WO2020078401A1

WO2020078401A1 - Influenza virus replication inhibitor and uses thereof

Info

Publication number: WO2020078401A1
Application number: PCT/CN2019/111559
Authority: WO
Inventors: Huichao LUO; Qingyun REN; Junjun YIN; Chunlin Wu; Yuxin Fan; Yufeng Mo; Yingjun Zhang
Original assignee: Sunshine Lake Pharma Co., Ltd.
Priority date: 2018-10-17
Filing date: 2019-10-17
Publication date: 2020-04-23
Also published as: CN111057074A; CN111057074B

Abstract

The invention belongs to the field of medicine, and particularly relates to a novel compound as a replication inhibitor of influenza virus and a preparation method thereof, a pharmaceutical composition comprising the compound and use of the compound and pharmaceutical composition thereof in treating influenza. The present invention provides a compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof, The compound of the present invention can inhibit influenza virus well, and/or has lower cytotoxicity, better in vivo pharmacokinetic properties and in vivo pharmacodynamic properties.

Description

INFLUENZA VIRUS REPLICATION INHIBITOR AND USES THEREOF

CROSS-REFERENCE TO RELATED APPLICATION

The present application claims the priority and the benefit of the patent application No. 201811205455.1, filed with the State Intellectual Property Office of China on October 17, 2018, the disclosure of which are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention belongs to the field of medicine, and specifically relates to a novel compound as an influenza virus replication inhibitor, and a preparing method thereof, a pharmaceutical composition comprising the compound and use of the compound and pharmaceutical composition thereof in treating Influenza. More specifically, the compounds of the present invention are useful as inhibitors of influenza virus cap-dependent endonucleases.

BACKGROUND OF THE INVENTION

Influenza (hereinafter referred to as flu) is an acute respiratory infection that is seriously harmful to human health. It is caused by influenza virus and has high prevalence, widespread epidemics, and rapid spread. Influenza virus can cause more serious symptoms in elderly and children with weak immunity and some patients with immune disorders, such as pneumonia or cardiopulmonary failure. The flu virus which was called H1N1 was first discovered in 1933 by the Englishman Wilson Smith. H stands for hemagglutinin; N stands for neuraminidase. Numbers represent different types. Since the discovery of the flu virus, it has caused many pandemics worldwide, and an outbreak will occur in a decade or so, causing huge losses on a global scale. The influenza virus epidemic can cause 250,000 to 500,000 deaths per year, 3 to 5 million severe cases, and about 5%to 15%of people worldwide are infected. Every pandemic is due to the emergence of new strains in humans. Usually, these new strains are caused by the spread of existing influenza viruses from other animal species to humans.

The influenza virus is an RNA virus of the Orthomyxovirus family and belongs to the genus of influenza virus. According to the difference of antigenic characteristics and gene characteristics of virion nucleoprotein (NP) and matrix protein (M) , influenza viruses are mainly divided into three types: A, B, and C, also called A, B, and C. Type III viruses have similar biochemical and biological characteristics. Viral particles are 80-120 nm in diameter and are usually similar to spheres, but filamentous forms may appear. The virus consists of three layers, the inner layer is the viral nucleocapsid, containing nuclear protein (NP) , P protein and RNA. NP is a soluble antigen (Santigen) , which is type-specific and antigen-stable. P protein (P1, P2, P3) may be a polymerase required for RNA transcription and replication. The middle layer is a viral envelope composed of a layer of lipids and a membrane protein (MP) . MP is antigenically stable and also has type specificity. The outer layer is a radial protrusion composed of two different glycoproteins, namely hemagglutinin H and neuraminidase N. H can cause red blood cell agglutination, which is a tool for the virus to suck on the surface of sensitive cells. N can hydrolyze mucus protein and hydrolyze N-acetylneuraminic acid at the end of cell surface receptor-specific glycoprotein. N is a tool for the virus to detach from the cell surface after viral replication is completed. Both H and N have mutating properties, so when H and N have only strain-specific antigenicity, their antibodies have a protective effect.

Influenza A virus has one species, namely influenza A virus. Wild waterbirds are the natural hosts of a large number of influenza A viruses. Sometimes, viruses spread to other species and can cause devastating outbreaks in poultry or human influenza pandemics. Among the three types of influenza, type A virus is the most toxic human pathogen causing most serious diseases, which can be transmitted to other species and cause a large-scale epidemic of human influenza. According to the antibody response to these viruses, influenza A virus can be subdivided into different serotypes. In the order of the number of deaths caused by known human pandemic, we have confirmed that the human serotypes are: H1N1 (Spain influenza in 1918) , H2N2 (Asian influenza in 1957) , H3N2 (Hongkong influenza in 1968) , H5N1 (the threat of influenza season's pandemic in 2007-08) , H7N7 (rare animal infectious potential) , H1N2 (endemic in humans and pigs) , H9N2, H7N2, H7N3 and H10N7.

Influenza B virus has one species, influenza B virus, which often causes local influenza epidemic, does not cause a worldwide influenza pandemic, and is only found in human and seals. This type of influenza mutates at a rate 2-3 times slower than type A, resulting in a low genetic diversity, with only one serotype of influenza B. Owing to the lack of diversity of these antigens, humans usually acquire a certain level of immunity to influenza B at an early age. However, the mutation of influenza B virus is enough to make it impossible to sustain immunity. But the rate of change of its antigen is low, combined with its restricted host change (inhibiting cross-species antigen transformation) , which ensures that there will be no pandemic of influenza B.

Influenza C virus has one species. Influenza C virus exists mostly in the form of dispersal. It mainly infects infants and young children, and generally does not cause influenza pandemic. It can infect humans and pigs.

After the epidemic virus enters the host cell, replication (vRNA-cRNA-vRNA) and transcription (vRNA-mRNA) processes are completed in the nucleus, both of which are catalyzed by RNA polymerase encoded by the influenza virus. RNA polymerase consists of PB1, PB2 and PA subunits. The PB1 subunit is mainly involved in the replication process of the viral genome; the PB2 subunit is mainly responsible for binding to the host pro-mRNA cap-like structure to assist in the endonuclease cleavage process; the PA subunit is a key protein in the influenza virus life cycle, which has endonuclease activity, and is an enzyme necessary for the synthesis of viral mRNA. In addition, there is no enzyme that is similar to the activity of the PA subunit in the host cell. The structure of influenza virus mRNA needs to have both a 5' cap structure and a 3'-poly (A) tail for recognition by the host cell translation system. The 5' cap-like structure is 10-13 nucleotides (ie, cap-snatching) which is cleaved from the 5' end of the host cell pro-mRNA by the endonuclease activity of the RNA polymerase PA subunit, which is required for transcription initiation of influenza virus. Cap-snatching is a key event in the life cycle of influenza virus. There is no similar time and corresponding enzyme in the host cell. Therefore, the endonuclease inhibitor against cap-snatching can selectively block the transcription process of influenza virus with no effect on the host cell.

Vaccination and use of antiviral drugs are important means to cope with influenza pandemic. However, due to the strong mutation ability of influenza virus antigen, it is almost impossible to produce large-scale vaccine before the pandemic. Currently available antiviral therapeutics are M2 ion channel blockers amantadine and rimantadine, and neuraminidase inhibitors oseltamivir, Zanamivir, and Peramivir and Lanimamivir. However, for all of these drugs, the influenza virus has developed resistance. Therefore, there is a continuing need for new anti-influenza therapeutics.

Baloxavir marboxil, a new anti-influenza agent with a new mechanism of action, is marketed, which inhibits the synthesis of viral mRNA by inhibiting cap-dependent endonuclease and ultimately inhibits viral proliferation. Other compounds for treating the influenza by this mechanism of action are still an urgent need for scientists to develop.

SUMMARY OF THE INVENTION

The present invention provides a novel class of compounds which are inhibitors of influenza virus RNA polymerase, and more particularly, the present invention provides a novel class of cap-dependent endonuclease inhibitors of influenza viruses, such compounds and the compositions can be used for the preparation of a medicament for preventing, managing, treating or ameliorating a viral infectious in a patient. Compared with the existing analogous compounds, the compounds of the present invention can inhibit influenza virus well, and/or have lower cytotoxicity, more excellent in vivo pharmacokinetics properties and in vivo pharmacodynamic properties. Therefore, the compound provided by the present invention has more excellent drug-taking properties than the existing compound of the same type.

In one aspect, the present invention relates to a compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein

Y is -O-, -S-, -S (=O) -, -S (=O) ₂-, -CR ⁷R ⁸-or -N (R ⁹) -;

Ring Cy is a C _3-5 carbocyclic ring, a heterocyclic ring consisting of 3 to 8 atoms or a heteroaromatic ring consisting of 5 to 10 atoms ;

each of R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

each of R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

R ⁹ is H, deuterium, C _1-6 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OR ^b, -NR ^cR ^d, -C (=O) R ^a, -C (=O) OR ^b, -C (=O) NR ^cR ^d, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-4 alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5 to 10 atoms or (heteroaryl consisting of 5 to 10 atoms) -C _1-4 alkylene, wherein each of the C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-4 alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5 to 10 atoms and (heteroaryl consisting of 5 to 10 atoms) -C _1-4 alkylene is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

each R ^a, R ^b, R ^c and R ^d is independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

or R ^c, R ^d together with the nitrogen atom to which they are attached form a heterocyclic ring consisting of 3 to 6 atoms or a heteroaromatic ring consisting of 5 to 6 atoms, wherein each of the heterocyclic ring consisting of 3 to 6 atoms and heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

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

In some embodiments, wherein the ring Cy is a C _3-5 carbocyclic ring, a heterocyclic ring consisting of 3 to 6 atoms, a heteroaromatic ring consisting of 5 atoms or a heteroaromatic ring consisting of 6 atoms.

In other embodiments, wherein the ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, ethylene oxide, azetidine, oxetane, thietane, 1, 3-dioxolane, 1, 3-dithiocyclopentane, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine, pyridazine or 1, 3, 5-triazine.

In other embodiments, wherein each of the R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, each of R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, R ⁹ is H, deuterium, C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, each of the R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCF ₃, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In still other embodiments, each of R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCF ₃, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In still other embodiments, R ⁹ is H, deuterium, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In some embodiments, each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OR ^b, -NR ^cR ^d, -C (=O) R ^a, -C (=O) OR ^b, -C (=O) NR ^cR ^d, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-2 alkylene, heteroaryl consisting of 5 to 6 atoms or (heteroaryl consisting of 5 to 6 atoms) -C _1-2 alkylene, wherein each of the C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-2 alkylene, heteroaryl consisting of 5 to 6 atoms and (heteroaryl consisting of 5 to 6 atoms) -C _1-2 alkylene is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In some embodiments, each R ^a, R ^b, R ^c and R ^d is independently H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino;

or R ^c, R ^d together with the nitrogen atom to which they are attached form a heterocyclyl consisting of 5 to 6 atoms or a heteroaromatic ring consisting of 5 to 6 atoms, wherein each of the heterocyclyl consisting of 5 to 6 atoms and heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OH, -OCH ₃, -OCH ₂CH ₃, -NH ₂, -NHCH ₃, -NHCH ₂CH ₃, -N (CH ₃) ₂, -C (=O) OH, -C (=O) OCH ₃, -C (=O) OCH ₂CH ₃, -C (=O) NH ₂, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, -OCHF ₂, -OCF ₃, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, -OCHF ₂, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In other embodiments, each R ^a, R ^b, R ^c and R ^d is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl consisting of 5 to 6 atoms, wherein each of the methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, heterocyclyl consisting of 3 to 6 atoms, phenyl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

or R ^c, R ^d together with nitrogen atom to which they are attached form a heterocyclic ring consisting of 5 to 6 atoms, or a heteroaromatic ring consisting of 5 to 6 atoms; wherein each of the heterocyclic ring consisting of 5 to 6 atoms and the heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.

In other embodiments, the compound of the present invention is a compound having Formula (II) , or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

In other aspect, provided herein is a pharmaceutical composition comprising the compound disclosed herein.

In some embodiments, the pharmaceutical composition further comprises pharmaceutically acceptable carriers, adjuvants, vehicles and a combination thereof.

In some embodiments, the pharmaceutical compositions of the present invention further comprise one or more other therapeutic agents.

In other embodiments, other therapeutic agent is selected from anti-influenza virus agents or vaccines.

In other embodiments, other therapeutic agents involved in the pharmaceutical compositions of the present invention are Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Lanimamivir, Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, Ribavirin, stachyflin, Ingavirin, Influenza Fludase, Drug of CAS No. 1422050-75-6, Pimodivir, Baloxavir marboxil, Flu Vaccine (FluMist

Quadrivalent,

or

) , or their combination.

In other embodiments, the pharmaceutical composition of the present invention can be in the dosage form of liquid, solid, semisolid, gel or spray.

In other aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture a medicament for preventing, treating or reducing viral infectious diseases.

In some embodiments, the viral infection is an influenza virus infection.

In some embodiments, the influenza virus is H1N1 A/Weiss/43.

In other aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.

In other embodiments, RNA polymerase is cap-dependent endonuclease.

In other aspect, provided herein is the compound or the pharmaceutical composition for use in preventing, managing, treating or lessening a viral infectious disease in a patient.

In some embodiments, the viral infection is an influenza virus infection.

In other aspect, provided herein is the compound or the pharmaceutical composition for use in inhibiting influenza virus RNA polymerase.

In other embodiments, RNA polymerase is cap-dependent endonuclease.

In other aspect, provided herein is the method of preventing, managing, treating or lessening a viral infectious disease in a patient, wherein the method comprises administering a therapeutically effective amount of the compound or the pharmaceutical composition of the invention to the patient.

In some embodiments, the viral infection is an influenza virus infection.

In other aspect, provided herein is the method of inhibiting influenza virus RNA polymerase in a patient, wherein the method comprises administering a therapeutically effective amount of the compound or the pharmaceutical composition of the invention to the patient.

In other embodiments, RNA polymerase is cap-dependent endonuclease.

Unless otherwise stated, all stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts and pharmaceutically acceptable prodrugs of the compounds disclosed herein are within the scope of the invention. The term “pharmaceutically acceptable” means that a substance or composition must be chemically and/or toxically compatible with other components of the preparation and/or with mammals treated with it.

Other salts of compounds provided herein are also included, which are not necessarily pharmaceutically acceptable salts, but can be used as intermediates for the preparation and/or purification of compounds of the present invention and/or for the separation of enantiomers of compounds of the present invention.

Moreover, the compounds of the present invention, including their salts, can also be obtained in the form of hydrates, or in the form of other solvents for their crystallization. The compounds of the present invention may inherently or by design form solvates with pharmaceutically acceptable solvents (including water) ; therefore, it is intended that the invention embrace both solvated and unsolvated forms.

