CN113980032A

CN113980032A - Condensed tetracyclic derivative, preparation method and application thereof in medicine

Info

Publication number: CN113980032A
Application number: CN202110844682.4A
Authority: CN
Inventors: 陆标; 桂斌; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2020-07-27
Filing date: 2021-07-26
Publication date: 2022-01-28
Anticipated expiration: 2041-07-26
Also published as: CN113980032B

Abstract

The present disclosure relates to fused tetracyclic derivatives, processes for their preparation and their use in medicine. Specifically, the disclosure relates to a fused tetracyclic derivative shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and application of the fused tetracyclic derivative as a therapeutic agent, especially as a KRAS inhibitor.

Description

Condensed tetracyclic derivative, preparation method and application thereof in medicine

Technical Field

The present disclosure is in the field of medicine and relates to fused tetracyclic derivatives, processes for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, particularly as KRAS inhibitors.

Background

The RAS (rat Sarcoma Viral Oncogene homolog) family belongs to the small GTP enzyme superfamily and is widely expressed in various eukaryotes. There are three RAS genes (HRAS, KRAS and NARS) in humans, which are expressed as four highly related RAS small gtpases (HRAS, KRAS4A, KARS4B and NRAS). It acts as a binary switch for GDP-GTP regulation. They generally exhibit two forms: a GDP (guanosine diphosphate) -bound form in the inactivated state and a GTP (guanosine triphosphate) -bound form in the activated state. RAS proteins regulate 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-. The RAS gene has high mutation rate in pancreatic cancer, colorectal cancer, non-small cell lung cancer and other tumors, and the activated mutant RAS protein can promote abnormal signal transduction, thereby causing the occurrence and development of cancer and generating drug resistance to targeted drugs. Wherein KRAS mutation is the gene with the highest mutation rate in human oncogenes and accounts for 20-30% of all tumors.

For the research of mutant forms and signal paths of KRAS protein, molecular biology has made great progress in recent years, however, the development of related targeted drugs is still challenging. In the aspect of chemical drug development, because the affinity of KRAS and GTP is very high and reaches 60pM, and the intracellular GTP concentration is at the level of mM, the affinity of the directly competing molecules to the compound is extremely high, and no successful case exists so far. In the aspect of biological drug development, the antibody drug penetrates cell membranes to target KRAS protein, and the drug delivery efficiency is low. Therefore, many researchers have tried to develop new approaches to inhibit the activity of kinases such as RAF, MEK and ERK in KRAS downstream signaling pathway to achieve the purpose of inhibiting KRAS pathway. The compounds have certain curative effect, but because the downstream inhibitor cannot completely block KRAS signals and the target point related toxic and side effects are large, the compounds have poor medicinal effect on KRAS mutant tumors. Therefore, KRAS inhibitors with new action mechanisms have great clinical application value.

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

Facing the difficulty of KRAS protein becoming drug property, professor Kevan Shokat of san Francisco university, California first verifies that certain special compounds can bind KRAS G12C mutant protein through covalent bonds. Through further research, the covalent compounds can be combined with the 12 th cysteine of KRAS mutant protein and occupy a hydrophobic allosteric regulatory pocket in a II molecular switch region (switch-II regions), and the bound KRAS G12C mutant can be irreversibly locked in an inactivated state, thereby blocking a signal path dependent on the protein and the viability of cancer cells (Nature 2013, 503, 548-. The KRAS G12C small-molecule inhibitor ARS-1620 can effectively inhibit tumor growth and even completely regress tumors in various KRAS G12C mutant tumor models. Since KRAS G12C is a mutant protein in tumor cells, while wild-type KRAS does not have this mutation site, it provides a perfect tumor-selective target (Cell,2018,572, 578-one 589). Companies represented by Araxas, Amgen and Mirati have issued several patents for KRAS G12C inhibitors (WO2014152588, WO2016164675, WO2017087528, WO2017201161, WO2018119183, etc.). No inhibitor drug of KRAS G12C is currently approved for marketing, and the most advanced small molecule KRAS G12C inhibitors of Amgen and Mirati enter clinical trials at 9 and 12 months in 2018, respectively, so there is a significant unmet medical need in the relevant patient population.

Disclosure of Invention

The purpose of the present disclosure is to provide a compound represented by the general formula (I) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture form thereof, or a pharmaceutically acceptable salt thereof,

wherein:

g is N or C;

R^1aand R^1bAre the same or different and are each independently selected from the group consisting of a hydrogen atom, a halogen, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;

R²the same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independentlyOptionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R³are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, and a hydroxyalkyl group;

R⁴is halogen;

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

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

In some preferred embodiments of the present disclosure, the compound represented by the general formula (I) or an atropisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by the general formula (Ia) or (Ib) or an atropisomer, a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:

g, R therein^1a、R^1b、R²-R⁴S and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound represented by formula (I), (Ia) or (Ib), or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (Ia-a), (Ia-b), (Ib-a) or (Ib-b), or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

g, R therein^1a、R^1b、R²-R⁴S and t are as defined in the general formula (I), (Ia) or (Ib).

In some preferred embodiments of the present disclosure, the compound represented by formula (I), (Ia) or (Ib), or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (Ia-1) or (Ia-2), or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

R³Are the same or different and are each independently selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl;

G、R^1a、R^1b、R²、R⁴and s is as defined in formula (I), (Ia) or (Ib).

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1) or (Ia-2) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (Ia-1a), (Ia-1b), (Ia-2a) or (Ia-2b) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

G、R^1a、R^1b、R²、R⁴and s is as defined in formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1) or (Ia-2).

In some preferred embodiments of the present disclosure, the compound represented by formula (I), (Ia) or (Ib), or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (Ia-3) or (Ia-4), or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

G、R^1a、R^1b、R²、R⁴and s is as defined in formula (I), (Ia) or (Ib).

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is N.

In some preferred embodiments of the present disclosure, the compounds of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b),A compound represented by (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is^1aAnd R^1bAre the same or different and are each independently a hydrogen atom or a halogen; preferably R^1aIs a hydrogen atom or a halogen, R^1bIs halogen.

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R²The same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, hydroxy, hydroxyalkyl, and cycloalkyl; preferably, R²Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group and a cycloalkyl group.

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R²Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, C_1-6Alkyl radical, C_1-6Alkoxy radical, C_1-6Haloalkyl, cyano, amino, hydroxy, C_1-6Hydroxyalkyl and 3-6 membered cycloalkyl; preferably, R²Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C_1-6Alkyl and 3-6 membered cycloalkyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3) or (Ia-4) or an atropisomer thereofA compound of formula (I), wherein R is selected from the group consisting of a tautomer, mesomer, racemate, enantiomer, diastereomer, and mixture thereof, and a pharmaceutically acceptable salt thereof²Are the same or different and are each independently C_1-6Alkyl, preferably methyl or isopropyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R³Are the same or different and are each independently C_1-6Alkyl, preferably methyl.

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R⁴Is fluorine or chlorine, preferably fluorine.

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein s is 1 or2, preferably 2.

In some preferred embodiments of the present disclosure, the compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), or (Ib-b) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein t is 0 or 1.

Another aspect of the present disclosure relates to a compound of formula (II) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

g is N or CH;

R^1aand R^1bThe same or different and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl group, alkoxy group, haloalkyl group, amino group, hydroxyl group and hydroxyalkyl group;

R^2aand R^2bThe same or different, and each is independently selected from the group consisting of hydrogen atom, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R³selected from the group consisting of alkyl, haloalkyl, and hydroxyalkyl; and is

R⁴Is a hydrogen atom or a halogen.

In some preferred embodiments of the present disclosure, the compound of formula (II) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (IIa) or (IIb) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

g, R therein^1a、R^1b、R^2a、R^2b、R³And R⁴As defined in formula (II).

In some preferred embodiments of the present disclosure, the compound represented by formula (II) or (IIa) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound represented by formula (IIa-a), (IIa-b), (IIa-c), or (IIa-d) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

g, R therein^1a、R^1b、R^2a、R^2b、R³And R⁴As defined in general formula (II) or (IIa).

In some preferred embodiments of the present disclosure, the compound of formula (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), or (IIa-d) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein G is N.

In some preferred embodiments of the present disclosure, the compound of formula (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), or (IIa-d) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R^1aAnd R^1bAre the same or different and are each independently hydroxy or halogen; preferably R^1aIs halogen, and R^1bIs a hydroxyl group.

In some preferred embodiments of the present disclosure, the compound of formula (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), or (IIa-d) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R^2aAnd R^2bAre the same or different and are each independently C_1-6Alkyl, preferably methylOr isopropyl, more preferably R^2aIs isopropyl, and R^2bIs methyl.

In some preferred embodiments of the present disclosure, the compound of formula (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), or (IIa-d) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R³Is C_1-6Alkyl, preferably methyl.

In some preferred embodiments of the present disclosure, the compound of formula (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), or (IIa-d) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is R⁴Is halogen, preferably fluorine or chlorine, more preferably fluorine.

Typical compounds of the present disclosure include, but are not limited to: the following table 1 structure:

table 1 Structure and nomenclature of Compounds

Another aspect of the present disclosure relates to a compound represented by the general formula (I-a) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein M is an inorganic acid or an organic acid;

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

G、R^1a、R^1b、R²-R⁴s and t are as defined in formula (I).

Another aspect of the present disclosure relates to a compound represented by the general formula (I-a) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, wherein M is selected from the group consisting of hydrogen chloride, a1, 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-toluenesulfonic acid, and TMSOTf, preferably hydrochloric acid or trifluoroacetic acid.

Another aspect of the present disclosure relates to a compound represented by formula (Ia-a) or (Ib-a), or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

g, R therein^1a、R^1b、R²-R⁴M, n, s and t are as defined in formula (I-A).

Another aspect of the present disclosure relates to a compound represented by the general formula (Ia-1-a) or (Ia-2-a) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

wherein

G、R^1a、R^1b、R²、R⁴m, n and s are as defined in formula (I-A).

Another aspect of the present disclosure relates to a compound represented by the general formula (II-a) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

G、R^1a、R^1b、R^2a、R^2b、R³and R⁴As defined in formula (II).

Another aspect of the present disclosure relates to a compound of formula (IIa-a) or (IIb-a) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof:

G、R^1a、R^1b、R^2a、R^2b、R³and R⁴As defined in formula (II-A).

The intermediate compounds of the present disclosure are shown in table 2 below:

table 2 intermediate structures and nomenclature

Another aspect of the present disclosure relates to a method of preparing a compound of formula (I) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound of formula (I-a) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (I) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R²-R⁴s, M, n and t are as defined in formula (I-A).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (Ia) and (Ib), or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound of formula (Ia-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (Ia) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

reacting a compound of formula (Ib-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (Ib) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R²-R⁴s, M, n and t are as defined in formula (I-A).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formulae (Ia-1) and (Ia-2) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, the method comprising:

reacting a compound of the general formula (Ia-1-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof, with a compound of the general formula (I-B) under basic conditions to give a compound of the general formula (Ia-1) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

reacting a compound of formula (Ia-2-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (Ia-2) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R²、R⁴s, M and n are as defined in formula (I-A).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (II) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound of formula (II-a) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (II) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R^2a、R^2b、R³and R⁴As defined in formula (II).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IIa) and (IIb), or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

reacting a compound of formula (IIa-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (IIa) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

reacting a compound of formula (IIb-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (IIb) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R^2a、R^2b、R³and R⁴As defined in formula (II).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of the present disclosure of the general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and Table 1 or an atropisomer, tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier, and a pharmaceutically acceptable carrier, A diluent or excipient.

