WO2021000885A1 - Quinazoline derivatives, preparation process and medical use thereof - Google Patents

Abstract

A quinazoline derivative as represented by general formula (I), a preparation process therefor, a pharmaceutical composition containing the derivative and use of the derivative as a therapeutic agent, in particular as a KRAS inhibitor.

Description

Quinazolinone derivatives, preparation method thereof and application in medicine Technical field

The present disclosure belongs to the field of medicine, and relates to a quinazolinone derivative represented by general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a therapeutic agent, especially a KRAS inhibitor use.

Background technique

The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the small GTPases superfamily and is widely expressed in various eukaryotes. There are three RAS genes (HRAS, KRAS and NARS) in humans, which can be expressed as four highly related RAS small GTPases (HRAS, KRAS4A, KARS4B and NRAS). It acts as a binary switch regulated by GDP-GTP. Under normal circumstances, they have two manifestations: GDP (guanosine diphosphate) binding form in the inactive state and GTP (guanosine triphosphate) binding form in the activated state. The RAS protein regulates multiple downstream pathways including RAF-MEK-ERK, PI3K/Akt/mTOR by switching between two active states, thereby affecting cell growth, proliferation and differentiation (Nat Rev Cancer, 2007, 7,295 -308). The RAS gene has a high mutation rate in pancreatic cancer, colorectal cancer, non-small cell lung cancer and other tumors. The activated mutant RAS protein promotes abnormal signal transduction, leading to the occurrence and development of cancer and resistance to targeted drugs. Medicinal properties. Among them, KRAS mutation is the gene with the highest mutation rate among human oncogenes, accounting for 20-30% of all tumors.

In recent years, molecular biology has made significant progress in the study of mutation forms and signaling pathways of KRAS protein. However, the development of related targeted drugs is still challenging. In terms of chemical drug development, because the affinity of KRAS and GTP is very high, reaching 60pM, and the intracellular GTP concentration is at the mM level, this type of directly competing molecule requires extremely high affinity for the compound. So far, there have been no successful cases. In terms of biological drug development, antibody drugs penetrate cell membranes to target KRAS protein, and the drug delivery efficiency is relatively low. Therefore, many researchers have tried to find another way, hoping to inhibit the activity of kinases such as RAF, MEK and ERK in the downstream signaling pathway of KRAS, and achieve the purpose of inhibiting the KRAS pathway. These compounds have certain curative effects, but because downstream inhibitors cannot completely block KRAS signaling, and the target-related side effects are great, these compounds have poor efficacy on KRAS mutant tumors. Therefore, the development of KRAS inhibitors with new mechanisms of action has great clinical application value.

KRAS mutations are mainly point mutations, including mutations of amino acids 12, 13, and 61. Among them, the mutation of glycine at position 12 to cysteine (G12C) is the most common. This mutation is more common in lung cancer, especially non-small cell lung cancer (14%), in addition to some colorectal cancers (4%), pancreas It is expressed in cancer (2%) patients. In the American cancer population, the incidence of this gene mutation is even greater than the sum of ALK, RET, and TRK gene mutations.

Facing the difficulty of KRAS protein formulation, Professor Kevan Shokat of the University of California, San Francisco took the lead in verifying that certain special compounds can bind KRAS G12C mutant proteins through covalent bonds. Through further research, it is found that these covalent compounds can bind to the cysteine at position 12 of the KRAS mutant protein and occupy a hydrophobic allosteric regulatory pocket in the switch-II regions of the molecule. The bound KRAS G12C mutation The experience is irreversibly locked in an inactive state, thereby blocking the protein-dependent signaling pathways and cancer cell viability (Nature 2013, 503, 548-551). The KRAS G12C small molecule inhibitor ARS-1620 can effectively inhibit tumor growth in a variety of KRAS G12C mutant tumor models, and even make the tumor completely regress. Since KRAS G12C is a mutant protein in tumor cells, and wild-type KRAS does not have this mutation site, it provides a perfect tumor selective target (Cell, 2018, 572, 578-589). Companies represented by Araxas, Amgen and Mirati have published several KRAS G12C inhibitor patents (WO2014152588, WO2016164675, WO2017087528, WO2017201161, WO2018119183, etc.). At present, no KRAS G12C inhibitor drugs have been approved for marketing. The fastest-growing small molecule KRAS G12C inhibitors from Amgen and Mirati entered Phase I clinical trials in September and December 2018, respectively. Therefore, there are significant problems in the relevant patient population. Unmet medical needs.

Summary of the invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Y is O or S;

W ¹ is N or CR ⁷ ;

W ² is N or CR ⁸ ;

G ^{1 is} selected from O, S(O) _m and NR ⁹ ;

G ^{2 is} selected from CR ¹⁰ R ¹¹ , CR ¹⁰ R ¹¹ CR ^10a R ^11a , C=O and C(O)CR ¹⁰ R ¹¹ ;

R ^{1 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R ^{2 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R ^{3 are the} same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl Group, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{4 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -(CH ₂ ) _q NR ¹² R ¹³ , cycloalkyl and heterocycle base;

R ⁵ and R ^{6 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -(CH ₂ ) _q NR ¹² R ¹³ , cycloalkyl and heterocyclic group;

R ^{7 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group;

R ^{8 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group;

R ^{9 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, cycloalkyl group and heterocyclic group;

R ¹⁰ , R ¹¹ , R ^10a and R ^{11a are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl and heterocyclyl; or, R ¹⁰ and R ¹¹ together with the attached C atom form a cycloalkyl; or, R ^10a and R ^11a together with the attached C atom form a cycloalkyl;

R ¹² and R ^{13 are the} same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group; or, R ¹² and R ^{13 are the} same as The connected N atoms together form a heterocyclic group, and the heterocyclic group is optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy and hydroxyalkyl. Replaced by multiple substituents;

r is 0, 1, 2, 3, 4 or 5;

s is 0, 1, 2, 3, 4 or 5;

t is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

q is 0, 1, 2, 3, or 4.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (Ia) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ⁶ , r, s, and t are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (Ib) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ⁶ , r, s, and t are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is aryl or heteroaryl, preferably C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl , More preferred are phenyl, pyridyl and pyrimidinyl.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer In the form of a isomer, a diastereomer, or a mixture thereof or a pharmaceutically acceptable salt thereof, ring B is an aryl or heteroaryl group, preferably a phenyl group or a pyridyl group.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein Y is O.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein

W ¹ is N or CR ⁷ ; W ² is CR ⁸ ;

R ⁷ and R ⁸ are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer A isomer, a diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W ¹ is N; W ² is CR ⁸ ; R ^{8 is} as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein W ¹ is CR ⁷ ; W ² is CR ⁸ ; R ⁷ and R ⁸ are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein G ¹ is O.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ² is CR ¹⁰ R ¹¹ ; R ¹⁰ and R ¹¹ are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIM) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

G ³ , G ⁴ and G ^{5 are the} same or different, and each independently is N or CH, provided that at most two of G ³ , G ⁴ and G ⁵ are N;

R ^2a , R ^2b and R ^{2c are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally One or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Replaced by

R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkane Oxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p is 0, 1, 2 or 3;

Rings A, Y, W ¹ , R ¹ , R ⁴ to R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ and r are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIMa) or (IIMb) or atropisomers or tautomers , Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in general formula (IIM).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIMa-1) or (IIMa-2) or atropisomers, mutual Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R ^{3a is} selected from halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl groups, preferably alkyl groups, more preferably C _1-6 alkyl groups;

Rings A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r are as general formula (IIM).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIMb-7) or (IIMb-8) or atropisomers or mutual Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R ^{3a is} selected from halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl groups, preferably alkyl groups, more preferably C _1-6 alkyl groups;

Rings A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r are as general formula (IIM).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are represented by the general formula (IIMa-3), (IIMa-4), (IIMb-1) or (IIMb-2) The compound shown or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The salt:

among them:

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in general formula (IIM).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are represented by the general formula (IIMa-5), (IIMa-6), (IIMa-7) or (IIMa-8) The compound shown or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The salt:

among them:

R ^{3a is} selected from halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl groups; preferably alkyl groups; more preferably C _1-6 alkyl groups;

Rings A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r are as general formula (IIM).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are represented by the general formula (IIMb-3), (IIMb-4), (IIMb-5) or (IIMb-6) The compound shown or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or its mixture form, or its pharmaceutically acceptable The salt:

among them:

R ^{3a is} selected from halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl groups; preferably alkyl groups; more preferably C _1-6 alkyl groups;

Rings A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r are as general formula (IIM).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIM) or its atropisomer, tautomer, meso, racemate, enantiomer G ³ and G ^{5 are the} same or different, and are each independently selected from N or CH, and G ⁴ is CH; preferably G ³ , G ⁴ and G ⁵ are CH.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (II) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkane Oxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring A, R ¹ , R ² , R ⁴ to R ⁸ , R ¹⁰ , R ¹¹ , r, and s are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIa) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkane Oxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring A, R ¹ , R ² , R ⁴ to R ⁸ , R ¹⁰ , R ¹¹ , r, and s are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (IIb) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkane Oxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring A, R ¹ , R ² , R ⁴ to R ⁸ , R ¹⁰ , R ¹¹ , r, and s are as defined in the general formula (I).

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is aryl or heteroaryl.

其中环D为芳基或杂芳基，环D优选为苯基或5元杂芳基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from phenyl, pyridyl, or

Among them, ring D is aryl or heteroaryl, and ring D is preferably phenyl or 5-membered heteroaryl.

其中环D为芳基或杂芳基，环D优选为苯基或5元杂芳基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is phenyl or

Among them, ring D is aryl or heteroaryl, and ring D is preferably phenyl or 5-membered heteroaryl.

其中环D为芳基或杂芳基，环D优选为苯基或5元杂芳基。 In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is

Among them, ring D is aryl or heteroaryl, and ring D is preferably phenyl or 5-membered heteroaryl.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Ring A is selected from phenyl, pyridyl, naphthyl, indazolyl, indolyl, benzimidazolyl and benzene And triazolyl.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Ring A is selected from phenyl, naphthyl, indazolyl, indolyl, benzimidazolyl, and benzotriazole in the form of a isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof base.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from:

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from:

优选选自

Preferably selected from

选自： In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein

Selected from:

R ^1a , R ^1b , R ^1c , R ^1d and R ^{1e are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyl Alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Each independently is optionally selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl One or more substituents are substituted.

j is 0, 1, 2 or 3; and

k is 0, 1, 2, 3 or 4;

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer R ^1a and R ^{1b are the} same or different, and are each independently selected from halogen, hydroxyl and amino; preferably R ^1a is halogen, or a mixture thereof, or a pharmaceutically acceptable salt thereof, And R ^1b is a hydroxyl group or an amino group.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Wherein R ^1c is a hydrogen atom or a halogen, and j is 0, 1 or 2; j is preferably 0 in the form of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer In the form of a isomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^1d is an alkyl group, preferably a C _1-6 alkyl group.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer R ^1e is a hydrogen atom or an alkyl group, preferably, R ^1e is a hydrogen atom or a C _1-6 alkyl group, and k is a hydrogen atom or a C _1-6 alkyl group, or a pharmaceutically acceptable salt thereof. 0 or 1.

为

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein

for

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{1 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, an alkyl group, a hydroxyl group, and an amino group, preferably, R ^{1 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a hydroxyl group, and an amino group; and r is 0, 1, 2, 3, or 4, and r is preferably 0, 1, or 2.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{1 is the} same or different, and each is independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, Hydroxy and hydroxyalkyl are preferably selected from hydrogen atom, halogen, alkyl and hydroxyl; and r is 0, 1, or 2.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{2 is the} same or different, and each is independently selected from a hydrogen atom, an alkyl group, and a cycloalkyl group. Preferably, R ² The same or different, and are each independently selected from a hydrogen atom, a C _1-6 alkyl group, and a C _3-6 cycloalkyl group; and s is 0, 1, or 2.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁷ is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer R ⁸ is a hydrogen atom or a halogen, preferably a hydrogen atom, in the form of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹⁰ and R ¹¹ are each independently selected from a hydrogen atom or an alkyl group; or, R ¹⁰ and R ¹¹ are connected to C The atoms together form a cycloalkyl group; R ¹⁰ and R ^{11 are} preferably hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{3 is the} same or different, and each is independently selected from a hydrogen atom or an alkyl group, and t is 0, 1 or 2; Preferably it is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (II) or its atropisomer, tautomer, meso, racemate, enantiomer R ^3a and R ^3b are each independently selected from a hydrogen atom or an alkyl group. Preferably, R ^3a and R ^3b are hydrogen atoms, or a mixture thereof, or a pharmaceutically acceptable salt thereof. Or R ^3a is a C _1-6 alkyl group, and R ^3b is a hydrogen atom.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIM) or its atropisomer, tautomer, meso, racemate, enantiomer R ^3a is an alkyl group, preferably a methyl group, and R ^3b is a hydrogen atom, in the form of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer R ⁴ is a hydrogen atom or a halogen, preferably a hydrogen atom, in the form of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof.

In some preferred embodiments of the present disclosure, the compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁵ and R ⁶ are hydrogen atoms.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIM) or its atropisomer, tautomer, meso, racemate, enantiomer R ^2a is an alkyl group or a cycloalkyl group, preferably, R ^2a is a C _1-6 alkyl group or a C _3-6 Cycloalkyl, more preferably R ^2a is isopropyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIM) or its atropisomer, tautomer, meso, racemate, enantiomer R ^{2b is} selected from a hydrogen atom, an alkyl group and a cycloalkyl group, preferably R ^{2b is} selected from a hydrogen atom, C _1-6 , or a mixture thereof, or a pharmaceutically acceptable salt thereof. Alkyl and C _3-6 cycloalkyl.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IIM) or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^2c is a hydrogen atom.

Typical compounds of the present disclosure include but are not limited to:

Or its atropisomer, tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture form thereof, or pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a compound represented by the general formula (IA) or its atropisomer, tautomer, meso, racemate, enantiomer, or non-pair Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them:

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Y is O or S;

W ¹ is N or CR ⁷ ;

W ² is N or CR ⁸ ;

G ^{1 is} selected from O, S(O) _m and NR ⁹ ;

G ^{2 is} selected from CR ¹⁰ R ¹¹ , CR ¹⁰ R ¹¹ CR ^10a R ^11a , C=O and C(O)CR ¹⁰ R ¹¹ ;

R ^{1 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R ^{2 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents;

R ^{3 are the} same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl Group, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ^{7 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group;

R ^{8 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group;

R ^{9 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, cycloalkyl group and heterocyclic group;

R ¹⁰ , R ¹¹ , R ^10a and R ^{11a are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl and heterocyclyl; or, R ¹⁰ and R ¹¹ together with the attached C atom form a cycloalkyl; or, R ^10a and R ^11a together with the attached C atom form a cycloalkyl;

r is 0, 1, 2, 3, 4 or 5;

s is 0, 1, 2, 3, 4 or 5;

t is 0, 1, 2, 3 or 4;

m is 0, 1 or 2; and

n is 0, 1, 2 or 3.

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (Ia-A) or (Ib-A):

among them:

Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ³ , M, n, r, s, and t are as defined in the general formula (IA).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer Forms of isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIM-A):

among them:

G ³ , G ⁴ and G ^{5 are the} same or different, and each independently is N or CH, provided that at most two of G ³ , G ⁴ and G ⁵ are N;

R ^2a , R ^2b and R ^{2c are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally One or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Replaced by

R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkane Oxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

p is 0, 1, 2 or 3;

Rings A, Y, W ¹ , R ¹ , R ⁸ , R ¹⁰ , R ¹¹ , M, n, and r are as defined in general formula (IA).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer It is a compound represented by the general formula (IIMa-A) or (IIMb-A) in the form of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

Rings A, Y, W ¹ , G ³ to G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁸ , R ¹⁰ , R ¹¹ , M, n, p, and r are as common Defined in formula (IIM-A).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer It is a compound represented by the general formula (IIMa-1-A) or (IIMa-2-A) in the form of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

among them:

R ^{3a is} selected from halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl groups, preferably alkyl groups;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3b , R ⁸ , R ¹⁰ , R ¹¹ , M, n, p and r are as in the general formula (IIM -As defined in A).

In some preferred embodiments of the present disclosure, the compound represented by the general formula (IA) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein n is 0 or 1, preferably 1.

Typical compounds of general formula (I-A) of the present disclosure include but are not limited to:

Or its atropisomer, tautomer, mesoisomer, racemate, enantiomer, diastereomer, or mixture form thereof, or pharmaceutically acceptable salt thereof.

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (IA) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form, or The pharmaceutically acceptable salt reacts with the compound of general formula (IB) under alkaline conditions to obtain the compound of general formula (I) or its atropisomer, tautomer, meso, and exoisomer. Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ⁶ , r, s, and t are as defined in the general formula (I).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formula (II) or its atropisomer, tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of the general formula (II-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, reacts with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (II) or its atropisomer, tautomer, meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, R ¹ , R ² , R ^3a , R ^3b , R ⁴ to R ⁸ , R ¹⁰ , R ¹¹ , r and s are as defined in the general formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) of the present disclosure or its atropisomer, tautomer, or internal elimination Rotate, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients Agent.

The present disclosure further relates to compounds represented by general formula (I) or atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers or The use of the mixture in the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, in the preparation of a medicine for inhibiting KRAS, preferably in the preparation of a medicine for inhibiting KRAS G12C.

The present disclosure further relates to compounds represented by general formula (I) or atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers or The use of the mixture form, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same in the preparation of a medicament for the treatment or prevention of cancer, inflammation, or other proliferative diseases, preferably in the preparation for the treatment or prevention of cancer The use of the medicine; the cancer is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, nasopharyngeal cancer, colorectal cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), Kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma , Malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumors.

The present disclosure also relates to a method for inhibiting KRAS, which comprises administering to a patient a therapeutically effective amount of a compound represented by general formula (I) or atropisomer, tautomer, meso, and exoisomer. Racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions containing them.

The present disclosure also relates to a method for treating or preventing KRAS-mediated diseases, which comprises administering to a patient a therapeutically effective amount of a compound represented by the general formula (I) or atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same.

The present disclosure also relates to a method for treating or preventing cancer, inflammation, or other proliferative diseases, preferably a method for treating cancer, which comprises administering to a desired patient a therapeutically effective amount of a compound represented by general formula (I) or its inhibition Isomers, tautomers, mesosomes, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical combinations containing them The cancer is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, nasopharyngeal cancer, colorectal cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), kidney cancer, Breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymph Tumors, polycythemia vera, leukemia, thyroid tumors, ureteral tumors, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumors.

The present disclosure further relates to a compound represented by the general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer Body, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, which is used as a medicine.

The present disclosure also relates to compounds represented by general formula (I) or atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, it is used as a KRAS inhibitor, preferably as a KRAS G12C inhibitor.

The present disclosure also relates to compounds represented by general formula (I) or atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers or In the form of a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing the same, the treatment or prevention of KRAS-mediated diseases is preferably used as the treatment or prevention of KRASG12C-mediated diseases.

The present disclosure also relates to compounds represented by general formula (I) or atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers or In the form of a mixture, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition containing it, it is used for the treatment or prevention of cancer, inflammation, or other proliferative diseases, preferably for the treatment or prevention of cancer; wherein the cancer is preferably selected From melanoma, brain tumor, esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, nasopharyngeal cancer, colorectal cancer, lung cancer (such as non-small cell lung cancer or small cell lung cancer), kidney cancer, breast cancer, ovarian cancer, prostate cancer, Skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, Thyroid tumors, ureteral tumors, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumors.

The active compound can be prepared in a form suitable for administration by any appropriate route, and the active compound is preferably in a unit dose form, or a form in which the patient can self-administer in a single dose. The expression mode of the unit dose of the compound or composition of the present disclosure can be tablet, capsule, cachet, bottled syrup, powder, granule, lozenge, suppository, regenerating powder or liquid preparation.

The dosage of the compound or composition used in the treatment methods of the present disclosure will generally vary with the severity of the disease, the weight of the patient, and the relative efficacy of the compound. However, as a general guide, a suitable unit dose can be 0.1-1000 mg.

In addition to the active compound, the pharmaceutical composition of the present disclosure may contain one or more auxiliary materials selected from the following ingredients: fillers (diluents), binders, wetting agents, disintegrants or excipients Wait. Depending on the method of administration, the composition may contain 0.1 to 99% by weight of the active compound.

The pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, dragees, lozenges, water or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Elixirs. Oral compositions can be prepared according to any method known in the art for preparing pharmaceutical compositions. Such compositions can contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents and preservatives, In order to provide pleasing and delicious medicinal preparations. The tablet contains the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.

Aqueous suspensions contain the active substance and excipients suitable for the preparation of aqueous suspensions for mixing. The aqueous suspension may also contain one or more preservatives such as ethyl paraben or n-propyl paraben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agent.

Oil suspensions can be formulated by suspending active ingredients in vegetable oils. The oil suspension may contain thickening agents. The above-mentioned sweeteners and flavoring agents can be added to provide a palatable preparation.

By adding water, dispersible powders and granules suitable for preparing aqueous suspensions can be provided with active ingredients and dispersing or wetting agents for mixing, suspending agents or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can illustrate the above examples. Other excipients such as sweetening agents, flavoring agents and coloring agents may also be added. These compositions are preserved by adding antioxidants such as ascorbic acid.

The pharmaceutical composition of the present disclosure may also be in the form of an oil-in-water emulsion.

The pharmaceutical composition may be in the form of a sterile injectable aqueous solution. Acceptable solvents or solvents that can be used are water, Ringer's solution and isotonic sodium chloride solution. The sterile injection preparation may be a sterile oil-in-water injection microemulsion in which the active ingredient is dissolved in an oil phase. For example, the active ingredient is dissolved in a mixture of soybean oil and lecithin. Then the oil solution is added to the mixture of water and glycerin to form a microemulsion. The injection or microemulsion can be injected into the patient's bloodstream by local large injections. Alternatively, it is best to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the compound of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device can be used. An example of such a device is the Deltec CADD-PLUS.TM. 5400 intravenous pump.

The pharmaceutical composition may be in the form of a sterile injection water or oil suspension for intramuscular and subcutaneous administration. The suspension can be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents mentioned above. The sterile injection preparation may also be a sterile injection solution or suspension prepared in a parenterally acceptable non-toxic diluent or solvent. In addition, sterile fixed oil can be conveniently used as a solvent or suspension medium.

The compounds of the present disclosure can be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid in the rectum and thus will melt in the rectum to release the drug. Such substances include cocoa butter, glycerinated gelatin, hydrogenated vegetable oils, polyethylene glycols of various molecular weights and mixtures of fatty acid esters of polyethylene glycol.

As is well known to those skilled in the art, the dosage of the drug depends on many factors, including but not limited to the following factors: the activity of the specific compound used, the age of the patient, the weight of the patient, the health of the patient, and the behavior of the patient , The patient’s diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; in addition, the best mode of treatment such as the mode of treatment, the daily dosage of compound (I) or the amount of pharmaceutically acceptable salt The type can be verified according to the traditional treatment plan.

Detailed description of the invention

Unless stated to the contrary, the terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group, which is a straight or branched chain group containing 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably containing 1 to 6 carbon atoms An alkyl group of carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1 ,2-Dimethylpropyl, 2,2-Dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2- Methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3 -Dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -Methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethyl Pentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2 ,5-Dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethyl Hexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethyl Hexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched isomers. More preferred is a lower alkyl group containing 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Group, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl Group, 2,3-dimethylbutyl, etc. Alkyl groups may be substituted or unsubstituted. When substituted, the substituents may be substituted at any available attachment point. The substituents are preferably independently selected from H atom, D atom, halogen, and alkane. Is substituted by one or more substituents in the group, alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl.

The term "alkoxy" refers to -O- (alkyl) and -O- (unsubstituted cycloalkyl), where alkyl is defined as described above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy. The alkoxy group may be optionally substituted or unsubstituted. When substituted, the substituent is preferably one or more of the following groups, which are independently selected from H atom, D atom, halogen, alkyl, and alkoxy , Haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl substituted by one or more substituents.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent. The cycloalkyl ring contains 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms, preferably 3 to 8 (E.g. 3, 4, 5, 6, 7 or 8) carbon atoms, more preferably 3 to 6 carbon atoms. Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene Groups, cyclooctyl, etc.; polycyclic cycloalkyls include spiro, fused, and bridged cycloalkyls.

The term "spirocycloalkyl" refers to a polycyclic group that shares one carbon atom (called a spiro atom) between 5- to 20-membered monocyclic rings. It may contain one or more double bonds, but none of the rings have complete conjugate Π electronic system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan (for example, 7, 8, 9 or 10 yuan). According to the number of spiro atoms shared between the ring and the ring, the spirocycloalkyl group is classified into a single spirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a single spirocycloalkyl group and a bispirocycloalkyl group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

The term "fused cycloalkyl" refers to a 5- to 20-membered all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic condensed cycloalkyls, preferably bicyclic or tricyclic, more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic alkyl. Non-limiting examples of fused cycloalkyl groups include:

The term "bridged cycloalkyl" refers to a 5- to 20-membered, all-carbon polycyclic group with any two rings sharing two carbon atoms that are not directly connected. It may contain one or more double bonds, but no ring has complete Conjugated π electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. It can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyls according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

The cycloalkyl ring includes the cycloalkyl as described above (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein it is connected to the parent structure The ring together is a cycloalkyl group, and non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, etc.; preferably phenylcyclopentyl, tetrahydronaphthyl.

Cycloalkyl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent which contains 3 to 20 ring atoms, one or more of which is selected from nitrogen, oxygen or S(O) z (where z is an integer of 0 to 2) heteroatoms, but does not include the ring part of -OO-, -OS- or -SS-, and the remaining ring atoms are carbon. It preferably contains 3 to 12 ring atoms, of which 1 to 4 are heteroatoms; more preferably contains 3 to 8 ring atoms, of which 1-3 are heteroatoms; more preferably contains 3 to 6 ring atoms, of which 1-3 One is a heteroatom; most preferably contains 5 or 6 ring atoms, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholine Base, homopiperazinyl, etc. Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.

The term "spiroheterocyclic group" refers to a polycyclic heterocyclic group sharing one atom (called a spiro atom) between monocyclic rings of 5 to 20 members, wherein one or more ring atoms are selected from nitrogen, oxygen or S(O ) _z (where z is an integer of 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It can contain one or more double bonds, but none of the rings have a fully conjugated π-electron system. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of shared spiro atoms between the ring and the ring, the spiro heterocyclic group is classified into a single spiro heterocyclic group, a dispiro heterocyclic group or a polyspiro heterocyclic group, preferably a single spiro heterocyclic group and a dispiro heterocyclic group. More preferably, it is a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered, or 5-membered/6-membered monospiro heterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

The term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more Double bond, but none of the rings have a fully conjugated π-electron system, one or more of the ring atoms are heteroatoms selected from nitrogen, oxygen, or S(O) _z (where z is an integer from 0 to 2), and the remaining rings The atom is carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, and more preferably 5-membered/5-membered or 5-membered/6-membered bicyclic fused heterocyclic group. Non-limiting examples of fused heterocyclic groups include:

The term "bridged heterocyclic group" refers to a 5- to 14-membered polycyclic heterocyclic group with any two rings sharing two atoms that are not directly connected. It may contain one or more double bonds, but none of the rings has a complete common A conjugated π-electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) _z (where z is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14 yuan, more preferably 7 to 10 yuan. According to the number of constituent rings, it can be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

The heterocyclyl ring includes the heterocyclic group (including monocyclic, spiro heterocyclic, fused heterocyclic and bridged heterocyclic ring) as described above fused to an aryl, heteroaryl or cycloalkyl ring, wherein the group is The structures linked together are heterocyclic groups, non-limiting examples of which include:

等。

Wait.

The heterocyclic group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "aryl" refers to a 6 to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings sharing adjacent pairs of carbon atoms) with a conjugated π-electron system, preferably 6 to 10 members, such as benzene Base and naphthyl. The aryl ring includes the aryl ring as described above fused to a heteroaryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include :

The aryl group may be substituted or unsubstituted. When substituted, the substituent may be substituted at any available point of attachment. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, and alkyl groups. One or more substituents of oxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclic, aryl, and heteroaryl are substituted.

The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 14 ring atoms, where the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl groups are preferably 5 to 10 members (for example, 5, 6, 7, 8, 9 or 10 members), more preferably 5 members or 6 members, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkane Pyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, etc. The heteroaryl ring includes the aforementioned heteroaryl group fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples thereof include :

Heteroaryl groups can be substituted or unsubstituted. When substituted, the substituents can be substituted at any available attachment point. The substituents are preferably independently optionally selected from hydrogen atoms, halogens, alkyl groups, Alkoxy, haloalkyl, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, and heteroaryl are substituted by one or more substituents.

The term "cycloalkyloxy" refers to cycloalkyl-O-, where cycloalkyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, where the alkyl group is as defined above.

The term "deuterated alkyl" refers to an alkyl group substituted with one or more deuterium atoms, where the alkyl group is as defined above.

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

The term "hydroxyalkyl" refers to an alkyl group substituted with a hydroxy group, where the alkyl group is as defined above.

The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group, where alkoxy and alkyl are as defined above.

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

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

The term "amino" refers to -NH ₂ .

The term "cyano" refers to -CN.

The term "cyanoalkyl" refers to an alkyl group substituted with a cyano group, wherein the alkyl group is as defined above.

The term "nitro" refers to -NO ₂ .

The term "carbonyl" refers to C=O.

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

The term "carboxylate group" refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl and cycloalkyl are as defined above.

"Organic acid" refers to a compound that can accept electron pairs according to the broad acid-base theory. Organic acids include carboxylic acids, halogenated acids, hydroxy acids, keto acids, amino acids, sulfonic acids, sulfinic acids, thiocarboxylic acids, phenolic acids, etc. Non-limiting examples include formic acid, acetic acid, methanesulfonic acid, and ethanesulfonic acid. , Dodecylbenzenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, isethionic acid, etc., preferably trifluoroacetic acid; "inorganic acid" refers to the dissociation of hydrogen Ionic inorganic compounds, according to their composition, inorganic acids can be divided into oxo acids, anaerobic acids, complex acids, mixed acids, super acids, etc. Non-limiting examples include hydrochloric acid, carbonic acid, nitric acid, nitrous acid, hypochlorous acid, Sulfuric acid or phosphoric acid, etc., preferably hydrochloric acid.

The present disclosure also includes compounds of formula (I) in various deuterated forms. Each available hydrogen atom connected to a carbon atom can be independently replaced by a deuterium atom. Those skilled in the art can synthesize the compound of formula (I) in deuterated form with reference to relevant literature. Commercially available deuterated starting materials can be used when preparing the deuterated form of the compound of formula (I), or they can be synthesized using conventional techniques using deuterated reagents. Deuterated reagents include but are not limited to deuterated borane and tri-deuterated. Borane tetrahydrofuran solution, deuterated lithium aluminum hydride, deuterated ethyl iodide and deuterated methyl iodide, etc.

"Optional" or "optionally" means that the event or environment described later can but does not necessarily occur, and the description includes the occasion where the event or environment occurs or does not occur. For example, "heterocyclic group optionally substituted by an alkyl group" means that an alkyl group may but need not be present, and the description includes the case where the heterocyclic group is substituted by an alkyl group and the case where the heterocyclic group is not substituted by an alkyl group .

"Substituted" refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3 hydrogen atoms, independently of each other, substituted with a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art can determine (by experiment or theory) possible or impossible substitutions without too much effort. For example, an amino group or a hydroxyl group with free hydrogen may be unstable when combined with a carbon atom with an unsaturated (eg, olefinic) bond.

"Pharmaceutical composition" means a mixture containing one or more of the compounds described herein or their physiologically/pharmaceutically acceptable salts or prodrugs and other chemical components, and other components such as physiological/pharmaceutically acceptable carriers And excipients. The purpose of the pharmaceutical composition is to promote the administration to the organism, which is beneficial to the absorption of the active ingredients and thus the biological activity.

"Pharmaceutically acceptable salt" refers to the salt of the compound of the present disclosure. Such salt is safe and effective when used in the body of a mammal, and has due biological activity.

The compounds of the present disclosure may also include isotopic derivatives thereof. The term "isotopic derivatives" refers to compounds that differ in structure only in the presence of one or more isotopically enriched atoms. For example, with the structure of the present disclosure, in addition to using "deuterium" or "tritium" instead of hydrogen, or using ¹⁸ F-fluorine label ( ¹⁸ F isotope) instead of fluorine, or using ¹¹ C-, ¹³ C-, or ¹⁴ C-rich Compounds in which collective carbons ( ¹¹ C-, ¹³ C-, or ¹⁴ C-carbon labels; ¹¹ C-, ¹³ C-, or ¹⁴ C- isotopes) replace carbon atoms are within the scope of the present disclosure. Such compounds can be used, for example, as analytical tools or probes in biological assays, or as tracers for in vivo diagnostic imaging of diseases, or as tracers for pharmacodynamics, pharmacokinetics, or receptor studies. Deuterated compounds can generally retain activity comparable to that of non-deuterated compounds, and when deuterated at certain specific sites, they can achieve better metabolic stability, thereby obtaining certain therapeutic advantages (such as increased in vivo half-life or reduced dosage requirements) ).

The compounds of the present disclosure may include all forms of rotamers and conformationally restricted states. Atropisomers are also included. The term "atropisomers" refers to stereoisomers due to hindered rotation around a single bond, in which the energy difference due to steric strain or other contributing factors forms a sufficiently high rotation Barriers to allow the separation of individual conformers. For example, some of the compounds of the present disclosure may exist in the form of a mixture of atropisomers or in the form of a purified atropisomer, or exist in a form enriched in an atropisomer. A further description of atropisomerism and axial chirality and configuration rules can be found in "Eliel, E.L. & Wilen, S. H. ‘Stereochemistry of Organic Compounds’ John Wiley and Sons, Inc. 1994".

For drugs or pharmacologically active agents, the term "therapeutically effective amount" refers to a sufficient amount of a drug or agent that is non-toxic but can achieve the desired effect. The determination of the effective amount varies from person to person, and depends on the age and general conditions of the recipient, as well as the specific active substance. The appropriate effective amount in a case can be determined by those skilled in the art according to routine experiments.

Synthetic method of the compound of the present disclosure

In order to accomplish the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

Option One

The compound represented by the general formula (I) of the present disclosure or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or The preparation method of the mixture form, or its pharmaceutically acceptable salt, includes the following steps:

In the first step, the compound of general formula (I-1) is reacted with thionyl chloride, the reaction solution is concentrated and ammonia is added to react to obtain the compound of general formula (I-2);

In the second step, the compound of general formula (I-2) is reacted with an acylating reagent (preferably oxalyl chloride). After the reaction solution is concentrated, the compound of general formula (I-3) is added to obtain the compound of general formula (I-4). Compound

In the third step, the compound of general formula (I-5) is reacted under basic conditions (the reagent providing basic conditions is preferably sodium hydride), and then the compound of general formula (I-4) is added to react to obtain general formula (I -6) compound;

In the fourth step, the compound of general formula (I-6) is in the presence of a condensation reagent (preferably benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) in the presence of alkaline Conditions (reagents providing basic conditions are preferably 1,8-diazabicyclo[5.4.0]undec-7-ene) to obtain a compound of general formula (I-7);

In the fifth step, the compound of general formula (I-7) and the compound of general formula (I-8), under the action of a catalyst (preferably tetrakis(triphenylphosphine) palladium), under basic conditions (providing basic conditions The reagent is preferably sodium carbonate) to obtain the compound of the general formula (I-9); or the compound of the general formula (I-7) and boric acid or a borate compound (preferably pinacol biborate), in Under the action of a catalyst (preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride), the reaction is obtained under alkaline conditions (the reagent providing alkaline conditions is preferably potassium acetate). The compound of formula (I-8a), the compound of general formula (I-8a) and the compound of general formula (I-8b), under the action of a catalyst (preferably tetrakis(triphenylphosphine)palladium), under basic conditions (The reagent providing alkaline conditions is preferably sodium carbonate) to obtain a compound of general formula (I-9);

In the sixth step, the compound of general formula (I-9) is subjected to acidic conditions (the reagent providing acidic conditions is preferably a 1,4-dioxane solution of hydrogen chloride) to remove the amino protecting group to obtain general formula (IA) compound of;

In the seventh step, the compound of general formula (IA) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, and a compound of general formula (IB) are reacted under alkaline conditions (the reagent providing alkaline conditions is preferably triethylamine) to obtain a compound of general formula (I) or its hindrance Transisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

R ^w is an amino protecting group; preferably tert-butoxycarbonyl;

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ⁶ , r, s, and t are as defined in the general formula (I).