In other aspect, the compounds of the present invention may contain several asymmetric centers or the forms of racemic mixtures commonly described. The invention also further comprises racemic mixtures, partial racemic mixtures and separated enantiomers and non-enantiomers.

Compounds of the invention may exist in the form of a possible isomer, a rotating isomer, a atropisomer isomer, a tautomer or a mixture thereof. The invention may further comprise a mixture of isomers, rotating isomers, atropisomer isomers and tautomers of the compounds of the invention, or a partial mixture of isomers, rotating isomers, atropisomer isomers, tautomers or separated isomers, rotating isomers, atropisomer isomers and tautomers.

In another aspect, the compounds of the invention include isotopically labeled compounds as defined herein, for example those within radioactive isotopes, such as ³H, ¹⁴C and ¹⁸F, or those within non-radioactive isotopes, such as ²H and ¹³C.

In other aspect, provided herein is a method of preparing, separating or purifying the compound of Formula (I) or Formula (II) .

The foregoing merely summarizes certain aspects disclosed herein and is not intended to be limited in nature. These aspects and other aspects and embodiments are described more fully below.

DETAILED DESCRIPTION

DEFINITIONS AND GENERAL TERMINOLOGY

Reference will now be made in detail to certain embodiments of the invention, examples of which are illustrated in the accompanying structures and formulas. The invention is intended to cover all alternatives, modifications, and equivalents which may be included within the scope of the present invention as defined by the claims. One skilled in the art will recognize many methods and materials similar or equivalent to those described herein, which could be used in the practice of the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application (including but not limited to defined terms, term usage, described techniques, or the like) , this application controls.

It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.

As used herein, the following definitions shall apply unless otherwise indicated. For purposes of this invention, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, and the Handbook of Chemistry and Physics, 75th Ed. 1994. Additionally, general principles of organic chemistry are described in “Organic Chemistry” , Thomas Sorrell, University Science Books, Sausalito: 1999, and Smith et al., “March’s Advanced Organic Chemistry” , by Michael B. Smith and Jerry March, John Wiley & Sons, New York: 2007, the entire contents of which are hereby incorporated by reference.

The grammatical articles “a” , “an” and “the” , as used herein, are intended to include “at least one” or “one or more” unless otherwise indicated herein or clearly contradicted by the context. Thus, the articles are used herein to refer to one or more than one (i.e. at least one) of the grammatical objects of the article. By way of example, “a component” means one or more components, and thus, possibly, more than one component is contemplated and may be employed or used in an implementation of the described embodiments.

As used herein, the term “subject” refers to an animal. Typically the animal is a mammal. A subject also refers to primates (e.g., humans) , cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds and the like. In certain embodiments, the subject is a primate. In yet other embodiments, the subject is a human.

The terms “subject” and “patient” as used herein are used interchangeably. The terms “subject” and “patient” refer to animals (eg, birds or mammals such as chickens, quails, or turkeys) , particularly “mammals” including non-primates (eg, cows, pigs) ., horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (eg, monkeys, chimpanzees, and humans) , and more particularly humans. In one embodiment, subject is non-human animal, for example livestock (eg. horse, cow, pig or sheep) or pets (eg. dogs, cats, guinea pigs or rabbits) . In other embodiments, “patient” refers to a human.

The term “comprise” is an open expression, it means comprising the contents disclosed herein, but don’t exclude other contents.

The invention also includes isotopically-labeled compounds of the invention which are identical to those described herein except the fact that one or more atoms are replaced by an atom having an atomic mass or mass different from the natural common atomic mass or mass number. Exemplary isotopes that may also be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, for example ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁶O, ¹⁷O, ³¹P, ³²P, ³⁶S, ¹⁸F and ³⁷Cl.

Compounds of the invention comprising the aforementioned isotopes and/or other isotopes of other atoms, as well as pharmaceutically acceptable salts of said compounds are included within the scope of the invention. Certain isotopically-labeled compounds of the present invention, for example those into which radioactive isotopes eg. ³H and ¹⁴C are incorporated, are useful in drug and/or substrate tissue distribution assays. Deuterated, i.e., ³H, and carbon-14, i.e., ¹⁴C isotope is particularly preferred because of its ease of preparation and detection. In addition, substitution with heavy isotopes such as deuterium, i.e., ²H, may provide some therapeutic advantages resulting from greater metabolic stability, such as increased half-life in vivo or reduced dosage requirements. Therefore, it may be preferable in some cases.

“Stereoisomers” refers to compounds which have identical chemical constituton, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer) , geometric (cis/trans) isomer, atropisomer, etc.

Stereochemical definitions and conventions used herein generally follow S.P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984) McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S., “Stereochemistry of Organic Compounds” , John Wiley & Sons, Inc., New York, 1994. The compounds disclosed herein may contain asymmetric or chiral centers, and therefore exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds disclosed herein, including, but not limited to, diastereomers, enantiomers and atropisomers, as well as mixtures thereof such as racemic mixtures, form part of the present invention. Many organic compounds exist in optically active forms, i.e., they have the ability to rotate the plane of plane-polarized light. In describing an optically active compound, the prefixes D and L, or R and S, are used to denote the absolute configuration of the molecule about its chiral center (s) . The prefixes d and l or (+) and (-) are employed to designate the sign of rotation of plane-polarized light by the compound, with (-) or l meaning that the compound is levorotatory. A compound prefixed with (+) or d is dextrorotatory. A specific stereoisomer may be referred to as an enantiomer, and a mixture of such stereoisomers is called an enantiomeric mixture. A 50: 50 mixture of enantiomers is referred to as a racemic mixture or a racemate, which may occur where there has been no stereoselection or stereospecificity in a chemical reaction or process.

Any asymmetric atom (e.g., carbon or the like) of the compound (s) disclosed herein can be present in racemic or enantiomerically enriched, for example the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configuration. In certain embodiments, each asymmetric atom has at least 50 %enantiomeric excess, at least 60 %enantiomeric excess, at least 70 %enantiomeric excess, at least 80 %enantiomeric excess, at least 90 %enantiomeric excess, at least 95 %enantiomeric excess, or at least 99 %enantiomeric excess in the (R) -or (S) -configuration. If possible, a substituent on an atom having an unsaturated double bond may exist in the form of cis- (Z) -or trans- (E) -.

Depending on the choice of the starting materials and procedures, the compounds can be present in the form of one of the possible stereoisomers or as mixtures thereof, such as racemates and diastereoisomer mixtures, depending on the number of asymmetric carbon atoms. Optically active (R) -and (S) -isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. If the compound contains a double bond, the substituent may be E or Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis-or trans-configuration.

Any resulting mixtures of stereoisomers can be separated on the basis of the physicochemical differences of the constituents, into the pure or substantially pure geometric isomers, enantiomers, diastereomers, for example, by chromatography and/or fractional crystallization.

Any resulting racemates of final products or intermediates can be resolved into the optical antipodes by methods known to those skilled in the art, e.g., by separation of the diastereomeric salts thereof. Racemic products can also be resolved by chiral chromatography, e.g., high performance liquid chromatography (HPLC) using a chiral adsorbent. Preferred enantiomers can also be prepared by asymmetric syntheses. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981) ; Principles of Asymmetric Synthesis (2 ^nd Ed. Robert E. Gawley, Jeffrey Aubé, Elsevier, Oxford, UK, 2012) ; Eliel, E.L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962) ; Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E.L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972) ; Chiral Separation Techniques: A Practical Approach (Subramanian, G. Ed., Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2007) .

The term “tautomer” or “tautomeric form” refers to structural isomers of different energies which are interconvertible via a low energy barrier. Where tautomerization is possible (e.g. in solution) , a chemical equilibrium of tautomers can be reached. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons. A specific example of keto-enol tautomerization is the interconversion of pentane-2, 4-dione and 4-hydroxypent-3-en-2-one tautomers. Another example of tautomerization is phenol-keto tautomerization. The specific example of phenol-keto tautomerization is pyridin-4-ol and pyridin-4 (1H) -one tautomerism. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

Thus, as described herein, the compounds of the invention may exist in the form of one of the possible isomers, rotamers, atropisomers, tautomers, or mixtures thereof, for example, substantially pure geometric (cis or trans) isomer, diastereomer, optical isomer (enantiomer) , racemate or a mixture thereof.

The term “N-oxide” refers to one or more than one nitrogen atoms oxidised to form an N-oxide, when a compound contains several amine functions. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid) (See, Advanced Organic Chemistiy, by Jerry March, 4th Edition, Wiley Interscience, pages) . More particularly, N-oxides can be made by the procedure of L.W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (MCPBA) , for example, in an inert solvent such as dichloromethane.

The term “solvate” refers to an association or complex of one or more solvent molecules and a compound disclosed herein. Some non-limiting examples of the solvent that form solvates include water, isopropanol, ethanol, methanol, dimethylsulfoxide (DMSO) , ethyl acetate, acetic acid and ethanolamine. The term “hydrate” refers to the complex where the solvent molecule is water.

The term “metabolite” refers to a product produced through metabolism in the body of a specified compound or salt thereof. The metabolites of a compound may be identified using routine techniques known in the art and their activities determined using tests such as those described herein. Such products may result for example from oxidation, reduction, hydrolysis, amidation, deamidation, esterification, deesterification, enzyme cleavage, and the like, of the administered compound. Accordingly, the invention includes metabolites of compounds disclosed herein, including metabolites produced by contacting a compound disclosed herein with a mammal for a sufficient time period.

The term “pharmaceutically acceptable salt” refers to organic or inorganic salts of a compound disclosed herein. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1-19, which is incorporated herein by reference. Some non-limiting examples of pharmaceutically acceptable and nontoxic salts include salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid and malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, laurylsulfate, malate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N ⁺ (C _1-4 alkyl) ₄ salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds disclosed herein. Water or oil soluble or dispersable products may be obtained by such quaternization. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, C _1-8 sulfonate or aryl sulfonate.

The term “prodrug” refers to that a compound is transformed in vivo into a compound of Formula (I) . Such a transformation can be affected, for example, by hydrolysis of the prodrug form in blood or enzymatic transformation to the parent form in blood or tissue. Prodrugs of the compounds disclosed herein may be, for example, esters. Some common esters which have been utilized as prodrugs are phenyl esters, aliphatic (C _1-24) esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound disclosed herein that contains a hydroxy group may be acylated at this position to give a compound in its prodrug form. Other prodrug forms include phosphates, such as, those phosphate compounds derived from the phosphonation of a hydroxy group on the parent compound. A thorough discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, J. Rautio et al., Prodrugs: Design and Clinical Applications, Nature Reviews Drug Discovery, 2008, 7, 255-270, and Hecker et al., Prodrugs of Phosphates and Phosphonates, J. Med. Chem., 2008, 51, 2328-2345, all of which are incorporated herein by reference in their entireties.

In general, the term “substituted” refers to the replacement of one or more hydrogen radicals in a given structure with the radical of a specified substituent. As described herein, the compounds disclosed herein may optionally be substituted with one or more substituents, such as are illustrated generally below, or as exemplified by particular classes, subclasses, and species of the invention. The term “optionally substituted by “may be used interchangeably with the term “unsubstituted or substituted by” , ie the structure is unsubstituted or substituted by one or more substituents described herein.

Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group. When more than one position in a given structure can be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. The substituents are not limited to H, deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, oxo (=O) , -COOH, -OR ^b, -NR ^cR ^d, -C (=O) R ^a, -C (=O) OR ^b, -C (=O) NR ^cR ^d, haloalkyl, alkoxy, alkylthio, alkylamino, haloalkoxy, alkyl, alkenyl, alkynyl, cycloalkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, carbocyclyl-alkylene, heterocyclyl-alkylene, aryl-alkylene or heteroaryl-alkylene, wherein each of R ^a, R ^b, R ^c, and R ^d has definitions as described in the present invention.

Furthermore, what need to be explained is that the phrase “each…is independently” and “each of…and…is independently” , unless otherwise stated, should be broadly understood. The specific options expressed by the same symbol are independent of each other in different groups; or the specific options expressed by the same symbol are independent of each other in same groups.

At various places in the present specification, substituents of compounds disclosed herein are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “C _1-6 alkyl” especially refers to independently disclosed methyl, ethyl, C ₃ alkyl, C ₄ alkyl, C ₅ alkyl and C ₆ alkyl, the term “heteroaryl consisting of 5 to 10 atoms” especially refers to independently disclosed heteroaryl consisting of 5 atoms, heteroaryl consisting of 6 atoms, heteroaryl consisting of 7 atoms, heteroaryl consisting of 8 atoms, heteroaryl consisting of 9 atoms and heteroaryl consisting of 10 atoms.

At various places in the present specification, linking substituents are described. Where the structure clearly requires a linking group, the Markush variables listed for that group are understood to be linking groups. For example, if the structure requires a linking group and the Markush group definition for that variable lists “alkyl” or “aryl” then it is understood that the “alkyl” or “aryl” represents a linking alkylene group or arylene group, respectively.

The term “alkyl” or “alkyl group” as used herein, denotes a saturated straight or branched monovalent hydrocarbon radical containing 1 to 20 carbon atoms. Unless otherwise specified, the alkyl group contains 1-20 carbon atoms; in some embodiments, the alkyl group contains 1-12 carbon atoms; in some embodiments, the alkyl group contains 1-10 carbon atoms; in other embodiments, the alkyl group contains 1-9 carbon atoms; in still other embodiments, the alkyl group contains 1-8 carbon atoms; in still yet other embodiments, the alkyl group contains 1-6 carbon atoms; in still yet other embodiments, the alkyl group contains 1-4 carbon atoms; in still yet other embodiments, the alkyl group contains 1-2 carbon atoms.

Examples of alkyl group include, but are not limited to methyl (Me, -CH ₃) , ethyl (Et, -CH ₂CH ₃) , n-propyl (n-Pr, -CH ₂CH ₂CH ₃) , isopropyl (i-Pr, -CH (CH ₃) ₂) , n-butyl (n-Bu, -CH ₂CH ₂CH ₂CH ₃) , isobutyl (i-Bu, -CH ₂CH (CH ₃) ₂) , sec-butyl (s-Bu, -CH (CH ₃) CH ₂CH ₃) , tert-butyl (t-Bu, -C (CH ₃) ₃) , n-pentyl (-CH ₂CH ₂CH ₂CH ₂CH ₃) , 2-pentyl (-CH (CH ₃) CH ₂CH ₂CH ₃) , 3-pentyl (-CH (CH ₂CH ₃) ₂) , 2-methyl-2-butyl (-C (CH ₃) ₂CH ₂CH ₃) , 3-methyl-2-butyl (-CH (CH ₃) CH (CH ₃) ₂) , 3-methyl-1-butyl (-CH ₂CH ₂CH (CH ₃) ₂) , 2-methyl-1-butyl (-CH ₂CH (CH ₃) CH ₂CH ₃) , n-hexyl (-CH ₂CH ₂CH ₂CH ₂CH ₂CH ₃) , 2-hexyl (-CH (CH ₃) CH ₂CH ₂CH ₂CH ₃) , 3-hexyl (-CH (CH ₂CH ₃) (CH ₂CH ₂CH ₃) ) , 2-methyl-2-pentyl (-C (CH ₃) ₂CH ₂CH ₂CH</pt989> ₃) , 3-methyl-2-pentyl (-CH (CH ₃) CH (CH ₃) CH ₂CH ₃) , 4-methyl-2-pentyl (-CH (CH ₃) CH ₂CH (CH ₃) ₂) , 3-methyl-3-pentyl (-C (CH ₃) (CH ₂CH ₃) ₂) , 2-methyl-3-pentyl (-CH (CH ₂CH ₃) CH (CH ₃) ₂) , 2, 3-dimethyl-2-butyl (-C (CH ₃) ₂CH (CH ₃) ₂) , 3, 3-dimethyl-2-butyl (-CH (CH ₃) C (CH ₃) ₃) , n-heptyl, n-octyl, etc.