The present disclosure further relates to compounds of the general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and shown in Table 1 or in the form of atropisomers, tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, use in the manufacture of a medicament for inhibiting KRAS, preferably use in the manufacture of a medicament for inhibiting KRAS G12C.

The disclosure further relates to the use of compounds of the general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and shown in Table 1 or in the form of atropisomers, tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for the preparation of a medicament for the treatment or prophylaxis of cancer, inflammation or other proliferative disorders, preferably for the manufacture of a medicament for the treatment or prevention of cancer; preferably, the cancer is 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, osteochondrosis, osteoma, osteosarcoma, seminoma, testicular tumor, endometrial cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, and pediatric tumor (the tumors are corresponding malignancies).

The disclosure also relates to a method of inhibiting KRAS comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and table 1 or an atropisomer, tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating or preventing a KRAS-mediated disease comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and the compounds shown in Table 1 or their atropisomers, tautomers, racemates, enantiomers, diastereomers or their mixtures, or their pharmaceutically acceptable salts, or a pharmaceutical composition comprising them.

The disclosure also relates to a method of treating or preventing cancer, inflammation, or other proliferative disease, preferably treating cancer, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d), and the compounds shown in Table 1 or an atropisomer, tautomer, racemate, enantiomer, diastereomer or mixture thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable salt thereof, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the cancer is preferably selected from the group consisting of 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, osteochondrosis, osteoma, osteosarcoma, seminoma, testicular tumor, endometrial cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, and pediatric tumor (the tumors referred to above are corresponding malignancies).

The present disclosure further relates to a compound of the general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and table 1 or an atropisomer, tautomer, racemate, enantiomer, diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The disclosure also relates to compounds of the general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and table 1 or atropisomers, tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use as KRAS inhibitors, preferably as KRAS G12C inhibitors.

The disclosure also relates to compounds of the general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and shown in Table 1 or in the form of atropisomers, tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment or prevention of a KRAS mediated disease, preferably for use in the treatment or prevention of a KRAS G12C mediated disease.

The disclosure also relates to compounds of the general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1a), (Ia-1b), (Ia-2a), (Ia-2b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and shown in Table 1 or in the form of atropisomers, tautomers, racemates, enantiomers, diastereomers or mixtures thereof, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the same, for use in the treatment or prevention of cancer, inflammation, or other proliferative disease, preferably for use in the treatment or prevention of cancer; wherein the cancer is preferably selected from the group consisting of 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, osteochondrosis, osteoma, osteosarcoma, seminoma, testicular tumor, endometrial cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureter tumor, bladder cancer, gallbladder cancer, bile duct cancer, choriocarcinoma, and pediatric tumor (the tumors referred to above are corresponding malignancies).

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers to formulate compositions of the disclosure by conventional methods. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in sustained release dosage forms, such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

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, the active compound is preferably in unit dosage form, or in such a way that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be 0.1 to 1000 mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of antioxidants.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump model Deltec CADD-PLUS. TM.5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may 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 which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound employed, the age of the patient, the weight of the patient, the health condition of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, 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 (e.g., 1,2,3,4, 5,6,7, 8,9, 10, 11, and 12) carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 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-dimethylpentyl, 3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2, 3-dimethylhexyl, 2, 4-dimethylhexyl, 2, 5-dimethylhexyl, 2-dimethylhexyl, 3-dimethylhexyl, 4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-dimethylpentyl, 2-dimethylhexyl, 3-dimethylpentyl, 2-ethylhexyl, 3-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-dimethylhexyl, 2-ethylhexyl, 2-ethyl, 2-2, 2-2, 2-2, or, 2, 2-diethylpentyl, n-decyl, 3-diethylhexyl, 2-diethylhexyl, and various branched isomers thereof. More preferred are lower alkyl groups having 1 to 6 carbon atoms, non-limiting examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-dimethylpropyl, 1, 2-dimethylpropyl, 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1, 2-trimethylpropyl, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2, 3-dimethylbutyl and the like. The alkyl group may be substituted or unsubstituted and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of D atom, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl, heteroaryl.

The term "alkylene" refers to a saturated straight or branched aliphatic hydrocarbon group, which is a residue derived from the parent alkane by removal of two hydrogen atoms from the same carbon atom or two different carbon atoms, and is a straight or branched group containing 1 to 20 carbon atoms, preferably an alkylene group containing 1 to 12 carbon atoms (e.g., 1,2,3,4, 5,6,7, 8,9, 10, 11, and 12), more preferably 1 to 6 carbon atoms. Non-limiting examples of alkylene groups include, but are not limited to, methylene (-CH)₂-), 1-ethylidene (-CH (CH)₃) -), 1, 2-ethylene (-CH)₂CH₂) -, 1-propylene (-CH (CH)₂CH₃) -), 1, 2-propylene (-CH)₂CH(CH₃) -), 1, 3-propylene (-CH)₂CH₂CH₂-) 1, 4-butylene (-CH₂CH₂CH₂CH₂-) and the like. The alkylene group may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of alkenyl, alkynyl, alkoxy, haloalkoxy, cycloalkyloxy, heterocyclyloxy, alkylthio, alkylamino, halogen, mercapto, hydroxy, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocyclylthio and oxo.

The term "alkenyl" refers to an alkyl compound containing at least one carbon-carbon double bond in the molecule, wherein alkyl is as defined above. Alkenyl groups having 2 to 12 (e.g., 2,3,4, 5,6,7, 8,9, 10, 11, and 12) carbon atoms are preferred, and alkenyl groups having 2 to 6 carbon atoms are more preferred. The alkenyl group may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups having 2 to 12 (e.g., 2,3,4, 5,6,7, 8,9, 10, 11, and 12) carbon atoms are preferred, and alkynyl groups having 2 to 6 carbon atoms are more preferred. Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

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

The term "spirocycloalkyl" refers to a 5 to 20 membered polycyclic group sharing one carbon atom (referred to as a spiro atom) between single rings, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" 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 of the rings may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused ring alkyls according to the number of constituent rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicycloalkyl groups. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a 5 to 20 membered all carbon polycyclic group in which any two rings share two carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl groups 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 a cycloalkyl (including monocyclic, spiro, fused and bridged rings) fused to an aryl, heteroaryl or heterocycloalkyl ring as described above, whichWherein the ring to which the parent structure is attached is cycloalkyl, non-limiting examples of which include indanyl (e.g., indanyl)

) Tetrahydronaphthyl (e.g. tetrahydronaphthyl)

) Benzocycloheptalkyl (e.g. phenyl-cycloheptyl)

) Etc.; preference is given to

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms, one or more of which is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include the ring portion of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably 3 to 12 (e.g., 3,4, 5,6,7, 8,9, 10, 11 and 12) ring atoms, of which 1 to 4 (e.g., 1,2,3 and 4) are heteroatoms; more preferably from 3 to 8 ring atoms (e.g., 3,4, 5,6,7, and 8), wherein 1-3 are heteroatoms (e.g., 1,2, and 3); more preferably 3 to 6 ring atoms, of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms, of which 1-3 (e.g. 1,2 and 3) are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1, 2.3.6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group which shares a single atom (referred to as the spiro atom) between single rings, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). The spiro heterocyclic group is classified into a mono-spiro heterocyclic group, a di-spiro heterocyclic group or a multi-spiro heterocyclic group, preferably a mono-spiro heterocyclic group and a di-spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferred are 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclic groups. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to a 5 to 20 membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic or tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a 5 to 14 membered polycyclic heterocyclic group in which any two rings share two atoms not directly attached, which may contain one or more double bonds, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14, more preferably 7 to 10 (e.g.7, 8,9 or 10). They may be classified into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups according to the number of constituent rings, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes a heterocyclyl (including monocyclic, spiroheterocyclic, fused heterocyclic and bridged heterocyclic) fused to an aryl, heteroaryl or cycloalkyl ring as described above, wherein the ring to which the parent structure is attached is a heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, said substituents preferably being independently optionally one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered all carbon monocyclic or fused polycyclic (fused polycyclic is a ring sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system, preferably 6 to 10 membered, such as phenyl and naphthyl. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system comprising 1 to 4(1, 2,3 and 4) heteroatoms, 5 to 14 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g. 5,6,7, 8,9 or 10 membered), more preferably 5 or 6 membered, e.g. furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl or cycloalkyl ring as described above, wherein the ring joined together with the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, said substituents preferably being independently optionally selected from one or more substituents of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from the parent ring atom by removal of one hydrogen atom, or residues derived from the parent ring atom by removal of two hydrogen atoms from the same or two different ring atoms, i.e., "divalent cycloalkyl", "divalent heterocyclyl", "arylene" and "heteroarylene".

The term "amino protecting group" is intended to protect an amino group with a group that can be easily removed in order to keep the amino group unchanged when the rest of the molecule is subjected to a reaction. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl, acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxyl-protecting group" is a suitable group for hydroxyl protection known in the art, see the literature ("Protective Groups in Organic Synthesis", 5)^Th Ed.T.W.Greene&P.g.m.wuts). By way of example, the hydroxyl protecting group may preferably be (C)_1-10Alkyl or aryl)₃Silane groups, for example: triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl and the like; may be C_1-10Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C_1-6Alkoxy-substituted C_1-6Alkyl or phenyl substituted C_1-6Alkyl, most preferably C_1-4Alkoxy-substituted C_1-4Alkyl groups, for example: methyl, t-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; may be (C)_1-10Alkyl or aryl) acyl groups, such as: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C)_1-6Alkyl or C_6-10Aryl) sulfonyl; or (C)_1-6Alkoxy or C_6-10Aryloxy) carbonyl.

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

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "aryloxy" refers to aryl-O-wherein aryl is as defined above.

The term "heteroaryloxy" refers to heteroaryl-O-, wherein heteroaryl is as defined above.

The term "alkylthio" refers to an alkyl-S-group wherein alkyl is as defined above.

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

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

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

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

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

The term "hydroxy" refers to-OH.

The term "mercapto" refers to-SH.

The term "amino" refers to the group-NH₂。

The term "cyano" refers to — CN.

The term "nitro" means-NO₂。

The term "oxo" means "═ O".

The term "carbonyl" refers to C ═ O.

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

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

The compounds of the present disclosure may also comprise isotopic derivatives thereof. The term "isotopic derivative" means that the structures differ only by the presence of one or moreA variety of isotopically enriched atom compounds. For example, having the structure of the present disclosure except that "deuterium" or "tritium" is substituted for hydrogen, or¹⁸F-fluorine labeling: (¹⁸Isotope of F) instead of fluorine, or with¹¹C-，¹³C-, or¹⁴C-enriched carbon (C¹¹C-，¹³C-, or¹⁴C-carbon labeling;¹¹C-，¹³c-, or¹⁴C-isotopes) instead of carbon atoms are within the scope of the present disclosure. Such compounds are useful as analytical tools or probes in, for example, biological assays, or as tracers for in vivo diagnostic imaging of disease, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The disclosure also includes various deuterated forms of the compounds of formula (I) and formula (II). Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom. The person skilled in the art is able to synthesize the deuterated forms of the compounds of formula (I) and (II) with reference to the relevant literature. Commercially available deuterated starting materials can be used in preparing the deuterated forms of compounds of formula (I) and formula (II), or they can be synthesized using conventional techniques using deuterated reagents including, but not limited to, deuterated boranes, trideuterioborane tetrahydrofuran solutions, deuterated lithium aluminum hydrides, deuterated iodoethanes, deuterated iodomethanes, and the like. Deuterations can generally retain activity comparable to non-deuterated compounds and can achieve better metabolic stability when deuterated at certain specific sites, thereby achieving certain therapeutic advantages.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally substituted with an alkyl" means that an alkyl may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl and the heterocyclic group is not substituted with an alkyl.

