -phenol dihydrochloride 306b

The synthetic route is as follows:

step 1

4-Methoxybenzylamine was slowly added to a solution of diethyl 2,5-dibromoadipate (200 g, 527.716 mmol, 1 eq.) in toluene (2 liters) under nitrogen protection at 25 °C with stirring (228.61 g, 1583.148 mmol, 3 equiv). The mixture was reacted at 110 degrees Celsius for 16 hours under stirring conditions, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the insolubles were removed by filtration, the filter cake was washed with toluene (50 ml x 3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 10% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 306-1 (light yellow oil, 150 g , yield 85%). MS(ESI,m/z):336.2[M+H] ⁺ ; ¹ H NMR(300MHz,CDCl ₃ )δ7.34–7.19(m,2H),6.90–6.77(m,2H),4.07(q, J=7.1Hz, 4H), 3.92(s, 2H), 3.80(s, 3H), 3.45(s, 2H), 2.13–2.04(m, 4H), 1.22(t, J=7.1Hz, 6H).

step 2

Under the condition of nitrogen protection and stirring at -40 degrees Celsius, lithium diisopropylamide (1 mol/L, 1062.16 ml , 1062.165 mmol, 2.5 equivalents). After the resulting mixture was stirred and reacted at -40°C for 0.5 hours, methyl iodide (158.70 g, 424.866 mmol, 2.5 equivalents) was slowly added dropwise to the reaction solution at the same temperature. The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, saturated ammonium chloride (500 mL) was added to the mixture at 0°C to quench the reaction. The mixture was extracted with ethyl acetate (300 mL x 3), the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 10% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 306-2 (colorless oil, 96 g , yield 59%). MS (ESI, m/z): 364.2[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ7.33–7.16(m,2H),6.86–6.74(m,2H),4.20–3.93( m,5H),3.79(d,J＝4.6Hz,3H),2.43(m,1H),2.21–1.90(m,3H),1.81–1.71(m,1H),1.47(s,4H),1.31 –1.25(m,4H),1.21(m,4H).

step 3

Under the condition of nitrogen protection and stirring at zero degrees Celsius, to compound 306-2 (62 g, 162.056 mmol, 1 equivalent) in tetrahydrofuran (650 ml) was slowly added lithium aluminum hydride in tetrahydrofuran (2.5 mol/L, 194.47 ml, 486.168 mmol, 3 equivalents). The resulting mixture was stirred and reacted at 25 degrees Celsius for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, water (18.5 ml), 15% sodium hydroxide solution (18.5 ml) and water (55.5 ml) were successively added dropwise to the reaction solution under stirring at zero degrees Celsius. The insolubles were then removed by filtration, and the filter cake was washed with tetrahydrofuran (50 mL x 5). The filtrate was concentrated under reduced pressure to obtain crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fractions were removed by rotary evaporation under reduced pressure to obtain compound 306-3 (light yellow oil, 45 g, Yield 94%). MS (ESI, m/z): 280.2 [M+H] ⁺ .

step 4

Compound 306-3 (45 grams) obtained in step 3 was subjected to chiral resolution, and the resolution conditions were: chiral column CHIRAL ART Cellulose-SC, 5 x 25 cm, 10 microns; mobile phase A: supercritical carbon dioxide fluid, Mobile phase B: methanol/dichloromethane (1/1); flow rate: 150 ml/min; column temperature: 35 degrees Celsius; eluted with 30% mobile phase B for 8 minutes; detector UV220 nanometers; two products were obtained. The compound with shorter retention time (4.5 minutes) is 306-4' (pale yellow oil, 30 grams, recovery rate 66%), MS (ESI, m/z): 280.2[M+H] ⁺ ; longer retention time (5.69 minutes) The compound was 306-4 (pale yellow oil, 11 g, recovery 24%), MS (ESI, m/z): 280.2 [M+H] ⁺ .

step 5

Oxalyl chloride (11.81 ml, 88.412 mmol) was added dropwise to a solution of dimethyl sulfoxide (7.44 ml, 99.464 mmol, 4.5 eq) in dichloromethane (80 ml) at -78°C under nitrogen protection with stirring. , 4 equivalents). After stirring the reaction at -78°C for 0.5 hours, compound 306-4 (6.5 g, 22.103 mmol, 1.0 equiv) was added dropwise to the reaction solution at the same temperature. The resulting mixture was continued to react for 1 hour at -78°C under nitrogen protection and stirring. Then, N,N-diisopropylethylamine (32.42 mL, 176.82 mmol, 8 eq) was added to the above reaction solution at -78°C. The resulting mixture was continued to react for 1 hour at room temperature under nitrogen protection with stirring. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 306-5 (light yellow oil, 6 g, Yield 69%). MS (ESI, m/z): 276.2 [M+H] ⁺ .

step 6

Under the condition of stirring at 25 degrees Celsius, to benzylamine (2.06 g, 18.30 mmol, 1.2 equivalents), acetic acid (1.16 g, 18.30 mmoles, 1.2 equivalents) in methanol (60 ml) was added sodium cyanoborohydride (3.03 g, 45.76 mmol, 3.0 eq) and compound 306-5 (6 g, 15.253 mmol, 1.0 eq). The reaction solution was stirred and reacted at 25 degrees Celsius for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 306-6 (light yellow oil, 2.2 g, Yield 39%). MS(ESI,m/z):351.2[M+H] ⁺ ; ¹ H NMR(300MHz,CDCl ₃ )δ7.40–7.27(m,7H),6.89–6.82(m,2H),3.82(s, 3H),3.66(s,2H),3.52(s,2H),2.33–2.18(m,4H),2.02–1.90(m,2H),1.64–1.51(m,2H),0.97(s,6H) .

step 7

To a solution of compound 306-6 (980 mg, 2.656 mmol, 1.0 eq) in ethanol (10 mL) was added palladium hydroxide/carbon (20%, 196 mg) under stirring at 25°C. The mixture was reacted at 60°C for 6 hours in a hydrogen atmosphere of 10 atmospheres. After the reaction was over, the reaction was depressurized and cooled to 25°C. The insoluble matter was removed by filtration, and the filter cake was washed with ethanol (20 mL x 3). The filtrate was concentrated to give crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 306-7 (white solid, 520 mg, yield rate of 71%). MS(ESI,m/z):261.1[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ7.34–7.28(m,2H),6.84–6.79(m,2H),3.79(s, 3H), 3.72(s, 2H), 2.93(d, J=12.7Hz, 2H), 2.26(d, J=12.8Hz, 2H), 1.86–1.78(m, 2H), 1.69–1.60(m, 2H ),0.91(s,6H).

Step 8

Under stirring conditions under nitrogen protection at zero degrees Celsius, triethylamine (502.89 mg, 4.722 mmol, 3.0 eq. ) and compound 306-7 (431.33 mg, 1.574 mmol, 1.0 equiv). The mixture was stirred and reacted at 25° C. for 1 hour, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the reaction solution was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0%→30% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 306-8 (yellow solid, 910 mg, Yield 96%). MS (ESI, m/z): 539.1/541.1 [M+H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.49–7.45 (m, 1H), 7.34 (d, J＝8.2Hz, 2H) ,6.86(d,J=8.2Hz,2H),3.99(d,J=12.8Hz,2H),3.85–3.79(m,5H),3.51(d,J=12.8Hz,2H),1.73–1.60( m, 4H), 1.08 (s, 6H).

step 9

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, (2R,7aS)-2- Fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol (142.09 mg, 0.848 mmol, 1.2 equiv), triethylenediamine (16.69 mg, 0.141 mmol, 0.2 equiv) and cesium carbonate (486.64 mg, 1.414 mmol, 2.0 equivalents). The reaction solution was stirred and reacted at 60 degrees Celsius for 16 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the reaction solution was cooled to 25 degrees Celsius. After the reaction was over, water (50 ml) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (50 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (50 ml x 3), and then washed with Dry over sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 306-9 (yellow solid, 402 mg, yield rate 86%). MS(ESI,m/z):660.2/662.2[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ7.43–7.40(m,1H),7.34(d,J＝8.5Hz,2H) ,6.90–6.80(m,2H),5.37–5.23(m,1H),4.32–4.23(m,2H),3.91–3.86(m,2H),3.81–3.79(m,5H),3.49(s, 3H),3.44–3.41(m,2H),3.29–3.16(m,2H),3.03–3.97(m,1H),2.35–2.09(m,3H),2.00–1.94(m,1H),1.77– 1.63(m,4H),1.07(s,6H).

Step 10

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, compound 282-2 (124.34 mg, 0.346 mg mol, 1.2 equiv), potassium phosphate (128.53 mg, 0.576 mmol, 2.0 equiv), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzene And[D][1,3]oxo,phosphpentyl conjugate (20 mg, 0.058 mmol, 0.2 equiv) and tris(dibenzylideneacetone)dipalladium(0) (27.73 mg, 0.029 mmol, 0.1 equiv) . The reaction solution was stirred and reacted at 80 degrees Celsius for 4 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the reaction solution was cooled to room temperature. After the reaction solution was concentrated, it was purified by silica gel column chromatography, the mobile phase was dichloromethane/methanol=10/1, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 306-10 (light yellow solid, 203 mg, yield 80 %). MS (ESI, m/z): 796.4 [M+H] ⁺ .

step 11

Compound 306-10 (203 mg, 0.239 mmol, 1.0 equiv), trifluoroacetic acid (2.5 mL) and anisole (2.5 mL) were sequentially added to a 40 mL reaction flask under stirring at 25 °C. The resulting mixture was stirred and reacted at 100° C. for 1 hour, and the reaction process was monitored by liquid quality. After the reaction was finished, cool to room temperature, concentrate under reduced pressure to remove excess reagents and redissolve with chloroform/isopropanol (3/1), wash the organic phase with saturated sodium bicarbonate solution (10 ml x 3), and dry over anhydrous sodium sulfate , filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purify by reverse-phase chromatography (C18 column), elute with 30% → 95% methanol/water (0.1% ammonia) mobile phase in 25 minutes; detector: UV254 nanometers; obtain compound 306-11 (two Mixture of stereoisomers, pale yellow solid, 97 mg, 60% yield). MS (ESI, m/z): 632.3 [M+H] ⁺ .

Step 12

The compound 306-11 (97 mg) obtained in step 11 was chirally resolved by preparative chiral high-performance liquid chromatography, and the resolution conditions were: chiral column CHIRALPAK IC, 2x 25 cm, 5 microns; mobile phase A : n-hexane (10 mmol/l ammonia methanol solution), mobile phase B: ethanol; flow rate: 20 ml/min; elution with 30% phase B in 12 minutes, detector UV 224/206 nanometers. Obtain two products, the product of shorter retention time (2.86 minutes) is compound 306-11a (white solid, 45 mg, recovery rate 46%), MS (ESI, m/z): 632.3[M+H] ⁺ ; The product with a longer retention time (6.93 minutes) was compound 306-11b (white solid, 40 mg, recovery 41%), MS (ESI, m/z): 632.3[M+H] ⁺ .

Step 13

Compound 306-11a (45 mg, 0.066 mmol, 1.00 equiv) was purified by reverse phase chromatography (C18 column), eluting with 5% → 50% acetonitrile/water (0.1% hydrochloric acid) mobile phase within 15 minutes ; Detector: UV220 nm; Compound 306a was obtained (yellow solid, 34.7 mg, yield 69%). MS(ESI,m/z):632.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.60(s,1H),10.38-10.36(m,1H),9.99–9.97( m,1H),7.83–7.80(m,1H),7.69(d,J=8.0Hz,1H),7.40–7.37(m,1H),7.33(d,J=2.6Hz,1H),7.15(d ,J=7.0Hz,1H),7.00(d,J=2.6Hz,1H),5.65–5.49(m,1H),4.63(s,2H),4.48–4.45(m,1H),4.31–4.28( m,1H),3.95–3.65(m,5H),3.32–3.24(m,1H),2.68–2.45(m,3H),2.40–2.32(m,3H),2.25–1.98(m,5H), 1.94–1.83(m,2H),1.56(d,J＝11.0Hz,6H),0.87-0.83(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-116.00,-116.01,-123.59 ,-123.60,-172.68.

Step 14

Compound 306-11b (40mg, 0.063mmol, 1.00eq) was purified by reverse phase chromatography (C18 column), eluting with 5% → 50% acetonitrile/water (0.1% hydrochloric acid) mobile phase within 15 minutes ; Detector: UV220 nm; Compound 306b was obtained (yellow solid, 36.3 mg, yield 81%). MS(ESI,m/z):632.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.55(s,1H),10.37-10.34(m,1H),9.98–9.96( m,1H),7.83–7.80(m,1H),7.69(d,J=8.0Hz,1H),7.40–7.37(m,1H),7.33(d,J=2.6Hz,1H),7.15(d ,J=7.0Hz,1H),7.00(d,J=2.6Hz,1H),5.65–5.49(m,1H),4.63(s,2H),4.48–4.45(m,1H),4.31–4.28( m,1H),3.95–3.65(m,5H),3.32–3.24(m,1H),2.67–2.44(m,3H),2.40–2.32(m,3H),2.25–1.98(m,5H), 1.94–1.83(m,2H),1.56(d,J＝11.0Hz,6H),0.87-0.83(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-116.02,-116.04,-123.56 , -123.57, -172.70.

Example 12

4-((S or R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-(( 2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-cyclopropylnaphthalene-2-ol 307a; 4- ((R or S)-4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-cyclopropylnaphthalene-2-ol 307b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection stirring at 25 degrees centigrade, compound 1-bromo-8-iodonaphthalene (6.00 g, 17.119 mmol, 1 equivalent), cyclopropylboronic acid (1.55 g, 17.119 mmol, 1 equivalent) and potassium phosphate ( 7.65 g, 34.238 mmol, 2 equivalents) in a mixed solution of toluene (60 ml) and water (12 ml) was added [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloro Methane complex (1.47 g, 1.712 mmol, 0.1 equiv). The mixture was stirred at 60°C under nitrogen protection for 6 hours, and the reaction process was monitored by thin layer chromatography. After the reaction was completed, it was cooled to room temperature, and 20 ml of saturated ammonium chloride aqueous solution was added to the mixture to dilute the reaction solution. The mixture was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% ethyl acetate/petroleum ether, and the obtained fraction was concentrated under reduced pressure to remove the solvent to obtain compound 307-1 (pale yellow solid, 2.4 g , yield 53%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.93–7.87(m,1H),7.84–7.78(m,1H),7.74–7.69(m,1H),7.52–7.47(m,1H),7.43–7.36 (m,1H), 7.28–7.22(m,1H), 3.08–2.94(m,1H), 1.18–1.08(m,2H), 0.93–0.84(m,2H).

Step 2:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, to compound 307-1 (1.5 g, 5.776 mmol, 1 eq) in heptane (20 ml) solution was added successively diboronic acid pinacol ester (1.34 g, 7.496 mmol, 1.3 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (330 mg, 1.153 mmol, 0.2 eq) and (1,5-cyclooctadiene) iridium(I) chloride di polymer (410 mg, 0.577 mmol, 0.1 equiv). The mixture was stirred at 80°C for 2 hours, and the progress of the reaction was monitored by TLC. After the reaction, the solvent was concentrated under reduced pressure to obtain a mixture. The resulting mixture was dissolved in tetrahydrofuran (10 ml), and water (5 ml), acetic acid (30 ml) and hydrogen peroxide (30%, 15 ml) were slowly and sequentially added dropwise to the mixture with stirring at 0°C. The mixture was stirred at 0°C for 30 minutes, and the progress of the reaction was monitored by thin layer chromatography. After the reaction was completed, a saturated sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to 8 under stirring at 0°C. The mixture was extracted with ethyl acetate (100 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 20% methyl tert-butyl ether/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 307-2 (yellow oily liquid, 700 mg, 44.75% yield). ¹ H NMR (400MHz,DMSO-d ₆ )δ10.05(s,1H),7.65–7.58(m,1H),7.50(d,J=2.6Hz,1H),7.33–7.27(m,1H), 7.24–7.17(m,2H), 2.83(m,1H), 1.08–1.01(m,2H), 0.83–0.77(m,2H).

Step 3:

N,N-diisopropylethylamine (860.56 μg liters, 4.694 mmol, 2 eq) and chloromethyl methyl ether (298.32 mg, 3.521 mmol, 1.5 eq). The mixture was stirred at 25°C for 2 hours, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→12% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 307-3 (yellow oil, 660 mg , yield 88%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.68(d, J=2.6Hz, 1H), 7.63–7.57(m, 1H), 7.38(d, J=2.6Hz, 1H), 7.36–7.31(m, 2H), 5.28(s,2H), 3.53(s,3H), 2.99–2.90(m,1H), 1.16–1.07(m,2H), 0.94–0.83(m,2H).

Step 4:

Under the condition of nitrogen protection and stirring at -78 degrees Celsius, a solution of n-butyllithium in n-hexane (2.5 mol /L, 0.59 ml, 1.485 mmol, 1.6 equiv). After the mixture was reacted for 1 hour at -78 degrees Celsius under nitrogen protection and stirring, anhydrous isopropanol pinacol borate (327.07 mg, 1.670 mmol, 1.8 equivalents) was slowly added dropwise to the above reaction solution at the same temperature. Tetrahydrofuran (1 mL) solution. The mixture was stirred at -78°C for 1 hour, then returned to room temperature, and stirred at room temperature for 30 minutes. The reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, 50 ml of saturated ammonium chloride aqueous solution was added to quench the reaction at 0°C. The mixture was extracted with ethyl acetate (60 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→12% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 307-4 (colorless oily liquid, 290 mg, yield 79%). MS (ESI, m/z): 355.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ7.61–7.56 (m, 1H), 7.44–7.39 (m, 2H), 7.35–7.29 ( m,1H),7.23–7.19(m,1H),5.29(s,2H),3.51(s,3H),2.72–2.57(m,1H),1.40(s,12H),1.05–0.97(m, 2H), 0.69–0.59 (m, 2H).

Step 5:

Under nitrogen protection stirring condition at 25 degrees centigrade, toluene (5 milliliters) and water ( 1 ml) of the mixed solution was sequentially added 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxygen, Phospentyl conjugate (29.13 mg, 0.084 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (40.37 mg, 0.042 mmol, 0.10 equiv) and potassium phosphate (187.14 mg, 0.838 mmol, 2 equiv) . The mixture was stirred at 80°C for 4 hours, and the reaction progress was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, the solvent was removed by concentration under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→7% methanol/dichloromethane, and the solvent was removed by rotary evaporation under reduced pressure to obtain compound 307-5 (yellow solid, 270 mg, Yield 78%). MS (ESI, m/z): 760.5 [M+H] ⁺ .

Step 6:

Compound 307-5 (270 mg, 0.352 mmol) obtained in step 5 was subjected to chiral resolution by preparative supercritical liquid chromatography: chiral column CHIRAL ART Amylose-SA, 3 x 25 cm, 5 microns; mobile phase A: Supercritical carbon dioxide, mobile phase B: isopropanol; flow rate: 60 ml/min; elution with 40% phase B in 15 minutes, detector UV 224/210 nm, two products were obtained. The product with shorter retention time (6.52 minutes) is compound 307-5a (white solid, 103 mg, recovery 38%), MS (ESI, m/z): 760.5[M+H] ⁺ ; longer retention time ( 10.18 minutes) was compound 307-5b (white solid, 110 mg, recovery 39%), MS (ESI, m/z): 760.5[M+H] ⁺ .

Step 7:

Under the condition of stirring at 0 degrees Celsius, a solution of hydrochloric acid in 1,4-dioxane (4 mol/L , 2 ml). The reaction solution was reacted at room temperature for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was concentrated under reduced pressure to obtain a crude product. Under the condition of stirring at 0°C, a saturated sodium bicarbonate solution was added to the crude product to adjust the pH to 8. The resulting mixture was extracted with chloroform/isopropanol (3/1, 30 mL x 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol (0.1% 7 mol/liter ammonia methanol)/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain the compound 307a (white solid, 52.9 mg, 70% yield). MS(ESI,m/z)616.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ9.98(s,1H),7.72–7.66(m,1H),7.64–7.58(m ,1H),7.36–7.27(m,2H),7.15–7.09(m,1H),6.98(d,J＝2.6Hz,1H),5.39–5.15(m,1H),4.35–4.17(m,2H ),4.12–4.04(m,1H),4.03–3.93(m,1H),3.63–3.44(m,5H),3.14–2.99(m,3H),2.86–2.78(m,1H),2.15–1.96 (m,3H),1.87–1.66(m,7H),1.60–1.50(m,1H),0.58–0.41(m,2H),0.31–0.22(m,1H),0.12–0.03(m,1H) ; ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-118.10, -118.12, -123.96, -123.98, -172.13.

Step 8:

Compound 307b (white solid, 33 mg, yield 42%) can also be obtained according to the method of step 7. MS (ESI, m/z): 616.2 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ9.97 (s, 1H), 7.72–7.66 (m, 1H), 7.63–7.57 ( m,1H),7.37–7.28(m,2H),7.16–7.10(m,1H),6.98(d,J＝2.6Hz,1H),5.37–5.17(m,1H),4.33–4.26(m, 1H),4.24–4.18(m,1H),4.11–4.07(m,1H),4.01–3.93(m,1H),3.56–3.47(m,3H),3.46–3.39(m,1H),3.14– 2.99(m,3H),2.86–2.77(m,1H),2.20–1.96(m,3H),1.89–1.74(m,3H),1.70–1.59(m,4H),1.58–1.50(m,1H ),0.56–0.39(m,2H),0.31–0.23(m,1H),0.12–0.04(m,1H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-118.31,-118.33,-124.00, -124.02, -172.12.

Example 13

4-((S or R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-cyclobutylnaphthalene-2-ol dihydrochloride 308a ; 4-((R or S)-4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-( (2R,7aS)-2-Fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-cyclobutylnaphthalene-2-ol dihydrochloride 308b

The synthetic route is as follows:

step 1

Under stirring condition under nitrogen protection at 25 degrees centigrade, 5-bromo-1-naphthylamine (20 grams, 85.55 mmoles, 1 equivalent), cesium carbonate (88.02 grams, 256.66 mmoles, 3 equivalents) and cyclobutylboronic acid (18 g, 171.1 mmol, 2 equivalents) in a mixed solution of toluene (200 milliliters) and water (20 milliliters) was added [1,1-bis(diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex compound (7.34 g, 8.56 mmol, 0.1 equiv). The mixture was reacted at 100°C for 16 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the mixture was cooled to room temperature. The insoluble matter was removed by filtration, the filter cake was washed with ethyl acetate (160 ml x 3), and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and eluted with a gradient of 0%→30% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 308-1 (pink solid, 3.8 g , yield 21%). MS (ESI, m/z): 198.1[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.74–7.71(m,1H),7.49–7.40(m,2H),7.40–7.34( m,1H),7.34–7.27(m,1H),6.86–6.81(m,1H),4.16–4.03(m,1H),2.59–2.47(m,2H),2.36–2.24(m,2H), 2.21–2.08(m,1H),1.95–1.84(m,1H).

step 2

To a solution of compound 308-1 (3.8 g, 19.29 mmol, 1 eq) in acetic acid (38 mL) was slowly added liquid bromine (4.63 g, 28.94 mmol, 1.5 eq) under stirring at 0 °C. The mixture was reacted at 40°C for 1.5 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the mixture was cooled to room temperature. The solvent was removed by filtration, and the filter cake was washed with acetic acid (30 mL x 4). Under stirring at 0°C, the crude product was dissolved in acetic acid (50 mL), and liquid bromine (3.40 g, 21.22 mmol, 1.1 eq) was added slowly. The mixture continued to react for 0.5 hour under the condition of stirring at 40 degrees Celsius, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was complete, the mixture was cooled to room temperature. The solvent was removed by filtration, and the filter cake was washed with acetic acid (40 mL x 4). Drying gave compound 308-2 (brown solid, 6.3 g, yield 92%). MS(ESI,m/z):353.9/355.9/357.9[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ )δ8.16–8.10(m,1H),7.77(s,1H), 7.66–7.59(m,1H),7.53–7.45(m,1H),6.07(s,2H),4.89–4.76(m,1H),2.47–2.41(m,1H),2.11–1.91(m,4H ), 1.85–1.75(m,1H).

step 3

Under stirring condition at 0°C, sodium nitrite (1.31 g, 19.04 mmol, 1.2 equivalents). The mixture was reacted at 0°C for 0.5 hour under stirring condition, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, add water (200 ml) to dilute the reaction solution, extract the resulting mixture with dichloromethane (200 ml x 3), and combine the organic phases; the organic phase is dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate is concentrated under reduced pressure to obtain crude product. The obtained crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0%→50% ethyl acetate/petroleum ether mobile phase. g, yield 27%). MS (ESI, m/z): 302.9/304.8 [M+H] ⁺ .

step 4

To a solution of compound 308-3 (1.3 g, 4.3 mmol, 1 eq) in ethanol (13 mL) was slowly added sodium borohydride (244 mg, 6.45 mmol, 1.5 eq) under stirring at 0°C. The mixture was reacted at 0°C for 3 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, water (1 ml) was added to the reaction solution at 0° C. to quench the reaction. The mixture was purified by reverse-phase chromatography column (C18 column), eluted with 5% → 95% methanol/water mobile phase (0.1% formic acid) within 30 minutes; detector, UV 254/220 nm; compound 308 was obtained -4 (grey solid, 430 mg, 36% yield). MS(ESI,m/z):274.8/276.7[MH] ^- ; ¹ H NMR(400MHz,DMSO-d ₆ )δ10.02(s,1H),7.64–7.59(m,1H),7.45(d, J=2.6Hz,1H),7.43–7.38(m,2H),7.17(d,J=2.6Hz,1H),4.90–4.80(m,1H),2.49–2.39(m,2H),2.17–2.02 (m,2H), 2.01–1.89(m,1H), 1.84–1.74(m,1H).

step 5

Under the condition of stirring under nitrogen protection at zero degrees Celsius, the dichloro Chloromethyl methyl ether (134.1 g, 1.916 mmol, 1.3 equiv) was slowly added to the solution in methane (4 mL). The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was over, the reaction solution was poured into ice water (20 ml) to quench the reaction, the aqueous phase was extracted with ethyl acetate (25 ml x 3), and the organic phase was combined; the organic phase was dried with anhydrous sodium sulfate, filtered to remove the dryness agent, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0%→25% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 308-5 (light yellow oil, mg, yield 86%). MS(ESI,m/z):320.9/323.0[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl3)δ7.55–7.49(m,2H),7.42–7.38(m,1H),7.36–7.31 (m,1H),7.30–7.27(m,1H),5.18(s,2H),4.95–4.84(m,1H),3.44(s,3H),2.53–2.42(m,2H),2.13–2.03 (m,2H), 1.99–1.89(m,1H), 1.82–1.71(m,1H).

step 6

Under the condition of nitrogen protection and stirring at -78 degrees Celsius, a solution of n-butyllithium in n-hexane (2.5 mol /L, 625 μL, 1.562 mmol, 1.6 eq). The mixture was reacted at -78°C for 1 hour with stirring. A solution of isopropanol pinacol borate (344.07 mg, 1.757 mmol, 1.8 equiv) in anhydrous THF (1 mL) was then slowly added dropwise to the mixture. The mixture was stirred at -78°C for 1 hour, then returned to room temperature, and stirred at room temperature for 30 minutes. The reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, 20 ml of saturated ammonium chloride aqueous solution was added to the reaction solution at 0° C. to quench the reaction. The reaction solution was extracted with ethyl acetate (30 ml x 3), the organic phases were combined, and the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, eluted with a gradient of 0%→25% ethyl acetate/petroleum mobile phase ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 308-6 (colorless liquid, 300 mg , yield 79%). MS(ESI,m/z):369.1[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ7.61–7.55(m,1H),7.44–7.35(m,4H),5.28(s, 2H),4.46–4.35(m,1H),3.50(s,3H),2.57–2.47(m,2H),2.20–2.09(m,2H),2.05–1.95(m,1H),1.90–1.80( m,1H), 1.48(s,12H).

step 7

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 300-10 (200 mg, 0.310 mmol, 1 equivalent), compound 308-6 (144.31 mg, 0.372 mmol, 1.2 equivalents), 3-(tert-butyl)- 4-(2,6-Dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxophosphapentyl conjugate (21.58 mg, 0.062 mmol, 0.2 equiv) and potassium phosphate (138.62 mg, 0.620 mmol, 2 eq) in toluene (2 mL) and water (0.4 mL) was added tris(dibenzylideneacetone)dipalladium (29.9 mg, 0.031 mmol, 0.1 eq). The resulting mixture was reacted at 80°C for 4 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature. After the reaction, add 20 ml of water to dilute the reaction solution, then extract with ethyl acetate (20 ml x 3), and combine the organic phase; the organic phase is dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate is concentrated under reduced pressure to obtain the crude product . The crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 308-7 (pale yellow solid, 210 mg , yield 83%). MS (ESI, m/z): 774.5 [M+H] ⁺ .