Option II

The compound represented by the general formula (II) of the present disclosure or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof The preparation method of the form, or its pharmaceutically acceptable salt, includes the following steps:

In the first step, the compound of general formula (II-1) is reacted with thionyl chloride, the reaction solution is concentrated and ammonia water is added to react to obtain the compound of general formula (II-2);

In the second step, the compound of general formula (II-2) is reacted with an acylating reagent (preferably oxalyl chloride). After the reaction solution is concentrated, the compound of general formula (II-3) is added to obtain a compound of general formula (II-4). Compound

In the third step, the compound of general formula (II-5) is reacted under alkaline conditions (the reagent providing alkaline conditions is preferably sodium hydride), and then the compound of general formula (II-4) is added to react to obtain general formula (II -6) compound;

In the fourth step, the compound of general formula (II-6) is in the presence of a condensation reagent (preferably benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate) in the presence of alkaline Conditions (reagents providing basic conditions are preferably 1,8-diazabicyclo[5.4.0]undec-7-ene) to obtain a compound of general formula (II-7);

In the fifth step, the compound of general formula (II-7) and the compound of general formula (I-8), under the action of a catalyst (preferably tetrakis(triphenylphosphine) palladium), under basic conditions (providing basic conditions The reagent is preferably sodium carbonate) to obtain a compound of general formula (II-9); or a compound of general formula (II-7) with boric acid or a borate compound (preferably pinacol biborate), in Under the action of a catalyst (preferably [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride), the reaction is obtained under alkaline conditions (the reagent providing alkaline conditions is preferably potassium acetate). The compound of formula (II-8a), the compound of general formula (II-8a) and the compound of general formula (I-8b), under the action of a catalyst (preferably tetrakis(triphenylphosphine)palladium), under basic conditions (The reagent providing alkaline conditions is preferably sodium carbonate) to obtain a compound of general formula (II-9);

In the sixth step, the compound of general formula (II-9) is subjected to acidic conditions (the reagent providing acidic conditions is preferably a 1,4-dioxane solution of hydrogen chloride) to remove the amino protecting group to obtain the general formula (II- A) the compound;

The seventh step, the compound of general formula (II-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, Or a mixture thereof, or a pharmaceutically acceptable salt thereof, and a compound of general formula (IB) are reacted under alkaline conditions (the reagent providing alkaline conditions is preferably triethylamine) to obtain a compound of general formula (II) or Its atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof,

among them:

R ^w is an amino protecting group; preferably tert-butoxycarbonyl;

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, R ¹ , R ² , R ^3a , R ^3b , R ⁴ to R ⁸ , R ¹⁰ , R ¹¹ , r and s are as defined in the general formula (II).

third solution

The compound represented by the general formula (Ia) or (Ib) of the present disclosure or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer The preparation method of the body, its mixture form, or its pharmaceutically acceptable salt includes the following steps:

The compound of the general formula (Ia-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or a pharmaceutically acceptable salt thereof, reacts with a compound of general formula (IB) under basic conditions to obtain a compound of general formula (Ia) or its atropisomer, tautomer, and meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (Ib-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt reacts with the compound of general formula (IB) under basic conditions to obtain the compound of general formula (Ib) or its atropisomer, tautomer, meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ⁶ , r, s, and t are as defined in the general formula (I).

Option Four

The compound represented by the general formula (IIM) of the present disclosure or its atropisomer, tautomer, mesoisomer, racemate, enantiomer, diastereomer, or The preparation method of the mixture form, or its pharmaceutically acceptable salt, includes the following steps:

The compound of the general formula (IIM-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt reacts with the compound of general formula (IB) under alkaline conditions to obtain the compound of general formula (IIM) or its atropisomer, tautomer, meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in general formula (IIM).

Option Five

The compound represented by the general formula (IIMa) or (IIMb) of the present disclosure or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer The preparation method of the body, its mixture form, or its pharmaceutically acceptable salt includes the following steps:

The compound of the general formula (IIMa-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt reacts with the compound of general formula (IB) under alkaline conditions to obtain the compound of general formula (IIMa) or its atropisomer, tautomer, meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of general formula (IIMb-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt reacts with the compound of general formula (IB) under basic conditions to obtain the compound of general formula (IIMb) or its atropisomer, tautomer, meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in general formula (IIM).

Option Six

The compound represented by the general formula (IIMa-1) or (IIMa-2) of the present disclosure or its atropisomer, tautomer, meso, racemate, enantiomer, non- The preparation method of enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof includes the following steps:

The compound of the general formula (IIMa-1-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMa-1) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMa-2-A) and its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of its mixture, or its pharmaceutically acceptable salt, the compound of general formula (IB) reacts under alkaline conditions to obtain the compound of general formula (IIMa-2) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in the general formula (IIMa-1).

Option Seven

The compound represented by the general formula (IIMa-3), (IIMa-4), (IIMb-1) or (IIMb-2) of the present disclosure or its atropisomer, tautomer, meso, The preparation method of racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

The compound of the general formula (IIMa-3-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, and a compound of general formula (IB) react under alkaline conditions to obtain a compound of general formula (IIMa-3) or atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMa-4-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with the compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMa-4) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMb-1-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, and a compound of general formula (IB) react under alkaline conditions to obtain a compound of general formula (IIMb-1) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMb-2-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMb-2) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in general formula (IIM).

Option Eight

The compound represented by the general formula (IIMa-5), (IIMa-6), (IIMa-7) or (IIMa-8) of the present disclosure or its atropisomer, tautomer, meso, The method for preparing racemates, enantiomers, diastereomers, or mixtures thereof or their pharmaceutically acceptable salts includes the following steps:

The compound of the general formula (IIMa-5-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, reacts with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMa-5) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMa-6-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, and a compound of general formula (IB) are reacted under alkaline conditions to obtain a compound of general formula (IIMa-6) or atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMa-7-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMa-7) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMa-8-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, and a compound of general formula (IB) react under alkaline conditions to obtain a compound of general formula (IIMa-8) or atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in the general formula (IIMa-1).

Option 9

The compound represented by the general formula (IIa) or (IIb) of the present disclosure or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer The preparation method of the body or its mixture form, or its pharmaceutically acceptable salt, comprises the following steps:

The compound of the general formula (IIa-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt reacts with the compound of general formula (IB) under alkaline conditions to obtain the compound of general formula (IIa) or its atropisomer, tautomer, meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIb-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof , Or its pharmaceutically acceptable salt reacts with the compound of general formula (IB) under alkaline conditions to obtain the compound of general formula (IIb) or its atropisomer, tautomer, meso , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, R ¹ , R ² , R ^3a , R ^3b , R ⁴ to R ⁸ , R ¹⁰ , R ¹¹ , r and s are as defined in the general formula (II).

Option ten

The compound represented by the general formula (IIMa-3), (IIMa-4), (IIMb-1) or (IIMb-2) of the present disclosure or its atropisomer, tautomer, meso, The preparation method of racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

General formula (IIMa) or its atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers, or mixtures thereof, or The medicinal salt is chirally prepared to obtain compounds of general formula (IIMa-3) and general formula (IIMa-4) or atropisomers, tautomers, meso forms, and racemates , Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

Chiral preparation of general formula (IIMb) to obtain compounds of general formula (IIMb-1) and general formula (IIMb-2) or their atropisomers, tautomers, mesoisomers, racemates Isomers, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in general formula (IIM).

Option 11

The compound represented by the general formula (IIMa-5), (IIMa-6), (IIMa-7) or (IIMa-8) of the present disclosure or its atropisomer, tautomer, meso, The preparation method of racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

General formula (IIMa-1) or its atropisomers, tautomers, mesoisomers, racemates, enantiomers, diastereomers, or mixtures thereof, or The pharmaceutically acceptable salts are chirally prepared to obtain compounds of general formula (IIMa-5) and general formula (IIMa-6) or atropisomers, tautomers, mesoisomers, exogenous Rotators, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

General formula (IIMa-2) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form, or Its pharmaceutically acceptable salts are chirally prepared to obtain compounds of general formula (IIMb-7) and general formula (IIMb-8) or atropisomers, tautomers, mesoisomers, exogenous Rotators, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in the general formula (IIMa-1).

Scheme 12

The compound represented by the general formula (IIMb-7) or (IIMb-8) of the present disclosure or its atropisomer, tautomer, meso, racemate, enantiomer, non- The preparation method of enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof includes the following steps:

The compound of the general formula (IIMb-7-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMb-7) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMb-8-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMb-8) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in the general formula (IIMb-7).

Scheme 13

The compound represented by the general formula (IIMb-3), (IIMb-4), (IIMb-5) or (IIMb-6) of the present disclosure or its atropisomer, tautomer, meso, The preparation method of racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

The compound of the general formula (IIMb-3-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, and a compound of general formula (IB) react under basic conditions to obtain a compound of general formula (IIMb-3) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMb-4-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMb-4) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMb-5-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMb-5) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The compound of the general formula (IIMb-6-A) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof, react with a compound of general formula (IB) under alkaline conditions to obtain a compound of general formula (IIMb-6) or its atropisomer, tautomer, Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

X is halogen, preferably chlorine;

M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid;

n is 0, 1, 2 or 3, preferably 0 or 1;

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in the general formula (IIMb-7).

Scheme Fourteen

The compound represented by the general formula (IIMb-3), (IIMb-4), (IIMb-5) or (IIMb-6) of the present disclosure or its atropisomer, tautomer, meso, The preparation method of racemate, enantiomer, diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, includes the following steps:

General formula (IIMb-7) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form, or The pharmaceutically acceptable salts are chirally prepared to obtain compounds of general formula (IIMb-3) and general formula (IIMb-4) or atropisomers, tautomers, mesoisomers, and exogenous Rotators, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

The general formula (IIMb-8) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or a mixture thereof, or The pharmaceutically acceptable salts are chirally prepared to obtain compounds of general formula (IIMb-5) and general formula (IIMb-6) or atropisomers, tautomers, mesoisomers, and exogenous Rotators, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof;

among them:

Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in the general formula (IIMb-7).

Reagents that provide acidic conditions include, but are not limited to, hydrogen chloride, 1,4-dioxane solution of hydrogen chloride, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-benzene Methanesulfonic acid and TMSOTf.

The reagents that provide alkaline conditions include organic bases and inorganic bases. The organic bases include, but are not limited to, triethylamine, N,N-diisopropylethylamine, n-butyllithium, and lithium diisopropylamide. , Lithium bistrimethylsilylamide, potassium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide and sodium n-butoxide, the inorganic bases include but are not limited to sodium bicarbonate, potassium bicarbonate, hydrogenation Sodium, potassium phosphate, sodium carbonate, potassium carbonate, potassium acetate, cesium carbonate, sodium hydroxide and lithium hydroxide.

The catalyst includes, but is not limited to, palladium/carbon, tetrakis (triphenylphosphine) palladium, palladium dichloride, palladium acetate, bis(dibenzylideneacetone) palladium, chlorine (2-dicyclohexylphosphino-2) ',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium, [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride, 1,1'-bis(dibenzylphosphorus)dipentyliron palladium or tris(dibenzylideneacetone)dipalladium.

The above reaction is preferably carried out in a solvent. The solvents used include but are not limited to: acetic acid, methanol, ethanol, n-butanol, tert-butanol, toluene, acetonitrile, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, n-hexane, Methyl sulfoxide, 1,4-dioxane, ethylene glycol dimethyl ether, water or N,N-dimethylformamide and mixtures thereof.

Detailed ways

The following embodiments are used to further describe the present disclosure, but these embodiments do not limit the scope of the present disclosure.

Example

The structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS). The NMR shift (δ) is given in units of 10 ^-6 (ppm). NMR was measured with Bruker AVANCE-400 nuclear magnetic instrument, and the solvent was deuterated dimethyl sulfoxide (DMSO-d ₆ ), deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD), and the internal standard was four Methylsilane (TMS).

For MS measurement, Agilent 1200/1290 DAD-6110/6120 Quadrupole MS liquid-mass spectrometer (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS); waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS Model: waters ACQuity Qda Detector/waters SQ Detector); THERMO Ultimate 3000-Q Exactive (manufacturer: THERMO, MS model: THERMO Q Exactive).

High performance liquid chromatography (HPLC) analysis uses Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 high pressure liquid chromatograph.

Chiral HPLC analysis and determination use Agilent 1260 DAD high performance liquid chromatograph.

The HPLC preparation uses Waters 2545-2767, Waters 2767-SQ Detecor2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs.

For chiral preparation, Shimadzu LC-20AP preparative chromatograph was used.

CombiFlash rapid preparation instrument uses Combiflash Rf200 (TELEDYNE ISCO).

The thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used in thin layer chromatography (TLC) is 0.15mm～0.2mm, and the size of thin layer chromatography separation and purification products is 0.4mm ~0.5mm.

Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica as the carrier.

The average value of ₅₀ measured kinase inhibition rate and IC NovoStar using a microplate reader (BMG, Germany).

The known starting materials of the present disclosure can be synthesized by or according to methods known in the art, or can be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Darui Chemicals and other companies.

There is no special description in the examples, and the reaction can all be carried out under an argon atmosphere or a nitrogen atmosphere.

The argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon with a volume of about 1L.

The hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses Parr 3916EKX hydrogenator and Qinglan QL-500 hydrogen generator or HC2-SS hydrogenator.

The hydrogenation reaction is usually evacuated, filled with hydrogen, and repeated three times.

The microwave reaction uses the CEM Discover-S 908860 microwave reactor.

There is no special description in the examples, and the solution refers to an aqueous solution.

There are no special instructions in the examples, and the reaction temperature is room temperature, which is 20°C to 30°C.

The monitoring of the reaction progress in the examples adopts thin-layer chromatography (TLC). The developing reagent used in the reaction, the eluent system of column chromatography used in the purification of the compound and the developing reagent system of thin-layer chromatography include: A: Dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: petroleum ether/ethyl acetate system, D: acetone, E: dichloromethane/acetone system, F: ethyl acetate/dichloromethane system , G: ethyl acetate/dichloromethane/n-hexane, H: ethyl acetate/dichloromethane/acetone, I: methanol/ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound. It can be adjusted by adding a small amount of alkaline or acidic reagents such as triethylamine and acetic acid.

Example 1

2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a-hexahydropyridine Azino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one 1

first step

4-bromo-2,6-difluorobenzamide 1b

Dissolve 4-bromo-2,6-difluorobenzoic acid 1a (10.0g, 42.29mmol, finished) in thionyl chloride (50mL, Titan), stir and react at 70°C for 5 hours, stop the reaction, Liquid concentrate. Next, 40 mL of 1,4-dioxane was added to the reaction solution, and ammonia water (65 mL, Titan) was added to the reaction solution at 0° C., and the reaction was stirred for 1 hour. The reaction solution was extracted with dichloromethane (100 mL×3), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The title product 1b (8.5g) was obtained, yield: 85%.

MS m/z(ESI): 237.9[M+1].

Second step

4-bromo-2,6-difluoro-N-((2-isopropylphenyl)carbamoyl)benzamide 1c

Compound 1b (8.0 g, 33.89 mmol) was dissolved in 500 mL 1,2-dichloroethane, oxalyl chloride (50 mL, Admas) was added, the reaction solution was stirred at 80° C. for 5 hours, the reaction was stopped, and the reaction solution was concentrated. Then 100 mL of dichloromethane was added to the residue, and 2-isopropylaniline (5.5 g, 40.68 mmol, completed) was added to the residue at 0° C., and the reaction was stirred for 30 minutes. The reaction solution was added with water and extracted with dichloromethane (30 mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purified by silica gel column chromatography with eluent system B to obtain the title product 1c (11.5g), yield: 85%.

MS m/z(ESI): 396.9[M+1].

third step

3-(((7-bromo-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)oxy) (Methyl) piperazine-1-carboxylic acid tert-butyl ester 1d

Dissolve tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate (5.4g, 25.18mmol, Shaoyuan) in 250mL N,N-dimethylformamide, stir and use the reaction solution under argon atmosphere Cool down in an ice bath. Then, sodium hydride (3.0 g, 125.9 mmol, 60% purity, Titan) was slowly added to the reaction solution, and after the addition, the reaction solution was kept at 0° C. and stirred for 5 hours. Then, 50 mL of compound 1c (5.0 g, 12.59 mmol) was dissolved in N,N-dimethylformamide, slowly poured into the reaction solution, and reacted at room temperature for 16 hours. The reaction solution was added with saturated ammonium chloride solution and extracted with dichloromethane (30 mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purified by silica gel column chromatography with eluent system C to obtain the title product 1d (4.8 g), yield: 66%.

MS m/z(ESI): 573.4[M+1].

the fourth step

10-Bromo-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2',1':3,4][ 1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 1e

Compound 1d (4.5g, 7.86mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (10.4g, 23.50mmol, Shanghai Shao Yuan Reagent Co., Ltd.) was dissolved in acetonitrile/tetrahydrofuran (150mL/150mL), the reaction solution was stirred under an argon atmosphere for 10 minutes, and then 1,8-diazabicyclo[5.4.0]undec- 7-ene (DBU) (7.2g, 47.16mmol, Anaiji), after the addition, the reaction solution was raised to room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title product 1e (3.0 g), yield: 68%.

MS m/z(ESI): 557.3[M+1].

the fifth step

8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-7-oxo-3,4,7,8,13,13a-hexahydropyridine Azino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 1f

Compound 1e (300mg, 0.541mmol), (5-methyl-1H-indazol-4-yl)boronic acid (142mg, 0.810mmol, complete), tetrakis(triphenylphosphine)palladium (62mg, 0.054mmol, Greenchemer) and sodium carbonate (172mg, 1.623mmol, Titan) were dissolved in N,N-dimethylformamide/water (2mL/0.2mL) and stirred at 120°C for 16 hours under argon atmosphere. The reaction solution was concentrated under reduced pressure to obtain a crude product, which was purified by silica gel column chromatography with eluent system B to obtain the title product 1f (162 mg), yield: 44%.

MS m/z(ESI): 607.2[M+1].

Sixth step

8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a-hexahydropyrazino[2' ,1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 1g

Compound 1f (162 mg, 0.267 mmol) was dissolved in 5 mL of dichloromethane, and hydrogen chloride/1,4-dioxane solution (4M, 5 mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain 1 g (130 mg) of the crude title product, which was directly used in the next reaction without purification.

MS m/z(ESI): 507.3[M+1].

Seventh step

2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a-hexahydropyridine Azino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one 1

1g (130mg, 0.257mmol) of the crude compound was dissolved in 5mL of dichloromethane, and acryloyl chloride (23.0mg, 0.257mmol, Anaiji) was added dropwise to the reaction solution at 0°C, and then triethylamine (78.0mg, Titan ). The reaction was stirred at room temperature for 30 minutes. Water (20 mL) was added to the reaction solution, extracted with dichloromethane (20 mL × 3), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by high performance liquid chromatography to obtain the title product 1 (29.09 mg), yield: 20%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.09 (s, 1H), 7.49-7.42 (m, 2H), 7.38-7.30 (m, 3H), 7.18-7.16 (m, 2H), 6.91 6.82 (m, 2H), 6.21 (d, 1H), 5.95 (dd, 1H), 5.77 (dd, 1H), 4.77-4.62 (m, 3H), 4.45-4.07 (m, 3H), 3.56-3.46 ( m, 2H), 3.24-3.14 (m, 1H), 2.72-2.64 (m, 1H), 2.13 (d, 3H), 1.12-1.09 (m, 3H), 1.05-0.98 (m, 3H).

MS m/z(ESI): 561.6[M+1].

Example 1-1,1-2,1-3,1-4

(8S,4S)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one block Transisomer 1-1

(8S,4R)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one block Transisomer 1-2

(8R,4S)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one block Transisomer 1-3

(8R,4R)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one block Transisomer 1-4

Chiral preparation of compound 1 (110mg) (Separation conditions: chiral preparation column CHIRALCEL OD-H (ODH0CD-TC012), column model: 0.46cm ID×15cm L; mobile phase: methanol=100%, flow rate: 2.0mL /min), the corresponding components were collected and concentrated under reduced pressure to obtain a title product (20.33mg, retention time: 8.413 minutes) and mixture. Then the mixture was subjected to a second chiral preparation (separation conditions: chiral preparation column CHIRALPAK OZ-H (OZH0CD-VF004), column model: 0.46cm ID×15cm L; mobile phase: methanol=100%, flow rate: 4.0mL /min), the corresponding components were collected and concentrated under reduced pressure to obtain 3 title products (15.11 mg, retention time 6.133 minutes), (15.55 mg, retention time 6.962 minutes), (17.72 mg, retention time 9.343 minutes).

Single configuration compound (retention time 6.133 minutes):

Chiral HPLC analysis method: retention time 6.133 minutes (column: CHIRALPAK OZ-H (OZH0CD-VF004), 0.46 cm I.D.×15 cm L; mobile phase: methanol = 100%).

MS m/z(ESI): 561.6[M+H];

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.09 (s, 1H), 7.48 (m, 2H), 7.42-7.36 (m, 2H), 7.32-7.29 (m, 1H), 7.19-7.16 ( m,2H),6.89-6.82(m,2H),6.22-6.18(d,1H),5.94-5.94(d,1H),5.78-5.76(dd,1H),4.72-4.06(m,6H), 3.53-3.40(m,2H),3.24-3.17(m,1H),2.67-2.65(m,1H),2.13(s,3H),1.12-1.10(d,3H),0.97-0.95(d,3H) ).

Single configuration compound (retention time 6.962 minutes):

Chiral HPLC analysis method: retention time 6.962 minutes (chromatographic column: CHIRALPAK OZ-H (OZH0CD-VF004), 0.46 cm I.D.×15 cm L; mobile phase: methanol = 100%).

MS m/z(ESI): 561.6[M+H];

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.09 (s, 1H), 7.47-7.47 (m, 2H), 7.42-7.37 (m, 2H), 7.32-7.32 (m, 1H), 7.22 7.18(m,2H),6.89-6.83(m,2H),6.23-6.18(d,1H),5.96-5.95(d,1H),5.78-5.75(dd,1H),4.75-4.06(m,6H) ), 3.49-3.44 (m, 2H), 3.20-3.17 (m, 1H), 2.72-2.68 (m, 1H), 2.13 (s, 3H), 1.11-1.09 (d, 3H), 1.00-0.98 (d ,3H).

Single configuration compound (retention time 8.413 minutes):

Chiral HPLC analysis method: retention time 8.413 minutes (column: CHIRALCEL OD-H (ODH0CD-TC012), 0.46 cm I.D.×15 cm L; mobile phase: methanol = 100%).

MS m/z(ESI): 561.6[M+H];

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.09 (s, 1H), 7.49 (m, 2H), 7.42-7.36 (m, 2H), 7.32-7.29 (m, 1H), 7.22-7.18 ( m,2H),6.90-6.82(m,2H),6.22-6.18(d,1H),5.96-5.95(d,1H),5.78-5.75(dd,1H),4.78-4.05(m,6H), 3.49-3.39(m,2H), 3.25-3.17(m,1H), 2.72-2.68(m,1H), 2.13(s,3H), 1.09(d,3H), 1.00-0.98(d,3H).

Single configuration compound (retention time 9.343 minutes):

Chiral HPLC analysis method: retention time 9.343 minutes (column: CHIRALPAK OZ-H (OZH0CD-VF004), 0.46 cm I.D.×15 cm L; mobile phase: methanol = 100%).

MS m/z(ESI): 561.5[M+H];

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.09 (s, 1H), 7.48-7.46 (m, 2H), 7.42-7.38 (m, 2H), 7.32-7.29 (m, 1H), 7.21 7.18(m,2H),6.91-6.82(m,2H),6.22-6.18(d,1H),5.94-5.94(d,1H),5.78-5.75(dd,1H),4.72-4.06(m,6H) ), 3.53-3.40 (m, 2H), 3.21-3.18 (m, 1H), 2.67-2.65 (m, 1H), 2.13 (s, 3H), 1.12-1.10 (d, 3H), 0.97-0.95 (d ,3H).

Example 2

2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazino[2 ',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 2

first step

10-(2-Fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2 ',1': 3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 2a

Compound 1e (300mg, 0.541mmol), (2-fluoro-6-hydroxyphenyl) boronic acid (168mg1.083mmol Dingdong Chemical), tetrakistriphenylphosphine palladium (62mg, 0.054mmol, Greenchem) and sodium carbonate ( 172mg, 1.623mmol, Titan) was dispersed in N,N-dimethylformamide/water (2mL/0.2mL), and the reaction was stirred at 120°C for 16 hours under an argon atmosphere. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title product 2a (150 mg), yield: 47%.

MS m/z(ESI): 587.1 [M+1].

Second step

10-(2-Fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazino[2',1': 3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 2b

Compound 2a (130 mg, 0.221 mmol) was dissolved in 5 mL of dichloromethane, hydrogen chloride/1,4-dioxane solution (4M, 5 mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 30 minutes. The reaction solution was concentrated to obtain the title product crude product 2b (107 mg), which was directly used in the next reaction without purification.

MS m/z(ESI): 487.1[M+1].

third step

2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazino[2 ',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 2

The crude compound 2b (107mg, 0.204mmol) was dissolved in 5mL of dichloromethane, and acryloyl chloride (19.0mg, 0.204mmol, Anaiji) was added dropwise to the reaction solution at 0°C, and then triethylamine (62.0mg, 0.612 mmol, Titan). The reaction was stirred at room temperature for 30 minutes. The reaction solution was quenched with water (20 mL), extracted with dichloromethane (20 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by high performance liquid chromatography to obtain the title product 2 (24.92 mg), yield: 22%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.52-7.47 (m, 2H), 7.31-7.30 (m, 2H), 7.19-7.17 (m, 1H), 7.15-7.13 (m, 1H), 7.09- 7.06(m,1H),6.97-6.58(m,3H),6.43-6.35(m,2H), 5.87-5.84(d,1H), 5.12-5.10(m,1H),4.73-4.70(m,1H) ), 4.57-4.47 (m, 2H), 4.01-4.00 (m, 2H), 3.53-3.51 (m, 1H), 3.50-3.33 (m, 1H), 2.70-2.66 (m, 1H), 1.23-1.20 (m, 3H), 1.09-1.07 (m, 3H).

¹⁹ F NMR (376MHz, CDCl ₃ ): δ-75.88 (s, 1F), -114.70 (d, 1F).

MS m/z(ESI): 541.5[M+1].

Example 3

2-acryloyl-8-(2-isopropylphenyl)-10-(8-methylnaphthalene-1-yl)-1,2,3,4,13,13a-hexahydropyrazino[2 ',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 3

first step

1-bromo-8-methylnaphthalene 3b

1,8-Dibromonaphthalene 3a (5.0 g, 17.5 mmol, Shanghai Bi De Pharmaceutical Technology Co., Ltd.) was dissolved in dry 100 mL tetrahydrofuran, and the reaction solution was cooled to 0° C. under an argon atmosphere. Methyl lithium (1.6M tetrahydrofuran solution, 13.1 mL, 21 mmol, damas-bata) was added dropwise to the reaction solution, and then the reaction solution was stirred at 0°C for 30 minutes. Iodomethane (734 mL, 119 mmol, Longsheng) was added dropwise to the reaction solution. Then the reaction solution was slowly heated to 25°C and stirred for 1 hour. The reaction solution was cooled to 0°C, and then 100 mL of water was slowly added, extracted with ethyl acetate (50 mL×2), the organic phases were combined, washed with saturated sodium chloride, dried with anhydrous sodium sulfate, filtered, and the filtrate was spin-dried. The crude product was purified by silica gel column chromatography with eluent system B to obtain the title product 3b (2.1 g), yield: 54%.

¹ H NMR (400MHz, CDCl ₃ ): δ7.82 (d, J = 7.2Hz, 1H), 7.76 (d, J = 8.0Hz, 1H), 7.70-7.68 (m, 1H), 7.35-7.32 (m , 2H), 7.22 (t, J = 10.0 Hz, 1H), 3.12 (s, 3H).

Second step

(2-(tert-Butoxycarbonyl)-8-(2-isopropylphenyl)-7-oxo-1,2,3,4,7,8,13,13a-octahydropyrazino[ 2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-10-yl)boronic acid 3c

Compound 1e (1.0g, 1.80mmol), pinacol biborate (548mg, 2.16mmol, completed), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride ( 132 mg, 0.18 mmol, Greenchemer) and potassium acetate (529 mg, 5.40 mmol, Titan) were dissolved in 20 mL of dimethyl sulfoxide, and the reaction was stirred at 120°C for 16 hours under an argon atmosphere. The reaction solution was cooled and concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system A to obtain the title product 3c (500 g), yield: 53%.

MS m/z(ESI): 521.0[M+1].

third step

8-(2-isopropylphenyl)-10-(8-methylnaphthalene-1-yl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2 ',1': 3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 3d

Compound 3c (500mg, 0.96mmol), compound 3b (212mg, 0.64mmol), tetrakis(triphenylphosphine) palladium (74mg, 0.064mmol, Greenchemer) and sodium carbonate (204mg, 1.92mmol, Titan) were dissolved in In N,N-dimethylformamide/water (10 mL/1 mL), the reaction was stirred at 100°C for 16 hours under an argon atmosphere. The reaction solution was cooled and concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system A to obtain the title product 3d (300 mg), yield: 50%.

MS m/z(ESI): 617.1 [M+1].

the fourth step

8-(2-isopropylphenyl)-10-(8-methylnaphthalene-1-yl)-1,2,3,4,13,13a-hexahydropyrazino[2',1': 3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 3e

Compound 3d (300 mg, 0.49 mmol) was dissolved in 5 mL of dichloromethane, hydrogen chloride (4M, 1,4-dioxane solution, 10 mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the title product 3e (250 mg), which was directly used in the next reaction without purification.

MS m/z(ESI): 517.1 [M+1].

the fifth step

2-acryloyl-8-(2-isopropylphenyl)-10-(8-methylnaphthalene-1-yl)-1,2,3,4,13,13a-hexahydropyrazino[2 ',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 3

Compound 3e (250 mg, 0.48 mmol) was dissolved in 5 mL of dichloromethane, acryloyl chloride (52.3 mg, Anaiji) was added dropwise to the reaction solution at 0°C, and then triethylamine (145 mg, Titan) was added. The reaction was stirred at room temperature for 1 hour. After adding saturated sodium bicarbonate aqueous solution to the reaction solution, it was extracted with dichloromethane (50 mL×3), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by high performance liquid chromatography to obtain the title product 3 (80 mg), yield: 28%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.91(d,J=7.6Hz,1H), 7.81(d,J=8.4Hz,1H),7.43-7.41(m,4H),7.28-7.23 (m,2H),7.12-7.08(m,2H),6.93-6.89(m,1H),6.81-6.77(m,1H),6.23-6.18(m,1H),5.86-5.83(m,1H) ,5.77(dd,J=6.4,2.4Hz,1H),4.78-4.03(m,6H),3.50-3.44(m,2H),3.24-3.21(m,1H),2.68-2.55(m,1H) , 2.04-2.00 (m, 3H), 1.10 (t, J=5.8 Hz, 3H), 0.98-0.95 (m, 3H).

MS m/z(ESI): 571.3[M+1].

Example 4

2-acryloyl-10-(8-methylnaphthalene-1-yl)-8-(o-tolyl)-1,2,3,4,13,13a-hexahydropyrazino[2',1' :3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 4

first step

4-bromo-2,6-difluoro-N-((o-tolyl)carbamoyl)benzamide 4a

Compound 1b (5.0 g, 21.18 mmol) was dissolved in 300 mL of 1,2-dichloroethane, oxalyl chloride (30 mL, Admas) was added, the reaction solution was stirred at 80° C. for 5 hours, the reaction was stopped, and the reaction solution was concentrated. Then, 80 mL of dichloromethane was added to the reaction solution, dropped to 0° C., o-methylaniline (2.3 g, 21.18 mmol, finished) was added, and the reaction was stirred for 30 minutes. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by silica gel column chromatography with eluent system C to obtain the title product 4a (7.0 g), yield: 89%.

MS m/z(ESI): 366.9[M-1].

Second step

(3-(((7-Bromo-1-(o-tolyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)oxy)methyl) Piperazine-1-carboxylic acid tert-butyl ester 4b

Dissolve tert-butyl 3-hydroxymethylpiperazine-1-carboxylate (8.2g, 37.94mmol, Shaoyuan) in 250mL N,N-dimethylformamide, stir the reaction solution under argon atmosphere and use an ice bath Cool down. Then, sodium hydride (4.5 g, 189.7 mmol, Titan) was slowly added to the reaction solution, and after the addition, the reaction solution was kept at 0° C. and stirred for 5 hours. Then compound 4a (7.0 g, 18.97 mmol) was dissolved in 50 mL of N,N-dimethylformamide, slowly injected into the reaction solution, and reacted at room temperature for 16 hours. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (30 mL×2), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. Purified by silica gel column chromatography with eluent system C to obtain the title product 4b (8.6g), yield: 83%.

MS m/z(ESI): 545.5[M+1].

third step

10-bromo-7-oxo-8-(o-tolyl)-3,4,7,8,13,13a-hexahydropyrazino[2',1':3,4][1,4] Oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 4c

At 0°C, compound 4b (8.6g, 15.77mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (20.9g, 47.33mmol, Shao Far) was dissolved in acetonitrile/tetrahydrofuran (200mL/200mL), the reaction solution was stirred under an argon atmosphere for 10 minutes, and then 1,8-diazabicyclo[5.4.0]undec-7-ene was added to the reaction solution (DBU) (14.4g, 94.67mmol, Anaiji), after the addition, the reaction solution was raised to room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title product 4c (5.1 g), yield: 61%.

MS m/z(ESI): 526.9[M+1].

the fourth step

(2-(tert-Butoxycarbonyl)-7-oxo-8-(o-tolyl)-1,2,3,4,7,8,13,13a-octahydropyrazino[2',1 ':3,4][1,4]oxazepine[5,6,7-de]quinazolin-10-yl)boronic acid 4d

The compound 4c (2.0g, 3.80mmol), pinacol biborate (1.1g, 4.56mmol, complete), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (278 mg, 0.38 mmol, Greenchemer) and potassium acetate (1.1 g, 11.4 mmol, Titan) were dissolved in 20 mL of dimethyl sulfoxide, and the reaction was stirred at 80°C for 16 hours under an argon atmosphere. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system A to obtain the title product crude product 4d (1.0 g), yield: 53%.

MS m/z(ESI): 493[M+1].

the fifth step

10-(8-Methylnaphthalene-1-yl)-7-oxo-8-(o-tolyl)-3,4,7,8,13,13a-hexahydropyrazino[2',1' :3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 4e

The crude compound 4d (1.0g, 2.03mmol), compound 3b (449mg, 2.03mmol), tetrakis(triphenylphosphine) palladium (234mg, 0.203mmol, Greenchemer) and sodium carbonate (645mg, 6.09mmol, Titan) Dissolved in N,N-dimethylformamide/water (10 mL/1 mL), the reaction was stirred at 80°C for 16 hours under an argon atmosphere. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title product 4e (600 mg), yield: 50%.

MS m/z(ESI): 589[M+1].

Sixth step

10-(8-Methylnaphthalene-1-yl)-8-(o-tolyl)-1,2,3,4,13,13a-hexahydropyrazino[2',1':3,4] [1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 4f

Compound 4e (600 mg, 1.02 mmol) was dissolved in 5 mL of dichloromethane, hydrogen chloride/1,4-dioxane solution (4M, 10 mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the title product 4f (490mg), which was directly used in the next step without purification.

MS m/z(ESI): 489[M+1].

Seventh step

2-acryloyl-10-(8-methylnaphthalene-1-yl)-8-(o-tolyl)-1,2,3,4,13,13a-hexahydropyrazino[2',1' :3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 4

The crude product 4f (490 mg, 1.00 mmol) was dissolved in 5 mL of dichloromethane, acryloyl chloride (91.0 mg, 1.00 mmol, Anaiji) was added dropwise to the reaction solution at 0°C, and then triethylamine (303 mg, Titan) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by high performance liquid chromatography to obtain the title product 4 (230 mg), yield: 42%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.92 (d, 1H), 7.81 (d, 1H), 7.43-7.37 (m, 3H), 7.30-7.28 (m, 3H), 7.18-7.17 ( m, 2H), 6.93-6.78 (m, 2H), 6.21 (d, 1H), 5.84-5.75 (m, 2H), 4.69-4.02 (m, 6H), 3.53-3.45 (m, 2H), 3.26 3.09 (m, 1H), 2.04-1.97 (m, 6H).

MS m/z(ESI): 543.3[M+1].

Example 5

2-acryloyl-8-(2-cyclopropylphenyl)-10-(8-methylnaphthalene-1-yl)-1,2,3,4,13,13a-hexahydropyrazino[2 ',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 5

first step

1-cyclopropyl-2-nitrobenzene 5b

Combine 1-bromo-2-nitrobenzene 5a (20.0g, 99.0mmol, Aladdin), cyclopropylboronic acid (17.0g, 198.0mmol, WuXibo), palladium acetate (665mg, 2.97mmol, Zhejiang Metallurgical Research Institute) and 2-Dicyclohexylphosphine-2',6'-dimethoxy-biphenyl (S-Phos) (1.6g, 3.96mmol, Greenchem) dissolved in toluene/water (20mL/1mL) Under argon atmosphere, the reaction was stirred at 100°C for 3 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title product 5b (12.0 g), yield: 74%.

MS m/z(ESI): 164[M+1].

Second step

2-cyclopropylaniline 5c

Compound 5b (5.0 g, 30.67 mmol) was dissolved in 100 mL tetrahydrofuran. Then, zinc powder/ammonium chloride (20.0g/16.0g, 300.67mmol/300.67mmol, Titan/Titan) was slowly added to the reaction solution, and after the addition, the reaction solution was stirred and reacted at 80°C for 1 hour. The reaction was cooled to room temperature, filtered with celite, and the filtrate was concentrated under reduced pressure to obtain the crude title product 5c (4.0 g). The product was directly used in the next step without purification.

