CN113980032B

CN113980032B - Fused tetracyclic derivative, preparation method thereof and application thereof in medicines

Info

Publication number: CN113980032B
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: 2023-06-16
Anticipated expiration: 2041-07-26
Also published as: CN113980032A

Abstract

The present disclosure relates to fused tetracyclic derivatives, methods of preparation and pharmaceutical uses thereof. 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 derivative as a therapeutic agent, particularly as a KRAS inhibitor.

Description

Fused tetracyclic derivative, preparation method thereof and application thereof in medicines

Technical Field

The present disclosure relates to fused tetracyclic derivatives, methods for their preparation, pharmaceutical compositions containing them and their use as therapeutic agents, in particular as KRAS inhibitors.

Background

The RAS (Rat Sarcoma Viral Oncogene Homolog) family belongs to the superfamily of small gtpases and is widely expressed in various eukaryotes. There are three RAS genes (HRAS, KRAS and NARS) in humans that can be expressed as four highly related RAS small gtpases (HRAS, KRAS4A, KARS B and NRAS). It acts as a binary switch for GDP-GTP regulation. They generally take two forms: a GDP (guanosine diphosphate) bound form in the inactive state and a GTP (guanosine triphosphate) bound form in the active 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,2007,7,295-308). The RAS gene has higher mutation rate in various tumors such as pancreatic cancer, colorectal cancer, non-small cell lung cancer and the like, and activated mutant RAS protein can promote abnormal signal transduction, so that the occurrence and development of cancer and drug resistance to targeted drugs are caused. Wherein the KRAS mutation is the highest mutation rate gene in human oncogenes, accounting for 20-30% of all tumors.

For mutant forms of KRAS proteins and signal pathway studies, significant advances in molecular biology have been made in recent years, however, the development of related targeted drugs remains a challenge. In chemical development, since the affinity of KRAS and GTP is very high, reaching 60pM, and the intracellular GTP concentration is at the level of mM, such directly competing molecules have extremely high affinity requirements for compounds, and so far there has been no successful case. In terms of development of biological drugs, antibody drugs penetrate cell membrane targeting KRAS proteins, and drug delivery efficiency is low. Therefore, many researchers have tried to develop a new way to inhibit the activities of RAF, MEK, ERK and other kinases in the KRAS downstream signal channel, so as to achieve the purpose of inhibiting the KRAS channel. The compounds have certain curative effects, but the downstream inhibitors can not completely block KRAS signals, and the target related toxic and side effects are large, so that the compounds have poor medicinal effects on KRAS mutant tumors. Therefore, the KRAS inhibitor for developing a new action mechanism has great clinical application value.

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

Faced with the difficulty of KRAS protein drug formulation, the professor Kevan Shokat, san Francisco, california university, first verified that certain specific compounds bind KRAS G12C muteins via covalent bonds. Through further studies, these covalent compounds were found to bind to cysteine at position 12 of KRAS muteins and occupy a hydrophobic allosteric regulatory pocket in the molecular switch-II region (switch-II regions), and the bound KRAS G12C mutations could be irreversibly locked in an inactivated state, blocking signaling pathways and cancer cell viability dependent on the protein (Nature 2013, 503, 548-551). The KRAS G12C small molecule inhibitor ARS-1620 can effectively inhibit tumor growth and even completely regress tumors on various KRAS G12C mutant tumor models. Since KRAS G12C is a mutein in tumor cells, whereas wild-type KRAS does not have this mutation site, a perfect tumor-selective target is provided (Cell, 2018,572,578-589). Several KRAS G12C inhibitors have been issued by companies typified by Araxas, amgen and Mirati (WO 2014152588, WO2016164675, WO2017087528, WO2017201161, WO2018119183, etc.). At present, no inhibitor drugs of KRAS G12C are approved for marketing, and the fastest-growing small molecule KRAS G12C inhibitors of Amgen and Mirati enter clinical primary trials in 9 and 12 months of 2018, respectively, thus there is a significant unmet medical need in the relevant patient population.

Disclosure of Invention

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

wherein:

g is N or C;

R ^1a and R is ^1b 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;

R ² the alkyl, alkoxy, haloalkyl, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl groups are each independently optionally substituted with one or more substituents selected from halogen, alkyl, alkoxy, haloalkyl, cyano, amino, nitro, hydroxy, hydroxyalkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ³ 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;

R ⁴ is 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 of formula (I) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, is a compound of formula (Ia) or (Ib), or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

therein G, R ^1a 、R ^1b 、R ² -R ⁴ S and t are as defined in formula (I).

In some preferred embodiments of the present disclosure, the compound of 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 of 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:

therein G, R ^1a 、R ^1b 、R ² -R ⁴ S and t are as defined in the general formulae (I), (Ia) or (Ib).

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

wherein the method comprises the steps of

R ³ The same or different and are each independently selected from alkyl, haloalkyl and hydroxyalkyl;

G、R ^1a 、R ^1b 、R ² 、R ⁴ and 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-1 a), (Ia-1 b), (Ia-2 a) or (Ia-2 b) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

Wherein the method comprises the steps of

G、R ^1a 、R ^1b 、R ² 、R ⁴ and 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 of 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 of formula (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (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 compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ^1a And R is ^1b The same or different, and are each independently a hydrogen atom or a halogen; preferably R ^1a Is a hydrogen atom or halogen, R ^1b Is 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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, cyano, amino, hydroxy, hydroxyalkyl, and cycloalkyl; preferably, R ² 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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, cyano, amino, hydroxy, C _1-6 Hydroxyalkyl and 3-6 membered cycloalkyl; preferably, R ² Identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl 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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ² Identical or different and are each independently C _1-6 Alkyl is 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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3) or (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereoisomer or mixture thereof, or a pharmaceutically acceptable salt thereof, wherein R ³ Identical or different and are each independently C _1-6 Alkyl is preferably methyl.

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

wherein:

g is N or CH;

R ^1a and R is ^1b The same or different and are each independently selected from the group consisting of hydrogen, halogen, alkyl, alkoxy, haloalkyl, amino, hydroxy, and hydroxyalkyl;

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

R ³ selected from alkyl, haloalkyl and hydroxyalkyl; and is also provided with

R ⁴ Is a hydrogen atom or a halogen.

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

Therein G, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ³ And R is ⁴ As defined in formula (II).

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

therein G, R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ³ And R is ⁴ As defined in the general formulae (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, 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 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 ^1a And R is ^1b The same or different and are each independently hydroxyl or halogen; preferably R ^1a Is halogen, and R ^1b Is hydroxyl.

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 ^2a And R is ^2b Identical or different and are each independently C _1-6 Alkyl, preferably methyl or isopropyl, more preferably R ^2a Is isopropyl, and R ^2b Is 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 ³ Is C _1-6 Alkyl is 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 ⁴ Halogen is 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 of formula (I-a) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof:

wherein M is an inorganic or organic acid;

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

G、R ^1a 、R ^1b 、R ² -R ⁴ s and t are as defined in formula (I).

Another aspect of the present disclosure relates to a compound of formula (I-a) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a salt thereof, wherein M is selected from hydrogen chloride, a 1, 4-dioxane solution of hydrogen chloride, ammonium chloride, trifluoroacetic acid, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, nitric acid, phosphoric acid, p-toluenesulfonic acid, and TMSOTf, preferably hydrochloric acid or trifluoroacetic acid.

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

Therein G, R ^1a 、R ^1b 、R ² -R ⁴ M, n, s and t are as defined in formula (I-A).

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

wherein the method comprises the steps of

G、R ^1a 、R ^1b 、R ² 、R ⁴ m, n and s are as defined in formula (I-A).