The term “alkylene” refers to a saturated divalent hydrocarbon group derived from a saturated hydrocarbon by the removal of two hydrogen atoms. Unless otherwise specified, the alkylene group contains 1-12 carbon atoms. In other embodiments, the alkylene group contains 1-6 carbon atoms. In other embodiments, the alkyl group contains 1-4 carbon atoms. In still other embodiments, the alkyl group contains 1-2 carbon atoms. And alkylene group is exemplified by methylene (-CH ₂-) , ethylene (-CH ₂CH ₂-) , isopropylene (-CH (CH ₃) CH ₂-) , and the like.

The term “alkenyl” refers to linear or branched-chain monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp ² double bond, wherein the alkenyl radical may be optionally substituted independently with one or more substituents described herein, and includes radicals having “cis” and “trans” orientations, or alternatively, “E” and “Z” orientations. In some embodiments, the alkenyl contains 2 to 8 carbon atoms. In other embodiments, the alkenyl contains 2 to 6 carbon atoms. In still other embodiments, the alkenyl contains 2 to 4 carbon atoms. Some non-limiting examples of the alkenyl group include ethenyl or vinyl (-CH=CH ₂) , allyl (-CH ₂CH=CH ₂) , propenyl (CH ₃-CH=CH-) , and the like.

The term “alkynyl” refers to a linear or branched monovalent hydrocarbon radical of 2 to 12 carbon atoms with at least one site of unsaturation, i.e., a carbon-carbon, sp triple bond, wherein the alkynyl radical may be optionally substituted independently with one or more substituents described herein. In some embodiments, the alkynyl contains 2 to 8 carbon atoms. In other embodiments, the alkynyl contains 2 to 6 carbon atoms. In still other embodiments, the alkynyl contains 2 to 4 carbon atoms. Examples of such groups include, but are not limited to, ethynyl (-C≡CH) , propargyl (-CH ₂C≡CH) , 1-propynyl (-C≡C-CH ₃) , and the like.

The term “alkoxy” refers to an alkyl group, as previously defined, attached to the parent molecular moiety via an oxygen atom. Unless otherwise specified, the alkoxy group contains 1-12 carbon atoms. In some embodiments, the alkoxy group contains 1-6 carbon atoms. In other embodiments, the alkoxy group contains 1-4 carbon atoms. In still other embodiments, the alkoxy group contains 1-3 carbon atoms.

Some non-limiting examples of the alkoxy group include methoxy (MeO, -OCH ₃) , ethoxy (EtO, -OCH ₂CH ₃) , 1-propoxy (n-PrO, n-propoxy, -OCH ₂CH ₂CH ₃) , 2-propoxy (i-PrO, i-propoxy, -OCH (CH ₃) ₂) , 1-butoxy (n-BuO, n-butoxy, -OCH ₂CH ₂CH ₂CH ₃) , 2-methyl-1-propoxy (i-BuO, i-butoxy, -OCH ₂CH (CH ₃) ₂) , 2-butoxy (s-BuO, s-butoxy, -OCH (CH ₃) CH ₂CH ₃) , 2-methyl-2-propoxy (t-BuO, t-butoxy, -OC (CH ₃) ₃) , 1-pentyloxy (n-pentyloxy, -OCH ₂CH ₂CH ₂CH ₂CH ₃) , 2-pentyloxy (-OCH (CH ₃) CH ₂CH ₂CH ₃) , 3-pentyloxy (-OCH (CH ₂CH ₃) ₂) , 2-methyl-2-butoxy (-OC (CH ₃) ₂CH ₂CH ₃) , 3-methyl-2-butoxy (-OCH (CH ₃) CH (CH ₃) ₂) , 3-methyl-1-butoxy (-OCH ₂CH ₂CH (CH ₃) ₂) , 2-methyl-1-butoxy (-OCH ₂CH (CH ₃) CH ₂CH ₃) , etc.

The term “alkylthio “refers to radicals containing a linear or branched C _1-10 alkyl radical attached to a divalent sulfur atom. In some embodiments, alkylthio is C _1-6 alkylthio; in some embodiments, alkylthio is a lower C _1-4 alkylthio group. Such examples include but are not limited to methylthio (-SCH ₃) . Wherein the alkylthio radical is optionally substituted with one or more substitutents described herein.

The terms “haloalkyl” , “haloalkenyl” or “haloalkoxy” refer to alkyl, alkenyl or alkoxy may be substituted with one or more halogen atoms. Such examples include but are not limited to fluoromethyl (-CH ₂F) , difluoromethyl (-CHF ₂) , trifluoromethyl (-CF ₃) , fluoroethyl (-CHFCH ₃, -CH ₂CH ₂F) , difluoroethyl (-CF ₂CH ₃, -CHFCH ₂F, -CH ₂CHF ₂) , perfluoroethyl, fluoropropyl (-CHFCH ₂CH ₃, -CH ₂CHFCH ₃, -CH ₂CH ₂CH ₂F) , difluoropropyl (-CF ₂CH ₂CH ₃, -CFHCFHCH ₃, -CH ₂CH ₂CHF ₂, -CH ₂CF ₂CH ₃, -CH ₂CHFCH ₂F) , trifluoroethyl (-CH ₂CF ₃, -CHFCHF ₂, -CF ₂CH ₂F) , trifluoropropyl, 1, 1-dichloroethyl, 1, 2-dichloropropyl, trifluoromethoxy (-OCF ₃) , difluoromethoxy (-OCHF ₂) , 2, 2, 2-trifluoroethoxy (-OCH ₂CF ₃) , etc.

The term “carbocyclyl” , “carbocycle” or “carbocyclic group” refers to a monovalent or multivalent, nonaromatic, saturated or partially unsaturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic or tricyclic ring system. Carbon bicyclic group includes spirocarbon bicyclic group, fused carbon bicyclic group, and bridged carbon bicyclic group. In some embodiments, the number of carbon atoms is 3 to 12; in other embodiments, the number of carbon atoms is 3 to 10; in some embodiments, the number of carbon atoms is 3 to 8; in other embodiments, the number of carbon atoms is 3 to 6; in other embodiments, the number of carbon atoms is 5 to 6; in other embodiments, the number of carbon atoms is 5 to 8. Examples of the carbocycle group include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl (1-cyclopentyl-1-enyl, 1-cyclopentyl-2-enyl, 1-cyclopentyl-3-enyl) , cyclohexyl, 1-cyclohexyl-1-enyl, 1-cyclohexyl-2-enyl, 1-cyclohexyl-3-enyl, cyclopentadienyl, cyclohexadienyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl and the like.

The term “cycloalkyl” refers to a monovalent or multivalent non-aromatic saturated ring having 3 to 12 carbon atoms as a monocyclic, bicyclic, or tricyclic ring system. In some embodiments, the cycloalkyl contains 3 to 12 carbon atoms. In still other embodiments, the cycloalkyl contains 3 to 8 carbon atoms. In yet other embodiments, the cycloalkyl contains 3 to 6 carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. The cycloalkyl is optionally substituted with one or more substituents described herein.

The term “heteroatom” refers to oxygen, sulfur, nitrogen, phosphorus and silicon, including any oxidized form of nitrogen, sulfur, or phosphorus; the quaternized form of any basic nitrogen; or a substitutable nitrogen of a heterocyclic ring, for example, N (as N in 3, 4-dihydro-2H-pyrrolyl) , NH (as NH in pyrrolidinyl) or NR (as NR ^T in N-substituted pyrrolidinyl, R ^T represents a substituent described in the present invention) .

The term “heterocycle” , “heterocyclic group” , “heterocyclyl” , or “heterocyclic” as used interchangeably herein refers to a monocyclic, bicyclic or tricyclic ring containing 3-14 ring atoms of which one or more ring atoms is substituted by hetero atom as defined herein, and which is completely saturated or contains one or more units of unsaturation, but an aromatic ring can not exist in the heterocyclyl group. In some embodiments, heterocyclyl is a ring system composed of 3 to 8 ring atoms; in other embodiments, heterocyclyl is a ring system composed of 3 to 6 ring atoms; in other embodiments, heterocyclyl is a ring system composed of 5 to 6 ring atoms; in other embodiments, heterocyclyl is a ring system composed of 4 ring atoms; in other embodiments, heterocyclyl is a ring system composed of 5 ring atoms; in other embodiments, heterocyclyl is a ring system composed of 6 ring atoms; in other embodiments, heterocyclyl is a ring system composed of 7 ring atoms. In some embodiments, the “heterocycle” , “heterocyclic” , “heterocyclyl” or “heterocyclic group” is a monocycle having 3 to 8 ring members (e.g., 2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S) , or a bicycle having 7 to 12 ring members (e.g., 4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P and S) , and wherein the “heterocycle” , “heterocyclyl” or “heterocyclic” group is optionally substituted with one or more substituents described herein.

Unless otherwise specified, the heterocyclyl group may be a carbonyl group or a nitrogen group, and a -CH ₂-group can be optionally replaced by a -C (=O) -group. In which, the sulfur can be optionally oxygenized to S-oxide. And the nitrogen atom of the ring can be optionally oxygenized to N-oxide. Some non-limiting examples of the heterocyclyl group include ethylene oxide, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiolanyl (i.e. 1, 3-dithiocyclopentyl) , tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thioxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 2-oxa-5-azabicyclo [2.2.1] hept-5-yl, and the like. Some non-limiting examples of heterocyclyl in which -CH ₂-group is replaced by -C (=O) -moiety include 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, etc. Some non-limiting examples of the heterocyclyl group of which the ring sulfur atom is oxidized include sulfolanyl, 1, 1-dioxo-thiomorpholinyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents disclosed herein.

The term “aryl” or “aromatic ring” used interchangeably herein refers to monocyclic, bicyclic and tricyclic carbocyclic ring systems having a total of 6 to 14 ring members, or 6 to 12 ring members, or 6 to 10 ring members, wherein at least one ring in the system is aromatic, wherein each ring in the system contains 3 to 7 ring members and that has a single point or multipoint of attachment to the rest of the molecule. Examples of aryl may include phenyl, naphthyl and anthracenyl. The aryl group may be optionally substituted with one or more substituents disclosed herein.

The terms “heteroaryl” , “heteroaromatic ring” or “heteroaromatic compound” used interchangeably herein refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 5 to 14 ring members, preferably, 5 to 10 ring members, and more preferably 5 to 6 ring members, and wherein at least one ring in the system is aromatic and at least one ring contains one or more heteroatoms When a -CH ₂-group is present in a heteroaryl group, the -CH ₂-group can be optionally replaced by -C (=O) -. In other embodiments, a heteroaryl group is a heteroaryl group consisting of 5 to 10 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, a heteroaryl group is a heteroaryl group consisting of 5 to 6 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, a heteroaryl group is a heteroaryl group consisting of 5 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N. In other embodiments, a heteroaryl group is a heteroaryl group consisting of 6 atoms containing 1, 2, 3 or 4 heteroatoms independently selected from O, S and N.

Some non-limiting examples of heteroaryl include furanyl (such as 2-furyl, 3-furyl) , imidazolyl (such as N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl) , isoxazolyl (such as 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl) , oxazolyl (eg 2-oxazolyl, 4-oxazolyl, 5-oxazolyl) , pyrrolyl (eg. N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl) , pyridyl (eg. 2-pyridyl, 3-pyridyl, 4-pyridyl) , pyrimidinyl (eg. 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl) , pyridazinyl (such as 3-pyridazinyl) , thiazolyl (such as 2-thiazolyl, 4-thiazolyl, 5-thiazolyl) , tetrazolyl (such as 5H-tetrazolyl, 2H-tetrazolyl) , triazolyl (such as 2-triazolyl, 5-triazolyl, 4H-1, 2, 4-triazolyl, 1H-1, 2, 4-triazolyl, 1, 2, 3-triazolyl) , thienyl (eg. 2-thienyl, 3-thienyl) , pyrazolyl (eg. 2-pyrazolyl, 3-pyrazolyl) , isothiazolyl, oxadiazolyl (eg. 1, 2, 3-oxadiazolyl, 1, 2, 5-oxadiazolyl, 1, 2, 4-oxadiazolyl, 1, 3, 4-oxadiazolyl) , thiodiazolyl (eg. 1, 2, 3-thiodiazolyl, 1, 3, 4-thiodiazolyl, 1, 2, 5-thiodiazolyl) , pyrazinyl, 1, 3, 5-triazinyl; also include the following bicyclic groups, but are not limited to bicyclic rings: benzimidazolyl, benzofuranyl, benzothienyl, indolyl (eg. 2-indolyl) , purinyl, quinolyl (eg. 2-quinolinyl, 3-quinolinyl, 4-quinolinyl) , isoquinolinyl (such as 1-isoquinolinyl, 3-isoquinolinyl or 4-isoquinolinyl) , imidazo [1, 2-a] pyridyl, pyrazolo [1, 5-a] pyridyl, pyrazolo [1, 5-a] pyrimidinyl, imidazo [1, 2-b] pyridazinyl, [1, 2, 4] triazolo [4, 3-b] pyridazinyl, [1, 2, 4] triazolo [1, 5-a] pyrimidinyl, [1, 2, 4] triazolo [1, 5-a] pyridinyl, indolinyl, 1, 2, 3, 4-tetrahydroisoquinolinyl. The heteroaryl group is optionally substituted with one or more substituents disclosed herein.

The term “consisting of n atoms” or “n-membered” , wherein n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a heterocyclyl consisting of 6 atoms and naphthyl is an example of an aryl consisting of 10 atoms.

The term “unsaturated” refers to a moiety having one or more units of unsaturation.

The term “halogen” refers to fluoro (F) , chloro (Cl) , bromo (Br) , or iodo (I) .