Step 8

Compound 308-7 (210 mg) obtained in step 7 was subjected to chiral resolution by preparative liquid chromatography: chiral column CHIRALPAK IC, 2 x 25 cm, 5 microns; mobile phase A: n-hexane: dichloromethane=5: 1 (0.5% 2 mol/liter of ammonia methanol), mobile phase B: ethanol; flow rate: 20 ml/min; within 13 minutes with 50% phase B for elution, detector UV 212/270 nanometers, two products. The product with shorter retention time (2.5 minutes) is compound 308-7a (white solid, 65.8 mg, recovery 31%), MS (ESI, m/z): 774.5[M+H] ⁺ ; longer retention time ( 8.5 minutes) was compound 308-7b (white solid, 59.8 mg, recovery 28%), MS (ESI, m/z): 774.5[M+H] ⁺ .

step 9

Under the condition of stirring at 0 degrees Celsius, compound 308-7a (70 mg, 0.081 mmol, 1.0 equivalent), methanol (2.0 ml) and 1,4-dioxane solution of hydrochloric acid (4 mol/ ml, 2.0 ml). The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5% → 80% methanol/water (0.1% hydrochloric acid) mobile phase within 25 minutes; detector, UV254/220 nm ; Compound 308a was obtained (yellow solid, 54.9 mg, yield 96%). MS(ESI,m/z):630.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.84–7.76(m,1H),7.75–7.67(m,1H ),7.50–7.40(m,2H),7.33(d,J＝2.7Hz,1H),6.98(d,J＝2.7Hz,1H),5.68–5.50(m,1H),4.66–4.58(m, 2H),4.57–4.48(m,2H),4.27–4.12(m,2H),3.98–3.74(m,5H),3.39–3.24(m,2H),2.70–2.54(m,1H),2.39– 2.29(m,2H),2.24–2.14(m,2H),2.11–1.95(m,6H),1.92–1.78(m,2H),1.71–1.54(m,2H),1.38–1.25(m,1H ); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-116.11, -116.12, -123.45, -123.46, -172.70. The chiral analysis conditions of compound 308a are: N-Lux 3 μm Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol/L Ammonia); flow rate: 2 ml/min; isocratic elution with 50% phase B in 6 min; detector UV 254 nm; retention time: 3.417 min; dr>40:1.

Step 10

Compound 308b (yellow solid, 48.4 mg, yield 98%) can also be obtained according to the method of step 9. MS(ESI,m/z):630.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.84–7.77(m,1H),7.73–7.68(m,1H ),7.50–7.42(m,2H),7.33(d,J＝2.6Hz,1H),6.99(d,J＝2.6Hz,1H),5.69–5.48(m,1H),4.68–4.58(m, 2H),4.57–4.44(m,2H),4.26–4.11(m,2H),4.00–3.92(m,1H),3.91–3.72(m,4H),3.42–3.23(m,2H),2.69– 2.54(m,1H),2.50–2.42(m,1H),2.39–2.28(m,1H),2.26–2.13(m,2H),2.11–1.94(m,6H),1.92–1.78(m,2H ), 1.72-1.56 (m, 2H), 1.40-1.27 (m, 1H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-116.13, -123.42, -172.73. The chiral analysis conditions of compound 308b are: N-Lux 3 μm Cellulose-4 (H17-388767), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol/L Ammonia); flow rate: 2 ml/min; isocratic elution with 50% phase B in 6 min; detector UV 254 nm; retention time: 4.479 min; dr>40:1.

Example 14

4-((S or R)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-(2-fluoroethyl)naphthalene-2-ol Dihydrochloride 309a; 4-((R or S)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-di Fluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-(2-fluoroethyl ) Naphthalene-2-ol dihydrochloride 309b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 1-bromo-5-nitronaphthalene (50.0 g, 188.42 mmol, 1.0 equivalent), 1-ethoxyvinyl-2-boronic acid pinacol were added successively to a 1-liter three-necked flask. Esters (47.15 g, 226.14 mmol, 1.2 eq), potassium carbonate (52.61 g, 376.88 mmol, 2.0 eq), [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloride Methane complex (14.51 grams, 18.84 mmoles, 0.1 equivalent), 1,4 dioxane (400 milliliters) and water (80 milliliters) mixture were reacted for 2 hours under nitrogen protection stirring conditions at 80 degrees Celsius, and the reaction process passed through liquid quality and thin layer chromatography to monitor. After the reaction, water (500 ml) was added to the reaction solution, and the resulting mixture was extracted with ethyl acetate (500 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (500 ml x 1), anhydrous Dry over sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→20% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 309-1 (yellow solid, 29 g, Yield 60%). ¹ H NMR (300MHz, CDCl ₃ )δ8.44–8.31(m,2H),8.20–8.13(m,1H),7.67–7.50(m,3H),6.94(d,J＝12.5Hz,1H), 6.47 (d, J=12.5Hz, 1H), 4.05 (q, J=7.0Hz, 2H), 1.44 (t, J=7.0Hz, 3H).

Step 2:

Under the condition of stirring at 0 degrees Celsius, 309-1 (12.0 g, 46.8 mmol, 1.0 equivalent), tetrahydrofuran (150 ml) and aqueous hydrochloric acid (12 moles per liter, 50 ml) were added successively to a 500 ml three-necked flask, and the mixture React for 1 hour under stirring condition at 25 degrees Celsius. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, water (100 ml) was added to the reaction solution, the resulting mixture was extracted with ethyl acetate (100 ml x 2), and the organic phases were combined; the organic phase was washed with saturated brine (100 ml x 1), and anhydrous sulfuric acid Dry over sodium, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain the intermediate. Sodium borohydride (2.69 g, 70.29 mmol, 1.5 equivalents) and methanol (120 ml) were added to the obtained intermediate under stirring condition at 0°C, and the mixture was reacted under stirring condition at 25°C for 1 hour. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, water (100 ml) was added to the reaction solution, extracted with ethyl acetate (100 ml x 2), and the organic phases were combined; the organic phase was washed with saturated brine (100 ml x 1), dried over anhydrous sodium sulfate, The desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 50% ethyl acetate/petroleum ether, and the solvent obtained was removed by rotary evaporation under reduced pressure to obtain compound 309 -2 (yellow solid, 9 g, 84% yield). ¹ H NMR (400MHz, CDCl ₃ )δ8.41–8.34(m,2H),8.18–8.13(m,1H),7.68–7.51(m,3H),4.01(t,J＝6.7Hz,2H), 3.40 (t, J=6.7Hz, 2H).

Step 3:

Under the condition of nitrogen protection and stirring at minus 20 degrees Celsius, 309-2 (8.9 g, 38.9 mmol, 1.0 equivalent), dichloromethane (90 ml) and diethylaminosulfur trifluoride ( 12.2 grams, 68.11 mmol, 1.75 mmol), the mixture was reacted for 2 hours at subzero 20 degrees centigrade under nitrogen protection stirring conditions, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was over, add water (50 milliliters) to the reaction solution at minus 20 degrees Celsius to quench, the resulting mixture was extracted with dichloromethane (100 milliliters x 2), and the organic phases were combined; the organic phase was saturated brine (100 milliliters) Wash, dry over anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→50% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 309-3 (yellow solid, 4 g, yield rate 45%). ¹ H NMR (300MHz, CDCl ₃ ) δ8.50–8.30(m,2H),8.23–8.12(m,1H),7.74–7.52(m,3H),4.93–4.83(m,1H),4.79–4.67 (m,1H),3.68–3.44(m,2H).

Step 4:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 309-3 (3.8 g, 16.46 mmol, 1.0 equivalent), iron powder (4.64 g, 82.34 mmol, 5.0 mmol), absolute ethanol were successively added to a 250 ml three-necked flask (30.0 mL), water (6.0 mL) and ammonium chloride (4.45 g, 82.34 mmol, 5.0 equiv). The mixture was reacted at 80° C. for 2 hours under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, filtered through a sand core funnel, and the filter cake was washed with dichloromethane (50.0 ml x 2). The filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 30%→80% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 309-4 (yellow solid, 3.2 g, yield rate 99%). MS(ESI,m/z):190.2[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ )δ8.04–7.93(m,1H),7.38–7.22(m,4H),6.81– 6.69 (m, 1H), 4.86–4.74 (m, 1H), 4.71–4.58 (m, 1H), 3.45–3.38 (m, 1H), 3.37–3.30 (m, 1H).

Step 5:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 309-4 (3.2 g, 16.5 mmol, 1.0 equivalent), acetic acid (33.0 ml) and bromine (8.83 g, 49.7 mmol, 3.0 mmol) were successively added to a 100 ml three-necked flask. mol), the mixture was reacted for 1 hour at 70 degrees centigrade under nitrogen protection stirring conditions, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, filtered through a sand core funnel, and the filter cake was washed with acetic acid (20.0 ml x 5), and the resulting filter cake was the crude product 309-5 (yellow solid, 4.0 grams, 55% yield) . The obtained crude product was directly used in the next reaction without purification. MS(ESI,m/z):345.9/347.9/349.9[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ8.27–8.20(m,1H),7.84(s,1H), 7.55–7.39(m,2H),4.81–4.73(m,1H),4.69–4.61(m,1H),3.96–3.82(m,2H).

Step 6:

Under the condition of stirring under nitrogen protection at 0 degrees Celsius, 309-5 (2.5 g, 5.04 mmol, 1.0 equivalent), sodium nitrite (732.49 mg, 10.08 mmol, 2.0 mmol), acetic acid ( 18.0 milliliters) and formic acid (3.0 milliliters), the mixture was reacted for 1 hour at 0 ℃ under nitrogen protection stirring condition, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, water (50.0 ml) was added to the reaction solution, extracted with dichloromethane (100 ml x 2), and the organic phases were combined; the organic phase was washed with saturated brine (100 ml), dried over anhydrous sodium sulfate, and filtered The desiccant was removed, and the filtrate was concentrated under reduced pressure to obtain a crude product. To the crude product were added ethanol (20.0 mL) and sodium borohydride (301.22 mg, 7.56 mmol, 1.5 eq) sequentially. The mixture was reacted for 1 hour at 0°C under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, water (20.0 ml) was added to the reaction solution, and the resulting mixture was extracted with dichloromethane (50 ml x 2), and the organic phases were combined; the organic phase was washed with saturated brine (50 ml), and dried over anhydrous sodium sulfate , filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 30%→80% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 309-6 (yellow solid, 400 mg, yield rate 28%). MS (ESI, m/z): 266.9/268.9 [MH] ^- ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ10.12 (s, 1H), 7.76–7.64 (m, 1H), 7.41–7.14 ( m,3H), 4.83–4.74(m,1H), 4.73–4.62(m,1H), 3.96–3.76(m,2H).

Step 7:

Under the condition of stirring under nitrogen protection at 0 degrees Celsius, 309-6 (400.0 mg, 1.41 mmol, 1.0 equivalent), dichloromethane (4.0 ml), chloromethyl methyl ether (149.28 mg, 1.83 millimoles, 1.3 equivalents) and N,N-diisopropylethylamine (553.04 mg, 4.23 mmoles, 3.0 equivalents), the resulting mixture was reacted at 25 degrees Celsius for 1 hour under stirring conditions, and the reaction process passed liquid mass and TLC analysis to monitor. After the reaction, water (20 ml) was added to the reaction solution, and the resulting mixture was extracted with dichloromethane (20 ml x 2), and the organic phases were combined; the organic phase was washed with saturated brine (20 ml), and dried over anhydrous sodium sulfate , filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→40% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 309-7 (yellow solid, 300 mg, yield rate of 64%). ¹ H NMR (400MHz, DMSO-d ₆ )δ7.71–7.66(m,1H),7.64(d,J=2.6Hz,1H),7.42–7.29(m,3H),5.27(s,2H), 4.90–4.79(m,1H),4.78–4.69(m,1H),4.06–3.90(m,2H),3.52(s,3H).

Step 8:

Under the condition of nitrogen protection and stirring, 309-8 (130.0 mg, 0.39 mmol, 1.0 equivalent) and anhydrous tetrahydrofuran (2.0 ml) were successively added to a 25 ml Shrek tube, and then the temperature was lowered to minus 78 degrees Celsius. Add n-butyllithium n-hexane solution (2.5 mol/liter, 0.22 milliliters, 0.55 mmol, 1.4 equivalents) dropwise to the reaction solution under the nitrogen protection stirring condition at minus 78 degrees Celsius, and complete the addition under the nitrogen protection condition at minus 78 degrees Celsius Stirred for 30 minutes, then added isopropanol pinacol borate (123.5 mg, 0.63 mmol, 1.3 equivalents) in the reaction solution, and the resulting mixture was reacted for 1 hour at minus 78 degrees Celsius under nitrogen protection conditions. and thin-layer chromatography to monitor. After the reaction was completed, saturated ammonium chloride solution (20 milliliters) was added to the reaction solution to quench, the resulting mixture was extracted with ethyl acetate (20 milliliters x 2), the organic phases were combined, and the organic phase was washed with saturated brine (20 milliliters). , dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 309-8 (white semi-solid, 80 mg, Yield 54%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.67–7.62(m,1H),7.44–7.33(m,3H),7.27(s,1H),5.29(s,2H),4.83–4.77(m,1H ), 4.72–4.65(m,1H), 3.63–3.53(m,2H), 3.51(s,3H), 1.44(s,12H).

Step 9:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 300-10 (135.0 mg, 0.2 mmol, 1.0 equivalent), 309-8 (79.4 mg, 0.20 mmol, 1.0 equivalent), potassium phosphate (93.57 mg , 0.41 mmol, 2.0 equivalents), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxygen, Fospentyl conjugate (14.56 mg, 0.04 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (20.18 mg, 0.02 mmol, 0.1 equiv), toluene (1.5 mL) and water (0.3 mL). The resulting mixture was reacted at 80° C. under nitrogen protection and stirring for 8 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was over, water (20 ml) was added to the reaction solution for dilution, and the resulting mixture was extracted with dichloromethane (20 ml x 3), the organic phases were combined, and the organic phase was washed with saturated brine (20 ml), anhydrous sodium sulfate After drying, the desiccant was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 309-9 (white solid, 100 mg, yield rate 59%). MS (ESI, m/z): 766.5 [M+H] ⁺ .

Step 10:

Compound 309-9 (100 mg) obtained in step 9 was subjected to chiral resolution by preparative supercritical liquid chromatography: chiral column Cellulose-SC, 2 x 25 cm, 5 microns; mobile phase A: n-hexane (10 moles / liter of ammonia methanol), mobile phase B: ethanol; flow rate: 20 ml/min; in 18 minutes with 20% B phase for elution, detector UV 225/209 nanometers, to obtain two products. The product with shorter retention time (8.92 minutes) is compound 309-9a (white solid, 35 mg, recovery 35%), MS (ESI, m/z): 766.5[M+H] ⁺ ; longer retention time ( 13.99 minutes) was compound 309-9b (white solid, 35 mg, recovery 35%), MS (ESI, m/z): 766.5[M+H] ⁺ .

Step 11:

Under the condition of stirring at 25 degrees Celsius, 309-9a (30 mg, 0.03 mmol, 1.0 equivalent), methanol (0.5 ml) and 1,4-dioxane solution of hydrochloric acid (4 mol/ ml, 0.5 ml). The mixture was reacted at 0°C for 1 hour under stirring condition, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5% → 95% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 25 minutes; detector, UV254/220 nm ; Compound 309a was obtained (white solid, 20 mg, yield 76%). MS(ESI,m/z):622.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.54–11.31(m,1H),10.43–9.90(m,2H),9.73( d,J=9.6Hz,1H),7.86–7.72(m,2H),7.45–7.33(m,2H),7.21(d,J=7.0Hz,1H),7.05(d,J=2.6Hz,1H ), 5.69–5.46(m,1H), 4.62(s,2H), 4.54–4.41(m,2H), 4.39–4.32(m,1H), 4.28–4.21(m,1H), 4.16(d,J ＝11.3Hz,2H),3.99–3.84(m,5H),3.35–3.22(m,1H),2.85–2.69(m,2H),2.70–2.58(m,1H),2.49–2.42(m,1H ),2.38–2.28(m,1H),2.24–2.10(m,2H),2.10–1.93(m,5H); ¹⁹ F NMR(377MHz,DMSO)δ-116.76,-116.76,-123.58,-123.59, -172.68, -212.78. The chiral analysis conditions of compound 309a are: Optichiral C9-3, 3.0x100 mm, 3 microns; mobile phase A: supercritical carbon dioxide mobile phase, B: isopropanol (20 mmol/L ammonia), within 6 minutes 40% mobile phase B was used for elution, the detector was UV220 nm, and the retention time was 2.513 minutes; dr>40:1.

Step 11':

Compound 309b (white solid, 20 mg, yield 76%) was obtained by the same method as step 11. MS(ESI,m/z):622.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.41(s,1H),10.49–9.86(m,2H),9.73(s, 1H),7.99–7.66(m,2H),7.48–7.25(m,2H),7.21(d,J＝7.0Hz,1H),7.05(d,J＝2.4Hz,1H),5.69–5.44(m ,1H),4.62(s,2H),4.54–4.39(m,2H),4.39–4.32(m,1H),4.29–4.21(m,3H),3.95(d,J＝13.5Hz,1H), 3.91–3.68(m,4H),3.34–3.21(m,1H),2.85–2.69(m,2H),2.68–2.54(m,1H),2.46(d,J＝15.5Hz,1H),2.41– 2.27 (m, 1H), 2.26-2.10 (m, 2H), 2.10-1.88 (m, 5H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ-116.75, -123.57, -172.71, -212.76. The chiral analysis conditions of compound 309b are: Optichiral C9-3, 3.0x100 mm, 3 microns; mobile phase A: supercritical carbon dioxide mobile phase, B: isopropanol (20 mmol/L ammonia), within 6 minutes 40% mobile phase B was used for elution, the detector was UV220 nm, and the retention time was 3.766 minutes; dr>40:1.

Example 15

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl-5,5-d2)methoxy-d2)quinazolin-7-yl)-5-ethylnaphthalene- 2-Phenol dihydrochloride 310a; (R or S)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6, 8-difluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl-5,5-d2)methoxy-d2)quinazoline-7- Base)-5-ethylnaphthalene-2-ol dihydrochloride 310b

The synthetic route is as follows:

step 1:

Compound 310-1 was synthesized with reference to the patent (WO2021041671).

Under the condition of nitrogen protection and stirring at 0 ℃, to the solution of compound 310-1 (985 mg, 4.34 mmol, 1.00 eq) in anhydrous tetrahydrofuran (10 ml) was slowly added deuterated aluminum tetrahydrolithium lithium (384 mg, 8.69 mmol , 2.00 equivalent). The mixture was reacted at 20°C for 1 hour with stirring, and then at 60°C for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, ice water (0.4 ml), sodium hydroxide solution (15% by mass, 1.2 ml) and water (1.2 ml) were slowly added to the reaction solution at 0° C. to quench the reaction. The insoluble matter was removed by filtration, and the filter cake was washed with tetrahydrofuran (5 ml x 2). The filtrate and washings were combined and concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 310-2 (colorless oil, 350 mg, Yield 46%). MS (ESI, m/z): 164.4[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ5.31–5.14(m,1H),3.52–3.03(m,3H),2.21–2.09( m,1H), 2.09–2.04(m,1H), 1.98–1.83(m,2H), 1.83–1.73(m,2H).

Step 2:

Under the condition of nitrogen protection and stirring at 20 degrees Celsius, compound 288-18 (200 mg, 0.30 mmol, 1.00 equivalent), triethylenediamine (7 mg, 0.06 mmol, 0.20 equivalent) and compound 310-2 (57 mg, To a solution of 0.34 mmol, 1.10 eq) in N,N-dimethylformamide (3 mL) was added cesium carbonate (208 mg, 0.61 mmol, 2.00 eq). The mixture was stirred at 95°C under nitrogen protection for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, it was cooled to room temperature, and 20 ml of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of dichloromethane/methanol/ammonia methanol (7 mol/L)=15/1/0.1, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 310 -3 (white solid, 210 mg, 87% yield). MS (ESI, m/z): 752.4 [M+H] ⁺ .

Step 3:

The compound 310-3 (200.0 mg) obtained in step 2 was chirally resolved by preparative chiral high-performance liquid chromatography: chiral column CHIRAL ART Cellulose-SC, 2x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol/liter ammonia methanol), mobile phase B: ethanol; flow rate: 20 ml/min; eluted with 40% phase B in 13.2 minutes, detector UV 230/225 nanometers, two products were obtained. The product with shorter retention time (3.325 minutes) is compound 310-3a (white solid, 83.0 mg), MS (ESI, m/z): 752.4[M+H] ⁺ ; the product with longer retention time (7.385 minutes) It is compound 310-3b (white solid, 78.0 mg), MS (ESI, m/z): 752.4[M+H] ⁺ .

Step 4:

Under stirring condition at 0°C, to compound 310-3a (80 mg, 0.10 mmol, 1.00 eq) in methanol (1 mL) was slowly added dropwise a solution of hydrochloric acid in 1,4-dioxane (4 mol/L , 1 ml). The mixture was reacted at room temperature for 1 hour, and the reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by a reverse phase chromatographic column (C18 column), and eluted with 5% → 40% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 20 minutes; detector, UV254/220 nm; to obtain the compound 310a (yellow solid, 47 mg, 66% yield). MS(ESI,m/z):608.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.83–7.75(m,1H),7.74–7.67(m,1H ),7.45–7.37(m,1H),7.36–7.32(m,1H),7.20–7.15(m,1H),7.01–6.96(m,1H),5.69–5.49(m,1H),4.62–4.43 (m,2H),4.30–4.13(m,2H),3.97–3.76(m,4H),2.70–2.56(m,2H),2.43–2.30(m,3H),2.28–1.93(m,7H) , 0.88–0.81 (m, 3H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ +D ₂ O) δ-116.27, -116.28, -123.63, -123.64, -172.83. The chiral analysis conditions of compound 310a are: N-CHIRALPAK IC-3 (Lot No.IC30CS-VF008), 4.6 x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / liter of ammonia); flow rate: 2 ml/min; isocratic elution with 50% phase B in 10 minutes; detector UV 220 nm; retention time: 4.954 minutes; dr>40:1.

Step 5:

Compound 310b (white solid, 46 mg, yield 70%) can also be obtained according to the method of step 4. MS(ESI,m/z):608.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.82–7.75(m,1H),7.73–7.67(m,1H ),7.45–7.38(m,1H),7.36–7.33(m,1H),7.20–7.14(m,1H),6.99(d,J＝2.6Hz,1H),5.69–5.50(m,1H), 4.63–4.52(m,1H),4.52–4.40(m,1H),4.26–4.13(m,2H),3.99–3.72(m,4H),2.65–2.54(m,2H),2.43–2.31(m ,3H),2.24–1.93(m,7H),0.90–0.77(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ +D ₂ O)δ-116.29,-116.30,-123.58,-123.59, -172.86. The chiral analysis conditions of compound 310b are: N-CHIRALPAK IC-3 (Lot No.IC30CS-VF008), 4.6 x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (20 mmol / liter of ammonia); flow rate: 2 ml/min; isocratic elution with 50% phase B in 10 minutes; detector UV220 nanometers; retention time: 6.444 minutes; dr>40:1.

Example 16

(S or R)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(2 -((2R, 7aR)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)ethyl)quinazolin-7-yl)-5-ethylnaphthalene-2-ol dihydrochloride Salt 311a; (R or S)-4-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2 -(2-((2R,7aR)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)ethyl)quinazolin-7-yl)-5-ethylnaphthalene-2-ol Dihydrochloride 311b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, dimethyl sulfoxide (4.42 grams, 53.706 mmoles, 3.0 equivalents) was dissolved in 40 ml of dichloromethane, then dropped to minus 78 degrees Celsius, and then slowly added dropwise to it successively. Oxalyl chloride (3.59 g, 26.853 mmol, 1.5 equiv) in dichloromethane (40 mL) and (2R,7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol (3 g, 17.90 mmoles, 1.0 equivalents) in dichloromethane (10 milliliters) solution, the resulting mixture was reacted at minus 78 degrees Celsius for 1 hour, then slowly added triethylamine (9.53 grams, 89.51 mmoles, 5 equivalents) dropwise in the reaction solution , naturally warmed to room temperature after the addition, and reacted at room temperature for 1 hour, and the reaction process was monitored by thin-layer chromatography. After the reaction was completed, the reaction solution was poured into ice water to quench, extracted with a mixed solvent of chloroform and isopropanol (3/1, 100 ml x 3), and the organic phases were combined. The organic phase was washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 311-1 (white solid, 2.3 g , 80% yield). ¹ H NMR (400MHz, CDCl ₃ ) δ9.27(s,1H),5.29–5.14(m,1H),3.30–3.19(m,2H),3.07–2.92(m,2H),2.44–2.26(m ,2H), 2.03–1.72(m,4H).