MS m/z(ESI): 134.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ 6.87 (t, 1H), 6.79 (d, 1H), 6.60 (dd, 1H), 6.45 (t, 1H), 4.91 (s, 2H), 1.66 -1.60 (m, 1H), 0.86-0.80 (m, 2H), 0.48-0.43 (m, 2H).

third step

4-bromo-N-((2-cyclopropylphenyl)carbamoyl)-2,6-difluorobenzamide 5d

Compound 5c (5.0 g, 21.18 mmol) was dissolved in 300 mL 1,2-dichloroethane, oxalyl chloride (30 mL, Admas) was added, the reaction solution was stirred at 80° C. for 5 hours, the reaction was stopped, and the reaction solution was concentrated. Then, 80 mL of dichloromethane was added to the reaction solution, the temperature was reduced to 0° C., compound 1b (2.8 g, 21.18 mmol) was added, and the reaction was stirred for 30 minutes. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by silica gel column chromatography with eluent system C to obtain the title product 5d (6.8g), yield: 81%.

MS m/z(ESI): 396.8[M+1].

the fourth step

3-(((7-bromo-1-(2-cyclopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl)oxy) (Methyl) piperazine-1-carboxylic acid tert-butyl ester 5e

Dissolve tert-butyl 3-hydroxymethylpiperazine-1-carboxylate (7.4g, 34.43mmol, Shaoyuan) in 200mL N,N-dimethylformamide, and stir the reaction solution under an argon atmosphere and use an ice bath Cool down. Then, sodium hydride (4.1 g, 60%, 172.15 mmol, Titan) was slowly added to the reaction solution, and after the addition, the reaction solution was kept at 0° C. and stirred for 5 hours. Then compound 5d (6.8 g, 17.21 mmol) was dissolved in 50 mL of N,N-dimethylformamide, slowly injected into the reaction solution, and reacted at room temperature for 16 hours. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (30 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by silica gel column chromatography with eluent system C to obtain the title product 5e (6.1 g), yield: 62%.

MS m/z(ESI): 570.9[M+1].

the fifth step

10-Bromo-8-(2-cyclopropylphenyl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2',1':3,4][ 1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 5f

Compound 5e (6.1g, 10.67mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (14.1g, 32.02mmol, Shaoyuan) at 0°C ) Was dissolved in acetonitrile/tetrahydrofuran (200mL/200mL), the reaction solution was stirred under an argon atmosphere for 10 minutes, and then 1,8-diazabicyclo[5.4.0]undec-7-ene ( DBU) (9.7g, 64.04mmol, Anaiji), after the addition, the reaction solution was raised to room temperature and stirred for 16 hours. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title product 5f (4.7 g), yield: 79%.

MS m/z(ESI): 554.9[M+1].

Sixth step

(2-(tert-Butoxycarbonyl)-8-(2-cyclopropylphenyl)-7-oxo-1,2,3,4,7,8,13,13a-octahydropyrazino[ 2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-10-yl)boronic acid 5g

Compound 5f (2.0g, 3.62mmol), pinacol diborate (1.09g, 4.34mmol, complete), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (265 mg, 0.36 mmol, Greenchemer) and potassium acetate (1.06 g, 10.85 mmol, Titan) were dissolved in 20 mL of dimethyl sulfoxide, and the reaction was stirred at 100°C for 16 hours under an argon atmosphere. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system A to obtain 5 g (850 mg) of the title product crude product, yield: 45%.

MS m/z(ESI): 519.0[M+1].

Seventh step

8-(2-Cyclopropylphenyl)-10-(8-methylnaphthalene-1-yl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2 ',1': 3,4-tert-butyl][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 5h

Dissolve crude compound 5g (850mg, 1.64mmol), compound 3b (363mg, 1.64mmol), tetrakis(triphenylphosphine)palladium (189mg, 0.164mmol, Greenchem) and sodium carbonate (520mg, 4.92mmol, Titan) The reaction was stirred at 80°C for 16 hours in N,N-dimethylformamide/water (10 mL/1 mL) under argon atmosphere. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with eluent system C to obtain the title product 5h (450 mg), yield: 44%.

MS m/z(ESI): 615.3[M+1].

Eighth step

8-(2-Cyclopropylphenyl)-10-(8-methylnaphthalene-1-yl)-1,2,3,4,13,13a-hexahydropyrazino[2',1': 3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 5i

Compound 5h (450 mg, 0.73 mmol) was dissolved in 5 mL of dichloromethane, hydrogen chloride/1,4-dioxane solution (4M, 10 mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated to obtain the title product crude product 5i (370 mg), which was directly used in the next step without purification.

MS m/z(ESI): 515.3[M+1].

Step 9

2-acryloyl-8-(2-cyclopropylphenyl)-10-(8-methylnaphthalene-1-yl)-1,2,3,4,13,13a-hexahydropyrazino[2 ',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 5

The crude compound 5i (370mg, 0.719mmol) was dissolved in 10mL of dichloromethane, and acryloyl chloride (65.0mg, 0.719mmol, Anaiji) was added dropwise to the reaction solution at 0°C, and then triethylamine (218mg, Titan) was added. . The reaction was stirred at room temperature for 1 hour. The reaction solution was quenched with water (50 mL), extracted with dichloromethane (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by high performance liquid chromatography to obtain the title product 5 (90 mg), yield: 22%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.91(d,1H), 7.81(d,1H), 7.43-7.39(m,2H), 7.27-7.23(m,3H), 7.16-7.13( m, 2H), 7.01-6.76 (m, 3H), 6.20 (d, 1H), 5.88 (d, 1H), 5.77 (d, 1H), 4.74-4.03 (m, 6H), 3.50-3.39 (m, 2H), 3.14-3.08 (m, 1H), 2.04 (t, 3H), 1.55-1.53 (m, 1H), 0.84-0.71 (m, 3H), 0.42-0.35 (m, 1H).

MS m/z(ESI): 569.5[M+1].

Example 6

(S)-2-acryloyl-10-(2-hydroxy-6-methylphenyl)-8-(2-isopropyl-6-methylphenyl)-1,2,3,4,13 ,13a-Hexahydropyrazine[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 6

Using the synthetic route of Example 1, the second step raw material 2-isopropylaniline was replaced with 2-methyl-6-isopropylaniline, and the third step raw material 3-(hydroxymethyl)piperazine-1- Replace tert-butyl formate with tert-butyl (S)-3-(hydroxymethyl)piperazine-1-carboxylate, and replace the raw material (5-methyl-1H-indazol-4-yl)boronic acid in the fifth step with The title product 6 (240 mg) was prepared by 2-fluoro-6-hydroxyphenylboronic acid, and the yield was 27.1%.

MS m/z(ESI): 555.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.03 (s, 1H), 7.34 (s, 1H), 7.33-7.20 (m, 3H), 7.15-6.80 (m, 2H), 6.71-6.64 ( m, 2H), 6.20 (d, 1H), 5.99 (s, 1H), 5.76 (d, 1H), 4.73 (s, 1H), 4.62 (s, 2H), 4.58-4.55 (m, 2H), 4.33 -4.02 (m, 2H), 3.22 (s, 2H), 2.22 (s, 1H), 1.89 (t, 3H), 1.45 (s, 1H), 1.08-1.01 (m, 4H), 0.75 (t, 1H) ).

Example 7

(13aS)-2-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 7

first step

4-bromo-2,3,6-trifluorobenzoic acid 7b

2,2,6,6-Tetramethylpiperidine (3.35g, 23.70mmol, Titan) was dissolved in dry 50mL tetrahydrofuran, and the reaction solution was cooled to -78°C under an argon atmosphere. N-butyllithium (2.5M n-hexane solution, 9.5 mL, 23.75 mmol, Warren Chemical) was added dropwise to the reaction solution, and the reaction solution was stirred at -78°C for 1 hour. 1-Bromo-2,3,5-trifluorobenzene 7a (5.0g, 23.70mmol, Shanghai Hanhong Technology) was added dropwise to the reaction solution, and the reaction was stirred at -78°C for 2 hours. Then, carbon dioxide was introduced into the reaction solution and stirred for 30 minutes. The reaction was added to 50mL of water, extracted with ethyl acetate (30mL×2), the aqueous phase was adjusted to pH about 1 with 1M hydrochloric acid, and then extracted with ethyl acetate (30mL×2). The combined organic phase was washed with water. After drying with sodium sulfate and filtering, the filtrate was concentrated under reduced pressure to obtain the target compound 7b (1.4 g, yield: 23%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ 14.40 (br, 1H), 7.82-7.77 (m, 1H).

Second step

4-bromo-2,3,6-trifluorobenzamide 7c

7b (1.4g, 5.49mmol, 8070309-A1) was dissolved in thionyl chloride (8.2g, 27.45mmol, 5mL, Titan), stirred at 70°C for 5 hours, the reaction was stopped, and the reaction solution was concentrated. Then, 1,4-dioxane (5 mL, Runjie) was added to the reaction solution, and ammonia water (2.73 g, 16.47 mmol, 3 mL, Titan) was added to the reaction solution at 0° C. and stirred for 1 hour. The reaction solution was added with water and extracted with dichloromethane (50 mL×3), the combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 7c (1.2 g, yield: 86%).

MS m/z(ESI): 254[M+1].

third step

4-bromo-2,3,6-trifluoro-N-((2-isopropylphenyl)carbamoyl)benzamide 7d

Dissolve 7c (1.2g, 3.51mmol) in 1,2-dichloroethane (50mL, Titan), add oxalyl chloride (2.1g, 16.54mmol, 5mL, Titan), and stir the reaction solution at 80°C for 5 hours. The reaction was stopped, and the reaction solution was concentrated. Next, dichloromethane (10 mL, Runjie) was added to the residue, and 2-isopropylaniline (745 mg, 5.51 mmol, Anaiji) was added to the residue at 0° C., and the mixture was stirred for 30 minutes. After adding water to the reaction solution, it was extracted with dichloromethane (30mL X 2), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column to obtain the eluent (ethyl acetate: Petroleum ether) was purified to obtain the title product 7d (1.2 g, yield: 52%).

MS m/z(ESI): 415.2[M+1].

the fourth step

(S)-3-(((7-Bromo-6-fluoro-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline -5-yl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 7e

Under argon atmosphere, dissolve (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (1.25g, 5.78mmol, Nanjing Medicine Stone) in 15mL N,N-dimethylformamide, Cool to 0°C. Then, sodium hydride (693 mg, 17.34 mmol, 60% purity, Titan) was slowly added to the reaction solution, and after the addition, the reaction solution was kept at 0° C. and stirred for 5 hours. Then, a solution of compound 7d (1.2 g, 2.89 mmol) in N,N-dimethylformamide (5 mL, Hengyue Chemical) was slowly added to the reaction solution and stirred at room temperature for 16 hours. The reaction solution was added with saturated aqueous ammonium chloride solution and extracted with dichloromethane (30mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by CombiFlash (eluent ethyl acetate : Petroleum ether=0:1-1:10) to obtain the title product 7e (900mg, yield: 52%).

MS m/z(ESI): 593.2[M+1].

the fifth step

(S)-10-Bromo-11-fluoro-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazino[2',1':3, 4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 7f

Compound 7e (500 mg, 0.845 mmol) was dissolved in phosphorus oxychloride (4 mL, Titan), and the reaction solution was raised to 120°C for 5 hours. The reaction solution was quenched with ice water and concentrated to obtain a crude product, which was separated by CombiFlash (eluent dichloromethane/methanol (containing 1% triethylamine) = 1:3) to obtain the title product 7f (170 mg, yield: 42 %).

MS m/z(ESI): 473.3[M+1].

Sixth step

(13aS)-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazine And[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 7g

Under an argon atmosphere, compound 7f (170mg, 0.359mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (155mg, 1.08mmol, WuXi AppTec), tetrakis (triphenylphosphine) palladium (41.5mg, 0.036mmol, Greenchemer), sodium carbonate (114mg, 1.08mmol, Titan) dissolved in 11mL N,N-dimethylformamide and water (V/V=10:1) mixed solvent, heated to 110℃ Stir for 16 hours. The reaction solution was cooled and concentrated to obtain a crude product, which was separated by CombiFlash (eluent: dichloromethane: methanol = 10:1) to obtain 7 g (80 mg, yield: 44%) of the title product.

MS m/z(ESI): 505.1[M+1].

Seventh step

(13aS)-2-acryloyl-11-fluoro-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 7

Compound 7g (80mg, 0.158mmol) was dissolved in 5mL of dichloromethane, acryloyl chloride (14mg, completed) was added dropwise to the reaction solution at 0°C, and then triethylamine (48mg, 0.474mmol titan) was added. The reaction was stirred at room temperature for 1 hour. The reaction solution was added with saturated aqueous sodium bicarbonate solution and extracted with dichloromethane (50mL X 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated by HPLC (Separation conditions: preparative column OD, 5um, 4.6*250 (Daicel); mobile phase: carbon dioxide: methanol = 60:40, flow rate: 2.8 mL/min) to obtain the title product 7 (8.53 mg, yield: 9.6%).

MS m/z(ESI): 559.1 [M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.34 (brs, 1H), 7.54-7.52 (m, 1H), 7.43-7.37 (m, 2H), 7.33-7.31 (m, 1H), 7.21 7.09(m,1H), 6.90-6.85(m,1H), 6.72-6.65(m,2H), 6.20(d,1H), 5.92-5.84(m,1H), 5.76(d,1H), 4.71 4.03 (m, 6H), 3.53-3.51 (m, 2H), 3.12-3.04 (m, 1H), 2.76-2.61 (m, 1H), 1.01-0.99 (m, 6H).

Example 8

(S)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylpyridin-3-yl)-1,2,3,4,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 8

first step

4-bromo-2,6-difluoro-N-((2-isopropylpyridin-3-yl)carbamoyl)benzamide 8a

Same as the second step of Example 1, except that the starting material 2-isopropylaniline was replaced with 2-isopropylpyridin-3-amine, the title product 8a (1.29 g) was obtained, and the yield was 95.6%.

MS m/z(ESI): 397.8[M+1].

Second step

(S)-3-(((7-Bromo-1-(2-isopropylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline- 5-yl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 8b

Same as the third step of Example 1, except that the raw material 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester is replaced with (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid For tert-butyl ester, compound 1c was replaced with compound 8a to obtain the title product 8b (565 mg), yield: 78.3%.

MS m/z(ESI): 573.8[M+1].

third step

(S)-10-Bromo-8-(2-isopropylpyridin-3-yl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2',1 ':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 8c

The same as the fourth step of Example 1, except that compound 1d was replaced with compound 8b, the title crude product 8c (558 mg) was obtained.

MS m/z(ESI): 555.8[M+1].

the fourth step

(S)-10-(2-Fluoro-6-hydroxyphenyl)-8-(2-isopropylpyridin-3-yl)-7-oxo-3,4,7,8,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 8d

The crude product 8c (60mg, 0.55mmol), 2-fluoro-6-hydroxyphenylboronic acid (100mg, 0.64mmol Leyan), tetrakis(triphenylphosphine) palladium (180mg, 0.05mmol, Adamas), anhydrous Sodium carbonate (100 mg, 0.94 mmol, Sinopharm) was dissolved in a mixed solvent of 6 mL of dioxane and 2 mL of water, and the reaction was stirred at 80°C for 16 hours under an argon atmosphere. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product 8d (200mg) was purified with the eluent system dichloromethane/methanol using CombiFlash rapid preparation instrument, yield: 75.7%.

MS m/z(ESI): 587.9[M+1].

the fifth step

(S)-10-(2-Fluoro-6-hydroxyphenyl)-8-(2-isopropylpyridin-3-yl)-1,2,3,4,13,13a-hexahydropyrazino [2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one Hydrochloride 8e

The same as the sixth step of Example 1, except that 1f was replaced with compound 8d, the title crude product 8e (165 mg) was obtained, and the product was directly used in the next step without purification.

Sixth step

(S)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylpyridin-3-yl)-1,2,3,4,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 8

Same as the seventh step of Example 1, except that compound 1g was replaced with compound 8e, the title product 8 (95mg) was obtained, yield: 51.8%.

MS m/z(ESI): 542.2[M+1].

¹ H NMR (400MHz, Methanol-d ₄ ): δ8.70-8.62 (m, 1H), 7.70-7.62 (m, 1H), 7.46-7.40 (m, 1H), 7.18-7.07 (m, 1H), 6.97(s,1H), 6.91-6.78(m,1H), 6.68-6.53(m,2H), 6.29(d,1H), 6.20(d,1H), 5.82(d,1H), 5.10-4.07( m, 7H), 3.70-3.35 (m, 2H), 2.95-2.81 (m, 1H), 1.27-1.18 (m, 3H), 1.17-1.07 (m, 3H).

Example 9

(S)-1-(10-(2-Fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-7-thio-3,4,7,8,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-2(1H)-yl)propan-2 -En-1-one 9

Using the synthetic route of Example 1, the second step raw material 2-isopropylaniline was replaced with 1-isopropyl-2-isothiocyanobenzene (using the well-known method "Bioorganic and Medicinal Chemistry Letters, 2007, 17( 14), 4030-4034" prepared), the third step raw material 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester is replaced with (S)-3-(hydroxymethyl)piperazine- 1-tert-butyl carboxylate, the fifth step raw material (5-methyl-1H-indazol-4-yl)boronic acid is replaced by (2-fluoro-6-hydroxyphenyl)boronic acid to obtain the title product 9( 145mg).

MS m/z(ESI): 557.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.17 (s, 1H), 7.52-7.50 (m, 1H), 7.43-7.40 (m, 1H), 7.33-7.29 (m, 1H), 7.17- 7.12(m,1H),7.02-7.00(m,1H),6.94-6.84(m,2H), 6.76-6.74(m,1H),6.65-6.61(m,1H),6.23-6.18(m,1H) ), 6.04-6.02 (m, 1H), 5.78-5.75 (m, 1H), 4.93-4.82 (m, 1H), 4.67-4.58 (m, 2H), 4.38-4.32 (m, 1H), 4.11-4.05 (m, 1H), 3.62-.41 (m, 3H), 2.63-2.55 (m, 2H), 1.21-1.18 (m, 3H), 0.99-0.97 (m, 3H).

Examples 10-1, 10-2

(12S,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 10-1

(12R,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 10-2

first step

(R)-2-((R)-2-(((Benzyloxy)carbonyl)amino)-3-hydroxypropionamido)methyl propionate 10c

D-alanine methyl ester hydrochloride 10a (10.0g, 71.64mmol, finished), N-benzyloxycarbonyl-D-serine 10b (17.2g, 71.89mmol, finished), 1-(3-di Methylaminopropyl)-3-ethylcarbodiimide hydrochloride (16.5g, 86.07mmol, Shaoyuan) was dissolved in dichloromethane (400mL, Sinopharm), cooled in an ice bath, and N,N-diiso Propyl ethylamine (28 g, 216.64 mmol, Adamas) was returned to room temperature and stirred for 18 hours, the reaction was stopped, and the reaction solution was concentrated. Then 400 mL of water was added to the residue, the reaction solution was extracted with dichloromethane (150 mL×3), the organic phase was dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude title product 10c (18.5 g, yield: 79.6%) was obtained, and the product was directly subjected to the next reaction without purification.

MS m/z(ESI): 325.0[M+1].

Second step

(R)-2-((R)-2-Amino-3-hydroxypropylamino)methyl propionate 10d

Under a hydrogen atmosphere, compound 10c (18.5 g, 57.04 mmol) was dissolved in 200 mL of methanol, 10% palladium/carbon (3 g, Shaoyuan, water content 50%) was added, and the reaction was stirred for 48 hours. The reaction solution was filtered through Celite, and the filtrate was concentrated under reduced pressure to obtain the title compound 10d (10.8 g, yield: 99.5%). The product was directly subjected to the next reaction without purification.

MS m/z(ESI): 191.1[M+1].

third step

(3R,6R)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione 10e

Compound 10d (10.8 g, 56.78 mmol) was dissolved in 200 mL of methanol, and the mixture was heated to reflux for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the title compound 10e (9.0 g, yield: 100.2%). The product was directly subjected to the next reaction without purification.

MS m/z(ESI): 159.1 [M+1].

the fourth step

((2S,5R)-5-methylpiperazin-2-yl)methanol 10f

Compound 10e (9.0 g, 56.90 mmol) was dissolved in a tetrahydrofuran solution of borane (290 ml, 1M, Adamas), and the mixture was heated and refluxed for 16 hours. After cooling the reaction solution to room temperature, 9 mL of methanol was added, and then hydrochloric acid (3 mL, 5M, Sinopharm) was added, and the reaction solution was heated to 70° C. and stirred for 2 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure to obtain the title compound 10f (7.4g, yield: 99.8%). The product was directly subjected to the next reaction without purification.

MS m/z(ESI): 130.9[M+1].

the fifth step

(2R,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 10g

Compound 10f (7.4g, 56.84mmol) was dissolved in 200mL methanol, triethylamine (28g, 276.70mmol, Sinopharm) and di-tert-butyl dicarbonate (25g, 114.54mmol, Shaoyuan) were added, and the reaction was stirred for 16 hours. After the reaction solution was concentrated under reduced pressure, 150 mL of ethanol, 150 mL of water and sodium hydroxide (11 g, 275.01 mmol, Sinopharm) were added, and the reaction solution was refluxed and stirred for 16 hours. After the reaction solution was cooled to room temperature, it was concentrated under reduced pressure. The residue was added dropwise with hydrochloric acid under ice cooling until the pH of the reaction solution was 7-8. The reaction solution was extracted with dichloromethane (150 mL×3), and the organic phases were combined, and anhydrous It was dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 10 g (4.38 g, yield: 33.4%) of the title compound. The product was directly subjected to the next reaction without purification.

MS m/z(ESI): 231.3[M+1].

Sixth step

(2R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 10h

Compound 10g (1.76g, 7.64mmol) was dissolved in 30mL of dichloromethane, and tert-butyldimethylchlorosilane (2g, 13.26mmol, Shaoyuan), N,N-dimethylaminopyridine (100mg, 818.5μmol) were added , Shaoyuan), triethylamine (1.97g, 19.46mmol, 2.7mL, Sinopharm), stirred for 16 hours. Add 20mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue with silica gel column Purification by chromatography with eluent system A gave the title compound 10h (1.86 g, yield 70.6%).

Seventh step

1-(2-isopropylphenyl)urea 10j

Dissolve 2-isopropyl aniline 10i (26.24g, 194.07mmol, Anaiji) in 300mL water and acetic acid (V/V=1:1), and add sodium cyanate (25.23g, 388.11mmol, Adama Stirring and reacting for 2 hours. The reaction solution was poured into water, filtered, the filter cake was washed with water, and dried under vacuum to obtain the target compound 10j (31.8 g, yield: 91.9%).

Eighth step

6-Amino-1-(2-isopropylphenyl)pyrimidine-2,4(1H,3H)-dione 10k

Compound 10j (31.8g, 178.42mmol, prepared by the well-known method "Tetrahedron, 1997, 53(13), 4601-4610"), ethyl cyanoacetate (20.3g, 179.46mmol, 19.2mL, Adama S.) and sodium tert-butoxide (20.6g, 214.35mmol, Shaoyuan) were sequentially added to 250mL of methanol, and heated to 70°C for 4 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 1L of water, and then acetic acid was added to adjust the pH<7, a solid precipitated out, filtered, the filter cake was washed with water, and dried under vacuum to obtain the title compound 10k (32.8g, yield: 74.9%).

MS m/z(ESI): 246.6[M+1].

Step 9

3-(6-Amino-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3-oxopropionitrile 10l

Dissolve cyanoacetic acid (28g, 329.17mmol, Adamas) in acetic anhydride (116.64g, 1.14mol, 108mL, Sinopharm), heat to 80°C for 10 minutes, then add compound 10k (40g, 163.08mmol), React at 80°C for 1 hour. The reaction solution was poured into water and stirred for 10 minutes. After filtration, the filter cake was washed with water, and dried under vacuum to obtain 10 l of the title compound (42.8 g, yield: 84.0%).

MS m/z(ESI): 313.2[M+1].

Tenth step

1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H)-tetraketone 10m

Compound 10l (45 g, 144.08 mmol) was added to 250 mL of hydrobromic acid, and heated to 90° C. to react for 45 minutes. The reaction solution was cooled to room temperature and poured into 1.5L of water. Ammonia was added to adjust the pH to 7, stirring for 10 minutes, filtered, the filter cake was washed with water, and vacuum dried. The residue was purified by silica gel column chromatography with eluent system A. The title compound 10m (31.4 g, yield: 69.5%).

MS m/z(ESI): 312.0[M-1].

Eleventh step

6,6-Dichloro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H)-tetraketone 10n

Dissolve compound 10m (10g, 31.91mmol) in 80mL 1,4-dioxane, heat to 40°C, add sulfonyl chloride (13g, 96.31mmol, 7.8mL, Sinopharm) dropwise with stirring, keep at 40°C for reaction 1 hour. The reaction solution was cooled to room temperature and poured into ice water. A solid precipitated out, filtered and dried in vacuo to obtain the title compound 10n (9.3 g, yield: 76.2%).

MS m/z(ESI): 382.0[M+1].

Twelfth step

6-chloro-5,7-dihydroxy-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 10o

Compound 10n (4g, 10.46mmol) was added to a mixed solvent of 80mL of acetic acid, ethanol and 1,4-dioxane (V/V/V=3:10:3), and then zinc powder (3.42g, 52.30mmol), heated to 90°C for 30 minutes. Cool to room temperature, filter, wash the filter cake with 50 mL methanol, combine the filtrate, and concentrate under reduced pressure. The residue was stirred with 500 mL of water for 10 minutes, filtered, and the filter cake was washed with a small amount of ethanol, then washed with n-hexane, and dried under vacuum to obtain the title compound 10o (2.46 g, yield: 67.5%).

MS m/z(ESI): 348.1[M+1].

Step 13

5,6,7-Trichloro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 10p

Compound 10o (2.46g, 7.07mmol) was added to 15mL of thionyl chloride, then 0.7mL of N,N-dimethylformamide was added, and the reaction was heated to 80°C for 3 hours. The reaction solution was cooled to room temperature and poured into 500 mL of ice water and stirred for 10 minutes. The mixture was extracted with dichloromethane (150 mL×3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate (100 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was chromatographed on silica gel column Purification with eluent system B was used to obtain the title compound 10p (2.51 g, yield: 92.2%).

MS m/z(ESI): 384.0[M+1].

Step Fourteen

4,5,6,7-Tetrachloro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 10q

Compound 10p (1.2g, 3.11mmol) was added to 30mL of acetonitrile, phosphorus oxychloride (2.31g, 15.06mmol, 1.4mL) and N,N-diisopropylethylamine (2.041g, 15.79mmol, 2.8 mL), heated to 80°C for 2 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure. The residue gave the title compound 10q (3.2 g, yield: 254.46%), and the product was used directly in the next step without purification.

Fifteenth step

(2R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(5,6,7-trichloro-1-(2-iso Propylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 10r

Compound 10q (3.2g, 7.93mmol) was dissolved in 40mL of dichloromethane, cooled to 0°C, compound 10h (1.3g, 3.77mmol) and triethylamine (2.187g, 16.92mmol, 3mL) were added in sequence, and the reaction was stirred 1 hour. Add 30mL saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (50mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue with silica gel column Purification by chromatography with eluent system B gave the title compound 10r (1.53 g, yield: 27.0%).

Step sixteen

(5aS,8R)-2,3-Dichloro-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6,8,9,11,12-hexahydro- 4-oxa-1,7,9a,10,12-pentaaza[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester 10s

Compound 10r (1.53 g, 2.15 mmol) was dissolved in 50 mL of tetrahydrofuran, tetrabutylammonium fluoride (1M, 6.5 mL) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate and then washed with water (30 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed using silica gel column chromatography with eluent system (Dichloromethane: ethyl acetate) purification to obtain the title compound 10s (655 mg, yield: 54.3%).

MS m/z(ESI): 560.1[M+1].

Seventeenth step

(12S,5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a, 6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -7(5H)-tert-butyl formate atropisomer 10t-1

(12R,5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a, 6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -7(5H)-tert-butyl formate atropisomer 10t-2

In an argon atmosphere, (2-fluoro-6-hydroxyphenyl)boronic acid (273mg, 1.75mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 10s (655mg, 1.16mmol), sodium bicarbonate (294mg, 3.49 mmol) and tetrakistriphenylphosphine palladium (135 mg, 116.82 μmol) were added to a mixed solvent of 24 mL of water and 1,4-dioxane (V/V=1:10), and heated to 90° C. to react for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 50 mL of dichloromethane was added to the residue to dissolve, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with a developing solvent system F to obtain the title compound 10t-1 (213 mg , Yield: 18.2%) and 10t-2 (136mg, Yield: 28.6%).

Single configuration compound 10t-1: (Retention time: 1.38 minutes)

MS m/z(ESI): 636.1[M+1].

UPLC analysis method: retention time: 1.38 minutes, (column: ALQUITY UPLC BEHC 18 1.7 μm 2.1×50 mm, mobile phase: acetonitrile: 0.1% formic acid = 30: 70-95: 5 (2 min), flow rate: 0.5 mL/min ).

Single configuration compound 10t-2: (Retention time: 1.40 minutes)

MS m/z(ESI): 636.1[M+1].

UPLC analysis method: retention time: 1.40 minutes, (column: ALQUITY UPLC BEHC 18 1.7μm 2.1×50mm, mobile phase: acetonitrile: 0.1% formic acid = 30:70-95:5 (2min), flow rate: 0.5mL/min ).

Step 18

(12S,5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a,6,7 ,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H) -Ketone Trifluoroacetate Atropisomer 10u-1

Compound 10t-1 (213 mg, 334.8 μmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound 10u-1 (486 mg, yield: 270.7%), which was used directly in the next step without purification.

MS m/z(ESI): 537.0[M+1].

Step Nineteen

(12S,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 10-1

Compound 10u-1 (486 mg, 906.7 μmol) was dissolved in 15 mL of dichloromethane, triethylamine (729 mg, 7.20 mmol, 1 mL) and acryloyl chloride (58 mg, 640.8 μmol, 52 μL) were added, and the reaction was stirred for 1 hour. Add 10mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue with 15mL methanol. Add 250mg of sodium bicarbonate, heat to 60°C and stir for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 30 mL of a mixture of dichloromethane and methanol (V/V=20:1) was added to dissolve and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (column: Boston Phlex Prep C18 5μm 30×150mm; mobile phase: water (10mmol ammonium bicarbonate): acetonitrile = 40%-60% (15min), flow rate: 30mL/min) The title compound 10-1 (50mg, yield: 9.3%).

A single configuration compound synthesized from the product with a retention time of 1.38 minutes in the 17th step (shorter retention time) 10-1:

MS m/z(ESI): 590.0[M+1].

Chiral HPLC analysis: retention time 4.700 minutes, chiral purity: 99.62% (column: CHIRALPAK IE 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=50/50(v/v), flow rate: 1.0mL /min);

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.98-10.04 (m, 1H), 7.35-7.37 (m, 1H), 7.26-7.30 (m, 1H), 7.17-7.20 (m, 2H), 6.98-7.00(m,1H),6.82-6.92(m,1H),6.60-6.68(m,2H),6.15-6.22(m,1H),5.73-5.76(m,1H),4.84-4.85(m ,2H),4.31-4.64(m,3H),4.01-4.10(m,1H),3.75-3.78(m,1H),3.17-3.63(m,1H),2.61-2.63(m,1H),1.21 (d, 3H), 1.05 (s, 3H), 0.96 (m, 3H).

Step 20

(12R,5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a,6,7 ,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H) -Ketone trifluoroacetate atropisomer 10u-2

Compound 10t-2 (136 mg, 213.7 μmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title compound 10u-2 (362 mg, yield: 315.8%), which was used directly in the next step without purification.

MS m/z(ESI): 537.0[M+1].

Step 21

(12R,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 10-2

Compound 10u-2 (362 mg, 675.3 μmol) was dissolved in 15 mL of dichloromethane, triethylamine (364 mg, 3.59 mmol, 0.5 mL) and acryloyl chloride (38 mg, 419.8 μmol, 34 μL) were added, and the reaction was stirred for 1 hour. Add 10mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue with 15mL methanol. Add 250mg of sodium bicarbonate, heat to 60°C and stir for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 30 mL of a mixture of dichloromethane and methanol (V/V=20:1) was added to dissolve and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (column: Boston Phlex Prep C18 5μm 30×150mm; mobile phase: water (10mmol ammonium bicarbonate): acetonitrile = 40%-60% (15min), flow rate: 30mL/min) The title compound 10-2 (52mg, yield: 13.0%).

A compound with a single configuration (longer retention time) synthesized from the product with a retention time of 1.40 minutes in the seventeenth step 10-2:

MS m/z(ESI): 590.1[M+1].

Chiral HPLC analysis: retention time 6.614 minutes, chiral purity: 99.36% (column: CHIRALPAK IE 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=50/50(v/v), flow rate: 1.0mL /min);

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.00 (s, 1H), 7.35-7.37 (m, 1H), 7.28-7.30 (m, 1H), 7.18-7.20 (m, 2H), 6.99- 7.00 (m, 1H), 6.78-6.92 (m, 1H), 6.60-6.68 (m, 2H), 6.18 (t, 1H), 5.71-5.76 (m, 1H), 4.77-4.91 (m, 2H), 4.43-4.62(m,2H),4.31-4.34(m,1H),4.14-4.19(m,2H),4.04-4.05(m,1H),3.26-3.71(m,1H),1.15-1.20(m , 3H), 1.03 (d, 3H), 0.96 (d, 3H).

Example 11

(R)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 11

first step

(R)-3-(((7-Bromo-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl )Oxy)methyl)tert-butyl piperazine-1-carboxylate 11a

The third step is the same as in Example 1, except that the raw material tert-butyl 3-(hydroxymethyl)piperazine-1-carboxylate is replaced with (R)-3-(hydroxymethyl)piperazine-1-carboxylate tert-butyl Ester, the title product 11a (4.66g) was obtained, yield: 80.7%.

MS m/z(ESI): 572.8[M+1].

Second step

(R)-10-Bromo-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2',1': 3 ,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 11b

Same as the fourth step of Example 1, except that compound 1d was replaced with compound 11a, the title product 11b (4.5g) was obtained, yield: 99%.

MS m/z(ESI): 554.8[M+1].

third step

(13aR)-8-(2-isopropylphenyl)-10-(5-methyl-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)- 7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7 -de]quinazoline-2(1H)-tert-butyl carboxylate 11d

The crude product 11b (2.8g, 5.0mmol), 5-methyl-1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1, 3,2-Dioxaborolan-2-yl)-1H-indazole 11c (prepared by the well-known method "Science, 2018, 359, 429-434") (1.9g, 5.5mmol), tetrakis ( Triphenylphosphine) palladium (400mg, 0.35mmol, Adamas), anhydrous sodium carbonate (1g, 9.4mmol, Sinopharm) were dissolved in a mixed solvent of 20mL dioxane and 6mL water, and reacted under argon atmosphere. Stir at 80°C for 16 hours. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Purified by CombiFlash with eluent system A, the title crude product 11d (3.2g) was obtained.

MS m/z(ESI): 691.0[M+1].

the fourth step

(R)-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a-hexahydropyrazine And[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one hydrochloride 11e

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 11d, the title crude product 11e (2.2g) was obtained, and the product was directly used in the next step without purification.

the fifth step

(R)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 11

Same as the seventh step of Example 1, except that compound 1g was replaced with compound 11e, the title product 11 (100mg) was obtained, yield: 9.0%.

MS m/z(ESI): 561.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.11 (s, 1H), 7.52-7.45 (m, 2H), 7.44-7.35 (m, 2H), 7.30 (t, 1H), 7.23-7.15 ( m, 2H), 6.95-6.83 (m, 1H), 6.82 (s, 1H), 6.20 (d, 1H), 5.95 (d, 1H), 5.80-5.73 (m, 1H), 4.83-4.00 (m, 6H), 3.62-3.30 (m, 2H), 3.28-3.01 (m, 1H), 2.75-2.53 (m, 1H), 2.13 (s, 3H), 1.16-1.07 (m, 3H), 1.02-0.93 ( m,3H).

Example 12

(13aS)-2-acryloyl-11-chloro-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4 ,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)- Ketone 12

first step

(S)-3-(((7-Bromo-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl )Oxy)methyl)tert-butyl piperazine-1-carboxylate 12a

Under argon atmosphere, dissolve (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (21.74g, 100.74mmol, medicine stone) in 250mL N,N-dimethylformamide, The reaction liquid was cooled to 0°C. Then, sodium hydride (12.1 g, 302.04 mmol, 60%, Titan) was slowly added to the reaction solution, and after the addition, the reaction was stirred for 5 hours. Then, compound 1c was dissolved in 50 mL of N,N-dimethylformamide, and then slowly injected into the above reaction solution, and the temperature was raised to room temperature to react for 16 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate (100 mL×2). The combined organic phase was washed with saturated sodium chloride solution (100 mL×5), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. It was then beaten with ethyl acetate: petroleum ether (V/V=1:10) to obtain the title compound 12a (23 g, yield: 80%).

MS m/z(ESI): 573.2[M+1].