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

G、R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ³ and R is ⁴ As 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, meso, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof:

G、R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ³ and R is ⁴ As 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, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, comprising:

Reacting a compound of formula (I-a) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or salt thereof, with a compound of formula (I-B) under basic conditions to obtain a compound of formula (I) 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 ² -R ⁴ s, M, n and t are as defined in formula (I-A).

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formulas (Ia) and (Ib) or an atropisomer, tautomer, meso, 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 salt thereof with a compound of formula (I-B) under basic conditions to obtain 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 obtain 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;

Another aspect of the present disclosure relates to a method for preparing a compound represented by general formulas (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 formula (Ia-1-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 obtain a compound of 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 obtain 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 、R ² 、R ⁴ s, M and n are as defined in the general formula (I-A).

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

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

X is halogen, preferably chlorine;

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

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

Another aspect of the present disclosure relates to a pharmaceutical composition comprising 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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-b), (IIa-c), (IIa-d) of the present disclosure, and a compound shown in 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, diluents or excipients.

The present disclosure further relates to the use of a compound of general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-C), (IIa-d) and table 1 or a atropisomer, tautomer, racemate, enantiomer, diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for inhibiting KRAS, preferably for the manufacture of a medicament for inhibiting KRAS G12C.

The present disclosure further relates to the use of a compound of general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and table 1 or a atropisomer, tautomer, racemate, enantiomer, diastereomer or a mixture form thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the manufacture of a medicament for the treatment or prevention of cancer, inflammation, or other proliferative diseases, preferably in the manufacture of a medicament for the treatment or prevention of cancer; the cancer is preferably selected from melanoma, brain tumor, esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, nasopharyngeal cancer, colorectal cancer, lung cancer (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondrima, osteosarcoma, seminoma, testicular tumor, endometrial cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gall bladder cancer, bile duct cancer, chorionic epithelial cancer and pediatric tumor (the tumors described above are the corresponding malignant tumors).

The present 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 general formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ib-b), (Ia-1), (Ia-2), (Ia-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) 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 KRAS-mediated diseases 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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) or an atropisomer, tautomer, racemate, enantiomer, diastereomer or mixture form 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 cancer, inflammation, or other proliferative disease, preferably a method of treating cancer, 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-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d), and a compound shown in 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; 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 (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, endometrial cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gall bladder cancer, bile duct cancer, chorionic epithelial cancer and pediatric tumor (the tumors described above are the corresponding malignant tumors).

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

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

The present disclosure also relates to a pharmaceutical composition comprising or in the form of a compound of formula (I), (Ia), (Ib), (Ia-a), (Ia-b), (Ib-a), (Ia-1), (Ia-2), (Ia-1 a), (Ia-1 b), (Ia-2 a), (Ia-2 b), (Ia-3), (Ia-4), (II), (IIa), (IIb), (IIa-a), (IIa-b), (IIa-c), (IIa-d) and Table 1 or a atropisomer, tautomer, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of cancer, inflammation, or other proliferative disease, preferably 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 (e.g., non-small cell lung cancer or small cell lung cancer), kidney cancer, breast cancer, ovarian cancer, prostate cancer, skin cancer, neuroblastoma, sarcoma, osteochondroma, osteosarcoma, seminoma, testicular tumor, endometrial cancer, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gall bladder cancer, bile duct cancer, chorionic epithelial cancer and pediatric tumor (the tumors described above are the corresponding malignant tumors).

The active compounds can be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers by conventional methods to formulate the compositions of the present disclosure. Accordingly, 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) administration, 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, troches or syrups.

The dosage of the compound or composition used in the disclosed methods of treatment 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 guideline, the active compounds are preferably administered in unit doses, or in a manner whereby the patient can self-administer a single dose. The unit dosage of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled lotion, powder, granule, lozenge, suppository, reconstituted powder or liquid formulation. Suitable unit doses may be in the range 0.1 to 1000mg.

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

The 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. The above-described sweeteners 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 an oil-in-water emulsion. The oil phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and 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 sterile injectable aqueous solutions. Acceptable vehicles or solvents that may be used 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, which is prepared by injecting a liquid or microemulsion into the blood stream of a patient by topical mass injection. Alternatively, it may be desirable to administer the solutions and microemulsions in a manner that maintains a constant circulating concentration of the compounds of the present disclosure. To maintain this constant concentration, a continuous intravenous delivery device may be used. An example of such a device is a Deltec CADD-PLUS. TM.5400 model intravenous pump.

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 suspensions may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents as described above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, nontoxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any blend fixed oil may be used. In addition, fatty acids can also be used to prepare 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 will therefore melt in the rectum to release the drug.

The compounds of the present disclosure may be administered by adding water to prepare water-suspended dispersible powders and granules. These pharmaceutical compositions may be prepared by mixing the active ingredient with a dispersing or wetting agent, suspending agent or one or more preservatives.

As is well known to those skilled in the art, the amount of drug administered depends on a variety of factors, including, but not limited to, the following: the activity of the specific compound used, the age of the patient, the weight of the patient, the health 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, etc.; in addition, the optimal mode of treatment, such as the mode of treatment, the daily amount of the compound, or the type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

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

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

The term "alkenyl" refers to an alkyl compound having 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. Alkenyl 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 "alkynyl" refers to an alkyl compound having at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above. Alkynyl groups containing 2 to 12 (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, and 12) carbon atoms are preferred, and alkynyl groups containing 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 from 3 to 12 carbon atoms, preferably from 3 to 8 carbon atoms (e.g., 3, 4, 5, 6, 7, and 8), more preferably from 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, monocyclic, polycyclic group sharing one carbon atom (referred to as the spiro atom) between the monocyclic rings, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spirocycloalkyl group is classified into a single spirocycloalkyl group, a double spirocycloalkyl group or a multiple spirocycloalkyl group according to the number of common spiro atoms between rings, and preferably a single spirocycloalkyl group and a double spirocycloalkyl group. More preferably 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered monocyclocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused ring alkyl" refers to 5 to 20 membered, all carbon polycyclic groups in which each ring in the system shares an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a bicyclic, tricyclic, tetra-cyclic or polycyclic condensed ring alkyl group, preferably a bicyclic or tricyclic, more preferably a 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, and the like. Non-limiting examples of fused ring alkyl groups include:

The term "bridged cycloalkyl" refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms that are not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Cycloalkyl groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes cycloalkyl (including monocyclic, spiro, fused, and bridged rings) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the ring attached to the parent structure is cycloalkyl, non-limiting examples include indanyl (e.g

) Tetrahydronaphthyl (e.g.)>

) Benzocycloheptyl radicals (e.g.)>

) Etc.; preferably

Cycloalkyl groups may be substituted or unsubstituted, and when substituted, they may be substituted at any available point of attachment, preferably independently optionally selected from one or more 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. The alkoxy groups may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more groups independently selected from the group consisting of D atom, 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 monocyclic or polycyclic cyclic substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form sulfoxides or sulfones), but excluding the ring portions of-O-, -O-S-or-S-, the remaining ring atoms being carbon. Preferably from 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 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 heterocyclyl groups include spiro, fused and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to a 5 to 20 membered, polycyclic heterocyclic group having a single ring sharing one atom (referred to as the spiro atom) therebetween, wherein one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which sulfur may optionally be oxo (i.e., form a sulfoxide or sulfone), the remaining ring atoms being carbon. Which may contain one or more double bonds. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The spiroheterocyclyl groups are classified into a single spiroheterocyclyl group, a double spiroheterocyclyl group or a multiple spiroheterocyclyl group according to the number of common spiro atoms between rings, and preferably a single spiroheterocyclyl group and a double spiroheterocyclyl group. More preferably a 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered single spiro heterocyclic group. Non-limiting examples of spiroheterocyclyl 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 which may contain one or more double bonds, wherein one or more ring atoms are heteroatoms selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., form sulfoxides or sulfones), and the remaining ring atoms are carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). The number of constituent rings may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic condensed heterocyclic group, preferably a bicyclic or tricyclic, more preferably a 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 fused heterocyclic group. Non-limiting examples of fused heterocyclyl groups include:

The term "bridged heterocyclyl" refers to a 5 to 14 membered, polycyclic heterocyclic group in which any two rings share two atoms which are not directly connected, 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., form sulfoxides or sulfones), the remaining ring atoms being carbon. Preferably 6 to 14 membered, more preferably 7 to 10 membered (e.g. 7, 8, 9 or 10 membered). Heterocyclic groups which may be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged according to the number of constituent rings are preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl groups include:

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

etc.