"substituted" means that one or more, preferably 1 to 5, more preferably 1 to 3, hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof in admixture with other chemical components, as well as other components such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to a sufficient amount of the drug or agent that is non-toxic but achieves the desired effect. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular forms "a", "an" and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

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

scheme one

The preparation method of the compound shown in the general formula (I) or the atropisomer, the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt form thereof comprises the following steps:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R²-R⁴s, M, n and t are as defined in formula (I-A).

Scheme two

The present disclosure relates to a process for the preparation of compounds of the general formulae (Ia) and (Ib) or atropisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the steps of:

wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R²-R⁴s, M, n and t are as defined in formula (I-A).

Scheme three

A process for the preparation of compounds of the general formulae (Ia-1) and (Ia-2) or their atropisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, comprising the steps of:

wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R²、R⁴s, M and n are as defined in formula (I-A).

Scheme four

A process for the preparation of compounds of the general formulae (Ia-3) and (Ia-4) or their atropisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, comprising the steps of:

reacting a compound of formula (Ia-3-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (Ia-3) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

reacting a compound of formula (Ia-4-A) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, with a compound of formula (I-B) under basic conditions to give a compound of formula (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R²、R⁴s, M and n are as defined in formula (I-A).

Scheme five

A process for the preparation of compounds of the general formulae (Ia-a) and (Ia-b) of the present disclosure, or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

chiral preparation of a compound of the general formula (I-a) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, to give a compound of the general formulae (Ia-a) and (Ia-b) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

g, R therein^1a、R^1b、R²-R⁴S and t are as defined in formula (I).

Scheme six

Disclosed is a method for preparing a compound represented by general formulae (Ib-a) and (Ib-b) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising the steps of:

chiral preparation of a compound of general formula (I-b) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, to obtain a compound of general formula (Ib-a) and (Ib-b) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

g, R therein^1a、R^1b、R²-R⁴S and t are as defined in formula (I).

Scheme seven

A process for the preparation of compounds of the general formulae (Ia-1a) and (Ia-1b) or their atropisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the steps of:

chiral preparation of a compound of formula (Ia-1) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, to give a compound of formula (Ia-1a) and (Ia-1b) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein

G、R^1a、R^1b、R²、R⁴and s is as defined in formula (I).

Scheme eight

A process for the preparation of compounds of the general formulae (Ia-2a) and (Ia-2b) or their atropisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof, comprising the steps of:

chiral preparation of a compound of formula (Ia-2) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, to give a compound of formula (Ia-2a) and (Ia-2b) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

wherein

G、R^1a、R^1b、R²、R⁴and s is as defined in formula (I).

Scheme nine

The preparation method of the compound shown in the general formula (II) or the atropisomer, the tautomer, the mesomer, the racemate, the enantiomer, the diastereomer or the mixture form thereof, or the pharmaceutically acceptable salt form thereof comprises the following steps:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R^2a、R^2b、R³and R⁴As defined in formula (II).

Scheme ten

A process for the preparation of compounds of the general formulae (IIa) and (IIb) or their atropisomers, tautomers, mesomers, racemates, enantiomers, diastereomers, or mixtures thereof, or their pharmaceutically acceptable salts, comprising the steps of:

wherein:

x is halogen, preferably chlorine;

G、R^1a、R^1b、R^2a、R^2b、R³and R⁴As defined in formula (II).

Scheme eleven

A process for the preparation of compounds of the general formulae (IIa-a), (IIa-b), (IIa-c) and (IIa-d) or their atropisomers, tautomers, meso-isomers, racemates, enantiomers, diastereomers or mixtures thereof, or their pharmaceutically acceptable salts, comprising the steps of:

chiral preparation of a compound of formula (IIa) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, to give a compound of formula (IIa-a), (IIa-b), (IIa-c) and (IIa-d) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof;

g, R therein^1a、R^1b、R^2a、R^2b、R³And R⁴As defined in formula (II).

The reagents that provide basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylamide, potassium acetate, sodium t-butoxide, potassium t-butoxide, and sodium N-butoxide, and inorganic bases including, but not limited to, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, and lithium hydroxide, preferably triethylamine.

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

Detailed Description

The present disclosure is further described below with reference to examples, but these examples do not limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. delta.) of 10^-6The units in (ppm) are given. NMR was measured using a Bruker AVANCE-400 nuclear magnetic instrument or Bruker AVANCE NEO 500M in deuterated dimethyl sulfoxide (DMSO-d)₆) Deuterated chloroform (CDCl)₃) Deuterated methanol (CD)₃OD), internal standard Tetramethylsilane (TMS).

MS was determined using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC MS (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS); waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector); THERMO Ultimate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active).

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, Agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High performance liquid phase preparation Waters 2545-2767, Waters 2767-SQ Detector 2, Shimadzu LC-20AP and Gilson GX-281 preparative chromatographs were used.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

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

The thin layer chromatography silica gel plate adopts HSGF254 of tobacco yellow sea or GF254 of Qingdao, the specification of the silica gel plate used by Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm.

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

Average inhibition rate of kinase and IC₅₀The values were determined with a NovoStar microplate reader (BMG, Germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, Acros Organics, Aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

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

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction used a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 type microwave reactor.

In the examples, the solution means an aqueous solution unless otherwise specified.

In the examples, the reaction temperature is, unless otherwise specified, from 20 ℃ to 30 ℃ at room temperature.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system, C: ethyl acetate/dichloromethane system, D: in the methanol/ethyl acetate system, the volume ratio of the solvent is adjusted according to different polarities of the compounds, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Examples 1, 1-1, 1-2

(5aR) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 1

(12S,5aR) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 1-1

(12R,5aR) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 1-2

First step of

1- (2-isopropyl-4-methylpyridin-3-yl) urea 1b

The compound 2-isopropyl-4-methylpyridin-3-amine 1a (10.8g, 71.89mmol, Biyao) was dissolved in 500mL of dichloromethane, triethylamine (36.45g, 360.21mmol, 50mL) was added, the mixture was cooled to 0 ℃, triphosgene (12.8g, 43.13mmol) was added, the mixture was stirred for reaction for 1 hour, a1, 4-dioxane solution of ammonia (0.4M, 220mL) was added, and the mixture was stirred for reaction for 1 hour. The reaction mixture was concentrated under reduced pressure, and 1L of water was added to the residue, stirred for 10 minutes, filtered, the filter cake was washed with water, and dried in vacuo to give the title product 1b (9.73g, yield: 70.0%).

Second step of

6-amino-1- (2-isopropyl-4-methylpyridin-3-yl) pyrimidine-2, 4(1H,3H) -dione 1c

Compound 1b (9.2g, 47.60mmol) was added to 150mL of methanol, ethyl cyanoacetate (5.913g, 52.27mmol,5.6mL) and sodium tert-butoxide (5.490g, 57.12mmol) were added, and the mixture was heated to 75 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and 1M hydrochloric acid was added to the residue to pH 7, followed by stirring for 10 minutes, filtration and vacuum drying of the filter cake to give the title compound 1c (9.2g, yield: 74.2%).

The third step

3- (6-amino-1- (2-isopropyl-4-methylpyridin-3-yl) -2, 4-dioxo-1, 2,3, 4-tetrahydropyrimidin-5-yl) -3-oxopropanenitrile 1d

Cyanoacetic acid (6g, 70.53mmol) was added to 50mL of acetic anhydride, heated to 85 ℃ for 5 minutes, and the reaction mixture was poured into Compound 1c (9.2g, 35.34mmol) and heated to 85 ℃ for 1 hour. The reaction solution was cooled to room temperature, poured into 1L of water, and stirred for 10 minutes. Filtration and drying gave the title compound 1d (9.03g, 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) -tetrone 1e

Compound 1d (12.5g, 38.18mmol) was added to 40mL hydrobromic acid and heated to 80 ℃ for 1 hour. The reaction solution was cooled to room temperature, poured into 1L of ice water, added with ammonia water to adjust the pH of the reaction solution to 7, filtered, the filter cake was washed with water, and dried under vacuum to give the title compound 1e (9.03g, yield: 72.0%).

The fifth step

6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4,5,7(1H,3H,6H,8H) -tetrone 1f

Compound 1e (10g, 30.45mmol) was added to 200mL of water, sodium hydroxide (4.3g, 107.5mmol) was added at room temperature, and stirred for 30 minutes, and then 1- (chloromethyl) -4-fluoro-1, 4-diazabicyclo [2.2.2] heptaneditetrafluoroborate (32.4g, 91.45mmol, Shaosuan) was added and stirred for reaction for 1 hour. Then, 140mL of 2M hydrochloric acid was slowly added to the reaction solution until the pH of the reaction solution became 1, sodium sulfite (7.68g,60.93mmol) was added, stirring was carried out for 5 minutes, zinc powder (10g, 152.9mmol) was further added, and the mixture was heated to 60 ℃ to react for 5 hours. The reaction solution was cooled to room temperature, filtered, and the filter cake was stirred with a mixed solvent of 400mL of acetonitrile and N, N-diisopropylethylamine (V/V ═ 10:1) for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the target compound 1f (3.15g, yield: 29.8%), which was used without further purification in the next step.

The sixth step

5, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 1g Compound 1f (2g, 5.77mmol) was added to 50mL acetonitrile, phosphorus oxychloride (4.29g, 27.97mmol, 2.6mL) and N, N-diisopropylethylamine (3.79g, 29.32mmol, 5.2mL) were added, and heated to 80 ℃ for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure, the residue was poured into 50mL of ice water, a saturated sodium bicarbonate solution was added until the pH of the reaction solution was >7, 100mL of dichloromethane was added to dissolve the residue, the solution was separated, the aqueous phase was extracted with dichloromethane (50 mL. times.2), the organic phases were combined, 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 1g of the objective compound (396mg, yield: 17.8%).

Seventh step

4,5, 7-trichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one 1H

Compound 1g (396mg, 1.0334mmol) was dissolved in 30mL of acetonitrile, and phosphorus oxychloride (462mg, 3.01mmol, 0.28mL) and N, N-diisopropylethylamine (408mg, 3.15mmol, 0.56mL) were added, followed by heating to 80 ℃ for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the title compound 1h (620mg, yield: > 100%) which was used directly in the next step without further purification.

Eighth step

(R) -4- (5, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ] pyrimidin-4-yl) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester 1i

Compound 1h (620mg, 1.54mmol) was dissolved in 40mL of dichloromethane, cooled to 0 deg.C, added with tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate (250mg, 1.15mmol, Bi De medicine), then added with N, N-diisopropylethylamine (408mg, 3.15mmol, 0.56mL), and stirred for 1 hour. After addition of 30mL of a saturated aqueous solution of sodium hydrogencarbonate, the mixture was separated, the aqueous phase was extracted with methylene chloride (100 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1i (920mg, yield: 102.4%) which was used directly in the next reaction without further purification.

The ninth step

(R) -2-chloro-3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -11-oxo-5 a,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 1j

Compound 1i (920mg, 1.58mmol) was dissolved in 30mL tetrahydrofuran, 1, 8-diazabicycloundecen-7-ene (472mg, 3.10mmol, 0.46mL, Shaoyuan) was added, and the reaction was stirred for 3 hours. 30mL of water and 50mL of ethyl acetate were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (50 mL. times.2), the organic phases were combined, 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 C to give the objective compound 1j (396mg, yield: 45.9%).