Second step

(S)-10-Bromo-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2',1': 3 ,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 12b

Under an argon atmosphere, compound 12a (23.3 g, 40.63 mmol) was dissolved in 1540 mL of a mixed solvent of acetonitrile and tetrahydrofuran (V/V=1:1), and the reaction solution was cooled to 0°C. Add benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (54.1g, 121.89mmol, Shaoyuan), stir and react for 10 minutes, then add 1, to the reaction solution 8-diaza[5,4,0]bicycloundec-7-ene (36.6 mL, 243.78 mmol, Anaiji), after the addition, the reaction solution was raised to room temperature and stirred for 16 hours. The reaction solution was poured into ice water, and extracted with ethyl acetate (200 mL×3). The combined organic phases were washed with saturated sodium chloride solution (100mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent (ethyl acetate: petroleum ether) to obtain the title Compound 12b (23.6 g, yield: 98%).

third step

(S)-10-Bromo-11-chloro-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazino[2',1':3, 4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 12c

Compound 12b (3.0 g, 5.4 mmol) was dissolved in 620 mL of isopropanol, N-chlorosuccinimide (793 mg, 5.94 mmol, completed) was added, and the temperature was raised to 85° C. and stirred for 16 hours. After the reaction solution was cooled to room temperature, N-chlorosuccinimide (793 mg, 5.94 mmol, completed) was added again, and the temperature was increased to 85° C. and stirred for 20 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in water and ethyl acetate, extracted with ethyl acetate (50mL×3), the organic phases were combined, washed with saturated sodium chloride solution (30mL×1), anhydrous sulfuric acid Sodium is dry. After filtration, the filtrate was concentrated under reduced pressure to obtain the product 12c (580 mg).

the fourth step

(13aS)-11-chloro-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 12d

Under argon atmosphere, compound 12c (450mg, 918.76umol), (5-methyl-1H-indazol-4-yl)boronic acid (480mg, 2.73mmol, finished), sodium carbonate (300mg, 2.83mmol, Titan) and tetrakis (triphenylphosphine) palladium (100g, 86.54mmol, Greenchem) were added to 11mL N,N-dimethylformamide and water (V/V=10:1), and heated to 120℃ Stir for 16 hours. Add 20 mL of water to the cooled reaction solution, and extract with ethyl acetate (40 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent A system to obtain the target compound 12d (140 mg, yield: 28%).

MS m/z(ESI): 541.2[M+1].

the fifth step

(13aS)-2-acryloyl-11-chloro-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4 ,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)- Ketone 12

Compound 12d (140mg, 258.76umol) was dissolved in 5mL of dichloromethane, cooled to 0°C, acryloyl chloride (47mg, 519.29μmol, Titan) was added dropwise, and then triethylamine (60mg, 592.94μmol, Titan) was added. The reaction was stirred for 30 minutes. It was quenched by adding 20 mL of saturated sodium bicarbonate aqueous solution, separated, and the aqueous phase was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (20.21 mg, yield: 12.5%).

MS m/z(ESI): 595.2[M+1].

Examples 13-1, 13-2

(12S,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 13-1

(12R,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 13-2

first step

(S)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 13b

(3S)-3-(Hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester 13a (5g, 23.11mmol, Shaoyuan) was dissolved in 150mL of dichloromethane, and N,N-dimethylaminopyridine (282mg , 2.30mmol, Adamas), tert-butyldimethylchlorosilane (6.1g, 40.47mmol, Shaoyuan) and triethylamine (5.9g, 58.30mmol, 8.1mL), stirred and reacted for 16 hours. Add 100mL saturated aqueous sodium bicarbonate solution, separate the layers, extract the aqueous phase with dichloromethane (50mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue with silica gel column chromatography Purified with eluent system A to obtain the title compound 13b (7.3 g, yield: 95.5%).

Second step

(S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,6,7-trichloro-1-(2-isopropylphenyl)-2 -Oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 13c

Compound 10q (1.25g, 3.10mmol) was dissolved in 30mL of dichloromethane, cooled to 0°C, compound 13b (1g, 3.02mmol) and N,N-diisopropylethylamine (0.6g, 4.64mmol, 823μL), stirred and reacted for 1 hour. Add 20mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, concentrate the filtrate under reduced pressure, and chromatograph the residue with silica gel column chromatography Purified with eluent system B to obtain the title compound 13c (739 mg, yield: 34.1%).

third step

(S)-2,3-Dichloro-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-1,7 ,9a,10,12-Pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-tert-butyl carboxylate 13d

Compound 13c (1.08 g, 1.54 mmol) was dissolved in 40 mL of tetrahydrofuran, tetrabutylammonium fluoride (1M, 3.1 mL, 3.1 mmol) was added, and the reaction was stirred for 2 hours. The reaction solution was concentrated under reduced pressure, and 100mL ethyl acetate was added to dissolve it, and then washed with water (30mL×3), saturated sodium chloride solution (20mL), and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and the residue was layered with a silica gel column. Purification by chromatography with eluent system F gave the title compound 13d (497 mg, yield: 58.7%).

MS m/z(ESI): 546.0[M+1].

the fourth step

(12S,5aS)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11, 12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert Butyl ester atropisomer 13e-1

(12R,5aS)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11, 12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert Butyl ester atropisomer 13e-2

Under argon atmosphere, compound 13d (497mg, 909.5μmol), (2-fluoro-6-hydroxyphenyl)boronic acid (212.71mg, 1.36mmol, Leyan), sodium bicarbonate (230mg, 2.73mmol), tetrabenzene Phosphine palladium (105 mg, 90.8 μmol) was added to a mixed solvent of 24 mL of water and 1,4-dioxane (V/V=1:5), heated to 80° C. and stirred for reaction for 2 hours. The reaction solution was cooled to room temperature, 40 mL of water was added, and then extracted with ethyl acetate (40 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to determine the eluent system The crude product was purified by F, and then purified by thin-layer chromatography with developer system A and then by thin-layer chromatography with developer system G to obtain two target compounds 13e-2 (78mg, yield: 13.7%) and 13e- 1 (123 mg, yield: 21.7%).

Single configuration compound 13e-2 (longer retention time)

MS m/z(ESI): 622.1[M+1].

Retention time: 1.35 minutes, (column: ALQUITY UPLC BEHC 18 1.7μm 2.1×50mm, mobile phase: acetonitrile: 0.1% formic acid = 30:70-95:5 (2min), flow rate: 0.5mL/min).

Single configuration compound 13e-1 (shorter retention time)

MS m/z(ESI): 622.1[M+1].

Retention time: 1.33 minutes, (column: ALQUITY UPLC BEHC 18 1.7μm 2.1×50mm, mobile phase: acetonitrile: 0.1% formic acid = 30:70-95:5 (2min), flow rate: 0.5mL/min).

the fifth step

(12S,5aS)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro -4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one trifluoroacetate Atropisomer 13f-1

Using the synthetic routes of Examples 10-1 and 10-2, the eighteenth step raw material 10t-1 was replaced with compound 13e-1 to obtain the title compound 13f-1 (240 mg).

Sixth step

(12S,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 13-1

Using the synthetic routes of Examples 10-1 and 10-2, the 19th step raw material 10u-1 was replaced with compound 13f-1 to obtain the title compound 13-1 (45 mg).

Single-configuration compound 13-1 synthesized from the product with a retention time of 1.33 minutes in the fourth step:

MS m/z(ESI): 576.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.97-10.02 (m, 1H), 7.35-7.37 (m, 1H), 7.29 (t, 1H), 7.19-7.20 (m, 2H), 6.96 6.98(m,1H), 6.80-6.92(m,1H), 6.59-6.67(m,2H), 6.20(dd,1H), 5.76(d,1H), 4.89-4.94(m,1H), 4.79- 4.82(m,1H),4.35-4.85(m,2H),4.01-4.21(m,2H),3.54-3.57(m,2H),3.20-3.26(m,1H),2.61-2.69(m,1H) ), 1.15-1.19 (m, 3H), 0.97 (d, 3H).

Seventh step

(12R,5aS)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro -4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one trifluoroacetate Atropisomer 13f-2

Using the synthetic routes of Examples 10-1 and 10-2, the 20th step raw material 10t-2 was replaced with compound 13e-2 to obtain the title compound 13f-2 (242 mg).

Eighth step

(12R,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 13-2

Using the synthetic routes of Examples 10-1 and 10-2, the 21st step raw material 10u-2 was replaced with compound 13f-2 to obtain the title compound 13-2 (45 mg).

Single-configuration compound 13-2 synthesized from the product with a retention time of 1.35 minutes in the fourth step:

MS m/z(ESI): 576.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.00 (s, 1H), 7.35-7.37 (m, 1H), 7.29 (t, 1H), 7.18-7.19 (m, 2H), 6.98 (d, 1H), 6.78-6.91 (m, 1H), 6.60-6.67 (m, 2H), 6.20 (dd, 1H), 5.76 (d, 1H), 4.85 (s, 2H), 4.33-4.53 (m, 2H) ,4.22-4.23(m,1H),4.04-4.10(m,1H),3.65-3.72(m,2H),3.31-3.32(m,1H),2.52-2.53(m,1H),1.05(d, 3H), 0.97 (d, 3H).

Example 14

(S)-1-(8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-7-thioylidene-3,4,7,8 ,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)- Yl)prop-2-enyl-1-one 14

Using the synthetic route of Example 1, the second step raw material 2-isopropylaniline was replaced with 1-isopropyl-2-isothiocyanobenzene (using the well-known method "Bioorganic and Medicinal Chemistry Letters, 2007, 17( 14), 4030-4034" prepared), the third step raw material 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester is replaced with (S)-3-(hydroxymethyl)piperazine- Tert-butyl 1-carboxylate, the title product 14 (77 mg) was obtained.

MS m/z(ESI): 577.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.20 (s, 1H), 7.48-7.42 (m, 3H), 7.37-7.29 (m, 2H), 7.21-7.19 (m, 1H), 7.14 7.11 (m, 1H), 6.94-6.85 (m, 2H), 6.23-6.19 (m, 1H), 5.98-5.96 (m, 1H), 5.79-5.76 (m, 1H), 4.90-4.86 (m, 1H) ), 4.70-4.66 (m, 2H), 4.38-4.35 (m, 1H), 4.15-4.12 (m, 1H), 3.63-3.49 (m, 3H), 2.66-2.56 (m, 2H), 2.11 (s , 3H), 1.19-1.17 (m, 3H), 0.89-0.84 (m, 3H).

Example 15, 15-1, 15-2

(S)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyridine Azino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one 15

(8S,13aS)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 15-1

(8R,13aS)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 15-2

first step

(S)-3-(((7-Bromo-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-5-yl )Oxy)methyl)tert-butyl piperazine-1-carboxylate 15a

Same as the third step of Example 1, except that the raw material 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester is replaced with (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid Tert-butyl ester, the title product 15a (1.8g) was prepared, and the yield: 31%.

MS m/z(ESI): 572.8[M+1].

Second step

(S)-10-Bromo-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2',1': 3 ,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 15b

The same as the fourth step of Example 1, except that compound 1d was replaced with compound 15a, the title product 15b (1.7 g) was obtained, yield: 97%.

MS m/z(ESI): 554.8[M+1].

third step

(S)-8-(2-isopropylbenzene)-7-oxo-10-(4,4,5,5-tetramethyl-1,3,2-dioxaboroborane-2- Base)-3,4,7,8,13,13a-hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de ]Quinazoline-2(1H)-tert-butyl carboxylate 15c

Compound 15b (5.5g, 9.9mmol), [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (700mg, 0.956mmol, Bailingwei), pinacol biborate (3.8 g, 14.9mmol, Shaoyuan), potassium acetate (2g, 20.4mmol, Sinopharm) were dissolved in 50mL of dioxane, and heated to 100°C under argon atmosphere and stirred for 16 hours. The reaction solution was quenched with water (150 mL), extracted with ethyl acetate (50 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product 15c (8g) was purified by CombiFlash rapid preparation device with eluent system dichloromethane/methanol.

the fourth step

(S)-10-(2-Amino-6-fluorophenyl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a-hexahydropyridine Azino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 15d

The crude product 15c (1.0g, 1.6mmol), 2-bromo-3-fluoroaniline (450mg, 2.3mmol, complete), tetrakis (triphenylphosphine) palladium (180mg, 0.15mmol, Adamas), no Sodium carbonate hydrate (350 mg, 3.3 mmol, Sinopharm) was dissolved in a mixed solvent of 8 mL dioxane and 2 mL water, and the reaction was stirred at 80° C. for 16 hours under an argon atmosphere. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product 15d (960mg) was purified by CombiFlash rapid preparation device with eluent system dichloromethane/methanol.

MS m/z(ESI): 585.9[M+1].

the fifth step

(S)-10-(2-Amino-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazino[2' ,1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 15e

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 15d, the title crude product 15e (795 mg) was obtained, and the product was directly used in the next step without purification.

Sixth step

(S)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyridine Azino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one 15

Same as the seventh step of Example 1, except that compound 1g was replaced with 15e, the title product 15 (99mg) was prepared, yield: 11%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.52 (d, 1H), 7.43 (t, 1H), 7.36-7.31 (m, 1H), 7.12-7.05 (m, 1H), 7.02-6.96 ( m, 1H), 6.95-6.80 (m, 1H), 6.70 (s, 1H), 6.45 (d, 1H), 6.29 (t, 1H), 6.24 (d, 1H), 5.88 (d, 1H), 5.80 -5.72(m,1H),5.05-3.95(m,7H),3.55-3.39(m,1H),3.20-3.00(m,1H),2.75-2.50(m,1H),1.15-1.05(m, 3H), 1.03-0.90 (m, 3H).

MS m/z(ESI): 540.1[M+1].

Seventh step

(8S,13aS)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 15-1

(8R,13aS)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 15-2

Compound 15 (95mg, 0.17mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALCEL OD-H (ODH0CD-TC013); mobile phase: n-hexane: ethanol = 50: 50, flow rate: 1 mL/min), The corresponding fractions were collected and concentrated under reduced pressure to obtain two title products: 15-2 (46 mg) and 15-1 (39 mg).

Single-configuration compound 15-2 (longer retention time):

MS m/z(ESI): 540.1[M+1].

Chiral HPLC analysis: retention time 8.587 minutes, chiral purity: 99.1% (column: OD-H Phenomenex Lux Cellulose-1 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=50/50(v/v )).

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.52 (d, 1H), 7.43 (t, 1H), 7.32 (t, 1H), 7.12-7.05 (m, 1H), 7.02-6.96 (m, 1H), 6.95-6.80 (m, 1H), 6.69 (s, 1H), 6.45 (d, 1H), 6.29 (t, 1H), 6.20 (d, 1H), 5.88 (d, 1H), 5.80-5.72 (m,1H),5.05-3.95(m,7H),3.55-3.39(m,1H),3.20-3.00(m,1H),2.75-2.50(m,1H),1.20-1.05(m,3H) ,1.05-0.96(m,3H).

Single configuration compound 15-1 (shorter retention time):

MS m/z(ESI): 540.1[M+1].

Chiral HPLC analysis: retention time 6.009 minutes, chiral purity: 100% (column: OD-H Phenomenex Lux Cellulose-1 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=50/50(v/v )).

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.52 (d, 1H), 7.43 (t, 1H), 7.32 (t, 1H), 7.12-7.05 (m, 1H), 7.02-6.96 (m, 1H), 6.95-6.80 (m, 1H), 6.70 (s, 1H), 6.45 (d, 1H), 6.29 (t, 1H), 6.20 (d, 1H), 5.88 (d, 1H), 5.80-5.72 (m,1H),5.05-3.95(m,7H),3.55-3.39(m,1H),3.20-3.00(m,1H),2.75-2.50(m,1H),1.18-1.04(m,3H) ,1.04-0.95(m,3H).

Example 16

(S)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(4,6-diisopropylpyrimidin-5-yl)-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 16

Using the synthetic route of Example 4, the first step material 2-methylaniline was replaced by 4,6-diisopropylpyrimidin-5-amine (using patent application "Example 7 on page 46 of the specification in US201977801" Method), the second step raw material 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester is replaced with (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert Butyl ester, the fifth step raw material 1-bromo-8-methylnaphthalene was replaced with 2-bromo-3-fluoroaniline to obtain the title product 16 (4mg).

MS m/z(ESI): 584.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.15 (s, 1H), 7.54-7.15 (m, 1H), 7.00-6.77 (m, 4H), 6.48-6.18 (m, 3H), 5.78 ( m,2H),5.03-4.98(m,2H),4.65-4.59(m,3H),4.38-4.31 (m,2H),4.15-4.07(m,2H),2.81-2.72(m,2H), 1.10-1.07 (m, 6H), 1.02-1.00 (m, 6H).

Example 17

(S)-2-acryloyl-8-(2-isopropyl-4-methylpyridin-3-yl)-10-(5-methyl-1H-indazol-4-yl)-1,2 ,3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7 (8H)-ketone 17

Using the synthetic route of Example 1, the second step raw material 2-isopropylaniline was replaced with 2-isopropyl-6-picoline-3-amine, and the third step raw material 3-(hydroxymethyl)piper The tert-butyl oxazine-1-carboxylate was replaced with (S)-3-(hydroxymethyl)piperazine-1-carboxylate to obtain the title compound 17 (160 mg, yield: 12.0%).

MS m/z(ESI): 576.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.52(d,1H), 7.57(d,1H), 7.38-7.40(m,1H), 7.22-7.24(m,1H), 7.15-7.16( m, 1H), 6.88 (s, 1H), 6.60-6.67 (m, 1H), 6.42 (d, 1H), 6.09 (s, 1H), 5.84 (m, 1H), 5.15-5.19 (m, 1H) ,4.73-4.74(m,1H),4.50-4.73(m,2H),4.01-4.07(m,2H),3.57-3.60(m,1H),3.24-3.49(m,2H),2.87-2.92( m, 1H), 2.15 (d, 6H), 1.25-1.28 (m, 3H), 1.11 (t, 3H).

Example 18

(3R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 18

(8R,3R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3, 4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H) -Ketone atropisomer 18-1

(8S,3R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3, 4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H) -Ketone atropisomer 18-2

first step

(2R,5S)-5-(((7-Bromo-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-5 -Yl)oxy)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 18a

10 g (2.07 g, 8.99 mmol) of compound was dissolved in 80 mL of N,N-dimethylformamide, and the reaction solution was cooled to 0°C. Sodium hydride (901 mg, 22.53 mmol, 60% purity, Adamas) was slowly added to the reaction solution, and the reaction was stirred for 1 hour. Then compound 1c (2.98 g, 7.49 mmol) was dissolved in 10 mL of N,N-dimethylformamide, slowly added to the reaction solution, and stirred at room temperature for 17 hours. The reaction was stopped, 150mL saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (150mL×3), and the combined organic phases were washed with water (150mL×3) and saturated sodium chloride solution (250mL×1) successively to obtain organic The phase was concentrated under reduced pressure, and the residue was purified with the eluent system A using CombiFlash rapid preparation device to obtain the title product 18a (2.54 g), yield: 57.7%.

MS m/z(ESI): 587.1 [M+1].

Second step

(3R,13aS)-10-Bromo-8-(2-isopropylphenyl)-methyl-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[2' ,1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 18b.

Combine compound 18a (2.54g, 4.325mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (3.83g, 8.651mmol), Shanghai Biotech Co., Ltd.) was dissolved in 120 mL of tetrahydrofuran, the reaction solution was cooled to 0°C, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (2.64g, 17.37mmol, Shanghai Shaoyuan Reagent Co., Ltd.), the temperature was raised to room temperature, and the reaction was stirred for 17 hours to terminate the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A using CombiFlash rapid preparation device to obtain the title product 18b (1.99 g), yield: 80.7%.

MS m/z(ESI): 569.1 [M+1].

third step

(3R,13aS)-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-7-oxo-3,4,7,8, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxy Tert-butyl ester 18c

Under argon atmosphere, compound 18b (1.00g, 1.76mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (302mg, 1.94mmol, Leyan), tetrakis(triphenylphosphine)palladium (203mg, 0.18 mmol, Adamas) and sodium carbonate (559mg, 5.27mmol, Sinopharm) were dissolved in 50mL 1,4-dioxane and water (V/V=4:1) mixed solvent, heated to 85℃, stirred for 6 The reaction was terminated after hours. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A using CombiFlash rapid preparation apparatus to obtain the title product 18c (970 mg), yield: 92.0%.

MS m/z(ESI): 600.9[M+1].

the fourth step

(3R,13aS)-10-(2-Fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 18d

Compound 18c (970 mg, 1.62 mmol) was dissolved in 50 mL of a mixed solvent of dichloromethane and trifluoroacetic acid (V/V=1:1), and the reaction was stirred for 1 hour to terminate the reaction. The reaction solution was concentrated under reduced pressure to obtain the title product crude product 18d (770 mg), which was directly used in the next reaction without purification.

MS m/z(ESI): 501.0[M+1].

the fifth step

(3R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 18

Compound 18d (770mg, 1.54mmol), N,N-diisopropylethylamine (1.194g, 9.24mmol, Adamas) were dissolved in 50mL of dichloromethane, the reaction solution was cooled to 0°C, and acryloyl chloride was added dropwise (139mg, 1.54mmol, TCI), the reaction was stirred for 30 minutes to terminate the reaction. 50ml saturated sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane (50mL×3), the organic phase obtained was concentrated under reduced pressure, and the residue was purified with CombiFlash rapid preparation instrument using eluent system A to obtain the title product 18 (336.9 mg), yield: 39.5%.

MS m/z(ESI): 555.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.05-10.04 (m, 1H), 7.54-7.52 (m, 1H), 7.45-7.42 (m, 1H), 7.33-7.29 (m, 1H), 7.17-7.08(m,2H),6.91-6.82(m,1H),6.80-6.78(m,1H),6.72-6.70(m,1H),6.66-6.61(m,1H),6.21-6.17(m ,1H), 6.03-6.00 (m, 1H), 5.77-5.72 (m, 1H), 4.87-4.48 (m, 5H), 3.97-3.86 (m, 1H), 3.62-3.53 (m, 1H), 2.67 -2.54 (m, 2H), 1.20-1.08 (m, 6H), 1.05-1.03 (m, 3H).

Sixth step

(8R,3R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3, 4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H) -Ketone atropisomer 18-1

(8S,3R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3, 4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H) -Ketone atropisomer 18-2

Compound 18 (336.9mg, 0.608mmol) was chirally prepared (Separation conditions: chiral column CHIRALCEL OD-H (ODH0CD-TC012), 0.46cm ID*15cm L, 2um; mobile phase: methanol=100%, flow rate : 1.0 mL/min), the corresponding components were collected, and concentrated under reduced pressure to obtain the title products of single configuration compounds 18-1 (135 mg), 18-2 (140 mg).

Single configuration compound 18-1 (longer retention time):

MS m/z(ESI): 555.1[M+1].

Chiral HPLC analysis: retention time 5.002 minutes, chiral purity: 99.9% (column: CHIRALCEL OD-H (ODH0CD-TC012), 0.46cm I.D.*15cm L, 2um; mobile phase: methanol=100%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.02 (s, 1H), 7.53-7.51 (m, 1H), 7.45-7.42 (m, 1H), 7.33-7.29 (m, 1H), 7.17- 7.08(m,2H),6.91-6.82(m,1H),6.78(s,1H),6.71-6.61(m,2H),6.21-6.14(m,1H),6.00(s,1H),5.77- 5.71 (m, 1H), 4.75-4.47 (m, 5H), 3.97-3.88 (m, 1H), 3.62-3.54 (m, 2H), 2.59-2.56 (m, 1H), 1.20-1.13 (m, 3H) ), 1.11-1.02 (m, 6H).

Single configuration compound 18-2 (shorter retention time):

MS m/z(ESI): 555.1[M+1].

Chiral HPLC analysis: retention time 3.192 minutes, chiral purity: 99.9% (column: CHIRALCEL OD-H (ODH0CD-TC012), 0.46cm I.D.*15cm L, 2um; mobile phase: methanol=100%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.03 (s, 1H), 7.54-7.52 (m, 1H), 7.46-7.42 (m, 1H), 7.33-7.29 (m, 1H), 7.17- 7.10(m,2H),6.91-6.85(m,1H),6.80(s,1H),6.71-6.62(m,2H),6.21-6.16(m,1H),6.03(s,1H),5.78- 5.73 (m, 1H), 4.87-4.48 (m, 5H), 3.93-3.86 (m, 1H), 3.59-3.53 (m, 2H), 2.69-2.62 (m, 1H), 1.19-1.11 (m, 3H) ), 1.10-1.03 (m, 6H).

Example 19

(S)-2-acryloyl-8-(2-isopropyl-6-methylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3, 4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H) -Ketone 19

Using the synthetic route of Example 1, the second step raw material 2-isopropylaniline was replaced with 2-methyl-6-isopropylaniline, and the third step raw material 3-(hydroxymethyl)piperazine-1- Replace tert-butyl formate with tert-butyl (S)-3-(hydroxymethyl)piperazine-1-carboxylate to obtain title product 19 (70 mg), yield: 9.1%.

MS m/z(ESI): 575.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.13 (s, 1H), 7.46-7.41 (m, 2H), 7.29-7.21 (m, 4H), 7.19-6.23 (m, 2H), 5.89 (d ,1H), 5.79 (s, 1H), 5.77 (d, 1H), 4.75-4.07 (m, 6H), 3.52 (s, 1H), 2.61 (s, 1H), 2.25 (d, 1H), 2.13 ( s, 3H), 2.11 (s, 3H), 1.95 (d, 1H), 1.77 (d, 1H), 1.08-1.06 (m, 2H), 0.96 (t, 2H).

Example 20

(S)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-benzo(d)imidazol-4-yl)-1,2,3,4 ,13,13a-Hexahydropyrazine[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 20

Using the synthetic route of Example 15, the fourth step raw material 2-bromo-3-fluoroaniline was replaced with 4-bromo-5-methyl-1H-benzo[d]imidazole (Nanjing Yaoshi) to obtain the title compound 20( 3.18mg)

MS m/z(ESI): 561.6[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.13 (s, 1H), 7.58-7.50 (m, 3H), 7.40-7.40 (m, 1H), 7.32 (m, 1H), 7.25-7.23 ( m,1H),7.10(m,1H),7.0.3-7.02(m,1H),6.91-6.88(m,1H),6.37-6.36(m,1H),6.22-6.18(m,1H), 5.78-5.75(m,1H),4.78-4.05(m,6H), 3.50-3.46(m,2H),3.22-3.20(m,1H),2.71-2.66(m,1H),2.41(m,3H) ), 1.13 (t, J = 6.8 Hz, 3H), 1.01-1.00 (m, 3H).

Example 21

(3R,13aS)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one twenty one

first step

(3R,13aS)-8-(2-isopropylphenyl)-3-methyl-7-oxo-10-(4,4,5,5-tetramethyl-1,3,2-bis Oxaborin-2-yl)-3,4,7,8,13,13a-hexahydropyrazino[2',1':3,4][1,4]oxazepine[ 5,6,7-de]quinazoline-2(1H)-tert-butyl carboxylate 21a

The third step was the same as in Example 15, except that compound 15b was replaced with compound 18b to obtain the title crude product 21a (2.38 g).

Second step

(3R,13aS)-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-7-oxo-3,4,7,8, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxy Tert-butyl ester 21b

The fourth step was the same as in Example 15, except that compound 15c was replaced with 21a to obtain the titled crude product 21b (2.38 g).

MS m/z(ESI): 600.0[M+1].

third step

(3R,13aS)-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 21c

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 21b, the title crude product 21c (795 mg) was obtained, and the product was directly used in the next step without purification.

the fourth step

(3R,13aS)-2-acryloyl-10-(2-amino-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one twenty one

Same as the seventh step of Example 1, except that compound 1g was replaced with 21c, the title product 21 (26mg) was obtained, yield: 2.4%.

MS m/z(ESI): 554.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.51 (d, 1H), 7.43 (t, 1H), 7.31 (t, 1H), 7.18-7.05 (m, 1H), 7.02-6.95 (m, 1H), 6.93-6.80 (m, 1H), 6.71 (d, 1H), 6.45 (d, 1H), 6.29 (t, 1H), 6.24-6.15 (m, 1H), 5.90 (d, 1H), 5.80 -5.70(m,1H),5.01(s,2H),4.90-4.21(m,5H),4.00-3.81(m,1H),3.72-3.20(m,2H),2.70-2.51(m,1H) ,1.25-0.95(m,9H).

Examples 22, 22-1, 22-2

(3S,13aS)-2-acryloyl-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1,2, 3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7( 8H)-ketone 22

(8R,3S,13aS)-2-acryloyl-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1, 2,3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline- 7(8H)-ketone atropisomer 22-1

(8S,3S,13aS)-2-acryloyl-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1, 2,3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline- 7(8H)-ketone atropisomer 22-2

first step

(S)-2-((R)-2-(((Benzyloxy)carbonyl)amino)-3-hydroxypropionamido)methyl propionate 22b

The L-alanine methyl ester hydrochloride (5.0g, 35.82mmol, completed), N-benzyloxycarbonyl-D-serine (8.57g, 35.82mmol, completed), 1-(3-dimethylamino) Propyl)-3-ethylcarbodiimide hydrochloride (8.24g, 42.99mmol, Shaoyuan) was dissolved in 400mL dichloromethane, the reaction solution was cooled to 0℃, and N,N-diisopropyl was added dropwise Ethylamine (14.82g, 114.64mmol, Adamas) was heated to room temperature and stirred for 17 hours. The reaction was stopped, the reaction solution was concentrated under reduced pressure, 300mL saturated sodium bicarbonate solution was added, the reaction solution was extracted with ethyl acetate (300mL×3), and the organic phase was sequentially used 2M hydrochloric acid solution (200mL×2), saturated sodium chloride solution ( 200 mL×2) was washed, the organic phase was dried with anhydrous sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product (8.60 g), which was directly subjected to the next reaction without purification.

MS m/z(ESI): 325.2[M+1].

Second step

(3R,6S)-3-(hydroxymethyl)-6-methylpiperazine-2,5-dione 22c

Compound 22b (7.41 g, 22.85 mmol) was dissolved in 250 mL of methanol, and wet palladium/carbon (2.43 g, Shaoyuan) was added, replaced with hydrogen six times, and stirred for 17 hours to stop the reaction. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain a white solid. The obtained solid was dissolved in 150 mL of methanol and stirred at reflux for 24 hours to stop the reaction. The reaction solution was concentrated under reduced pressure to obtain the crude title product (3.60 g), which was directly subjected to the next reaction without purification.

MS m/z(ESI): 159.1 [M+1].

third step

((2S,5S)-5-methylpiperazin-2-yl)methanol 22d

Compound 22c (3.60g, 22.76mmol) was dissolved in borane in tetrahydrofuran (151.8ml, 0.9M, TCI), the reaction solution was heated to 70°C, stirred for 17 hours, and the reaction was terminated. The reaction solution was cooled to 0°C, approximately 3.5 mL of methanol was added, and hydrochloric acid (1 mL, 5M, Sinopharm) was added, and the reaction solution was heated to 70°C and stirred for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product (3.28 g). The product was directly subjected to the next reaction without purification.

MS m/z(ESI): 131.1[M+1].

the fourth step

(2S,5S)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 22e

Compound 22d (2.80g, 13.79mmol) was dissolved in 120mL methanol, the reaction solution was cooled to 0°C, and triethylamine (6.976g, 68.94mmol, Sinopharm) and di-tert-butyl dicarbonate (6.319g, 28.95mmol, Shaoyuan), stirring at room temperature for 17 hours. The reaction solution was concentrated under reduced pressure, 60 mL of ethanol, 60 mL of water and sodium hydroxide (2.76 g, 68.98 mmol, Sinopharm) were added to the residue, and the reaction solution was refluxed and stirred for 17 hours to terminate the reaction. The reaction solution was cooled to room temperature, and hydrochloric acid was added dropwise until the pH of the reaction solution was about 9. The reaction solution was extracted with dichloromethane (100mL×3), the organic phase was washed with saturated sodium chloride solution (150mL×2), and then with anhydrous It was dried over sodium sulfate for 15 minutes, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude title product (2.75 g), which was directly subjected to the next reaction without purification.

MS m/z(ESI): 231.1[M+1].

the fifth step

(2S,5S)-5-(((7-Bromo-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydroquinazoline-5 -Yl)oxy)methyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 22f

Dissolve compound 22e (2.75g, 11.92mmol) in 120mL N,N-dimethylformamide, cool the reaction solution to 0°C, slowly add sodium hydride (1.301g, 32.53mmol, 60% purity, Adamas) , The reaction was stirred for 1 hour, and then compound 1c (4.31 g, 10.84 mmol) was dissolved in 10 mL N,N-dimethylformamide, slowly added to the reaction solution, and stirred at room temperature for 17 hours. The reaction was stopped, 150mL saturated ammonium chloride solution was added to the reaction solution, extracted with dichloromethane (150mL×3), and the combined organic phases were washed with water (150mL×3) and saturated sodium chloride solution (250mL×1) in order to obtain organic The phase was concentrated under reduced pressure, and the residue was purified with the eluent system A using CombiFlash rapid preparation device to obtain the title product 22f (4.20 g), yield: 66.0%.

MS m/z(ESI): 587.1[M+1].

Sixth step

(3S,13aS)-10-bromo-8-(2-isopropylphenyl)-3-methyl-7-oxo-3,4,7,8,13,13a-hexahydropyrazino[ 2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 22g.

Compound 22f (4.20g, 7.15mmol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP) (6.323g, 14.30mmol), Shanghai Bide Pharmaceutical Technology Co., Ltd.) was dissolved in 140mL of tetrahydrofuran, the reaction solution was cooled to 0°C, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (4.35g, 28.59mmol, Shanghai Shaoyuan) was added Reagent Co., Ltd.), the temperature was raised to room temperature, and the reaction was stirred for 17 hours to terminate the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified with the eluent system A using CombiFlash rapid preparation apparatus to obtain 22 g (3.70 g) of the title product, yield: 90.8%.

MS m/z(ESI): 569.1 [M+1].

Seventh step

(3S,13aS)-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-7-oxo-3,4, 7,8,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2( 1H)-tert-butyl carboxylate 22h

Under an argon atmosphere, compound 22g (800mg, 1.40mmol), (5-methyl-1H-indazol-4-yl)boronic acid (272mg, 1.55mmol, complete), tetrakis(triphenylphosphine)palladium ( 163mg, 0.141mmol, Adamas) and sodium carbonate (447mg, 4.22mmol, Sinopharm) were dissolved in 50mL 1,4-dioxane and water (V/V=4:1) mixed solvent, heated to 85 Stir at ℃ for 17 hours to terminate the reaction. The reaction solution was concentrated under reduced pressure, and the residue was purified using CombiFlash rapid preparation instrument with eluent system A to obtain the title product 22h (800 mg), yield: 91.7%.

MS m/z(ESI): 621.3[M+1].

Eighth step

(3S,13aS)-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 22i

Compound 22h (800 mg, 1.29 mmol) was dissolved in 40 mL of a mixed solvent of dichloromethane and trifluoroacetic acid (V/V=1:1), and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the title product crude product 22i (695 mg), which was directly used in the next reaction without purification.

MS m/z(ESI): 251.2[M+1].

Step 9

(3S,13aS)-2-acryloyl-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1,2, 3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7( 8H)-ketone 22

Compound 22i (670mg, 1.29mmol), N,N-diisopropylethylamine (998mg, 7.72mmol, Adamas) were dissolved in 40mL of dichloromethane, the reaction solution was cooled to 0°C, and acryloyl chloride ( 117 mg, 1.29 mmol, TCI), the reaction was stirred for 30 minutes, and the reaction was terminated. 50ml of saturated sodium bicarbonate solution was added to the reaction solution, extracted with dichloromethane (50mL×3), the organic phase obtained was concentrated under reduced pressure, and the residue was purified with CombiFlash rapid preparation instrument using eluent system A to obtain the title product 22 (203mg ), yield: 27.5%.

MS m/z(ESI): 575.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.09 (s, 1H), 7.50-7.45 (m, 2H), 7.42-7.36 (m, 2H), 7.32-7.27 (m, 1H), 7.21 7.16 (m, 2H), 6.83-6.76 (m, 2H), 6.24-6.20 (m, 1H), 5.92-5.90 (m, 1H), 5.78-5.76 (m, 1H), 4.67-4.63 (m, 1H) ),4.52-4.30(m,4H),3.99-3.82(m,2H),2.74-2.55(m,2H),2.14-2.12(m,3H),1.28-1.23(m,3H),1.11-1.08 (m, 3H), 1.01-0.93 (m, 3H).

Tenth step

(8R,3S,13aS)-2-acryloyl-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1, 2,3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline- 7(8H)-ketone atropisomer 22-1

(8S,3S,13aS)-2-acryloyl-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1, 2,3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline- 7(8H)-ketone atropisomer 22-1

Compound 22 (203mg, 0.353mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALCEL OD-H (ODH0CD-TC012), 0.46cm ID*15cm L, 100ul; mobile phase: ethanol=100%, flow rate: 0.5mL/min), the corresponding components were collected and concentrated under reduced pressure to obtain the title products 22-1 (13.9 mg) and 22-2 (95 mg).