The term “D” refers to the deuteration, i.e. ²H.

The term “carboxy” , whether used alone or in conjunction with other terms, such as “carboxyalkyl” , means -CO ₂H.

The term “carbonyl” , whether used alone or with other terms, such as “aminocarbonyl” or “acyloxy” , refers to (C=O) -.

The term “alkylamino” refers to “N-alkylamino” and “N, N-dialkylamino” wherein amino groups are independently substituted with one alkyl radical or two alkyl radicals, respectively. In some embodiments, the alkylamino group is alkylamino group having one or two C _1-6 alkyl groups attached to nitrogen atom. In some embodiments, the alkylamino group is alkylamino group having one or two C _1-3 alkyl groups attached to nitrogen atom. Some non-limiting examples of suitable alkylamino radical include mono or dialkylamino. Some examples include, but not limited to, N-methylamino, N-ethylamino, N, N-dimethylamino and N, N-diethylamino, and the like.

The term “cycloalkyl-alkylene” , “carbocyclyl-alkylene” , “heterocyclyl-alkylene” , “aryl-alkylene” , “heteroaryl-alkylene” denotes a cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl group attached to the rest of the molecule through an alkylene group, wherein alkylene, cycloalkyl, carbocyclyl, heterocyclyl, aryl and heteroaryl groups all have the meanings as described herein. The “cycloalkyl-alkylene” , “carbocyclyl-alkylene” , “heterocyclyl-alkylene” , “aryl-alkylene” , “heteroaryl-alkylene” are optionally substituted with one or more substituents described herein.

As described herein, a bond drawn from a substituent (R) _f to the center of one ring within a ring system represents substitution of f substituents R at any substitutable position or any reasonable position on the ring. For example, Formula a represents that the D ring may be substituted by f R, and when f is greater than 1, each R may be independently selected from the same or different substituent groups.

As described herein, a bond drawn from a substituent R to the center of polycyclic within a ring system (as shown in Formula b) represents substitution of the substituent R at any substitutable position or any reasonable position on the ring (as H ring in Formula b) . For example, formula b represents the substituent R at any of the substitutable positions on the H ring, as shown in formula b-1 to b-3:

The phrase “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The term “carrier” refers to a diluent, adjuvant, excipient, or matrix with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. Water or aqueous solution saline solutions and aqueous dextrose and glycerol solutions are preferably employed as carriers, particularly for injectable solutions. Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences” by E.W. Martin.

As used herein, the term “inhibiting replication of an influenza virus” includes reducing the amount of viral replication (e.g., reducing at least 10%) and completely preventing viral replication (i.e., 100%reducing the amount of viral replication) . In some embodiments, influenza virus replication is inhibited by at least 50%, at least 65%, at least 75%, at least 85%, at least 90%, or at least 95%.

The term “effective amount” of a compound of the invention refers to an amount that causes the desired biological response. In the present invention, it is expected that the biological reaction is to inhibit influenza virus replication, reduce the amount of influenza virus or reduce or improve the severity, duration, progression or onset of influenza virus infection, prevent the spread of influenza virus infection, and prevent recurrence, evolution, onset or progression of symptoms associated with influenza virus infection, or enhance the prophylactic or therapeutic effect of another anti-influenza infection therapy used. The exact amount of compound administered to a subject will depend on the mode of administration, the type and severity of the infection, and the characteristics of the subject, such as health, age, sex, weight, and tolerance to the drug. The skilled person will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other antiviral agents, such as in combination with an anti-influenza drug, the “effective amount” of the second agent will depend on the type of drug employed. Suitable dosages of the approved agents are known and can be adjusted by the skilled depending on the symptoms of the subject, the type of condition being treated and the amount of the compound of the invention employed. In cases where the amount is not explicitly stated, an effective amount should be taken. For example, a compound of the invention can be administered to a subject in a dosage range of about 0.01 to 100 mg per body weight per day for therapeutic or prophylactic treatment.

The term “treatment” as used herein refers to both therapeutic and prophylactic treatment. Therapeutic treatment includes alleviating or ameliorating the progression, severity and/or duration of an influenza virus-mediated condition, or ameliorating one or more symptoms of an influenza virus-mediated condition (in particular, one or more discernible symptoms) , by administration of one or more therapies. (for example, one or more therapeutic agents, e.g. compounds and compositions of the present invention) In a particular embodiment, the therapeutic treatment comprises ameliorating at least one measurable physical parameter of influenza virus-mediated condition. In other embodiments, therapeutic treatment includes physical suppression of influenza virus-mediated symptoms by, for example, stabilizing identifiable symptoms, or physiological suppression of influenza virus-mediated symptoms by, for example, stabilizing physical parameters. In other implementations, therapeutic treatment includes mitigation or stabilization of influenza virus-mediated infections. Antiviral drugs can be used in the community to treat people already suffering from influenza to reduce the severity of symptoms and reduce days of illness.

The term “protecting group” or “PG” refers to a substituent that is commonly employed to block or protect a particular functionality while reacting with other functional groups on the compound. For example, an “amino-protecting group” is a substituent attached to an amino group that blocks or protects the amino functionality in the compound. Non-limited suitable amino-protecting groups include acetyl, trifluoroacetyl, P-toluenesulfonyl (Ts) , t-butoxy-carbonyl (BOC, Boc) , benzyloxycarbonyl (CBZ, Cbz) and 9-fluorenylmethylenoxy-carbonyl (Fmoc) . Similarly, a “hydroxy-protecting group” refers to a substituent of a hydroxy group that blocks or protects the hydroxy functionality. Suitable protecting groups include acetyl and silyl. A “carboxy-protecting group” refers to a substituent of the carboxy group that blocks or protects the carboxy functionality. Common carboxy-protecting groups include -CH ₂CH ₂SO ₂Ph, cyanoethyl, 2- (trimethylsilyl) ethyl, 2- (trimethylsilyl) ethoxy-methyl, 2- (p-toluenesulfonyl) ethyl, 2- (p-nitrophenylsulfonyl) -ethyl, 2- (diphenylphosphino) -ethyl, nitroethyl and the like. For a general description of protecting groups and their use, see T. W. Greene, Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; and P. J. Kocienski, Protecting Groups, Thieme, Stuttgart, 2005.

DESCRIPTION OF COMPOUNDS OF THE INVENTION

The present invention provides a novel class of compounds which are inhibitors of influenza virus RNA polymerase, and more particularly, the present invention provides a novel class of inhibitors of influenza virus cap-dependent endonuclease, such compounds and the composition thereof can be used to prevent, manage, treat or ameliorate a viral infection in a patient. Compared with the existing analogous compounds, the compounds of the present invention have better pharmacological activities, and/or have lower toxicity, more excellent in vivo pharmacokinetic properties and in vivo pharmacodynamic properties. Therefore, the compound provided by the present invention has more excellent drug-taking properties than the conventional compound of the same type.

wherein Y, ring Cy, R ^x, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶ and m have a definition as described in the present invention.

In some embodiments, Y is -O-, -S-, -S (=O) -, -S (=O) ₂-, -CR ⁷R ⁸-or -N (R ⁹) -, wherein R ⁷, R ⁸ and R ⁹ have a definition as described in the present invention.

In some embodiments, each R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino.

In other embodiments, R ⁹ is H, deuterium, C _1-6 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino.

In other embodiments, each R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, R ⁹ is H, deuterium, C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl group and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, each R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCF ₃, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In some embodiments, ring Cy is a C _3-5 carbocyclic ring, a heterocyclic ring consisting of 3 to 8 atoms or a heteroaromatic ring consisting of 5 to 10 atoms.

In other embodiments, wherein the ring Cy a C _3-5 carbocyclic ring, a heterocyclic ring consisting of 3 to 6 atoms, a heteroaromatic ring consisting of 5 atoms or a heteroaromatic ring consisting of 6 atoms.

In other embodiments, the ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, ethylene oxide, azetidine, oxetane, thietane, 1, 3-dioxolane, 1, 3-dithiocyclopentane, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine, pyridazine or 1, 3, 5-triazine.

In other embodiments, wherein each of R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino.

In other embodiments, each of R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, each of R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCF ₃, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In some embodiments, each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OR ^b, -NR ^cR ^d, -C (=O) R ^a, -C (=O) OR ^b, -C (=O) NR ^cR ^d, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-4 alkylene, heterocyclyl consisting of 3to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5 to 10 atoms or (heteroaryl consisting of 5 to 10 atoms) -C _1-4 alkylene, wherein each of the C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-4 alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5 to 10 atoms or (heteroaryl consisting of 5 to 10 atoms) -C _1-4 alkylene is unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino; wherein R ^a, R ^b, R ^c and R ^d have definitions described herein.

In some embodiments, each R ^a, R ^b, R ^c and R ^d is independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl , heterocyclyl consisting of 3 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

or R ^c, R ^d together with the nitrogen atom to which they are attached form the heterocyclyl consisting of 3 to 6 atoms or heteroaromatic ring consisting of 5 to 6 atoms, wherein each of the heterocyclyl consisting of 3 to 6 atoms and heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino.

In some embodiments, m is 0, 1, 2, 3 or 4.

In other embodiments, each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OR ^b, -NR ^cR ^d, -C (=O) R ^a, -C (=O) OR ^b, -C (=O) NR ^cR ^d, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-2 alkylene, heteroaryl consisting of 5 to 6 atoms or (heteroaryl consisting of 5 to 6 atoms) -C _1-2 alkylene, wherein each of the C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-2 alkylene, heteroaryl consisting of 5 to 6 atoms and (heteroaryl consisting of 5 to 6 atoms) -C _1-2 alkylene is unsubstituted or substituted by 1, 2, 3 or 4 substitutents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino, wherein R ^a, R ^b, R ^c and R ^d have definitions described herein.

In other embodiments, each R ^a, R ^b, R ^c and R ^d is independently H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl group, heterocyclyl consisting of 3 to 6 ring atoms, phenyl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 alkyl group, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl group, heterocyclyl consisting of 3 to 6 ring atoms, phenyl or heteroaryl consisting of 5 to 6 atoms is independently unsubstitued or substituted by 1, 2, 3, or 4 substituents selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino;

or R ^c, R ^d together with the nitrogen atom to which they are attached form the heterocyclyl consisting of 5 to 6 atoms or heteroaromatic ring consisting of 5 to 6 atoms, wherein each of the heterocyclyl consisting of 5 to 6 atoms and heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.

In other embodiments, each R ^x is H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OH, -OCH ₃, -OCH ₂CH ₃, -NH ₂, -NHCH ₃, -NHCH ₂CH ₃, -N (CH ₃) ₂, -C (=O) OH, -C (=O) OCH ₃, -C (=O) OCH ₂CH ₃, -C (=O) NH ₂, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, -OCHF ₂, -OCF ₃, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propylenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, -OCHF ₂, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.

In other embodiments, each R ^a, R ^b, R ^c and R ^d is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl group consisting of 5 to 6 atoms, wherein each of the methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

In other embodiments, the present invention provides a compound having Formula (II) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof:

wherein Y, ring Cy, R ¹, R ², R ³, R ⁴, R ⁵, R ⁶, and m have a definition as described in the present invention.

In other embodiments, the present invention relates to one of the following compounds or stereoisomers, tautomers, N-oxides, solvents, metabolites, pharmaceutically acceptable salts or prodrugs thereof, but is by no means limited to these compounds:

In other aspect, provided herein is a pharmaceutical composition comprising an effective amount of the compound disclosed herein.

In some embodiments, the compound further comprises at least one of pharmaceutically acceptable carriers, adjuvants, vehicles and a combination thereof.

In other embodiments, other therapeutic agent is selected from anti-influenza agents or vaccines.

In other embodiments, the pharmaceutical composition can be in the dosage form of liquid, solid, semisolid, gel or spray.

In other embodiments, other therapeutic agent of the pharmaceutical compositions relates to Amantadine, Rimantadine, Oseltamivir, Zanamivir, Peramivir, Lanimamivir, Laninamivir Octanoate Hydrate, Favipiravir, Arbidol, Ribavirin, stachyflin, Ingavirin, Influenza Fludase, Drug of CAS No. 1422050-75-6, Pimodivir, Baloxavir marboxil, Flu Vaccine (FluMist

Quadrivalent,

or

) , or their combination.

In other aspect, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for preventing, treating or reducing viral infectious diseases.

In some embodiments, the viral infection is an influenza virus infection.

In other embodiments, the influenza virus is H1N1 A/Weiss/43.

In other embodiments, provided herein is use of the compound or the pharmaceutical composition disclosed herein in the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.

In other embodiments, RNA polymerase is cap-dependent endonuclease.

The present invention also comprises uses of the compound and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating Influenza virus infectious disease in patients including those diseases described in the invention. The present invention provides a pharmaceutical composition comprising effective therapeutic dose of the combination of the compound of Formula (I) or Formula (II) with at least one of pharmaceutically acceptable carriers. The carrier of the present invention includes, but is not limited to, an excipient, a diluent, an adjuvant, a vehicle or any combination thereof.

The present invention also provides a method of treating or alleviating, or sensitive to influenza virus infectious diseases in a patient comprising administering to the patient a therapeutically effective amount of the compound of Formula (I) or Formula (II) .

Unless otherwise stated, all stereoisomers, tautomers, N-oxides, hydrates, solvates, metabolites, and pharmaceutically acceptable salts and prodrugs of the compounds disclosed herein are within the scope of the invention.

In certain embodiments, the salt is a pharmaceutically acceptable salt. The phrase “pharmaceutically acceptable” refers to that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients comprising a formulation, and/or the mammal being treated therewith.

The salts of the compounds disclosed herein also include salts which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for preparing and/or purifying compounds of Formula (I) or Formula (II) , and/or for separating enantiomers of compounds of Formula (I) .

PHARMACEUTICAL COMPOSITION OF THE COMPOUND OF THE INVENTION AND PREPARATIONS AND ADMINISTRATION

The invention provides a pharmaceutical composition comprising the compound of formula (I) or stereoisomers, mixtures of racemic or non-racemic of isomers or pharmaceutically acceptable salts or solvents thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, and optionally other therapeutic and/or preventive components. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, adjuvant, vehicle or a combination thereof. The amount of compound in the compositions of the present invention is effective in treating or reducing Influenza virus infectious disease.

It will also be appreciated that certain of the compounds disclosed herein can exist in free form for treatment, or where appropriate, as a pharmaceutically acceptable derivative thereof. Some non-limiting examples of the pharmaceutically acceptable derivative include pharmaceutically acceptable prodrugs, salts, esters, salts of such esters, or any other adducts or derivatives which upon administration to a patient in need is capable of providing, directly or indirectly, a compound as otherwise described herein, or a metabolite or residue thereof.