The tenth step

(5aR) -3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -11-oxo-5 a,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 1k

Under a nitrogen atmosphere, 2-fluoro-6-hydroxyphenylboronic acid (168mg, 1.07mmol, Shanghai Haohnhong biomedical science and technology Co., Ltd.), compound 1j (393mg, 721.0. mu. mol), disodium hydrogen phosphate dodecahydrate (775mg, 2.16mmol), and tetratriphenylphosphine palladium (84mg, 72.69. mu. mol) were added to a mixed solvent of 30mL of water and 1, 4-dioxane (V/V ═ 1:5), and the mixture was heated to 95 ℃ for reaction for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved in 50mL of dichloromethane, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D to give the objective compound 1k (383mg, yield: 85.5%).

The eleventh step

(5aR) -3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 1l

Compound 1k (383mg, 617.1. mu. mol) was dissolved in 10mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to a reaction solution pH of more than 7, 100mL of dichloromethane was added thereto, the mixture was separated, the aqueous phase was extracted with dichloromethane (30 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 1l (335mg, yield: 104.2%) which was used in the next reaction without further purification.

The twelfth step

Compound 1L (335mg, 643.5. mu. mol) was dissolved in 30mL of dichloromethane, cooled to 0 ℃, triethylamine (365mg, 3.60mmol, 0.5mL) was added, acryloyl chloride (87mg, 961.2. mu. mol, 78. mu.L) was added dropwise, and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in 30mL of methanol, followed by addition of sodium hydrogencarbonate (250mg, 2.97mmol), heating to 60 ℃ and stirring for reaction for 1 hour. Cooling the reaction solution to room temperature, filtering, concentrating the filtrate under reduced pressure, purifying the residue with silica gel column chromatography using eluent system A, and performing high performance liquid chromatography (column: Boston Phlex Prep C185 μm 30 x 150 mm; mobile phase: A-water (10mmol NH)₄HCO₃): b-acetonitrile 30% -50% B (15min), flow rate: 30mL/min) to obtain the objective compound 1(209mg, yield: 56.5%).

MS m/z(ESI):575.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.15(s,1H),8.35-8.36(m,1H),7.24(q,1H),7.17(d,1H),6.79-6.91(m,1H),6.70(d,1H),6.66(t,1H),6.22(dd,1H),5.78(dd,1H),4.80-4.92(m,2H),4.30-4.61(m,3H),4.01-4.10(m,1H),3.65-3.84(m,2H),3.38-3.45(m,1H),2.65-2.80(m,1H),1.90-1.94(m,3H),1.06(d,3H),0.92-0.95(m,3H)。

Thirteenth step

Compound 1(209mg, 0.364mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IF,20 × 250mm,5 μm; mobile phase: n-hexane: ethanol ═ 50/50, flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the objective compounds 1-1(90mg) and 1-2(95 mg).

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

chiral HPLC analysis retention time 4.277 min, chiral purity: 100% (chromatographic column: CHIRALPAK IF 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.15(s,1H),8.35(d,1H),7.24(q,1H),7.17(d,1H),6.79-6.91(m,1H),6.70(d,1H),6.66(t,1H),6.22(dd,1H),5.78(dd,1H),4.82-4.91(m,2H),4.29-4.62(m,3H),4.02-4.08(m,1H),3.66-3.84(m,2H),3.38-3.42(m,1H),2.65-2.71(m,1H),1.93(s,3H),1.06(d,3H),0.92(d,3H)。

Single configuration Compounds 1-2 (longer Retention time)

Chiral HPLC analysis retention time 7.574 minutes, chiral purity: 98.3% (column: CHIRALPAK IF 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.15(s,1H),8.35(d,1H),7.24(q,1H),7.17(d,1H),6.79-6.91(m,1H),6.70(d,1H),6.66(t,1H),6.22(dd,1H),5.78(dd,1H),4.80-4.92(m,2H),4.30-4.64(m,3H),4.01-4.10(m,1H),3.65-3.87(m,2H),3.40-3.45(m,1H),2.75-2.80(m,1H),1.90(s,3H),1.06(d,3H),0.94(d,3H)。

Examples 2, 2-1, 2-2

(5aR,8S) -7-acryloyl-3-fluoro-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-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 2

(12S,5aR,8S) -7-acryloyl-3-fluoro-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-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 2-1

(12R,5aR,8S) -7-acryloyl-3-fluoro-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-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 2-2

The title compound 2(450mg) was obtained by replacing the tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate, which is the starting material in the eighth step, with tert-butyl (2S,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate, prepared by a known method "Journal of medical Chemistry,2020,63(9), 4468-4483", using the synthetic route of example 1.

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.13(s,1H),8.35(d,1H),7.24(q,1H),7.15(d,1H),6.81-6.91(m,1H),6.71(d,1H),6.66(t,1H),6.22(dd,1H),5.75(dd,1H),4.79-4.97(m,2H),4.45-4.64(m,2H),4.10-4.34(m,3H),3.30-3.74(m,1H),2.58-2.82(m,1H),1.87-1.95(m,3H),1.15-1.24(m,3H),1.04-1.07(m,3H),0.91-0.96(m,3H)。

First step of

Compound 2(450mg, 0.764mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IC,5.0cm i.d. × 25cm L,10 μm; mobile phase: methanol ═ 100%, flow rate: 30mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the objective compound 2-1(201mg)/2-2(170 mg).

Single configuration Compound 2-1 (longer Retention time)

Chiral HPLC analysis retention time 18.139 minutes, chiral purity: 99.7% (column: CHIRALPAK IC 250X 4.6mm, 5 μm; mobile phase: A- (methanol: ethanol: 1): B-n-hexane: 40/60, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.10(s,1H),8.35(d,1H),7.24(q,1H),7.15(d,1H),6.80-6.91(m,1H),6.70(d,1H),6.66(t,1H),6.22(dd,1H),5.75(dd,1H),4.81-4.88(m,2H),4.45-4.64(m,2H),4.28-4.34(m,3H),3.30-3.74(m,1H),2.60-2.65(m,1H),1.95(d,3H),1.16-1.24(m,3H),1.06(d,3H),0.92(d,3H)。

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

chiral HPLC analysis retention time 8.693 minutes, chiral purity: 100% (column: CHIRALPAK IC 250X 4.6mm, 5 μm; mobile phase: A- (methanol: ethanol: 1): B-n-hexane: 40/60, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.11(s,1H),8.35(d,1H),7.24(q,1H),7.15(d,1H),6.81-6.91(m,1H),6.71(d,1H),6.66(t,1H),6.22(dd,1H),5.75(dd,1H),4.82-4.90(m,2H),4.46-4.64(m,2H),4.10-4.35(m,3H),3.30-3.74(m,1H),2.78-2.82(m,1H),1.87(s,3H),1.15-1.21(m,3H),1.06(d,3H),0.95(d,3H)。

Examples 3, 3-1, 3-2

(5aR) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 3(12S,5aR) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 3-1

(12R,5aR) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 3-2

First step of

(R) -3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -11-oxo-5 a,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 3a

Under a nitrogen atmosphere, 2-fluorobenzeneboronic acid (206mg, 1.47mmol, shaoyuan), compound 1j (534mg, 979.8 μmol), disodium hydrogenphosphate dodecahydrate (1.05g, 2.93mmol), and tetratriphenylphosphine palladium (113mg, 97.7 μmol) were added to a mixed solvent of 24mL of water and 1, 4-dioxane (V/V ═ 1:5), and heated to 95 ℃ for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure, the residue was dissolved in 100mL of dichloromethane and filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3a (854mg) which was used in the next reaction without further purification.

Second step of

(R) -3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 3b

Compound 3a (854mg, 1.41mmol) was dissolved in 15mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction was concentrated under reduced pressure, a saturated aqueous solution of sodium bicarbonate was added to the residue until the reaction solution had a pH of more than 7, 100mL of dichloromethane was added thereto, the mixture was separated, the aqueous phase was extracted with dichloromethane (30 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 3b (788mg) which was used in the next reaction without further purification.

The third step

(5aR) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 3

Compound 3b (788mg, 1.56mmol) was dissolved in 30mL of dichloromethane, cooled to 0 deg.C, triethylamine (546mg, 5.39mmol, 0.75mL) was added, acryloyl chloride (140mg, 1.54mmol, 0.125mL) was added dropwise, and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D and then by high performance liquid chromatography (column: Boston Phlex Prep C185. mu.m 30 x 150 mm; mobile phase: A-water (10mmol NH)₄HCO₃): b-acetonitrile 35% -55% B (15min), flow rate: 30mL/min) to obtain the objective compound 1(280mg, yield: 32.1%).

MS m/z(ESI):559.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.41(d,1H),7.50-7.54(m,1H),7.25-7.33(m,2H),7.17-7.20(m,2H),6.79-6.91(m,1H),6.22(dd,1H),5.78(dd,1H),4.80-4.93(m,2H),4.31-4.59(m,3H),3.65-4.04(m,3H),3.41-3.46(m,1H),2.68-2.81(m,1H),1.93-1.96(d,3H),1.07(d,3H),0.95-0.97(m,3H)。

The fourth step

(12S,5aR) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 3-1

Compound 3(280mg, 0.502mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IC,20 × 250 mm; mobile phase: n-hexane: ethanol ═ 50/50, flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the target compound 3-1(125mg)/3-2(140 mg).

Single configuration compound 3-1 (shorter retention time):

chiral HPLC analysis retention time 5.917 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):559.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.41(d,1H),7.50-7.54(m,1H),7.25-7.34(m,2H),7.17-7.20(m,2H),6.79-6.91(m,1H),6.22(dd,1H),5.78(dd,1H),4.82-4.91(m,2H),4.31-4.59(m,3H),3.66-4.04(m,3H),3.42-3.46(m,1H),2.71(qant,1H),1.97(s,3H),1.07(d,3H),0.96(d,3H)。

Single configuration compound 3-2 (longer retention time):

chiral HPLC analysis retention time 8.400 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):559.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.40(d,1H),7.50-7.54(m,1H),7.25-7.33(m,2H),7.17-7.20(m,2H),6.79-6.91(m,1H),6.22(dd,1H),5.78(dd,1H),4.80-4.93(m,2H),4.31-4.65(m,3H),3.65-4.10(m,3H),3.42-3.46(m,1H),2.80(qant,1H),1.93(s,3H),1.07(d,3H),0.96(d,3H)。

Examples 4, 4-1, 4-2

(5aR,8S) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 4

(12S,5aR,8S) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 4-1

(12R,5aR,8S) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 4-2

Using the synthetic route of example 1, the starting material tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate of the eighth step was replaced with tert-butyl (2S,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by a well-known method "Journal of medical Chemistry,2020,63(9), 4468-4483") and the starting material 2-fluoro-6-hydroxyphenylboronic acid of the tenth step was replaced with 2-fluorophenylboronic acid to give the title compound 4(398 mg).

MS m/z(ESI):573.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.39(d,1H),7.49-7.54(m,1H),7.24-7.33(m,2H),7.17-7.20(m,2H),6.80-6.92(m,1H),6.15-6.24(m,1H),5.73-5.78(m,1H),4.81-4.89(m,2H),4.45-4.66(m,2H),4.05-4.37(m,3H),3.30-3.76(m,1H),2.63-2.85(m,1H),1.96-1.98(m,3H),1.15-1.22(m,3H),1.06-1.08(m,3H),0.95-0.97(m,3H)。

First step of

Compound 4(398mg, 0.695mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IC,20 × 250 mm; mobile phase: n-hexane: ethanol ═ 80/20, flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the objective compound (196mg,198 mg).

Single configuration compound (shorter retention time):

chiral HPLC analysis retention time 15.394 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 80/20, flow rate: 1.0 mL/min).