Single configuration compound 22-1 (long retention time):

MS m/z(ESI): 575.2[M+1].

Chiral HPLC analysis: retention time 10.865 minutes, chiral purity: 99.6% (column: CHIRALCEL OD-H (ODH0CD-TC012), 0.46cm I.D.*15cm L, 100ul; mobile phase: ethanol=100%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.10 (s, 1H), 7.48-7.45 (m, 2H), 7.42-7.35 (m, 2H), 7.31-7.28 (m, 1H), 7.21 7.17 (m, 2H), 6.83-6.76 (m, 2H), 6.24-6.20 (m, 1H), 5.90 (s, 1H), 5.78-5.75 (m, 1H), 4.67-4.62 (m, 1H), 4.52-4.49(m,1H),4.43-4.39(m,3H),3.96-3.89(m,2H),2.64-2.55(m,2H),2.12(m,3H),1.25-1.23(m,3H) ), 1.11-1.09 (m, 3H), 0.94-0.93 (m, 3H).

Single configuration compound 22-2 (shorter retention time):

MS m/z(ESI): 575.1[M+1].

Chiral HPLC analysis: retention time 8.458 minutes, chiral purity: 99.8% (column: CHIRALCEL OD-H (ODH0CD-TC012), 0.46cm I.D.*15cm L, 0.5ul; mobile phase: ethanol=100%).

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.07 (s, 1H), 7.50-7.45 (m, 2H), 7.42-7.36 (m, 2H), 7.32-7.29 (m, 1H), 7.21 7.16 (m, 2H), 6.83-6.76 (m, 2H), 6.24-6.20 (m, 1H), 5.92 (s, 1H), 5.77-5.75 (m, 1H), 4.67-4.64 (m, 1H), 4.52-4.40(m,3H), 4.35-4.30(m,1H), 4.01-3.97(m,1H), 3.85-3.79(m,1H), 2.74-2.60(m,2H), 2.14(m,3H) ), 1.26-1.25 (m, 3H), 1.10-1.08 (m, 3H), 1.01-0.99 (m, 3H).

Example 23

(S)-2-acryloyl-10-(1,6-dimethyl-1H-indazol-7-yl)-8-(2-isopropylphenyl)-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one twenty three

first step

(S)-10-(1,6-Dimethyl-1H-indazol-7-yl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxy Tert-butyl ester 23a

The same as the fourth step of Example 15, except that the starting material 2-bromo-3-fluoroaniline was replaced with 7-bromo-1,6-dimethyl-indazole, the title crude product 23a (675 mg) was obtained.

MS m/z(ESI): 621.0[M+1].

Second step

(S)-10-(1,6-Dimethyl-1H-indazol-7-yl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 23b

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 23a, the title crude product 23b (566 mg) was obtained, and the product was directly used in the next step without purification.

third step

(S)-2-acryloyl-10-(1,6-dimethyl-1H-indazol-7-yl)-8-(2-isopropylphenyl)-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one twenty three

The seventh step was the same as in Example 1, except that compound 1g was replaced with compound 23b to obtain the title product 23 (99 mg).

MS m/z(ESI): 575.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.96 (s, 1H), 7.63-7.57 (m, 1H), 7.50-7.42 (m, 1H), 7.40-7.25 (m, 2H), 7.18- 7.07(m,1H),7.02-7.65(m,1H),6.95-6.83(m,1H),6.81(s,1H),6.20(d,1H),5.86-5.72(m,2H),4.80- 4.01(m,6H),3.62-3.03(m,6H),2.71-2.56(m,1H),2.06-1.98(m,3H),1.16-1.05(m,3H),1.00-0.88(m,3H) ).

Example 24

(S)-2-acryloyl-10-(2-amino-4-fluoropyridin-3-yl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 24

first step

(S)-10-(2-Amino-4-fluoropyridin-3-yl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 24a

As in the fourth step of Example 15, the starting material 2-bromo-3-fluoroaniline was replaced with 3-bromo-4-fluoropyridin-2-amine to obtain the title crude product 24a (142 mg).

MS m/z(ESI): 587.2[M+1].

Second step

(S)-10-(2-Amino-4-fluoropyridin-3-yl)-8-(2-isopropylbenzene)-1,2,3,4,13,13a-hexahydropyrazino[ 2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one hydrochloride 24b

The same as in the sixth step of Example 1, the compound 1f was replaced with compound 24a to obtain the title crude product 24b (117 mg), which was directly used in the next step without purification.

third step

(S)-2-acryloyl-10-(2-amino-4-fluoropyridin-3-yl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 24

Same as the seventh step of Example 1, the compound 1g was replaced with compound 24b to obtain the title product 24 (44mg), the yield: 33.8%.

MS m/z(ESI): 541.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.95-7.85(m,1H), 7.52(d,1H), 7.44(t,1H), 7.32(t,1H), 7.15-7.06(m, 1H), 6.95-6.82 (m, 1H), 6.74 (s, 1H), 6.49-6.40 (m, 1H), 6.20 (d, 1H), 5.87-5.84 (m, 3H), 5.80-5.70 (m, 1H), 4.79-3.93 (m, 6H), 3.55-3.32 (m, 2H), 3.27-3.00 (m, 1H), 2.70-2.55 (m, 1H), 1.15-1.05 (m, 3H), 1.05- 0.96 (m, 3H).

Example 25

(S)-2-acryloyl-10-(2,6-dimethyl-2H-indazol-7-yl)-8-(2-isopropylphenyl)-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 25

first step

(S)-10-(2,6-Dimethyl-2H-indazol-7-yl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid Tert-butyl ester 25a

The same as the fourth step of Example 15, except that the raw material 2-bromo-3-fluoroaniline was replaced with 7-bromo-2,6-dimethyl-2H-indazole (using patent application "WO2014144747 in the specification page 117 Example 5" prepared by the disclosed method), the title crude product 25a (820 mg) was obtained.

MS m/z(ESI): 621.0[M+1].

Second step

(S)-10-(2,6-Dimethyl-2H-indazol-7-yl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one hydrochloride 25b

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 25a, the title crude product 25b (687 mg) was obtained, and the product was directly used in the next step without purification.

third step

(S)-2-acryloyl-10-(2,6-dimethyl-2H-indazol-7-yl)-8-(2-isopropylphenyl)-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 25

In the seventh step of Example 1, except that compound 1g was replaced with compound 25b, the title product 25 (164 mg) was obtained, with a yield of 21.9%.

¹ H NMR (400MHz, DMSO-d ₆ ): δ8.24(s,1H), 7.54(d,1H), 7.52-7.45(m,1H), 7.39(t,1H), 7.28(t,1H) ,7.14-7.06(m,1H),6.95-6.85(m,2H),6.82(d,1H),6.20(d,1H),6.01(d,1H),5.76(d,1H),4.86-3.00 (m, 12H), 2.75-2.61 (m, 1H), 1.90 (s, 3H), 1.16-0.99 (m, 6H).

MS m/z(ESI): 575.2[M+1].

Example 26

(S)-2-acryloyl-8-(4,6-diisopropylpyrimidin-5-yl)-10-(2-fluoro-6-hydroxyphenyl)-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 26

Using the synthetic route of Example 1, the second step raw material 2-isopropylaniline was replaced with 4,6-diisopropylpyrimidin-5-amine (using patent application "Example 7 on page 46 of the specification in US201977801" Prepared by the disclosed method), the third step raw material 3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester is replaced with (S)-3-(hydroxymethyl)piperazine-1-carboxylic acid Tert-butyl ester, the fifth step raw material (5-methyl-1H-indazol-4-yl)boronic acid was replaced with (2-fluoro-6-hydroxyphenyl)boronic acid to obtain the title product 26 (64.9mg).

MS m/z(ESI): 585.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.14 (brs, 1H), 9.16 (s, 1H), 7.18-7.12 (m, 1H), 6.93-6.83 (m, 2H), 6.73-6.71 ( m,1H),6.66-6.62(m,1H),6.22-6.18(m,1H),5.98-5.96(m,1H),5.78-5.75(m,1H),4.80-4.72(m,1H), 4.65-4.30(m,4H),4.09-4.04(m,2H),3.58-3.39(m,2H),2.81-2.68(m,2H),1.11-1.08(m,6H),1.03-0.99(m ,6H).

Example 27

(3R,13aS)-2-acryloyl-8-(2-isopropylphenyl)-3-methyl-10-(5-methyl-1H-indazol-4-yl)-1,2, 3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7( 8H)-ketone 27

Using the synthetic route of Example 18, the raw material (2-fluoro-6-hydroxyphenyl)boronic acid in the third step was replaced with (5-methyl-1H-indazol-4-yl)boronic acid (Bide Pharmaceutical) to prepare The title product 27 (243.3 mg) was obtained.

MS m/z(ESI): 575.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.09 (s, 1H), 7.52-7.46 (m, 2H), 7.43-7.36 (m, 2H), 7.32-7.28 (m, 1H), 7.21 7.17 (m, 2H), 6.92-6.82 (m, 2H), 6.23-6.15 (m, 1H), 5.98-5.94 (m, 1H), 5.78-5.72 (m, 1H), 4.78-4.49 (m, 4H) ),4.05-3.93(m,1H),3.70-3.48(m,2H),2.73-2.57(m,2H),2.14-2.13(m,3H),1.24-1.21(m,3H),1.11-1.09 (m,3H), 0.99-0.95(m,3H).

Example 28

(5aS)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9 -Hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one 28

first step

6,6-Difluoro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H)-tetraketone 28a

Compound 10m (5.5g, 17.55mmol) and N-fluorobisbenzenesulfonamide (11.63g, 36.89mmol) were dissolved in 500mL of tetrahydrofuran, cooled to 0°C, and added dropwise to lithium hexamethyldisilazide (1M , 55mL), after the addition, the reaction was stirred for 2 hours. It was quenched by adding 100mL saturated aqueous ammonium chloride solution, separated, the aqueous phase was extracted with ethyl acetate (100mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude target compound 28a (16g) , The product is directly used in the next reaction without purification.

MS m/z(ESI): 350.0[M+1].

Second step

6-Fluoro-5,7-dihydroxy-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 28b

The crude compound 28a (16 g, 45.80 mmol) was added to 80 mL of acetic acid, zinc powder (6 g, 91.75 mmol) was added, and the mixture was heated to 85° C. to react for 2 hours. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, 200 mL of water was added to the residue, extracted with ethyl acetate (150 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain The target compound (5.2g, yield: 34.2%), the product was directly used in the next reaction without purification.

MS m/z(ESI): 330.0[M-1].

third step

5,7-Dichloro-6-fluoro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 28c

The crude compound 28b (5.2 g, 15.69 mmol) was added to 40 mL of thionyl chloride, 1 mL of N,N-dimethylformamide was added, and the reaction was heated to 80° C. for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was poured into 100 mL ice water, dichloromethane was added for extraction (100 mL×3), the organic phases were combined, washed with saturated sodium bicarbonate aqueous solution (100 mL×2), and washed with water (100 mL×1), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 28c (2.2 g, yield: 38.0%).

MS m/z(ESI): 368.0[M+1].

the fourth step

4,5,7-Trichloro-6-fluoro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 28d

Compound 28c (1.3g, .53mmol) was dissolved in 10mL of acetonitrile, and phosphorus oxychloride (2.64g, 17.21mmol, 1.6mL) and N,N-diisopropylethylamine (2.33g, 18.05mmol, 3.2 mL), heated to 80°C for 1.5 hours. The reaction solution was cooled to room temperature, and concentrated under reduced pressure to obtain the crude target compound 28d (3.2g). The product was directly used in the next reaction without purification.

the fifth step

(S)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,7-dichloro-6-fluoro-1-(2-isopropylphenyl) Tert-Butyl-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 28e

The crude compound 28d (1.2g, 3.10mmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, compound 13b (0.64g, 1.93mmol) was added, and N,N-diisopropylethylamine (802mg, 6.20mmol, 1.1mL), the reaction was stirred for 1 hour. Add 20mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and apply the residue to silica gel column chromatography Purification by chromatography with eluent system B gave the title compound 28e (634 mg, yield 30.0%).

Sixth step

(S)-2-chloro-3-fluoro-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-1 ,7,9a,10,12-Pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-tert-butyl carboxylate 28f

Compound 28e (634 mg, 931.3 μmol) was dissolved in 40 mL of tetrahydrofuran, tetrabutylammonium fluoride (1M, 2.5 mL) was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in 100 mL of ethyl acetate, washed with water (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and passed through the column with eluent system F to obtain the target Compound 28f (96 mg, yield: 19.4%).

MS m/z(ESI): 530.1[M+1].

Seventh step

(5aS)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11,12 -Hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-tert-butyl carboxylate 28g of ester

In an argon atmosphere, (2-fluoro-6-hydroxyphenyl)boronic acid (42mg, 269.3μmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 28f (96mg, 181.1μmol), sodium bicarbonate (46mg, 547.5 μmol) and tetrakistriphenylphosphine palladium (21 mg, 18.1 μmol) were added to a mixed solvent of 12 mL of water and 1,4-dioxane (V/V=1:5), and heated to 90° C. to react for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved by adding 50 mL of dichloromethane, filtered, spin-dried and concentrated under reduced pressure. The residue was purified by thin-layer chromatography with developing solvent A to obtain 28 g (120 mg, yield) of the target compound : 109.3%).

MS m/z(ESI): 606.1[M+1].

Eighth step

(5aS)-3-Fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro-4 -Oxa-1,7,9a,10,12-Pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one trifluoroacetate 28h

Compound 28g (120 mg, 198.1 μmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 28h (286 mg, yield: 285.5%). The product was directly used in the next reaction without purification.

MS m/z(ESI): 506.1[M+1].

Step 9

(5aS)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9 -Hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one 28

纯化得到目标化合物28(25mg，产率：7.89％)。 The crude compound 28h (286 mg, 565.7 μmol) was dissolved in 15 mL of dichloromethane, acryloyl chloride (40 mg, 441.9 μmol, 36 μL) and triethylamine (364 mg, 3.59 mmol, 0.5 mL) were added, and the reaction was stirred for 1 hour. Add 10mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue in 30ml methanol , Add 250mg sodium bicarbonate, heat to 50°C and react for 30 minutes. After the reaction solution was cooled to room temperature, 30 mL of a mixed solvent of dichloromethane and methanol (V/V=10:1) was added to dissolve, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by thin layer chromatography with developing solvent A to obtain a crude product , Followed by high performance liquid chromatography (column: Boston Phlex Prep C18 5μm 30×150mm; mobile phase: water (10mmol ammonium bicarbonate): acetonitrile = 40%-60% (15min), flow rate: 30mL/min)

Purification gave target compound 28 (25mg, yield: 7.89%).

MS m/z(ESI): 559.9[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.12(s,1H), 7.37-7.39(m,1H), 7.30-7.32(m,1H), 7.19-7.24(m,2H), 6.98( t, 1H), 6.78-6.91 (m, 1H), 6.63-6.70 (m, 2H), 6.21 (d, 1H), 5.77 (d, 1H), 4.77-4.87 (m, 2H), 4.55-4.62 ( m,1H),4.33-4.46(m,1H),4.23-4.23(m,1H),4.04-4.13(m,1H),3.57-3.72(m,2H),3.29-3.30(m,1H), 2.63-2.67 (m, 1H), 1.05 (d, 3H), 0.98 (t, 3H).

Example 29

(S)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 29

first step

(S)-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-7-oxo-3,4,7,8,13,13a -Hexahydropyrazine[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 29a

In an argon atmosphere, compound 12b (500mg, 0.902mmol), (5-methyl-1H-indazol-4-yl)boronic acid (477mg, 2.71mmol, finished), tetrakistriphenylphosphine palladium (104mg , 0.09mmol, Greenchem), sodium carbonate (287mg, 2.71mmol, Titan) were added to 11mL N,N-dimethylformamide and water (V/V=10:1) mixed solvent, heated to 120 Stir at °C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to obtain the title compound 29a (450 mg, yield: 82%).

MS m/z(ESI): 607.1[M+1].

Second step

(S)-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a hexahydropyrazino [2',1': 3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one hydrochloride 29b

Compound 29a (300mg, 0.4945mmol) was dissolved in 5mL 1,4-dioxane, and 1,4-dioxane solution of hydrogen chloride (4M, 5mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred for 30 minutes . The reaction solution was concentrated under reduced pressure to obtain the crude title compound 29b (210 mg), which was directly used in the next reaction without purification.

MS m/z(ESI): 507.3[M+1].

third step

(S)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 29

The crude compound 29b (214mg, 0.42mmol) was dissolved in 4.0mL of dichloromethane, acryloyl chloride (42mg, 0.46mmol, Anaiji) was added dropwise to the reaction solution at 0°C, and then triethylamine (90mg, 0.888 mmol, Titan). The reaction was stirred for 30 minutes. It was quenched by adding 20 mL of water, separated into layers, and the aqueous phase was extracted with dichloromethane (20 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to high-performance liquid chromatography (column: Sharpsil-T Prep C18 5um 21.2*250mm; mobile phase: A-water (10mmol NH4OAc): B-acetonitrile, 37%-57% B within 14min gradient elution, flow rate : 18 mL/min) to obtain the title compound 29 (35.00 mg, yield: 15%).

MS m/z(ESI): 561.3[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ) δ 13.10 (s, 1H), 7.48 (d, 2H), 7.40 (dd, 2H), 7.31 (t, 1H), 7.19 (dd, 2H), 7.00- 6.76 (m, 2H), 6.21 (d, 1H), 5.95 (dd, 1H), 5.77 (dd, 1H), 4.88-3.93 (m, 6H), 3.64-3.36 (m, 2H), 3.28-3.07 ( m, 1H), 2.75-2.61 (m, 1H), 2.14 (d, 3H), 1.11 (dd, 3H), 0.98 (dd, 3H).

Example 30, 30-1, 30-2

(5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 30

(12S,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 30-1

(12R,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 30-2

first step

1-(2-isopropyl-6-methylphenyl)urea 30b

Add 2-isopropyl-6-methylaniline 30a (25g, 167.5mmol) to 300mL of a mixed solvent of water and acetic acid (V/V=2:1), then add sodium cyanate (21.8g, 335.3mmol) ) 300mL aqueous solution, add 500mL water, stir and react for 2 hours. The reaction solution was filtered, the filter cake was washed with water, and dried under vacuum to obtain the target compound 30b (30.5 g, yield: 94.6%).

Second step

2-cyano-N-((2-isopropyl-6-methylphenyl)carbamoyl)acetamide 30c

Cyanoacetic acid (19.24g, 226.1mmol) was added to 50mL of acetic anhydride, heated to 80°C for 10 minutes, then compound 30b (29g, 150.8mmol) was added, and heated to 80°C for 1 hour. The reaction solution was cooled to room temperature, 1 L of water was added, and the mixture was stirred for 1 hour. After filtering, the filter cake was washed with water, and suction filtered to dryness to obtain the target compound 30c (46 g, yield: >100%), which was directly used in the next reaction without further drying.

third step

6-Amino-1-(2-isopropyl-6-methylphenyl)pyrimidine-2,4(1H,3H)-dione 30d

Compound 30c (46 g, 177.3 mmol) was added to a 200 mL aqueous solution of sodium hydroxide (13.6 g, 340.0 mmol), and heated to 80° C. to react for 15 minutes. The reaction solution was cooled to room temperature, 1L of water was added, and then acetic acid was added to adjust the pH of the reaction solution to be about 7, filtered, the filter cake was washed with water, and vacuum dried to obtain the target compound 30d (35g, yield: 76.0).

the fourth step

3-(6-Amino-1-(2-isopropyl-6-methylphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-3 -Oxypropionitrile 30e

Cyanoacetic acid (23.6g, 277.4mmol) was added to 80mL of acetic anhydride, heated to 80°C for 10 minutes, then compound 30d (36g, 138.8mmol) was added, heated to 85°C for 1 hour. The reaction solution was cooled to room temperature, then poured into 1 L of water, and stirred for 15 minutes. The target compound 30e (76g, yield: >100%) was obtained by filtration, and it was directly used in the next step without further drying.

the fifth step

1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H)-tetraketone 30f

Compound 30e (76 g, 232.8 mmol) was added to 250 mL of hydrobromic acid, and the mixture was heated to 85° C. to react for 1 hour. The reaction solution was cooled to room temperature, 1L of water was added, and the reaction pH was adjusted to about 7 with ammonia water, filtered, the filter cake was washed with water, and vacuum dried to obtain the target compound 30f (35.5 g, yield: 46.6%).

Sixth step

6,6-Dichloro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H) -Tetraketone 30g

Compound 30f (35.5g, 108.4mmol) was added to 200mL 1,4-dioxane, heated to 40°C, sulfonyl chloride (43.34g, 321.1mmol, 26mL) was added dropwise, after the addition, reacted at 40°C for 1 hour. The reaction solution was cooled to room temperature and poured into ice water, stirred for 10 minutes, filtered, the filter cake was washed with water, and dried under vacuum to obtain 30 g (40.55 g, yield: 94.3%) of the target compound.

Seventh step

6-Chloro-5,7-Dihydroxy-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 30h

30 g (40.55 g, 102.3 mmol) of compound was added to 200 mL of acetic acid, zinc powder (14.6 g, 223.2 mmol) was added, and the mixture was heated to 90° C. to react for 2 hours. The filtrate was filtered while hot, and the filtrate was concentrated under reduced pressure. The obtained residue was poured into water, stirred for 10 minutes, filtered, and the filter cake was washed with water and vacuum dried to obtain the target compound 30h (35.5 g, yield: 95.8%).

Eighth step

5,6,7-Trichloro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 30i

120mL of thionyl chloride was added to compound 30h (35.5g, 98.12mmol), 10mL of N,N-dimethylformamide was added, and the reaction was heated to 80°C overnight. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was poured into ice water, extracted with dichloromethane (300mL×3), the organic phases were combined, and then saturated sodium bicarbonate solution (200mL×2) and water (100mL ×1) Wash, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue through silica gel column chromatography with eluent system B to obtain the target compound 30i (43 g, yield: >100%).

Step 9

4,5,6,7-Tetrachloro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 30j

Compound 30i (20g, 50.1mmol) was added to 350mL of acetonitrile, phosphorus oxychloride (23.1g, 150.6mmol, 14mL) and N,N-diisopropylethylamine (20.42g, 157.9mmol, 28mL) were added, Heat to 85°C and stir to react for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the target compound 30j (45 g, yield: >100%), which was directly used in the next reaction without further purification.

Tenth step

(2R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(5,6,7-trichloro-1-(2-iso Propyl-6-methylphenyl)-2-oxa-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 30k

Compound 30j (45g, 107.8mmol) was dissolved in 350mL of dichloromethane, cooled to 0°C, compound 10h (18.75g, 54.41mmol) and N,N-diisopropylethylamine (20.41g, 157.9mmol, 28mL were added) ), the reaction is stirred for 1 hour. Then add 200mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (300mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue through a silica gel column The target compound 30k (23.6 g, yield: 30.1%) was obtained by purification with eluent system B by chromatography.

Eleventh step

(5aS,8R)-2,3-Dichloro-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo-5a,6,8,9,11, 12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid Tert-butyl ester 30l

Compound 30k (17.5 g, 24.13 mmol) was dissolved in 300 mL tetrahydrofuran, 72 mL 1M tetrabutylammonium fluoride tetrahydrofuran solution was added, and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 800 mL of ethyl acetate and then washed with water (300 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with eluent system Purification by F gave the target compound 30l (8.11 g, yield: 58.5%).

MS m/z(ESI): 574.0[M+1].

Twelfth step

(5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo -5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-7(5H)-tert-butyl carboxylate 30m

Under an argon atmosphere, mix 2-fluoro-6-hydroxyphenylboronic acid (3g, 19.2mmol), compound 30l (8.11g, 14.1mmol), disodium hydrogen phosphate dodecahydrate (15.2g, 42.4mmol), tetratriphenyl Phosphine palladium (3.26 g, 2.82 mmol) was added to a mixed solvent of 200 mL water and 1,4-dioxane (V/V=1:4), and heated to 100° C. to react overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 500 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system E to obtain the target compound 30m (4g, Yield: 43.5%).

MS m/z(ESI): 650.0[M+1].

Step 13

(5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone trifluoroacetate 30n

Compound 30m (715 mg, 1.09 mmol) was dissolved in 10 mL of dichloromethane, 2 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the target compound 30n (1.2 g, yield: >100%), which was directly used in the next reaction without further purification.

Step Fourteen

(5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 30

Compound 30n (1.2g, 2.18mmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, triethylamine (1.093g, 10.8mmol, 1.5mL) was added, and acryloyl chloride (140mg, 1.54mmol, 0.125 mL), react for 1 hour. Add 20mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative chromatography Obtain target compound 30 (95mg, yield: 7.2%)

MS m/z(ESI): 604.0[M+1].

¹ H NMR (400MHz, CD ₃ CN): δ7.61 (brs, 1H), 7.23-7.30 (m, 3H), 7.13-7.14 (m, 1H), 6.65-6.78 (m, 3H), 6.25 (t ,1H),5.75(t,1H),4.70-4.77(m,3H),4.55-4.58(m,1H),4.17-4.42(m,1H),3.93-4.01(m,2H),3.24-3.70 (m, 1H), 2.59-2.79 (m, 1H), 1.79-1.99 (m, 3H), 1.22-1.29 (m, 3H), 1.10-1.12 (m, 3H), 0.97-0.98 (m, 3H) .

Fifteenth step

(12S,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 30-1

(12R,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 30-2

Compound 30 (106.6mg, 0.176mmol) was chirally prepared (Separation conditions: chiral preparation column CHIRALPAK IG, 5.0cm ID*25cm L, 10μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 60mL/ min), collect the corresponding components and concentrate under reduced pressure to obtain the title products 30-1 (28mg) and 30-2 (30mg).

Single configuration compound 30-2 (long retention time):

MS m/z(ESI): 604.0[M+1].

Chiral HPLC analysis: retention time 4.981 minutes, chiral purity: 99.9% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol = 60/40, flow rate: 1.0 mL/min).

¹ H NMR (400MHz, CD ₃ CN): δ7.60 (brs, 1H), 7.24-7.31 (m, 3H), 7.13-7.15 (m, 1H), 6.66-6.80 (m, 3H), 6.25 (t ,1H), 5.75(t,1H),4.71-4.79(m,3H),4.57-4.59(m,1H),4.18-4.42(m,1H),4.00-4.10(m,2H),3.27-3.71 (m, 1H), 2.72-2.79 (m, 1H), 1.95 (s, 3H), 1.21-1.30 (m, 3H), 1.11-1.13 (m, 3H), 0.98-0.99 (m, 3H).

Single configuration compound 30-1 (shorter retention time):

MS m/z(ESI): 604.0[M+1].

Chiral HPLC analysis: retention time 4.417 minutes, chiral purity: 99.8% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol = 60/40, flow rate: 1.0 mL/min).

¹ H NMR (400MHz, CD ₃ CN): δ7.60 (brs, 1H), 7.24-7.30 (m, 3H), 7.14-7.15 (m, 1H), 6.66-6.80 (m, 3H), 6.22-6.25 (m, 1H), 5.75 (t, 1H), 4.70-4.77 (m, 3H), 4.48-4.59 (m, 1H), 4.17-4.43 (m, 1H), 3.91-4.05 (m, 2H), 3.24 -3.65(m,1H), 2.59-2.64(m,1H), 2.00(s,3H), 1.23-1.31(m,3H), 1.11-1.12(d,3H), 0.97-0.99(m,3H) .

Example 31

(S)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indol-4-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 31

first step

(S)-(2-(tert-Butoxycarbonyl)-8-(2-isopropylphenyl)-7-oxo1,2,3,4,7,8,13,13a-octahydropyrazine And [2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-10-yl)boronic acid 31a

Under argon atmosphere, compound 12c (1.6g, 2.88mmol), diboronic acid pinacol ester (877mg, 3.46mmol, complete), [1,1'-bis(diphenylphosphino)ferrocene] Palladium dichloride (210 mg, 0.288 mmol, Greenchem) and potassium acetate (848 mg, 8.64 mmol, Titan) were added to 10 mL of dimethyl sulfoxide, and the mixture was heated to 120°C and stirred for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain target compound 31a (800 mg, yield: 53%).

MS m/z(ESI): 521.1[M+1].

Second step

(S)-8-(2-isopropylphenyl)-10-(5-methyl-1H-indol-4-yl)-7-oxo-3,4,7,8,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl Ester 31b

Under argon atmosphere, compound 31a (400mg, 0.768mmol), 4-bromo-5-methyl-1H-indole (107mg, 0.512mmol, Bidd Medicine), tetrakis(triphenylphosphine)palladium (59mg, 0.051) mmol, Greenchem) and sodium carbonate (163mg, 1.54mmol, Titan) were added to 12mL N,N-dimethylformamide and water (V/V=5:1) mixed solvent, and the reaction was stirred at 120℃ 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system C to obtain target compound 31b (250 mg, yield: 80%).

MS m/z(ESI): 606.4[M+1].

third step

(S)-8-(2-isopropylphenyl)-10-(5-methyl-1H-indol-4-yl)-1,2,3,4,13,13a-hexahydropyrazine And [2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 31c

Compound 31b (225 mg, 0.371 mmol) was dissolved in 5 mL of dichloromethane, 5 mL of trifluoroacetic acid was added dropwise to the reaction solution, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude title compound 31c (187 mg). The product was directly used in the next reaction without purification.

MS m/z(ESI): 506.3[M+1].

the fourth step

(S)-2-acryloyl-8-(2-isopropylphenyl)-10-(5-methyl-1H-indol-4-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 31

Compound 31c (187 mg, 0.369 mmol) was dissolved in 5 mL of dichloromethane, acryloyl chloride (33.5 mg, Beide Pharmaceutical) was added dropwise to the reaction solution at 0°C, and then triethylamine (112 mg, Titan) was added. The reaction was stirred for 1 hour. Add 10mL saturated sodium bicarbonate aqueous solution for quenching and extract with dichloromethane (50mL×3). Combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. : Sharpsil-T Prep C18 5um 21.2*250mm; Mobile phase: A-water (10mmol NH4OAc): B-acetonitrile, 37%-57% B within 14min gradient elution, flow rate: 18mL/min), to obtain the title compound 31 ( 13.51mg, yield: 6.5%).

MS m/z(ESI): 560.3[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ11.08 (s, 1H), 7.47 (d, 1H), 7.36 (d, 1H), 7.26-7.21 (m, 3H), 7.14 (m, 1H) ,6.93-6.89(m,2H),6.75-6.74(m,1H),6.22-6.18(m,1H),5.94-5.93(m,1H),5.90-5.89(m,1H),5.78(dd, 1H), 4.76-4.06 (m, 5H), 4.05-4.05 (m, 1H), 3.52-3.46 (m, 1H), 3.30-3.17 (m, 2H), 2.69-2.65 (m, 1H), 2.08- 2.08 (m, 3H), 1.10 (t, 3H), 1.01-0.98 (m, 3H).

Examples 32, 32-1, 32-2

(S)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyridine Azino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one 32

(8S,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 32-1

(8R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 32-2

Using the synthetic route of Example 29, the first step material (5-methyl-1H-indazol-4-yl)boronic acid was replaced with (2-fluoro-6-hydroxyphenyl)boronic acid to obtain the title compound 32 (170mg , Yield: 38%).

MS m/z(ESI): 541.5[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.01-10.00 (m, 1H), 7.54-7.52 (m, 1H), 7.45-7.42 (m, 1H), 7.33-7.31 (m, 1H), 7.17-7.07 (m, 2H), 6.89-6.86 (m, 1H), 6.77-6.77 (m, 1H), 6.70-6.61 (m, 2H), 6.22-6.17 (d, 1H), 6.00-6.00 (m ,1H),5.78-5.75(d,1H),4.74-4.15(m,5H),4.00-4.00(m,1H),3.51-3.45(m,1H),3.27-3.13(m,2H),2.64 -2.62 (m, 1H), 1.12-1.09 (m, 3H), 1.05-1.02 (m, 3H).

first step

(8S,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 32-1

(8R,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one atropisomer 32-2

Compound 32 (173mg) was chirally resolved by supercritical fluid chromatography (separation conditions: chiral preparation column: CHIRALCEL OD-H (ODH0CD-TC013); column model: 0.46 cm ID×15 cm L; sample volume: 1.0 micro Liter; mobile phase: ethanol = 100%; flow rate: 1.0 ml/min; wavelength: UV 214 nm; temperature: 35°C; instrument model: Shimadzu LC-20AD CP-HPLC-05) to obtain the target compound 32-1 (47.81 mg) ), 32-2 (79.62 mg).

Single configuration compound 32-1 (shorter retention time):

MS m/z(ESI): 541.5[M+1].

Chiral HPLC analysis: retention time 6.102 minutes, chiral purity: 99% (CHIRALCEL OD-H (ODH0CD-TC013); column model: 0.46 cm ID×15 cm L; sample volume: 1.0 μl; mobile phase: ethanol = 100%; Flow rate: 1.0 ml/min;

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.01-10.00 (s, 1H), 7.54-7.52 (m, 1H), 7.45-7.44 (m, 1H), 7.33-7.31 (m, 1H), 7.15-7.07 (m, 2H), 6.89-6.87 (m, 1H), 6.78-6.78 (m, 1H), 6.70-6.61 (m, 2H), 6.21-6.17 (d, 1H), 6.01-6.01 (m ,1H),5.78-5.74(d,1H),4.74-4.74(m,1H),4.60-4.16(m,4H),4.01-4.01(m,1H),3.46-3.42(m,1H),3.32 -3.13 (m, 2H), 2.67-2.64 (m, 1H), 1.10-1.09 (m, 3H), 1.05-1.04 (m, 3H).

Single configuration compound 32-2 (longer retention time):

MS m/z(ESI): 541.5[M+1].

Chiral HPLC analysis: retention time 7.787 minutes, chiral purity: 99% (CHIRALCEL OD-H (ODH0CD-TC013); column model: 0.46 cm ID×15 cm L; injection volume: 1.0 μl; mobile phase: ethanol = 100%; flow rate: 1.0 ml/min;)

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.00 (s, 1H), 7.54-7.52 (m, 1H), 7.45-7.44 (m, 1H), 7.33-7.31 (m, 1H), 7.15 7.07(m,2H),6.90-6.87(m,1H),6.77-6.77(m,1H),6.70-6.63(m,2H),6.22-6.17(d,1H),6.00-6.00(m,1H) ),5.77-5.74(d,1H),4.76-4.68(m,1H),4.58-4.57(m,2H),4.46-4.12(m,2H),4.03-4.00(m,1H),3.54-3.46 (m, 1H), 3.22-3.10 (m, 2H), 2.62-2.57 (m, 1H), 1.12-1.10 (m, 3H), 1.04-1.02 (m, 3H).

Example 33

(3S,13aS)-2-acryloyl-10-(2-fluoro-6-hydroxyphenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 33

Using the synthetic route of Example 22, the seventh step raw material (5-methyl-1H-indazol-4-yl)boronic acid was replaced with (2-fluoro-6-hydroxyphenyl)boronic acid to obtain the title product 33( 423.9mg).

MS m/z(ESI): 555.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.03-10.01 (m, 1H), 7.53-7.51 (m, 1H), 7.44-7.41 (m, 1H), 7.33-7.29 (m, 1H), 7.17-7.06 (m, 2H), 6.82-6.69 (m, 3H), 6.65-6.61 (m, 1H), 6.24-6.19 (m, 1H), 5.98-5.96 (m, 1H), 5.77-5.74 (m ,1H),4.62-4.58(m,1H),4.48-4.28(m,4H),3.96-3.78(m,2H),2.70-2.53(m,2H),1.26-1.23(m,3H),1.10 -0.99 (m, 6H).

Example 34

(5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 34

(12R,5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]naphthalene-11(12H)-ketone 34-1

(12S,5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]naphthalene-11(12H)-ketone 34-2

first step

6,6-Difluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H) -Tetraketone 34a

The first step was the same as in Example 28, except that compound 10m was replaced with compound 30f to obtain the title compound 34a (14.5 g, yield: >100%).

Second step

6-Fluoro-5,7-dihydroxy-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 34b

The second step was the same as in Example 28, except that 28a was replaced with compound 34a to obtain the title compound 34b (6.2 g, yield: 44.9%).

third step

5,7-Dichloro-6-fluoro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 34c

The third step was the same as in Example 28, except that compound 28b was replaced with compound 34b to obtain the title compound 34c (1.1 g, yield: 16.0%).

the fourth step

4,5,7-Trichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 34d

Compound 34c (1.6g, 4.18mmol) was dissolved in 20ml of acetonitrile, and phosphorus oxychloride (1.5g, 9.78mmol, 0.9ml) and N,N-diisopropylethylamine (1.4g, 10.83mmol, 1.9mL), heated to 80°C for 1.5 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the crude target compound 34d (1.74 g), which was directly used in the next reaction without purification.

the fifth step

(2R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,7-dichloro-6-fluoro-1-(2-isopropyl- 6-Methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 34e

The crude compound 34d (1.74g, 4.34mmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, compound 10h (1.50g, 4.35mmol) was added, and N,N-diisopropylethylamine (1.0g , 7.73mmol, 1.3mL), the reaction was stirred for 1 hour. Add 20mL saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue on silica gel column chromatography Purified with eluent system B to obtain the title compound 34e (2.7 g, yield 87.7%).