The heterocyclic group may be substituted or unsubstituted, and when substituted, it may be substituted at any available point of attachment, preferably independently optionally selected from one or more of 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 being 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. The aryl ring includes aryl rings fused to heteroaryl, heterocyclyl, or cycloalkyl rings as described above, 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, they may be substituted at any available point of attachment, preferably independently optionally selected from one or more 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 containing 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, such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes heteroaryl condensed onto an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

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

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

The term "amino protecting group" is intended to mean an amino group that is protected by an easily removable group in order to keep the amino group unchanged when the reaction is carried out at other positions of the molecule. Non-limiting examples include (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butoxycarbonyl, acetyl, benzyl, allyl, p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy or nitro.

The term "hydroxy protecting group"is a suitable group for hydroxy protection known in the art, see literature (" Protective Groups in Organic Synthesis ", 5) ^Th Ed.T.W.Greene&P.g.m.wuts). As an example, preferably, the hydroxyl protecting group may be (C _1-10 Alkyl or aryl radicals ₃ Silyl groups, for example: triethylsilyl, triisopropylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, and the like; may be C _1-10 Alkyl or substituted alkyl, preferably alkoxy or aryl substituted alkyl, more preferably C _1-6 Alkoxy substituted C _1-6 Alkyl-or phenyl-substituted C _1-6 Alkyl, most preferably C _1-4 Alkoxy substituted C _1-4 Alkyl groups such as: methyl, tert-butyl, allyl, benzyl, methoxymethyl (MOM), ethoxyethyl, 2-Tetrahydropyranyl (THP), and the like; may be (C) _1-10 Alkyl or aryl) acyl groups, for example: formyl, acetyl, benzoyl, p-nitrobenzoyl and the like; may be (C) _1-6 Alkyl or C _6-10 Aryl) sulfonyl; may also be (C) _1-6 Alkoxy or C _6-10 Aryloxy) carbonyl.

The term "cycloalkyloxy" refers to a cycloalkyl-O-group, 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-, 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-NH ₂ 。

The term "cyano" refers to-CN.

The term "nitro" refers to-NO ₂ 。

The term "oxo" refers to "=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 include isotopic derivatives thereof. The term "isotopically-enriched derivative" refers to a compound that differs in structure only in the presence of one or more isotopically-enriched atoms. For example, having the structure of the present disclosure, except that "deuterium" or "tritium" is used in place of hydrogen, or ¹⁸ F-fluorine labeling [ ] ¹⁸ F isotope) instead of fluorine, or with ¹¹ C-， ¹³ C-, or ¹⁴ C-enriched carbon ¹¹ C-， ¹³ C-, or ¹⁴ C-carbon labeling; ¹¹ C-， ¹³ c-, or ¹⁴ C-isotopes) are within the scope of this disclosure. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as diagnostic imaging tracers in vivo for diseases, or as tracers for pharmacodynamic, pharmacokinetic or receptor studies. The present 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 with a deuterium atom. Those skilled in the art are able to synthesize deuterated forms of the compounds of formula (I) and formula (II) with reference to the relevant literature. Commercially available deuterated compounds of formula (I) and formula (II) can be used in the preparation of deuterated formsStarting materials, or they may be synthesized using conventional techniques with deuterated reagents including, but not limited to, deuterated borane, tridentate borane in tetrahydrofuran, deuterated lithium aluminum hydride, deuterated iodoethane, deuterated iodomethane, and the like. Deuterated compounds generally retain activity comparable to non-deuterated compounds and may achieve better metabolic stability when deuterated at certain specific sites, thus 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 group" means that an alkyl group may be, but is not necessarily, present, and the description includes cases where the heterocyclic group is substituted with an alkyl group and cases where the heterocyclic group is not substituted with an alkyl group.

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

"pharmaceutical composition" means a mixture comprising one or more of the compounds described herein or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, such as physiologically/pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.

By "pharmaceutically acceptable salts" is meant salts of the compounds of the present disclosure which are safe and effective when used in a mammal, and which possess the desired biological activity. Salts may be prepared separately during the final isolation and purification of the compounds, or by reacting the appropriate groups 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 and 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 intended effect. 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, a suitable effective amount in an individual case can be determined by one skilled in the art according to routine experimentation.

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 are effective for the intended use.

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

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

Methods of synthesizing compounds of the present disclosure

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

scheme one

A process for the preparation of a compound of formula (I) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

X is halogen, preferably chlorine;

Scheme II

A process for the preparation of a compound of the general formulae (Ia) and (Ib) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

Wherein:

x is halogen, preferably chlorine;

Scheme III

A process for the preparation of a compound of the general formulae (Ia-1) and (Ia-2) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

Wherein:

x is halogen, preferably chlorine;

Scheme IV

A process for the preparation of a compound of the general formulae (Ia-3) and (Ia-4) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, 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 obtain 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 obtain 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;

Scheme five

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

chiral preparation of a compound of the general formula (I-a) or an atropisomer, tautomer, meso, 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, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof;

therein G, R ^1a 、R ^1b 、R ² -R ⁴ S and t are as defined in formula (I).

Scheme six

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

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

therein G, R ^1a 、R ^1b 、R ² -R ⁴ S and t are as defined in formula (I).

Scheme seven

A process for the preparation of a compound of the general formulae (Ia-1 a) and (Ia-1 b) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

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

Wherein the method comprises the steps of

G、R ^1a 、R ^1b 、R ² 、R ⁴ and s is as defined in formula (I).

Scheme eight

A process for the preparation of a compound of the general formulae (Ia-2 a) and (Ia-2 b) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

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

wherein the method comprises the steps of

G、R ^1a 、R ^1b 、R ² 、R ⁴ and s is as defined in formula (I).

Scheme nine

A process for the preparation of a compound of formula (II) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

x is halogen, preferably chlorine;

G、R ^1a 、R ^1b 、R ^2a 、R ^2b 、R ³ and R is ⁴ As in the general formula (II)And (5) defining.

Scheme ten

A process for the preparation of a compound of the general formulae (IIa) and (IIb) or an atropisomer, tautomer, meso, racemate, enantiomer, diastereomer, or mixture thereof, or a pharmaceutically acceptable salt thereof, according to the present disclosure, comprising the steps of:

wherein:

x is halogen, preferably chlorine;

Scheme eleven

A process for the preparation of a compound of the general formulae (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, according to the present disclosure, 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;

Reagents for providing basic conditions include organic bases including, but not limited to, triethylamine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, lithium bistrimethylsilylaminide, 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 in conjunction with the examples, which are not intended to 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 ^-6 Units of (ppm) are given. NMR was performed using Bruker AVANCE-400 nuclear magnetic resonance apparatus or Bruker AVANCE NEO M with deuterated dimethyl sulfoxide (DMSO-d) ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard is Tetramethylsilane (TMS).

The MS measurement is carried out by using an Agilent 1200/1290DAD-6110/6120 Quadranipole MS liquid chromatography-mass spectrometer (manufacturer: agilent, MS model: 6110/6120 Quadranipole MS); waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector); thermo Ultimate 3000-Q actual (manufacturer: thermo, MS model: THERMO Q Exactive).