Step 2:

Under the condition of nitrogen stirring at 25 degrees Celsius, 311-1 (500 mg, 3.022 mmol, 1.00 equivalent), potassium carbonate (500 mg, 3.022 mmol, 1.00 equivalent) were dissolved in 5 ml of anhydrous methanol, and the system was To 0 degrees Celsius, then slowly add (1-diazo-2-oxopropyl) dimethyl phosphonate (916.63 mg, 4.533 mmol, 1.5 equivalents), the reaction solution was reacted at 25 degrees Celsius for 1 hour, and the reaction The process is monitored by liquid quality. After the reaction was finished, the reaction solution was concentrated first, then diluted with water (50 milliliters), the resulting mixture was extracted with dichloromethane (30 milliliters x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was Concentration under reduced pressure gave the crude product compound 311-2 (yellow oil, 380 mg, yield 62%), which was directly used in the next reaction. MS (ESI, m/z): 154.1 [M+H] ⁺ .

Step 3:

Under nitrogen stirring conditions at 25 degrees Celsius, compound 311-2 (211.01 mg, 1.308 mmol, 3.00 equivalents), 288-18 (287 mg, 0.436 mmoles, 1.00 equivalents), bistriphenylphosphine palladium dichloride ( 16.11 mg, 0.022 mmol, 0.05 equiv), cuprous iodide (8.74 mg, 0.044 mmol, 0.1 equiv) and cesium carbonate (448.77 mg, 1.308 mmol, 3.00 equiv) were dissolved in 5 mL of N,N-di In methylformamide, the resulting mixture was reacted at 100°C under nitrogen for 2 hours, and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was cooled to room temperature, then poured into water (100 ml) to quench, ethyl acetate (100 ml x 3) was extracted, the organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate Concentration under reduced pressure gave crude product. The resulting crude product was purified by silica gel column chromatography, eluted with a 0%-5% methanol/dichloromethane flow phase gradient, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 311-3 (yellow solid, 290 mg , yield 89.6%). MS (ESI, m/z): 742.4 [M+H] ⁺ .

Step 4:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, compound 311-3 (290 mg, 0.371 mmol, 1.00 equivalent), anhydrous methanol (10 ml) and palladium on carbon (10% palladium content, 30 mg) were sequentially added to the reaction flask , and then the nitrogen is replaced by hydrogen through the gas replacement operation, and then the reaction solution is reacted for 2 hours under a stirring condition of a hydrogen atmosphere (1.5 atmospheres) at 25 degrees Celsius, and the reaction process is monitored by liquid quality. After the reaction, the reaction solution was filtered, the filter cake was washed with methanol, and the filtrate and washing liquid were combined and concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, eluted with a 0%-10% methanol/dichloromethane flow phase gradient, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 311-4 (white solid, 160 mg , yield 68%). MS (ESI, m/z): 746.4 [M+H] ⁺ .

Step 5:

Compound 311-4 (160 mg) obtained in step 4 was subjected to chiral resolution by supercritical liquid chromatography: chiral column CHIRALPAK IC, 2x 25 cm, 5 microns; mobile phase A: n-hexane (0.1%, 10 mol/ Liter ammonia methanol), mobile phase B: ethanol; Flow rate: 20 milliliters/minute; With 50% mobile phase B elution; Detector UV224/203 nanometers, obtain two products. The product with shorter retention time (5.52 minutes) is compound 311-4a (white solid, 62 mg, recovery rate 38%), MS (ESI, m/z): 764.4[M+H] ⁺ ; longer retention time ( 10.65 minutes) was compound 311-4b (white solid, 53 mg, yield 33%), MS (ESI, m/z): 764.4[M+H] ⁺ .

Step 6:

Under the condition of stirring at 25 degrees Celsius, compound 311-4a (62 mg, 0.079 mmol, 1.00 equivalent) was dissolved in 2 ml of methanol, then cooled to 0 degrees Celsius, and then hydrochloric acid in 1,4-dioxane was slowly added thereto. Ring solution (4 moles per liter, 2 milliliters), reacted at 25 degrees Celsius for 2 hours after addition, and the reaction process was monitored by liquid quality. After the reaction was finished, the reaction solution was concentrated, and the resulting crude product was purified by a reverse phase chromatographic column (C18 column), and eluted with 0% → 30% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 20 minutes; Detector, UV254/220 nm; Compound 311a was obtained (yellow solid, 36.5 mg, yield 68%). MS(ESI,m/z):602.3[M+H] ⁺ ; ¹ HNMR(400MHz,DMSO-d ₆ )δ11.66(s,1H),10.18-9.94(m,2H),9.73(s,1H ),7.84(d,J=9.8Hz,1H),7.71-7.69(m,1H),7.41-7.37(m,1H),7.35(d,J=2.8Hz,1H),7.16-7.14(m, 1H),7.02(d,J=2.8Hz,1H),5.55-5.40(m,1H),4.65-4.51(m,2H),4.17(d,J=14.0Hz,2H),3.98(d,J ＝13.4Hz,1H),3.92–3.82(m,2H),3.80–3.67(m,2H),3.26–3.19(m,1H),3.06-3.02(m,2H),2.47–2.32(m,6H ),2.23–2.06(m,3H),2.01–1.89(m,5H),0.86-0.82(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-113.17,-122.48,-122.50, -172.91.

Step 7:

Referring to the method in step 6 of this example, compound 311b (yellow solid, 27.2 mg, yield 59%) can also be obtained. MS(ESI,m/z):602.3[M+H] ⁺ ; ¹ HNMR(400MHz,DMSO-d ₆ )δ11.63(s,1H),10.15-9.93(m,2H),9.71(s,1H ),7.83(d,J=9.8Hz,1H),7.71-7.69(m,1H),7.41-7.37(m,1H),7.35(d,J=2.8Hz,1H),7.16-7.14(m, 1H), 7.01(d, J=2.8Hz, 1H), 5.55-5.40(m, 1H), 4.64-4.50(m, 2H), 4.17(d, J=14.0Hz, 2H), 3.97(d, J ＝13.4Hz,1H),3.92–3.82(m,2H),3.81–3.67(m,2H),3.26–3.19(m,1H),3.06-3.02(m,2H),2.47–2.32(m,6H ),2.23–2.06(m,3H),2.01–1.89(m,5H),0.86-0.82(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-113.21,-122.45,-122.47, -172.91.

Example 18

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-2-(2-chloro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)vinyl)-6,8-difluoroquinazolin-7-yl)-5-ethylnaphthalene-2- Phenol dihydrochloride 313a; (R or S)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-2-(2 -Chloro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)vinyl)-6,8-difluoroquinazolin-7-yl)-5 -Ethylnaphthalene-2-ol dihydrochloride 313b

The synthetic route is as follows:

step 1:

Compound 311-3 (210 mg) was chirally resolved by high performance liquid chromatography: chiral column CHIRALPAK IC, 2 x 25 cm, 5 microns; mobile phase A: n-hexane (0.1%, 10 mol/L ammonia methanol ), Mobile phase B: ethanol; Flow rate: 20 milliliters/minute; With 50% mobile phase B elution; Detector UV205/289 nanometer, obtain two products. The product with shorter retention time (4.00 minutes) is compound 311-3a (white solid, 109 mg, recovery 52%), MS (ESI, m/z): 742.3[M+H] ⁺ ; longer retention time ( 13.00 minutes) the product was compound 311-3b (white solid, 89 mg, recovery 42%), MS (ESI, m/z): 742.3[M+H] ⁺ .

Step 2:

Compound 311-3a (108.0 mg, 0.138 mmol, 1.00 equiv) was dissolved in 2 mL of methanol under stirring at 25°C. The temperature was lowered to 0°C, and then a solution of hydrogen chloride in 1,4-dioxane (4 mol/L, 2 ml) was slowly added thereto. After the addition, the reaction solution was reacted at 25 degrees Celsius for 2 hours, and the reaction process was monitored by liquid quality. After the reaction was finished, the reaction solution was concentrated, and the resulting crude product was purified by a reverse phase chromatographic column (C18 column), and eluted with 0% → 30% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 20 minutes; Detector, UV254/220 nm; Compound 313a was obtained (yellow solid, 46 mg, yield 45%). MS(ESI,m/z):634.0/636.0[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.37(s,1H),10.34–9.25(m,3H),7.82( d,J＝9.8Hz,1H),7.75–7.65(m,1H),7.44–7.30(m,3H),7.19–7.11(m,1H),7.05–6.98(m,1H),5.59(d, J＝53.0Hz, 1H), 4.61(d, J＝13.6Hz, 1H), 4.43(d, J＝13.5Hz, 1H), 4.23–4.14(m, 2H), 4.00–3.96(m, 3H), 3.81(s,3H),3.41(s,1H),2.78(s,2H),2.41–2.29(m,3H),2.25(s,1H),2.11–1.89(m,5H),0.90–0.77( m, 3H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -111.68, -121.07, -172.16.

Step 2':

Compound 313b (yellow solid, 53 mg, yield 66%) was obtained by the same method as step 2. MS(ESI,m/z):634.0/636.0[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ11.47(s,1H),10.01(s,1H),9.75(s, 1H),7.87–7.76(m,1H),7.74–7.64(m,1H),7.43–7.30(m,3H),7.19–7.09(m,1H),7.03(d,J＝2.6Hz,1H) ,5.60(d,J=53.1Hz,1H),4.61(d,J=13.6Hz,1H),4.44(d,J=13.5Hz,1H),4.18(d,J=18.0Hz,2H),4.09 –3.78(m,5H),3.40(d,J＝12.2Hz,1H),2.99–2.65(m,3H),2.48–2.17(m,4H),2.17–1.81(m,5H),0.83(t , J=7.4Hz, 3H); ¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-111.67, -121.06, -172.13.

Example 19

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)ethynyl)quinazolin-7-yl)-5-ethylnaphthalene-2-ol 314a; (R or S )-4-(4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-((2R, 7aS) -2-Fluorotetrahydro-1H-pyrroline-7a(5H)-yl)ethynyl)quinazolin-7-yl)-5-ethylnaphthalene-2-ol 314b

The synthetic route is as follows:

step 1:

Under the condition of stirring at zero degrees Celsius, 311-3a (79.0 mg, 0.101 mmol, 1.00 equivalent), dichloromethane (3 ml), triethylsilane (49.53 mg, 0.404 mmol, 4.00 equiv) and trifluoroacetic acid (1 ml). The resulting mixture was reacted at 25°C for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was finished, the reaction solution was concentrated, and the resulting crude product was purified by a reverse-phase chromatographic column (C18 column), and carried out gradient washing with 0% → 30% acetonitrile/water mobile phase (0.1% ammonium bicarbonate) within 20 minutes. The solvent was removed by rotary evaporation under reduced pressure to obtain compound 314a (yellow solid, 38 mg, yield 62%). MS(ESI,m/z):598.1[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ10.00(s,1H),7.80–7.63(m,2H),7.43–7.35( m,1H),7.32(d,J=2.7Hz,1H),7.17–7.10(m,1H),6.97(d,J=2.6Hz,1H),5.43–5.18(m,1H),4.47–4.14 (m,2H),3.78–3.66(m,2H),3.66–3.57(m,1H),3.54–3.45(m,1H),3.29–3.15(m,3H),3.15–3.01(m,1H) ,2.89–2.77(m,1H),2.48–2.39(m,1H),2.38–2.31(m,2H),2.28–2.21(m,1H),2.12–2.02(m,1H),2.00–1.81( m, 2H), 1.82-1.64 (m, 4H), 0.86-0.80 (m, 3H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -113.02, -121.74, -172.48. The chiral analysis conditions of compound 314a were: Optichiral C9-3, 3.0x100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; B: isopropanol (20 mmol/L ammonia); flow rate: 3 mL min; Elute with 50% mobile phase B within 8 minutes; detector: UV220 mm; retention time: 2.468 minutes; dr>40:1.

step 1':

Compound 314b (yellow solid, 28 mg, yield 51%) was obtained by the same method as Step 1. MS(ESI,m/z):598.1[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ9.99(s,1H),7.77–7.64(m,2H),7.42–7.34( m,1H),7.32(d,J=2.7Hz,1H),7.14(d,J=7.1Hz,1H),6.97(d,J=2.6Hz,1H),5.42–5.20(m,1H), 4.41–4.13(m,2H),3.63–3.53(m,3H),3.46–3.41(m,1H),3.25–3.16(m,2H),3.14–3.05(m,1H),2.87–2.78(m ,1H),2.54(s,1H),2.44–2.30(m,4H),2.29–2.20(m,1H),2.12–2.02(m,1H),1.96–1.81(m,2H),1.74–1.59 (m,4H), 0.85 - 0.79 (m,3H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -113.40, -121.87, -172.45. The chiral analysis conditions of compound 314b were: Optichiral C9-3, 3.0x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide; B: isopropanol (20 mmol/L ammonia); flow rate 3 ml min; Elute with 50% mobile phase B within 8 minutes; detector: UV220 mm; retention time: 4.002 minutes; dr>40:1.

Example 20

4-((S or R)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 1R, 2R)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)cyclopropyl)quinazolin-7-yl)-5-ethylnaphthalene -2-Phenol dihydrochloride 315a; 4-((R or S)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6 ,8-difluoro-2-((1R, 2R)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)cyclopropyl)quinazoline- 7-yl)-5-ethylnaphthalene-2-ol dihydrochloride 315b;

4-((S or R)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 1S, 2S)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)cyclopropyl)quinazolin-7-yl)-5-ethylnaphthalene -2-Phenol dihydrochloride 315c; 4-((R or S)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6 , 8-difluoro-2-((1S, 2S)-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)cyclopropyl)quinazoline- 7-yl)-5-ethylnaphthalene-2-ol dihydrochloride 315d

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at zero degrees Celsius, ethyl dimethylphosphonoacetate (7.79 g, 39.70 mmol, 1.20 equivalents), anhydrous tetrahydrofuran (100.0 ml) and sodium hydride (60% , 1.51 g, 37.72 mmol, 1.20 equiv). The mixture was reacted at 0°C for 1 hour. A solution of compound 311-1 (5.20 g, 31.42 mmol, 1.00 eq) in anhydrous tetrahydrofuran (100 mL) was slowly added to the above reaction solution under nitrogen protection and stirring at zero degrees Celsius. The mixture was reacted for 1 hour under nitrogen protection at 0°C, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, a saturated ammonium chloride solution (500 ml) was added to the reaction solution at zero degrees Celsius to quench the reaction. The mixture was extracted with dichloromethane (500 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (500 ml x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 315-1 (colorless oil, 7.14 g , yield 95%). MS (ESI, m/z): 228.1 [M+H] ⁺ .

Step 2:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, trimethylsulfoxide iodide (4.61 g, 19.88 mmol, 4.10 equivalents), dimethyl sulfoxide (15 ml) and sodium hydride (60 %, 775.72 mg, 19.40 mmol, 4.00 equiv). The mixture was stirred at 25°C under nitrogen protection until clear. Then, a solution of 315-1 (1.16 g, 4.84 mmol, 1.00 equiv) in dimethyl sulfoxide (10 mL) was added dropwise to the above reaction solution. After the addition, the reaction was carried out for 10 minutes at 25° C. under nitrogen protection and stirring, and then at 50° C. under nitrogen protection and stirring for 3 hours. The reaction process was monitored by liquid quality. After the reaction was completed, ice water (100 ml) was added to the reaction solution at zero degrees Celsius to quench the reaction. The mixture was extracted with ethyl acetate (80 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (100 ml x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0→10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 315-2 (light yellow oil, 594 mg, Yield 48%). MS (ESI, m/z): 242.3 [M+H] ⁺ .

Step 3:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 288-11 (5.68 g, 19.26 mmol, 1.00 equivalent), tetrahydrofuran (10 ml), methanol (30 ml), water (10 ml) and Lithium hydroxide monohydrate (1.70 g, 38.53 mmol, 2.00 equiv). The mixture was reacted at 20° C. for 3 hours under nitrogen protection and stirring. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, concentrate under reduced pressure to remove excess solvent, add water (10 milliliters) to dilute, adjust the pH to 6 with 1 mole per liter of hydrochloric acid under ice-water bath conditions, the product is precipitated, filtered, and the filter cake is washed twice with water to obtain the compound 315-3 (pale yellow solid, 4.11 g, 81% yield). MS (ESI, m/z) 292.9/294.9 [M+ACN+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ7.49 (dd, J=9.5, 2.2Hz, 1H); ¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -124.41, -126.37.

Step 4:

Under the condition of stirring under nitrogen protection at zero degrees Celsius, to a solution of 315-3 (3.13 g, 11.81 mmol, 2.00 eq) in toluene (10 ml) was added dropwise lithium bistrimethylsilylamide (24.80 ml, 24.80 mmol, 4.2 eq), after half an hour at room temperature, a solution of 315-2 (1.5 g, 5.91 mmol, 1.00 eq) in toluene (10 ml) was added. The mixture was reacted at 50° C. for 3 hours under nitrogen protection and stirring. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, water (0.5 ml) was added to the reaction solution at 0°C to quench the reaction. The mixture was concentrated under reduced pressure to obtain a crude product, which was purified by a reverse phase chromatography column (C18 column), and eluted with 5% → 95% acetonitrile/water mobile phase (0.1% ammonia water) within 20 minutes, and the obtained fraction The solvent was removed by rotary evaporation under reduced pressure to obtain compound 315-4 (white solid, 2.4 g, yield 89%). MS (ESI, m/z): 447.1/449.1 [M+H] ⁺ .

Step 5:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 315-4 (2.19 g, 4.65 mmol, 1.00 equivalent), N-hydroxybenzotriazole (1.32 g, 9.31 mmol, 2.00 equivalent), ammonium chloride (2.10 g, 37.21 mmol, 8.00 equivalent), N,N-dimethylformyl (35 ml), N,N-diisopropylethylamine (3.41 ml, 18.61 mmol, 4.00 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.88 g, 9.31 mmol, 2.00 equiv). The mixture was reacted for 10 hours at 25° C. under nitrogen protection and stirring, and then continued to react at 100° C. under nitrogen protection and stirring for 16 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, ice water (200 ml) and saturated sodium bicarbonate (80 ml) were added to the reaction solution at zero degrees Celsius to quench the reaction. The mixture was extracted with ethyl acetate (80 mL x 3), the combined organic phases were washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by slurrying with acetonitrile (30 mL) to obtain compound 315-5 (white solid, 1.07 g, yield 51%). MS (ESI, m/z): 428.0/430.1 [M+H] ⁺ .

Step 6:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 315-5 (970 mg, 2.15 mmol, 1.00 equivalent), tripyrrolidinyl phosphorus bromide hexafluorophosphate (1.58 g, 3.23 mmol, 1.50 equiv), N-methylpyrrolidone (10 ml), N,N-diisopropylethylamine (1.18 ml, 6.45 mmol, 3.00 equiv) and 8-Boc-3,8-diazabicyclo[3.2 .1] Octane (721 mg, 3.23 mmol, 1.50 equiv). The mixture was reacted for 10 hours at 25° C. under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated to obtain a crude product. The obtained crude product was purified by a reverse-phase chromatographic column (C18 column), and was eluted with a gradient of 5%→95% acetonitrile/water (0.1% ammonia water) mobile phase within 20 minutes, and the obtained fraction was desolventized by rotary evaporation under reduced pressure, Compound 315-6 was obtained (white solid, 885 mg, yield 62%). MS (ESI, m/z): 621.8/623.8 [M+H] ⁺ .

Step 7:

Compound 315-6 (880 mg) obtained in step 6 was chirally resolved by preparative chiral high performance liquid chromatography: chiral column CHIRALPAK AD, 3 x 25 cm, 5 microns; mobile phase A: supercritical carbon dioxide, mobile Phase B: Methanol (0.1%, 2 moles of methanol per liter of ammonia); flow rate: 60 ml/min; elution with 20% phase B in 6 minutes, detector UV 236 nm, two products were obtained. The product with shorter retention time (4.61 minutes) is compound 315-6a (white solid, 360 mg), MS (ESI, m/z): 621.9/623.9[M+H] ⁺ ; longer retention time (5.35 minutes) The product was compound 315-6b (white solid, 330 mg), MS (ESI, m/z): 621.9/623.9[M+H] ⁺ .

Step 8:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 315-6a (170 mg, 0.26 mmol, 1.00 equivalent), 282-2 (111 mg, 0.31 mmol, 1.20 equivalent), potassium phosphate (115 mg , 0.52 mmol, 2.00 equiv), tris(dibenzylideneacetone) dipalladium (0) (25 mg, 0.026 mmol, 0.10 equiv), 3-(tert-butyl)-4-(2,6-di Methoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxophosphapentyl (18 mg, 0.052 mmol, 0.20 equiv), toluene (3.0 mL) and water (0.6 mL ). The mixture was reacted at 80°C for 3 hours under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 315-7a (white solid, 200 mg, Yield 97%). MS (ESI, m/z): 758.2 [M+H] ⁺ .

Step 8':

Compound 315-7b (white solid, 170 mg, yield 83%) was obtained by the same method as Step 8. MS (ESI, m/z): 758.2 [M+H] ⁺ .

Step 9:

The compound 315-7a (200 mg) obtained in step 8 was chirally resolved by preparative chiral high performance liquid chromatography: chiral column CHIRAL ART Cellulose-SZ, 3x 25 cm, 5 microns; mobile phase A: supercritical Carbon dioxide, mobile phase B: isopropanol (0.5%, 2 moles per liter of ammonia methanol); flow rate: 80 ml/min; eluted with 35% phase B in 6 minutes, detector UV 202 nanometers, two products. The product with shorter retention time (2.98 minutes) is compound 315-7aa (white solid, 87 mg, recovery rate 43%), MS (ESI, m/z): 758.0[M+H] ⁺ ; longer retention time ( 5.28 minutes) was compound 315-7ab (white solid, 88 mg, recovery 44%), MS (ESI, m/z): 758.0 [M+H] ⁺ .

Step 9':

Chiral resolution of compound 315-7b (200 mg) obtained in step 8' by preparative chiral high performance liquid chromatography: Chiral column CHIRAL ART Cellulose-SZ, 3x 25 cm, 5 microns; mobile phase A: Ultra Critical carbon dioxide, mobile phase B: methanol; flow rate: 80 ml per minute; eluted with 40% B phase in 11 minutes, detector 204 nanometers, two products were obtained. The product of shorter retention time (6.83 minutes) is compound 315-7ba (white solid, 70 mg, recovery 41%) MS (ESI, m/z): 758.2[M+H] ⁺ ; longer retention time (9.77 minutes) was compound 315-7bb (white solid, 70 mg, recovery 41%) MS (ESI, m/z): 758.2[M+H] ⁺ .

Step 10:

Under stirring conditions at 0°C, to a solution of compound 315-7aa (86 mg, 0.11 mmol, 1.00 eq) in methanol (2 mL) was added dropwise a solution of hydrochloric acid in 1,4-dioxane (4 mol/L, 2 ml). The mixture was reacted at 25°C for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated to obtain a crude product. The resulting crude product was purified by a reverse phase chromatography column (C18 column), and carried out gradient elution with 5% → 40% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 20 minutes to obtain compound 315a (yellow solid, 38 mg , yield 50%)). MS(ESI,m/z):614.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ12.04(s,1H),10.14(d,J=9.9Hz,1H),9.95 (s,1H),7.94(d,J=9.8Hz,1H),7.71(d,J=8.1Hz,1H),7.45–7.29(m,2H),7.17(d,J=7.0Hz,1H) ,7.04(d,J=2.6Hz,1H),5.51(d,J=52.8Hz,1H),4.81–4.53(m,2H),4.24–3.91(m,4H),3.70(s,3H), 3.18(d,J＝7.0Hz,1H),2.76(s,1H),2.47–2.30(m,4H),2.30–2.22(m,1H),2.20–1.78(m,8H),1.61–1.42( m,2H), 0.95 - 0.82 (m,3H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ ) δ -112.85, -122.69, -172.65.

The chiral analysis conditions of compound 315a are: Optichiral C9-3, 3.0x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol/L ammonia); flow rate 3 ml min; Elute with 50% mobile phase B within 2.5 minutes; detector: UV220 mm; retention time: 1.196 minutes; dr>40:1.

Step 10':

Compound 315b (yellow solid, 48 mg, yield 61%) was obtained by the same method as Step 10. MS(ESI,m/z):614.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.85–7.78(m,1H),7.75–7.68(m,1H ),7.46–7.33(m,2H),7.18(d,J＝7.1Hz,1H),6.99(d,J＝2.6Hz,1H),5.63–5.39(m,1H),4.73–4.41(m, 2H),4.24–4.11(m,2H),3.96–3.69(m,5H),3.31–3.16(m,1H),2.49–2.30(m,5H),2.30–1.85(m,10H),1.53– 1.35 (m, 2H), 0.91 - 0.78 (m, 3H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ +D ₂ O) δ -113.44, -122.77, -172.79. The chiral analysis conditions of compound 315b were: Optichiral C9-3, 3.0x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol/L ammonia); flow rate 3 ml min; Elute with 50% mobile phase B within 2.5 minutes; detector: UV220 mm; retention time: 0.903 minutes; dr>40:1.

Step 10":

Compound 315c (yellow solid, 47 mg, yield 90%) could be obtained by the same method as Step 10. MS (ESI, m/z): 614.5[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O) δ7.86 (d, J=9.5Hz, 1H), 7.71 (d, J＝8.2Hz, 1H), 7.44–7.38(m, 1H), 7.36(d, J＝2.6Hz, 1H), 7.17(d, J＝7.1Hz, 1H), 7.03–6.98(m, 1H), 5.63–5.39(m,1H),4.73–4.48(m,2H),4.17(d,J＝14.6Hz,2H),4.08–3.66(m,5H),3.28–3.14(m,1H),2.65( s,1H),2.45–2.26(m,3H),2.26–2.05(m,5H),1.94(d,J＝38.1Hz,5H),1.53(d,J＝8.5Hz,1H),1.44–1.31 (m,1H), 0.93 - 0.81 (m,3H); ¹⁹ F NMR (377MHz, DMSO-d ₆ +D ₂ O) δ -113.24, -122.85, -168.00, -172.78. The chiral analysis conditions of compound 315c are: chiral column: N-CHIRALART Cellulose-SZ (Ser.No.110IB10023), 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol/L ammonia water); flow rate 2 ml min; elution with 10% mobile phase B within 6.5 min; detector: UV220 mm; retention time: 3.981 min; dr>40:1.