Sixth step

(5aS,8R)-2-chloro-3-fluoro-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo-5a,6,8,9,11 ,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid Tert-butyl ester 34f

Compound 34e (1.0 g, 1.41 mmol) was dissolved in 15 mL of tetrahydrofuran, tetrabutylammonium fluoride (1M, 4.4 mL) was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure, dissolved in 100 mL of ethyl acetate, washed with water (30 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.

The target compound 34f (273 mg, yield: 34.6%) was obtained by chromatography and eluent system F.

MS m/z(ESI): 558.1[M+1].

Seventh step

(5aS,8R)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo -5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-7(5H)-tert-butyl formate 34g

(2-Fluoro-6-hydroxyphenyl)boronic acid (100mg, 0.64mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 34f (273mg, 0.49mmol), disodium hydrogen phosphate dodecahydrate (400mg, 1.11mmol) ), tetrakistriphenylphosphine palladium (50mg, 0.043mmol) was added to 10mL of water and 1,4-dioxane (V/V=1:4) mixed solvent, heated to 95 ℃ under argon atmosphere to react 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of dichloromethane was added to the residue to dissolve, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system F to obtain 370 mg of the title crude compound.

MS m/z(ESI): 634.1[M+1].

Eighth step

(5aS,8R)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone hydrochloride 34h

Compound 34g (370mg, 0.58mmol) was dissolved in 2mL 1,4-dioxane solution, and hydrogen chloride/1,4-dioxane solution (4M, 4mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature 60 minutes. The reaction solution was concentrated to obtain the title product crude product 34h (311 mg), which was directly used in the next reaction without purification.

Step 9

(5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 34

Compound 34h (311 mg, 2.07 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (180 mg, 1.78 mmol, 0.25 mL) and acryloyl chloride (50 mg, 0.55 mmol, 45 μL) were added, and the reaction was stirred for 1 hour. Add 10mL saturated sodium bicarbonate solution, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue with 15mL methanol, add 250mg Sodium bicarbonate, heated to 60°C and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 30 mL of a mixture of dichloromethane and methanol (V/V=20:1) was added to dissolve and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (column: Boston Phlex Prep C18 5μm 30×150mm; mobile phase: water (10mmol ammonium bicarbonate): acetonitrile=40%-60% (15min), flow rate: 30mL/min) The title compound 34 (180mg, yield: 18.9%) was purified ).

MS m/z(ESI): 588.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.06 (s, 1H), 7.28-7.14 (m, 3H), 7.07 (d, 1H), 6.92-6.75 (m, 1H), 6.69 (d, 1H), 6.65 (t, 1H), 6.26-6.10 (m, 1H), 5.80-5.70 (m, 1H), 4.84 (d, 2H), 4.66-4.52 (m, 1H), 4.46 (s, 1H) ,4.31(d,1H),4.23-3.98(m,2H),3.69(t,1H), 2.50-2.40(m,1H),1.94-1.77(m,3H),1.30-1.15(m,3H) , 1.04 (t, 3H), 0.96-0.89 (m, 3H).

Tenth step

(12R,5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]naphthalene-11(12H)-ketone 34-1

(12S,5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]naphthalene-11(12H)-ketone 34-2

Compound 34 (50mg, 0.085mmol) was chirally prepared (Separation conditions: chiral preparation column CHIRALPAK IF 150*4.6mm, 5um; mobile phase: n-hexane: ethanol = 60/40 (v/v), flow rate: 1mL /min), the corresponding components were collected and concentrated under reduced pressure to obtain the title products 34-1 (21 mg) and 34-2 (23 mg).

34-1:

MS m/z(ESI): 588.1[M+1].

Chiral HPLC analysis: retention time 6.461 minutes, chiral purity: 96.1% (column: CHIRALPAK IF 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=60/40(v/v), flow rate: 1.0mL /min).

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.07 (s, 1H), 7.28-7.15 (m, 3H), 7.12-7.03 (m, 1H), 6.96-6.78 (m, 1H), 6.69 (d ,1H),6.65(t,1H),6.25-6.10(m,1H),5.80-5.68(m,1H),4.90-4.76(m,2H),4.64-4.53(m,1H),4.50-4.40 (m,1H),4.35-4.27(m,1H),4.23-4.02(m,2H),3.69(t,0.5H),3.31-3.25(m,0.5H),2.48-2.40(m,1H) , 1.90 (d, 3H), 1.24-1.09 (m, 3H), 1.03 (d, 3H), 0.91 (d, 3H).

34-2:

MS m/z(ESI): 588.1[M+1].

Chiral HPLC analysis: retention time 5.082 minutes, chiral purity: 99.1% (column: CHIRALPAK IF 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=60/40(v/v), flow rate: 1.0mL /min).

¹ H NMR (500MHz, DMSO-d ₆ ) δ 10.08 (s, 1H), 7.29-7.14 (m, 3H), 7.10-7.03 (m, 1H), 6.93-6.78 (m, 1H), 6.69 (d ,1H),6.65(t,1H),6.24-6.12(m,1H),5.78-5.69(m,1H),4.90-4.75(m,2H),4.65-4.41(m,2H),4.36-4.25 (m,1H),4.24-4.17(m,1H),4.12-4.01(m,1H),3.69(t,0.5H),3.31-3.25(m,0.5H),2.70-2.57(m,1H) , 1.82 (s, 3H), 1.23-1.09 (m, 3H), 1.05 (d, 3H), 0.93 (d, 3H).

Example 35

(S)-2-acryloyl-8-(2-isopropylphenyl)-10-(6-methyl-1H-indazol-7-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 35

first step

(S)-8-(2-isopropylphenyl)-10-(6-methyl-1H-indazol-7-yl)-7-oxo-3,4,7,8,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 35a

Same as the fourth step of Example 15, except that the starting material 2-bromo-3-fluoroaniline was replaced with 7-bromo-6-methyl-1H-indazole (finished), the title crude product 35a (710mg) was obtained .

MS m/z(ESI): 607.0[M+1].

Second step

(S)-8-(2-isopropylphenyl)-10-(6-methyl-1H-indazol-7-yl)-1,2,3,4,13,13a-hexahydropyrazine And[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one hydrochloride 35b

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 35a, the title crude product 35b (592 mg) was obtained, and the product was directly used in the next step without purification.

third step

(S)-2-acryloyl-8-(2-isopropylphenyl)-10-(6-methyl-1H-indazol-7-yl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 35

Same as the seventh step of Example 1, except that compound 1g was replaced with compound 35b, the title product 35 (102 mg) was obtained, yield: 15.6%.

MS m/z(ESI): 561.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ12.54 (s, 1H), 7.99 (s, 1H), 7.59 (d, 1H), 7.52-7.43 (m, 1H), 7.42-7.35 (m, 1H), 7.34-7.25(m, 1H), 7.12-7.03(m, 1H), 6.96(d, 1H), 6.95-6.85(m, 1H), 6.79(s, 1H), 6.21(d, 1H) ,5.88(d,1H),5.82-5.73(m,1H),4.85-4.01(m,6H),3.61-3.32(m,2H),3.25-3.00(m,1H),2.75-2.56(m, 1H), 2.09 (s, 3H), 1.15-1.03 (m, 3H), 1.01-0.90 (m, 3H).

Example 36

(S)-2-acryloyl-10-(6-amino-3-chloro-2-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 36

first step

2-bromo-4-chloro-3-fluoroaniline 36a

2-Bromo-6-chloro-3-fluoroaniline 36b

The compound 2-bromo-3-fluoroaniline (500mg, 2.63mmol, completion) and N-chlorosuccinimide (NCS) (280mg, 2.09mmol, completion) were dissolved in acetonitrile (10mL) and reacted The solution was stirred at 70°C for 16 hours under an argon atmosphere. The reaction solution was concentrated to obtain a crude product, which was purified by silica gel column chromatography with the eluent system n-hexane/ethyl acetate to obtain the title product 36a (361mg), yield: 61%; 36b (200mg), yield: 34% .

36a: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.20 (t, 1H), 6.61 (dd, 1H), 5.81 (br, 2H).

36b: ¹ H NMR (400 MHz, DMSO-d ₆ ): δ 7.30 (dd, 1H), 6.58 (t, 1H), 5.76 (br, 2H).

Second step

(S)-10-(6-Amino-3-chloro-2-fluorophenyl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 36c

The fourth step was the same as in Example 15, except that the starting material 2-bromo-3-fluoroaniline was replaced with 36a to obtain the title crude product 36c (412 mg).

MS m/z(ESI): 620.2[M+1].

third step

(S)-10-(6-Amino-3-chloro-2-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazine And[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one hydrochloride 36d

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 36c, the title crude product 36e (345 mg) was obtained, and the product was directly used in the next step without purification.

the fourth step

(S)-2-acryloyl-10-(6-amino-3-chloro-2-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 36

Same as the seventh step of Example 1, except that compound 1g was replaced with 36d, the title product 36 (29mg) was obtained, yield: 7.6%.

MS m/z(ESI): 574.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.52 (d, 1H), 7.52-7.40 (m, 1H), 7.38-7.30 (m, 1H), 7.18-7.06 (m, 2H), 6.98- 6.80 (m, 1H), 6.87 (s, 1H), 6.47 (d, 1H), 6.20 (d, 1H), 5.86 (d, 1H), 5.83-5.71 (m, 1H), 5.17 (s, 2H) ,4.73-3.98(m,6H),3.56-3.31(m,2H),3.25-2.97(m,1H),2.71-2.55(m,1H),1.15-1.05(m,3H),1.05-0.95( m,3H).

Example 37, 37-1, 37-2

(5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a,6, 7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H )-Ketone 37

(12S,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone atropisomer 37-1

(12R,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone atropisomer 37-2

first step

Using the synthetic route of Example 30, the 10h step raw material 10h was replaced with 13b to obtain the title compound 37 (116 mg).

MS m/z(ESI): 590.0[M+1].

¹ H NMR (400MHz, CD ₃ CN): δ7.68 (brs, 1H), 7.23-7.31 (m, 3H), 7.13-7.15 (m, 1H), 6.65-6.77 (m, 3H), 6.27 (dd ,1H),5.77(dd,1H),4.67-4.82(m,3H),4.00-4.53(m,3H),3.52-3.65(m,2H),3.35-3.38(m,1H),2.62-2.73 (m, 1H), 1.98-1.99 (m, 3H), 1.11-1.12 (m, 3H), 0.97-0.98 (m, 3H).

Second step

(12S,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone atropisomer 37-1

(12R,5aS)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone atropisomer 37-2

Compound 37 (99.7mg, 0.168mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK IC, 2.5cm ID*25cm L, 10μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 30mL/ min), collect the corresponding components and concentrate under reduced pressure to obtain the title products 37-1 (25mg) and 37-2 (28mg).

Single configuration compound 37-2 (long retention time):

MS m/z(ESI): 590.0[M+1].

Chiral HPLC analysis: retention time 4.715 minutes, chiral purity: 99.8% (column: AY-H Phenomenex Lux Amylose-2 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 1.0 mL/min).

¹ H NMR (400MHz, CD ₃ CN): δ7.59 (brs, 1H), 7.24-7.31 (m, 3H), 7.14-7.15 (m, 1H), 6.66-6.77 (m, 3H), 6.27 (d ,1H),5.77(d,1H),4.66-4.82(m,3H),4.01-4.57(m,3H),3.63-3.74(m,2H),3.35-3.38(m,1H),2.65(pant , 1H), 1.96 (s, 3H), 1.11 (d, 3H), 0.97 (d, 3H).

Single configuration compound 37-1 (shorter retention time):

MS m/z(ESI): 590.0[M+1].

Chiral HPLC analysis: retention time 3.622 minutes, chiral purity: 99.8% (column: AY-H Phenomenex Lux Amylose-2 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 1.0 mL/min).

¹ H NMR (400MHz, CD ₃ CN): δ7.59 (brs, 1H), 7.24-7.31 (m, 3H), 7.14-7.15 (m, 1H), 6.66-6.81 (m, 3H), 6.27 (d ,1H),5.77(d,1H),4.67-4.82(m,3H),4.01-4.56(m,3H),3.66-3.80(m,2H),3.40-3.41(m,1H),2.70(pant , 1H), 1.96 (s, 3H), 1.11 (d, 3H), 0.97 (d, 3H).

Example 38

(S)-2-acryloyl-10-(2-amino-3-chloro-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 38

first step

(S)-10-(2-Amino-3-chloro-6-fluorophenyl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8,13,13a -Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxylic acid tert-butyl ester 38a

The fourth step was the same as in Example 15, except that the starting material 2-bromo-3-fluoroaniline was replaced with compound 36b to obtain the title crude product 38a (381 mg).

MS m/z(ESI): 620.2[M+1].

Second step

(S)-10-(2-Amino-3-chloro-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexahydropyrazine And[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one hydrochloride 38b

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 38a, the title crude product 38b (319 mg) was obtained, and the product was directly used in the next step without purification.

third step

(S)-2-acryloyl-10-(2-amino-3-chloro-6-fluorophenyl)-8-(2-isopropylbenzene)-1,2,3,4,13,13a- Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 38

Same as the seventh step of Example 1, except that compound 1g was replaced with compound 38b, the title product 38 (76mg) was obtained, yield: 21.6%.

MS m/z(ESI): 574.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ7.52 (d, 1H), 7.48-7.40 (m, 1H), 7.38-7.28 (m, 1H), 7.27-7.18 (m, 1H), 7.13 7.05(m,1H), 6.96-6.80(m,1H), 6.71(s,1H), 6.42(t,1H), 6.20(d,1H), 5.85(d,1H), 5.80-5.70(m, 1H), 5.08 (s, 2H), 4.80-3.98 (m, 6H), 3.56-3.30 (m, 2H), 3.25-2.99 (m, 1H), 2.70-2.52 (m, 1H), 1.15-1.05 ( m, 3H), 1.03-0.95 (m, 3H).

Example 39

(S)-2-(2-Fluoroacryloyl)-8-(2-isopropylphenyl)-10-(5-methyl-1H-indazol-4-yl)-1,2,3, 4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H) -Ketone 39

first step

The crude product 29b (60mg, 0.55mmol), 2-fluoroacrylic acid (65mg, 0.72mmol, completion), Carter condensing agent (560mg, 1.2mmol, completion) were dissolved in a mixed solvent of 10mL tetrahydrofuran and 5mL acetonitrile, and ice Under bath cooling, N,N-diisopropylethylamine (220 mg, 1.7 mmol, Adamas) was added dropwise, and the reaction was stirred at room temperature for 16 hours. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. High performance liquid chromatography (column: Sharpsil-T Prep C18 5um 21.2*250mm; mobile phase: A-water (10mmol NH4OAc): B-acetonitrile, 37%-57% B within 14min gradient elution, flow rate: 18mL /min) purification to obtain the title product 39 (140 mg), yield: 20%.

MS m/z(ESI): 579.1 [M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ13.10 (s, 1H), 7.55-7.45 (m, 2H), 7.45-7.35 (m, 2H), 7.32-7.25 (m, 1H), 7.22 7.07 (m, 2H), 6.82 (s, 1H), 6.00-5.90 (m, 1H), 5.45-5.20 (m, 2H), 4.80-4.00 (m, 6H), 3.45-3.25 (m, 3H), 2.80-2.58 (m, 1H), 2.13 (s, 3H), 1.20-1.03 (m, 3H), 1.02-0.90 (m, 3H).

Example 40

(S)-7-acryloyl-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro- 4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one 40

first step

5,7-Dichloro-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 40a

Compound 10m (1.6g, 5.10mmol) was added to 20mL of thionyl chloride, then 1mL of N,N-dimethylformamide was added, and the reaction was heated to 80°C for 3 hours. The reaction solution was cooled to room temperature, the residue was poured into 200 mL ice water, extracted with dichloromethane (50 mL×3), the organic phases were combined, and then saturated sodium bicarbonate aqueous solution (30 mL×2), water (30 mL×1) It was washed, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 40a (490 mg, yield: 27.3%).

Second step

(S)-3-(((7-chloro-1-(2-isopropylphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrido[2,3- d)pyrimidin-5-yl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 40b

Compound 40a (216mg, 616.7μmol) was dissolved in 10mL N,N-dimethylformamide, and (3S)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (134mg, 619.5μmol) was added , Completed), cooled to 0°C, added sodium hydride (75mg, 1.87mmol, purity 60%), stirred and reacted for 1 hour. It was quenched by adding 20 mL of ammonium chloride aqueous solution, and a solid precipitated out. Filtered. The filter cake was dissolved with 20 mL of dichloromethane, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Target compound 40b (166 mg, yield 50.7%).

MS m/z(ESI): 530.3[M+1].

third step

(S)-2-Chloro-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a ,10,12-Pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester 40c

Compound 40b (166mg, 313.1μmol) was dissolved in 10mL tetrahydrofuran, and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (416mg, 940.5μmol, Shaoyuan) was added And 1,8-diaza[5,4,0]bicycloundec-7-ene (285mg, 1.87mmol, 280μL, Shaoyuan), and the reaction was stirred overnight. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 50 mL of ethyl acetate, washed with 1N hydrochloric acid (40 mL×2), water (25 mL×1), saturated sodium chloride aqueous solution (25 mL×1), and dried over anhydrous sodium sulfate After filtering, the filtrate was concentrated under reduced pressure, and the residue was purified by thin-layer chromatography with developing solvent A to obtain target compound 40c (20 mg, yield: 12.4%).

MS m/z(ESI): 512.2[M+1].

the fourth step

(S)-2-(2-Fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11,12-hexahydro- 4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester 40d

In an argon atmosphere, (2-fluoro-6-hydroxyphenyl)boronic acid (15mg, 96.2μmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 40c (40mg, 78.1μmol), tetratriphenylphosphine palladium ( 12 mg, 10.3 μmol) and sodium bicarbonate (17 mg, 160.3 μmol) were added to a mixed solvent of 12 mL of water and 1,4-dioxane (V/V=1:5), and heated to 90° C. for reaction for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 50 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent A to obtain the target compound 40d (40mg, yield: 87.1 %).

MS m/z(ESI): 588.1[M+1].

the fifth step

(S)-2-(2-Fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro-4-oxa- 1,7,9a,10,12-Pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one trifluoroacetate 40e

Compound 40d (40 mg, 68.0 μmol) was dissolved in 5 mL of dichloromethane, 0.75 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude target compound 40e (95mg), which was directly used in the next reaction without purification.

Sixth step

(S)-7-acryloyl-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro- 4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one 40

Compound 40e (95mg, 194.8μmol) was dissolved in 10mL of dichloromethane, cooled to 0°C, triethylamine (29mg, 286.5μmol, 40μL) and acryloyl chloride (5.6mg, 61.8μmol, 5.0μL) were added, and the reaction was stirred 1 hour. Add 10mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (10mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and subject the residue to thin layer chromatography Purified with developing reagent A to obtain target compound 40 (15 mg, yield: 14.2%).

MS m/z(ESI): 542.2[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ11.90-11.94 (m, 1H), 7.47-7.53 (m, 2H), 7.25-7.35 (m, 3H), 7.13-7.15 (m, 1H), 6.78-6.91(m,1H),6.69-6.74(m,1H),6.55-6.57(m,1H),6.21(d,1H),5.77(d,1H),4.57-4.78(m,3H), 4.43-4.60 (m, 1H), 4.22-4.23 (m, 1H), 4.03-4.05 (m, 1H), 3.60-3.79 (m, 2H), 3.40-3.42 (m, 1H), 2.57-2.69 (m , 1H), 1.09-1.11 (m, 3H), 0.93-0.98 (m, 3H).

Example 41

(S)-2-acryloyl-10-(2-amine-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 41

first step

2-bromo-4,6-dichloro-3-fluoroaniline 41a

Dissolve 2-bromo-3-fluoroaniline (1g, 5.3mmol, complete), N-chlorosuccinimide (1.45g, 10.8mmol Shaoyuan) in 20mL acetonitrile, under argon atmosphere, the reaction is Stir at 70°C for 16 hours. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL×3), the organic phase was washed with saturated brine, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product 41a (1.4 g).

¹ H NMR (400MHz, DMSO-d ₆ ): δ 7.59 (d, 1H), 5.94 (s, 2H).

Second step

(S)-10-(2-Amino-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-7-oxo-3,4,7,8, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-2(1H)-carboxy Tert-butyl ester 41b

The same as the fourth step of Example 15, except that the starting material 2-bromo-3-fluoroaniline was replaced with 41a, the title crude product 41b (645 mg) was obtained.

MS m/z(ESI): 654.1[M+1].

third step

(S)-10-(2-Amino-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4,13,13a-hexa Hydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H)-one hydrochloride 41c

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 41b, the title crude product 41c (546 mg) was obtained, and the product was directly used in the next step without purification.

the fourth step

(S)-2-acryloyl-10-(2-amine-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-1,2,3,4, 13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 41

Same as the seventh step of Example 1, except that compound 1g was replaced with compound 41c, the title product 41 (135mg) was obtained, yield: 22.5%.

MS m/z(ESI): 608.1[M+1].

¹ H NMR (400MHz, CDCl ₃ ): δ7.55-7.45 (m, 2H), 7.40-7.30 (m, 1H), 7.29-7.25 (m, 1H), 7.13-7.04 (m, 1H), 6.76 ( s, 1H), 6.70-6.56 (m, 1H), 6.40 (d, 1H), 6.15 (s, 1H), 5.82 (d, 1H), 5.15-3.05 (m, 11H), 2.78-2.65 (m, 1H), 1.28-1.18 (m, 3H), 1.13-1.02 (m, 3H).

Example 42

(3R,13aS)-2-acryloyl chloride-10-(2-amino-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-1 ,2,3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline -7(8H)-ketone 42

first step

(3R,13aS)-10-(2-amino-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-7-oxo-3 ,4,7,8,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline -2(1H)-tert-butyl carboxylate 42a

The crude product 21a (1.19g, 1.9mmol), compound 41a (450mg, 1.7mmol), tetrakis(triphenylphosphine) palladium (200mg, 0.17mmol, Adamas), anhydrous sodium carbonate (400mg, 3.7mmol, Sinopharm) was dissolved in a mixed solvent of 8 mL of dioxane and 2 mL of water, and the reaction was stirred at 80°C for 16 hours under an argon atmosphere. The reaction solution was quenched with water (100 mL), extracted with ethyl acetate (30 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product 42a (1.17g) was purified with the eluent system A using CombiFlash rapid preparation instrument.

MS m/z(ESI): 667.8[M+1].

Second step

(3R,13aS)-10-(2-amino-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3, 4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline-7(8H) -Ketone Hydrochloride 42b

The same as the sixth step of Example 1, except that compound 1f was replaced with compound 42a, the title crude product 42b (546 mg) was obtained, and the product was directly used in the next step without purification.

third step

(3R,13aS)-2-acryloyl chloride-10-(2-amino-3,5-dichloro-6-fluorophenyl)-8-(2-isopropylphenyl)-3-methyl-1 ,2,3,4,13,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazoline -7(8H)-ketone 42

Same as the seventh step of Example 1, except that compound 1g was replaced with 42b, the title product 42 (33mg) was obtained, yield: 3.0%.

MS m/z(ESI): 622.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ 7.58-7.40 (m, 3H), 7.38-7.26 (m, 1H), 7.15-7.05 (m, 1H), 6.98-6.80 (m, 1H), 6.74(d,1H), 6.25-6.13(m,1H), 5.85(d,1H), 5.80-5.70(m,1H), 5.26(br,2H), 4.85-3.40(m,7H), 3.30- 3.10 (m, 1H), 2.70-2.55 (m, 1H), 1.25-0.95 (m, 9H).

Examples 43-1, 43-2

(12S,5aS)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 43-1

(12R,5aS)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 43-2

first step

(12S,5aS)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11 ,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxy Tert-butyl atropisomer 43a-1

(12R,5aS)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-11-oxo-5a,6,8,9,11 ,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxy Tert-butyl atropisomer 43a-2

In an argon atmosphere, compound 28f (530mg, 1.00mmol), (2-fluoro-6-hydroxyphenyl)boronic acid (233.9mg, 1.50mmol, Leyan), sodium bicarbonate (210mg, 2.49mmol), four three Phenylphosphine palladium (116mg, 100.3μmol) was added to a mixed solvent of 24mL water and 1,4-dioxane (V/V=1:5), heated to 80°C for 1 hour, and the reaction solution was cooled to Concentrate under reduced pressure at room temperature, add 50mL of dichloromethane to dissolve and filter, and concentrate the filtrate under reduced pressure. The residue is purified by silica gel column chromatography with eluent system F, and then purified by thin layer chromatography with developing solvent F to obtain the title Compound 43a-1 (193 mg), 43a-2 (136 mg).

Single configuration compound 43a-1 (shorter retention time):

MS m/z(ESI): 606.1[M+1].

Retention time: 2.38 minutes, (column: ALQUITY UPLC BEHC 18 1.7μm 2.1×50mm, mobile phase: acetonitrile: water (5mM ammonium bicarbonate)=30:70-95:5 (3.5min), flow rate: 0.5mL/ min).

Single configuration compound 43a-2 (long retention time):

MS m/z(ESI): 606.1[M+1].

Retention time: 2.41 minutes, (Column: ALQUITY UPLC BEHC 18 1.7μm 2.1×50mm, mobile phase: acetonitrile: water (5mM ammonium bicarbonate) = 30:70-95:5 (3.5min), flow rate: 0.5mL/ min).

Second and third steps

(12S,5aS)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro -4-oxa-1,7,9a,10,12-Pentazaphenyl[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one 2,2,2 -Trifluoroacetate atropisomer 43b-1

(12R,5aS)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8,9-hexahydro -4-oxa-1,7,9a,10,12-Pentazaphenyl[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one 2,2,2 -Trifluoroacetate atropisomer 43b-2

Same as the eighth step of Example 28, except that compound 28g was replaced with compound 43a-1/43a-2, the title compound 43b-1 (403mg/43b-2 (263mg) was prepared.

Fourth and fifth steps

(12S,5aS)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 43-1

(12R,5aS)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Atropisomer 43-2

The ninth step was the same as in Example 28, except that compound 28h was replaced with compound 43b-1/43b-2 to obtain the title compound 43-1 (54 mg)/43-2 (52 mg).

Single configuration compound 43-1 synthesized from the product with a retention time of 2.38 minutes in the first step:

MS m/z(ESI): 560.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.11 (s, 1H), 7.37-7.39 (m, 1H), 7.29-7.31 (m, 1H), 7.19-7.24 (m, 2H), 6.96 ( d, 1H), 6.79-6.91 (m, 1H), 6.65-6.70 (-1-m, 2H), 6.18-6.23 (m, 1H), 5.76-5.79 (m, 1H), 4.86-4.92 (m, 1H), 4.96-4.81 (m, 1H), 4.58-4.67 (m, 1H), 4.33-4.49 (m, 1H), 4.23-4.24 (m, 1H), 4.04-4.16 (m, 1H), 3.57- 3.63 (m, 2H), 3.28-3.32 (m, 1H), 2.59-2.66 (m, 1H), 1.05-1.09 (m, 3H), 0.97-0.99 (m, 3H).

Single configuration compound 43-2 synthesized from the product with a retention time of 2.41 minutes in the first step:

MS m/z(ESI): 560.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.12 (brs, 1H), 7.37-7.39 (m, 1H), 7.28-7.32 (m, 1H), 7.18-7.26 (m, 2H), 6.98- 7.00 (m, 1H), 6.78-6.90 (m, 1H), 6.62-6.70 (m, 2H), 6.18-6.22 (m, 1H), 5.75-5.79 (m, 1H), 4.82-4.83 (m, 2H) ),4.52-4.59(m,2H),4.32-4.62,4.25-4.26(m,1H),4.03-4.13(m,1H),3.57-3.82(m,3H),2.53-2.55(m,1H) , 1.05-1.06 (m, 3H), 0.96-0.98 (m, 3H).

Example 44

(5aR)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a,6, 7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H )-Ketone 44

first step

(R)-3-(((tert-butyldimethylsilyl)oxy)methyl)piperazine-1-carboxylic acid tert-butyl ester 44b

Same as the first step of Examples 13-1 and 13-2, except that the raw material compound 13a is replaced with (R)-3-(hydroxymethyl)piperazine-1-carboxylic acid tert-butyl ester (Bide Pharmaceutical) The title compound 44b (2.35 g, yield: 102.5%).

Second step

6,6-Difluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H) -Tetraketone 44c

The first step was the same as in Example 28, except that compound 10m was replaced with compound 30f to obtain the title compound 44c (14.5 g, yield: >100%).

third step

6-Fluoro-5,7-dihydroxy-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 44d

The second step was the same as in Example 28, except that compound 28a was replaced with compound 44c to obtain the title compound 44d (6.2 g, yield: 44.9%).

the fourth step

5,7-Dichloro-6-fluoro-1-(2-isopropylphenyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione 44e

The third step was the same as in Example 28, except that compound 28b was replaced with compound 44d to obtain the title compound 44e (1.1 g, yield: 16.0%).

the fifth step

4,5,7-Trichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)pyrido[2,3-d]pyrimidin-2(1H)-one 44f

The fourth step was the same as in Example 28, except that compound 28c was replaced with compound 44e to obtain the title compound 44f (3.2 g, yield: >100%).

Sixth step

(R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-4-(5,7-dichloro-6-fluoro-1-(2-isopropyl-6- (Methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 44g

The fifth step was the same as in Example 28, except that compound 28d was replaced with compound 44f to obtain the title compound 44g (1.617g, yield: 29.1%).

Seventh step

(R)-2-chloro-3-fluoro-12-(2-isopropyl-6-methylphenyl)-11-oxo-5a,6,8,9,11,12-hexahydro-4 -Oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-t-butyl carboxylate 44h

The sixth step was the same as in Example 28, except that compound 28e was replaced with compound 44g to obtain the title compound 44h (356 mg, yield: 28.1%).

Eighth step

(5aR)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-11-oxo-5a,6,8, 9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H )-Tert-butyl formate 44i

The seventh step was the same as in Example 28, except that compound 28f was replaced with compound 44h to obtain the title compound 44i (376 mg, yield: 92.7%).

Step 9

(5aR)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a,6,7,8,9 -Hexahydro-4-oxa-1,7,9a,10,12-Pentazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Trifluoro Acetate 44j

The same as the eighth step of Example 28, except that compound 28g was replaced with compound 44i to obtain the title compound 44j (625 mg, yield: >100%).

Tenth step

(5aR)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-5,5a,6, 7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H )-Ketone 44

The ninth step was the same as in Example 28, except that compound 28h was replaced with compound 44j to obtain the title compound 44 (64 mg, yield: 9.27%).

MS m/z(ESI): 574.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.08 (s, 1H), 7.18-7.24 (m, 3H), 7.06-7.08 (m, 1H), 6.78-6.90 (m, 1H), 6.65 6.70(m,2H),6.18-6.22(m,1H),5.75-5.78(m,1H),4.79-4.89(m,2H),4.55-4.58(m,1H),4.26-4.45(m,2H) ), 4.02-4.04 (m, 1H), 3.56-3.72 (m, 2H), 3.38-3.42 (m, 1H), 2.58-2.67 (m, 1H), 1.85 (d, 3H), 1.05 (d, 3H) ), 0.92 (d, 3H).

Example 45, 45-1, 45-2

(5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 45

(12S,5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 45-1

(12R,5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 45-2

first step

(2R,5S)-5-(((tert-butyldimethylsilyl)oxo)methyl)-4-(5,7-dichloro-6-fluoro-1-(2-isopropylbenzene) Yl)-2-oxo-1,2-dihydropyridine[2,3-d]pyrimidin-4-yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 45a

Compound 28d (3.8g, 9.82mmol) was dissolved in 50mL of dichloromethane, cooled to 0°C, compound 10h (1.38g, 4.00mmol) was added, and N,N-diisopropylethylamine (2.26g, 17.48mmol, 3.1mL), the reaction was stirred for 1 hour. Add 30mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and pass the residue to silica gel column chromatography Purified with eluent system B to obtain target compound 45a (1.92 g, yield: 28.1%).

Second step

(5aS,8R)-2-chloro-3-fluoro-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6,8,9,11,12-hexahydro -4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester 45b

Compound 45a (1.92 g, 2.76 mmol) was dissolved in 50 mL of tetrahydrofuran, 5.6 mL of 1M tetrabutylammonium fluoride tetrahydrofuran solution was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 150 mL of ethyl acetate and washed with water (40 mL×3) and saturated brine (25 mL×1) successively, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Purified by silica gel column chromatography with eluent system F to obtain the target compound 45b (731 mg, yield: 48.6%).

MS m/z(ESI): 544.0[M+1].

third step

(5aS,8R)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6, 8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7 (5H)-tert-butyl carboxylate 45c

Under an argon atmosphere, 2-fluoro-6-hydroxyphenylboronic acid (314mg, 2.01mmol), compound 45b (731mg, 1.34mmol), sodium bicarbonate (282mg, 3.35mmol), tetrakistriphenylphosphine palladium (155mg, 134.1 μmol) was added to a mixed solvent of 24 mL of water and 1,4-dioxane (V/V=1:5), and heated to 80° C. and stirred for 3 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 100 mL of dichloromethane and then filtered. The filtrate was concentrated under reduced pressure. Yield: 84.3%).

MS m/z(ESI): 620.1[M+1].

the fourth step

(5aS,8R)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Trifluoroacetate 45d

Compound 45c (703 mg, 1.13 mmol) was dissolved in 10 mL dichloromethane, 2 mL trifluoroacetic acid TFA was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the target compound 45d (1.3 g, yield: >100%), which was directly used in the next reaction without further purification.

the fifth step

(5aS,8R)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 45

Dissolve compound 45d (1.3g, 2.50mmol) in 40mL of dichloromethane, cool to 0°C, add triethylamine (1.09g, 10.7mmol, 1.5mL), and then add acryloyl chloride (159mg, 1.7567mmol, 142μL) dropwise ), the reaction is stirred for 1 hour. Add 20mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the resulting residue with 50mL methanol Then, 250 mg of sodium bicarbonate was added, and the mixture was heated to 60° C. and stirred for 1 hour. The reaction solution was cooled to room temperature, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with an eluent system (ethyl acetate: methanol) to obtain a crude product. After purification by preparative chromatography, target compound 45 (180 mg, yield: 12.5%) was obtained.

MS m/z(ESI): 574.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.08 (s, 1H), 7.21-7.37 (m, 4H), 6.97-6.98 (m, 1H), 6.84-6.87 (m, 1H), 6.65 6.68(m,2H),6.12-6.22(m,1H),5.76-5.77(m,1H), 4.82-4.84(m,2H),4.49-4.57(m,2H),4.29-4.32(m,1H) ), 3.90-4.04 (m, 2H), 3.70-3.90 (m, 1H), 2.65-2.66 (m, 1H), 1.15-1.20 (d, 3H), 0.97-1.04 (d, 6H).

Sixth step

(12S,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 45-1

(12R,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 45-2

Compound 45 (180mg, 0.314mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK OD, 5.0cm ID*25cm L, 10μm; mobile phase: methanol = 100%, flow rate: 60mL/min), and collect it The corresponding components were concentrated under reduced pressure to obtain title products 45-1 (80 mg) and 45-2 (82 mg).

Single configuration compound 45-2 (longer retention time):

MS m/z(ESI): 574.0[M+1].

Chiral HPLC analysis: retention time 7.621 minutes, chiral purity: 99.7% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol = 50/50, flow rate: 1.0 mL/min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.08(d,1H), 7.38(d,1H), 7.31(t,1H), 7.19-7.27(m,2H), 7.02(d,1H) ,6.79-6.91(m,1H),6.64-6.72(m,2H),6.14-6.24(m,1H),5.72-5.78(m,1H),4.77-4.86(m,2H),4.41-4.63( m, 2H), 4.30-4.34 (m, 1H), 4.06-4.23 (m, 2H), 3.30-3.74 (m, 1H), 2.49-2.51 (m, 1H), 1.16-1.23 (m, 3H), 1.06 (d, 3H), 0.98 (d, 3H).

Single configuration compound 45-1 (shorter retention time):

MS m/z(ESI): 574.0[M+1].

Chiral HPLC analysis: retention time 6.037 minutes, chiral purity: 99.8% (column: CHIRALPAK IE 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol = 50/50, flow rate: 1.0 mL/min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.08 (d, 1H), 7.38 (d, 1H), 7.31 (t, 1H), 7.20-7.25 (m, 2H), 6.98 (d, 1H) ,6.85-6.92(m,1H),6.64-6.72(m,2H),6.16-6.24(m,1H),5.73-5.79(m,1H),4.78-4.89(m,2H),4.48-4.62( m,2H),4.31-4.38(m,1H),4.05-4.33(m,2H),3.25-3.69(m,1H),2.64-2.67(m,1H),1.15-1.21(m,3H), 1.06 (d, 3H), 0.99 (d, 3H).

Example 46, 46-1, 46-2

(5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 46

(12R,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 46-1

(12S,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 46-2

first step

(2S,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(5,6,7-trichloro-1-(2-iso (Propylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 46b

Compound 10q (2.0g, 4.96mmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, and compound 46a (1.75g, 5.08mmol) was added sequentially, using the synthetic route of Example 10-1, 10-2 intermediate 10h , The first step raw material 10a was replaced by L-alanine methyl ester hydrochloride, and 10b was replaced by the compound N-benzyloxycarbonyl-L-serine, and N,N-diisopropylethylamine (1.2g , 9.28mmol, 1.53mL), the reaction was stirred for 1 hour. Add 30mL saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (50mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue using silica gel column chromatography Chromatography purification with eluent system B gave the title compound 46b (2.52 g, yield: 71.4%).