High Performance Liquid Chromatography (HPLC) analysis used Agilent HPLC 1200DAD, agilent HPLC 1200VWD, and Waters HPLC e2695-2489 high pressure liquid chromatography.

Chiral HPLC analysis was determined using an Agilent 1260DAD high performance liquid chromatograph.

The high performance liquid phase was prepared by using a Waters 2545-2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson GX-281 preparative chromatograph.

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

The CombiFlash flash rapid prep instrument used CombiFlash Rf200 (teldyne ISCO).

The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the 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 the yellow sea silica gel of the smoke table 200-300 meshes as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were measured using a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or following methods known in the art, or may be purchased from ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemicals, and the like.

The examples are not particularly described, and the reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.

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

The hydrogen atmosphere is defined as the reaction flask being connected to a balloon of hydrogen gas of about 1L volume.

The pressure hydrogenation reaction uses a Parr 3916 model EKX hydrogenometer and a clear blue QL-500 type hydrogen generator or HC2-SS type hydrogenometer.

The hydrogenation reaction is usually vacuumized, filled with hydrogen and repeatedly operated for 3 times.

The microwave reaction used was a CEM Discover-S908860 type microwave reactor.

The examples are not specifically described, and the solution refers to an aqueous solution.

The reaction temperature is room temperature and is 20-30 deg.c without specific explanation in the examples.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: 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 the polarity of the compound, and small amount of alkaline or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Examples 1,1-2

(5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 1

(12S, 5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 1-1

(12R, 5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 1-2

First step

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

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

Second step

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

Compound 1b (9.2 g,47.60 mmol) was added to 150mL of methanol, followed by ethyl cyanoacetate (5.803 g,52.27mmol,5.6 mL) and sodium tert-butoxide (5.490 g,57.12 mmol) and heated to 75deg.C for 16 h. 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, and then filtration, and the cake was dried under vacuum to give the title compound 1c (9.2 g, yield: 74.2%).

Third step

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

Cyanoacetic acid (6 g,70.53 mmol) was added to 50mL of acetic anhydride, heated to 85℃for 5 minutes, and the reaction mixture was poured into compound 1c (9.2 g,35.34 mmol) 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. The resultant was filtered and dried to give the title compound 1d (9.03 g, yield: 70.8%).

Fourth step

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

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

Fifth step

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

Compound 1e (10 g,30.45 mmol) was added to 200mL of water, sodium hydroxide (4.3 g,107.5 mmol) was added at room temperature, stirred for 30 minutes, and 1- (chloromethyl) -4-fluoro-1, 4-diazabicyclo [2.2.2] heptane bis tetrafluoroborate (32.4 g,91.45mmol, shao) was added and the reaction stirred for 1 hour. 140mL of 2M hydrochloric acid was then slowly added to the reaction mixture until the pH of the reaction mixture became 1, sodium sulfite (7.68 g,60.93 mmol) was added, stirred for 5 minutes, and zinc powder (10 g,152.9 mmol) was added and heated to 60℃for reaction for 5 hours. The reaction solution was cooled to room temperature, filtered, and the 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 the target compound 1f (3.15 g, yield: 29.8%) which was used directly in the next step without further purification.

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 (2 g,5.77 mmol) was added to 50mL of acetonitrile, phosphorus oxychloride (4.29 g,27.97mmol,2.6 mL) and N, N-diisopropylethylamine (3.79 g,29.32mmol,5.2 mL) were added and reacted for 2 hours at 80 ℃. The reaction solution was cooled to room temperature, concentrated under reduced pressure, the residue was poured into 50mL of ice water, saturated sodium bicarbonate solution was added until the pH of the reaction solution was >7, 100mL of methylene chloride was added to dissolve and then the solution was separated, the aqueous phase was extracted with methylene chloride (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 give 1g (396 mg, yield: 17.8%) of the objective compound.

Seventh step

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

1g (390 mg,1.0334 mmol) of the compound was dissolved in 30mL of acetonitrile, followed by addition of phosphorus oxychloride (460 mg,3.01mmol,0.28 mL) and N, N-diisopropylethylamine (408 mg,3.15mmol,0.56 mL), and reaction was heated to 80℃for 2 hours. The reaction was cooled to room temperature and concentrated under reduced pressure to give the title compound (620 mg, 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 (620 mg,1.54 mmol) was dissolved in 40mL of dichloromethane, cooled to 0deg.C, tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate (250 mg,1.15mmol, as a drug) was added, N-diisopropylethylamine (408 mg,3.15mmol,0.56 mL) was added, and the reaction stirred for 1 h. 30mL of saturated aqueous sodium bicarbonate solution was added to quench, the solution was separated, the aqueous phase was 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 title compound 1i (920 mg, yield: 102.4%) which was used directly in the next reaction without further purification.

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 (920 mg,1.58 mmol) was dissolved in 30mL of tetrahydrofuran, and 1, 8-diazabicyclo undec-7-ene (470 mg,3.10mmol,0.46mL, shao) was added and reacted for 3 hours with stirring. 30mL of water and 50mL of ethyl acetate were added, the mixture was separated, 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 (396 mg, yield: 45.9%).

Tenth step

(5 aR) -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-pentaaza-benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-7 (5H) -carboxylic acid tert-butyl ester 1k

2-fluoro-6-hydroxyphenylboric acid (168 mg,1.07mmol, shanghai Haohong biomedical technologies Co., ltd.) compound 1j (393 mg, 721.0. Mu. Mol), disodium hydrogen phosphate dodecahydrate (775 mg,2.16 mmol), and tetrakis triphenylphosphine palladium (84 mg, 72.69. Mu. Mol) were added to a mixed solvent of 30mL of water and 1, 4-dioxane (V/V=1:5) under a nitrogen atmosphere, and the mixture was heated to 95℃to react for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, dissolved in 50mL of methylene chloride, filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography with eluent system D to give the objective compound 1k (383 mg, yield: 85.5%).

Eleventh step

(5 aR) -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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 1l

Compound 1k (383 mg, 617.1. Mu. Mol) was dissolved in 10mL of methylene chloride, 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 sodium hydrogencarbonate solution was added to the residue to a pH of more than 7, and after further addition of 100mL of methylene chloride, the liquid phase was separated, extracted with methylene chloride (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 (335 mg, yield: 104.2%) which was used directly in the next reaction without further purification.

Twelfth step

Compound 1L (335 mg, 643.5. Mu. Mol) was dissolved in 30mL of methylene chloride, cooled to 0℃and triethylamine (365 mg,3.60mmol,0.5 mL) was added thereto, followed by dropwise addition of acryloyl chloride (87 mg, 961.2. Mu. Mol, 78. Mu.L) and the reaction was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in 30mL of methanol, and sodium hydrogencarbonate (250 mg,2.97 mmol) was added thereto, and the mixture was heated to 60℃and stirred 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 with eluent system A, and high performance liquid chromatography (column: boston Phlex Prep C, 5 μm 30 x 150mm; mobile phase: A-water (10 mmol NH) ₄ HCO ₃ ): b-acetonitrile = 30% -50% B (15 min), flow rate: purification at 30mL/min gave the title compound 1 (209 mg, yield: 56.5%).

MS m/z(ESI):575.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

Chiral preparation (isolation conditions: chiral preparation CHIRALPAK IF, 20X 250mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 20 mL/min) of compound 1 (209 mg, 0.264 mmol), the corresponding fractions were collected and concentrated under reduced pressure to give the objective compounds 1-1 (90 mg), 1-2 (95 mg).