As described above, the pharmaceutical compositions disclosed herein further comprise a pharmaceutically acceptable carrier, an adjuvant, a vehicle or a combination thereof, which, as used herein, includes any and all solvents, diluents, or other liquid vehicle, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. As described in the following: In Remington: Troy et al., Remington: The Science and Practice of Pharmacy, 21st ed., 2005, Lippincott Williams & Wilkins, Philadelphia, and Swarbrick et al., Encyclopedia of Pharmaceutical Technology, eds. 1988-1999, Marcel Dekker, New York, both of which are herein incorporated by reference in their entireties, discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for the preparation thereof. Except insofar as any conventional carrier medium incompatible with the compounds disclosed herein, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other components of the pharmaceutically acceptable composition, its use is contemplated to be within the scope of this invention.

Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to ion exchanger, alumina, aluminum stearate, lecithin, serum protein (eg. human serum albumin) , buffer substances (eg. Tween 80, phosphate, glycine, sorbic acid or potassium sorbate) , partial glyceride mixture of saturated plant fatty acids , water, salt or electrolyte (eg. protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride or zinc salt) , silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-block copolymer, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (eg. lactose, glucose and sucrose) , starch (eg. corn starch and potato starch) , fiber and its derivatives (eg. sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate) , powdered tragacanth, malt, gel, talc, excipients (eg. cocoa butter and suppository wax) , oil (eg. peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil) , ethylene glycol (eg. propylene glycol or polyethylene glycol) , esters (eg. ethyl oleate and ethyl dodecanoate) ) , agar, buffer (eg. magnesium hydroxide and aluminum hydroxide) , alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, and phosphate buffer, other non-toxic compatible lubricants (eg. sodium lauryl sulfate and magnesium stearate) , and colorants, anti-adhesives, coatings, sweeteners and flavoring agents, preservatives and antioxidants may also be present in the compositions according to the formulator's judgment.

The compounds or compositions of the invention may be administered by any suitable means, which are administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as with powders, ointments or drops) , nasal spray according to the severity of the infection.

Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compound, the liquid dosage forms may contain inert diluent commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butanediol, dimethylformamide, oils (in particular, cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil) , glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral compositions may also contain adjuvants such as wetting agents, emulsifying or suspending agents, sweetening agents, flavoring agents and fragrances.

Injectable preparations, such as sterile injectable aqueous or oily suspensions, may be formulated using suitable dispersing or wetting agents and suspensions in accordance with common techniques. The sterile injectable preparation may also be a non-toxic parenterally acceptable diluent or sterile injectable solution in solvent, a suspension or an emulsion such as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents, what can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any odorless, fixed oil may be employed including synthetic monoglycerides or diglycerides. In addition, fatty acids, such as oleic acid, are used in the preparation of injectables.

For example, the injectable preparation can be sterilized by filtration through a bacterial retention filter or by the addition of a bactericidal agent which is previously dissolved or dispersible in sterile water or other sterile injectable medium.

In order to prolong the action of the compounds or compositions of the invention, it is often desirable to slow the absorption of the compound by subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material having poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of the parenterally administered compound can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable storage forms are made by forming a microcapsule matrix of a compound in a biodegradable polymer such as polylactide-polyglycolic acid. The rate of compound release can be controlled based on the ratio of compound to polymer and the nature of the particular polymer employed. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Injectable depot formulations are also prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.

Compositions for rectal or vaginal administration may in particular be by mixing a compound of the invention together with a suitable non-irritating excipient or carrier, such as cocoa butter, polyethylene glycol or suppository wax. The excipient or carrier is solid at ambient temperature but liquid at body temperature and thus melting and releasing the active compound in the rectum or vaginal cavity.

Oral solid dosage forms include capsules, tablets, pills, powders and granules. In these solid dosage forms, the active compounds are mixed with at least one pharmaceutically acceptable inert excipient or carrier such as sodium citrate or dicalcium phosphate or a) fillers or expansion agents such as starch, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) blocker solutions such as paraffin, f) absorption enhancers such as quaternary amines, g) wetting agents such as cetyl alcohol and glyceryl monostearate, h) absorbents such as kaolin and bentonite, i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the formulations may also comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers in soft and hard gel capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols. Solid dosage forms of tablets, lozenges, capsules, pills and granules can be prepared with coatings and shells, for example enteric coatings and other coatings well known in the pharmaceutical arts. They may optionally contain opacifying agents and may also be of a nature of the composition such that the active ingredient is optionally released in a delayed manner or, preferably, in a portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

The active compounds may also be presented in microencapsulated form with one or more of the above-mentioned excipients. In these solid dosage forms, the active compound may be mixed with at least one inert diluent, such as sucrose, lactose or starch. In general, such dosage forms may also contain additional materials other than inert diluents, such as tableting lubricants and other tableting aids, eg. magnesium stearate and microcrystalline cellulose. They may optionally contain opacifying agents and may also be of a nature of the composition such that the active ingredient is optionally released in a delayed manner or, preferably, in a portion of the intestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes.

Topical or transdermal administration forms of the compounds of the invention include ointments, ointments, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers which may be required. Ophthalmic formulations, ear drops, and eye drops are also considered as being within the scope of the invention. Additionally, the present invention contemplates the use of a dermal patch that provides the added benefit of controlling the delivery of the compound to the body. This dosage form can be prepared by dissolving or dispersing the compound in an appropriate medium. Absorption accelerant can also be used to increase the flow of compounds through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

The composition of the invention may also be administered orally, parenterally, by inhalation spray via topical, rectal, nasal, buccal, vaginal or by implantation of a kit. The term “parenteral” as used in the present invention includes, but is not limited to, subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. The composition of the invention is administered orally, intraperitoneally or intravenously particularlly.

The sterile injectable form of the composition of the prevention may be water or oil suspension. These suspensions can be prepared following techniques known in the art using suitable dispersing or wetting agents and suspension. In addition, sterile fixed oils are conventionally employed as a solvent or suspension medium. For this purpose, any odorless, fixed oil may be employed including synthetic monoglycerides or diglycerides. In addition, it is as with that natural pharmaceutically acceptable oils, especially in the form of polyoxyethylenated, such as olive oil or castor oil, fatty acids such as oleic acid and its glyceride derivatives are used in the preparation of injectables. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethylcellulose or similar dispersants which are conventionally employed in the formulation of pharmaceutically acceptable dosage forms (including emulsions and suspensions) . Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid or other dosage forms can also be used for formulation purposes.

The pharmaceutical compositions of the present invention can be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of oral tablets, conventional carriers include, but are not limited to, lactose and starch. A lubricant such as magnesium stearate is also usually added. For oral administration in capsule form, useful diluents include lactose and dried cornstarch. When an aqueous suspension is required orally, the active ingredient is combined with emulsifier and suspension. Some sweeteners, flavor enhancers or colorants may also be added if desired.

Alternatively, the pharmaceutical compositions of the invention may be administered in the form of a suppository for rectal use. These pharmaceutical compositions can be prepared by mixing agents and non-irritating excipients. Such substances include, but are not limited to, cocoa butter, beeswax, and polyethylene glycol.

The pharmaceutical compositions of the present invention may also be administered topically, especially when the therapeutic target includes areas or organs that are readily accessible by topical administration, including ocular, cutaneous or low intestinal disease. It is easy to prepare suitable topical formulations for each of these areas or organs.

Topical administration to the lower intestinal tract can be achieved in a rectal suppository formulation (see above) or a suitable enema formulation. A topical skin patch can also be used.

For topical administration, the pharmaceutical compositions may be formulated as a suitable ointment containing the active component suspended or dissolved in one or more carriers. Suitable carriers of compounds for topical administration of the present invention include, but are not limited to, mineral oil, vaseline oil, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsified waxes and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or creamcontaining the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetostearyl alcohol, 2-octyl dodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or especially solution in isotonic pH adjusted sterile saline, with or without a preservative such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition can be formulated as a salve, such as petrolatum.

The pharmaceutical composition can also be administered by nasal aerosolized spray or by inhalation. This composition is prepared according to techniques well known in the pharmaceutical arts and prepared into solutions in brine using benzyl alcohol and other suitable preservatives, absorption enhancer for improving bioavailability, fluorocarbons and/or other conventional solubilizers or dispersants.

The compounds used in the methods of the invention can be formulated in unit dosage form. The term “unit dosage form” refers to physically discrete units suitable as unitary dosages of the subject, each unit containing a predetermined amount of active substance calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be one of a single daily dose or multiple daily doses (e.g., about 1 to 4 or more times per day) . When multiple daily doses are used, the unit dosage form for each dose may be the same or different.

USE OF THE COMPOUNDS AND PHARMACEUTICAL COMPOSITIONS

The above compounds and pharmaceutical compositions provided by the present invention are used in the manufacture of medicaments for preventing, treating or ameliorating a viral infectious disease in a patient. Preferably, the viral infection is an influenza virus infection.

The present invention also provides the use of the above compound or a pharmaceutical composition thereof in the manufacture of a medicament for inhibiting influenza virus RNA polymerase, preferably the RNA polymerase inhibitor is a cap-dependent endonuclease.

The present invention provides a method for treating, preventing or delaying an infection caused by a virus, the method comprising administering to a patient in need of treatment a therapeutically effective amount of the above compound or a pharmaceutical composition thereof. Wherein the virus is an influenza virus. Furthermore, the above compounds or pharmaceutical compositions thereof provided by the present invention may be co-administered with other therapies or therapeutic agents. The mode of administration can be simultaneous, sequential or at regular intervals.

The dosage of the compound or pharmaceutical composition required for the treatment, prevention or delay will generally depend on the specific compound being administered, the patient, the specific disease or condition and its severity, the route and frequency of administration, etc., and it is judged by attending physician according to the specific situation. For example, when the compound or pharmaceutical composition provided by the present invention is administered by the intravenous route, it can be administered once a week or even at a longer interval.

In summary, the present invention provides a novel compound which is useful as an influenza virus RNA polymerase inhibitor. The compounds of the present invention are suitable for the manufacture of a variety of dosage forms and are widely used in the treatment of seasonal influenza, avian influenza, swine influenza, and influenza virus mutant strains resistant to oseltamivir.

Besides being useful for human treatment, these compounds and pharmaceutical compositions are also useful for veterinary treatment of animals such as companion animals, exotic animals and mammals in farm animals. In other embodiments, the animals disclosed herein include horses, dogs, and cats. As used herein, the compounds disclosed herein include the pharmaceutically acceptable derivatives thereof.

GENERAL SYNTHETIC PROCEDURES

In the present invention, if the chemical name of the compound doesn’t match the corresponding structure, the compound is characterized by the corresponding structure.

To describe the invention, the examples are listed below. However, it should be understood that the invention is not limited to the embodiments, but merely provides a method of practicing the invention.

Generally, the compounds disclosed herein may be prepared by methods described herein, wherein the substituents are as defined for Formula (I) , except where further noted. The following non-limiting schemes and examples are presented to further exemplify the invention.

Persons skilled in the art will recognize that the chemical reactions described may be readily adapted to prepare a number of other compounds disclosed herein, and alternative methods for preparing the compounds disclosed herein are deemed to be within the scope disclosed herein. For example, the synthesis of non-exemplified compounds according to the invention may be successfully performed by modifications apparent to those skilled in the art, e.g., by appropriately protecting interfering groups, by utilizing other suitable reagents known in the art other than those described, and/or by making routine modifications of reaction conditions. Alternatively, the reactions or known reaction conditions disclosed herein will be recognized as having applicability for preparing other compounds disclosed herein.

In the examples described below, unless otherwise indicated all temperatures are set forth in degrees Celsius. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company, Arco Chemical Company and Alfa Chemical Company, J&K Scientific Ltd., and were used without further purification unless otherwise indicated. Common solvents were purchased from commercial suppliers such as Shantou XiLong Chemical Factory, Guangdong Guanghua Reagent Chemical Factory Co. Ltd., Guangzhou Reagent Chemical Factory, Tianjin YuYu Fine Chemical Ltd., Tianjin Fuchen Reagent Chemical Factory, Wuhan Xinhuayuan Technology Development Co., Ltd. Qingdao Tenglong Reagent Chemical Ltd., and Qingdao Ocean Chemical Factory, Beijing Coupling Technology Co., Ltd., Shanghai Tebo Chemical Technology Co., Ltd. and Accela ChemBio Co., Ltd (Shanghai) .

Anhydrous THF, 1, 4-dioxane, toluene, and ether were obtained by refluxing the solvent with sodium. Anhydrous CH2Cl2 and CHCl3 were obtained by refluxing the solvent with CaH2. EtOAc, PE, hexane, N, N-DMAC and N, N-DMF were treated with anhydrous Na ₂SO ₄ prior use.

The reactions set forth below were done generally under a positive pressure of nitrogen or argon or with a drying tube (unless otherwise stated) in anhydrous solvents, and the reaction flasks were typically fitted with rubber septa for the introduction of substrates and reagents via syringe. Glassware was oven dried and/or heat dried. Glassware was oven dried and/or heat dried.

Column chromatography was conducted using a silica gel column. Silica gel (300-400 mesh) was purchased from Qingdao Ocean Chemical Factory.

1H NMR spectra were recorded at room temperature with a Bruker 400 MHz or 600 MHz spectrometer using CDCl ₃, d ₆-DMSO, CD ₃OD or d ₆-acetone as solvents (reported in ppm) , and using TMS (0 ppm) or chloroform (7.26 ppm) as the reference standard. When peak multiplicities were reported, the following abbreviations were used: s (singlet) , d (doublet) , t (triplet) , m (multiplet) , br (broadened) , dd (doublet of doublets) , and dt (doublet of triplets) . Coupling constant, expressed in J, were reported in Hertz (Hz) .

Low-resolution mass spectral (MS) data were determined on an Agilent 6120 Quadrupole HPLC-MS spectrometer equipped with an Agilent Zorbax SB-C18 (2.1 x 30 mm, 3.5 μm, 6 min, flow rate 0.6 mL/min) ; the mobile phases consisted of a combination of (0.1%formic acid in CH ₃CN) and (0.1%formic acid in H ₂O) in gradient mode (5%to 95%) , and an electrospray ionization (ESI) source was used, the peak of HPLC was recorded with UV detection at 210 nm /254 nm.

Purification of compound by preparative chromatography was detecteded on Agilent 1260 Series high performance liquid chromatography (Pre-HPLC) or Calesep Pump 250 Series high performance liquid chromatography (Pre-HPLC) with UV detection at 210/254 nm (NOVASEP, 50/80 mm, DAC) .

The LC/MS/MS system for analysis in bioassay experiments includes Agilent 1200 Series Vacuum Degassing Furnace, Binary Syringe Pump, Orifice Autosampler, Column Incubator, Electrospray Ionization (ESI) Source AB Sciex 4000 Triple Four Polar mass spectrometer.