Second step

(5aR,8S)-2,3-Dichloro-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6,8,9,11,12-hexahydro- 4-oxa-1,7,9a,10,12-pentaaza[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester 46c

Compound 46b (2.52 g, 3.54 mmol) was dissolved in 20 mL of tetrahydrofuran, tetrabutylammonium fluoride (1M, 9.5 mL) was added, and the reaction was stirred for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate and then washed with water (60 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column chromatography with eluent system Purification (dichloromethane: ethyl acetate) gave the title compound 46c (1.2 g, yield: 60.4%).

MS m/z(ESI): 560.1[M+1].

third step

(5aR,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6, 8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7 (5H)-tert-Butyl formate 46d

In an argon atmosphere, (2-fluoro-6-hydroxyphenyl) boric acid (500mg, 3.20mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 46c (1.2g, 2.14mmol), dodecahydrate hydrogen phosphate Sodium (2g, 5.58mmol), tetrakistriphenylphosphine palladium (200mg, 173.08μmol) were added to 10mL of water and 1,4-dioxane (V/V=1:10) mixed solvent, heated to 90 Reaction at °C for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 50 mL of dichloromethane was added to the residue to dissolve, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with a developing solvent system F to obtain the title compound (1.31 g, product). Rate: 96.7%).

the fourth step

(5aR,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Hydrochloride 46e

Compound 46d (1.32g, 2.07mmol) was dissolved in 6mL 1,4-dioxane solution, and hydrogen chloride/1,4-dioxane solution (4M, 8mL, Chemart) was added dropwise to the reaction solution, and the reaction was at room temperature Stir for 60 minutes. The reaction solution was concentrated to obtain the title product 46e (1.3g), which was directly used in the next reaction without purification.

the fifth step

(5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 46

Compound 46e (1.3 g, 2.07 mmol) was dissolved in 15 mL of dichloromethane, triethylamine (800 mg, 7.90 mmol, 1.1 mL) and acryloyl chloride (185 mg, 2.04 mmol, 165 μL) were added, and the reaction was stirred for 1 hour. Add 10mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue with 15mL methanol. Add 250mg of sodium bicarbonate, heat to 60°C and stir for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 30 mL of a mixture of dichloromethane and methanol (V/V=20:1) was added to dissolve and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (column: Boston Phlex Prep C18 5μm 30×150mm; mobile phase: water (10mmol ammonium bicarbonate): acetonitrile = 40%-60% (15min), flow rate: 30mL/min) Purified to obtain the title compound (265mg, yield: 21.7%) .

MS m/z(ESI): 590.0[M+1].

¹ H NMR (500MHz, DMSO-d ₆ )δ9.98(t,1H), 7.36(d,1H), 7.28(t,1H), 7.19(t,2H), 7.03-6.95(m,1H), 6.92-6.76 (m, 1H), 6.71-6.56 (m, 2H), 6.25-6.11 (m, 1H), 5.74 (d, 1H), 4.95-4.75 (m, 2H), 4.68-4.24 (m, 3H) ),4.21-3.97(m,2H),3.90-3.54(m,1H),2.69-2.56(m,1H),1.26-1.11(m,3H),1.05(d,J=6.6Hz,3H), 0.97 (d, J=6.8 Hz, 3H).

Sixth step

(12R,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 46-1

(12S,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 46-2

Compound 46 (262mg, 0.444mmol) was chirally prepared (Separation conditions: chiral preparation column CHIRALCEL OZ-H (OZH0CD-VF004), 5cm ID*25cm L, 10um; mobile phase: n-hexane: ethanol=50/50 (v/v, flow rate: 60 mL/min), collect the corresponding components, and concentrate under reduced pressure to obtain the title products 46-1 (123 mg) and 46-2 (126 mg).

Single configuration compound 46-1 (shorter retention time component):

MS m/z(ESI): 590.0[M+1].

Chiral HPLC analysis: retention time 6.069 minutes, chiral purity: 100% (column: CHIRALPAK IE 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=60/40(v/v), flow rate: 1.0mL /min).

¹ H NMR (500MHz, DMSO-d ₆ )δ9.97(d,1H), 7.36(d,1H), 7.29(t,1H), 7.19(t,2H), 6.99(d,1H), 6.93 6.79 (m, 1H), 6.67 (d, 1H), 6.62 (t, 1H), 6.19 (t, 1H), 5.75 (t, 1H), 4.95-4.79 (m, 2H), 4.72-4.27 (m, 3H), 4.18-3.98 (m, 1H), 3.88-3.67 (m, 1H), 3.65-3.55 (m, 0.5H), 3.25-3.15 (m, 0.5H), 2.63 (s, 1H), 1.23- 1.13 (m, 3H), 1.10-1.01 (m, 3H), 0.97 (d, 3H).

Single configuration compound 46-2 (the component with longer retention time):

MS m/z(ESI): 590.0[M+1].

Chiral HPLC analysis: retention time 6.951 minutes, chiral purity: 100% (column: CHIRALPAK IE 150*4.6mm, 5um; mobile phase: n-hexane/ethanol=60/40(v/v), flow rate: 1.0mL /min).

¹ H NMR(500MHz, DMSO-d ₆ ) δ9.97(s,1H), 7.36(d,1H), 7.29(t,1H), 7.19(s,2H), 6.99(s,1H), 6.93 6.76 (m, 1H), 6.70-6.55 (m, 2H), 6.25-6.13 (m, 1H), 5.80-5.67 (m, 1H), 4.93-4.76 (m, 2H), 4.65-3.62 (m, 6H) ), 3.32-3.23 (m, 1H), 1.28-1.19 (m, 3H), 1.04 (d, 3H), 0.97 (d, 3H).

Example 47, 47-1, 47-2

(5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 47

(12R,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 47-1

(12S,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 47-2

first step

(2S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(5,6,7-trichloro-1-(2-iso (Propylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 47b

Compound 10q (5.099g, 12.64mmol) was dissolved in 200mL of dichloromethane, cooled to 0°C, and compound (2S,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl was added sequentially Yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 47a (4.795g, 13.91mmol, using the synthetic route of Example 10-1, 10-2 intermediate 10h, the first step raw material 10a was replaced by L-alanine methyl ester hydrochloride) and N,N-diisopropylethylamine (9.81g, 75.9mmol, 12.54mL), stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system B to obtain the title compound 47b (5.21 g, yield: 57.9%).

Second step

(5aS,8S)-2,3-Dichloro-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6,8,9,11,12-hexahydro- 4-oxa-1,7,9a,10,12-pentaaza[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester 47c

Dissolve compound 47b (1.6g, 2.25mmol) in 50mL of tetrahydrofuran, cool to -10°C, add tetrabutylammonium fluoride (1M, 6.75mL), stir and react for 1 hour, then warm to room temperature and continue stirring for 2 hours . The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate and then washed with water (60 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system F The title compound 47c (181 mg, yield: 14.3%) was obtained.

third step

(5aS,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6, 8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7 (5H)-tert-Butyl formate 47d

In an argon atmosphere, (2-fluoro-6-hydroxyphenyl)boronic acid (93mg, 0.596mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 47c (234mg, 0.417mmol), dodecahydrate hydrogen phosphate Sodium (449mg, 1.25mmol), tetrakistriphenylphosphine palladium (123mg, 106μmol) were added to a mixed solvent of 10mL water and 1,4-dioxane (V/V=1:4) and heated to 80°C React for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 47d (291 mg, yield: 109.5 %).

the fourth step

(5aS,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one 47e

Compound 47d (265 mg, 0.416 mmol) was dissolved in 10 mL of dichloromethane, 10 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium bicarbonate solution was added until the pH of the reaction solution was greater than 7, and then 30 mL of dichloromethane was added for liquid separation. The aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 47e (223 mg, yield: 99.8%).

the fifth step

(5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 47

Compound 47e (223mg, 0.42mmol) was dissolved in 15mL of dichloromethane, triethylamine (323mg, 2.50mmol, 0.78mL) was added, the reaction solution was cooled to 0°C, and acryloyl chloride (36mg, 0.40mmol, 32μL) was added dropwise , Stir the reaction for 30 minutes. Add 50mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and subject the residue to high performance liquid chromatography The method was purified to obtain the title compound 47 (16.5mg, yield: 6.7%).

MS m/z(ESI): 590.1[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ): δ10.00-9.97 (m, 1H), 7.37-7.35 (m, 1H), 7.30-7.27 (m, 1H), 7.21-7.17 (m, 2H), 7.02-6.93 (m, 1H), 6.82-6.79 (m, 1H), 6.69-6.59 (m, 2H), 6.25-6.22 (m, 1H), 5.78-5.76 (m, 1H), 4.93-4.87 (m ,1H),4.74-4.60(m,1H),4.52-4.33(m,3H),4.19-3.96(m,3H),2.62-2.60(m,1H),1.25(s,3H),1.07-1.04 (m, 3H), 0.98-0.96 (m, 3H).

Sixth step

(12R,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 47-1

(12S,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5, 5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene -11(12H)-ketone atropisomer 47-2

Compound 47 (2.78g, 4.71mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK AD, 5.0cm ID×25cm L, 10μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 30mL/ min), collect the corresponding components and concentrate under reduced pressure to obtain the title products 47-1 (1.17g) and 47-2 (1.31g).

Single configuration compound 47-1 (long retention time):

MS m/z(ESI): 590.3[M+1].

Chiral HPLC analysis: retention time 19.788 minutes, chiral purity: 100% (column: OZ Phenomenex Lux Cellulose-2 150×4.6mm, 5μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 1.0mL/ min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.95-9.97 (m, 1H), 7.35-7.36 (d, 1H), 7.27-7.30 (m, 1H), 7.17-7.20 (m, 2H), 6.93-6.97 (m, 1H), 6.79 (s, 1H), 6.60-6.68 (m, 2H), 6.23 (d, 1H), 5.77 (d, 1H), 4.91-4.94 (m, 1H), 4.60- 4.64(m,1H),4.34-4.46(m,3H),4.05-4.09(m,2H),3.75-3.96(m,1H),2.60-2.65(m,1H),1.24-1.26(m,3H) ), 1.02-1.06 (m, 3H), 0.97-0.98 (m, 3H).

Single configuration compound 47-2 (shorter retention time):

MS m/z(ESI): 590.3[M+1].

Chiral HPLC analysis: retention time 9.639 minutes, chiral purity: 100% (column: OZ Phenomenex Lux Cellulose-2 150×4.6mm, 5μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 1.0mL/ min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.97-9.98 (m, 1H), 7.35-7.38 (d, 1H), 7.27-7.30 (m, 1H), 7.16-7.22 (m, 2H), 7.00-7.02 (m, 1H), 6.80 (s, 1H), 6.59-6.69 (m, 2H), 6.23 (d, 1H), 5.78 (d, 1H), 4.88-4.90 (m, 1H), 4.71 4.75(m,1H),4.34-4.47(m,3H),4.13-4.19(m,2H),3.90-3.91(m,1H),2.51-2.52(m,1H),1.24-1.30(m,3H) ), 1.02-1.06(m,3H), 0.92-0.98(m,3H).

Example 48, 48-1, 48-2

(5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 48

(12R,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 48-1

(12S,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 48-2

first step

(2S,5R)-5-(hydroxymethyl)-2-methyl-4-(5,6,7-trichloro-1-(2-isopropyl-6-methylphenyl)-2- Tert-butyl oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylate 48b

Compound 30j (8.5g, 20.38mmol) was dissolved in 100mL of dichloromethane, cooled to 0℃, and compound (2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid was added in sequence Tert-butyl ester 48a (5.0g, 21.7mmol, prepared by using the synthetic route of Example 22 Intermediate 22e, replacing the first step raw material 10b with the compound N-benzyloxycarbonyl-L-serine) and N,N-diiso Propylethylamine (3g, 23.2mmol, 3.83mL) was stirred and reacted for 1 hour. Add 300mL saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (60mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the title crude compound 48b (12.5g ).

MS m/z(ESI): 610.0[M+1].

Second step

(5aR,8S)-2,3-Dichloro-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo-5a,6,8,9,11, 12-hexahydro-4-oxa-1,7,9a,10,12-pentaaza[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl Ester 48c

Compound 48b (12.45 g, 20.37 mmol) was dissolved in 200 mL of tetrahydrofuran, and 1,8-diazabicycloundec-7-ene (9.0 g, 59.11 mmol, 8.8 mL) was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure. The residue was dissolved in 300 mL of ethyl acetate and then washed with water (80 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column chromatography with eluent system Purification by A gave the title compound 48c (8.99 g, yield: 76.8%).

MS m/z(ESI): 574.1[M+1].

third step

(5aR,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo -5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]naphthalene-7(5H)-tert-butyl formate 48d

Combine (2-fluoro-6-hydroxyphenyl)boronic acid (4.0g, 25.65mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 48c (8.99g, 15.65mmol), disodium hydrogen phosphate dodecahydrate (15.0g) , 41.88mmol), tetrakistriphenylphosphine palladium (2.0g, 1.73mmol) were added to a mixed solvent of 100mL water and 1,4-dioxane (V/V=1:4), and heated under argon atmosphere React at 95°C for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 100 mL of dichloromethane was added to the residue to dissolve, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with a developing solvent system F to obtain the title crude compound 48d (10.17g). ).

MS m/z(ESI): 650.1[M+1].

the fourth step

(5aR,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone trifluoroacetate 48e

Compound 48d (10.17 g, 15.64 mmol) was dissolved in 100 mL of dichloromethane solution, 50 mL of trifluoroacetic acid was added to the reaction solution, and the reaction was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain the crude title product 48e (1.3g), which was directly used in the next reaction without purification.

MS m/z(ESI): 550.1[M+1].

the fifth step

(5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 48

Compound 48e (8.6g, 15.63mmol) was dissolved in 150mL of dichloromethane, triethylamine (3.5g, 34.58mmol, 4.8mL) and acryloyl chloride (1.4g, 15.46mmol, 1.25mL) were added, and the reaction was stirred for 1 hour. Add 200mL saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (60mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue with 100mL methanol. Add 3g of sodium bicarbonate, heat to 60°C and stir for 6 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 30 mL of a mixture of dichloromethane and methanol (V/V=20:1) was added to dissolve and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (column: Boston Phlex Prep C18 5um 30*150mm; mobile phase: water (10mmol NH ₄ HCO ₃ ): acetonitrile=38%-58% (15min, flow rate: 30mL/min) to obtain the title compound 48 (2.5g, yield: 26.4%).

MS m/z(ESI): 604.0[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ10.02-9.92 (m, 1H), 7.25-7.13 (m, 3H), 7.10-7.03 (m, 1H), 6.94-6.78 (m, 1H), 6.67 (dd,1H),6.62(t,1H),6.19(t,1H),5.75(t,1H),4.90-4.80(m,2H),4.66-4.29(m,3H),4.22-3.84(m ,2H),3.70-3.60(m,0.5H),3.30-3.20(m,0.5H),2.66-2.55(m,1H),1.93-1.79(m,3H),1.23-1.10(m,3H) ,1.04(t,3H),0.95-0.86(m,3H).

Sixth step

(12R,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 48-1

(12S,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 48-2

Compound 48 (2.08g, 3.44mmol) was chirally prepared ((Separation conditions: chiral preparation column CHIRALPAK IB N), 5.0cm ID×25cm L, 10μm; mobile phase: (MeOH80ACN20)/CO2=30/70( V/V), 140ml/min), collect the corresponding components and concentrate under reduced pressure to obtain the title product (48-1:848mg, 48-2:751mg).

Single configuration compound 48-1 (the component with longer retention time):

MS m/z(ESI): 604.0[M+1].

Chiral HPLC analysis: retention time 15.883 minutes, chiral purity: 100% (column: CHIRALPAK IF 150*4.6mm, 5um; mobile phase: n-hexane: ethanol = 85:15, flow rate: 1.0 mL/min).

¹ H NMR (500MHz, DMSO-d ₆ ) δ9.98 (d, 1H), 7.23-7.14 (m, 3H), 7.09-7.02 (m, 1H), 6.93-6.79 (m, 1H), 6.70-6.58 (m, 2H), 6.19 (t, 1H), 5.75 (t, 1H), 4.87 (t, 2H), 4.66-4.27 (m, 3H), 4.19-3.81 (m, 2H), 3.68-3.60 (m ,0.5H),3.30-3.20(m,0.5H),2.66-2.56(m,1H),1.88-1.77(m,3H),1.22-1.10(m,3H),1.05(d,3H),0.92 (d, 3H).

Single configuration compound 48-2 (shorter retention time component):

MS m/z(ESI): 604.0[M+1].

Chiral HPLC analysis: retention time 13.978 minutes, chiral purity: 99.4% (column: CHIRALPAK IF 150*4.6mm, 5um; mobile phase: n-hexane: ethanol = 85:15, flow rate: 1.0 mL/min).

¹ H NMR (500MHz, DMSO-d ₆ ) δ9.98 (d, 1H), 7.26-7.13 (m, 3H), 7.06 (s, 1H), 6.94-6.78 (m, 1H), 6.70-6.65 (m ,1H),6.65-6.58(m,1H),6.18(t,1H),5.75(t,1H),4.93-4.79(m,2H),4.66-4.29(m,3H),4.19-3.83(m , 2H), 3.68-3.60 (m, 0.5H), 3.30-3.20 (m, 0.5H), 2.49-2.42 (m, 1H), 1.89 (s, 3H), 1.18 (dt, 3H), 1.04 (dd ,3H),0.91(d,3H).

Example 49, 49-1, 49-2

(5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl-4-methylpyridin-3-yl) -8-Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1 ,2,3-de)naphthalene-11(12H)-one 49

(12S,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl-4-methylpyridine-3- Base)-8-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta [1,2,3-de]Naphthalene-11(12H)-ketone atropisomer 49-1

(12R,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl-4-methylpyridine-3- Base)-8-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta [1,2,3-de]Naphthalene-11(12H)-ketone atropisomer 49-2

first step

1-(2-isopropyl-4-methylpyridin-3-yl)urea 49b

The compound 2-isopropyl-4-methylpyridin-3-amine 49a (10.8 g, 71.89 mmol, Bi De Medicine) was dissolved in 500 mL of dichloromethane, and triethylamine (36.45 g, 360.21 mmol, 50 mL) was added , Cooled to 0°C, added triphosgene (12.8g, 43.13mmol), stirred and reacted for 1 hour, then added ammonia 1,4-dioxane solution (0.4M, 220mL), stirred and reacted for 1 hour. The reaction solution was concentrated under reduced pressure, 1 L of water was added to the residue, stirred for 10 minutes, filtered, the filter cake was washed with water, and dried under vacuum to obtain the title product 49b (9.73 g, yield: 70.0%).

Second step

6-Amino-1-(2-isopropyl-4-methylpyridin-3-yl)pyrimidine-2,4(1H,3H)-dione 49c

Compound 49b (9.2g, 47.60mmol) was added to 150mL of methanol, then ethyl cyanoacetate (5.913g, 52.27mmol, 5.6mL) and sodium tert-butoxide (5.490g, 57.12mmol) were added and heated to 75°C for reaction 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, 1M hydrochloric acid was added to the residue to pH 7, stirred for 10 minutes, filtered, and the filter cake was vacuum dried to obtain the title compound 49c (9.2 g, yield: 74.2%).

third step

3-(6-Amino-1-(2-isopropyl-4-methylpyridin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl )-3-oxopropionitrile 49d

Cyanoacetic acid (6g, 70.53mmol) was added to 50mL of acetic anhydride, heated to 85°C for 5 minutes, then the reaction solution was poured into compound 49c (9.2g, 35.34mmol), heated to 85°C for 1 hour. The reaction solution was cooled to room temperature and poured into 1 L of water, and stirred for 10 minutes. It was filtered and dried to obtain the title compound 49d (9.03 g, yield: 70.8%).

the fourth step

1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H,8H)-tetraketone 49e

Compound 49d (12.5 g, 38.18 mmol) was added to 40 mL of hydrobromic acid, and heated to 80° C. to react for 1 hour. The reaction solution was cooled to room temperature and poured into 1L ice water, ammonia water was added to the reaction solution pH value of 7, filtered, the filter cake was washed with water, and vacuum dried to obtain the title compound 49e (9.03 g, yield: 72.0%).

the fifth step

6,6-Dichloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4,5,7(1H,3H,6H ,8H)-tetraketone 49f

Compound 49e (9.03 g, 27.50 mmol) was added to 100 mL 1,4-dioxane, and sulfonyl chloride (11.168 g, 82.75 mmol, 6.7 mL) was added, and the mixture was heated to 60° C. and stirred for 2 hours. The reaction solution was poured into 1 L of ice water, stirred for 10 minutes, filtered, the filter cake was washed with water, and dried to obtain the title compound 49f (13.1 g). The product was directly used in the next step without purification.

Sixth step

6-Chloro-5,7-Dihydroxy-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)- Diketone 49g

Compound 49f (13.1 g, 32.97 mmol) was added to 80 mL of acetic acid, zinc powder (4.3 g, 65.75 mmol) was added, and the mixture was heated to 90° C. and stirred for reaction for 2 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in methanol and filtered. After the filtrate was concentrated under reduced pressure, 500 mL of water was added and stirred for 10 minutes. After filtration, the filter cake was washed with water and dried to obtain 49 g (12.04 g) of the title compound.

Seventh step

4,5,6,7-Tetrachloro-1-(2-isopropyl-4-methylpyridin-3-yl)pyrido[2,3-d]pyrimidin-2(1H)-one 49h

Compound 49g (10.15g, 27.97mmol) was added to 200mL of acetonitrile, then phosphorus oxychloride (20.625g, 134.51mmol, 12.5mL) and N,N-diisopropylethylamine (18.225g, 141.01mmol, 25mL), heated to 80°C and stirred for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to obtain the title compound 49h (34g), which can be used directly in the next reaction without further purification.

Eighth step

(2R,5S)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(5,6,7-trichloro-1-(2-iso Propyl-4-methylpyridin-3-yl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1 carboxylic acid tert-butyl ester 49i

Compound 49h (34g, 81.31mmol) was dissolved in 300mL of dichloromethane, cooled to 0°C, compound 13b (9.6g, 27.86mmol) was added, and N,N-diisopropylethylamine (18.225g, 141.0mmol) , 25mL), stirred for 1 hour. It was quenched by adding 100 mL saturated sodium bicarbonate aqueous solution and separated. The aqueous phase was extracted with dichloromethane (100 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on a silica gel column. The title compound 49i (7.2g, yield: 12.1%) was purified by chromatography with eluent system A.

Step 9

(5aS,8R)-2,3-Dichloro-12-(2-isopropyl-4-methylpyridin-3-yl)-8-methyl-11-oxo-5a,6,8,9 ,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H) -Tert-butyl carboxylate 49j

Compound 49i (7.2 g, 9.91 mmol) was dissolved in 150 mL of tetrahydrofuran, and tetrabutylammonium fluoride (1M, 30 mmol, 30 mL) was added, and the reaction was stirred for 3 hours. The reaction solution was concentrated under reduced pressure and then dissolved in 300 mL ethyl acetate, washed with water (50 mL×3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A. The title compound 49j (1.27 g, yield: 22.2%).

Tenth step

(5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-8-methyl-11 -Oxo-5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1,2 ,3-de)naphthalene-7(5H)-tert-butyl carboxylate 49k

In a nitrogen atmosphere, 2-fluoro-6-hydroxyphenylboronic acid (465mg, 2.98mmol), compound 49j (1.27g, 2.20mmol), tetratriphenylphosphine palladium (510mg, 441.34μmol), dodecahydrate phosphoric acid Disodium hydrogen (2.37 g, 6.61 mmol) was added to a mixed solvent of 50 mL of water and 1,4-dioxane (V/V=1:5), and the mixture was heated to 95° C. to react for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure and dissolved by adding 150 mL of dichloromethane, then filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system A to obtain the title compound 49k (735 mg, yield : 51.1%).

Eleventh step

(5aS,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-8-methyl-5 ,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de] Naphthalene-11(12H)-ketone 49l

Compound 49k (735 mg, 1.12 mmol) was dissolved in 15 mL of dichloromethane, 3 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure and saturated aqueous sodium bicarbonate solution was added until the pH of the reaction solution was greater than 7, and then 30 mL of dichloromethane was added for liquid separation. The aqueous phase was extracted with dichloromethane (20 mL×2), and the organic phases were combined and anhydrous sulfuric acid The sodium was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound 49l (583 mg, yield: 93.7%).

Twelfth step

(5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl-4-methylpyridin-3-yl) -8-Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1 ,2,3-de)naphthalene-11(12H)-one 49

Compound 49l (583mg, 1.05mmol) was dissolved in 25mL of dichloromethane, cooled to 0°C, triethylamine (364mg, 3.59mmol, 0.500mL) was added, and acryloyl chloride (134mg, 1.48mmol, 0.12mL) was added dropwise, The reaction was stirred for 1 hour. Add 20mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (20mL×3), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue in 20mL methanol , Then add 250mg of sodium bicarbonate, heat to 60°C and stir for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A and then purified by preparative chromatography to obtain the title compound 49 (210 mg, yield: 32.8%) .

MS m/z(ESI): 605.1[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.97-10.04 (m, 1H), 8.34 (s, 1H), 7.13-7.23 (m, 2H), 6.81-6.92 (m, 1H), 6.61 6.69(m,2H),6.16-6.23(m,1H),5.73-5.78(m,1H),4.86-4.90(m,2H),4.32-4.61(m,3H),4.00-4.18(m,2H) ), 3.25-3.67 (m, 1H), 2.61-2.79 (m, 1H), 1.87-2.08 (m, 3H), 1.14-1.24 (m, 3H), 1.05-1.08 (m, 3H), 0.91-0.95 (m,3H).

Step 13

(12S,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl-4-methylpyridine-3- Base)-8-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta [1,2,3-de]Naphthalene-11(12H)-ketone atropisomer 49-1

(12R,5aS,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl-4-methylpyridine-3- Base)-8-methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta [1,2,3-de]Naphthalene-11(12H)-ketone atropisomer 49-2

Compound 49 (210mg, 0.347mmol) was chirally prepared (Separation conditions: chiral preparation column CHIRALCEL OZ, 5.0cm ID×25cm L, 10μm; mobile phase: n-hexane: ethanol=70/30, flow rate: 60mL/min ), the corresponding components were collected and concentrated under reduced pressure to obtain the title products 49-1 (98.2 mg) and 49-2 (103.9 mg).

Single configuration compound 49-1 (shorter retention time):

MS m/z(ESI): 605.1[M+1].

Chiral HPLC analysis: retention time 7.170 minutes, chiral purity: 97.9% (column: OZ Phenomenex Lux Cellulose-2 150×4.6mm, 5μm; mobile phase: n-hexane: ethanol=70/30, flow rate: 1.0mL/ min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.98 (d, 1H), 8.34 (d, 1H), 7.14-7.23 (m, 2H), 6.81-6.92 (m, 1H), 6.61-6.69 ( m,2H),6.15-6.23(m,1H),5.73-5.78(m,1H),4.86-4.91(m,2H),4.32-4.63(m,3H),4.00-4.18(m,2H), 3.25-3.70(m,1H),2.61-2.66(m,1H),1.91-1.95(m,3H),1.15-1.22(m,3H),1.05-1.07(m,3H),0.88-0.94(m ,3H).

Single configuration compound 49-2 (longer retention time):

MS m/z(ESI): 605.1[M+1].

Chiral HPLC analysis: retention time 10.236 minutes, chiral purity: 100% (column: OZ Phenomenex Lux Cellulose-2 150×4.6mm, 5μm; mobile phase: n-hexane: ethanol=70/30, flow rate: 1.0mL/ min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.00 (d, 1H), 8.34 (d, 1H), 7.13-7.23 (m, 2H), 6.81-6.92 (m, 1H), 6.62-6.69 ( m,2H),6.16-6.23(m,1H),5.73-5.78(m,1H),4.86-4.91(m,2H),4.34-4.64(m,3H),3.97-4.21(m,2H), 3.24-3.70(m,1H),2.77-2.81(m,1H),1.87-1.89(m,3H),1.14-1.21(m,3H),1.05-1.08(m,3H),0.92-0.94(m ,3H).

Example 50, 50-1, 50-2

(5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 50

(12S,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 50-1

(12R,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 50-2

first step

Using the synthetic route of Example 47, the first step raw material 10q was replaced with compound 30j to obtain the title compound 50 (420 mg).

MS m/z(ESI): 604.1[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ): δ9.99 (s, 1H), 7.22-7.17 (m, 3H), 7.08-7.06 (m, 1H), 6.80-6.60 (m, 3H), 6.26 6.22(m,1H),5.78-5.76(m,1H),4.92-4.89(m,1H),4.75-4.67(m,1H),4.50-4.37(m,3H),4.17-3.96(m,3H) ), 2.60-2.57(m,1H), 1.90-1.84(m,3H), 1.25(s,3H), 1.05-1.04(m,3H), 0.94-0.91(m,3H).

Second step

(12S,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 50-1

(12R,5aS,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 50-2

Compound 50 (420mg, 0.347mmol) was chirally prepared (Separation conditions: chiral preparation column CHIRALCEL OZ, 5.0cm ID×25cm L, 10μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 60mL/min ), the corresponding components were collected and concentrated under reduced pressure to obtain the title products 50-1 (130 mg) and 50-2 (161 mg).

Single configuration compound 50-1 (longer retention time):

MS m/z(ESI): 604.1[M+1].

Chiral HPLC analysis: retention time 7.845 minutes, chiral purity: 100% (chromatographic column: OZ Phenomenex Lux Cellulose-2 150×4.6mm, 5μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 1.0mL/ min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.97-9.99 (m, 1H), 7.16-7.21 (m, 3H), 7.05-7.08 (m, 1H), 6.80 (s, 1H), 6.60- 6.68 (m, 2H), 6.63 (d, 1H), 5.76-5.79 (m, 1H), 4.89-4.92 (m, 1H), 4.67-4.71 (m, 1H), 4.50-4.53 (m, 1H), 4.42-4.45(m,2H),4.08-4.12(m,2H),3.97(s,1H),2.55-2.59(m,1H),1.83-1.86(m,3H),1.24-1.26(m,3H) ), 1.05-1.06 (m, 3H), 0.92-0.94 (m, 3H).

Single configuration compound 50-2 (shorter retention time):

MS m/z(ESI): 604.1[M+1].

Chiral HPLC analysis: retention time 5.760 minutes, chiral purity: 97.7% (chromatographic column: OZ Phenomenex Lux Cellulose-2 150×4.6mm, 5μm; mobile phase: n-hexane: ethanol=60/40, flow rate: 1.0mL/ min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.95-9.99 (m, 1H), 7.16-7.22 (m, 3H), 7.05-7.08 (m, 1H), 6.80 (s, 1H), 6.60- 6.68 (m, 2H), 6.63 (d, 1H), 5.76-5.79 (m, 1H), 4.89-4.92 (m, 1H), 4.71-4.74 (m, 1H), 4.38-4.49 (m, 3H), 4.11-4.17 (m, 2H), 3.94 (s, 1H), 2.47-2.50 (m, 1H), 1.89 (s, 3H), 1.24 (s, 3H), 1.04-1.06 (m, 3H), 0.91- 0.93(m,3H).

Example 51

(5aR,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-one 51

first step

(2R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(5,6,7-trichloro-1-(2-iso Propyl-6-methylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 51b

Compound 30j (1.67g, 4.00mmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, and compound (2R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl was added in sequence Yl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 51a (1.4g, 4.06mmol, using the synthetic route of Example 10-1, 10-2 intermediate 10h, 10b was replaced by the compound N-benzyloxy Prepared by carbonyl-L-serine) and N,N-diisopropylethylamine (600mg, 4.64mmol, 0.77mL), stirred and reacted for 1 hour. It was quenched by adding 100mL saturated sodium bicarbonate solution, separated, the aqueous phase was extracted with dichloromethane (30mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title crude compound 51b (1.85g) ).

Second step

(5aR,8R)-2,3-Dichloro-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo-5a,6,8,9,11, 12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert Butyl 51c

Compound 51b (1.85 g, 2.55 mmol) was dissolved in 20 mL of tetrahydrofuran, tetrabutylammonium fluoride (1M, 6 mL) was added, and the reaction was stirred for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 100 mL of ethyl acetate and then washed with water (60 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed on silica gel column chromatography with eluent system Purification (dichloromethane: ethyl acetate) gave the title compound 51c (131 mg, yield: 8.9%).

MS m/z(ESI): 574.0[M+1].

third step

(5aR,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo -5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-7(5H)-tert-butyl formate 51d

(2-Fluoro-6-hydroxyphenyl)boronic acid (50mg, 0.32mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 51c (131mg, 0.23mmol), disodium hydrogen phosphate dodecahydrate (240mg, 0.67mmol) ), tetrakistriphenylphosphine palladium (25mg, 0.021mmol) was added to 7.5mL water and 1,4-dioxane (V/V=1:4) mixed solvent, heated to 95℃ under argon atmosphere React for 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 50 mL of dichloromethane was added to the residue to dissolve, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with developing solvent system F to obtain the title crude compound 51d (200mg) .

MS m/z(ESI): 650.0[M+1].

the fourth step

(5aR,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone hydrochloride 51e

Compound 51d (200mg, 0.31mmol) was dissolved in 2mL 1,4-dioxane solution, hydrogen chloride/1,4-dioxane solution (4M, 4mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature 60 minutes. The reaction solution was concentrated under reduced pressure to obtain the title product 51d (2.1g), which was directly used in the next reaction without purification.

the fifth step

(5aR,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-one 51

Compound 51e (169 mg, 0.31 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (90 mg, 0.89 mmol, 0.12 mL) and acryloyl chloride (27 mg, 0.3 mmol, 0.024 mL) were added, and the reaction was stirred for 1 hour. Add 80mL saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue with 6mL methanol. 100mg sodium bicarbonate was added, heated to 60°C and stirred for 6 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 30 mL of a mixture of dichloromethane and methanol (V/V=20:1) was added to dissolve and filtered. The filtrate was concentrated under reduced pressure, and the residue was subjected to high performance liquid chromatography (column: Boston Phlex Prep C18 5um 30*150mm; mobile phase: water (10mmol NH ₄ HCO ₃ ): acetonitrile=38%-58% (15min, flow rate: 30mL/min) to obtain the title compound 51 (72mg), yield: 37.8%.

MS m/z(ESI): 604.0[M+1].

¹ H NMR(500MHz,DMSO-d ₆ )δ9.98(s,1H), 7.24-6.99(m,4H), 6.79(s,1H), 6.70-6.55(m,2H), 6.23(d,1H) ), 5.77 (d, 1H), 4.90 (d, 1H), 4.78-4.63 (m, 1H), 4.56-4.27 (m, 3H), 4.22-4.04 (m, 2H), 3.95 (s, 1H), 2.62-2.50 (m, 1H), 1.92-1.80 (m, 3H), 1.24 (s, 3H), 1.04 (d, 3H), 0.91 (t, 3H).

Example 52

(3R,13aS)-2-acryloyl-10-(2,6-difluorophenyl)-8-(2-isopropylphenyl)-3-methyl-1,2,3,4,13 ,13a-Hexahydropyrazino[2',1':3,4][1,4]oxazepine[5,6,7-de]quinazolin-7(8H)-one 52

Using the synthetic route of Example 18, the third step raw material (2-fluoro-6-hydroxyphenyl)boronic acid was replaced with 2-(2,6-difluorophenyl)-4,4,5,5-tetramethyl Yl-1,3,2-dioxaborane (Shaoyuan) to obtain the title compound 52 (27 mg).

MS m/z(ESI): 557.2[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ): δ7.54-7.52 (m, 1H), 7.46-7.43 (m, 2H), 7.34-7.31 (m, 1H), 7.17-7.11 (m, 3H), 6.89-6.82(m,2H),6.21-6.15(m,1H),6.03-6.00(m,1H),5.77-5.71(m,1H),4.85-4.23(m,5H),4.01-3.89(m , 1H), 3.68-3.54 (m, 1H), 3.45-3.17 (m, 1H), 2.68-2.55 (m, 1H), 1.20-1.08 (m, 6H), 1.02-1.02 (m, 3H).

Example 53

(5aR,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 53

first step

(2R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-2-methyl-4-(5,6,7-trichloro-1-(2-iso (Propylphenyl)-2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 53a

Compound 10q (2.0g, 4.96mmol) was dissolved in 20mL of dichloromethane, cooled to 0°C, compound 51a (1.80g, 5.22mmol,) and N,N-diisopropylethylamine (1.3g, 10.06mmol, 1.66mL), the reaction was stirred for 1 hour. Add 30mL saturated sodium bicarbonate solution to quench, separate the layers, extract the aqueous phase with dichloromethane (50mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and chromatograph the residue using silica gel column chromatography Chromatography was purified with eluent system B to obtain the title compound 53a (2.75 g, yield: 77.9%).