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

chiral HPLC analysis, retention time 4.277 min, chiral purity: 100% (column: CHIRALPAK IF X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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)。

Compounds 1-2 of single configuration (longer retention time)

Chiral HPLC analysis, retention time 7.574 min, chiral purity: 98.3% (column: CHIRALPAK IF X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

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

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

Using the synthetic route of example 1, substituting tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate, the eighth step starting material, with tert-butyl (2S, 5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared using well-known methods "Journal of Medicinal Chemistry,2020,63 (9), 4468-4483"), gave title compound 2 (450 mg).

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

Single configuration Compound 2-1 (longer retention time)

Chiral HPLC analysis, retention time 18.139 min, chiral purity: 99.7% (column: CHIRALPAK IC X4.6 mm,5 μm; mobile phase: A- (methanol: ethanol=1:1): B-n-hexane=40/60, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 100% (column: CHIRALPAK IC X4.6 mm,5 μm; mobile phase: A- (methanol: ethanol=1:1): B-n-hexane=40/60, flow rate: 1.0 mL/min).

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

(5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 3 (12S, 5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 3-1

(12R, 5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 3-2

First step

(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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalene-7 (5H) -carboxylic acid tert-butyl ester 3a

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

Second step

(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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 3b

Compound 3a (854 mg,1.41 mmol) was dissolved in 15mL of dichloromethane, 3mL of trifluoroacetic acid was added, and the reaction was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, a saturated aqueous sodium hydrogencarbonate solution was added to the residue to a pH of more than 7, and after further addition of 100mL of methylene chloride, the solution was separated, the aqueous phase was extracted with methylene chloride (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 (788 mg), which was used directly in the next reaction without further purification.

Third step

(5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 3

Compound 3b (788 mg,1.56 mmol) was dissolved in 30mL of dichloromethane, cooled to 0 ℃, triethylamine (540 mg,5.39mmol,0.75 mL) and then acryloyl chloride (140 mg,1.54mmol,0.125 mL) were added dropwise and the reaction stirred for 1 hour. Concentrating under reduced pressure, purifying the residue with silica gel column chromatography with eluent system D, and high performance liquid chromatography (column Boston Phlex Prep C: 5 μm 30 x 150mm; mobile phase: A-water (10 mmol NH) ₄ HCO ₃ ): b-acetonitrile=35% -55%b (15 min), flow rate: purification at 30mL/min gave the title compound 1 (280 mg, yield: 32.1%).

MS m/z(ESI):559.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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)。

Fourth step

(12S, 5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 3-1

Chiral preparation (separation conditions: chiral preparation CHIRALPAK IC, 20X 250mm; mobile phase: n-hexane: ethanol=50/50, flow rate: 20 mL/min) of compound 3 (280 mg,0.502 mmol), the corresponding components were collected and concentrated under reduced pressure to give the objective compound 3-1 (125 mg)/3-2 (140 mg).

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

chiral HPLC analysis, retention time 5.917 min, chiral purity: 100% (column: CHIRALPAK IG X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):559.3[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 100% (column: CHIRALPAK IG X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):559.3[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

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

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

Using the synthetic route of example 1, substituting tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate as the eighth step starting material with tert-butyl (2 s, 5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared using well-known methods "Journal of Medicinal Chemistry,2020,63 (9), 4468-4483"), substituting 2-fluoro-6-hydroxyphenylboronic acid as the tenth step starting material with 2-fluorophenylboronic acid gave the title compound 4 (398 mg).

MS m/z(ESI):573.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

Chiral preparation of compound 4 (398 mg,0.695 mmol) (separation conditions: chiral preparation CHIRALPAK IC, 20X 250mm; mobile phase: n-hexane: ethanol=80/20, flow rate: 20 mL/min), collection of the corresponding components thereof, concentration under reduced pressure, and yield the objective compound (196 mg, 198mg).

Single configuration compounds (shorter retention time):

chiral HPLC analysis, retention time 15.394 min, chiral purity: 100% (column: CHIRALPAK IG X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=80/20, flow rate: 1.0 mL/min).

MS m/z(ESI):573.4[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 compounds (longer retention time):

chiral HPLC analysis, retention time 19.150 min, chiral purity: 99.7% (chromatographic column: CHIRALPAK IG X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=80/20, flow rate: 1.0 mL/min).

MS m/z(ESI):573.4[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

(12R, 5aR, 8S) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 5-1

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

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

MS m/z(ESI):591.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 5-1

Chiral preparation (separation conditions: chiral preparation CHIRALPAK IF, 20X 250mm; mobile phase: n-hexane: isopropanol=70/30, flow rate: 20 mL/min) of compound 5 (164 mg,0.284 mmol), the corresponding components were collected and concentrated under reduced pressure to give the objective compound 5-1 (40 mg)/5-2 (42 mg).

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

chiral HPLC analysis, retention time 9.190 min, chiral purity: 99.7% (chromatographic column: AY Phenomenex Lux Amylose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 99.4% (chromatographic column: AY Phenomenex Lux Amylose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 6

(12S, 5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 6-1

(12R, 5 aR) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 6-2

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

MS m/z(ESI):577.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

Chiral preparation (isolation conditions: chiral preparation CHIRALPAK ID, 20X 250mm; mobile phase: n-hexane: ethanol=50/50, flow rate: 20 mL/min) of compound 6 (126 mg,0.502 mmol), the corresponding fractions were collected and concentrated under reduced pressure to give the objective compound 6-1 (30 mg)/6-2 (30 mg).

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

chiral HPLC analysis: retention time 5.618 min, chiral purity: 100% (column: CHIRALPAK ID X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):577.3[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 98.1% (column: CHIRALPAK ID X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):577.3[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

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

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

First step

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

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

Second step

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

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

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 (10.15 g,27.97 mmol) was added to 200mL of acetonitrile, followed by phosphorus oxychloride (20.245 g,134.51mmol,12.5 mL) and N, N-diisopropylethylamine (18.225 g,141.01mmol,25 mL) and heated to 80℃and stirred for 1 hour. The reaction solution was cooled to room temperature and concentrated under reduced pressure to give the title compound 7c (34 g), which was used in the next reaction without further purification.

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

MS m/z(ESI):611.0[M+1]。

Fifth step

(5 aR, 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-pentaaza-benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-7 (5H) -carboxylic acid tert-butyl ester 7e

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

MS m/z(ESI):575.1[M+1]。

Sixth step

(5 aR, 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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalene-7 (5H) -carboxylic acid tert-butyl ester 7f

2-Fluorophenylboronic acid (0.4815 g,3.4663 mmol), compound 7e (1.33 g,2.3111 mmol), disodium hydrogen phosphate dodecahydrate (2.48 g,6.9246 mmol), and Tetratriphenylphosphine palladium (267 mg, 231.0569. Mu. Mol) were added to 60mL of water and 1, 4-dioxane (V/V=1:5) under a nitrogen atmosphere and heated to 100deg.C for 16 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, and the residue was dissolved with 300mL of methylene chloride and filtered, and the filtrate was concentrated under reduced pressure to give the objective compound 7f (2 g, yield: > 100%) which was used directly in the next reaction without further purification.

Seventh step

7g of (5 aR, 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-pentaaza-benzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one

Compound 7f (2 g,3.149 mmol) 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, 30mL of a saturated aqueous sodium hydrogencarbonate solution was added to the residue, 50mL of methylene chloride was added thereto and dissolved, the aqueous phase was extracted with methylene chloride (50 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 7g (1.686 g, yield: 100.0%) of the objective compound.

Eighth step

7g (1.686 g,3.151 mmol) of the compound was added to 50mL of methylene chloride, cooled to 0℃and triethylamine (0.729 g,7.204mmol,1 mL) was added thereto, followed by dropwise addition of acryloyl chloride (29 mg,3.215mmol,0.26 mL) and the reaction was stirred for 1 hour. 50mL of saturated aqueous sodium bicarbonate solution was added to quench, the solution was separated, the aqueous phase was extracted with methylene chloride (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 D, followed by high performance liquid chromatography (column: boston Phlex Prep C, 5 μm, 30X 150mm; mobile phase: A-water (10 mmol ammonium bicarbonate): B-acetonitrile=35% -55%B (15 min), flow rate: 30 mL/min) to obtain the objective compound 7 (600 mg, yield: 32.3%).