MS m/z(ESI):573.4[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.39(d,1H),7.49-7.54(m,1H),7.24-7.34(m,2H),7.17-7.20(m,2H),6.80-6.92(m,1H),6.15-6.24(m,1H),5.73-5.78(m,1H),4.83-4.89(m,2H),4.43-4.65(m,2H),4.09-4.38(m,3H),3.34-3.76(m,1H),2.61-2.68(m,1H),1.97(d,3H),1.19(dd,3H),1.06(d,3H),0.96(d,3H)。

Single configuration compound (longer retention time):

chiral HPLC analysis retention time 19.150 minutes, chiral purity: 99.7% (chromatographic column: CHIRALPAK IG 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 80/20, flow rate: 1.0 mL/min).

MS m/z(ESI):573.4[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.39(d,1H),7.49-7.54(m,1H),7.24-7.33(m,2H),7.17-7.20(m,2H),6.81-6.92(m,1H),6.15-6.24(m,1H),5.73-5.78(m,1H),4.82-4.89(m,2H),4.46-4.65(m,2H),4.11-4.37(m,3H),3.30-3.76(m,1H),2.81-2.86(m,1H),1.90(s,3H),1.15-1.21(dd,3H),1.07(d,3H),0.97(d,3H)。

Examples 5, 5-1, 5-2

(5aR,8S) -7-acryloyl-2- (2, 6-difluorophenyl) -3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 5

(12R,5aR,8S) -7-acryloyl-2- (2, 6-difluorophenyl) -3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 5-1

(12S,5aR,8S) -7-acryloyl-2- (2, 6-difluorophenyl) -3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 5-2

Using the synthetic route of example 1, the tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate used as the starting material in the eighth step was replaced with tert-butyl (2S,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by a known method "Journal of Medicinal Chemistry,2020,63(9),4468 and 4483") and the 2-fluoro-6-hydroxyphenylboronic acid used as the starting material in the tenth step was replaced with pinacol 2, 6-difluorophenylboronate to give the title compound 5(164 mg).

MS m/z(ESI):591.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.35-8.37(m,1H),7.54-7.60(m,1H),7.16-7.23(m,3H),6.79-6.91(m,1H),6.15-6.23(m,1H),5.73-5.78(m,1H),4.80-4.93(m,2H),4.43-4.65(m,2H),4.14-4.35(m,3H),3.31-3.77(m,1H),2.59-2.81(m,1H),1.86-1.99(m,3H),1.16-1.23(m,3H),1.06-1.07(m,3H),0.89-0.95(m,3H)。

First step (12R,5aR,8S) -7-acryloyl-2- (2, 6-difluorophenyl) -3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 5-1

Compound 5(164mg, 0.284mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IF,20 × 250 mm; mobile phase: n-hexane: isopropanol ═ 70/30, flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the target compound 5-1(40mg)/5-2(42 mg).

Single configuration compound 5-1 (longer retention time):

chiral HPLC analysis retention time 9.190 minutes, chiral purity: 99.7% (column: AY Phenomenex Lux Amylose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol ═ 70/30, flow rate: 1.0 mL/min).

MS m/z(ESI):591.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.36(d,1H),7.54-7.60(m,1H),7.16-7.23(m,3H),6.80-6.92(m,1H),6.15-6.24(m,1H),5.73-5.78(m,1H),4.80-4.93(m,2H),4.43-4.66(m,2H),4.14-4.36(m,3H),3.36-3.77(m,1H),2.79-2.85(m,1H),1.86(s,3H),1.16-1.22(dd,3H),1.06(d,3H),0.94(d,3H)。

Single configuration compound 5-2 (shorter retention time):

chiral HPLC analysis retention time 7.302 minutes, chiral purity: 99.4% (column: AY Phenomenex Lux Amylose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol ═ 70/30, flow rate: 1.0 mL/min).

MS m/z(ESI):591.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.36(d,1H),7.54-7.60(m,1H),7.17-7.23(m,3H),6.79-6.91(m,1H),6.15-6.24(m,1H),5.72-5.78(m,1H),4.85-4.90(m,2H),4.43-4.65(m,2H),4.12-4.35(m,3H),3.27-3.78(m,1H),2.58-2.62(m,1H),1.96(d,3H),1.16-1.23(dd,3H),1.05(d,3H),0.90(d,3H)。

Examples 6, 6-1, 6-2

(R) -7-acryloyl-2- (2, 6-difluorophenyl) -3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 6

(12S,5aR) -7-acryloyl-2- (2, 6-difluorophenyl) -3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 6-1

(12R,5aR) -7-acryloyl-2- (2, 6-difluorophenyl) -3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 6-2

Using the synthetic route of example 1, the starting material 2-fluoro-6-hydroxyphenylboronic acid from the tenth step was replaced with pinacol 2, 6-difluorophenylboronate to give the title compound 6(126 mg).

MS m/z(ESI):577.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.36(d,1H),7.51-7.61(m,1H),7.16-7.23(m,3H),6.78-6.90(m,1H),6.19-6.23(m,1H),5.76-5.79(m,1H),4.82-4.95(m,2H),4.33-4.57(m,3H),3.73-4.03(m,3H),3.30-3.49(m,1H),2.65-2.81(m,1H),1.90-1.94(m,3H),1.06-1.07(m,3H),0.91-0.95(m,3H)。

First step of

Compound 6(126mg, 0.502mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK ID,20 × 250 mm; mobile phase: n-hexane: ethanol ═ 50/50, flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the target compound 6-1(30mg)/6-2(30 mg).

Single configuration compound 6-1 (shorter retention time):

chiral HPLC analysis: retention time 5.618 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK ID 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):577.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.36(d,1H),7.55-7.61(m,1H),7.16-7.23(m,3H),6.78-6.90(m,1H),6.19-6.23(m,1H),5.77-5.79(m,1H),4.85-4.93(m,2H),4.33-4.61(m,3H),3.67-4.03(m,3H),3.24-3.47(m,1H),2.65-2.71(m,1H),1.94(s,3H),1.06(d,3H),0.91(d,3H)。

Single configuration compound 6-2 (longer retention time):

chiral HPLC analysis: retention time 6.748 minutes, chiral purity: 98.1% (column: CHIRALPAK ID 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):577.3[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.37(d,1H),7.55-7.61(m,1H),7.17-7.23(m,3H),6.78-6.90(m,1H),6.19-6.23(m,1H),5.77-5.79(m,1H),4.82-4.95(m,2H),4.34-4.60(m,3H),3.67-4.03(m,3H),3.30-3.49(m,1H),2.76-2.81(m,1H),1.91(s,3H),1.07(d,3H),0.94(d,3H)。

Examples 7, 7-1, 7-2

(5aR,8S) -7-acryloyl-3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 7

(12S,5aR,8S) -7-acryloyl-3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 7-1

(12R,5aR,8S) -7-acryloyl-3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 7-2

First step of

6, 6-dichloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4,5,7(1H,3H,6H,8H) -tetrone 7a

Compound 1e (9.03g, 27.50mmol) was added to 100mL of 1, 4-dioxane, and sulfuryl chloride (11.168g, 82.75mmol, 6.7mL) was added, and the reaction was heated to 60 ℃ and stirred for 2 hours. The reaction solution was poured into 1L of ice water, stirred for 10 minutes, filtered, the filter cake washed with water and dried to give the title compound 7a (13.1g), which was used in the next step without purification.

Second step of

6-chloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidine-2, 4(1H,3H) -dione 7b

Compound 7a (13.1g, 32.97mmol) was added to 80mL of acetic acid, zinc powder (4.3g, 65.75mmol) was added, and the reaction was heated to 90 ℃ and stirred for 2 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in methanol and then filtered, and the filtrate was concentrated under reduced pressure and then stirred with 500mL of water for 10 minutes. Filtration, washing of the filter cake with water and drying gave the title compound 7b (12.04 g).

The third step

4,5,6, 7-tetrachloro-1- (2-isopropyl-4-methylpyridin-3-yl) pyrido [2,3-d ] pyrimidin-2 (1H) -one 7c

Compound 7b (10.15g, 27.97mmol) was added to 200mL acetonitrile, phosphorus oxychloride (20.625g, 134.51mmol, 12.5mL) and N, N-diisopropylethylamine (18.225g, 141.01mmol,25mL) were added, and the reaction was stirred at 80 ℃ for 1 hour. The reaction was cooled to room temperature and concentrated under reduced pressure to give the title compound 7c (34g) which was used directly in the next reaction without further purification.

The fourth 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 7d

Compound 7c (23g, 55.01mmol) was dissolved in 150mL of dichloromethane, cooled to 0 ℃ and added with the compound tert-butyl (2S,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (5g, 21.71mmol, prepared by the well-known method "Journal of Medicinal Chemistry,2020,63(9),4468 and 4483"), and N, N-diisopropylethylamine (10.206g, 78.96mmol,14mL) was added and stirred for reaction for 1 hour. 100mL of saturated aqueous sodium bicarbonate solution was added, the mixture was stirred for 15 minutes to quench, the aqueous phase was separated, extracted with dichloromethane (100 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 7d (19.1g, yield: 56.7%) which was used directly in the next reaction without further purification.

MS m/z(ESI):611.0[M+1]。

The fifth step

(5aR,8S) -2, 3-dichloro-12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-11-oxo-5 a,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 7e

Compound 7d (19.1g, 31.21mmol) was dissolved in 150mL of tetrahydrofuran, 1, 8-diazabicycloundecen-7-ene (10.18g, 66.86mmol, 10mL) was added, and the reaction was stirred for 3 hours. 100mL of water and 150mL of ethyl acetate were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (100 mL. times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system D to give the objective compound 7e (8.2g, yield: 45.6%).

MS m/z(ESI):575.1[M+1]。

The sixth step

(5aR,8S) -3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-11-oxo-5 a,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 7f

Under a nitrogen atmosphere, 2-fluorobenzeneboronic acid (0.485g,3.4663mmol), compound 7e (1.33g,2.3111mmol), disodium hydrogenphosphate dodecahydrate (2.48g,6.9246mmol), and tetratriphenylphosphine palladium (267mg, 231.0569. mu. mol) were added to 60mL of water and 1, 4-dioxane (V/V ═ 1:5), and heated to 100 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was dissolved in 300mL of methylene chloride and then filtered, and the filtrate was concentrated under reduced pressure to give the target compound 7f (2g, yield: > 100%) which was used directly in the next reaction without further purification.

Seventh step

(5aR,8S) -3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 7g

Compound 7f (2g,3.149mmol) was dissolved in 20mL of dichloromethane, 4mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and 30mL of a saturated aqueous sodium bicarbonate solution and 50mL of dichloromethane were added to the residue to dissolve the residue, followed by liquid separation, the aqueous phase was extracted with dichloromethane (50 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 7g of the objective compound (1.686g, yield: 100.0%).