Step 10"':

Compound 315d (yellow solid, 45 mg, yield 74%) was obtained by the same method as Step 10. MS(ESI,m/z):614.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.90–7.65(m,2H),7.46–7.28(m,2H ),7.18(d,J=7.1Hz,1H),7.00(d,J=2.6Hz,1H),5.63–5.40(m,1H),4.73–4.48(m,2H),4.27–4.09(m, 2H),4.03–3.69(m,5H),3.28–3.10(m,1H),2.59(s,1H),2.44–2.28(m,3H),2.28–2.05(m,5H),2.04–1.81( m,5H),1.57–1.45(m,1H),1.45–1.32(m,1H),0.94–0.78(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-113.12,-122.94, -172.98. The chiral analysis conditions of compound 315d are: N-CHIRALART Cellulose-SZ (Ser.No.110IB10023), 4.6x 100 mm, 3 microns; mobile phase A: supercritical carbon dioxide, mobile phase B: methanol (20 mmol/L ammonia water); flow rate 2 milliliters minutes; elution with 10% mobile phase B in 6.5 minutes; detector: UV220 mm; retention time: 4.320 minutes; dr>40:1.

Example 21

4-((S or R)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-2-(1,1-difluoro-2 -((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)ethyl)-6,8-difluoroquinazolin-7-yl)-5-ethylnaphthalene -2-Phenol dihydrochloride 316a; 4-((R or S)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octan-3-yl)-2 -(1,1-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)ethyl)-6,8-difluoroquinazoline- 7-yl)-5-ethylnaphthalene-2-ol dihydrochloride 316b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at zero degrees Celsius, 2-fluorophosphine-2-acylacetate triethyl ester (7.69 g, 31.4 mmol, 1.2 equivalents), tetrahydrofuran (40.0 ml) and sodium hydride were successively added to a 250 ml three-necked flask (60%, 1.26 g, 31.4 mmol, 1.2 equiv). The mixture was reacted at 0°C for 1 hour. A solution of compound 311-1 (4.0 g, 24.17 mmol, 1.0 eq) in anhydrous tetrahydrofuran (10 mL) was slowly added to the above reaction solution under nitrogen protection and stirring at zero degrees Celsius. The mixture was reacted for 1 hour under nitrogen protection at 0°C, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, a saturated ammonium chloride solution (100 ml) was added to the reaction liquid at zero degrees Celsius to quench the reaction. The mixture was extracted with dichloromethane (100 ml x 3), the organic phases were combined, washed with saturated brine (100 ml x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 316-1 (white solid, 2.5 g , 40% yield). MS(ESI,m/z):246.2[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ6.01(d,J=21.9Hz,1H),5.26–5.08(m,1H),4.26 (q,J=7.1Hz,2H),3.18–3.00(m,3H),2.90–2.81(m,1H),2.63–2.47(m,1H),2.18–1.98(m,3H),1.93–1.73 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H).

Step 2:

Under nitrogen protection conditions at 25 degrees Celsius, compound 316-1 (2.2 g, 8.52 mmol, 1.0 eq), palladium/carbon (220 mg, 10%), ethyl acetate (100 ml) were sequentially added to a 250 ml two-necked flask and THF (100 mL). After the addition, the nitrogen gas was replaced by hydrogen gas by gas replacement operation, and the mixture was reacted for 16 hours under a hydrogen atmosphere (1.5 atmospheric pressure) at 25 degrees Celsius, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the insoluble matter was removed by filtration, the filter cake was washed with tetrahydrofuran (20.0 ml x 3), and the filtrate was concentrated under reduced pressure to obtain compound 316-2 (white liquid, 2.1 g, yield 95%). MS (ESI, m/z): 248.2[M+H] ⁺ ; ¹ H NMR (400MHz, CDCl ₃ ) δ5.27–4.92(m,2H),4.29–4.14(m,2H),3.23–2.81( m, 4H), 2.19–1.73 (m, 8H), 1.30 (t, J=7.1Hz, 3H).

Step 3:

Under the condition of nitrogen protection and stirring at minus 78 degrees centigrade, a tetrahydrofuran solution of lithium diisopropylamide (2 mol/L, 2.88 mL, 5.763 mmol, 1.5 equiv). The mixture was reacted at minus 78 degrees Celsius for 30 minutes. A solution of N-fluorobisbenzenesulfonamide (1.91 g, 5.763 mmol, 1.5 eq) in anhydrous tetrahydrofuran (5.0 ml) was slowly added to the above reaction solution under nitrogen protection at -78°C. The mixture was reacted at minus 78 degrees centigrade for 2 hours under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, saturated ammonium chloride solution (20 ml) was added to the reaction solution to quench the reaction. The mixture was extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 316-3 (yellow oil, 600.0 mg, Yield 56%). MS (ESI, m/z): 266.1 [M+H] ⁺ .

Step 4:

Under the condition of nitrogen protection and stirring at zero degrees Celsius, compound 315-4 (1.14 g, 4.29 mmol, 2.0 equivalents), toluene (6.0 ml) and lithium bistrimethylsilylamide were added successively to a 50 ml Shrek tube. Tetrahydrofuran solution (1 mol/L, 8.59 mL, 8.59 mmol, 4.0 equiv). The mixture was reacted at 0°C for 30 minutes. A solution of compound 316-3 (600 mg, 2.14 mmol, 1.0 eq) in toluene (4.0 mL) was slowly added to the above reaction solution under nitrogen protection and stirring at 0 °C. The mixture was reacted at 50°C under nitrogen protection for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, water (5 mL) was added to the mixture to quench the reaction at zero degrees Celsius, and the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5% → 50% methanol/water (0.1% trifluoroacetic acid) mobile phase within 20 minutes; detector, UV254/220 nm; Compound 316-4 (white solid, 300 mg, yield 28%). MS (ESI, m/z): 471.0/473.0 [M+H] ⁺ .

Step 5:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 316-4 (300 mg, 0.6 mmol, 1.0 equivalent), ammonium chloride (272.43 mg, 4.84 mmol, 8.0 equivalent), 1 -(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (244.09 mg, 1.21 mmol, 2.0 equivalents), 1-hydroxybenzotriazole (172.05 mg, 1.21 mmol, 2.0 eq), N,N-diisopropylethylamine (411.42 mg, 3.02 mmol, 5.0 eq) and N,N-dimethylformamide (3.0 mL). The mixture was reacted at 50°C for 16 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5% → 50% methanol/water (0.1% trifluoroacetic acid) mobile phase within 20 minutes; detector, UV254/ 220 nm; compound 316-5 was obtained (white solid, 120 mg, yield 42%). MS (ESI, m/z): 452.0/454.0 [M+H] ⁺ .

step 6

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 316-5 (120 mg, 0.25 mmol, 1.0 equivalent), tert-butyl 3,8-diazabicyclo[3.2. 1] Octane-8-carboxylate (84.50 mg, 0.37 mmol, 1.5 eq), tripyrrolidinylphosphonium bromide hexafluorophosphate (247.41 mg, 0.50 mmol, 2.0 eq), triethylamine (107.41 mg, 10.0 mmol, 4.0 equiv) and N-methylpyrrolidone (1.0 mL). The mixture was reacted at 25°C for 1 hour under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5% → 95% methanol/water (0.1% ammonium bicarbonate) mobile phase within 20 minutes; detector, UV254/ 220 nm; compound 316-6 was obtained (white solid, 120 mg, yield 70%). MS (ESI, m/z): 646.2/648.2 [M+H] ⁺ .

Step 7:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 316-6 (100.0 mg, 0.14 mmol, 1.0 equivalent), compound 282-2 (68.82 mg, 0.19 mmol, 1.3 equivalent) were successively added to a 25 ml Shrek tube, Potassium phosphate (65.67 mg, 0.29 mmol, 2.0 equiv), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1 ,3] Oxyphosphine (10.22 mg, 0.02 mmol, 0.2 eq), tris(dibenzylideneacetone) dipalladium (14.16 mg, 0.01 mmol, 0.1 eq), toluene (1.0 mL) and water ( 0.2 ml). The mixture was reacted at 80°C for 8 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, water (15 ml) was added to dilute the reaction solution. The mixture was extracted with dichloromethane (20 mL x 3), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 316-7 (white solid, 110 mg, yield rate 91%). MS (ESI, m/z): 782.5 [M+H] ⁺ .

Step 8:

Chiral resolution of compound 316-7 (110.0 mg) obtained in step 7 by preparative supercritical liquid chromatography: CHIRAL ART Cellulose-SB, 3 x 25 cm, 5 microns; mobile phase A: supercritical carbon dioxide, mobile phase B : methanol (0.1% 2 mol/l ammonia methanol); flow rate: 80 ml/min; elution with 25% phase B in 10 minutes, detector UV 222 nm, two products were obtained. The product with shorter retention time (8.02 minutes) is compound 316-7a (white solid, 40 mg, recovery rate 36%), MS (ESI, m/z): 782.5[M+H] ⁺ ; longer retention time ( 9.05 minutes) was compound 316-7b (white solid, 40 mg, recovery 36%), MS (ESI, m/z): 782.5[M+H] ⁺ .

Step 9:

Under the condition of stirring at 25 degrees Celsius, compound 316-7a (40 mg, 0.05 mmol, 1.0 equivalent), methanol (0.5 ml) and 1,4-dioxane solution of hydrochloric acid (4 mol/ ml, 0.5 ml). The mixture was reacted at 0°C for 1 hour under stirring condition, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5% → 95% acetonitrile/water (0.1% hydrochloric acid) mobile phase within 25 minutes; detector, UV254/220 nm ; Obtained compound 316a (yellow solid, 30 mg, yield 85%). MS(ESI,m/z):638.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ12.10–11.90(m,1H),10.32–9.83(m,2H),9.76– 9.56(m,1H),7.95–7.87(m,1H),7.76–7.68(m,1H),7.44–7.33(m,2H),7.19–7.14(m,1H),7.04–7.00(m,1H ),5.58–5.37(m,1H),4.76–4.67(m,1H),4.62–4.53(m,1H),4.21–4.11(m,2H),4.07–3.97(m,1H),3.97–3.78 (m,2H),3.77–3.63(m,2H),3.40–3.15(m,3H),2.69–2.54(m,1H),2.48–2.40(m,1H),2.39–2.30(m,2H) ,2.28–2.21(m,1H),2.19–2.08(m,2H),2.06–1.86(m,5H),0.88–0.81(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ- 95.43, -96.12, -96.43, -97.11, -110.87, -110.89, -120.74, -120.76, -172.41.

Step 10:

Compound 316b (yellow solid, 30 mg, yield 85%) was obtained by the same method as Step 9. MS(ESI,m/z):638.4[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ12.05–11.93(m,1H),10.46–9.53(m,3H),7.94– 7.87(m,1H),7.75–7.66(m,1H),7.44–7.33(m,2H),7.21–7.13(m,1H),7.03(d,J＝2.6Hz,1H),5.61–5.35( m,1H),4.76–4.53(m,2H),4.31–4.11(m,2H),4.08–3.99(m,1H),3.98–3.91(m,2H),3.75–3.65(m,2H), 3.34–3.19(m,3H),2.70–2.53(m,1H),2.49–2.41(m,1H),2.39–2.30(m,2H),2.28–2.07(m,3H),2.04–1.81(m ,5H),0.89–0.81(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-95.06,-95.74,-96.92,-97.60,-110.88,-110.90,-120.76,-120.78,- 172.44.

Example 22

(S or R)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-(2-methoxyethyl)naphthalene-2- Phenol dihydrochloride 317a; (R or S)-4-(4-((1R,5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8- Difluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H-yl)methoxy)quinazolin-7-yl)-5-(2-methoxy Ethyl)naphthalene-2-ol dihydrochloride 317b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at -78 degrees Celsius, to 1,8-dibromonaphthalene (20 g, 66.441 mmol, 1.0 equivalent) in anhydrous tetrahydrofuran (200 ml) solution, slowly add n-butyllithium in n-hexane solution (2.5 mol per liter, 31.9 mL, 79.729 mmol, 1.2 equiv). The mixture was reacted at -78°C under nitrogen protection and stirring for 0.5 hours, and then a solution of ethylene oxide in anhydrous tetrahydrofuran (2.5 moles per liter, 265.8 mL, 664.410 mmol, 10 equivalents) was slowly added dropwise to the mixture. The mixture was reacted at 0°C for 0.5 hour under nitrogen protection and stirring. The reaction was monitored by liquid chromatography and TLC. After the reaction, at zero degrees Celsius, water (500 ml) was added to the reaction solution to quench the reaction, the mixture was extracted with ethyl acetate (1 liter x 3), and the combined organic phases were washed with saturated brine (500 ml). After drying over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain the crude product. The resulting crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 40%→95% acetonitrile/water mobile phase (10 mmol per liter of ammonium bicarbonate aqueous solution) in 30 minutes; The solvent was removed by rotary evaporation to obtain compound 317-1 (white solid, 9.5 g, yield 54%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.91–7.76(m,3H),7.51–7.40(m,2H),7.29–7.24(m,1H),4.10–3.99(m,2H),3.94–3.83 (m,2H).

Step 2:

Under the condition of stirring under nitrogen protection at 0 degrees Celsius, sodium hydride (60%, 1.51 g, 37.83 mmol , 2.0 equivalents), after the addition was completed, the mixture was stirred for 30 minutes under nitrogen protection at 0°C, and then methyl iodide (4.24 g, 28.372 mmol, 1.5 equivalents) was added dropwise thereto. After the addition, the mixture was reacted for 1 hour at 25° C. under nitrogen protection and stirring, and the reaction process was monitored by thin-layer chromatography. After the reaction was over, the reaction solution was carefully poured into ice water (250 ml) to quench, followed by extraction with ethyl acetate (250 ml x 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate Concentration under reduced pressure gave crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0→10% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 317-2 (orange liquid, 5.1 g , yield 97%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.88–7.72(m,3H),7.48–7.37(m,2H),7.25–7.18(m,1H),3.89–3.82(m,2H),3.79–3.72 (m,2H), 3.39(s,3H).

Step 3:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 317-2 (2.6 g, 9.315 mmol, 1.0 equivalent), n-hexane (26 ml), double pinacol borate (3.24 g , 12.110 mmol, 1.3 equiv), bis(1,5-cyclooctadiene) bis-methoxyiridium (I) dimer (0.65 g, 0.931 mmol, 0.1 equiv) and 4,4'-di tert-Butyl-2,2'-dipyridine (0.53 g, 1.863 mmol, 0.2 equiv). The mixture was reacted at 60° C. for 2 hours under nitrogen protection and stirring. The reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated, and tetrahydrofuran (8 ml), water (4 ml), acetic acid (12 ml) and hydrogen peroxide (6 ml) were sequentially added to the resulting mixture with stirring at 0°C. The mixture was reacted at 0°C for 0.5 hour with stirring. The progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, a saturated sodium bicarbonate saturated solution (100 ml) was added under stirring conditions at 0 degrees Celsius, and the resulting mixture was extracted with ethyl acetate (100 ml x 3), the combined organic phases were dried, and the desiccant was removed by filtration, and the filtrate was decompressed Concentration gave the crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0→30% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 317-3 (white solid, 870 mg, Yield 32%). MS(ESI,m/z):278.9/280.9[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ7.60–7.53(m,1H),7.52(d,J＝2.7Hz,1H) , 7.34–7.27 (m, 2H), 7.13 (d, J=2.7Hz, 1H), 3.83–3.77 (m, 2H), 3.76–3.70 (m, 2H), 3.39 (s, 3H).

Step 4:

Under the condition of nitrogen protection and stirring at 0 degrees Celsius, 317-3 (850 mg, 2.872 mmol, 1.00 equivalent), dichloromethane (9 ml), N,N-diisopropylethylamine were successively added to a 50 ml three-necked flask (390.75 mg, 2.872 mmol, 1.0 equiv) and chloromethyl methyl ether (301.48 mg, 4.308 mmol, 1.5 equiv). The mixture was reacted at 25°C for 1 hour under nitrogen protection and stirring. The progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction was over, water (50 ml) was added to the reaction solution at 0°C to quench the reaction, the mixture was extracted with dichloromethane (50 ml x 3), the combined organic phases were washed with saturated brine (100 ml), and anhydrous After drying over sodium sulfate, the desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0→10% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 317-4 (light yellow solid, 780 mg, yield 79%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.67–7.61(m,2H),7.40–7.28(m,3H),5.26(s,2H),3.84–3.77(m,2H),3.76–3.70(m ,2H), 3.51(s,3H), 3.38(s,3H).

Step 5:

Under the condition of nitrogen protection and stirring at -78 degrees Celsius, a solution of 317-4 (400 mg, 1.169 mmol, 1.00 equivalent) in anhydrous tetrahydrofuran (4 ml) was added to a 25 ml Shrek tube, and then n-butyl was added dropwise thereto. Lithium in n-hexane solution (2.5 mol per liter, 0.61 ml, 1.52 mmol, 1.3 equivalents,). The mixture was reacted at -78 degrees Celsius for 0.5 hours. Then, a solution of isopropanol pinacol borate (411.94 mg, 2.104 mmol, 1.8 eq) in anhydrous tetrahydrofuran (1 ml) was slowly added dropwise to the reaction solution under nitrogen protection and stirring at -78°C. The mixture was reacted for 1 hour at -78°C under nitrogen protection and stirring, and then continued to react for 0.5 hour at 25°C under nitrogen protection and stirring. The reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was over, a saturated ammonium chloride solution (50 milliliters) was added to the reaction solution to quench the reaction under stirring conditions at 0 degrees Celsius, and the mixture was extracted with ethyl acetate (50 milliliters x 3), and the organic phase was combined with saturated brine ( 100 ml) was washed, dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0→10% methyl tert-butyl ether/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 317-5 (colorless oily , 440 mg, yield 97%). ¹ H NMR (400MHz, CDCl ₃ ) δ7.64–7.58(m,1H),7.40(d,J=2.7Hz,1H),7.37–7.32(m,2H),7.30–7.25(m,1H), 5.28(s,2H),3.68(t,J=7.5Hz,2H),3.50(s,3H),3.43(t,J=7.5Hz,2H),3.34(s,3H),1.45(s,12H ).

Step 6:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 300-10 (206 mg, 0.320 mmol, 1.00 equivalent), 317-5 (150.25 mg, 0.384 mmol, 1.2 equivalent), 3-( tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxo,phosphapentyl conjugate (22.22 mg, 0.064 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (30.80 mg, 0.032 mmol, 0.1 equiv), potassium phosphate (142.78 mg, 0.64 mmol, 2.0 equiv), toluene (2 ml) and water ( 0.4 ml). The mixture was reacted at 80° C. for 2 hours under nitrogen protection and stirring. The reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was over, water (20 ml) was added to the reaction solution with stirring at 25 degrees Celsius to quench the reaction, the mixture was extracted with ethyl acetate (20 ml x 3), and the combined organic phases were washed with saturated brine (40 ml) , dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0→10% dichloromethane/methanol, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 317-6 (off-white solid, 200 mg, yield rate of 76%). MS (ESI, m/z): 778.6 [M+H] ⁺ .

Step 7:

The compound 317-6 (200 mg) obtained in step 6 was subjected to chiral resolution (high performance liquid chromatography), and the resolution conditions were: chiral column CHIRAL ART Cellulose-SZ, 3x25 cm, 5 microns; mobile phase A: n-Hexane (0.5% methanol solution of 2 mol/liter ammonia), mobile phase B: ethanol; flow rate: 40 ml/min; eluted with 30% mobile phase B for 20 minutes; detector UV209/266 nanometers; two product. The compound with shorter retention time (16 minutes) is 317-6a (white solid, 89 mg, recovery rate 45%), MS (ESI, m/z): 778.6[M+H] ⁺ ; longer retention time (18.2 minutes) was 317-6b (white solid, 78 mg, recovery 3:%). MS (ESI, m/z): 778.6 [M+H] ⁺ .

Step 8:

317-6a (84 mg, 0.103 mmol, 1.00 eq), methanol (2 ml) and hydrochloric acid in 1,4-dioxane (2 ml , 4 mol/L). The mixture was reacted at 25°C for 1 hour with stirring, and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was concentrated to obtain a crude product. The resulting crude product was purified by a reverse-phase chromatographic column (C18 column), using 5% → 95% (acetonitrile/methanol=1/1)/water (10 mmol per liter of ammonium bicarbonate aqueous solution) mobile phase within 30 minutes Elution was carried out, and the obtained fraction was evaporated under reduced pressure to remove the solvent to obtain compound 317a (yellow solid, 48.5 mg, yield 65%). MS (ESI, m/z): 634.2[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O) δ7.85–7.67(m,2H),7.45–7.30(m,2H ),7.17(d,J=7.0Hz,1H),7.02(d,J=2.7Hz,1H),5.69–5.45(m,1H),4.68–4.55(m,2H),4.53–4.40(m, 2H),4.24–4.13(m,2H),4.00–3.69(m,5H),3.36–3.13(m,3H),2.94(s,3H),2.69–2.52(m,4H),2.40–2.27( m, 1H), 2.27-2.12 (m, 2H), 2.11-1.88 (m, 5H); ¹⁹ F NMR (377 MHz, DMSO-d ₆ +D ₂ O) δ -116.50, -123.50, -172.76. The chiral analysis conditions of compound 317a are: chiral column: Optichiral C9-3, 3.0x100 mm, 3 microns; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (20 mmol/L ammonia); flow rate 2 ml min; elution with 50% mobile phase B in 3.5 min; detector: UV220 mm; retention time: 1.229 min; dr>40:1.

Step 8':

Compound 317b (yellow solid, 66.4 mg, yield 97%) could be obtained by the same method as step 8. MS(ESI,m/z):634.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ7.86–7.65(m,2H),7.44–7.32(m,2H),7.17( d,J=7.0Hz,1H),7.01(d,J=2.6Hz,1H),5.70–5.46(m,1H),4.68–4.41(m,4H),4.25–4.12(m,2H),3.98 –3.69(m,5H),3.36–3.12(m,3H),2.94(s,3H),2.69–2.52(m,4H),2.39–2.28(m,1H),2.25–1.89(m,7H) ; ¹⁹ F NMR (377 MHz, DMSO-d ₆ +D ₂ O) δ-116.49, -116.50, -123.50, -123.50, -172.76. The chiral analysis conditions of compound 317b are: chiral column: Optichiral C9-3, 3.0x100 mm, 3 microns; mobile phase A: supercritical carbon dioxide, mobile phase B: isopropanol (20 mmol/L ammonia); flow rate 2 ml min; elution with 50% mobile phase B in 3.5 min; detector: UV220 mm; retention time: 1.790 min; dr>40:1.

Example 23

7'-((7S or 7R)-4-(3,8-diazacyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-((R)-2- Methoxy-3-((1R,3S,5S)-3-methoxy-8-azabicyclo[3.2.1]octane-8-yl)propoxy)quinazolin-7-yl) -2',3'-dihydrospiro[1,1'-indene-5'-phenol dihydrochloride 318a; 7'-((7R or 7S)-4-(3,8-diazacyclo [3.2.1] Octane-3-yl)-6,8-difluoro-2-((R)-2-methoxy-3-((1R,3S,5S)-3-methoxy- 8-Azabicyclo[3.2.1]octane-8-yl)propoxy)quinazolin-7-yl)-2',3'-dihydrospiro[1,1'-indene-5' -phenol dihydrochloride 318b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 20 degrees Celsius, compound 279-1 (200 mg, 0.388 mmol, 1.0 equivalent), triethylenediamine (9.16 mg, 0.078 mmol, 0.2 equivalent) and compound 288-17 (112.38 mg, To a solution of 0.466 mmol, 1.2 eq) in N,N-dimethylformamide (2 mL) was added cesium carbonate (266.11 mg, 0.776 mmol, 2.0 eq). The mixture was stirred at 60°C under nitrogen protection for 16 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and 20 ml of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of dichloromethane/methanol/ammonia methanol (7 mol/L)=15/1/0.1, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 318 -1 (pale yellow solid, 209 mg, yield 75%). MS (ESI, m/z): 682.0/684.0 [M+H] ⁺ .

Step 2:

Under the condition of stirring under nitrogen protection at 20 degrees Celsius, compound 318-1 (209 mg, 0.291 mmol, 1.0 equivalent), compound 302-6 (126.49 mg, 0.349 mmol, 1.2 equivalent), three (two Benzylideneacetone) dipalladium (28.04 mg, 0.029 mmol, 0.1 equiv), 3-(tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo [D][1,3]oxo,phosphapentyl conjugate (20.23mg, 0.058mmol, 0.2eq), potassium phosphate (129.98mg, 0.582mmol, 2.0eq), toluene (2ml) and water (0.4ml) . The mixture was stirred at 80°C under nitrogen protection for 3 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and 20 ml of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (20 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of dichloromethane/methanol/ammonia methanol (7 mol/L)=15/1/0.1, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 318 -2 (pale yellow solid, 220 mg, 88% yield). MS (ESI, m/z): 820.3 [M+H] ⁺ .

Step 3:

Compound 318-2 (220 mg) obtained in step 2 was subjected to chiral resolution by high performance liquid chromatography: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 microns; mobile phase A: n-hexane (0.5% 2 Mole/liter of ammonia methanol), mobile phase B: ethanol; flow rate: 40 ml/min; within 17 minutes with 10% phase B for elution, detector UV 210/226 nanometers, to obtain two products. The product with shorter retention time (9 minutes) is compound 318-2a (light yellow solid, 60 mg, recovery rate 27%), MS (ESI, m/z): 820.3[M+H] ⁺ ; longer retention The product after time (13 minutes) was compound 318-2b (pale yellow solid, 80 mg, recovery 36%), MS (ESI, m/z): 820.3[M+H] ⁺ .

Step 4:

Under stirring condition at 0°C, to a solution of compound 318-2a (60 mg, 0.070 mmol, 1.00 equiv) in methanol (2 ml) was slowly added a solution of hydrogen chloride in 1,4-dioxane (4 mol/L , 2 ml). The mixture was reacted at 25°C for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by a reversed-phase chromatographic column (C18 column), and eluted with 5% → 95% methanol/water mobile phase (0.1% hydrochloric acid) within 20 minutes; detector, UV254/220 nm; to obtain the compound 318a (white solid, 39.3 mg, 72% yield). MS(ESI,m/z):676.5[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.81–7.72(m,1H),6.77–6.72(m,1H ),6.43–6.38(m,1H),4.68–4.60(m,1H),4.53–4.36(m,3H),4.28–4.09(m,4H),4.09–3.96(m,1H),3.95–3.88 (m,1H),3.86–3.77(m,1H),3.72–3.65(m,1H),3.51–3.44(m,3H),3.31–3.14(m,5H),2.81–2.73(m,2H) ,2.28–2.10(m,6H),2.06–1.81(m,12H),1.76–1.68(m,1H),1.20–1.07(m,1H); ¹⁹ F NMR(377MHz,DMSO-d ₆ +D ₂ O) δ -115.08, -121.88. The chiral analysis conditions of compound 318a are: N-Lux 3 μm Cellulose-4 (H18-063498), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethyl amine); flow rate: 2 ml/min; isocratic elution with 50% phase B in 7 min; detector UV 220 nm; retention time: 4.109 min; dr>40:1.