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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)。

Ninth step

Chiral preparation (separation conditions: chiral preparation CHIRALPAK IF, 20X 250mm; mobile phase: n-hexane: isopropanol=80/20, flow rate: 20 mL/min) of compound 7 (600 mg,0.695 mmol), the corresponding components were collected and concentrated under reduced pressure to give the objective compound 7-1 (250 mg)/7-2 (248 mg).

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

chiral HPLC analysis, retention time 7.929 min, chiral purity: 98.4% (column: AY Phenomenex Lux Amylose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 99.8% (chromatographic column: AY Phenomenex Lux Amylose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 8 (12S, R) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 8-1

(12R, R) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 8-2

The synthetic route of example 7 was used to replace the fourth step starting material (2 s, 5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylic acid tert-butyl ester with the compound (3R) -3- (hydroxymethyl) piperazine-1-carboxylic acid tert-butyl ester (pichia medicine) to give the title compound 8 (520 mg).

MS m/z(ESI):575.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

(12S, R) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one atropisomer 8-1

Chiral preparation of compound 8 (520 mg, 0.906 mmol) (separation conditions: chiral preparation CHIRALPAK IG x 250mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 20 mL/min), collection of the corresponding components thereof, concentration under reduced pressure gave the objective compound 8-1 (207 mg)/8-2 (192 mg).

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

chiral HPLC analysis, retention time 5.674 min, chiral purity: 100% (column: CHIRALPAK IG X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 100% (column: CHIRALPAK IG X4.6 mm,5 μm; mobile phase: n-hexane: ethanol=50/50, flow rate: 1.0 mL/min).

MS m/z(ESI):575.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

(5 aR, 8R) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 9

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

MS m/z(ESI):573.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

Using the synthetic route of example 1, substituting tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate as the eighth step starting material with tert-butyl (2R, 5R) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (Pichia) gave title compound 10 (490 mg).

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

The synthetic route of example 1 was used to prepare the title compound 11 (480 mg) by substituting tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate as the eighth step starting material with tert-butyl (2S, 5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by the well-known method "WO2020/6018,2020, A1, 740-741") and substituting 2-fluorophenylboronic acid as the tenth step starting material with 2-fluoro-6-hydroxyphenylboronic acid.

MS m/z(ESI):573.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )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

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

Using the synthetic route of example 1, substituting tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate as the eighth step starting material with tert-butyl (2S, 5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by known methods "WO2020/6018,2020, A1, 740-741") gave title compound 12 (360 mg).

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,CDCl ₃ )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

(5 aS, 8R) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 13

The synthetic route of example 1 was used to prepare the title compound 13 (250 mg) by substituting tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate as the eighth step starting material with tert-butyl (2R, 5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by the well-known method "WO2019/215203,2019,A1,Page 44") and substituting 2-fluoro-6-hydroxyphenylboronic acid as the tenth step starting material with 2-fluorophenylboronic acid.

MS m/z(ESI):573.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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

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

Using the synthetic route of example 1, substituting tert-butyl (3R) -3- (hydroxymethyl) piperazine-1-carboxylate as the eighth step starting material with tert-butyl (2R, 5S) -5- (hydroxymethyl) -2-methylpiperazine-1-carboxylate (prepared by known method "WO2019/215203,2019,A1,Page 44") gave title compound 14 (310 mg).

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15

(12S, 5aS, 9S) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-1

(12R, 5aS, 9S) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-2

(12S, 5aR, 9S) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-3

(12R, 5aR, 9S) -7-propenoyl-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-pentaazabenzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15-4

First step

(S)-N ¹ ,N ² -dibenzylpropane-1, 2-diamine 15b

(2S) -propane-1, 2-diamine dihydrochloride 15a (20 g,136.0mmol, hao hong Kong) was dissolved in 200mL of methanol, diisopropylethylamine (36.1 g,219.3 mmol) was added, cooled to 0℃and benzaldehyde (29 g,273.2 mmol) was added dropwise, and after warming to room temperature, the reaction was stirred for 2 hours, cooled to 0℃and then sodium borohydride (10 g,264.3 mmol) was added in portions, and then allowed to react at room temperature for 2 hours, 1M hydrochloric acid was added to the reaction mixture to pH 7, filtered, the filtrate was concentrated under reduced pressure, 500mL of ethyl acetate and 300mL of water were added, and sodium carbonate was added to pH 9, the separated liquid was extracted with ethyl acetate (150 mL. Times.2), then mixed solvent (200 mL. Times.2) of dichloromethane and methanol (V/V=10:1) was used, the organic phase was combined, dried over anhydrous sodium sulfate was filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography with eluent system A to give the title compound 15b (21.7 g, yield: 62%).

Second step

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

Compound 15b (10 g,39.3 mmol) was dissolved in 50mL of toluene, triethylamine (10.7 g,105.7 mmol) was added, heated to 40℃and a solution of ethyl 2, 3-dibromopropionate (11.2 g,43.1 mmol) in 50mL of toluene was added dropwise, and the temperature was raised to 80℃and the reaction was stirred for 6 hours. The reaction solution was cooled to room temperature, 300mL of ethyl acetate and 150mL of water were added, the solution was separated, 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 (6.78 g, yield: 48.9%).

Third step

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

Compound 15c (5.6 g,15.88 mmol) was dissolved in 200mL tetrahydrofuran, cooled to 0deg.C, lithium aluminum hydride (640 mg,19.01mmol,19 mL) was added dropwise, and the reaction was stirred for 1 hour after the addition. 0.6mL of water, 0.6mL of 15% aqueous sodium hydroxide solution, 1.8mL of water, and anhydrous sodium sulfate were added in this order, stirred for 10 minutes, filtered, and the filtrate was concentrated under reduced pressure to give the title compound 15d (5.12 g, yield: > 100%).

Fourth step

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

Compound 15d (6.2 g,19.97 mmol) was dissolved in 70mL of methanol under hydrogen atmosphere, 10% palladium on carbon (1.78 g,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 (2.6 g, yield: 100%).

Fifth step

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

Compound 15e (2.61 g,20.04 mmol) was dissolved in 50mL of methanol, cooled to 0deg.C, triethylamine (7.29 g,72.04mmol,10 mL) was added, di-tert-butyl dicarbonate (9.7 g,44.44 mmol) was added, and after the addition was warmed to room temperature, the mixture was 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 thereto for dissolution, and sodium hydroxide (2.4 g,460.04 mmol) was further added thereto, and the mixture was heated to 90 ℃ and stirred for reaction for 16 hours. The reaction was cooled to room temperature, concentrated under reduced pressure, 1N hydrochloric acid was added to the residue to a pH of about 10, then extracted with methylene chloride (100 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 (3.2 g, yield: 69.30%).