Waters Xbridge-C18, 2.1 × 30 mm, 3.5 μm column with 5 μL of sample injected was used for analysis. Analysis condition: the mobile phase is 0.5%aqueous formic acid (A) and the mixture solution (B) of acetonitrile: isopropanol (v/v: 2: 1) . Flow rate is 0.5 mL/min. The mobile phase gradient is shown in Table A:

Table A

Time	The gradient of mobile phase B
0.5 min	20 %
1.0 min	90 %
1.8 min	90 %
1.83 min	20 %
2.2 min	20 %
2.3 min	90 %
3.0 min	90 %
3.01 min	20 %
4.0 min	termination

The following abbreviations are used throughout the specification:

The experimental steps for preparing the compounds disclosed in the present invention were listed in the following synthetic scheme. Wherein, each ring Cy, R ¹, R ², R ³, R ⁴, R ^x and m has a definition as described in the present invention. R ^j is C _1-6 alkyl. Further, each of R ¹, R ², R ³ and R ⁴ is independently preferably H or F. R ^j is methyl or ethyl.

Scheme 1

The intermediate of Formula (6) can be prepared by the method disclosed in the scheme 1. First, reaction of compound (1) and compound (2) can give compound (3) . Then, compound (3) can be hydrolysed in the basic conditions to give compound (4) ; compound (4) can be suffered from ring-closed under the action of polyphosphoric acid (PPA) to give compound (5) . Finally, compound (5) can give the intermediate (6) under the action of sodium borohydride.

Scheme 2

The compound of Formula (9) can be prepared by the method disclosed in the scheme 2. Reaction of compound (6) and compound (7) in the present of condensing agent such as 1-propylphosphoric anhydride can give compound (8) . Compound (8) can be suffered from deprotection of protecting group on the hydroxy to give compound (9) . Compound (9) can be isolated under preparative chromatography to give the corresponding isomer.

Scheme 3

The compound of Formula (12) can be prepared by the method disclosed in the scheme 3. Reaction of compound (6) and compound (10) in the present of condensing agent such as 1-propylphosphoric anhydride can give compound (11) . Compound (11) can be suffered from deprotection of protecting group on the hydroxy to give compound (12) . Compound (12) can be isolated under preparative chromatography to give the corresponding isomer.

Scheme 4

The intermediate of Formula (3) can be prepared by the method disclosed in the scheme 4. First compound (13) can form Grignard reagent in the present of magnesium and iodine. The Grignard reagent further can react with elemental sulfur to give compound (14) . Then, reaction of compound (14) and compound (2) can give intermediate (3) .

EXAMPLES

The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.

Preparation examples

In the following preparation examples, the preparation process of the compound of the present invention has been described in detail by taking a part of the compounds of the present invention as an example.

Example 1 The mixture of (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione and (S) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

Mixture:

Step 1) Synthesis of 7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

The title compound was prepared by the synthetic method disclosed in the patent application WO 2016175224.

Step 2) : synthesis of benzo [b] thiophene-7-thiol

7-Bromobenzothiophene (5.00 g, 23.5 mmol) was added into THF (50 mL) , and the mixture was cooled to -78℃. Then sulfur powder (0.79 g, 25 mmol) was added. The mixture was stirred for 0.5 h at -78℃. A solution of tert-butyllithium in tetrahydrofuran (36 mL, 47 mmol, 1.3 mol/L) was added slowly and the resulting solution was continuously stirred at -78℃ for 4.5 h. The reaction was quenched with saturated aqueous solution of ammonium chloride (50 mL) . The mixture was warmed to rt and stirred for 10 minutes, and extracted with ether (50 mL) . The reaction mixture was poured into separator funnel and separated. The organic phase was washed with 2N aqueous sodium hydroxide solution (50 mL × 2) . The aqueous phase was adjusted to pH 2～3 with 6N hydrochloric acid and extracted with EA (50 mL × 3) . The combined organic phases were washed with saturated saline (50 mL) , dried over anhydrous sodium sulfate, concentrated in vacuo to dryness under reduced pressure to give light yellow liquid (2.20 g, 56.4%) .

Step 3) : synthesis of ethyl 2- ( (benzo [b] thiophen-7-ylthio) methyl) -3, 4-difluorobenzoate

Ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (4.10 g, 14.7 mmol) , benzo [b] thiophene-7-thiol (2.20 g, 13.2 mmol) and DMF (15 mL) were added to a round-bottomed flask, and then potassium carbonate (3.66 g, 26.5 mmol) and aluminum oxide (2.02 g, 19.8 mmol) were added. The resulting solution was stirred overnight at rt under protection of nitrogen. The reaction was quenched with water (20 mL) and ethyl acetate (10 mL × 3) was added for extraction. The combined organic phases were washed with saturated brine (20 mL) , dried over anhydrous sodium sulfate, and concentrated in vacuo, and the residue was purified by silica gel column chromatography (PE/EA (v/v) = 20/1) to give the title compound as light yellow liquid (2.70 g, 56.0%) .

MS (ESI, pos. ion) m/z: 364.9 [M+H] ⁺;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.77 (dd, J = 7.0, 1.8 Hz, 1H) , 7.67 (ddd, J = 8.7, 5.1, 1.8 Hz, 1H) , 7.46 (d, J = 5.5 Hz, 1H) , 7.37 (d, J = 5.5 Hz, 1H) , 7.33 –7.21 (m, 2H) , 7.06 (dd, J = 16.7, 8.9 Hz, 1H) , 4.67 (d, J = 1.7 Hz, 2H) , 4.23 –4.04 (m, 2H) , 1.31 (m, 3H) .

Step 4) Synthesis of 2- ( (benzo [b] thiophen-7-ylthio) methyl) -3, 4-difluorobenzoic acid

Ethyl 2- ( (benzo [b] thiophen-7-ylthio) methyl) -3, 4-difluorobenzoate (2.70 g, 7.41 mmol) was added into ethanol (20 mL) , and sodium hydroxide (1.50 g, 37.5 mmol) and water (10 mL) were added to the reaction solution. The mixture was stirred overnight at rt. After the reaction was finished, water (20 mL) was added, and the solution was adjusted to pH 2-3 with 1N HCl and was extracted with EA (20 mL × 3) . The combined organic phases were washed with saturated saline solution (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE/EA (v/v) = 4/1) to give the title compound as a light yellow solid (2.1 g, 84%) .

MS (ESI, pos. ion) m/z: 359.0 [M+Na] ⁺;

¹H NMR (600 MHz, DMSO-d ₆) δ (ppm) 13.36 (s, 1H) , 7.85 (d, J = 7.7 Hz, 1H) , 7.79 –7.69 (m, 2H) , 7.50 (d, J = 5.4 Hz, 1H) , 7.44 –7.37 (m, 1H) , 7.35 (t, J = 7.6 Hz, 1H) , 7.30 (d, J = 7.2 Hz, 1H) , 4.66 (d, J = 13.6 Hz, 2H) .

Step 5) : synthesis of 9, 10-difluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6- (11H) -one

2- ( (Benzo [b] thiophen-7-ylthio) methyl) -3, 4-difluorobenzoic acid (1.00 g, 2.97 mmol) and PPA (10 mL) were added to the reaction bottle, and the mixture was warmed to 120 ℃ and stirred for 8 h. The reaction was stopped and cooled to rt, the reaction solution was added to water (30 mL) , and extracted with DCM (15 mL × 3) . The combined organic phases were washed with saturated saline solution (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE/EA (v/v) = 8/1) to give the title compound as a light yellow solid (800 mg, 84.5%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 8.30 (t, J = 13.1 Hz, 1H) , 7.75 (t, J = 8.2 Hz, 1H) , 7.67 (d, J = 5.4 Hz, 1H) , 7.55 –7.46 (m, 1H) , 7.41 (d, J = 5.4 Hz, 1H) , 7.18 (dd, J = 16.7, 8.9 Hz, 1H) , 4.34 (d, J = 9.0 Hz, 2H) .

Step 6) : synthesis of 9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol

9, 10-Difluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one (800 mg, 2.513 mmol) , THF (10 mL) and methanol (10 mL) were added into the reaction bottle, the mixture was cooled to 0℃, sodium borohydride (480 mg, 12.69 mmol) was then added, and the reaction solution was warmed to rt and stirred for 2.5 h. After the reaction was completed, water (20 mL) was added, and the reaction mixture was extracted with ethyl acetate (10 mL× 3) . The combined organic phases were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated in vacuo to give the title compound as a light yellow solid (730 mg, 90.68%) .

¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) 7.78 –7.59 (m, 3H) , 7.42 (t, J = 10.5 Hz, 1H) , 7.38 –7.27 (m, 2H) , 6.51 (t, J = 10.5 Hz, 1H) , 6.31 (d, J = 3.6 Hz, 1H) , 4.92 –4.63 (m, 2H) .

Step 7) Synthesis of 7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

9, 10-Difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol (370 mg, 1.155 mmol) and 7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6-, 8-dione (380 mg, 1.161 mmol) were added to reaction bottle, then T3P (wt 50%, 10 mL) was added. The reaction system was warmed to 70℃ and stirred overnight. The reaction was cooled to rt, the reaction solution was added with water (30 mL) , and extracted with ethyl acetate (20 mL × 3) . The combined organic phases were washed with saturated saline solution (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (DCM/EA (v/v) = 1/1) to give the title compound as a light yellow solid (330 mg, 45.38%) .

MS (ESI, pos. ion) m/z: 630.0 [M+1] ⁺.

Step 8) Synthesis of the mixture of (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione and (S) -12 - ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dion e

7- (Benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (330 mg, 0.5241 mmol) , lithium chloride (222 mg, 5.237 mmol) , N, N-dimethylacetamide (10 mL) were added into the reaction bottle, and the mixure was warmed to 100℃ and stirred overnight under nitrogen. After the reaction was completed, the reaction solution was cooled to rt, added with water (20 mL) and extracted with ethyl acetate (10 mL × 3) . The combined organic phases were washed with saturated sodium bicarbonate aqueous solution (10 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 10/1) . The purified product was further purified by a preparative column (Column packing: LUNA; Mobile phase: phase A: 1‰aqueous solution of trifluoroacetic acid; phase B: acetonitrile, isocratic elution 42%B-58%A) to give the title compound as a light yellow solid (100 mg, 35.36%) .

MS (ESI, pos. ion) m/z: 539.8 [M+1] ⁺;

HRMS (ESI, pos. ion) m/z: 540.0852 [M+1] ⁺;

¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) 7.77 (d, J = 5.4 Hz, 1H) , 7.43 (ddd, J = 16.0, 13.1, 7.1 Hz, 4H) , 7.07 (d, J = 7.7 Hz, 1H) , 7.02 (d, J = 8.3 Hz, 1H) , 5.95 (s, 1H) , 5.59 (d, J = 14.1 Hz, 1H) , 5.41 (d, J = 7.7 Hz, 1H) , 4.57 (dd, J = 9.9, 2.9 Hz, 1H) , 4.46 (d, J = 12.2 Hz, 1H) , 4.32 (d, J = 14.2 Hz, 1H) , 4.01 (dd, J = 10.7, 2.8 Hz, 1H) , 3.68 –3.56 (m, 2H) , 3.54 –3.39 (m, 2H) , 3.06 (dd, J = 17.6, 7.4 Hz, 1H) .

Example 2 (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazi ne-6, 8-dione (2-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2-2)

Step 1) Synthesis of (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

The title compound was prepared by the synthetic method disclosed in the patent application WO 2017221869.

Step 2) Synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione

9, 10-Difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol (1.00 g, 3.12 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dio ne (1.124 g, 3.434 mmol) were mixtured in isopropyl acetate (10 mL) , and T3P (7.50 mL, 12.5 mmol, 1.67 mol/L) was added, the reaction system was heated at 90 ℃ oil bath and reacted overnight. After the reaction was completed, the reaction solution was added to water (30 mL) and the resulting mixture was extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 15/1) to give the title compound as an orange solid (1.26g, 64%) .

MS (ESI, pos. ion) m/z: 630.1 [M+1] ⁺.

Step 3) : Synthesis of (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2-2)

7- (Benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.23 g, 1.95 mmol) , lithium chloride (828 mg, 19.53 mmol) , and N, N'dimethyl acetamide (30 mL) were added into the reaction bottle, and the mixture was warmed to 100℃ under protection of nitrogen and stirred overnight. After the reaction was completed, the reaction solution was cooled to rt and water (20 mL) was added. The reaction solution was extracted with ethyl acetate (10 mL × 3) . The combined organic phases were washed with saturated brine (10 mL ) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated in vacuo, and the crude product was purified by LUNA preparative column chromatography (acetonitrile /0.1%trifluoroacetate aqueous solution (v/v) = 42/58) to give the title compound (2-1) as a light yellow solid (300 mg, 28.5%) and the title compound (2-2) as a light yellow solid (312 mg, 29.6%) .

MS (ESI, pos. ion) m/z: 539.8 [M+1] ⁺;

MS (ESI, pos. ion) m/z: 540.0852 [M+H] ⁺;

(R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7 -hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.46 (d, J = 5.3 Hz, 1H) , 7.36 (d, J = 8.1 Hz, 1H) , 7.25 (d, J = 5.4 Hz, 1H) , 7.09 (dt, J = 13.0, 8.3 Hz, 2H) , 6.96 (d, J = 7.7 Hz, 1H) , 6.72 (d, J = 8.1 Hz, 1H) , 5.60 (d, J = 7.7 Hz, 1H) , 5.48 (d, J = 10.7 Hz, 2H) , 4.74 –4.62 (m, 2H) , 4.29 (d, J = 13.8 Hz, 1H) , 4.01 (dd, J = 11.1, 2.6 Hz, 1H) , 3.85 (dd, J = 11.9, 2.9 Hz, 1H) , 3.64 (t, J = 10.6 Hz, 1H) , 3.50 (t, J = 11.0 Hz, 1H) , 3.02 (dd, J = 18.5, 7.0 Hz, 1H) ;

(R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7 -hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.68 (d, J = 8.2 Hz, 1H) , 7.58 (d, J = 5.4 Hz, 1H) , 7.39 (d, J = 5.4 Hz, 1H) , 7.34 (d, J = 8.2 Hz, 1H) , 6.95 (dd, J = 17.1, 8.6 Hz, 1H) , 6.75 (d, J = 7.7 Hz, 1H) , 6.71 –6.63 (m, 1H) , 5.96 (d, J = 7.7 Hz, 1H) , 5.56 (d, J = 14.1 Hz, 1H) , 5.37 (s, 1H) , 4.63 (d, J = 13.0 H z, 1H) , 4.52 (dd, J = 9.9, 2.8 Hz, 1H) , 4.31 (d, J = 14.2 Hz, 1H) , 4.03 (dd, J = 10.9, 2.8 Hz, 1H) , 3.7 8 (dd, J = 11.9, 3.1 Hz, 1H) , 3.59 (d, J = 10.3 Hz, 1H) , 3.46 (t, J = 10.7 Hz, 1H) , 2.85 (dd, J = 17.9, 7.6 Hz, 1H) .