Step 4':

Compound 318b (white solid, 42.1 mg, yield 57%) can also be obtained according to the method of step 4. MS (ESI, m/z): 676.5[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ +D ₂ O) δ7.80–7.73 (m, 1H), 6.74 (d, J＝2.3 Hz,1H),6.40(d,J＝2.3Hz,1H),4.71–4.64(m,1H),4.53–4.37(m,3H),4.25–4.08(m,4H),4.07–3.97(m, 1H),3.95–3.87(m,1H),3.87–3.79(m,1H),3.73–3.66(m,1H),3.50–3.43(m,3H),3.33–3.14(m,5H),2.82– 2.71(m,2H),2.26–2.09(m,6H),2.06–1.81(m,12H),1.79–1.68(m,1H),1.17–1.05(m,1H); ¹⁹ F NMR(377MHz,DMSO -d ₆ +D ₂ O) δ -115.10, -121.88. The chiral analysis conditions of compound 318b are: N-Lux 3 μm Cellulose-4 (H18-063498), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethyl amine); flow rate: 2 ml/min; isocratic elution with 50% phase B in 7 min; detector UV 220 nm; retention time: 5.329 min; dr>40:1.

Example 24

4-((S or R)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-6-(difluoromethyl)-8- Fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethylnaphthalene-2- Phenol dihydrochloride 319a; 4-((R or S)-4-((1R,5S)-3,8-diazacyclo[3.2.1]octane-3-yl)-6-(di Fluoromethyl)-8-fluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5 -Ethylnaphthalene-2-ol dihydrochloride 319b

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, a solution of the compound 2-amino-4-bromo-3-fluorobenzoic acid (20 g, 81.188 mmol, 1.0 equivalent) in N,N-dimethylformamide (200 ml) N-iodosuccinimide (28.84 g, 121.782 mmol, 1.5 equiv) was added to . The mixture was stirred at 70°C under nitrogen protection for 16 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and 1000 ml of water was added to dilute the reaction solution. The pH of the aqueous phase was adjusted to 5 with concentrated hydrochloric acid at 0 °C. The mixture was extracted with dichloromethane (800 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium carbonate solution (500 ml x 2), saturated sodium sulfite (500 ml) and saturated brine (500 ml), then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product of compound 319-1 ( black like solid, 36 g). The resulting crude product was used directly in the next step without further purification. MS (ESI, m/z): 357.9/359.8 [MH] ^- .

Step 2:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, iodoethane (10.40 g , 63.347 mmol, 1.2 equiv) and cesium carbonate (36.21 g, 105.578 mmol, 2.0 equiv). The mixture was stirred at 25°C under nitrogen protection for 16 hours, and the reaction progress was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to 25 degrees Celsius, and 1000 ml of water was added to dilute the reaction solution. The aqueous phase was extracted with dichloromethane (800 ml x 3), the combined organic phase was washed with saturated brine (500 ml x 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→10% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 319-2 (white solid, 11.8 g , yield 55%). MS (ESI, m/z): 387.9/389.9 [M+H] ⁺ . ¹ H NMR (300MHz, CDCl ₃ ) δ8.14(d, J=1.9Hz, 1H), 4.37(q, J=7.1Hz, 2H), 1.42(t, J=7.1Hz, 3H); ¹⁹ F NMR (282MHz, CDCl ₃ ) δ-117.76.

Step 3:

Under the condition of nitrogen protection and stirring at 20 degrees Celsius, trichloroacetyl isocyanate (6.4 g, 32.33 mmol, 1.5 equivalent). The mixture was reacted for 20 minutes at 20°C under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product, which was slurried with methyl tert-butyl ether (100 ml) to obtain compound 319-3 (white solid, 11 g, 89%). MS (ESI, m/z): 574.8/576.8/578.8 [M+H] ⁺ .

Step 4:

To a solution of compound 319-3 (6.77 g, 11.159 mmol, 1.00 eq) in methanol (70 mL) was slowly added dropwise a methanolic ammonia solution (7 mol/L, 7 mL) under stirring at 20°C. The mixture was reacted at 20 degrees Celsius for 20 minutes with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated to obtain a crude product. The obtained crude product was slurried by methyl tert-butyl ether (50 mL) to obtain compound 319-4 (white solid, 4.44 g, yield 98%). MS (ESI, m/z): 382.8/384.8/386.8 [MH] ^- .

Step 5:

Under the condition of stirring under nitrogen protection at 0°C, N,N-diisopropylethylamine ( 7 ml). After the mixture was reacted at 25°C for 10 minutes, the reaction was continued at 100°C for 5 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→20% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 319-5 (yellow solid, 4.2 g , yield 98%).

Step 6:

Under the condition of nitrogen protection and stirring at 0 ℃, to the solution of compound 319-5 (4.2 g, 9.459 mmol, 1.00 eq) in dichloromethane (30 ml) was added successively N,N-diisopropylethylamine (5.2 ml , 28.377 mmol, 3.0 equiv) and tert-butyl (1R,5S)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (2.01 g, 8.986 mmol, 0.95 equiv). The mixture was reacted at 20° C. for 14 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→15% ethyl acetate/dichloromethane, and the obtained fraction was evaporated under reduced pressure to remove the solvent to obtain compound 319-6 (brown yellow solid, 5.5 g, 97%). MS (ESI, m/z): 596.9/598.9/600.9 [M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ8.18 (d, J=1.9Hz, 1H), 4.54–4.31 (m, 4H), 3.78–3.54(m,2H), 2.06–1.88(m,2H), 1.78–1.63(m,2H), 1.53(s,9H).

Step 7:

Under the condition of nitrogen protection and stirring at 20 degrees Celsius, compound 319-6 (2.5 g, 3.974 mmol, 1.0 equivalent), (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a (5H )-methanol (799.2 mg, 4.769 mmol, 2.0 equiv), cesium carbonate (2.73 g, 7.948 mmol, 2.0 equiv) and triethylenediamine (93.9 mg, 0.795 mmol, 0.2 equiv) and N,N-di Methylformamide (25 mL) solution. The mixture was reacted at 60°C for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and water (200 mL) was added to the reaction solution to dilute the reaction solution. The mixture was extracted with ethyl acetate (200 ml x 3), and the organic phases were combined; the organic phase was washed with saturated brine (200 ml), dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→3% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 319-7 (white solid, 1.8 g, Yield 60%). MS (ESI, m/z): 720.1/722.1 [M+H] ⁺ .

Step 8:

Under the condition of nitrogen protection and stirring at minus 78 degrees Celsius, a solution of n-butyllithium in n-hexane (2.5 mole /L, 1.8 ml, 4.45 mmol, 1.8 eq). The mixture was reacted at minus 78 degrees Celsius under nitrogen protection for 30 minutes, and N-formylmorpholine (539.6 mg, 4.453 mmol, 1.8 equivalents) was slowly added dropwise to the above solution. The mixture was reacted at minus 78 degrees centigrade under a nitrogen protection stirring condition for 1 hour, then naturally warmed to room temperature, and continued to stir and react at room temperature for 1 hour. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction solution was poured into ice saturated sodium bicarbonate solution (200 mL) to quench, and the mixture was extracted with dichloromethane (200 mL x 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 35%→75% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 319-8 (light yellow solid, 715 mg, yield 41%). MS (ESI, m/z): 622.2/624.2 [M+H] ⁺ .

Step 9:

Under the condition of stirring under nitrogen protection at 0 degrees Celsius, to a solution of compound 319-8 (400 mg, 0.578 mmol, 1.0 eq) in dichloromethane (8 ml) was slowly added dropwise bis(2-methoxyethyl)aminotri Sulfur fluoride (1.35 g, 5.780 mmol, 10 equiv). The mixture was reacted for 20 minutes at 20° C. under nitrogen protection and stirring, and then heated to 40° C. for 16 hours. The reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, the reaction solution was added dropwise to ice saturated sodium bicarbonate solution (50 ml) to quench, the mixture was extracted with dichloromethane (50 ml x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 319-9 (white solid, 300 mg, Yield 75%). MS (ESI, m/z): 644.1/646.1 [M+H] ⁺ .

Step 10:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 319-9 (300 mg, 0.465 mmol, 1.0 eq), compound 282-2 (398.3 mg, 1.164 mmol, 2.5 eq), 3-( tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxo,phosphapentyl conjugate (30.7 mg, 0.093 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (42.6 mg, 0.047 mmol, 0.1 equiv), potassium phosphate (296.4 mg, 1.396 mmol, 3.0 equiv), toluene (3 mL) and water (0.6 mL) . After the mixture was reacted at 80°C under nitrogen protection for 8 hours, compound 282-2 (239.0 mg, 0.698 mmol, 1.5 equivalents) was added to the system, and then reacted at 80°C under nitrogen protection for 12 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature. Water (50 ml) was added to the mixture to dilute the reaction solution, the mixture was extracted with ethyl acetate (50 ml) and dichloromethane (50 ml x 2), and the organic phases were combined; the organic phase was dried over anhydrous sodium sulfate, filtered to remove the dryness agent, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by a reverse-phase chromatography column (C18 column) within 20 minutes with 50% → 95% (acetonitrile/methanol=4/6)/water (10 mmol/L ammonium bicarbonate) mobile phase Elution; detector, UV254/220 nm; compound 319-10 was obtained (white solid, 136 mg, yield 38%). MS (ESI, m/z): 780.3 [M+H] ⁺ .

Step 11:

Compound 319-10 (135 mg) obtained in step 10 was subjected to chiral resolution by high performance liquid chromatography: chiral column CHIRAL ART Cellulose-SZ, 3 x 25 cm, 5 microns; mobile phase A: n-hexane (10 mmol / liter ammonia methanol), mobile phase B: ethanol; 40 milliliters/minute of flow velocity; Carry out elution with 10% B phase in 13 minutes; Detector UV 222/240 nanometers, obtain two products. The product with shorter retention time (7.2 minutes) is compound 319-10a (white solid, 58 mg, recovery rate 43%), MS (ESI, m/z): 780.4[M+H] ⁺ ; longer retention time ( 10.2 minutes) was compound 319-10b (white solid, 67 mg, recovery 49%), MS (ESI, m/z): 780.4[M+H] ⁺ .

Step 12:

Under the condition of stirring at 20 degrees Celsius, a solution of hydrochloric acid in 1,4-dioxane (4 mol/L, 1.8 ml). The mixture was reacted at 25°C for 1 hour with stirring, and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with a mobile phase of 5%→95% (methanol/acetonitrile=1/1)/water (0.1% hydrochloric acid) within 20 minutes; , UV254/220 nm; Compound 319a was obtained (yellow solid, 35.1 mg, yield 68%). MS(ESI,m/z):636.5[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ +D ₂ O)δ8.12–8.03(m,1H),7.72–7.62(m,1H ),7.43–7.34(m,1H),7.31(d,J＝2.6Hz,1H),7.15–7.09(m,1H),6.91–6.51(m,2H),5.69–5.45(m,1H), 4.69–4.49(m,4H),4.27–4.17(m,2H),4.05–3.91(m,2H),3.88–3.73(m,3H),3.37–3.22(m,1H),2.71–2.54(m ,1H),2.49–2.46(m,1H),2.34–1.91(m,10H),0.89–0.78(m,3H); ¹⁹ F NMR(282MHz,DMSO-d ₆ )δ-107.03,-108.10,- 108.61, -109.68, -124.33, -172.74. The chiral analysis conditions of compound 319a are: N-Lux 3 μm Cellulose-4 (H18-063498), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethyl amine); flow rate: 3 ml/min; isocratic elution with 40% phase B in 7 min; detector UV 220 nm; retention time: 2.41 min; dr>40:1.

Step 13:

Compound 319b (yellow solid, 37.8 mg, yield 68%) was obtained by the same method as step 12. MS(ESI,m/z):636.5[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ )δ11.69–11.22(m,1H),10.42–9.60(m,3H),8.14– 8.03(m,1H),7.73–7.64(m,1H),7.43–7.34(m,1H),7.31(d,J＝2.6Hz,1H),7.16–7.08(m,1H),6.97–6.52( m,2H),5.71–5.44(m,1H),4.69–4.62(m,2H),4.59–4.44(m,2H),4.26–4.17(m,2H),4.15–3.96(m,2H), 3.89–3.64(m,3H),3.36–3.22(m,1H),2.75–2.55(m,1H),2.48–2.38(m,1H),2.37–2.12(m,5H),2.09–1.91(m , 5H), 0.88–0.80 (m, 3H); ¹⁹ F NMR (282 MHz, DMSO-d ₆ ) δ-107.06, -108.12, -108.62, -109.69, -124.28, -172.67. The chiral analysis conditions of compound 319b are: N-Lux 3 μm Cellulose-4 (H18-063498), 4.6 x 100 mm, 3 μm; mobile phase A: supercritical carbon dioxide fluid; mobile phase B: methanol (0.1% diethyl amine); flow rate: 3 ml/min; isocratic elution with 40% phase B in 7 min; detector UV 220 nm; retention time: 3.375 min; dr>40:1.

Example 25

4-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-8-fluoro-2-((2R,7aS)-2-fluorotetra Hydrogen-1H-pyrroline-7a(5H)-yl)methoxy)pyridyl[4,3-d]pyrimidin-7-yl)-5-cyclopropylnaphthalene-2-ol bistrifluoroacetate 320

step 1:

N-iodosuccinimide ( 1.84 g, 7.77 mmol, 1.2 eq) and p-toluenesulfonic acid (130 mg, 0.65 mmol, 0.1 eq). The mixture was reacted at 70°C for 16 hours. The reaction process was monitored by liquid quality. After the reaction, the mixture was cooled to 25°C, diluted with 30 mL of water, extracted with ethyl acetate (50 mL x 3), and the organic phases were combined. The organic phase was washed successively with 50 ml of saturated sodium carbonate solution, 50 ml of saturated sodium sulfite solution and 50 ml of saturated brine. After washing, the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→45% ethyl acetate/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 320-1 (yellow solid, 1.72 g , yield 95%). MS (ESI, m/z): 272.9/274.9 [M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ 8.17 (s, 1H), 4.84 (s, 2H).

Step 2:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, triethylamine (1.38 g, 12.96 mmol, 3.6 equivalents) and di Chlorobis(triphenylphosphine)palladium (266 mg, 0.36 mmol, 0.1 equiv). The mixture was reacted at 80° C. for 15 hours in a carbon monoxide atmosphere (3 atmospheres), and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was cooled to 25 degrees Celsius, filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→31% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 320-2 (yellow solid, 660 mg , yield 74%). MS (ESI, m/z): 219.3/221.3 [M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ8.56 (s, 1H), 4.41 (q, J = 7.1Hz, 2H), 1.43 (t,J=7.1,3H).

Step 3:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, trichloroacetyl isocyanate (853 mg, 4.30 mmol, 1.5 equiv) was added dropwise to a solution of compound 320-2 (660 mg, 2.87 mmol, 1.0 equiv) in tetrahydrofuran (6 ml). . The mixture was reacted at 25 degrees Celsius for 20 minutes, and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was concentrated to obtain a crude product. The obtained crude product was slurried with 10 ml of methyl tert-butyl ether, filtered, the filter cake was washed with methyl tert-butyl ether (2 ml x 3), and the filter cake was dried to obtain compound 320-3 (white solid, 1.0 g, yield 77%). MS(ESI,m/z):406.0/408.0/410.0[M+H] ⁺ ; ¹ H NMR(400MHz,CDCl ₃ )δ11.19(s,1H),8.91(s,1H),8.78(d, J=0.8Hz, 1H), 4.48(q, J=7.1Hz, 2H), 1.43(t, J=7.1, 3H).

Step 4:

To a solution of compound 320-3 (1 g, 2.334 mmol, 1.00 eq) in methanol (10 mL) was added dropwise ammonia methanol solution (7 mol/L, 1 mL) under stirring at 25°C. The mixture was reacted for 1 hour at 25°C. The reaction process was monitored by liquid quality. After the reaction, the reaction solution was concentrated to obtain a crude product. The resulting crude product was slurried by 10 ml of methyl tert-butyl ether, filtered, the filter cake was washed with methyl tert-butyl ether (2 ml x 3), and the filter cake was dried to obtain compound 320-4 (white solid, 594 mg, yield 94%). MS (ESI, m/z): 216.1/218.1 [M+H] ⁺ ; ¹ H NMR (400 MHz, DMSO-d ₆ ) δ8.34 (d, J=1.2 Hz, 1H).

Step 5:

Under nitrogen protection conditions at zero degrees Celsius, compound 320-4 (500 mg, 2.20 mmol, 1.0 equiv), phosphorus oxychloride (9 ml) and N,N-diisopropyl Ethylamine (0.9 mL). The mixture was stirred at zero degrees Celsius for 10 minutes, and then transferred to an oil bath at 90 degrees Celsius for reflux reaction for 12 hours. The reaction process was monitored by liquid quality. After the reaction, the reaction solution was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/petroleum ether, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain the compound 320-5 product (yellow solid, 425 mg, yield 72%).

Step 6:

Compound 320-5 (425 mg, 1.68 mmol, 1.0 equiv) was dissolved in dichloromethane (5 mL) at 25 °C under nitrogen protection with stirring. To this solution were sequentially added N,N-diisopropylethylamine (652 mg, 4.80 mmol, 3.0 eq) and (1R,5S)-3,8-diazabicyclo[3.2.1]octane - tert-butyl 8-formate (357 mg, 1.60 mmol, 1.0 equiv), then reacted at 25 degrees Celsius for 1 hour, and the reaction process was monitored by liquid quality. After the reaction, the reaction solution was concentrated to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→30% ethyl acetate/dichloromethane, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 320-6 (yellow solid, 700 mg, yield 97%). MS(ESI,m/z):428.2/430.2[M+H] ⁺ ; ¹ H NMR(300MHz,CDCl ₃ )δ8.86(d,J＝0.6Hz,1H),4.59–4.41(m,4H) , 3.78–3.71(m,2H), 2.04–1.96(m,2H), 1.75–1.65(m,2H), 1.54(s,9H).

Step 7:

Under the condition of nitrogen protection and stirring at 20 degrees Celsius, compound 320-6 (500 mg, 1.11 mmol, 1.0 equivalent) and (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol ( To a solution of 372 mg, 2.22 mmol, 2.0 eq) in 1,4-dioxane (5 mL) was slowly added dropwise N,N-diisopropylethylamine (453 mg, 3.33 mmol, 3.0 eq). The mixture was stirred at 80°C under nitrogen protection for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and 30 ml of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% dichloromethane/ethyl acetate, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 320-7 (yellow solid, 419 mg, yield 65%). MS (ESI, m/z): 551.2/553.2 [M+H] ⁺ .

Step 8:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 1,4-dioxane was added to compound 320-7 (100 mg, 0.173 mmol, 1.0 equivalent) and compound 307-4 (77 mg, 0.207 mmol, 1.2 equivalent). (1.0 mL) and water (0.2 mL) were added tetrakis(triphenylphosphine)palladium (21.0 mg, 0.017 mmol, 0.1 eq) and cesium carbonate (118.3 mg, 0.345 mmol, 2.0 eq). The mixture was reacted at 100°C under nitrogen protection for 6 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and 15 ml of water was added to dilute the reaction solution. The mixture was extracted with ethyl acetate (15 mL x 2) and dichloromethane (15 mL), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% methanol/dichloromethane, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 320-8 (light yellow solid, 47 mg , yield 35%). MS (ESI, m/z): 743.5 [M+H] ⁺ .

Step 9:

Under the condition of stirring under nitrogen protection at 0 degrees Celsius, to the solution of compound 320-8 (47 mg, 0.059 mmol, 1.00 eq) in acetonitrile (2 ml) was slowly added a solution of hydrogen chloride in 1,4-dioxane (4 mole /L, 0.4 ml). The mixture was reacted at 25°C for 1 hour under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The crude product was dissolved in methanol (2 mL), ammonia methanol solution (7 mol/L, 2 mL) was added dropwise at 0°C, and stirred at the same temperature for 15 minutes. Concentration under reduced pressure gave a crude product, which was then dissolved in methanol (2 mL), and formic acid (0.2 mL) was added dropwise at 0°C, and stirred at the same temperature for 5 minutes. Concentration under reduced pressure gave crude product. The obtained crude product was purified by a reverse-phase chromatography column (C18 column), and eluted with 5%→80% methanol/water (0.1% trifluoroacetic acid) mobile phase within 25 minutes; detector, UV254/220 nm; Compound 320 was obtained (yellow solid, 26.1 mg, yield 54%). MS(ESI,m/z):599.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ9.21–9.13(m,1H),7.73–7.65(m,1H ),7.40–7.28(m,2H),7.17–7.12(m,1H),7.01(d,J＝2.6Hz,1H),5.70–5.49(m,1H),4.77–4.56(m,4H), 4.26–4.16(m,2H),4.01–3.71(m,5H),3.37–3.26(m,1H),2.69–2.54(m,1H),2.41–1.87(m,9H),1.57–1.41(m ,1H),0.62–0.50(m,1H),0.35–0.20(m,2H),-0.02–-0.17(m,1H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-73.65,-138.17 ,-172.93.

Example 26

4-((S or R)-4-((1R, 5S)-3,8-diazacyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( 2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-5-(1-hydroxyethyl)naphthalene-2-ol 321; 4-((S or R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2- ((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-methoxy)quinazolin-7-yl)-5-((S or R)-1-hydroxyethyl )naphthalene-2-ol 321a; 4-((S or R)-4-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-6,8 -Difluoro-2-((2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-methoxy)quinazolin-7-yl)-5-((R or S) -1-Hydroxyethyl)naphthalene-2-ol 321b

The synthetic route is as follows:

step 1:

Under the condition of stirring at zero degrees Celsius, compound 300-3a (390 mg, 0.498 mmol, 1.0 equivalent), trifluoroacetic acid (3 ml), dichloromethane (6 ml) and triethyl Silane (170.4 mg, 1.49 mmol, 3 equiv). The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the pH of the reaction solution was adjusted to 7 with saturated sodium bicarbonate solution, and the resulting mixture was extracted with dichloromethane (35 mL x 3). The organic phases were combined, dried with anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was rotary evaporated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 30%→95% methanol/water mobile phase (0.5% ammonium bicarbonate) within 25 minutes; detector: UV254/220 nanometers; Compound 321-1 (yellow solid, 200.7 mg, yield 64%). MS (ESI, m/z): 618.0 [M+H] ⁺ .

Step 2:

Under the condition of nitrogen protection and stirring at minus 40 degrees centigrade, a solution of lithium aluminum hydride in tetrahydrofuran (2.5 mole /L, 1.05 ml, 1.044 mmol, 2 equivalents). The mixture was reacted at minus 40 degrees centigrade for 1 hour under nitrogen protection and stirring, and then continued to react for 1 hour at zero degrees centigrade. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, a saturated sodium potassium tartrate solution (0.5 ml) was added to the reaction solution in an ice-water bath to quench the reaction. The mixture was filtered, the filter cake was washed with methanol (2 mL x 3), and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The crude product was purified by high performance liquid chromatography: chromatographic column: XBridge Shield RP18 OBD Column, 30x 150 mm, 5 microns; mobile phase A: water (10 mmol/L ammonium bicarbonate + 0.1% ammonia water), mobile phase B: Acetonitrile; flow rate: 60 ml/min; detector: UV220; elute with 30% → 45% mobile phase B within 8 minutes, retention time is 5.84 minutes, and the obtained fraction is desolventized by rotary evaporation under reduced pressure to obtain compound 321 (White solid, 90 mg, 53% yield). MS(ESI,m/z):620.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ9.99(s,1H),7.75–7.59(m,3H),7.49–7.39( m,1H),7.30(d,J＝2.6Hz,1H),6.96–6.89(m,1H),5.39–5.15(m,1H),5.00–4.90(m,1H),4.76–4.58(m, 1H),4.36–4.15(m,2H),4.12–4.05(m,1H),4.03–3.93(m,1H),3.55–3.49(m,3H),3.15–2.95(m,3H),2.87– 2.75(m,1H),2.13(d,J＝5.3Hz,1H),2.09–1.92(m,2H),1.87–1.71(m,3H),1.71–1.55(m,4H),1.03–0.86( m,3H),0.86–0.76(m,1H); ¹⁹ F NMR (377MHz,DMSO-d ₆ )δ-73.40,-117.75,-117.75, -118.22,-118.23,-123.34,-123.35,-123.37, -123.38, -172.04, -172.14.

Step 3:

Compound 321 (75 mg, 0.121 mmol) obtained in step 2 was subjected to chiral resolution by preparative supercritical liquid chromatography: chiral column CHIRALPAK IG, 3 x 25 cm, 5 microns; mobile phase A: supercritical carbon dioxide, mobile Phase B: isopropanol; flow rate: 90 ml/min; elution with 55% of phase B in 8 minutes, detector UV 226/204 nm, two products were obtained. The product with shorter retention time (3.12 minutes) was compound 321a (white solid, 31.5 mg, recovery 42%), MS (ESI, m/z): 620.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO -d ₆ )δ9.95(s,1H),7.74–7.67(m,1H),7.67–7.59(m,2H),7.49–7.41(m,1H),7.30(d,J＝2.6Hz,1H ),6.94(d,J＝2.6Hz,1H),5.40–5.15(m,1H),5.02–4.88(m,1H),4.70–4.56(m,1H),4.35–4.27(m,1H), 4.27–4.17(m,1H),4.11–4.05(m,1H),4.05–3.97(m,1H),3.55–3.42(m,4H),3.16–3.04(m,2H),3.04–2.98(m ,1H),2.87–2.78(m,1H),2.64–2.54(m,1H),2.21–1.94(m,3H),1.89–1.73(m,3H),1.71–1.60(m,4H),1.28 –1.21(m,1H),0.93–0.86(m,3H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-118.20,-118.20,-123.32,-123.33,-172.14; longer retention time (6.18 minutes) is compound 321b (white solid, 12.9 mg, recovery 17%), MS (ESI, m/z): 620.3[M+H] ⁺ ; ¹ H NMR (400MHz, DMSO-d ₆ ) δ9. 94(s,1H),7.78–7.65(m,2H),7.63(d,J=7.2Hz,1H),7.48–7.41(m,1H),7.30(d,J=2.6Hz,1H),6.93 (d,J=2.7Hz,1H),5.37–5.17(m,1H),4.94–4.88(m,1H),4.76–4.66(m,1H),4.34–4.16(m,2H),4.12–4.05 (m,1H),4.00–3.94(m,1H),3.54–3.48(m,3H),3.15–3.04(m,2H),3.04–2.97(m,1H),2.89–2.78(m,1H) ,2.21–2.08(m,1H),2.10–1.94(m,2H),1.87–1.71(m,3H),1.70–1.60(m,4H),1.35–1.29(m,1H),1.02–0.96( m, 3H); ¹⁹ F NMR (377 MHz, DMSO d ₆ ) δ-117.74, -123.33, -172.04.