Sixth step

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

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

Compound 1h (3.8 g,9.46 mmol) was dissolved in 50mL of dichloromethane, cooled to 0deg.C, compound 15f (1.2 g,5.21 mmol) and diisopropylethylamine (2.916 g,22.56mmol,4 mL) were added and the reaction stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added and stirred for 30 minutes, the solution was separated, the aqueous phase was extracted with methylene chloride (50 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 15g (3.93 g, 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-pentaaza-benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-7 (5H) -carboxylic acid tert-butyl ester 15H

15g (3.93 g,6.60 mmol) of the compound was dissolved in tetrahydrofuran, and 1, 8-diazabicyclo undec-7-ene (4.072 g,26.74mmol,4 mL) was added and the reaction stirred for 16 hours. To the reaction solution were added 50mL of water and 50mL of ethyl acetate, the solution was separated after complete dissolution, the aqueous phase was extracted with ethyl acetate (50 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and 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 (155 mg, 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-pentaaza-benzo [4,5] cyclohepta [1,2,3-de ] naphthalene-7 (5H) -carboxylic acid tert-butyl ester 15i

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

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-pentaaza-benzo [4,5] cyclohepta [1,2,3-de ] naphthalen-11 (12H) -one 15j

Compound 15i (140 mg,0.22 mmol) 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, saturated aqueous sodium hydrogencarbonate solution was added to the residue to pH >7, methylene chloride (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 (134 mg, yield: > 100%).

Tenth step

Compound 15j (134 mg,0.25 mmol) was dissolved in 10mL of dichloromethane, triethylamine (182 mg,1.77mmol,0.25 mL) was added, cooled to 0℃and acryloyl chloride (45 mg,0.497mmol, 40. Mu.L) was added dropwise thereto, and the reaction was stirred for 1 hour. 10mL of saturated aqueous sodium bicarbonate solution was added to quench, the solution was separated, the aqueous phase was extracted with methylene chloride (30 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, dissolved in 20mL of methanol, added with 250mg of sodium bicarbonate, and heated to 60℃to react for 1 hour. The reaction solution was cooled to room temperature, filtered, and the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel thin layer chromatography to give the title compound 15 (80 mg, yield: 54.21 mmol) as a spread system A.

MS m/z(ESI):589.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )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)。

Chiral preparation of compound 15 (80 mg, 0.284 mmol) (separation condition: chiral preparation column CHIRALPAK ID x 250mm,10 μm; mobile phase: n-hexane: ethanol (+0.1% aminomethylanol) =50/50, flow rate: 30 mL/min), collection of the corresponding components thereof, concentration under reduced pressure, to give the target compound 15-2 (15.07 mg)/15-1 (15.93 mg) and a mixture, and chiral preparation of the resulting mixture (separation condition: chiral preparation column CHIRALPAK AD x 250mm,10 μm; mobile phase: n-hexane: ethanol (+0.1% aminomethylanol) =50/50, flow rate: 30 mL/min) to give the target compound 15-4 (10.91 mg)/15-3 (20.38 mg).

Single configuration compound 15-4:

chiral HPLC analysis, retention time 6.138 min, chiral purity: 95.4% (column: OZ Phenomenex Lux Cellulose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 100% (chromatographic column: OZ Phenomenex Lux Cellulose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 94.7% (column: OZ Phenomenex Lux Cellulose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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 min, chiral purity: 100% (chromatographic column: OZ Phenomenex Lux Cellulose-2X 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]。

¹ H NMR(500MHz,DMSO-d ₆ )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: biological evaluation of ERK phosphorylation inhibition experiment of H358 cells

1. Purpose of testing

The test is based on IC by detecting the inhibition of ERK phosphorylation of H358 cells by compounds ₅₀ Size evaluation the inhibition of KRAS targets (containing G12C mutations) by the compounds of the present disclosure.

2. Experimental method

H358 cells (ATCC, CRL-5807) were cultured in complete medium of RPMI1640 (Hyclone, SH 30809.01) containing 10% fetal bovine serum. On the first day of the experiment, H358 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℃and 5% CO ₂ The cell culture incubator was incubated overnight. The next day, 10. Mu.L of a test compound in a gradient dilution with complete medium was added to each well, the final concentration of the compound was 9 concentration points at 6-fold gradient dilutions from 10. Mu.M, a blank containing 0.5% DMSO was set, the well plate was placed at 37℃and 5% CO ₂ Is incubated for 3 hours. After 3 hours, the 96-well cell culture plate was removed, the medium was aspirated, and 200. Mu.L of PBS (Shanghai Source culture Biotech Co., ltd., B320) was added to each well and washed once. The PBS was pipetted off, 50. Mu.L of lysis buffer (lysbuffer, cisbio,64KL1 FDF) containing blocking reagent (Cisbio, 64KB1 AAC) was added to each well, and the well plate was placed on a shaker and lysed for 30 minutes with shaking at room temperature. After lysis, 16. Mu.L of lysate was transferred to each well separately to two HTRF 96-well assay plates (Cisbio, 66PL 96100) after which 4. Mu.L of either pre-mixed phospho-ERK1/2 antibody solution (Cisbio, 64 AERPEG) or 4. Mu.L of pre-mixed total-ERK1/2 antibody solution (Cisbio, 64 NRKPEG) was added to each plate. The microplate was sealed with a sealing plate membrane, centrifuged in a microplate centrifuge for 1 min, and incubated overnight at room temperature in the absence of light. On the third day, the fluorescence values of the 337nm wavelength excitation, 665nm and 620nm wavelength emissions were read using a PHERAstar multifunctional microplate reader (BMG Labtech, S/N471-0361).

3. Data analysis

IC for compound inhibitory activity was calculated using Graphpad Prism software based on the compound concentration and pERK/total ERK ratio ₅₀ Values, results are presented in table 3 below.

TABLE 3 IC of the inhibition of ERK phosphorylation of H358 cells by the compounds of the present disclosure ₅₀ Values.

Examples numbering	IC ₅₀ (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

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on the ERK phosphorylation of H358 cells.

Test example 2: biological evaluation of MIA PaCa-2 cell ERK phosphorylation inhibition experiments

1. Purpose of testing

The test is based on IC by detecting the inhibition of ERK phosphorylation of MIA PaCa-2 cells by compounds ₅₀ Size evaluation the inhibition of KRAS targets (containing G12C mutations) by the compounds of the present disclosure.

2. Experimental method

MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in complete medium of DMEM/HIGH GLUCOSE (GE, SH 30243.01) containing 10% fetal bovine serum and 2.5% horse serum. On the first day of the experiment, MIA PaCa-2 cells were seeded in 96-well plates at a density of 25,000 cells/well using complete medium, 190. Mu.L of cell suspension per well, placed at 37℃and 5% CO ₂ The cell culture incubator was incubated overnight. The next day, 10. Mu.L of a test compound in a gradient dilution with complete medium was added to each well, the final concentration of the compound was 9 concentration points at 6-fold gradient dilutions from 10. Mu.M, a blank containing 0.5% DMSO was set, the well plate was placed at 37℃and 5% CO ₂ For 4 hours. After 4 hours, the 96-well cell culture plate was removed, the medium was aspirated, and 200. Mu.L of PBS (Shanghai Source culture Biotech Co., ltd., B320) was added to each well and washed once. The PBS was pipetted off, 50. Mu.L of lysis buffer (lysbuffer, cisbio,64KL1 FDF) containing blocking reagent (Cisbio, 64KB1 AAC) was added to each well, and the well plate was placed on a shaker and lysed for 30 minutes with shaking at room temperature. After lysis, 16. Mu.L of lysate was transferred to each well separately to two HTRF 96-well assay plates (Cisbio, 66PL 96100) after which 4. Mu.L of either pre-mixed phospho-ERK1/2 antibody solution (Cisbio, 64 AERPEG) or 4. Mu.L of pre-mixed total-ERK1/2 antibody solution (Cisbio, 64 NRKPEG) was added to each plate. The microplate was sealed with a sealing plate membrane, centrifuged in a microplate centrifuge for 1 min, and incubated overnight at room temperature in the absence of light. On the third day, the fluorescence values of the 337nm wavelength excitation, 665nm and 620nm wavelength emissions were read using a PHERAstar multifunctional microplate reader (BMG Labtech, S/N471-0361).