Example 3 (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine -6, 8-dione (3-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (3-2)

Step 1) : synthesis of benzofuran-7-thiol

7-Bromobenzofuran (7.00 g, 35.50mmol) and sulfur (1.19 g, 37.20 mmol) were dissolved in THF (5 mL) , the reaction system was stirred at -78℃ for 20 minutes under protection of nitrogen, and tert-butyllithium (55.00 mL, 72.00mmol, 1.30 mol/L) was added dropwise slowly to the reaction solution. The reaction was continued at -78℃ for 1 h. The reaction was stopped and the reaction solution was added to saturated solution of ammonium chloride (50 mL) , extracted with ether (50 mL × 2) . The organic phases were combined and the obtained organic phases were extracted with 2N sodium hydroxide solution (50 mL × 2) . The aqueous phases were combined and adjusted with 6N hydrochloric acid to pH about 3-4. The aqueous phase was extrated ether (50 mL × 2) , the organic phases were combined. The combined organic phases were washed with saturated saline (25 mL) , dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give product as light yellow oily liquid (2.05 g, 39%) .

Step 2) Synthesis of ethyl 2- ( (benzofuran-7-ylthio) methyl) -3, 4-difluorobenzoate

Benzofuran-7-thiol (2.05 g, 13.68 mmol) and ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (4.20 g, 15.04 mmol) were mixtured in DMF (30 mL) . Then alumina (1.81 g, 17.80mmol) and potassium carbonate (2.46 g, 17.8 mmol) were added, and the mixture was reacted at rt for 15 minutes. The reaction was stopped and the reaction mixture was added with water (20 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (25 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 15/1) to give the title compound as a light yellow solid (4.76 g, 99.9%) .

MS (ESI, pos. ion) m/z: 349.10 [M+1] ⁺;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.67 (m, 1H) , 7.63 (d, J = 2.0 Hz, 1H) , 7.53 (d, J = 7.7 Hz, 1H) , 7.18 (d, J = 7.3 Hz, 1H) , 7.10 (d, J = 7.6 Hz, 1H) , 7.03 (d, J = 8.1 Hz, 1H) , 6.78 (d, J = 2.1 Hz, 1H) , 4.68 (m, 2H) , 4.21 (q, J = 7.1 Hz, 2H) , 1.33 (t, J = 7.1 Hz, 3H) .

Step 3) Synthesis of 2- ( (benzofuran-7-ylthio) methyl) -3, 4-difluorobenzoic acid

Ethyl 2- ( (benzofuran-7-ylthio) methyl) -3, 4-difluorobenzoate (4.76 g, 13.70 mmol) was dissolved in the mixture of tetrahydrofuran (3 mL) and methanol (3 mL) . The aqueous solution (1 mL) of sodium hydroxide (1.09 g, 27.30mmol) was added, and the resulting solution was stirred overnight at rt. The reaction was stopped and the reaction solution was added with water (20 mL) and extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (25 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 15/1) to give the title compound as a light yellow solid (4.76 g, 100%) .

MS (ESI, pos. ion) m/z: 321.05 [M+1] +;

Step 4) : synthesis of 9, 10-difluorobenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one

2- ( (Benzofuran-7-ylthio) methyl) -3, 4-difluorobenzoic acid (2.00 g, 6.24 mmol) was dissolved in dichloromethane (30 mL) . Then DMF (45 mg, 0.62 mmol) and oxalyl chloride (1.60 mL, 19.00 mmol) were added. The reaction solution was stirred at rt for 30 minutes. The above reaction solution was then added to DCM solution (30 mL) of aluminum chloride (3.33 g, 25.00 mmol) and stirred for 15 minutes at rt. The reaction was stopped and quenched with water (30 mL) . The reaction mixture was extracted with DCM (20 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a light yellow solid (272 mg, 14%) .

MS (ESI, pos. ion) m/z: 303.05 [M+1] +;

Step 5) : synthesis of 9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol

9, 10-difluorobenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one (270 mg, 0.89 mmol) was dissolved in THF (10 mL) and methanol (5 mL) . The mixture was cooled to 0℃. Sodium borohydride (110 mg, 3.57 mmol) was added in batches, after addition the reaction solution was reacted for 5 minutes and transfered to rt and reacted for 1 h. Then saturated ammonium chloride (20 mL) solution was added to quench the reaction, and the reaction solution was extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and the combined organic phases were washed with saturated saline (50 mL) , dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (270 mg, 100%) directly for next step reaction without purification.

Step 6) Synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

9, 10-Difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol (240mg, 0.79 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (284 mg, 0.87 mmol) were added to microwave tube, then 1-propylphosphoric anhydride (ethyl acetate solution, wt 50%, 10 mL) was added. Nitrogen was blowed in and the microwave tube was placed in a microwave at 100 ℃ for 45 minutes. The reaction solution was added to ice water (30 mL) and resulting mixture was extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and washed with saturated sodium bicarbonate aqueous solution (50 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 25/1) to give the title compound as a light yellow solid (180mg, 37%) .

MS (ESI, pos. ion) m/z: 614.2 [M+H] ⁺

Step 7) Synthesis of (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (3-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (3-2)

(12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (164 mg, 0.27 mmol) was dissolved in N, N-dimethylacetamide (4 mL) . Anhydrous lithium chloride (113 mg, 2.67mmol) was added under protection of nitrogen. The reaction solution was reacted overnight at 100℃, then added with water (10 mL) and adjusted with 1N hydrochloric acid to pH about 6, and extracted with ethyl acetate (10 mL× 3) . The organic phases were combined. The combined organic phases were washed with saturated saline (20 mL × 3) , dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by LUNA preparation column (1‰aqueous trifluoroacetic acid/acetonitrile=60%/40%) to give the title compound (3-1) as a light yellow solid (31 mg, 22%) and give the title compound (3-2) as a light yellow solid (30 mg, 21%) , respectively.

MS (ESI, pos. ion) m/z: 524.30 [M+H] ⁺;

(R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (3-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.64 (s, 1H) , 7.14 –7.04 (m, 2H) , 6.98 (d, J = 7.4 Hz, 1H) , 6.69 (s, 1H) , 6.58 (d, J = 7.9 Hz, 1H) , 5.69 (d, J = 7.3 Hz, 1H) , 5.50 –5.36 (m, 2H) , 4.75 –4.61 (m, 2H) , 4.24 (d, J = 13.8 Hz, 2H) , 4.01 (d, J = 8.5 Hz, 1H) , 3.89 –3.79 (m, 1H) , 3.72 –3.61 (m, 1H) , 3.51 (t, J = 10.9 Hz, 1H) , 3.04 (t, J = 11.2 Hz, 1H) .

(R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (3-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.74 (d, J = 1.6 Hz, 1H) , 7.42 (d, J = 8.0 Hz, 1H) , 7.22 (d, J = 8.1 Hz, 1H) , 6.93 (d, J = 8.4 Hz, 1H) , 6.81 (d, J = 1.7 Hz, 1H) , 6.71 (d, J = 7.5 Hz, 1H) , 6.65 (s, 1H) , 5.90 (d, J = 7.6 Hz, 1H) , 5.51 (d, J = 14.1 Hz, 1H) , 5.35 (s, 1H) , 4.64 (s, 1H) , 4.57 –4.47 (m, 1H) , 4.26 (d, J = 14.1 Hz, 1H) , 4.07 –3.95 (m, 1H) , 3.77 (d, J = 11.7 Hz, 1H) , 3.58 (t, J = 10.4 Hz, 1H) , 3.45 (t, J = 10.7 Hz, 1H) , 2.88 –2.79 (m, 1H) .

Example 4 (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazole-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (4-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazole-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (4-2)

Step 1) : synthesis of benzothiazole-7-thiol

7-Bromobenzothiazole (5.00 g, 23.36mmol) , ethanedithiol (3.92 mL, 46.70mmol) , cesium carbonate (38.10 g, 117.00mmol) and copper acetate (424 mg, 2.33mmol) were dissolved in DMSO (150 mL) . The reaction system was heated in an oil bath at 110 ℃ for reaction for 5 hours under nitrogen. The reaction was stopped, the reaction mixture was added with water (20 mL) , and adjusted with 2N hydrochloric acid to pH about 6, and extracted with ethyl acetate (20 mL × 3) . The combined organic phases were washed with saturated brine (30 mL× 3 ) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EA (v/v) = 2/1) to give the title compound as light yellow oily liquid (1.054 g, 27 %) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 9.03 (s, 1H) , 8.04 –7.97 (m, 1H) , 7.47 –7.42 (m, 2H) , 3.75 (s, 1H) .

Step 2) : Synthesis of ethyl 2- ( (benzothiazol-7-ylthio) methyl) -3, 4-difluorobenzoate

Benzothiazole-7-thiol (1.05 g, 6.30mmol) and ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (1.94 g, 6.93mmol) were mixtured in DMF (30 mL) , then alumina (835 mg, 8.20mmol) and potassium carbonate (1.13 g, 8.20mmol) were added. The reaction was conducted at rt for 15 min. The reaction was stopped and the reaction solution was added with water (20 mL) and extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (25 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 15/1) to give the title compound as a light yellow solid (1.76 g, 76%) .

MS (ESI, pos. ion) m/z: 366.15 [M+H] ⁺;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 8.99 (s, 1H) , 8.07 (d, J = 7.9 Hz, 1H) , 7.69 -7.60 (m, 1H) , 7.47 -7.34 (m, 2H) , 7.06 (dd, J = 16.8, 8.8 Hz, 1H) , 4.68 (s, 2H) , 4.19 (q, J = 7.1 Hz, 2H) , 1.33 (t, J = 7.1 Hz, 3H) .

Step 3) : Synthesis of 2- ( (benzothiazol-7-ylthio) methyl) -3, 4-difluorobenzoic acid

Ethyl 2- ( (benzothiazol-7-ylthio) methyl) -3, 4-difluorobenzoate (1.76 g, 4.82 mmol) was dissolved in tetrahydrofuran (3 mL) and methanol (3 mL) , then aqueous solution (1 mL) of sodium hydroxide (385 mg, 9.63mmol) was added. The reaction solution was stirred at rt overnight. The reaction was stopped and the reaction solution was added with water (20 mL) and extracted with ethyl acetate (25 mL × 3) . The combined organic phases were combined and washed with saturated brine (25 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 15/1) to give the title compound as a light yellow solid (1.54 g, 95%) .

MS (ESI, pos. ion) m/z: 338.10 [M+H] ⁺;

Step 4) : synthesis of 9, 10-difluorobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazole-6- (11H) -one

2- ( (Benzothiazol-7-ylthio) methyl) -3, 4-difluorobenzoic acid (600 mg, 1.78mmol) was added to polyphosphoric acid (10 mL) and the mixture was warmed to 125℃ and reacted overnight. The reaction was stopped. Water (30 mL) was added slowly, and the reaction mixture was quenched with dichloromethane (20 mL× 3) . The organic phases were combined, further methanol (20 mL) was added and the resulting organic phase was dried over anhydrous sodium sulfate, filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a white solid (560 mg, 98.59%) . It was used directly in the next reaction without purification.

MS (ESI, pos. ion) m/z: 320.05 [M+1] ⁺;

Step 5) : synthesis of 9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazole-6-ol

9, 10-Difluorobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazole-6- (11H) -one (560mg, 1.75 mmol) was dissolved in THF (10 mL) and methanol (5 mL) , and the mixture was cooled to 0℃. Sodium borohydride (276mg, 7.01 mmol) was added in batches. The resulting mixture was reacted at 0℃ for 5 minutes, and then reacted at rt for 1 hour. The resulting solution was quenched with saturated ammonium chloride solution (20 mL) and extracted with ethyl acetate (30 mL × 3) . The combined organic phases were washed with saturated saline solution (50 mL) and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give the title compound as a white solid (500mg, 89%) .

MS (ESI, pos. ion) m/z: 322.00 [M+H] ⁺;

¹H NMR (400 MHz, CDCl3) δ (ppm) 8.94 (s, 1H) , 7.89 (d, J = 8.4 Hz, 1H) , 7.67 (d, J = 8.4 Hz, 1H) , 7.22 (dd, J = 7.7, 4.8 Hz, 1H) , 7.06 (dd, J = 17.5, 8.5 Hz, 1H) , 6.26 (s, 1H) , 5.02 (d, J = 14.2 Hz, 1H) , 4.39 (d, J = 14.2 Hz, 1H) .

Step 6) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazol-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

9, 10-Difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazole-6-ol (50 mg, 0.16 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6-, 8-dione (59 mg, 0.17 mmol) were mixtured in isopropyl acetate (3 mL) , then T3P (0.60 mL, 1.0 mmol, 1.67 mol/L) was added. The reaction solution was reacted in an oil bath at 90 ℃ overnight; after the reaction was stopped, the reaction solution was added to ice water (30 mL) and resulting mixture was extracted with ethyl acetate (30 mL× 3) . The organic phases were combined and washed with saturated sodium bicarbonate aqueous solution (50 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 25/1) to give the title compound as a light yellow solid (69 mg, 70%) .

MS (ESI, pos. ion) m/z: 631.1 [M+H] ⁺

Step 7) : Synthesis of (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazol-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (4-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] thiazol-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2 , 1-f] [1, 2, 4] triazine-6, 8-dione (4-2)

(12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3 , 4] benzo [1, 2-d] thiazol-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (440 mg, 0.70 mmol) was dissolved in N, N-dimethylacetamide (30 mL) . Anhydrous lithium chloride (295 mg, 7.0 mmol) was added under protection of nitrogen. The reaction solution was reacted overnight at 100℃, then added with water (10 mL) and adjusted with 1N hydrochloric acid to pH about 6, and extracted with ethyl acetate (10 mL× 3) . The organic phases were combined. The combined organic phases were washed with saturated saline (20 mL × 3) , dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was separated and purified by LUNA preparation column (1‰aqueous solution of trifluoroacetic acid/acetonitrile=60%/40%) to give the title compound (4-1) as a light yellow solid (785 mg, 20%) and give the title compound (4-2) as a light yellow solid (79mg, 21%) , respectively.