Eighth step

Compound 7g (1.686g, 3.151mmol) was added to 50mL of dichloromethane, cooled to 0 deg.C, triethylamine (0.729g, 7.204mmol, 1mL) was added, acryloyl chloride (291mg, 3.215mmol, 0.26mL) was added dropwise, and the reaction was stirred for 1 hour. Adding 50mL of saturated aqueous sodium bicarbonate solution for quenching, separating, extracting an aqueous phase with dichloromethane (50mL multiplied by 2), combining organic phases, drying the organic phases with anhydrous sodium sulfate, filtering, concentrating a filtrate under reduced pressure, purifying a residue by silica gel column chromatography with an eluent system D, and purifying by high performance liquid chromatography (a chromatographic column: Boston Phlex Prep C185. mu.m 30 multiplied by 150 mm; a mobile phase: A-water (10mmol ammonium bicarbonate): B-acetonitrile 35% -55% B (15min), a flow rate: 30mL/min) to obtain the target compound 7(600mg, yield: 32.3%).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.35(d,1H),7.46-7.50(m,1H),7.22-7.29(m,2H),7.13-7.17(m,2H),6.80-6.93(m,1H),6.16-6.23(m,1H),5.73-5.79(m,1H),4.84-4.94(m,2H),4.46-4.64(m,2H),4.33-4.37(m,1H),4.01-4.19(m,2H),3.26-3.72(m,1H),2.62-2.82(m,1H),1.91-1.97(m,3H),1.15-1.22(m,3H),1.05-1.07(m,3H),0.94-0.95(m,3H)。

The ninth step

Compound 7(600mg, 0.695mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IF,20 × 250 mm; mobile phase: n-hexane: isopropanol ═ 80/20, flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the target compound 7-1(250mg)/7-2(248 mg).

Single configuration compound 7-1 (shorter retention time):

chiral HPLC analysis retention time 7.929 minutes, chiral purity: 98.4% (column: AY Phenomenex Lux Amylose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol ═ 70/30, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.35(d,1H),7.46-7.50(m,1H),7.22-7.29(m,2H),7.12-7.16(m,2H),6.80-6.93(m,1H),6.16-6.23(m,1H),5.73-5.78(m,1H),4.84-4.92(m,2H),4.46-4.65(m,2H),4.33-4.37(m,1H),4.01-4.19(m,2H),3.31-3.72(m,1H),2.62-2.69(m,1H),1.96(s,3H),1.16-1.23(dd,3H),1.05(d,3H),0.94(d,3H)。

Single configuration compound 7-2 (longer retention time):

chiral HPLC analysis retention time 10.020 minutes, chiral purity: 99.8% (column: AY Phenomenex Lux Amylose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol ═ 70/30, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.35(d,1H),7.46-7.50(m,1H),7.22-7.29(m,2H),7.14-7.16(m,2H),6.82-6.93(m,1H),6.16-6.23(m,1H),5.73-5.79(m,1H),4.84-4.94(m,2H),4.47-4.65(m,2H),4.34-4.37(m,1H),3.97-4.21(m,2H),3.26-3.70(m,1H),2.79-2.82(m,1H),1.91(s,3H),1.15-1.21(dd,3H),1.06(d,3H),0.94(d,3H)。

Examples 8, 8-1, 8-2

(R) -7-acryloyl-3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 8(12S, R) -7-acryloyl-3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomers 8-1

(12R, R) -7-acryloyl-3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer-8-2

The title compound 8(520mg) was obtained by substituting the fourth-step starting material, tert-butyl (2S,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate, for the compound, tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate (biuret drug), using the synthetic route of example 7.

MS m/z(ESI):575.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.35-8.36(m,1H),7.46-7.50(m,1H),7.22-7.29(m,2H),7.13-7.17(m,2H),6.80-6.92(m,1H),6.20-6.23(m,1H),5.76-5.79(m,1H),4.83-4.96(m,2H),4.55-4.61(m,1H),4.36-4.49(m,1H),4.28-4.29(m,1H),4.03-4.06(m,1H),3.66-3.78(m,2H),3.34-3.38(m,1H),2.68-2.80(m,1H),1.93-1.96(m,3H),1.06-1.07(m,3H),0.93-0.95(m,3H)。

First step of

(12S, R) -7-acryloyl-3-chloro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -5,5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer-8-1

Compound 8(520mg, 0.904mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK IG 20 × 250mm,5 μm; mobile phase: n-hexane: ethanol ═ 50/50, flow rate: 20mL/min), and the corresponding fractions were collected and concentrated under reduced pressure to give the objective compound 8-1(207mg)/8-2(192 mg).

Single configuration compound 8-1 (shorter retention time):

chiral HPLC analysis retention time 5.674 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.35-8.36(m,1H),7.46-7.48(m,1H),7.14-7.28(m,4H),6.79-6.90(m,1H),6.19-6.22(m,1H),5.76-5.78(m,1H),4.88-4.93(m,2H),4.54-4.62(m,1H),4.35-4.49(m,1H),4.27-4.28(m,1H),4.02-4.11(m,1H),3.65-3.77(m,2H),3.39-3.49(m,1H),2.66-2.75(m,1H),1.90-1.98(m,3H),1.05-1.07(m,3H),0.93-0.94(m,3H)。

Single configuration compound 8-2 (longer retention time):

chiral HPLC analysis retention time 7.708 minutes, chiral purity: 100% (chromatographic column: CHIRALPAK IG 150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.0[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.34-8.35(m,1H),7.45-7.49(m,1H),7.22-7.28(m,2H),7.13-7.16(m,2H),6.79-6.91(m,1H),6.19-6.23(m,1H),5.76-5.79(m,1H),4.82-4.96(m,2H),4.57-4.61(m,1H),4.35-4.49(m,1H),4.27-4.29(m,1H),4.01-4.05(m,1H),3.66-3.77(m,2H),3.37-3.50(m,1H),2.74-2.80(m,1H),1.91-1.95(m,3H),1.05-1.07(m,3H),0.93-0.94(m,3H)。

Example 9

(5aR,8R) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 9

Using the synthetic route of example 1, the starting material tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate of the eighth step was replaced with tert-butyl (2R,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (beidelyao) and the starting material 2-fluoro-6-hydroxyphenylboronic acid of the tenth step was replaced with 2-fluorophenylboronic acid to give the title compound 9(620 mg).

MS m/z(ESI):573.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.38-8.40(m,1H),7.49-7.54(m,1H),7.24-7.33(m,2H),7.16-7.20(m,2H),6.79-6.80(m,1H),6.22-6.25(m,1H),5.76-5.79(m,1H),4.90-4.93(m,1H),4.62-4.71(m,1H),4.40-4.54(m,3H),4.09-4.28(m,3H),2.64-2.80(m,1H),1.92-1.96(m,3H),1.23-1.24(m,3H),1.05-1.07(m,3H),0.94-0.97(m,3H)。

Example 10

(5aR,8R) -7-acryloyl-3-fluoro-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-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 10

The title compound 10(490mg) was obtained by substituting the starting material tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate from the eighth step with tert-butyl (2R,5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (beidelyao) using the synthetic route of example 1.

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.10-10.11(m,1H),8.34-8.35(m,1H),7.21-7.26(m,1H),7.14-7.15(m,1H),6.64-6.80(m,3H),6.22-6.25(m,1H),5.76-5.79(m,1H),4.87-4.90(m,1H),4.63-4.72(m,1H),4.41-4.54(m,3H),4.09-4.22(m,3H),2.61-2.78(m,1H),1.88-1.95(m,3H),1.19-1.24(m,3H),1.05-1.07(m,3H),0.90-0.96(m,3H)。

Example 11

(5aS,8S) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 11

Using the synthetic route of example 1, the starting material tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate from the eighth step was replaced with tert-butyl (2S,5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by the well-known method "WO 2020/6018,2020, A1, 740-741") and the starting material 2-fluoro-6-hydroxyphenylboronic acid from the tenth step was replaced with 2-fluorophenylboronic acid to give the title compound 11(480 mg).

MS m/z(ESI):573.1[M+1]。

¹H NMR(500MHz,CDCl₃)δ8.52-8.55(m,1H),7.35-7.41(m,1H),7.11-7.25(m,4H),6.51-6.68(m,2H),5.87-5.90(m,1H),5.20-5.25(m,1H),4.97-4.99(m,1H),4.30-4.53(m,4H),3.83-3.86(m,1H),3.65-3.68(m,1H),2.71-2.83(m,1H),2.05-2.09(m,3H),1.37-1.39(m,3H),1.24-1.25(m,3H),1.06-1.10(m,3H)。

Example 12

(5aS,8S) -7-acryloyl-3-fluoro-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-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 12

Using the synthetic route of example 1, the starting material tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate from the eighth step was replaced with the compound tert-butyl (2S,5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by the well-known method "WO 2020/6018,2020, A1, 740-741") to give the title compound 12(360 mg).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,CDCl₃)δ9.24-9.29(m,1H),8.63-8.65(m,1H),7.21-7.25(m,2H),6.48-6.69(m,4H),5.88-5.90(m,1H),5.20-5.25(m,1H),5.02-5.05(m,1H),4.36-4.56(m,4H),3.84-3.88(m,1H),3.50-3.65(m,1H),2.80-2.84(m,1H),2.10-2.14(m,3H),1.37-1.40(m,3H),1.27-1.29(m,3H),1.10-1.12(m,3H)。

Example 13

(5aS,8R) -7-acryloyl-3-fluoro-2- (2-fluorophenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -8-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxa-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 13

Using the synthetic route of example 1, the starting material tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate from the eighth step was replaced with tert-butyl (2R,5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared using the well-known method "WO 2019/215203,2019, A1, Page 44") and the starting material 2-fluoro-6-hydroxyphenylboronic acid from the tenth step was replaced with 2-fluorophenylboronic acid to give the title compound 13(250 mg).

MS m/z(ESI):573.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ8.39(d,1H),7.49-7.54(m,1H),7.20-7.33(m,2H),73.17-7.19(m,2H),6.80-6.92(m,1H),6.15-6.23(m,1H),5.73-5.79(m,1H),4.80-4.92(m,2H),4.46-4.65(m,2H),4.10-4.37(m,3H),3.35-3.76(m,1H),2.56-2.85(m,1H),1.90-1.98(m,3H),1.15-1.26(m,3H),1.06-1.08(m,3H),0.95-0.98(m,3H)。

Example 14

(5aS,8R) -7-acryloyl-3-fluoro-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-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 14

The title compound 14(310mg) was prepared using the synthetic route of example 1 substituting the starting material tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate from the eighth step for tert-butyl compound (2R,5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared using the well-known method "WO 2019/215203,2019, a1, Page 44").

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.11(s,1H),8.35-8.36(m,1H),7.15-7.25(m,2H),6.68-6.85(m,1H),6.64-6.72(m,2H),6.15-6.23(m,1H),4.84-4.88(m,2H),4.10-4.64(m,5H),3.55-3.74(m,1H),3.15-3.29(m,1H),2.61-2.81(m,1H),1.87-1.96(m,3H),1.05-1.08(m,3H),1.01-1.04(m,3H),0.92-0.96(m,3H)。

Example 15

(9S) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15

(12S,5aS,9S) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-1

(12R,5aS,9S) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-2

(12S,5aR,9S) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-3

(12R,5aR,9S) -7-acryloyl-3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-4

First step of

(S)-N¹,N²-dibenzylpropane-1, 2-diamine 15b

Dissolving (2S) -propane-1, 2-diamine dihydrochloride 15a (20g, 136.0mmol, Haohnheng biological (Leyao), in 200mL of methanol, adding diisopropylethylamine (36.1g, 219.3mmol), cooling to 0 ℃, dropwise adding benzaldehyde (29g, 273.2mmol), heating to room temperature, stirring for reaction for 2 hours, cooling to 0 ℃, adding sodium borohydride (10g, 264.3mmol) in portions, heating to room temperature, reacting for 2 hours, adding 1M hydrochloric acid until the reaction pH is 7, filtering, concentrating the filtrate under reduced pressure, adding 500mL of ethyl acetate and 300mL of water, adding sodium carbonate until the aqueous phase pH is 9, separating, extracting the aqueous phase with ethyl acetate (150 mL. times.2), extracting with a mixed solvent (200 mL. times.2) of dichloromethane and methanol (V/V. times.10: 1), combining the organic phases, drying with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography with eluent system A to give the title compound 15b (21.7g, yield: 62.7%).