The chiral analysis conditions of compound 321a are: N--CHIRALPAK IG (Lot No.IG30CS-VL001), 4.6x 100 mm; 3.0 microns; mobile phase A: supercritical carbon dioxide; B: isopropanol (20 mmol/L Ammonia); flow rate 2 ml min; elution with 10% mobile phase B in 6.5 min; detector: UV220 mm; retention time: 3.711 min; dr>40:1. The chiral analysis conditions of compound 321b are: N--CHIRALPAK IG (Lot No.IG30CS-VL001); 4.6x 100 mm; 3.0 microns; mobile phase A: supercritical carbon dioxide; B: isopropanol (20 mmol/L ammonia water); flow rate 2 milliliters of minutes; within 6.5 minutes with 10% mobile phase B for elution; detector: UV220 mm; retention time: 4.502 minutes; dr>40:1.

Example 27

(S or R)-7'-(4-((1R,5S)-3,8-diazabicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-( (2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-3',3'-difluoro-2',3 '-Dihydrospiro[1,1'-indene-5'-phenol dihydrochloride 322a; (R or S)-7'-(4-((1R,5S)-3,8-diazepine Bicyclo[3.2.1]octane-3-yl)-6,8-difluoro-2-((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy Base) quinazolin-7-yl)-3',3'-difluoro-2',3'-dihydrospiro[1,1'-indene-5'-phenol dihydrochloride 322

The synthetic route is as follows:

step 1

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, to compound 302-1 (2.5 g, 10.10 mmol, 1 eq) in tetrahydrofuran (30 ml) was slowly added 9-borabicyclo[3,3,1]nonane ( 1.49 g, 11.61 mmol, 1.15 equiv). The mixture was reacted at 70°C for 6 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, and the mixture was concentrated under reduced pressure to obtain a crude intermediate product. Pyridinium chlorochromate (9.63 g, 42.42 mmol, 4.2 equiv) was slowly added to a solution of the crude intermediate in dichloromethane (30 mL) under nitrogen protection at 0°C with stirring. The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0%→10% ethyl acetate/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 322-1 (white solid, 1.78 g , yield 66%). MS(ESI,m/z):251.1/253.1[M+H] ⁺ ; ¹ H NMR(400MHz,CD ₃ OD)δ7.94–7.89(m,1H),7.69–7.64(m,1H),7.39 –7.30 (m, 1H), 3.48 – 3.38 (m, 2H), 3.13 (s, 2H), 2.38 – 2.04 (m, 4H).

step 2

Slowly add ethanol to a solution of compound 322-1 (1 g, 3.783 mmol, 1 eq) in bis(2-methoxyethyl)aminosulfur trifluoride (8 ml) under stirring under nitrogen protection at 0°C (0.2 ml). The mixture was reacted at 90°C for 24 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature. With stirring at 0°C, the reaction solution was poured into saturated sodium bicarbonate solution (40 mL) to quench the reaction. The mixture was extracted with methyl tert-butyl ether (40 mL x 3), and the organic phases were combined; the organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, eluting with petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 322-2 (colorless liquid, 280 mg, yield 25%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.70–7.64(m,1H),7.51–7.44(m,1H),7.25–7.17(m,1H),3.35–3.18(m,2H),2.87(t , J=13.8Hz, 2H), 2.29–1.99 (m, 4H).

step 3

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, to compound 322-2 (280 mg, 0.974 mmol, 1 equivalent) in heptane (3 ml) solution was added successively diboronic acid pinacol ester (338.44 mg, 1.266 mmol, 1.3 eq), 4,4'-di-tert-butyl-2,2'-bipyridine (55.0 mg, 0.194 mmol, 0.2 eq) and (1,5-cyclooctadiene) iridium(I) chloride di polymer (68.86 mg, 0.097 mmol, 0.1 equiv). The mixture was stirred at 80°C for 2 hours, and the reaction progress was monitored by liquid chromatography and thin layer chromatography. The mixture was concentrated under reduced pressure to obtain crude product. Under the condition of stirring under nitrogen protection at 0°C, acetic acid (5.0 ml) and hydrogen peroxide (30%, 2.5 ml) were slowly added to a mixed solution of the above crude product in tetrahydrofuran (2.5 ml) and water (1.25 ml). The resulting mixture was stirred at 0°C for 30 minutes, and the progress of the reaction was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, a saturated sodium bicarbonate solution was slowly added to the reaction solution to adjust the pH to 8 under stirring at 0°C. The mixture was extracted with ethyl acetate (30 mL x 3), and the organic phases were combined. The organic phase was dried over anhydrous sodium sulfate, filtered to remove the desiccant, and the filtrate was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 20% methyl tert-butyl ether/petroleum ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 322-3 (white solid , 226 mg, yield 76%). MS(ESI,m/z):286.9/288.9[MH] ^- ; ¹ H NMR(300MHz, CDCl ₃ ) δ7.21–7.18(m,1H),6.92–6.88(m,1H),3.28–3.13( m,2H), 2.93–2.79(m,2H), 2.20–1.98(m,4H).

step 4

Under the condition of stirring under nitrogen protection at zero degrees Celsius, the dichloro Chloromethyl methyl ether (75.5 mg, 0.892 mmol, 1.2 equiv) was slowly added to the solution in methane (3 mL). The mixture was reacted at 25 degrees Celsius for 2 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was over, the reaction solution was poured into ice water (20 ml) to quench the reaction, the aqueous phase was extracted with dichloromethane (25 ml x 3), and the organic phase was combined; the organic phase was dried with anhydrous sodium sulfate, filtered to remove the dryness agent, and the filtrate was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, eluting with petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 322-4 (colorless oil, 200 mg, yield 76%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.39–7.35(m,1H),7.16–7.12(m,1H),5.18(s,2H),3.50(s,3H),3.28–3.14(m,2H ), 2.94–2.79(m,2H), 2.23–1.99(m,4H).

step 5

Under the condition of nitrogen protection and stirring at zero degrees Celsius, compound 322-4 (149 mg, 0.425 mmol, 1 equivalent), bis-pinacol borate (170.35 mg, 0.637 mmol, 1.5 equivalents) and potassium acetate (131.67 mg, 1.275 mmol, 3 eq) in 1,4-dioxane (2 mL) was slowly added to [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane compound (36.43 mg, 0.043 mmol, 0.1 equiv). The mixture was reacted at 90°C for 18 hours with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was cooled to room temperature, and the mixture was concentrated under reduced pressure to obtain a crude product. The resulting crude product was purified by silica gel column chromatography, eluting with 0% → 15% methyl tert-butyl ether/petroleum ether mobile phase, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 322-5 (white solid, 135 mg, yield 79%). ¹ H NMR (300MHz, CDCl ₃ ) δ7.61–7.57(m,1H),7.24–7.20(m,1H),5.21(s,2H),3.49(s,3H),3.07–2.94(m,2H ), 2.88–2.76(m,2H), 2.19–1.90(m,4H), 1.42(s,12H).

step 6

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, compound 300-10 (180 mg, 0.279 mmol, 1 equivalent), compound 322-5 (134.09 mg, 0.335 mmol, 1.2 equivalents), 3-( tert-butyl)-4-(2,6-dimethoxyphenyl)-2,3-dihydrobenzo[D][1,3]oxophosphpentyl conjugate (19.42 mg, 0.056 mmol, 0.2 equiv), tris(dibenzylideneacetone)dipalladium (26.91 mg, 0.028 mmol, 0.1 equiv), potassium phosphate (187.14 mg, 0.837 mmol, 3 equiv), toluene (2 mL) and water (0.4 mL) . The resulting mixture was reacted at 80°C for 16 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature. Add 25 ml of water to dilute the reaction solution, then extract with dichloromethane (25 ml x 3), combine the organic phase; dry the organic phase with anhydrous sodium sulfate, filter to remove the desiccant, and concentrate the filtrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, eluted with a gradient of 0% → 10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 322-6 (white solid, 200.0 mg, Yield 86%). MS (ESI, m/z): 786.3 [M+H] ⁺ .

step 7

Compound 322-6 (200 mg) obtained in step 6 was subjected to chiral resolution by preparative liquid chromatography: chiral column CHIRALPAK IC, 2 x 25 cm, 5 μm; mobile phase A: n-hexane (10 mmol/L ammonia Methanol), mobile phase B: isopropanol; flow rate: 20 ml/min; eluted with 30% phase B in 12 minutes, detector UV 212/233 nanometers, two products were obtained. The product with shorter retention time (6.603 minutes) is compound 322-6a (white solid, 88 mg, recovery 45%), MS (ESI, m/z): 786.3[M+H] ⁺ ; longer retention time ( 8.92 minutes) was compound 322-6b (white solid, 92.8 mg, recovery 48%), MS (ESI, m/z): 786.3[M+H] ⁺ .

Step 8

Under the condition of stirring at 0 degrees Celsius, compound 322-6a (88 mg, 0.111 mmol, 1.0 equivalent), methanol (2.0 ml) and 1,4-dioxane solution of hydrochloric acid (4 mol/ ml, 2.0 ml). The mixture was reacted at 25°C for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the mixture was concentrated under reduced pressure to obtain a crude product. The obtained crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5%→95% (acetonitrile/methanol=1/1)/water (0.1% hydrochloric acid) mobile phase within 20 minutes; UV254/220 nm; Compound 322a was obtained (white solid, 60.2 mg, yield 73%). MS(ESI,m/z):642.3[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ +D ₂ O)δ7.87–7.75(m,1H),7.02–6.96(m,1H ),6.86–6.79(m,1H),5.71–5.42(m,1H),4.63–4.41(m,4H),4.22–4.12(m,2H),3.93–3.69(m,5H),3.38–3.23 (m,1H),2.88–2.73(m,2H),2.68–2.53(m,1H),2.48–2.44(m,1H),2.37–2.26(m,1H),2.24–1.91(m,11H) ,1.86–1.69(m,1H),1.12–0.97(m,1H); ¹⁹ F NMR (282MHz,DMSO-d ₆ )δ-85.85,-86.73,-87.08,-87.97,-115.25,-121.19,- 172.66.

step 9

Compound 322b (white solid, 61.4 mg, yield 76%) can also be obtained according to the method of step 8. MS(ESI,m/z):642.3[M+H] ⁺ ; ¹ H NMR(300MHz,DMSO-d ₆ )δ11.63–11.20(m,1H),10.61–9.54(m,3H),7.83( d,J＝9.9Hz,1H),7.03–6.95(m,1H),6.90–6.81(m,1H),5.70–5.46(m,1H),4.65–4.56(m,2H),4.53–4.37( m,2H),4.21–4.10(m,2H),4.03–3.91(m,1H),3.82–3.66(m,4H),3.35–3.21(m,1H),2.90–2.75(m,2H), 2.74–2.53(m,1H),2.48–2.44(m,1H),2.37–2.26(m,1H),2.23–1.92(m,11H),1.86–1.67(m,1H),1.15–0.98(m , 1H); ¹⁹ F NMR (282MHz, DMSO-d ₆ ) δ-85.87, -86.74, -87.08, -87.96, -115.24, -121.17, -172.77.

Example 28

6-(4-(1R, 5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(((2R,7aS)- 2-Fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl)pyridin-2-amine 325 ; 6(R or S)-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-difluoro-2-(( (2R, 7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5-(trifluoromethyl) Pyridin-2-amine 325a; 6(S or R)-(4-(1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-di Fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrroline-7a(5H)-yl)methoxy)quinazolin-7-yl)-4-methyl-5- (Trifluoromethyl)pyridin-2-amine 325b

The synthetic route is as follows:

step 1

Compound 325-1 was synthesized with reference to the patent (WO2022035790A1).

Add compound 325-1 (1.2 g, 1 equivalent), hexamethylditin (1.8 equivalents), [1,1'-bis(diphenylphosphine ) ferrocene] palladium dichloride tetrahydrofuran complex (0.1 equiv) and 1,4-dioxane (12 ml). The resulting mixture was reacted at 100° C. for 20 hours under nitrogen protection and stirring. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5% → 95% acetonitrile/water mobile phase (0.1% ammonium bicarbonate) within 25 minutes; detector, UV 254 /200 nm; Compound 325-2 was obtained (yellow oil, 280 mg, 18% yield). MS(ESI,m/z):577.1/579.1/581.1[M+H] ⁺ ; ¹ H NMR(400MHz,CD ₃ OD)δ7.00–6.88(m,4H),6.72–6.60(m,4H) ,6.14(s,1H),4.56(s,4H),3.57(s,6H),2.13–2.02(m,3H),0.07(s,9H); ¹⁹ F NMR(377MHz,CD ₃ OD)δ- 56.55.

step 2

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, 325-2 (340 mg, 0.49 mmol, 1.2 equivalent), 300-10 (300 mg, 0.59 mmol, 1 equivalent), tetratriphenyl Palladium phosphine (283 mg, 0.24 mmol, 0.5 eq), cuprous iodide (46.6 mg, 0.24 mmol, 0.5 eq), lithium chloride in tetrahydrofuran (2.45 ml, 1.22 mmol, 2.5 eq, 0.5 mol /L) and N,N-dimethylformamide (3 mL). The resulting mixture was reacted at 100° C. for 16 hours under nitrogen protection and stirring. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5%→95% acetonitrile/water mobile phase (0.1% ammonium bicarbonate) within 25 minutes; detector, UV254/ 220 nm; Compound 325-3 was obtained (white solid, 108 mg, 23% yield).

step 3

To a solution of 325-3 (108 mg, 0.11 mmol, 1 eq) in anisole (1.5 mL) was added trifluoroacetic acid (1.5 mL) dropwise under stirring at 0°C. The resulting mixture was reacted at 100°C for 1.5 hours with stirring. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction, the solvent was removed from the reaction solution by rotary evaporation under reduced pressure to obtain a crude product. The resulting crude product was purified by high performance liquid chromatography: chromatographic column XBridge Prep OBD C18 Column, 30x150 mm, 5 microns; mobile phase A: water (10 mmol/L ammonium bicarbonate), mobile phase B: acetonitrile; flow rate: 60 mL/min; elution with 15% → 45% phase B in 10 min; detector: 220 nm. Compound 325 was obtained (66 mg, off-white solid, yield 95%). MS(ESI,m/z):608.2[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ )δ7.68–7.46(m,1H),6.99–6.74(m,2H),6.57– 6.21(m,1H),5.43–5.11(m,1H),4.32–4.23(m,1H),4.23–4.11(m,1H),4.11–4.02(m,1H),4.02–3.91(m,1H ),3.58–3.44(m,3H),3.44–3.38(m,1H),3.15–2.95(m,3H),2.88–2.76(m,1H),2.44–2.29(m,3H),2.23–1.93 (m,3H),1.93–1.69(m,3H),1.69–1.51(m,4H); ¹⁹ F NMR(377MHz,DMSO-d ₆ )δ-53.47,-121.32,-126.79,-172.10,-172.13 .

step 4

Compound 325 (64 mg) obtained in step 3 of this example was subjected to chiral resolution by high performance liquid chromatography: chiral column CHIRALPAK IC, 2x25 cm, 5 microns; mobile phase A: n-hexane (10 mmol/L ammonia methanol ), mobile phase B: ethanol; flow rate: 20 ml/min; elute with 50% phase B in 9 minutes; detector: 232/216 nm; two products are obtained. The product with shorter retention time (4.412 minutes) was compound 325a (white solid, 15.2 mg, recovery rate 23%), compound 325a: MS (ESI, m/z): 608.3[M+H] ⁺ , ¹ H NMR ( 400MHz,DMSO-d ₆ )δ7.65–7.53(m,1H),6.86(s,2H),6.51(s,1H),5.39–5.17(m,1H),4.35–4.24(m,1H), 4.24–4.14(m,1H),4.12–4.02(m,1H),4.02–3.92(m,1H),3.60–3.47(m,3H),3.46–3.41(m,1H),3.16–3.05(m ,2H),3.05–2.95(m,1H),2.88–2.70(m,1H),2.43–2.32(m,3H),2.19–2.09(m,1H),2.09–1.91(m,2H),1.91 –1.71 (m, 3H), 1.71 – 1.57 (m, 4H), ¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ-53.47, -121.18, -126.73, -172.11; longer retention time (6.892 minutes) The product is compound 325b (white solid, 15.8 mg, recovery 24%), compound 325b: MS (ESI, m/z): 608.3[M+H] ⁺ , ¹ H NMR (400MHz, DMSO-d ₆ ) δ7. 67–7.52(m,1H),6.86(s,2H),6.51(s,1H),5.42–5.16(m,1H),4.37–4.24(m,1H),4.24–4.13(m,1H), 4.13–4.02(m,1H),4.02–3.92(m,1H),3.59–3.46(m,3H),3.46–3.42(m,1H),3.16–2.96(m,3H),2.87–2.78(m ,1H), 2.45–2.31(m,3H), 2.19–1.93(m,3H), 1.92–1.71(m,3H), 1.71–1.55(m,4H), ¹⁹ F NMR (377MHz, DMSO-d ₆ ) δ -53.47, -121.24, -126.75, -172.13.

The chiral analysis conditions of compound 325a are: chiral column: CHIRALPAK IC-3, 4.6x100 mm, 3 microns; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 ml/ minutes; isocratic elution with 50% phase B in 7 minutes. Detector UV 254 nm; retention time: 3.989 minutes; dr>40:1.

The chiral analysis conditions of compound 325b are: chiral column: CHIRALPAK IC-3, 4.6x100 mm, 3 microns; mobile phase A: n-hexane (0.1% diethylamine), mobile phase B: ethanol; flow rate: 1 ml/ minutes; isocratic elution with 50% phase B in 7 minutes. Detector UV 254 nm; retention time: 4.759 min; dr>40:1.

Example 29

4-(((2R,6R,7aS)-7a-(((4-((1R,5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-7- ((R or S)-8-ethyl-7-fluoro-3-hydroxynaphthalen-1-yl)-6,8-bisfluoroquinolin-2-yl)oxy)methyl)-6-fluorohexa Hydrogen-1H-pyrroline-2-yl)methyl)-1-imino- ^1λ6 -thiomorpholine-1-oxide trihydrochloride 29

The synthetic route is as follows:

step 1:

Under the condition of nitrogen protection and stirring at 0 degrees Celsius, the compound (2R, 7aS)-2-fluorotetrahydro-1H-pyrrolazine-7a(5H)-methanol (30 g, 179.0 mmol, 1.0 equivalent) was sequentially added to the reaction flask , imidazole (15.4 grams, 214.8 millimoles, 1.2 equivalents) and 300 milliliters of dichloromethane, then slowly add tert-butyldiphenylchlorosilane (67.3 grams, 232.6 millimoles, 1.3 equivalents) wherein, the resulting mixture was heated at 25 degrees Celsius The reaction was carried out under nitrogen protection stirring condition for 2 hours, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was completed, the reaction solution was poured into saturated sodium bicarbonate solution to quench, extracted with dichloromethane (300 ml × 3), the organic phase was combined, the organic phase was dried with anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was reduced to Concentrate under reduced pressure to obtain the crude product. The crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0%→10% methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 29-1 (colorless oil, 63 g , yield 84%). MS (ESI, m/z): 398.2[M+H] ⁺ ; ¹ H NMR (300 MHz, CDCl ₃ ) δ7.77–7.64 (m, 4H), 7.50–7.35 (m, 6H), 5.35–5.09 ( m,1H),3.49(d,J=9.6Hz,1H),3.38(d,J=9.6Hz,1H),3.27–2.99(m,3H),2.98–2.83(m,1H),2.26–2.14 (m,1H), 2.13–1.94(m,2H), 1.95–1.63(m,3H), 1.09(s,9H).

Step 2:

Under stirring conditions at 0°C, to a solution of compound 29-1 (39 g, 93.2 mmol, 1.0 eq) in carbon tetrachloride (400 ml), add ruthenium trichloride hydrate (4.42 g, 18.6 mmol, 0.2 eq) in water (400 mL) and sodium periodide (104.9 g, 465.9 mmol, 5.0 eq). The mixture was reacted at 25°C for 1 hour with stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the reaction solution was cooled to room temperature, quenched with water (500 ml), the resulting mixture was extracted with dichloromethane (500 ml × 3), the organic phases were combined, dried with anhydrous sodium sulfate, and filtered to remove the desiccant , the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→60% petroleum ether/methyl tert-butyl ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 29-2 (white solid, 19 g, 47% yield). MS (ESI, m/z): 412.2[M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ7.66–7.59 (m, 4H), 7.48–7.37 (m, 6H), 5.38–5.15 ( m,1H),4.21–4.08(m,1H),3.63–3.53(m,1H),3.49–3.39(m,1H),3.17–3.00(m,1H),2.79–2.66(m,1H), 2.44–2.34(m,1H), 2.33–2.21(m,1H), 2.21–2.10(m,1H), 2.05–1.92(m,2H), 1.04(s,9H).

Step 3:

Under the condition of nitrogen protection and stirring at minus 78 degrees Celsius, add dropwise A solution of lithium diisopropylamide in tetrahydrofuran (46.5 ml, 1 mol/L, 1.5 equivalents), and the resulting mixture was reacted at minus 78 degrees Celsius under nitrogen protection for 30 minutes with stirring. Paraformaldehyde (3.5 g, 73.860 mmol, 2.0 equivalents) was added to the reaction system under nitrogen protection stirring at -78°C, and then the mixture was slowly raised to 25°C. The mixture was reacted for 2.5 hours at 25° C. under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction was over, slowly add saturated ammonium chloride aqueous solution (500 ml) to the reaction solution at zero degrees Celsius to quench the reaction, the mixture was extracted with ethyl acetate (500 ml × 3), the organic phases were combined, and then washed with anhydrous sodium sulfate After drying, the desiccant was removed by filtration, and the solvent was removed by rotary evaporation of the filtrate under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0%→100% petroleum ether/methyl tert-butyl ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 29-3 (yellow oil, 5.5 g, 32% yield). MS (ESI, m/z): 442.2[M+H] ⁺ ; ¹ H NMR (400 MHz, CDCl ₃ ) δ7.64–7.61 (m, 4H), 7.47–7.38 (m, 6H), 5.33–5.18 ( m,1H),4.21–4.12(m,1H),3.82–3.78(m,1H),3.68–3.62(m,1H),3.59(d,J＝10.4Hz,1H),3.44(d,J＝ 10.4Hz, 1H), 3.14–2.97(m, 2H), 2.33–2.16(m, 2H), 2.06–1.94(m, 1H), 1.84–1.80(m, 1H), 1.05(s, 9H).

Step 4:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 29-3 (2.8 g, 6.02 mmol, 1.0 equivalent), allyl bromide (0.92 g, 7.22 mmol, 1.2 equivalent) and N , N-dimethylformamide (39 ml). Then the reaction system was lowered to zero degrees Celsius. Under stirring conditions of nitrogen protection at zero degrees Celsius, sodium hydride (60%, 0.28 g, 7.22 mmoles, 1.2 equivalents) was added in batches to the reaction system, and the resulting mixture was slowly raised to 25 degrees Celsius, and then stirred under nitrogen protection at 25 degrees Celsius. React for 2 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, the reaction solution was lowered to zero degrees Celsius, and saturated aqueous ammonium chloride solution (500 ml) was added to the reaction solution with stirring at zero degrees Celsius to quench the reaction. The mixture was extracted with ethyl acetate (500 ml×3), the organic phases were combined, and dried over anhydrous sodium sulfate, the desiccant was removed by filtration, and the filtrate was evaporated under reduced pressure to remove the solvent to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 40% petroleum ether/methyl tert-butyl ether, and the obtained fraction was desolventized by rotary evaporation under reduced pressure to obtain compound 29-4 (yellow oil, 1.57 g, 51% yield). MS (ESI, m/z): 482.2[M+H] ⁺ ; ¹ H NMR (300MHz, CDCl ₃ ) δ7.73–7.57(m,4H),7.55–7.35(m,6H),6.02–5.74( m,1H),5.47–5.08(m,3H),4.24–4.09(m,1H),4.06–3.95(m,2H),3.86–3.75(m,1H),3.64–3.40(m,3H), 3.25–3.00(m,2H), 2.43–2.20(m,2H), 2.12–1.90(m,2H), 1.07(s,9H).

Step 5:

Under stirring under nitrogen protection at zero degrees Celsius, to a solution of compound 29-4 (1.5 g, 3.1 mmol, 1.0 eq) in N,N-dimethylformamide (15 ml) was added in batches lithium aluminum hydride (0.18 g, 4.67 mmol, 1.5 equiv). The resulting mixture was reacted at 60° C. for 2 hours under nitrogen protection and stirring. The progress of the reaction was monitored by and thin layer chromatography. After the reaction was finished, ice water (0.2 milliliters) was added to the reaction solution to quench the reaction, then 0.2 milliliters of 20% NaOH solution was added, and finally 0.6 milliliters of water was added, and after stirring for 15 minutes, the insolubles were removed by filtration and washed with tetrahydrofuran/methanol ( 10/1) The mixed solution washed the filter cake (10 ml x 3), and the filtrate was combined to remove the solvent by rotary evaporation under reduced pressure to obtain a crude product. The obtained crude product was purified by silica gel column chromatography, and the mobile phase was eluted with a gradient of 0% → 10% dichloromethane/ammonia methanol, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 29-5 (colorless oil, 0.53 g , yield 75%). MS (ESI, m/z): 230.2 [M+H] ⁺ .

Step 6:

Under the condition of stirring under nitrogen protection at 25 degrees Celsius, triethylenediamine (39 mg, 0.33 mmol, 0.2 equivalent), compound 297-2 (1230 mg, 1.80 mmol, 1.1 equivalent), cesium carbonate ( 1130 mg, 3.3 mmol, 2.0 equiv), compound 29-5 (400 mg, 1.816 mmol, 1.0 equiv) and N,N-dimethylformamide (5 mL). The resulting mixture was reacted for 2 hours at 80°C under nitrogen protection and stirring, and the reaction process was monitored by liquid mass and thin layer chromatography. After the reaction, the crude product was purified by a reverse-phase chromatographic column (C18 column), and eluted with 5%→95% methanol/water mobile phase (0.1% ammonium bicarbonate aqueous solution) within 25 minutes; detector UV254/ 220 nm; compound 29-6 was obtained (off-white solid, 760 mg, yield 51%). MS (ESI, m/z): 836.3 [M+H] ⁺ .