Second step

(5aR,8R)-2,3-Dichloro-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6,8,9,11,12-hexahydro- 4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid tert-butyl ester 53b

Compound 53a (2.75 g, 3.87 mmol) was dissolved in 30 mL of tetrahydrofuran, tetrabutylammonium fluoride (1M, 8 mL) was added, and the reaction was stirred for 6 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in 200 mL of ethyl acetate and then washed with water (100 mL×2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was chromatographed with silica gel column chromatography with eluent system Purification (dichloromethane: ethyl acetate) gave the title compound 53b (295 mg, yield: 13.6%).

MS m/z(ESI): 560.1[M+1].

third step

(5aR,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-11-oxo-5a,6, 8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7 (5H)-tert-Butyl formate 53c

(2-Fluoro-6-hydroxyphenyl) boric acid (100mg, 0.64mmol, Shanghai Haohong Biomedical Technology Co., Ltd.), compound 53b (295mg, 0.53mmol), disodium hydrogen phosphate dodecahydrate (600mg, 1.67mmol) ), tetrakistriphenylphosphine palladium (70mg, 60.57μmol) was added to 10mL of water and 1,4-dioxane (V/V=1:4) mixed solvent, heated to 90 ℃ under argon atmosphere to react 18 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. 50 mL of dichloromethane was added to the residue to dissolve, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by thin layer chromatography with a developing solvent system F to obtain the title compound (320 mg, yield : 95.57%).

MS m/z(ESI): 636.0[M+1].

the fourth step

(5aR,8R)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a,6,7,8 ,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11(12H)-one Hydrochloride 53d

Compound 53d (320mg, 0.50mmol) was dissolved in 2mL 1,4-dioxane solution, and hydrogen chloride/1,4-dioxane solution (4M, 4mL, Chemart) was added dropwise to the reaction solution, and the reaction was stirred at room temperature 60 minutes. The reaction solution was concentrated under reduced pressure to obtain the crude title product 53d, which was directly used in the next reaction without purification.

the fifth step

(5aR,8R)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 53

Compound 53d (269 mg, 0.50 mmol) was dissolved in 10 mL of dichloromethane, triethylamine (150 mg, 1.48 mmol, 0.2 mL) and acryloyl chloride (45 mg, 0.49 mmol, 38 μL) were added, and the reaction was stirred for 1 hour. Add 60mL saturated sodium bicarbonate aqueous solution to quench, separate the layers, extract the aqueous phase with dichloromethane (30mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and dissolve the residue with 15mL methanol. 200mg sodium bicarbonate was added, heated to 60°C and stirred for 1 hour. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 30 mL of a mixture of dichloromethane and methanol (V/V=20:1) was added to dissolve and filtered. The filtrate was concentrated under reduced pressure. Boston Phlex Prep C18 5μm 30×150mm; mobile phase: water (10mmol ammonium bicarbonate): acetonitrile = 40%-60% (15min), flow rate: 30mL/min) Purified to obtain the title compound (98mg, yield: 33.1%) .

MS m/z(ESI): 590.0[M+1].

¹ H NMR (500MHz, DMSO-d ₆ ) δ9.96 (t, 1H), 7.40-7.32 (m, 1H), 7.31-7.25 (m, 1H), 7.24-7.14 (m, 2H), 7.03-6.91 (m,1H),6.79(s,1H),6.71-6.55(m,2H),6.23(d,1H),5.77(d,1H),4.95-4.85(m,1H),4.75-4.58(m ,1H),4.54-4.26(m,3H),4.20-3.86(m,3H),2.66-2.56(m,1H),1.24(s,3H),1.11-1.00(m,3H),1.05-0.90 (m,3H).

Example 54

(5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-8 -Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1,2 ,3-de)naphthalene-11(12H)-one 54

(12R,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl) -8-Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1 ,2,3-de]naphthalene-11(12H)-ketone atropisomer 54-1

(12S,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl) -8-Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1 ,2,3-de]naphthalene-11(12H)-ketone atropisomer 54-2

first step

(2S,5R)-5-(hydroxymethyl)-2-methyl-4-(5,6,7-trichloro-1-(2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1,2-dihydropyrido[2,3-d]pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester 54a

Compound 49h (23g, 55.01mmol) was dissolved in 150mL of dichloromethane, cooled to 0°C, compound (2S,5R)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl Ester 48a (5g, 21.71mmol, prepared by using the synthetic route of Example 22 Intermediate 22e, replacing the first step raw material 10b with the compound N-benzyloxycarbonyl-L-serine), and then adding N,N-diisopropyl Ethylamine (10.206g, 78.96mmol, 14mL), stirred and reacted for 1 hour. Add 100 mL of saturated sodium bicarbonate aqueous solution and stir for 15 minutes to quench, separate the layers, extract the aqueous phase with dichloromethane (100 mL×2), combine the organic phases, dry with anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain the target compound 54a( 19.1g, yield: 56.7%), can be used directly in the next step without further purification.

MS m/z(ESI): 611.0[M+1].

Second step

(5aR,8S)-2,3-Dichloro-12-(2-isopropyl-4-methylpyridin-3-yl)-8-methyl-11-oxo-5a,6,8,9 ,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H) -Tert-butyl carboxylate 54b

Compound 54a (19.1 g, 31.21 mmol) was dissolved in 150 mL of tetrahydrofuran, 1,8-diazabicycloundec-7-ene (10.18 g, 66.86 mmol, 10 mL) was added, and the reaction was stirred for 3 hours. 100mL water and 150mL ethyl acetate were added to separate the layers, the aqueous phase was extracted with ethyl acetate (100mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography Purification by eluent system F gave the target compound 54b (8.2 g, yield: 45.6%).

MS m/z(ESI): 575.1[M+1].

third step

(5aR,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-8-methyl-11 -Oxo-5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1,2 ,3-de]naphthalene-7(5H)-tert-butyl carboxylate 54c

In a nitrogen atmosphere, the 2-fluoro-6-hydroxyphenylboronic acid (2.8g, 17.95mmol), compound 54b (8.2g, 14.24mmol), disodium hydrogen phosphate dodecahydrate (15.3g, 42.72mmol), four three Phenylphosphine palladium (1.65g, 1.42mmol) was added to 200mL of water and 1,4-dioxane (V/V=1:4), and the mixture was heated to 95°C for 16 hours. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in 300 mL of dichloromethane and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography with eluent system F to obtain the target compound 54c (9.17g, product). Rate: 98.8%).

MS m/z(ESI): 651.1[M+1].

the fourth step

(5aR,8S)-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-8-methyl-5 ,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de] Naphthalene-11(12H)-ketone 54d

Compound 54c (8.97 g, 13.77 mmol) was dissolved in 100 mL of dichloromethane, 20 mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and 200 mL of saturated sodium bicarbonate aqueous solution was added to the residue, and 500 mL of dichloromethane was added to dissolve the liquids. After drying and filtering, the filtrate was concentrated under reduced pressure to obtain the target compound 54d (7.82 g, yield: 103.0%).

MS m/z(ESI): 551.1[M+1].

the fifth step

(5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl)-8 -Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1,2 ,3-de)naphthalene-11(12H)-one 54

Compound 54d (7.82g, 14.19mmol) was added to 200mL of dichloromethane, cooled to 0°C, triethylamine (2.916g, 28.81mmol, 4mL) was added, and acryloyl chloride (1.288g, 14.23mmol, 1.15 mL), the reaction was stirred for 1 hour. It was quenched by adding 50 mL saturated sodium bicarbonate aqueous solution, and separated, the aqueous phase was extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in 100 mL of methanol, sodium bicarbonate (3 g, 35.71 mmol) was added, and the mixture was heated to 60° C. to react for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography with eluent system A, and then subjected to high performance liquid chromatography (column: Boston Phlex Prep C18 5μm 30× 150mm; mobile phase: A-water (10mmol ammonium bicarbonate): B-acetonitrile=30%-50% B (15min), flow rate: 30mL/min) After purification, the target compound 54 (3.5g, yield: 40.7%) ).

MS m/z(ESI): 605.0[M+1].

¹ H NMR (400MHz, DMSO-d ₆ ): δ9.97-10.04 (m, 1H), 8.33-8.35 (m, 1H), 7.13-7.23 (m, 2H), 6.81-6.90 (m, 1H), 6.61-6.69(m,2H),6.16-6.23(m,1H),5.73-5.78(m,1H),4.86-4.94(m,2H),4.32-4.64(m,3H),3.98-4.18(m ,2H),3.27-3.70(m,1H),2.62-2.81(m,1H),1.87-1.95(m,3H),1.14-1.23(m,3H),1.05-1.08(m,3H),0.91 -0.95(m,3H).

Sixth step

(12R,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl) -8-Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1 ,2,3-de]naphthalene-11(12H)-ketone atropisomer 54-1

(12S,5aR,8S)-7-acryloyl-3-chloro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-4-methylpyridin-3-yl) -8-Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cycloheptan[1 ,2,3-de]naphthalene-11(12H)-ketone atropisomer 54-2

Compound 54 (1.15g, 1.90mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK IC, 5.0cm ID*25cm L, 10μm; mobile phase: n-hexane: ethanol=50/50(V/V) , Flow rate: 60 mL/min), collect the corresponding components, and concentrate under reduced pressure to obtain the title products 54-1 (573 mg), 54-2 (603 mg).

54-1:

MS m/z(ESI): 605.0[M+1].

Chiral HPLC analysis: retention time 6.274 minutes, chiral purity: 100% (column: CHIRALPAK IC, 250*4.6mm, 5μm; mobile phase: n-hexane: ethanol = 50/50 (V/V), flow rate: 1.0 mL/min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.02 (s, 1H), 8.34 (d, 1H), 7.13-7.23 (m, 2H), 6.81-6.92 (m, 1H), 6.62-6.69 ( m,2H),6.19(t,1H),5.76(t,1H),4.86-4.94(m,2H),4.33-4.64(m,3H),3.97-4.21(m,2H),3.25-3.70( m, 1H), 2.77-2.81 (m, 1H), 1.87-1.89 (m, 3H), 1.14-1.21 (m, 3H), 1.05-1.08 (m, 3H), 0.93-0.95 (m, 3H).

54-2:

MS m/z(ESI): 605.0[M+1].

Chiral HPLC analysis: retention time 11.438 minutes, chiral purity: 99.9% (column: CHIRALPAK IC, 250*4.6mm, 5μm; mobile phase: n-hexane: ethanol = 50/50 (V/V), flow rate: 1.0 mL/min).

¹ H NMR (400MHz, DMSO-d ₆ ): δ10.01 (d, 1H), 8.34 (d, 1H), 7.14-7.23 (m, 2H), 6.80-6.92 (m, 1H), 6.61-6.69 ( m,2H),6.15-6.23(m,1H),5.73-5.78(m,1H),4.83-4.91(m,2H),4.32-4.63(m,3H),3.00-4.18(m,2H), 3.24-3.69(m,1H),2.61-2.66(m,1H),1.93-1.95(m,3H),1.15-1.24(m,3H),1.05-1.07(m,3H),0.91-0.94(m ,3H).

Example 55, 55-1, 55-2

(5aR,8S)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 55

(12R,5aR,8S)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 55-1

(12S,5aR,8S)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 55-2

first step

(2S,5R)-4-(5,7-Dichloro-6-fluoro-1-(2-isopropyl-6-methylphenyl)-2-oxo-1,2-dihydropyrido [2,3-d]pyrimidin-4-yl)-5-(hydroxymethyl)-2-methylpiperazine-1-carboxylic acid tert-butyl ester 55a

Dissolve compound 44f (0.57g, 1.43mmol) in dichloromethane (5mL, Sinopharm), add compound 48a (0.3g, 1.30mmol) in dichloromethane (2mL) solution, add N,N-diisopropyl Ethylamine (0.38g, 2.94mmol), stirred at room temperature for 2h. After quenching with 20 mL saturated sodium bicarbonate, the liquids were separated; washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 55a (0.85 g, yield: 100%), which was directly used in the next step .

MS m/z(ESI): 594.2[M+1].

Second step

(5aR,8S)-2-chloro-3-fluoro-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo-5a,6,8,9,11 ,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3-de]naphthalene-7(5H)-carboxylic acid Tert-butyl ester 55b

Compound 55a (0.85 g, 1.43 mmol) was dissolved in tetrahydrofuran (5 mL, Merck), DBU (0.65 g, 4.27 mmol) was added, and the mixture was stirred at room temperature for 16 h. Add water (20 mL) and ethyl acetate (20 mL) to the reaction solution; separate the layers, extract the aqueous phase with 20 mL ethyl acetate, combine the organic phases, and concentrate under reduced pressure. The resulting residue is subjected to silica gel column chromatography with eluent system Purification by C gave the title product 55b (0.46 g, yield: 57.5%).

MS m/z(ESI): 558.3[M+1].

third step

(5aR,8S)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-11-oxo -5a,6,8,9,11,12-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-7(5H)-tert-butyl carboxylate 55c

Compound 55b (0.46g, 0.82mmol), 2-fluoro-6-hydroxy-phenylboronic acid (193mg, 1.24mmol), potassium phosphate (612mg, 2.88mmol) and tetrakis (triphenylphosphine) palladium (95mg, 0.082mmol) ) Was added to water (2.5mL) and 1,4-dioxane (12.5mL, Sinopharm), replaced with nitrogen three times, and heated to 110°C in an oil bath for 2.5 hours. Cool to room temperature, add ethyl acetate (50mL) and water (50mL), separate the layers, extract the aqueous phase with ethyl acetate (50mL) once, combine the organic phases, wash with water (50mL), and wash with saturated sodium chloride solution (50mL) , Dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 55c (0.52 g, yield: 100%).

MS m/z(ESI): 634.3[M+1].

the fourth step

(5aR,8S)-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl-5,5a, 6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazaphenyl[4,5]cyclohepta[1,2,3-de]naphthalene-11 (12H)-ketone 55d

Compound 55c (0.52g, 0.82mmol) was dissolved in ethyl acetate (4.6mL, Sinopharm) and a 1,4-dioxane 4M solution (0.92mL, Adamas) of hydrochloric acid, and stirred at room temperature for 16 hours. After filtration, the solid obtained was rinsed with 3 mL of ethyl acetate. The above crude hydrochloride was dispersed in 2-methyltetrahydrofuran (50mL) and saturated sodium bicarbonate solution (50mL), separated, and the aqueous phase was extracted once with 2-methyltetrahydrofuran (50mL). The organic phases were combined, washed with water (30 mL), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the title product 55d (0.43 g, yield: 97.7%).

MS m/z(ESI): 534.3[M+1].

the fifth step

(5aR,8S)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8-methyl -5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2,3- de]Naphthalene-11(12H)-ketone 55

Compound 55d (0.43g, 0.80mmol) was dissolved in acetone (5mL, Sinopharm), added with anhydrous potassium carbonate (168mg, 1.22mmol), and cooled in an ice-salt bath. 3-Chloropropionyl chloride (113 mg, 0.89 mmol) was added dropwise, and the temperature was naturally raised to room temperature and stirred for 10 minutes. The reaction solution was cooled with an ice-salt bath, 5 mL of water, 0.4 mL of methanol were added, sodium hydroxide (129 mg, 3.22 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The pH of the reaction solution was adjusted to 6-7 with 6N hydrochloric acid in an ice bath, diluted with 50 mL of water and extracted with dichloromethane (50 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a residue Purified by silica gel column chromatography with elution system I to obtain the title product 55 (279 mg, yield: 58.9%).

MS m/z(ESI): 588.3[M+1].

¹ H NMR(500MHz, DMSO-d ₆ )δ10.09(s,1H), 7.29-7.15(m,3H), 7.11-7.05(m,1H), 6.93-6.79(m,1H), 6.70(d ,J=8.3Hz,1H), 6.68–6.63(m,1H), 6.19(ddd,J=23.8,15.9,2.3Hz,1H), 5.80–5.70(m,1H), 4.85(d,J=19.8 Hz, 2H), 4.65–4.52 (m, 1H), 4.47 (s, 1H), 4.32 (d, J = 14.2 Hz, 1H), 4.25–4.06 (m, 2H), 3.75–3.64 (m, 1H) ,2.49–2.39(m,1H),1.87(dd,J=40.9,2.8Hz,3H),1.22–1.13(m,3H),1.05(dd,J=8.3,6.8Hz,3H),0.96–0.88 (m,3H).

Sixth step

(12R,5aR,8S)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 55-1

(12S,5aR,8S)-7-acryloyl-3-fluoro-2-(2-fluoro-6-hydroxyphenyl)-12-(2-isopropyl-6-methylphenyl)-8- Methyl-5,5a,6,7,8,9-hexahydro-4-oxa-1,7,9a,10,12-pentaazabenzo[4,5]cyclohepta[1,2, 3-de]Naphthalene-11(12H)-ketone atropisomer 55-2

Compound 55 (262mg, 0.45mmol) was chirally prepared (separation conditions: chiral preparation column CHIRALPAK IF, 2.0cm ID*25cm L, 5μm; mobile phase: n-hexane: ethanol=75/25(V/V), Flow rate: 30 mL/min), collect the corresponding components, and concentrate under reduced pressure to obtain the title products 55-1 (111 mg), 55-2 (103 mg).

55-1:

MS m/z(ESI): 588.3[M+1].

Chiral HPLC analysis: retention time 5.439 minutes, chiral purity: 98.2% (column: CHIRALPAK IF, 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol (0.1% DEA) = 60/40 (V/V) ), flow rate: 1.0 mL/min).

¹ H NMR(500MHz,DMSO-d ₆ )δ10.09(s,1H), 7.31–7.14(m,3H), 7.07(dd,J=5.7,3.3Hz,1H), 6.93–6.79(m,1H ), 6.74–6.61(m,2H), 6.26–6.13(m,1H), 5.81–5.70(m,1H), 4.84(d,J=20.0Hz,2H), 4.65–4.53(m,1H), 4.47 (s, 1H), 4.32 (d, J = 13.7 Hz, 1H), 4.14 (d, J = 62.3 Hz, 2H), 3.70 (t, J = 12.5 Hz, 1H), 2.46-2.42 (m, 1H ), 1.82 (d, J = 2.3 Hz, 3H), 1.17 (dd, J = 23.5, 6.0 Hz, 3H), 1.06 (t, J = 7.0 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H ).

55-2:

MS m/z(ESI): 588.3[M+1].

Chiral HPLC analysis: retention time 4.608 minutes, chiral purity: 100% (column: CHIRALPAK IF, 150*4.6mm, 5μm; mobile phase: n-hexane: ethanol (0.1% DEA) = 60/40 (V/V) ), flow rate: 1.0 mL/min).

¹ H NMR(500MHz,DMSO-d ₆ )δ10.10(s,1H), 7.31–7.14(m,3H), 7.08(dd,J=6.8,2.3Hz,1H), 6.85(ddd,J=25.3 ,16.6,10.5Hz,1H),6.74–6.61(m,2H),6.24–6.12(m,1H),5.80–5.70(m,1H),4.85(d,J=18.5Hz,2H),4.59( t,J=12.5Hz,1H),4.46(s,1H),4.31(d,J=13.7Hz,1H),4.23-3.98(m,2H),3.74-3.64(m,1H),2.46-2.42 (m, 1H), 1.90 (d, J = 3.3 Hz, 3H), 1.18 (dd, J = 26.5, 6.2 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.91 (d, J = 6.9Hz, 3H).

Test case:

Biological evaluation

Test Example 1: Biological evaluation of H358 cell ERK phosphorylation inhibition experiment

1. Test purpose

In this experiment a test compound on the inhibition of ERK phosphorylation H358 cells, inhibition of target KRAS (including G12C mutation) evaluated in accordance with the size of the IC ₅₀ of the disclosed compounds.

2. Experimental method

H358 cells (ATCC, CRL-5807) were cultured with RPMI1640 (Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 25,000 cells/well using complete medium, with 190 μL of cell suspension per well, and placed in a 37°C, 5% CO ₂ cell incubator overnight. On the second day, add 10 μL of the test compound prepared in complete medium to each well. The final concentration of the compound is 9 concentration points with a 6-fold dilution starting from 10 μM. A blank control containing 0.5% DMSO is set. Place the plate in a 37°C, 5% CO ₂ cell incubator and incubate for 3 hours. After 3 hours, take out the 96-well cell culture plate, aspirate the medium, add 200 μL PBS (Shanghai Yuanpei Biotechnology Co., Ltd., B320) to each well and wash it again. The PBS was aspirated, 50 μL of lysis buffer (Cisbio, 64KL1FDF) containing blocking reagent (Cisbio, 64KB1AAC) was added to each well, and the well plate was placed on a shaker for 30 minutes at room temperature and shaken for lysis. After lysis, pipette and mix well, transfer 16μL of lysate from each well to two HTRF 96-well detection plates (Cisbio, 66PL96100), and then add 4μL of premixed phospho-ERK1/2 antibody solution to the two plates. (Cisbio, 64AERPEG) or 4μL of premixed total-ERK1/2 antibody solution (Cisbio, 64NRKPEG). The microplate was sealed with a sealing film, centrifuged in a microplate centrifuge for 1 minute, and incubated overnight in the dark at room temperature. On the third day, the PHERAstar multi-function microplate reader (BMG Labtech, S/N 471-0361) was used to read the fluorescence values excited by the 337nm wavelength and the 665nm and 620nm wavelength emission.

Three, data analysis

Graphpad Prism software was used to calculate the IC ₅₀ value of the compound inhibitory activity based on the compound concentration and the ratio of pERK/total ERK. The results are shown in Table 1 below.

Table 1 The IC ₅₀ value of the compound of the present disclosure on the inhibition of cell ERK phosphorylation.

Conclusion: The compound of the present disclosure has a good inhibitory effect on ERK phosphorylation of H358 cells.

Test Example 2: Biological Evaluation of H358 Cell Proliferation Experiment

1. Test purpose

By testing the inhibitory effect of the compounds of the present disclosure on the proliferation of H358 cells, the inhibitory effects of the compounds of the present disclosure on the KRAS target (containing the G12C mutation) are evaluated.

2. Experimental method

Luminescent Cell Viability Assay(发光细胞活性检测试剂)(Promega，G7573)，室温放置10分钟后，使用多功能微孔板酶标仪(PerkinElmer，VICTOR 3)读取发光信号值。 H358 cells (ATCC, CRL-5807) were cultured with complete medium, namely RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal calf serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded in a 96-well plate at a density of 1500 cells/well using complete medium, with 100 μL of cell suspension per well, and placed in a 37°C, 5% CO ₂ cell incubator overnight. On the second day, add 10 μL of the test compound prepared in complete medium to each well. The final concentration of the compound is 9 concentration points starting from 10 μM in 5-fold dilutions. A blank control containing 0.5% DMSO is set. The plate is placed in a 37°C, 5% CO ₂ cell incubator for 120 hours. On the seventh day, take out the 96-well cell culture plate and add 50μL to each well

Luminescent Cell Viability Assay (Promega, G7573), after standing at room temperature for 10 minutes, read the luminescence signal value with a multifunctional microplate reader (PerkinElmer, VICTOR 3).

Three, data analysis

Graphpad Prism software was used to calculate the IC ₅₀ value of the compound's inhibitory activity. The results are shown in Table 2 below.

Table 2 The IC ₅₀ value of the compounds of the present disclosure for inhibiting the proliferation of H358 cells.

Example number IC ₅₀ (nM) 1 96 Compounds with retention time of 6.133 minutes among 1-1, 1-2, 1-3 and 1-4 29 2 182 10-2 5 13-2 13 15 13 15-2 15 18 39 18-1 twenty two 19 64 twenty one 27 twenty two 29 25 33 26 34 27 35 28 39 29 48 30 17 30-2 5 30-1 94 31 49 32 83 32-2 59 36 92 37-1 56

37-2 6 43-2 28 44 twenty four 45 39 45-2 11 46 4 46-1 1 47 5 47-1 8 48 5 49 11 49-2 10 50 6 50-2 6 52 82 54-1 2 54-2 14 55 55 55-1 48 55-2 109

Conclusion: The compound of the present disclosure has a good inhibitory effect on the proliferation of H358 cells.

Pharmacokinetic evaluation

Test Example 3. Pharmacokinetic test of the compound of the present disclosure

1. Summary

Taking rats as the test animals, the LC/MS/MS method was used to determine that the rats were given Example 10-2 (the compounds with longer retention time in 10-1 and 10-2) and the compound of Example 30-2 ( The drug concentration in plasma at different times after the compound with longer retention time in 30-1 and 30-2) and the compound of Example 46-1 (the compound with shorter retention time in 46-1 and 46-2). To study the pharmacokinetic behavior of the compound of the present disclosure in rats and evaluate its pharmacokinetic characteristics.

2. Test plan

2.1 Experimental drugs

Example 10-2 (compounds with longer retention time in 10-1 and 10-2), Example 30-2 compound (compounds with longer retention time in 30-1 and 30-2) and Example 46-1 Compounds (compounds with shorter retention time among 46-1 and 46-2).

2.2 Experimental animals

12 healthy adult SD rats, half male and half male, were purchased from Weitong Lihua Experimental Animal Co., Ltd.

2.3 Drug preparation

Weigh a certain amount of medicine, add 5% DMSO, 5% Tween 80 and 90% normal saline to prepare a colorless and clear solution.

2.4 Administration

SD rats were fasted overnight and then administered by gavage. The dose was 10 mg/kg and the volume was 10.0 mL/kg.

3. Operation

Rats were intragastrically administered the compound of Example 10-2, compound 30-2 and compound 46-1, before and after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 hours 0.2 mL blood was collected from the orbit, placed in an EDTA-K2 anticoagulant (Shanghai Titan Technology Co., Ltd.) test tube, centrifuged at 4°C, 10,000 rpm for 1 minute, and the plasma was separated within 1 hour, and stored at -20°C. After administration 2 Eat every hour.

To determine the content of the test compound in rat plasma after gavage: Take 25μL of rat plasma at each time after administration, add 50μL of internal standard solution camptothecin (China Institute for the Control of Biological Products), acetonitrile (Merck Company) ) 175 μL, vortexed for 5 minutes, centrifuged for 10 minutes (3700 rpm), and 1.0 μL of supernatant was taken from the plasma sample for LC/MS/MS analysis.

4. Results of pharmacokinetic parameters

The pharmacokinetic parameters of the compounds of the present disclosure are shown in Table 3 below.

Table 3 Pharmacokinetic parameters of the compounds of the present disclosure

Conclusion: The compound of the present disclosure has good pharmacokinetic absorption and has obvious pharmacokinetic advantages.

Claims (32)

A compound represented by the general formula (I) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,

among them: Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Y is O or S; W ¹ is N or CR ⁷ ; W ² is N or CR ⁸ ; G ^{1 is} selected from O, S(O) _m and NR ⁹ ; G ^{2 is} selected from CR ¹⁰ R ¹¹ , CR ¹⁰ R ¹¹ CR ^10a R ^11a , C=O and C(O)CR ¹⁰ R ¹¹ ; R ^{1 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents; R ^{2 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents; R ^{3 are the} same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl Group, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ^{4 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -(CH ₂ ) _q NR ¹² R ¹³ , cycloalkyl and heterocycle base; R ⁵ and R ^{6 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, -(CH ₂ ) _q NR ¹² R ¹³ , cycloalkyl and heterocyclic group; R ^{7 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group; R ^{8 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group; R ^{9 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, cycloalkyl group and heterocyclic group; R ¹⁰ , R ¹¹ , R ^10a and R ^{11a are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl and heterocyclyl; or, R ¹⁰ and R ¹¹ together with the attached C atom form a cycloalkyl; or, R ^10a and R ^11a together with the attached C atom form a cycloalkyl; R ¹² and R ^{13 are the} same or different, and are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogenated alkyl group, a hydroxyl group, a hydroxyalkyl group, a cycloalkyl group, and a heterocyclic group; or, R ¹² and R ^{13 are the} same as The connected N atoms together form a heterocyclic group, and the heterocyclic group is optionally selected from one of halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy and hydroxyalkyl. Replaced by multiple substituents; r is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and q is 0, 1, 2, 3, or 4. The compound represented by the general formula (I) according to claim 1 or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by general formula (Ia) or (Ib) or atropisomers, tautomers, and mesoisomers , Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them: Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ⁶ , r, s, and t are as defined in claim 1. The compound represented by the general formula (I) according to claim 1 or 2 or its atropisomer, tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring B is aryl or heteroaryl, preferably C ₆ -C ₁₀ aryl or 5 to 10 membered heteroaryl, more preferably benzene Group, pyridyl and pyrimidinyl. The compound represented by the general formula (I) according to any one of claims 1 to 3 or its atropisomer, tautomer, meso, racemate, enantiomer Wherein Y is O in the form of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof. The compound represented by the general formula (I) according to any one of claims 1 to 4 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein W ¹ is N or CR ⁷ ; W ² is CR ⁸ ; R ⁷ and R ^{8 are} as defined in claim 1 . The compound represented by the general formula (I) according to any one of claims 1 to 5 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein G ¹ is O. The compound represented by the general formula (I) according to any one of claims 1 to 6 or its atropisomer, tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G ² is CR ¹⁰ R ¹¹ ; R ¹⁰ and R ^{11 are} as defined in claim 1. The compound represented by the general formula (I) according to any one of claims 1 to 7, or atropisomers, tautomers, mesoisomers, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIM) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them: G ³ , G ⁴ and G ^{5 are the} same or different, and each independently is N or CH, provided that at most two of G ³ , G ⁴ and G ⁵ are N; R ^2a , R ^2b and R ^{2c are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxyl, hydroxyalkyl, cycloalkyl , Heterocyclyl, aryl and heteroaryl, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally One or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl Replaced by R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkane Oxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; p is 0, 1, 2 or 3; Rings A, Y, W ¹ , R ¹ , R ⁴ to R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ and r are as defined in claim 1. The compound represented by the general formula (I) according to any one of claims 1 to 8 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIMa) or (IIMb) or atropisomers or tautomers , Meso, racemate, enantiomer, diastereomer, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them: Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3a , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r As defined in claim 8. The compound represented by the general formula (I) according to any one of claims 1 to 9 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (IIMa-1) or (IIMa-2) or atropisomers, mutual Tautomers, mesosomes, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them: R ^{3a is} selected from halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl, heterocyclyl, aryl And heteroaryl groups, preferably C _1-6 alkyl groups; Ring A, Y, W ¹ , G ³ ～G ⁵ , R ¹ , R ^2a , R ^2b , R ^2c , R ^3b , R ⁴ ～R ⁶ , R ⁸ , R ¹⁰ , R ¹¹ , p and r as claimed Defined in 8. The compound represented by the general formula (I) according to any one of claims 8 to 10 or its atropisomer, tautomer, meso, racemate, enantiomer G ³ and G ^{5 are the} same or different, and are each independently selected from N or CH; G ⁴ is CH. The compound represented by the general formula (I) according to any one of claims 1 to 11, or atropisomer, tautomer, meso, racemate, enantiomer thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are compounds represented by the general formula (II) or atropisomers, tautomers, meso Forms, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:

among them: R ^3a and R ^{3b are the} same or different, and are each independently selected from a hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkane Oxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring A, R ¹ , R ² , R ⁴ to R ⁸ , R ¹⁰ , R ¹¹ , r, and s are as defined in claim 1. The compound represented by the general formula (I) according to any one of claims 1 to 12 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from phenyl, pyridyl, or

Wherein ring D is phenyl or 5-membered heteroaryl; ring A is preferably selected from phenyl, pyridyl, naphthyl, indazolyl, indolyl, benzimidazolyl and benzotriazolyl. The compound represented by the general formula (I) according to any one of claims 1 to 13 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein ring A is selected from:

The compound represented by the general formula (I) according to any one of claims 1 to 14 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{1 is the} same or different, and each is independently selected from a hydrogen atom, a halogen, a C _1-6 alkyl group, a hydroxyl group, and an amino group ; And r is 0, 1, 2, 3 or 4. The compound represented by the general formula (I) according to any one of claims 1 to 7, or atropisomers, tautomers, mesoisomers, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^{2 is the} same or different, and each is independently selected from a hydrogen atom, a C _1-6 alkyl group and a C _3-6 ring Alkyl; and s is 0, 1, or 2. The compound represented by the general formula (I) according to any one of claims 1 to 16 or atropisomers, tautomers, mesoisomers, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁷ is a hydrogen atom. The compound represented by general formula (I) according to any one of claims 1 to 17, or atropisomer, tautomer, meso, racemate, enantiomer thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁸ is a hydrogen atom or a halogen. The compound represented by the general formula (I) according to any one of claims 1 to 18 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ¹⁰ and R ¹¹ are hydrogen atoms. The compound represented by the general formula (I) according to any one of claims 8, 9, 11 to 19, or an atropisomer, tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^3a and R ^3b are hydrogen atoms. The compound represented by the general formula (I) according to any one of claims 8 to 19 or its atropisomer, tautomer, meso, racemate, enantiomer A isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^3a is a C _1-6 alkyl group, and R ^3b is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 21, or atropisomers, tautomers, mesoisomers, racemates, enantiomers thereof Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁴ is a hydrogen atom or a halogen. The compound represented by the general formula (I) according to any one of claims 1 to 22 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ⁵ and R ⁶ are hydrogen atoms. The compound represented by general formula (I) according to any one of claims 8 to 11, 13 to 23, or atropisomer, tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^2a is C _1-6 alkyl or C _3-6 cycloalkyl, and R ^{2b is} selected from Hydrogen atom, C _1-6 alkyl group and C _3-6 cycloalkyl group. The compound represented by the general formula (I) according to any one of claims 8 to 11, 13 to 24, or atropisomer, tautomer, meso, racemate, Enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein R ^2c is a hydrogen atom. The compound represented by the general formula (I) according to any one of claims 1 to 25 or its atropisomer, tautomer, meso, racemate, enantiomer Isomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, which are selected from any of the following compounds:

A compound represented by the general formula (IA) or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or In the form of a mixture, or a pharmaceutically acceptable salt thereof,

among them: M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid; Ring A is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Ring B is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl; Y is O or S; W ¹ is N or CR ⁷ ; W ² is N or CR ⁸ ; G ^{1 is} selected from O, S(O) _m and NR ⁹ ; G ^{2 is} selected from CR ¹⁰ R ¹¹ , CR ¹⁰ R ¹¹ CR ^10a R ^11a , C=O and C(O)CR ¹⁰ R ¹¹ ; R ^{1 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents; R ^{2 are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclic, aryl And heteroaryl groups, wherein the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally selected from halogen, alkyl , Alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl substituted by one or more substituents; R ^{3 are the} same or different and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, cyanoalkyl, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl Group, cycloalkyl, heterocyclyl, aryl and heteroaryl; R ^{7 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group; R ^{8 is} selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, alkoxyalkyl, cycloalkyl and heterocyclic group; R ^{9 is} selected from hydrogen atom, alkyl group, haloalkyl group, hydroxyalkyl group, alkoxyalkyl group, cycloalkyl group and heterocyclic group; R ¹⁰ , R ¹¹ , R ^10a and R ^{11a are the} same or different, and are each independently selected from hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, Cycloalkyl and heterocyclyl; or, R ¹⁰ and R ¹¹ together with the attached C atom form a cycloalkyl; or, R ^10a and R ^11a together with the attached C atom form a cycloalkyl; r is 0, 1, 2, 3, 4 or 5; s is 0, 1, 2, 3, 4 or 5; t is 0, 1, 2, 3 or 4; m is 0, 1 or 2; and n is 0, 1, 2 or 3. The compound represented by the general formula (IA) according to claim 27, or its atropisomer, tautomer, meso, racemate, enantiomer, diastereomer The structure, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is selected from:

A method for preparing the compound represented by the general formula (I) according to claim 1 or its atropisomer, tautomer, meso, racemate, enantiomer, non- Enantiomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, the method comprising:

The compound of general formula (IA) or its atropisomer, tautomer, mesoisomer, racemate, enantiomer, diastereomer, or its mixture form, or The pharmaceutically acceptable salt reacts with the compound of general formula (IB) under alkaline conditions to obtain the compound of general formula (I) or its atropisomer, tautomer, meso, and exoisomer. Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, wherein: X is halogen; M is an inorganic acid or an organic acid, preferably hydrochloric acid or trifluoroacetic acid; n is 0, 1, 2 or 3, preferably 0 or 1; Ring A, ring B, Y, W ¹ , W ² , G ¹ , G ² , R ¹ to R ⁶ , r, s, and t are as defined in claim 1. A pharmaceutical composition containing a therapeutically effective amount of the compound represented by the general formula (I) according to any one of claims 1 to 26 or its atropisomer or tautomer Forms, meso, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers , Diluent or excipient. The compound represented by the general formula (I) according to any one of claims 1 to 26, or atropisomers, tautomers, mesoisomers, racemates, enantiomers thereof Use of a isomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30 in the preparation of a drug for inhibiting KRAS, preferably a drug for inhibiting KRAS G12C Use in. The compound represented by the general formula (I) according to any one of claims 1 to 26, or atropisomers, tautomers, mesoisomers, racemates, enantiomers thereof Isomer, diastereoisomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 30 in the preparation of a medicament for the treatment or prevention of cancer, inflammation, or other proliferative diseases The use of cancer is preferably cancer; the cancer is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, kidney cancer, breast cancer, ovarian cancer, Prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteoma, osteosarcoma, seminoma, testicular tumor, uterine cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera , Leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, choriocarcinoma and pediatric tumors.