Second step of

(6S) -1, 4-dibenzyl-6-methylpiperazine-2-carboxylic acid methyl ester 15c

Compound 15b (10g, 39.3mmol) was dissolved in 50mL of toluene, triethylamine (10.7g, 105.7mmol) was added, the mixture was heated to 40 ℃ and a solution of ethyl 2, 3-dibromopropionate (11.2g, 43.1mmol) in 50mL of toluene was added dropwise, and the reaction was stirred at 80 ℃ for 6 hours. The reaction solution was cooled to room temperature, 300mL of ethyl acetate and 150mL of water were added, liquid separation was performed, the aqueous phase was extracted with ethyl acetate (150 mL. times.1), the organic phases were combined, 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 A to give the title compound 15c (6.78g, yield: 48.9%).

The third step

((6S) -1, 4-dibenzyl-6-methylpiperazin-2-yl) methanol 15d

Compound 15c (5.6g, 15.88mmol) was dissolved in 200mL tetrahydrofuran, cooled to 0 deg.C, and lithium aluminum hydride (645mg, 19.01mmol, 19mL) was added dropwise and the reaction stirred for 1 hour after the addition. 0.6mL of water, 0.6mL of a 15% aqueous solution of sodium hydroxide and 1.8mL of water were successively added dropwise, and anhydrous sodium sulfate was further added thereto and stirred for 10 minutes, followed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound 15d (5.12g, yield: > 100%).

The fourth step

((6S) -6-methylpiperazin-2-yl) methanol 15e

Compound 15d (6.2g, 19.97mmol) was dissolved in 70mL of methanol under a hydrogen atmosphere, 10% palladium on carbon (1.78g, 50% water content) was added, and the reaction was stirred overnight. Filtration and concentration of the filtrate under reduced pressure gave the title compound 15e (2.6g, yield: 100%).

The fifth step

(5S) -3- (hydroxymethyl) -5-methylpiperazine-1-carboxylic acid tert-butyl ester 15f

Compound 15e (2.61g, 20.04mmol) was dissolved in 50mL of methanol, cooled to 0 ℃, triethylamine (7.29g, 72.04mmol, 10mL) was added, di-tert-butyl dicarbonate (9.7g, 44.44mmol) was added, and after the addition, the mixture was warmed to room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and then 100mL of a mixed solvent of water and ethanol (V/V ═ 1:1) was added to dissolve the reaction mixture, and sodium hydroxide (2.4g, 460.04mmol) was further added thereto, and the reaction mixture was heated to 90 ℃ and stirred for 16 hours. The reaction was cooled to room temperature and concentrated under reduced pressure, 1N hydrochloric acid was added to the residue to give a reaction solution having a pH of about 10, followed by extraction with methylene chloride (100 mL. times.3), the organic phases were combined, 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 A to give the title compound 15f (3.2g, yield: 69.30%).

The sixth step

(5S) -4- (5, 7-dichloro-6-fluoro-1- (2-isopropyl-4-methylpyridin-3-yl) -2-oxo-1, 2-dihydropyrido [2,3-d ]

Pyrimidin-4-yl) -3- (hydroxymethyl) -5-methylpiperazine-1-carboxylic acid tert-butyl ester 15g

Compound 1h (3.8g,9.46mmol) was dissolved in 50mL of dichloromethane, cooled to 0 deg.C and then compound 15f (1.2g, 5.21mmol) and diisopropylethylamine (2.916g, 22.56mmol, 4mL) were added and the reaction stirred for 3 h. Saturated aqueous sodium bicarbonate solution was added thereto, stirred for 30 minutes, separated, the aqueous phase was extracted with dichloromethane (50 mL. times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 15g (3.93g, yield: 69.8%) of the title compound.

Seventh step

(9S) -2-chloro-3-fluoro-12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-11-oxo-5 a,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 15H

15g (3.93g, 6.60mmol) of the compound was dissolved in tetrahydrofuran, and 1, 8-diazabicycloundecen-7-ene (4.072g, 26.74mmol, 4mL) was added to stir the reaction for 16 hours. To the reaction solution were added 50mL of water and 50mL of ethyl acetate, the mixture was completely dissolved, liquid was separated, the aqueous phase was extracted with ethyl acetate (50mL × 2), the organic phases were combined, 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 D to give the title compound 15h (155mg, yield: 4.2%).

Eighth step

(9S) -3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-11-oxo-5 a,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 15i

Compound 15h (155mg, 0.277mmol), 2-fluoro-6-hydroxyphenylboronic acid (64mg, 0.41mmol), disodium hydrogenphosphate dodecahydrate (300mg, 0.837mmol) and tetratriphenylphosphine palladium (32mg, 27.69 μmol) were added to a mixed solvent of 12mL of water and 1, 4-dioxane (V/V ═ 1:5) under a nitrogen atmosphere, and heated to 95 ℃ for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved in 100mL of methylene chloride and then filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography in developed system A to give the title compound 15i (140mg, yield: 79.5%).

The ninth step

(9S) -3-fluoro-2- (2-fluoro-6-hydroxyphenyl) -12- (2-isopropyl-4-methylpyridin-3-yl) -9-methyl-5, 5a,6,7,8, 9-hexahydro-4-oxo-1, 7,9a,10, 12-pentazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15j

Compound 15i (140mg, 0.22mmol) was dissolved in 10mL of dichloromethane, 2mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogencarbonate was added to the residue to a reaction solution pH of >7, dichloromethane (30 mL. times.3) was added for extraction, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 15j (134mg, yield: > 100%).

The tenth step

Compound 15j (134mg, 0.25mmol) was dissolved in 10mL of dichloromethane, triethylamine (182mg, 1.77mmol, 0.25mL) was added, the mixture was cooled to 0 ℃ and acryloyl chloride (45mg, 0.497mmol, 40. mu.L) was added dropwise and the reaction was stirred for 1 hour. After adding 10mL of saturated aqueous sodium bicarbonate solution and quenching, separating the solution, extracting the aqueous phase with dichloromethane (30 mL. times.2), combining the organic phases, drying over anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, dissolving in 20mL of methanol, adding 250mg of sodium bicarbonate, and heating to 60 ℃ for reaction for 1 hour. The reaction solution was cooled to room temperature, filtered, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography in developed system A to give the title compound 15(80mg, yield: 54.21 mmol).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.11-10.12(m,1H),8.35(d,1H),7.22-7.27(m,1H),7.15-7.16(m,1H),6.74-6.81(m,1H),6.64-6.71(m,2H),6.21-6.27(m,1H),5.77-5.83(m,1H),4.80-4.92(m,2H),4.42-4.72(m,3H),3.97-4.27(m,2H),3.42-3.88(m,1H),2.62-2.78(m,1H),1.88-1.95(m,3H),1.24-1.42(m,3H),1.05-1.09(m,3H),0.91-0.97(m,3H)。

Compound 15(80mg, 0.904mmol) was subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK ID 20 × 250mm, 10 μm; mobile phase: n-hexane: ethanol (+ 0.1% ammonia methanol) ═ 50/50, flow rate: 30mL/min), the corresponding fractions were collected and concentrated under reduced pressure to give target compound 15-2(15.07mg)/15-1(15.93mg) and a mixture, and the resulting mixture was further subjected to chiral preparation (separation conditions: chiral preparation column CHIRALPAK AD 20 × 250mm, 10 μm; mobile phase: n-hexane: ethanol (+ 0.1% ammonia methanol) — 50/50, flow rate: 30mL/min) to give target compound 15-4(10.91mg)/15-3(20.38 mg).

Single configuration compound 15-4:

chiral HPLC analysis retention time 6.138 minutes, chiral purity: 95.4% (column: OZ Phenomenex Lux Cellulose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol ═ 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.11(s,1H),8.35(d,1H),7.24(q,1H),7.15(d,1H),6.80(brs,1H),6.71(d,1H),6.66(t,1H),6.23-6.30(m,1H),5.78(d,1H),4.88-4.92(m,1H),4.69-4.72(m,1H),4.43-4.51(m,3H),3.97-4.23(m,3H),2.61-2.66(m,1H),1.95(s,3H),1.25(s,3H),1.06(d,3H),0.91(d,3H)。

Single configuration compound 15-3:

chiral HPLC analysis retention time 7.416 minutes, chiral purity: 100% (chromatographic column: OZ Phenomenex Lux Cellulose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol: 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.12(s,1H),8.35(d,1H),7.25(q,1H),7.15(d,1H),6.80(brs,1H),6.71(d,1H),6.66(t,1H),6.22-6.26(m,1H),5.77(d,1H),4.88-4.90(m,1H),4.63-4.67(m,1H),4.52-4.55(m,1H),4.41-4.43(m,2H),4.00-4.19(m,3H),2.73-2.78(m,1H),1.88(s,3H),1.25(s,3H),1.06(d,3H),0.96(d,3H)。

Single configuration compound 15-2:

chiral HPLC analysis retention time 21.443 minutes, chiral purity: 94.7% (column: OZ Phenomenex Lux Cellulose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol ═ 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.12(s,1H),8.35(d,1H),7.24(q,1H),7.15(d,1H),6.74-6.81(m,1H),6.71(d,1H),6.66(t,1H),6.22-6.27(m,1H),5.76-5.83(m,1H),4.80-4.92(m,2H),4.56-4.72(m,2H),4.17-4.27(m,1H),3.97-4.10(m,1H),3.75-3.87(m,1H),3.40-3.47(m,1H),2.65-2.71(m,1H),1.94(s,3H),1.39-1.42(m,3H),1.08(d,3H),0.93(d,3H)。

Single configuration compound 15-1:

chiral HPLC analysis retention time 8.421 minutes, chiral purity: 100% (chromatographic column: OZ Phenomenex Lux Cellulose-2150X 4.6mm, 5 μm; mobile phase: n-hexane: ethanol: 50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹H NMR(500MHz,DMSO-d₆)δ10.11(s,1H),8.35(d,1H),7.24(q,1H),7.15(d,1H),6.74-6.81(m,1H),6.71(d,1H),6.66(t,1H),6.22-6.27(m,1H),5.76-5.83(m,1H),4.86-4.92(m,2H),4.59-4.66(m,2H),4.17-4.27(m,1H),3.97-4.11(m,1H),3.75-3.89(m,1H),3.40-3.48(m,1H),2.73-2.78(m,1H),1.90(s,3H),1.39-1.48(m,3H),1.07(d,3H),0.94(d,3H)。

Biological evaluation

Test example 1: experimental biological evaluation of H358 cell ERK phosphorylation inhibition

First, test purpose

This experiment was performed by detecting the inhibitory effect of compounds on ERK phosphorylation in H358 cells, according to IC₅₀Size the compounds of the disclosure were evaluated for their inhibitory effect on the KRAS target (containing the G12C mutation).