Step 7:

Compound 29-6 (460 mg) obtained in step 6 of this example was subjected to chiral resolution by high performance liquid chromatography: chiral column CHIRAL ART Cellulose-SC, 2 × 25 cm, 5 microns; mobile phase A: n-hexane ( 0.5%, 2 mol/liter ammonia methanol), mobile phase B: ethanol; flow rate: 20 ml/min; elution was carried out with 20% phase B in 12 minutes, detector UV 205/226 nanometers, two products were obtained . The product with shorter retention time (6.0 minutes) is compound 29-6a (off-white solid, 170 mg, recovery rate 37%), MS (ESI, m/z): 836.4[M+H] ⁺ ; longer retention time (8.7 minutes) The product was compound 29-6b (off-white solid, 178 mg, recovery 39%), MS (ESI, m/z): 836.4[M+H] ⁺ .

Step 8:

Under the condition of nitrogen protection and stirring at 25 degrees Celsius, compound 29-6a (90 mg, 0.102 mmol, 1.0 equivalent), 1,3-dimethylbarbituric acid (33.62 mg, 0.204 mmol, 2 equivalents), tetrakis(triphenylphosphine) palladium (12.44 mg, 0.01 mmol, 0.05 equivalents) and dichloromethane (0.5 ml), the resulting mixture was reacted at 25 degrees Celsius for 48 hours, the reaction process was passed by liquid mass and thin chromatography Chromatographic monitoring. After the reaction, concentrated under reduced pressure to remove excess solvent to obtain crude product. The crude product was purified by silica gel column chromatography, and was eluted with a gradient of 0% → 8% ammonia methanol/dichloromethane mobile phase, and the obtained fraction was removed by rotary evaporation under reduced pressure to obtain compound 29-7 (yellow solid, 83 mg , yield 99%). MS (ESI, m/z): 796.3 [M+H] ⁺ .

Step 9:

To a solution of compound 29-7 (20 mg, 0.025 mmol, 1 eq) in ethyl acetate (10 mL) was added 2-iodylbenzoic acid (20 mg, 0.075 mmol, 3 eq. ), the mixture system was reacted at 80 degrees Celsius for 5 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, it was cooled to room temperature, and the reaction solution was filtered and concentrated to obtain the crude product 29-8 (white solid, 16 mg, yield 80%), which was directly used in the next step. MS (ESI, m/z): 794.4 [M+H] ⁺ .

Step 10:

Compound 29-8 (16 mg, 0.02 mmol, 1 equivalent), 1-imino-1λ ⁶ -thiomorpholine 1-oxide hydrochloride (14 mg, 0.08 mmol, 4 equivalents) and N,N-diisopropylethylamine (20 mg, 0.16 mmol, 8 equivalents) were successively dissolved in dichloromethane (12 ml), and after stirring for 15 minutes, triacetoxy Sodium borohydride (17 mg, 0.08 mmol, 4 equiv), and the resulting mixture was stirred at room temperature for 16 hours. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, the excess solvent was concentrated under reduced pressure, and the resulting mixture was separated and purified by preparative thin-layer chromatography {7M ammonia methanol: (dichloromethane: ethyl acetate = 13:3) = 1:16} to obtain compound 29-9 (Clear solid, 10 mg, 54% yield). MS (ESI, m/z): 912.4 [M+H] ⁺ .

Step 11:

To compound 29-9 (10 mg, 0.01 mmol, 1 equiv) in methanol (0.5 mL) was added dropwise a solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 7 mole /Lift). The resulting mixture was reacted at 25° C. for 2 hours with stirring. The reaction process was monitored by liquid quality. After the reaction, the solvent was removed from the reaction solution by rotary evaporation under reduced pressure to obtain a crude product. The obtained crude product was purified by a reverse phase chromatographic column (C18 column), and eluted with 10% → 50% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 25 minutes; detector, UV254/220 nm; to obtain the compound 29 (yellow solid, 6 mg, 64% yield). MS(ESI,m/z):768.3[M+H] ⁺ ; ¹ H NMR(400MHz,DMSO-d ₆ +D ₂ O)δ7.85–7.76(m,2H),7.44–7.35(m,2H ),7.06–7.02(m,1H),5.75–5.52(m,1H),4.70–4.57(m,2H),4.56–4.43(m,2H),4.26–4.16(m,2H),4.10–4.01 (m,1H),3.96–3.83(m,3H),3.83–3.72(m,5H),3.55–3.43(m,2H),3.25(s,2H),3.09–2.94(m,3H),2.95 –2.81(m,1H),2.71–2.55(m,3H),2.49–2.27(m,2H),2.08–1.87(m,5H),0.75(t,J＝7.4Hz,3H); ¹⁹ F NMR (376MHz, DMSO-d ₆ ) δ-116.24, -116.25, -119.17, -123.05, -172.98, -173.00.

Example 30

(4R or 4S)-(4-((1R, 5S)-3,8-diazabicyclo[3.2.1]octyl-3-yl)-6,8-bisfluoro-2-((( 2R, 6R, 7aS)-2-fluoro-6-((1-(hydroxymethyl)-3-azabicyclo[3.1.0]hexyl-3-yl)methyl)tetrahydro-1H-pyrroline- 7a(5H)-yl)methoxy)quinazolin-7-yl)-5-ethyl-6-fluoronaphthalene-2-ol trihydrochloride 30

The synthetic route is as follows:

step 1:

Compound 29-8 (16 mg, 0.02 mmol, 1 equivalent), (3-azabicyclo[3.1.0]hex-1-yl)methanol hydrochloride (15 mg, 0.1 Millimoles, 5 equivalents) and N,N-diisopropylethylamine (60 mg, 0.46 mmoles, 13 equivalents) were successively added in dichloromethane (12 ml), the mixture was stirred at room temperature for 10 minutes, and added to the above system Acetic acid (60 mg, 0.1 mmol, 5 eq) and sodium triacetoxyborohydride (20 mg, 0.094 mmol, 4.7 eq) were added successively, and the resulting mixture was stirred overnight at 25°C. The reaction process was monitored by liquid chromatography and thin layer chromatography. After the reaction was completed, 5 ml of saturated aqueous sodium carbonate solution was added to the reaction solution, extracted with dichloromethane (5 ml x 2), the combined organic phase was dried with anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, and the resulting crude product was prepared by preparing a thin layer Chromatographic separation and purification {7M ammonia methanol: (dichloromethane: ethyl acetate = 13:3) = 1:16} gave compound 30-1 (white solid, 14 mg, yield 78%). MS (ESI, m/z): 891.4 [M+H] ⁺ .

Step 2:

To a solution of compound 30-1 (10 mg, 0.01 mmol, 1 eq) in methanol (0.5 mL) was added dropwise a solution of hydrogen chloride in 1,4-dioxane (0.5 mL, 7 mole /Lift). The resulting mixture was reacted at 25° C. for 2 hours with stirring. The reaction process was monitored by liquid quality. After the reaction, the solvent was removed from the reaction solution by rotary evaporation under reduced pressure to obtain a crude product. The obtained crude product was purified by a reverse phase chromatographic column (C18 column), and eluted with 10% → 50% acetonitrile/water mobile phase (0.1% hydrochloric acid) within 25 minutes; detector, UV254/220 nm; to obtain the compound 30 (yellow solid, 2.9 mg, 33% yield). MS(ESI,m/z):747.3[M+H] ⁺ ; ¹ H NMR(400MHz,CD ₃ OD)δ7.89–7.80(m,1H),7.75–7.66(m,1H),7.37–7.31 (m,1H),7.32–7.23(m,1H),7.05–6.98(m,1H),5.82–5.43(m,1H),5.10–4.95(m,2H),4.83–4.71(m,2H) ,4.40–4.26(m,2H),4.26–4.17(m,1H),4.16–4.03(m,1H),4.02–3.90(m,3H),3.90–3.76(m,3H),3.77–3.69( m,1H),3.69–3.58(m,1H),3.58–3.38(m,4H),3.27–3.14(m,1H),2.95–2.83(m,1H),2.81–2.50(m,3H), 2.50–2.34(m,1H),2.34–2.07(m,5H),1.82–1.71(m,1H),1.42–1.08(m,1H),1.02–0.88(m,1H),0.87–0.75(m , 3H); ¹⁹ F NMR (376 MHz, CD ₃ OD) δ-114.77, -114.84, -120.77, -120.78, -125.16, -125.28, -172.83, -174.58.

Effect Example

1 Experiment purpose

The inhibitory ability of small molecule compounds to the binding activity of KRAS_WT and SOS1 was detected by a drug screening system based on the combination of KRAS_WT and SOS1.

2 Experimental materials and equipment

试剂Reagent	品牌brand	货号Item No.
KRAS-WT/SOS1 binding kitsKRAS-WT/SOS1 binding kits	CisbioCisbio	63ADK000CB15PEH63ADK000CB15PEH
GTPGTP	SigmaSigma	V900868V900868
耗材Consumables	品牌brand	货号Item No.
Topseal ATopseal A	PerkinElmerPerkinElmer	E5341E5341
384-Well Polypropylene microplate384-Well Polypropylene microplate	labcytelabcyte	PP-0200PP-0200
96 Well Plates96 Well Plates	NuncNunc	249944249944
384-well plates384-well plates	CorningCorning	CLS4514CLS4514
仪器instrument	品牌brand	货号Item No.
EnvisionEnvision	Perkin ElmerPerkin Elmer	21042104
CentrifugeCentrifuge	EppendorfEppendorf	5810R5810R
Multi-channel pipettesMulti-channel pipettes	Eppendorf/SartoriusEppendorf/Sartorius	//
EchoEcho	LabcyteLabcyte	//

3 Experimental methods

3.1 Experimental steps:

a) BI-2852 is used as a positive control, and its stock solution is the first point of dilution, 3-fold dilution, and 10+0 points of dilution. Similarly, the first point of dilution of the compound to be tested is also its stock solution, 3-fold dilution, 11+0 points of dilution. Use Echo to transfer 0.2 μL of gradiently diluted compound solution to a 384-well plate, and make 2 duplicate wells for each compound, and the final concentration of DMSO is 1%. 1000rpm/min, centrifuge for 1min. The final concentrations of positive controls were 100, 33.33, 11.11, 3.70, 1.23, 0.412, 0.137, 0.046, 0.015, 0.005, and 0 μM. The final concentrations of the compounds to be tested were 200, 66.67, 22.22, 7.41, 2.47, 0.27, 0.091, 0.03, 0.0152, 0.01, and 0 μM.

b) Prepare the KRAS_WT in the kit with the final concentration of 10μM GTP in the diluent, transfer 5μL to the 384 reaction plate, centrifuge at 1000rpm/min for 1min,

c) Transfer 5 μL of SOS1 mixture to a 384 reaction plate, centrifuge at 1000 rpm/min for 1 min, and incubate at 25°C for 15 min.

d) Transfer 10 μL of the detection mixture to a 384 reaction plate, centrifuge at 1000 rpm/min for 1 min, and incubate overnight at 4°C.

e) Use an Envision multifunctional plate reader to read the excitation wavelength at 665nm and the emission wavelength at 615nm. The 665/615 Ratio signal intensity is used to characterize the activity of the enzyme.

f) Analysis of raw data.

3.2 Experimental data processing method:

Compound _IC50 was fitted by Graphpad Prism 8 nonlinear regression equation:

Negative control: DMSO

Positive control: 100μM BI-2852

The _IC50 (half maximal inhibitory concentration) of the compound was obtained using the following non-linear fitting formula:

Y＝Bottom+(Top-Bottom)/(1+10^((LogIC ₅₀ -X)*HillSlope))

X: log value of compound concentration

Y:665/615 Ratio

table 3

Claims

A compound as shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotope compound:

Among them, R 1 is C 6 -C 18 aryl, "C 6 -C 18 aryl substituted by 1 or more R 1-1 ", 5-10 heteroaryl or "by 1 or more R 1-2 substituted 5-10 heteroaryl", said 5-10 heteroaryl and said "5-10 heteroaryl substituted by 1 or more R 1-2 " heteroatoms independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1 is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1 or more R 1-1-1 , C 2 -C 6 alkynyl,
C 3 -C 6 cycloalkyl or "3-membered or 4-10-membered cycloalkyl substituted by 1 or more R 1-1-2 ", or any two adjacent R 1-1 are connected to it The carbon atoms together form a 4-10-membered cycloalkyl group, "4-10-membered cycloalkyl group substituted by 1 or more R 1-1-3 ", 4-10-membered heterocycloalkyl group, "by 1 or more R 1-1-4 substituted 4-10 membered heterocycloalkyl", 5-10 heteroaryl and "5-10 heteroaryl substituted by 1 or more R 1-1-5 The heteroatoms in the "group" are independently one or more of N, O or S; the 4-10 membered heterocycloalkyl and "4 substituted by 1 or more R 1-1-4 The heteroatoms in -10-membered heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1-1 is independently halogen, deuterium, hydroxyl or -OC 1 -C 6 alkyl;

R 1-1-2a and R 1-1-2b are independently C 1 -C 6 alkyl;

R 1-1-2 are independently halogen or hydroxyl;

R 1-1-3 is independently halogen or C 1 -C 6 alkyl; R 1-1-4 is independently halogen or C 1 -C 6 alkyl;

R 1-2 is independently amino, C 3 -C 6 cycloalkyl, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by 1 or more halogens;

R 2 is H or halogen;

Y is -OR 3 , C 1 -C 6 alkyl substituted by 1 or more Y 1-1 , C 2 -C 6 alkenyl substituted by 1 or more Y 1-2 , substituted by 1 or C 2 -C 6 alkynyl substituted by multiple Y 1-3 , C 3 -C 6 cycloalkyl substituted by one or more Y 1-4 or -N=S(O)Y 1-5 Y 1 -6 ;

R 3 is C 1 -C 6 alkyl substituted by 1 or more R 3-1 ;

R 3-1 is defined as follows:

When R 1 is C 6 -C 18 aryl or "C 6 -C 18 aryl substituted by 1 or more R 1-1 ", R 3-1 is defined as case 1 or case 2:

Scenario 1:

R 3-1 is independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " or deuterium; and the number of R 3-1 is at least 2, wherein one R 3-1 is -OC 1 -C 6 alkyl, and the other R 3-1 is 4-10 membered heterocycloalkyl or replaced by one Or a 4-10 membered heterocycloalkyl group substituted by multiple R 3-1-1 ;

The heteroatoms in the 4-10 membered heterocycloalkyl and the "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " are independently N, O or One or more of S, the number of heteroatoms is 1-3;

R 3-1-1 is independently -OC 1 -C 6 alkyl;

Scenario 2:

R 3-1 is independently deuterium, hydroxyl, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " or "substituted by 1 or more R 3- 1- 3- substituted 8-membered heterocycloalkyl";

And at least one R 3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R 3-1-2 " or "substituted by one or more R 3-1-3 8-membered heterocycloalkyl";

When at least one of R 3-1 is a 5-6 membered monocyclic heterocycloalkyl group substituted by 1 or more R 3-1-2 , at least one R 3-1-2 and said "is 1 or more R 3-1-2 substituted 5-6 membered monocyclic heterocycloalkyl "heteroatoms of the 5-6 membered monocyclic heterocycloalkyl are connected;

The "5-6-membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " and the "8-membered substituted by 1 or more R 3-1-3 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-2 and R 3-1-3 are independently 3-6 membered heterocycloalkyl, C 1 -C 6 alkyl, C substituted by 1 or more R 3-1-1-1 1 -C 6 alkyl, -OC 1 -C 6 alkyl, halogen, deuterium or 3-6 membered cycloalkyl, or any two R 3-1-3 connected to the same atom The atoms together form a 3-10 membered cycloalkyl group or a 4-10 membered heterocycloalkyl group, and the heteroatoms of the 4-10 membered heterocycloalkyl group are independently one or more of N, O or S species, the number of heteroatoms is 1-3;

The heteroatoms in the 3-6 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1 is independently 3-6 membered cycloalkyl, halogen, 3-8 membered heterocycloalkyl or 3-substituted by one or more R 3-1-1-1-1 8-membered heterocycloalkyl; heteroatoms in the 3-8-membered heterocycloalkyl and 3-8-membered heterocycloalkyl substituted by one or more R 3-1-1-1-1 independently one or more of P, N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1-1 is independently oxo (=O), =NH, hydroxyl, C 1 -C 6 alkyl or replaced by 1 or more R 3-1-1-1-1- 1 substituted C 1 -C 6 alkyl;

R 3-1-1-1-1-1 is independently hydroxyl;

When R 1 is 5-10 heteroaryl or "5-10 heteroaryl substituted by 1 or more R 1-2 ", R 3-1 is independently 4-10 membered heterocycloalkyl or " 4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-4 "; said 5-10 heteroaryl and "5-10 substituted by 1 or more R 1-2 The heteroatoms in "heteroaryl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-4 are independently halogen;

Y 1-1 , Y 1-2 , Y 1-3 and Y 1-4 are independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "substituted by 1 or more halogens 4-10 membered heterocycloalkyl", hydroxyl, halogen or deuterium; the heteroatoms in the 4-10 membered heterocycloalkyl substituted by 1 or more halogens are independently N, O or S One or more, the number of heteroatoms is 1-3;

Y 1-5 and Y 1-6 are independently C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1 or more Y 1-5-1 (X2 compound) or "by 1 or multiple halogen substituted 4-10 membered heterocycloalkyl”; the heteroatoms in the 4-10 membered heterocycloalkyl substituted by one or more halogens are independently N, O or S One or more, the number of heteroatoms is 1-3;

Y 1-5-1 is a 4-10 membered heterocycloalkyl group substituted by one or more halogens, and the heteroatoms in the 4-10 membered heterocycloalkyl group substituted by one or more halogens are independently Ground is one or more of N, O or S, and the number of heteroatoms is 1-3

R4 is a bridged ring heterocycloalkyl group with 7-12 members, the heteroatoms in the bridged ring heterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1 -3;

R 4 is a 7-12-membered bridged ring heterocycloalkyl or "7-12-membered bridged ring heterocycloalkyl substituted by 1 or more R 4-1 ", the 7-12-membered bridge The heteroatoms in the cycloheterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 4-1 is C 1 -C 6 alkyl;

A is CR 5 or N;

R 5 is H, C 1 -C 6 alkyl, cyano, halogen or C 1 -C 6 alkyl substituted by one or more halogens;

Described compound as shown in formula I is not following compound:
The compound shown in formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that the compound shown in formula I satisfies one or more of the following conditions:

(1) In R 1 , the C 6 -C 18 aryl group and the C 6 -C 18 aryl group in the "C 6 -C 18 aryl group substituted by 1 or more R 1-1 " The radicals are independently C 6 -C 14 aryl, such as phenyl or naphthyl;

(2) In R 1-1 , said halogen is independently F, Cl, Br or I, such as F;

(3) In R 1-1 , the C 1 -C 6 alkyl and C 1 in "the C 1 -C 6 alkyl substituted by 1 or more R 1-1-1 " -C alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as ethyl;

(4) In R 1-1 , the C 2 -C 6 alkynyl is C 2 -C 4 alkynyl, such as ethynyl;

(5) In R 1-1 , the C 3 -C 6 cycloalkyl is cyclopropane, cyclobutane, cyclopentane or cyclohexane, such as cyclopropane or cyclobutane;

(6) In R 1-1 , said any adjacent two R 1-1 together with the carbon atoms connected to it form a 4-10 membered cycloalkyl group and said "one or more R 1 -1-3 substituted 4-10-membered cycloalkyl" in which the 4-10-membered cycloalkyl group is independently an 8-membered spirocycloalkyl group, such as spiro[3,4]octyl;

(7) R 1-1-1 , said halogen is independently F, Cl, Br or I, such as F;

(8) In R 1-1-1 , the -OC 1 -C 6 alkyl is independently methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butyl Oxy, isobutoxy or tert-butoxy, such as methoxy;

(9) Among R 1-1-2a , R 1-1-2b and R 1-1-3 , the C 1 -C 6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl , n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl;

(10) In R 1-10.1-2 and R 1-1-3 , the halogen is independently F, Cl, Br or I, such as F;

(11) In R 1-1-3 , the C 1 -C 6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl or ethyl;

(12) In R 1 , the 5-10 heteroaryl group or the 5-10 heteroaryl group in the "5-10 heteroaryl group substituted by 1 or more R 1-2 " is independently 5 or 6-membered heteroaryl;

(13) In R 1 , the heteroatoms in the 5-10 heteroaryl group or "5-10 heteroaryl group substituted by 1 or more R 1-2 " are independently N, and the number is 1 (13) In R 1-2 , the C 1 -C 6 alkyl in the C 1 -C 6 alkyl and the C 1 -C 6 alkyl substituted by 1 or more halogens are independently Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl;

(14) In R 1-2 , the halogen in the C 1 -C 6 alkyl substituted by 1 or more halogens is independently F, Cl, Br or I, such as F;

(15) In R 1-2 , the C 3 -C 6 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl;

(16) In R 2 , the halogen is F, Cl, Br or I, such as F;

(17) In R 3 , the C 1 -C 6 alkyl in the C 1 -C 6 alkyl substituted by 1 or more R 3-1 is methyl, ethyl, n-propyl, iso Propyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl or n-propyl;

(18) In R 3-1 and R 3-1-1 , the -OC 1 -C 6 alkyl is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy , sec-butoxy, isobutoxy or tert-butoxy, such as methoxy;

(19) In R 3-1 in case 1, the 4-10 membered heterocycloalkyl group and the "4-10 membered heterocycloalkyl group substituted by 1 or more R 3-1-1 " The heterocycloalkyl for is independently bicyclic heterocycloalkyl;

(20) In R 3-1 , the 4-10 membered heterocycloalkyl and 4-10 in the "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " The membered heterocycloalkyl group is independently an 8-membered heterocycloalkyl group, and can also be a bicyclo[3.2.1]octaneheterocycloalkyl group;

(21) In R 3-1 , the 4-10 membered heterocycloalkyl group and 4-10 in the "4-10 membered heterocycloalkyl group substituted by 1 or more R 3-1-1 " The heteroatoms in the membered heterocycloalkyl are independently N and/or O, and the number of heteroatoms is 1 or 2;

(22) In R 3-1 , the heteroatoms in the 5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 are independently N and/or O, hetero The number of atoms is 1 or 2;

(23) In R 3-1 , the 5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 is tetrahydropyrrolyl or morpholinyl;

(24) In R 3-1 , the 8-membered heterocycloalkyl substituted by 1 or more R 3-1-3 is bicyclo[3.2.1]octacycloalkyl or bicyclo [3.3.0] octaheterocycloalkyl;

(25) In R 3-1 , the heteroatom in the 8-membered heterocycloalkyl substituted by one or more R 3-1-3 is N, and the number is 1;

(26) In R 3-1-2 and R 3-1-3 , the 3-6 membered heterocycloalkyl is a 4 membered heterocycloalkyl;

(27) In R 3-1-2 and R 3-1-3 , the heteroatom in the 3-6 membered heterocycloalkyl group is O, and the number is 1;

(28) Among R 3-1-2 and R 3-1-3 , the C 1 -C 6 alkyl, "the C substituted by one or more R 3-1-1-1 The C 1 -C 6 alkyl in " 1 -C 6 alkyl" and the C 1 -C 6 alkyl in the -OC 1 -C 6 alkyl are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl or isopropyl;

(29) In R 3-1-2 and R 3-1-3 , the halogen is F, Cl, Br or I, such as F;

(30) In R 3-1-2 and R 3-1-3 , the C 3 - 6 cycloalkyl is independently cyclopropyl, cyclobutanyl, cyclopentyl or cyclobutanyl, for example Cyclopropanyl;

(31) Among R 3-1-2 and R 3-1-3 , any two adjacent R 3-1-3 and the carbon atoms connected together form a 3-10 membered cycloalkyl group as a ring Propyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl;

(32) In R 3-1-2 and R 3-1-3 , any two R 3-1-3 connected to the same atom form a 3-10-membered ring together with the atoms connected to it Alkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, for example cyclopropyl or cyclobutyl;

(33) Among R 3-1-2 and R 3-1-3 , any two R 3-1-3 connected to the same atom form a 4-10-membered hetero Cycloalkyl is 4-6 membered heterocycloalkyl;

(34) In R 3-1-2 and R 3-1-3 , any two R 3-1-3 connected to the same atom and the atom connected to it form a 4-10 membered heterocycle The heteroatoms in the alkyl group are independently N and/or O, and the number of heteroatoms is 1 or 2

(35) In R 3-1-1-1 , the 3-6 membered cycloalkyl group is cyclopropane, cyclobutane, cyclopentane or cyclohexane, such as cyclopropane;

(36) In R 3-1-1-1 , said halogen is independently F, Cl, Br or I, such as F;

(37) In Y, the C 1 -C 6 alkyl in the C 1 -C 6 alkyl substituted by one or more Y 1-1 is methyl, ethyl, n-propyl, isopropyl butyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as ethyl;

(38) In Y, the C 2 -C 6 alkenyl in the C 2 -C 6 alkenyl substituted by 1 or more Y 1-2 is C 2 -C 4 alkenyl, such as vinyl;

(39) In Y, the C 2 -C 6 alkynyl in the C 2 -C 6 alkynyl substituted by one or more Y 1-3 is C 2 -C 4 alkynyl, such as ethynyl ;

(40) In Y, the C 3 -C 6 cycloalkyl in the C 3 -C 6 cycloalkyl substituted by 1 or more Y 1-4 is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, such as cyclopropyl;

(41) Among Y 1-1 , Y 1-2 , Y 1-3 and Y 1-4 , the 4-10 membered heterocycloalkyl group and the "one or more Y 1-1 -1- substituted 4-10-membered heterocycloalkyl" in which the 4-10-membered heterocycloalkyl is independently an 8-membered heterocycloalkyl, and can also be a bicyclic [3.3.0] octaheterocycloalkyl;

(42) In Y 1-1 , Y 1-2 , Y 1-3 and Y 1-4 , the 4-10 membered heterocycloalkyl group and the "one or more Y 1-1 The heteroatom in the -1 substituted 4-10 membered heterocycloalkyl" is N, and the number is 1;

(43) In Y 1-1 , Y 1-2 , Y 1-3 , Y 1-4 and Y 1-1-1 , the C 1 -C 6 alkyl and the -OC 1 -C The C 1 -C 6 alkyl groups in the 6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

(44) In Y 1-1-1 , the halogen is F, Cl, Br or I, such as Cl or F;

(45) In Y 1-5 and Y 1-6 , the C 1 -C 6 alkane is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, such as methyl;

(46) In Y 1-5 and Y 1-6 , the 4-10 membered heterocycloalkyl group substituted by one or more halogens is an 8-membered heterocycloalkyl group, the number of heteroatoms is N, and the number is 1. It can also be bicyclo[3.3.0]octaneheterocycloalkyl;