3. Data analysis

IC for compound inhibitory activity was calculated using Graphpad Prism software based on the compound concentration and pERK/total ERK ratio ₅₀ Values, results are presented in table 4 below.

TABLE 4 IC of the inhibition of ERK phosphorylation of MIA PaCa-2 cells by the compounds of the present disclosure ₅₀ Values.

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on MIA PaCa-2 cell ERK phosphorylation.

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

1. Purpose of testing

Inhibition of KRAS targets (containing G12C mutations) by compounds of the present disclosure was evaluated by testing their proliferation inhibition of MIA PaCa-cells.

2. Experimental method

MIA PaCa-2 cells (ATCC, CRL-1420) were cultured in complete medium, i.e., DMEM/HIGH GLUCOSE (GE, SH 30243.01) complete medium containing 10% fetal bovine serum and 2.5% horse serum. On the first day of the experiment, MIA PaCa-2 cells were seeded in 96-well plates at a density of 500 cells/well using complete medium, 90. Mu.L of cell suspension per well, placed at 37℃and 5% CO ₂ The cell culture incubator was incubated overnight. The next day, 10. Mu.L of a test compound in a gradient dilution with complete medium was added to each well, the final concentration of the compound was 9 concentration points at 5-fold gradient dilution starting from 10. Mu.M, a blank containing 0.5% DMSO was set, the well plate was placed at 37℃and 5% CO ₂ Is cultured in a cell culture incubator for 72 hours. On the fifth day, 96-well cell culture plates were removed and 50. Mu.L of each well was added

Luminescent Cell Viability Assay (luminescence cell activity assay reagent) (Promega, G7573), after 10 minutes at room temperature, luminescence signal values were read using a multifunctional microplate reader (PerkinElmer, VICTOR 3).

3. Data analysis

IC for calculating Compound inhibitory Activity Using Graphpad Prism software ₅₀ Values, results are shown in table 5 below.

TABLE 5 IC of the compounds of the present disclosure for MIA PaCa-2 cell proliferation inhibition ₅₀ Values.

Examples numbering	IC ₅₀ (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

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on MIA PaCa-2 cell proliferation.

Test example 4: biological evaluation of H358 cell proliferation experiments

1. Purpose of testing

Inhibition of KRAS targets (containing G12C mutations) by compounds of the present disclosure was evaluated by testing the proliferation inhibition of H358 cells by compounds of the present disclosure.

2. Experimental method

H358 cell%ATCC, CRL-5807) was cultured in complete medium, namely RPMI1640 medium (Hyclone, SH 30809.01) containing 10% fetal bovine serum (Corning, 35-076-CV). On the first day of the experiment, H358 cells were seeded at a density of 1500 cells/well in 96-well plates using complete medium, 100. Mu.L of cell suspension per well, placed at 37℃and 5% CO ₂ The cell culture incubator was incubated overnight. The next day, 10. Mu.L of a test compound in a gradient dilution with complete medium was added to each well, the final concentration of the compound was 9 concentration points at 5-fold gradient dilution starting from 10. Mu.M, a blank containing 0.5% DMSO was set, the well plate was placed at 37℃and 5% CO ₂ Is cultured in a cell culture incubator for 120 hours. On day seven, 96-well cell culture plates were removed and 50. Mu.L of each well was added

3. Data analysis

IC for calculating Compound inhibitory Activity Using Graphpad Prism software ₅₀ Values, results are presented in table 6 below.

TABLE 6 IC of the compounds of the present disclosure for inhibition of H358 cell proliferation ₅₀ Values.

Examples numbering	IC ₅₀ (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

Conclusion: the compound disclosed by the disclosure has a good inhibition effect on proliferation of H358 cells.

Claims

1. A compound of the general formula (I) or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof,

wherein:

g is N;

R ^1a and R is ^1b Identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group;

R ² identical or different and are each independently selected from hydrogen atoms, halogen, C _1-6 Alkyl, C _1-6 Alkoxy, C _1-6 Haloalkyl, cyano, amino, nitro, hydroxy and C _1-6 A hydroxyalkyl group;

R ³ identical or different and are each independently selected from hydrogen atoms, C _1-6 Alkyl, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group;

R ⁴ is fluorine;

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

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

provided that it is not

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

therein G, R ^1a 、R ^1b 、R ² -R ⁴ S and t are as defined in claim 1.

3. A compound of formula (I) according to claim 1, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (Ia-1) or (Ia-2), or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof:

wherein the method comprises the steps of

R ³ Identical or different and are each independently selected from C _1-6 Alkyl, C _1-6 HaloalkanesGroup C _1-6 A hydroxyalkyl group;

G、R ^1a 、R ^1b 、R ² 、R ⁴ and s is as defined in claim 1.

4. A compound of formula (I) according to claim 1, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, which is a compound of formula (Ia-a), (Ia-b), (Ib-a) or (Ib-b), or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof:

Therein G, R ^1a 、R ^1b 、R ² -R ⁴ S and t are as defined in claim 1.

5. A compound of the general formula (I) or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ^1a And R is ^1b The same or different, and are each independently a hydrogen atom or a halogen.

6. A compound of the formula (I) or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ^1a Is a hydrogen atom or halogen, R ^1b Is halogen.

7. A compound of the general formula (I) or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R ² Identical or different and are each independently C _1-6 An alkyl group.

8. A compound of the formula (I) or its atropisomer as claimed in any one of claims 1 to 4Enantiomers, diastereomers, or pharmaceutically acceptable salts thereof, wherein R ³ Identical or different and are each independently C _1-6 An alkyl group.

9. A compound of formula (I) according to claim 1, 2 or 4, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, wherein s is 1 or 2; and t is 0 or 1.

10. A compound or atropisomer, diastereomer or pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

11. a compound, or atropisomer thereof, or a pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

12. a compound represented by the general formula (I-A) or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof,

wherein M is an inorganic or organic acid;

n is 0, 1, 2 or 3;

G、R ^1a 、R ^1b 、R ² -R ⁴ s and t are as defined in claim 1;

provided that it is not:

13. a compound of formula (I-a) according to claim 12, wherein n is 0 or 1, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof.

14. A compound or atropisomer, diastereomer or pharmaceutically acceptable salt thereof, selected from any one of the following compounds:

15. a compound or atropisomer, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, selected from the group consisting of:

16. a process for preparing a compound of formula (I) according to claim 1 or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, which comprises:

Reacting a compound of formula (I-a) or an atropisomer, enantiomer, diastereomer or salt thereof with a compound of formula (I-B) under basic conditions to obtain a compound of formula (I) or an atropisomer, enantiomer, diastereomer or pharmaceutically acceptable salt thereof, wherein:

x is halogen;

m is an inorganic acid or an organic acid;

n is 0, 1, 2 or 3;

G、R ^1a 、R ^1b 、R ² -R ⁴ s and t are as defined in claim 1.

17. The method of claim 16, wherein n is 0 or 1.

18. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-11, or a atropisomer, enantiomer, diastereomer, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

19. Use of a compound according to any one of claims 1-11, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for inhibiting KRAS.

20. Use of a compound according to any one of claims 1-11, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for inhibiting KRAS G12C.

21. Use of a compound according to any one of claims 1-11, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for the treatment or prevention of cancer, inflammation, or other proliferative disease.

22. Use of a compound according to any one of claims 1-11, or an atropisomer, enantiomer, diastereomer or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 18, in the manufacture of a medicament for the treatment or prevention of cancer.

23. The use according to claim 21 or 22, wherein the cancer is selected from 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, osteochondrioma, osteosarcoma, seminoma, testicular tumor, head and neck tumor, multiple myeloma, malignant lymphoma, polycythemia vera, leukemia, thyroid tumor, ureteral tumor, bladder cancer, gallbladder cancer, cholangiocarcinoma, chorioallantoic carcinoma and pediatric tumor.