Second, Experimental methods

H358 cells (ATCC, CRL-5807) were cultured in RPMI1640(Hyclone, SH30809.01) complete medium containing 10% fetal bovine serum. The first day of the experiment, H358 cells were seeded in 96-well plates at a density of 25,000 cells/well using complete medium, 190. mu.L cell suspension per well, placed at 37 ℃, 5% CO₂The cell culture box was cultured overnight. The following day, 10. mu.L of test compound diluted in a gradient of complete medium at 9 concentration points with a 6-fold gradient starting at 10. mu.M was added to each well, a blank containing 0.5% DMSO was set, and the well plate was placed at 37 ℃ and 5% CO₂The cell culture chamber of (3) was incubated for 3 hours. After 3 hours, the 96-well cell culture plate was removed, the medium was aspirated off, and 200. mu.L of PBS (Shanghai-derived culture) was added to each wellTech Ltd, B320) was washed once. PBS was aspirated, 50. mu.L of lysis buffer (lysis buffer, Cisbio, 64KL1FDF) containing blocking solution (blocking reagent, Cisbio, 64KB1AAC) was added to each well, and the well plates were placed on a shaker and lysed for 30 minutes at room temperature with shaking. After lysis, the mixture was pipetted and mixed, 16. mu.L of lysate was transferred to two HTRF96 well assay plates (Cisbio, 66PL96100) per well, and then 4. mu.L of premixed phospho-ERK1/2 antibody solution (Cisbio, 64AERPEG) or 4. mu.L of premixed total-ERK1/2 antibody solution (Cisbio, 64NRKPEG) was added to each plate. The plate was sealed with a sealing membrane, centrifuged for 1 min in a microplate centrifuge and incubated overnight at room temperature in the dark. On the third day, the fluorescence values emitted at wavelengths of 665nm and 620nm after excitation at 337nm were read using a PHERAstar multifunctional microplate reader (BMG Labtech, S/N471-.

Third, data analysis

IC of inhibitory Activity of Compounds was calculated from Compound concentration and pERK/Total ERK ratio using Graphpad Prism software₅₀See table 3 below for values, results.

TABLE 3 IC inhibition of ERK phosphorylation in H358 cells by compounds of the present disclosure₅₀The value is obtained.

Example numbering	IC₅₀(nM)
		1	10.6
1-1	35.8
		1-2	4.9
2	8.5
		2-1	14.2
2-2	2.6
		3	12
3-1	107.8
		3-2	3.5
5	13.8
		5-1	11
5-2	91.6
		6	10
6-1	61.9
		6-2	4.5
7	4.2
		7-1	12
7-2	1.7
		8	1.9
8-1	14.1
		8-2	0.6
11	58.3
		12	3.2
13	19
		14	11.4
15	0.7
		15-4	6.3
15-3	57.5
		15-2	0.5
15-1	6.6

And (4) conclusion: the compound disclosed by the invention has a good inhibition effect on ERK phosphorylation of H358 cells.

Test example 2: experimental biological evaluation of inhibition of ERK phosphorylation in MIA PaCa-2 cells

First, test purpose

This experiment was performed by detecting the inhibitory effect of compounds on the phosphorylation of MIA PaCa-2 cell ERK, according to IC₅₀Size the compounds of the disclosure were evaluated for their inhibitory effect on the KRAS target (containing the G12C mutation).

Second, Experimental methods

MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in DMEM/HIGH GLUCOSE (GE, SH30243.01) complete medium containing 10% fetal bovine serum and 2.5% horse serum. The first day of experiment, MIA PaCa-2 cells were seeded at a density of 25,000 cells/well in 96-well plates using complete medium, 190. mu.L of cell suspension per well, placed at 37 ℃ with 5% CO₂The cell culture box was cultured overnight. The following day, 10. mu.L of test compound diluted in a gradient of complete medium at 9 concentration points with a 6-fold gradient starting at 10. mu.M was added to each well, a blank containing 0.5% DMSO was set, and the well plate was placed at 37 ℃ and 5% CO₂The cell culture chamber of (2) was incubated for 4 hours. After 4 hours, the 96-well cell culture plate was removed, the medium was aspirated off, and 200. mu.L of PBS (Shanghai culture Biotech Co., Ltd., B320) was added to each well and washed once. PBS was aspirated, 50. mu.L of lysis buffer (lysis buffer, Cisbio, 64KL1FDF) containing blocking solution (blocking reagent, Cisbio, 64KB1AAC) was added to each well, and the well plates were placed on a shaker and lysed for 30 minutes at room temperature with shaking. After lysis, the mixture was pipetted and mixed, 16. mu.L of lysate was transferred to two HTRF96 well assay plates (Cisbio, 66PL96100) per well, and then 4. mu.L of premixed phospho-ERK1/2 antibody solution (Cisbio, 64AERPEG) or 4. mu.L of premixed total-ERK1/2 antibody solution (Cisbio, 64NRKPEG) was added to each plate. The plate was sealed with a sealing membrane, centrifuged for 1 min in a microplate centrifuge and incubated overnight at room temperature in the dark. On the third day, the reaction mixture was measured using a pheasator multifunctional microplate reader (BMG Labtech,S/N471-0361) read the fluorescence values emitted at wavelengths of 665nm and 620nm excited at a wavelength of 337 nm.

Third, data analysis

IC of inhibitory Activity of Compounds was calculated from Compound concentration and pERK/Total ERK ratio using Graphpad Prism software₅₀See table 4 below for values, results.

TABLE 4 IC inhibition of MIA PaCa-2 cell ERK phosphorylation by compounds of the present disclosure₅₀The value is obtained.

And (4) conclusion: the compound disclosed by the invention has a good inhibition effect on the ERK phosphorylation of MIA PaCa-2 cells.

Test example 3: biological evaluation of MIA PaCa-2 cell proliferation experiments

First, test purpose

The inhibitory effect of the compounds of the present disclosure on the KRAS target (containing the G12C mutation) was evaluated by testing the inhibitory effect of the compounds of the present disclosure on the proliferation of MIA PaCa-cells.

Second, Experimental methods

MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in complete medium, i.e., DMEM/HIGH GLUCOSE (GE, SH30243.01) complete medium containing 10% fetal bovine serum and 2.5% horse serum. The first day of experiment, MIA PaCa-2 cells were seeded at a density of 500 cells/well in 96-well plates using complete medium, 90. mu.L of cell suspension per well, placed at 37 ℃ with 5% CO₂The cell culture box was cultured overnight. The following day, 10. mu.L of test compound diluted in a gradient of complete medium at 9 concentration points with 5-fold gradient starting from 10. mu.M was added to each well, a blank containing 0.5% DMSO was set, and the well plate was placed at 37 ℃ and 5% CO₂The cell culture chamber of (2) was cultured for 72 hours. On the fifth day, 96-well cell culture plates were removed and 50. mu.L of each well was added

Luminescence Cell Viability Assay (reagent for detecting Luminescent Cell activity) (Promega, G7573) was left at room temperature for 10 minutes, and then the luminescence signal value was read using a multi-functional microplate reader (PerkinElmer, VICTOR 3).

Third, data analysis

IC of compound inhibitory activity was calculated using Graphpad Prism software₅₀See table 5 below for values, results.

TABLE 5 IC inhibition of MIA PaCa-2 cell proliferation by the compounds of this disclosure₅₀The value is obtained.

Example numbering	IC₅₀(nM)
		1	6.7
1-1	41.9
		1-2	6.8
2	11.5
		2-2	3.5
2-1	40.0
		5	39.3
6	10.3
		6-1	72.2
6-2	8.9
		7-1	61.1
7-2	9.8
		8	11
8-1	75.9
		8-2	11.8
12	41.5
		13	88.2
14	41.8
		15	2.3
15-4	13.4
		15-2	0.3
15-1	45.6

And (4) conclusion: the compound disclosed by the invention has a good inhibition effect on MIA PaCa-2 cell proliferation.

Test example 4: biological evaluation of H358 cell proliferation assay

First, test purpose

The inhibition of KRAS target (containing the G12C mutation) by the compounds of the disclosure was evaluated by testing the proliferation inhibition of H358 cells by the compounds of the disclosure.

Second, Experimental methods

H358 cells (ATCC, CRL-5807) were cultured in complete medium, RPMI1640 medium (Hyclone, SH30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). The first day of the experiment, H358 cells were seeded in 96-well plates at a density of 1500 cells/well using complete medium, 100. mu.L of cell suspension per well, placed at 37 ℃, 5% CO₂The cell culture box was cultured overnight. The following day, 10. mu.L of test compound diluted in a gradient of complete medium at 9 concentration points with 5-fold gradient starting from 10. mu.M was added to each well, a blank containing 0.5% DMSO was set, and the well plate was placed at 37 ℃ and 5% CO₂The cell culture chamber of (2) was cultured for 120 hours. On the seventh day, 96 well cell culture plates were removed and 50. mu.L of each well was added

Third, data analysis

IC of compound inhibitory activity was calculated using Graphpad Prism software₅₀See table 6 below for values, results.

TABLE 6 IC of compounds of this disclosure for inhibition of H358 cell proliferation₅₀The value is obtained.

Example numbering	IC₅₀(nM)
		1	3.7
1-1	31.7
		1-2	4.3
2	8.4
		2-1	21.1
2-2	3.6
		5	12.6
5-1	21.4
		5-2	86.4
6	6.3
		6-1	93.8
6-2	7.3
		7	3.5
7-1	19.3
		7-2	2
8	9.1
		8-2	5.7
15-4	7.1
		15-3	74.9
15-2	0.3
		15-1	16.7

And (4) conclusion: the compound disclosed by the invention has a good inhibition effect on H358 cell proliferation.

Claims

1. A compound of formula (I) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein:

g is N or C;

R²the same or different, and each is independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl, wherein said alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R⁴is halogen;

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

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

2. The compound of the general formula (I) according to claim 1, which is a compound of the general formula (Ia) or (Ib) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

g, R therein^1a、R^1b、R²-R⁴S and t are as defined in claim 1.

3. The compound represented by the general formula (I) according to claim 1 or2, which is a compound represented by the general formula (Ia-1) or (Ia-2) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein

G、R^1a、R^1b、R²、R⁴and s is as defined in claim 1.

4. A compound of formula (I) according to any one of claims 1 to 3, wherein G is N, or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof.

5. The compound of the general formula (I) according to any one of claims 1 to 4, or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereofA compound form, or a pharmaceutically acceptable salt thereof, wherein R^1aAnd R^1bAre the same or different and are each independently a hydrogen atom or a halogen; preferably R^1aIs a hydrogen atom or a halogen, R^1bIs halogen.

6. The compound of general formula (I) according to any one of claims 1 to 5, wherein R is atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof²Are the same or different and are each independently C_1-6An alkyl group.

7. The compound of general formula (I) according to any one of claims 1 to 6, wherein R is atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof³Are the same or different and are each independently C_1-6An alkyl group.

8. The compound of general formula (I) according to any one of claims 1 to 7, or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R is⁴Is fluorine or chlorine.

9. The compound of general formula (I) according to any one of claims 1 to 8, or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

10. a compound, or an atropisomer, tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

11. a compound represented by the general formula (I-A) or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof,

wherein M is an inorganic acid or an organic acid;

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

G、R^1a、R^1b、R²-R⁴s and t are as defined in claim 1.

12. The compound of the general formula (I-a) according to claim 11, or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

13. a compound, or an atropisomer, tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

14. a process for the preparation of a compound of formula (I) according to claim 1 or an atropisomer, tautomer, mesomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, which comprises:

x is halogen;

m is an inorganic acid or an organic acid;

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

G、R^1a、R^1b、R²-R⁴s and t are as defined in claim 1.

15. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-10, or an atropisomer, tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

16. Use of a compound according to any one of claims 1 to 10, or an atropisomer, tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for inhibiting KRAS, preferably for inhibiting KRAS G12C.

17. Use of a compound according to any one of claims 1 to 10, or an atropisomer, tautomer, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 15, for the manufacture of a medicament for the treatment or prevention of cancer, inflammation, or other proliferative disease, preferably cancer; preferably, the cancer is selected from the group consisting of melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, nasopharyngeal cancer, colorectal cancer, lung cancer, renal cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondrosis, osteoma, osteosarcoma, seminoma, testicular tumor, endometrial cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, bile duct cancer, chorioepithelial cancer, and pediatric tumor.