(47) In Y 1-5 and Y 1-6 , the heteroatom in the 4-10 membered heterocycloalkyl substituted by 1 or more halogens is N, and the number is 1;

(48) In R 4 , the 7-12 membered bridged ring heterocycloalkyl and the said "7-12 membered bridged ring heterocycloalkyl substituted by 1 or more R 4-1 " The 7-12-membered bridged ring heterocycloalkyl group is independently an 8-membered bridged ring heterocycloalkyl group, the heteroatom is N, the number is 2, and it can also be a bicyclo[3.2.1]octyl group, for example

(49) Among R 4-1 and R 5 , the C 1 -C 6 alkyl groups are independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl;

(50) In R 5 , the halogen is F, Cl, Br or I, such as F;

(51) In R 3-1-1-1 , the 3-8 membered heterocycloalkyl and the 3-8 membered substituted by one or more R 3-1-1-1-1 The 3-8-membered heterocycloalkyl in the heterocycloalkyl is independently a 5-6-membered monocyclic heterocycloalkyl or cyclopropyl and a 5-membered heterocycloalkyl, and the heteroatoms are N and/or S , the number is 1 or 2, for example

(52) In R 3-1-1-1-1 , the C 1 -C 6 alkyl and C 1 -C substituted by one or more R 3-1-1-1-1-1 C 1 -C 6 alkyl in 6 alkyl is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl or tert-butyl, for example methyl.
The compound shown in formula I as claimed in claim 2, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that the compound shown in formula I satisfies one or more of the following conditions:

(1) In R 1-1 , the C 1 -C 6 alkyl substituted by one or more R 1-1-1 is

(2) In R 1-1 , the 3-membered cycloalkyl group substituted by 1 or more R 1-1-2 is

(3) In R 1-1 , any two adjacent R 1-1 and the carbon atoms connected together form a 4-10 membered cycloalkane substituted by one or more R 1-1-3 The 4-10 membered cycloalkyl group substituted by 1 or more R 1-1-3 is

(4) In R 1-2 , the C 1 -C 6 alkyl substituted by one or more halogens is trifluoromethyl;

(5) In R 3-1 , the 4-10 membered heterocycloalkyl and 4-10 in the "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " Membered heterocycloalkyl is independently

(6) In R 3-1-2 and R 3-1-3 , the 3-6 membered heterocycloalkyl is oxetane, for example

(7) Among R 3-1-2 and R 3-1-3 , the C 1 -C 6 alkyl substituted by one or more R 3-1-1-1 is

(8) In Y, the C 1 -C 6 alkyl substituted by one or more Y 1-1 is

(9) In Y, the C 2 -C 6 alkenyl substituted by one or more Y 1-2 is

(10) In Y, the C 2 -C 6 alkynyl substituted by one or more Y 1-3 is

(11) In Y, the C 3 -C 6 cycloalkyl group substituted by one or more Y 1-4 is

(12) In Y 1-5 and Y 1-6 , the 4-10 membered heterocycloalkyl group substituted by 1 or more halogens is

(13) In R 4 , the "7-12 membered bridged ring heterocycloalkyl substituted by 1 or more R 4-1 " is

(14) In R 5 , the C 1 -C 6 alkyl substituted by one or more halogens is difluoromethyl.
The compound shown in formula I as claimed in claim 3, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that the compound shown in formula I satisfies one or more of the following conditions:

(1) In R 1 , the C 6 -C 18 aryl group substituted by one or more R 1-1 is

For example

(2) In R 1 , the 5-10 membered heteroaryl group substituted by 1 or more R 1-2 is

For example

(3) In R 3-1 , the 4-10 membered heterocycloalkyl group substituted by 1 or more R 3-1-1 is

(4) In R 3-1 , the 5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 is

(5) In R 3-1 , the 8-membered heterocycloalkyl group substituted by one or more R 3-1-3 is
The compound shown in formula I as claimed in claim 4, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that, in R 3 , the C 1 -C 6 alkyl substituted by one or more R 3-1 is
The compound shown in formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that, in the compound shown in formula I, R and Y are defined as follows:

R1 is

and, Y is

Alternatively, in the compound shown in formula I, R 1 , 4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 , 1 or more R 3-1- 2- substituted 5-6 membered monocyclic heterocycloalkyl and 8-membered heterocycloalkyl substituted by 1 or more R 3-1-3 are defined as follows;

R1 is

The 4-10 membered heterocycloalkyl group substituted by 1 or more R 3-1-1 is

The 5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 is

And, the 8-membered heterocycloalkyl group substituted by 1 or more R 3-1-3 is
The compound shown in formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that the compound shown in formula I is scheme 1, 2, 3 or 4:

Scheme 1: A compound represented by formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotopic compound :

Among them, R 1 is C 6 -C 18 aryl, "C 6 -C 18 aryl substituted by 1 or more R 1-1 ", 5-10 heteroaryl or "by 1 or more R 1-2 substituted 5-10 heteroaryl", said 5-10 heteroaryl and said "5-10 heteroaryl substituted by 1 or more R 1-2 " heteroatoms independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1 is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1 or more R 1-1-1 , C 2 -C 6 alkynyl,
C 3 -C 6 cycloalkyl or "4-10-membered or 3-membered cycloalkyl substituted by 1 or more R 1-1-2 ", or any adjacent two R 1-1 with The connected carbon atoms together form a 4-10-membered cycloalkyl group, "4-10-membered cycloalkyl group substituted by 1 or more R 1-1-3 ", 4-10-membered heterocycloalkyl group, " 4-10 membered heterocycloalkyl substituted by 1 or more R 1-1-4 ", 5-10 heteroaryl and "5-10 heterocycloalkyl substituted by 1 or more R 1-1-5 The heteroatoms in "aryl" are independently one or more of N, O or S; the 4-10 membered heterocycloalkyl and "substituted by 1 or more R 1-1-4 The heteroatoms in the "4-10 membered heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1-1 is independently halogen, deuterium, hydroxyl or -OC 1 -C 6 alkyl;

R 1-1-2a , R 1-1-2b and R 1-1-3 are independently C 1 -C 6 alkyl;

R 1-1-2 are independently halogen or hydroxyl;

R 1-1-3 is independently halogen or C 1 -C 6 alkyl; R 1-1-4 is independently halogen or C 1 -C 6 alkyl;

R 1-2 is independently amino, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens;

R 2 is H or halogen;

Y is -OR 3 , C 1 -C 6 alkyl substituted by 1 or more Y 1-1 , C 2 -C 6 alkenyl substituted by 1 or more Y 1-2 , substituted by 1 or C 2 -C 6 alkynyl substituted by multiple Y 1-3 , C 3 -C 6 cycloalkyl substituted by one or more Y 1-4 or -N=S(O)Y 1-5 Y 1 -6 ;

R 3 is C 1 -C 6 alkyl substituted by 1 or more R 3-1 ;

R 3-1 is defined as follows:

When R 1 is C 6 -C 18 aryl or "C 6 -C 18 aryl substituted by 1 or more R 1-1 ", R 3-1 is defined as case 1 or case 2:

Scenario 1:

R 3-1 is independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " or deuterium; and the number of R 3-1 is at least 2, wherein one R 3-1 is -OC 1 -C 6 alkyl, and the other R 3-1 is 4-10 membered heterocycloalkyl or replaced by one Or a 4-10 membered heterocycloalkyl group substituted by multiple R 3-1-1 ;

The heteroatoms in the 4-10 membered heterocycloalkyl and the "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " are independently N, O or One or more of S, the number of heteroatoms is 1-3;

R 3-1-1 is independently -OC 1 -C 6 alkyl;

Scenario 2:

R 3-1 is independently deuterium, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " or "substituted by 1 or more R 3-1-3 8-membered heterocycloalkyl";

And at least one R 3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R 3-1-2 " or "substituted by one or more R 3-1-3 8-membered heterocycloalkyl";

When at least one of R 3-1 is a 5-6 membered monocyclic heterocycloalkyl group substituted by 1 or more R 3-1-2 , at least one R 3-1-2 and said "is 1 or more R 3-1-2 substituted 5-6 membered monocyclic heterocycloalkyl "heteroatoms of the 5-6 membered monocyclic heterocycloalkyl are connected;

The "5-6-membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " and the "8-membered substituted by 1 or more R 3-1-3 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-2 and R 3-1-3 are independently 3-6 membered heterocycloalkyl, C 1 -C 6 alkyl, C substituted by 1 or more R 3-1-1-1 1 -C 6 alkyl, -OC 1 -C 6 alkyl, halogen, deuterium or 3-6 membered cycloalkyl;

The heteroatoms in the 3-6 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1 is independently 3-6 membered cycloalkyl, halogen, 3-8 membered heterocycloalkyl or 3-substituted by one or more R 3-1-1-1-1 8-membered heterocycloalkyl; heteroatoms in the 3-8-membered heterocycloalkyl and 3-8-membered heterocycloalkyl substituted by one or more R 3-1-1-1-1 independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1-1 is independently oxo (=O), =NH, C 1 -C 6 alkyl or substituted by 1 or more R 3-1-1-1-1-1 C 1 -C 6 alkyl;

R 3-1-1-1-1-1 is independently hydroxyl;

When R 1 is 5-10 heteroaryl or "5-10 heteroaryl substituted by 1 or more R 1-2 ", R 3-1 is independently 4-10 membered heterocycloalkyl or " 4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-4 "; said 5-10 heteroaryl and "5-10 substituted by 1 or more R 1-2 The heteroatoms in "heteroaryl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-4 are independently halogen;

Y 1-1 , Y 1-2 , Y 1-3 and Y 1-4 are independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "substituted by 1 or more halogens 4-10 membered heterocycloalkyl", hydroxyl or deuterium; the heteroatom in the 4-10 membered heterocycloalkyl substituted by 1 or more halogens is independently one of N, O or S or more, the number of heteroatoms is 1-3;

Y 1-5 and Y 1-6 are independently C 1 -C 6 alkyl or "4-10 membered heterocycloalkyl substituted by 1 or more halogens"; said 1 or more halogens The heteroatoms in the substituted 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R4 is a bridged ring heterocycloalkyl group with 7-12 members, the heteroatoms in the bridged ring heterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1 -3;

R 4 is a 7-12-membered bridged ring heterocycloalkyl or "7-12-membered bridged ring heterocycloalkyl substituted by 1 or more R 4-1 ", the 7-12-membered bridge The heteroatoms in the cycloheterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 4-1 is C 1 -C 6 alkyl;

A is CR 5 or N;

R 5 is H, C 1 -C 6 alkyl, cyano, halogen or C 1 -C 6 alkyl substituted by one or more halogens;

Scenario 2:

The compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotope compound:

Wherein, R 1 is C 6 -C 18 aryl, "C 6 -C 18 aryl substituted by 1 or more R 1-1 " or 5-10 heteroaryl, said 5-10 heteroaryl The heteroatoms in the group are independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1 is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1 or more R 1-1-1 , C 2 -C 6 alkynyl,
C 3 -C 6 cycloalkyl or "4-10 membered cycloalkyl substituted by 1 or more R 1-1-2 ", or any two adjacent carbon atoms connected by R 1-1 together form a 4-10 membered cycloalkyl group or "4-10 membered cycloalkyl group substituted by 1 or more R 1-1-3 ";

R 1-1-1 is independently halogen or deuterium;

R 1-1-2a , R 1-1-2b and R 1-1-3 are independently C 1 -C 6 alkyl;

R 1-1-2 are independently halogen or hydroxyl;

R 1-1-3 are independently halogen or C 1 -C 6 alkyl;

R 2 is H or halogen;

Y is -OR 3 , C 1 -C 6 alkyl substituted by 1 or more Y 1-1 , C 2 -C 6 alkenyl substituted by 1 or more Y 1-2 , substituted by 1 or C 2 -C 6 alkynyl substituted by multiple Y 1-3 , C 3 -C 6 cycloalkyl substituted by one or more Y 1-4 or -N=S(O)Y 1-5 Y 1 -6 ;

R 3 is C 1 -C 6 alkyl substituted by 1 or more R 3-1 ;

R 3-1 is defined as Case 1 or Case 2:

Scenario 1:

R 3-1 is independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " or deuterium; and the number of R 3-1 is at least 2, wherein one R 3-1 is -OC 1 -C 6 alkyl, and the other R 3-1 is 4-10 membered heterocycloalkyl or replaced by one Or a 4-10 membered heterocycloalkyl group substituted by multiple R 3-1-1 ;

The heteroatoms in the 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1 is independently -OC 1 -C 6 alkyl;

Scenario 2:

R 3-1 is independently deuterium, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " or "substituted by 1 or more R 3-1-3 8-membered heterocycloalkyl";

And at least one R 3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R 3-1-2 " or "substituted by one or more R 3-1-3 8-membered heterocycloalkyl", at least 1 R 3-1-2 and said "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " The heteroatom connection of 5-6 membered monocyclic heterocycloalkyl;

The "5-6-membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " and the "8-membered substituted by 1 or more R 3-1-3 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-2 and R 3-1-3 are independently 3-6 membered heterocycloalkyl, C 1 -C 6 alkyl, C substituted by 1 or more R 3-1-1-1 1 -C 6 alkyl, -OC 1 -C 6 alkyl, halogen, deuterium or 3-6 membered cycloalkyl;

The heteroatoms in the 3-6 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1 is independently 3-6 membered cycloalkyl or halogen;

Y 1-1 , Y 1-2 , Y 1-3 and Y 1-4 are independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "substituted by 1 or more halogens 4-10 membered heterocycloalkyl", hydroxyl or deuterium; the heteroatom in the 4-10 membered heterocycloalkyl substituted by 1 or more halogens is independently one of N, O or S or more, the number of heteroatoms is 1-3;

Y 1-5 and Y 1-6 are independently C 1 -C 6 alkyl or "4-10 membered heterocycloalkyl substituted by 1 or more halogens"; said 1 or more halogens The heteroatoms in the substituted 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R4 is a bridged ring heterocycloalkyl group with 7-12 members, the heteroatoms in the bridged ring heterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1 -3;

R 4 is a 7-12-membered bridged ring heterocycloalkyl or "7-12-membered bridged ring heterocycloalkyl substituted by 1 or more R 4-1 ", the 7-12-membered bridge The heteroatoms in the cycloheterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 4-1 is C 1 -C 6 alkyl;

A is CR 5 or N;

R 5 is H, C 1 -C 6 alkyl, cyano, halogen or C 1 -C 6 alkyl substituted by one or more halogens;

Option 3:

Described compound shown in formula I is the compound shown in formula Ia:

Wherein, R 1 is C 6 -C 18 aryl, "C 6 -C 18 aryl substituted by 1 or more R 1-1 " or 5-10 heteroaryl, said 5-10 heteroaryl The heteroatoms in the group are independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1 is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1 or more R 1-1-1 , C 2 -C 6 alkynyl,
Or C 3 -C 6 cycloalkyl, or any two adjacent R 1-1 together with the carbon atom to which they are connected form a 4-10 membered cycloalkyl;

R 1-1-1 is independently halogen or deuterium;

R 1-1-2a , R 1-1-2b and R 1-1-3 are independently C 1 -C 6 alkyl;

R 2 is H or halogen;

R 3 is C 1 -C 6 alkyl substituted by 1 or more R 3-1 ;

R 3-1 is defined as Case 1 or Case 2:

Scenario 1:

R 3-1 is independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " or deuterium; and the number of R 3-1 is at least 2, wherein one R 3-1 is -OC 1 -C 6 alkyl, and the other R 3-1 is 4-10 membered heterocycloalkyl or replaced by one Or a 4-10 membered heterocycloalkyl group substituted by multiple R 3-1-1 ;

The heteroatoms in the 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1 is independently -OC 1 -C 6 alkyl;

Scenario 2:

R 3-1 is independently deuterium, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " or "substituted by 1 or more R 3-1-3 8-membered heterocycloalkyl";

And at least one R 3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R 3-1-2 " or "substituted by one or more R 3-1-3 8-membered heterocycloalkyl", at least 1 R 3-1-2 and said "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " The heteroatom connection of 5-6 membered monocyclic heterocycloalkyl;

The "5-6-membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " and the "8-membered substituted by 1 or more R 3-1-3 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-2 and R 3-1-3 are independently 3-6 membered heterocycloalkyl, C 1 -C 6 alkyl, C substituted by 1 or more R 3-1-1-1 1 -C 6 alkyl, -OC 1 -C 6 alkyl, halogen or deuterium;

The heteroatoms in the 3-6 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1 is independently a 3-6 membered cycloalkyl group;

R 4 is a 7-12-membered bridged ring heterocycloalkyl or "7-12-membered bridged ring heterocycloalkyl substituted by 1 or more R 4-1 ", the 7-12-membered bridge The heteroatoms in the cycloheterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 4-1 is C 1 -C 6 alkyl;

A is CR 5 or N; R 5 is H, C 1 -C 6 alkyl, cyano or halogen;

Option 4:

Described compound shown in formula I is the compound shown in formula Ia:

Wherein, R 1 is C 6 -C 18 aryl, "C 6 -C 18 aryl substituted by 1 or more R 1-1 " or 5-10 heteroaryl, said 5-10 heteroaryl The heteroatoms in the group are independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1 is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1 or more R 1-1-1 , C 2 -C 6 alkynyl,
Or C 3 -C 6 cycloalkyl, or any two adjacent R 1-1 together with the carbon atom to which they are connected form a 4-10 membered cycloalkyl;

R 1-1-1 is independently halogen or deuterium;

R 1-1-2a , R 1-1-2b and R 1-1-3 are independently C 1 -C 6 alkyl;

R 2 is H or halogen;

R 3 is C 1 -C 6 alkyl substituted by 1 or more R 3-1 ;

R 3-1 is defined as Case 1 or Case 2:

Scenario 1:

R 3-1 is independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " or deuterium; and the number of R 3-1 is at least 2, wherein one R 3-1 is -OC 1 -C 6 alkyl, and the other R 3-1 is 4-10 membered heterocycloalkyl or replaced by one Or a 4-10 membered heterocycloalkyl group substituted by multiple R 3-1-1 ;

The heteroatoms in the 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1 is independently -OC 1 -C 6 alkyl;

Scenario 2:

R 3-1 is independently deuterium, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " or "substituted by 1 or more R 3-1-3 8-membered heterocycloalkyl";

And at least one R 3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R 3-1-2 " or "substituted by one or more R 3-1-3 8-membered heterocycloalkyl", at least 1 R 3-1-2 and said "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " The heteroatom connection of 5-6 membered monocyclic heterocycloalkyl;

The "5-6-membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " and the "8-membered substituted by 1 or more R 3-1-3 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-2 and R 3-1-3 are independently 3-6 membered heterocycloalkyl, C 1 -C 6 alkyl, C substituted by 1 or more R 3-1-1-1 1 -C 6 alkyl, -OC 1 -C 6 alkyl, halogen or deuterium;

The heteroatoms in the 3-6 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1 is independently a 3-6 membered cycloalkyl group;

R4 is a bridged ring heterocycloalkyl group with 7-12 members, the heteroatoms in the bridged ring heterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1 -3;

R 4 is a 7-12 membered bridged ring heterocycloalkyl group, and the heteroatoms in the 7-12 membered bridged ring heterocycloalkyl group are independently one or more of N, O or S, and hetero The number of atoms is 1-3;

A is CR 5 or N; R 5 is H, C 1 -C 6 alkyl, cyano or halogen;

Option 4:

The compound shown in formula I, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its isotope compound:

Among them, R 1 is C 6 -C 18 aryl, "C 6 -C 18 aryl substituted by 1 or more R 1-1 ", 5-10 heteroaryl or "by 1 or more R 1-2 substituted 5-10 heteroaryl", said 5-10 heteroaryl and said "5-10 heteroaryl substituted by 1 or more R 1-2 " heteroatoms independently one or more of N, O or S, and the number of heteroatoms is 1-4;

R 1-1 is independently hydroxyl, halogen, C 1 -C 6 alkyl, C 1 -C 6 alkyl substituted by 1 or more R 1-1-1 , C 2 -C 6 alkynyl,
C 3 -C 6 cycloalkyl or "4-10 membered cycloalkyl substituted by 1 or more R 1-1-2 ", or any two adjacent carbon atoms connected by R 1-1 Together form a 4-10 membered cycloalkyl, "4-10 membered cycloalkyl substituted by 1 or more R 1-1-3 ", 4-10 membered heterocycloalkyl, "by 1 or In the 4-10 membered heterocycloalkyl group substituted by multiple R 1-1-4 ", the 5-10 heteroaryl group and the "5-10 heteroaryl group substituted by 1 or more R 1-1-5 " The heteroatoms in are independently one or more of N, O or S; the 4-10-membered heterocycloalkyl and "4-10-membered substituted by 1 or more R 1-1-4 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-4; R 1-1-1 is independently halogen or deuterium;

R 1-1-2a , R 1-1-2b and R 1-1-3 are independently C 1 -C 6 alkyl;

R 1-1-2 are independently halogen or hydroxyl;

R 1-1-3 is independently halogen or C 1 -C 6 alkyl; R 1-1-4 is independently halogen or C 1 -C 6 alkyl;

R 1-2 is independently amino, C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted by one or more halogens;

R 2 is H or halogen;

Y is -OR 3 , C 1 -C 6 alkyl substituted by 1 or more Y 1-1 , C 2 -C 6 alkenyl substituted by 1 or more Y 1-2 , substituted by 1 or C 2 -C 6 alkynyl substituted by multiple Y 1-3 , C 3 -C 6 cycloalkyl substituted by one or more Y 1-4 or -N=S(O)Y 1-5 Y 1 -6 ;

R 3 is C 1 -C 6 alkyl substituted by 1 or more R 3-1 ;

R 3-1 is defined as follows:

When R 1 is C 6 -C 18 aryl or "C 6 -C 18 aryl substituted by 1 or more R 1-1 ", R 3-1 is defined as case 1 or case 2:

Scenario 1:

R 3-1 is independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " or deuterium; and the number of R 3-1 is at least 2, wherein one R 3-1 is -OC 1 -C 6 alkyl, and the other R 3-1 is 4-10 membered heterocycloalkyl or replaced by one Or a 4-10 membered heterocycloalkyl group substituted by multiple R 3-1-1 ;

The heteroatoms in the 4-10 membered heterocycloalkyl and the "4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-1 " are independently N, O or One or more of S, the number of heteroatoms is 1-3;

R 3-1-1 is independently -OC 1 -C 6 alkyl;

Scenario 2:

R 3-1 is independently deuterium, "5-6 membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " or "substituted by 1 or more R 3-1-3 8-membered heterocycloalkyl";

And at least one R 3-1 is "a 5-6 membered monocyclic heterocycloalkyl substituted by one or more R 3-1-2 " or "substituted by one or more R 3-1-3 8-membered heterocycloalkyl";

When at least one of R 3-1 is a 5-6 membered monocyclic heterocycloalkyl group substituted by 1 or more R 3-1-2 , at least one R 3-1-2 and said "is 1 or more R 3-1-2 substituted 5-6 membered monocyclic heterocycloalkyl "heteroatoms of the 5-6 membered monocyclic heterocycloalkyl are connected;

The "5-6-membered monocyclic heterocycloalkyl substituted by 1 or more R 3-1-2 " and the "8-membered substituted by 1 or more R 3-1-3 The heteroatoms in "heterocycloalkyl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-2 and R 3-1-3 are independently 3-6 membered heterocycloalkyl, C 1 -C 6 alkyl, C substituted by 1 or more R 3-1-1-1 1 -C 6 alkyl, -OC 1 -C 6 alkyl, halogen, deuterium or 3-6 membered cycloalkyl;

The heteroatoms in the 3-6 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-1-1 is independently 3-6 membered cycloalkyl or halogen;

When R 1 is 5-10 heteroaryl or "5-10 heteroaryl substituted by 1 or more R 1-2 ", R 3-1 is independently 4-10 membered heterocycloalkyl or " 4-10 membered heterocycloalkyl substituted by 1 or more R 3-1-4 "; said 5-10 heteroaryl and "5-10 substituted by 1 or more R 1-2 The heteroatoms in "heteroaryl" are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 3-1-4 are independently halogen;

Y 1-1 , Y 1-2 , Y 1-3 and Y 1-4 are independently -OC 1 -C 6 alkyl, 4-10 membered heterocycloalkyl, "substituted by 1 or more halogens 4-10 membered heterocycloalkyl", hydroxyl or deuterium; the heteroatom in the 4-10 membered heterocycloalkyl substituted by 1 or more halogens is independently one of N, O or S or more, the number of heteroatoms is 1-3;

Y 1-5 and Y 1-6 are independently C 1 -C 6 alkyl or "4-10 membered heterocycloalkyl substituted by 1 or more halogens"; said 1 or more halogens The heteroatoms in the substituted 4-10 membered heterocycloalkyl are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R4 is a bridged ring heterocycloalkyl group with 7-12 members, the heteroatoms in the bridged ring heterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1 -3;

R 4 is a 7-12-membered bridged ring heterocycloalkyl or "7-12-membered bridged ring heterocycloalkyl substituted by 1 or more R 4-1 ", the 7-12-membered bridge The heteroatoms in the cycloheterocycloalkyl group are independently one or more of N, O or S, and the number of heteroatoms is 1-3;

R 4-1 is C 1 -C 6 alkyl;

A is CR 5 or N;

R 5 is H, C 1 -C 6 alkyl, cyano, halogen or C 1 -C 6 alkyl substituted by one or more halogens.
The compound shown in formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that the compound shown in formula I is any one of the following compounds:

preferred,

Or, the pharmaceutically acceptable salt of the compound shown in formula I is any of the following compounds:

preferred,
The compound shown in formula I as claimed in claim 1, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomer, its prodrug, its metabolite or its Isotopic compounds, characterized in that the compound shown in formula I is any one of the following compounds:
A pharmaceutical composition, which comprises the compound shown in formula I as described in any one of claims 1-9, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its mutual Variants, their prodrugs, their metabolites or their isotopic compounds, and pharmaceutical excipients.
A use of substance A in the preparation of KRAS mutant protein inhibitors or medicines;

Described substance A is the compound shown in formula I as described in any one of claims 1-9, its pharmaceutically acceptable salt, its solvate, its stereoisomer, its tautomerism Construct, its prodrug, its metabolite, its isotope compound or the pharmaceutical composition as claimed in claim 9;

The drug is "for preventing or treating cancer" or "for preventing or treating cancer mediated by KRAS mutation".
application as claimed in claim 11, is characterized in that, described KRAS mutein is KRAS G12D mutein;

And/or, the cancer is blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer;

And/or, the cancer mediated by KRAS protein mutation is blood cancer, pancreatic cancer, MYH-associated polyposis, colorectal cancer or lung cancer.