MS (ESI, pos. ion) m/z: 541.1 [M+H] ⁺

Example 5: (R) -12- ( (S) -9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (5-1) and (R) -12- ( (R) -9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (5-2)

Step 1) : ethyl 3, 4-difluoro-2-methyl benzoate

3, 4-Difluoro-2-methyl benzoic acid (6.80 g, 0.40 mol) was dissolved in DMF (80 mL) , potassium carbonate (16.50 g, 1.19 mol) and iodoethane (4.80 mL, 0.60 mol) were added, and the reaction was kept overnight at rt. The reaction solution was added with water (200 mL) and extracted with ethyl acetate (100 mL × 3) , the combined organic phase was washed with saturated brine (200 mL × 3) , dried over anhydrous sodium sulphate, and filtered. The fliltrate was concentrated in vacuo, the residue was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to give the title compound as light yellow liquid (7.58 g, 96%) .

Step 2) : synthesis of ethyl 2- (bromomethyl) -3, 4-difluorobenzoate

Ethyl 3, 4-difluoro-2-methylbenzoate (7.58 g, 0.38 mol) was dissolved in carbon tetrachloride (20 mL) , then NBS (7.42 g, 0.42 mol) and benzoyl peroxide (0.94 g, 3.80 mmol) were added. The mixture was reacted for 6 h at 78 ℃ under protection of nitrogen. The reaction was stopped and after the reaction solution was cooled to rt, saturated sodium thiosulfate solution (50 mL) and dichloromethane (50 mL× 3) were added for extraction. The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as light yellow liquid (9.77 g, 93%) .

Step 3) : synthesis of 2, 3-dihydrobenzofuran-7-thiol

To the 100 mL double-necked flask were added 7-bromo-2, 3-dihydrobenzofuran (5.0 g, 25 mmol) and sulfur powder (0.88 g, 28 mmol, 100 mass%) , then THF (50 mL) was added under protection of nitrogen. The reaction system was cooled to -78℃ and stirred for 5 min. n-BuLi (39 mL, 51 mmol, 1.3 mol/L) was added dropwise and the reaction solution was stirred for 1 h at -78℃. Saturated ammonium chloride solution (30 mL) was added dropwise at -78℃ to quench the reaction. Then the reaction solution was warmed to rt, EtOAc (100 mL) and water (100 mL) were added to the reaction system for separation. The aqueous phase was extracted with EtOAc (80mL ×3) . The combined organic phase was washed with saturated saline and partitioned. The collected organic phase was washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give crude product of the title compound (3.8 g, 99%) as yellow liquid that was used for next step reaction without further purification.

Step 4) : synthesis of ethyl 2- ( ( (2, 3-dihydrobenzofuran-7-yl) thio) methyl) -3, 4-difluorobenzoate

To the reaction flask were added 2, 3-dihydrobenzofuran-7-thiol (3.7 g, 24 mmol) , ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (7.5 g, 27 mmol) , potassium carbonate (4.4 g, 32 mmol) , DMF (50 mL) and neutral alumina (3.2 g, 31 mmol) . Then the mixture was stirred for 15 h at rt. After the reaction was stopped, the reaction solution was added with EtOAc (150 mL) and saturated saline (150 mL) . The reaction solution was partitioned and the aqueous phase was extracted with EtOAc (100 mL × 3) . The organic phases were combined and washed with saturated brine (80 mL×4) . The collected organic phase was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as yellow oil (4.7 g, 55%) .

MS (ESI, pos. ion) m/z: 351.1 [M+H] ⁺;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.72-7.65 (m, 1H) , 7.09 (d, J = 7.2 Hz, 1H) , 7.05-6.98 (m, 1H) , 6.93 (d, J = 7.7 Hz, 1H) , 6.66 (t, J = 7.4 Hz, 1H) , 4.58 (d, J = 8.4 Hz, 2H) , 4.54 (d, J = 4.3 Hz, 2H) , 4.28 (q, J = 6.8 Hz, 2H) , 3.21 (t, J = 8.6 Hz, 2H) , 1.36 (t, J = 7.1 Hz, 3H) .

Step 5) : synthesis of 2- ( ( (2, 3-dihydrobenzofuran-7-yl) thio) methyl) -3, 4-difluorobenzoic acid

To the reaction flask were added ethyl 2- ( ( (2, 3-dihydrobenzofuran-7-yl) thio) methyl) -3, 4-difluorobenzoate (3.7 g, 11 mmol) , THF (30 mL) and MeOH (30 mL) , then sodium hydroxide (0.85 g, 21 mmol) in water (5 mL) was added. The reaction solution was heated to 70℃ and kept reaction for 15 h. After the reaction was completed, the reaction solution was cooled to rt, EtOAc (150 mL) and water (50 mL) were added. The reaction solution was adjusted by 3N hydrochloric acid to pH 5-6 and partitioned. The aqueous phase was extracted with EtOAc (100 mL × 3) and the organic phases were combined. The combined organic phases were washed with saturated saline (150 mL) and then collected. The collected organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound as a light yellow solid (3.121 g, 92%)

Step 6) : synthesis of 9, 10-difluoro-2, 3-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one

To the reaction flask were added 2- ( ( (2, 3-dihydrobenzofuran-7-yl) thio) methyl) -3, 4-difluorobenzoic acid (4.2 g, 13 mmol) , PhCl (50 mL) and PPA (40 mL) . The reaction solution was heated to 130℃ under protection of nitrogen and stirred for 16 h. After the reaction was completed, the reaction solution was cooled to rt, and EtOAc (200 mL) and ice water (100 g) were added. The reaction solution was partitoned and the aqueous phase was extracted with EtOAc (100 mL × 4) . The combined organic phases were washed with saturated saline (150 mL) , partitioned, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was used for next step reaction without further purification.

Step 7) : synthesis of 9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol

To the reaction flask were added 9, 10-difluoro-2, 3-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one (4.0 g, 13 mmol) obtained in the previous step, THF (60 mL) and MeOH (15 mL) . The reaction mixture was cooled to 0℃, and sodium borohydride (0.62 g, 16 mmol) was added in batches. After addition, the reaction mixture was stirred at rt for 2 h. After the reaction was completed, a saturated ammonium chloride solution (25 mL) was slowly added dropwise to the reaction solution to quench the reaction. Then the resulting mixture was extratced with EtOAc (150 mL) and water (80 mL) . The aqueous phase was extracted with EtOAc (80 mL ×3) , and the combined organic phases were washed with saturated brine (100 mL) , dried over anhydrous sodium sulfate. The resulting organic phase was concentrated under reduced pressure, and the obtained crude product was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to give the title compound as a light yellow solid (3.0 g, 75%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.34-7.28 (m, 1H) , 7.17-7.10 (m, 1H) , 7.02 -6.99 (m, 1H) , 6.91 (dd, J = 8.8, 2.4 Hz, 1H) , 6.02 (s, 1H) , 4.85 (d, J = 14.2 Hz, 1H) , 4.66-4.62 (m, 2H) , 4.22 (d, J = 14.2 Hz, 1H) , 3.19 (t, J = 8.7 Hz, 2H) ;

MS (ESI, pos. ion) m/z: 329.1 [M+Na] ⁺.

Step 8) : synthesis of (12aR) -7 - (benzyloxy) -12 - (9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -3, 4, 12, 12a-tetrahydro-1H - [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the reaction flask were added 9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol (450 mg, 1.469 mmol) , (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-di one (400 mg, 1.222 mmol) , T3P (5 mL, 50 mass%) and iPrOAc (8 mL) . The reaction solution was heated to 90℃ and stirred for 24 h. The reaction solution was cooled to rt, to the reaction flask was added saturated sodium bicarbonate solution (40 mL) , and gas was produced. Then the reaction was extracted with EtOAc (80 mL) and partitioned. The organic phase was combined. The aqueous phase was extracted with EtOAc (60 mL × 3) , and the combined organic phase was washed with saturated saline (80 mL) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (EA) to give the title compound as a light yellow solid (160 mg, 21%) .

MS (ESI, pos. ion) m/z: 616.1 [M+H] ⁺

Step 9) : synthesis of (R) -12- ( (S) -9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (5-1) and (R) -12- ( (R) -9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (5-2)

(12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-di one (475 mg, 0.7716 mmol) and lithium chloride (337 mg, 7.7108 mmol) were dissolved in DMAc (30 mL) , then the mixture was heated to 100℃ and reacted for 5 h. The reaction solution was cooled to rt, then added to water (20 mL) , the solution was extracted with ethyl acetate (10 mL × 3) . The combined organic phase was washed with saturated saline (10 mL × 3) , dried over anhydrous sodium sulfate, concentrated in vacuo to remove organic solvent. The obtained crude product was purified by preparative HPLC (Column packing: LUNA; Mobile phase: phase A: 1‰aqueous solution of trifluoroacetic acid; phase B: acetonitrile, isocratic elution 40%B-60%A) to give the title compound (5-1) as a light yellow solid (85 mg, 21%) and the title compound (5-2) as a light yellow solid (135 mg, 33%) .

(R) -12- ( (S) -9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (5-1)

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.37 (dd, J =16.7, 9.0 Hz, 1H) , 7.15-7.05 (m, 2H) , 7.00 (s, 1H) , 6.71 (d, J = 7.4 Hz, 1H) , 6.26 (d, J = 7.6 Hz, 1H) , 5.83 (d, J = 7.7 Hz, 1H) , 5.30 (d, J = 7.5 Hz, 2H) , 4.73-4.56 (m, 4H) , 4.18-4.11 (m, 1H) , 3.98 (d, J = 9.3 Hz, 1H) , 3.83 (d, J = 9.1 Hz, 1H) , 3.61 (t, J = 10.5 Hz, 1H) , 3.48 (t, J = 11.3 Hz, 1H) , 3.24-2.97 (m, 3H) ;

HRMS (ESI, pos. ion) m/z: 526.123 [M+H] ⁺;

(R) -12- ( (R) -9, 10-difluoro-2, 3, 6, 11-tetrahydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (5-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.28 (s, 1H) , 7.01 (d, J = 7.3 Hz, 1H) , 6.91-6.85 (m, 2H) , 6.68 (d, J = 7.6 Hz, 1H) , 6.61-6.60 (m, 1H) , 5.84 (d, J = 7.5 Hz, 1H) , 5.39 (d, J = 14.0 Hz, 1H) , 5.18 (s, 1H) , 4.82-4.50 (m, 4H) , 4.15 (d, J = 14.1 Hz, 1H) , 4.03 (d, J = 8.9 Hz, 1H) , 3.80 (d, J = 10.2 Hz, 1H) , 3.58 (t, J = 10.3 Hz, 1H) , 3.46 (t, J = 11.1 Hz, 1H) , 3.30-3.22 (m, 2H) , 2.86 (t, J = 11.0 Hz, 1H) .

HRMS (ESI, pos. ion) m/z: 526.1239 [M+H] ⁺.

Example 6 (12aR) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (6)

Step 1) : synthesis of benzo [d] [1, 3] dioxol-4-thiol

To the double-necked flask were added 4-bromobenzo [d] [1, 3] dioxol (5 g, 24.873 mmol) and sublimed sulfur (0.848 g, 26.2 mmol) . Then tetrahydrofuran (100 mL) was added under nitrogen protection. The mixture was cooled to -70℃ and stirred for 30 min, tert-butyllithium in hexane (38 mL, 49 mmol, 1.3mol/L) was added slowly dropwise. After addition, the reaction was kept for 2 h at -70℃, then quenched with saturated ammonium chloride solution (100mL) , extracted with ethyl acetate (200 mL) and partitioned. The organic phase was washed with 2N sodium hydroxide solution (20 mL) . The aqueous phase was combined. The combined aqueous phase was adjusted with 4N hydrochloric acid to pH about 4-5, and extracted with ethyl acetate (100mL × 2) . The organic phase was combined, washed with saturated sodium chloride solution (100mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (3.12g, 81.4%) .

Step 2) : synthesis of ethyl 2- ( (benzo [d] [1, 3] dioxol-4-yl-thio) methyl) -3, 4-difluorobenzoate

To the single-necked flask were added benzo [d] [1, 3] dioxol-4-thiol (105 mg, 0.68098 mmol) , ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (206 mg, 0.73814 mmol) , potassium carbonate (125 mg, 0.895415 mmol) and alumina (91 mg, 0.8924 mmol) , then DMF (3 mL) was added. The mixture was stirred overnight at rt and then filtered. The filter cake was washed with water (30 mL) and the filtrate was extracted with EA (15 mL × 2) . The organic phases were combined and washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as light yellow oil (154mg, 64.17%) .

MS (ESI, pos. ion) m/z: 353.1 [M+H] +;

1H NMR (400 MHz, CDCl ₃) δ (ppm) 7.74 –7.66 (m, 1H) , 7.05 (dd, J = 16.8, 8.8 Hz, 1H) , 6.75 (dd, J = 5.1, 3.8 Hz, 1H) , 6.67 (d, J = 3.7 Hz, 2H) , 5.95 (s, 2H) , 4.56 (s, 2H) , 4.29 (q, J = 7.1 Hz, 2H) , 1.37 (t, J = 7.1 Hz, 3H) .

Step 3) : synthesis of 2- ( (benzo [d] [1, 3] dioxol-4-yl-thio) methyl) -3, 4-difluorobenzoic acid

To the single-necked flask was added ethyl 2- ( (benzo [d] [1, 3] dioxol-4-yl-thio) methyl) -3, 4-difluorobenzoate (3.1 g, 8.8 mmol) which was dissolved with tetrahydrofuran (35 mL) and methanol (7 mL) . Then sodium hydroxide (1.4 g, 35 mmol) in water (7 mL) was added slowly dropwise. After the addition is completed, the mixture was heated to 50℃ and reacted for 4 h. The organic solvent was removed under reduced pressure, water (30 mL) was added, and the reaction mixture was adjusted with 2N hydrochloric acid to pH about 4-5, extracted with ethyl acetate (50 mL× 2) . The combined organic phases were washed with saturated aqueous sodium chloride solution (30 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (2.7g, 95%) .

MS (ESI, neg. ion) m/z: 323.0 [M-H] ^-

Step 4) : synthesis of 9, 10-difluorobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6- (11H) -one

2- ( (Benzo [d] [1, 3] dioxol-4-yl-thio) methyl) -3, 4-difluorobenzoic acid (1.5 g, 4.6 mmol) was added to PPA (15 mL) . The mixture was heated to 80℃ and reacted for 8 h. The reaction solution was cooled to rt, added with ice water (20 mL) and extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as a light yellow solid (400 mg, 28%) .

MS (ESI, pos. ion) m/z: 307.0 [M+H] ⁺

Step 5) : synthesis of 9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-ol

To the single-necked flask was added 9, 10-difluorobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6- (11H) -one (500 mg, 1.632 mmol) , tetrahydrofuran (4 mL) and methanol (0.4 mL) , then sodium borohydride (195 mg, 4.94811 mmol) was added slowly. The mixture was reacted at rt for 20 min and quenched with saturated ammonium chloride solution (10 mL) . The reaction mixture was extracted with EA (20 mL × 2) . The organic phases were combined and washed with saturated sodium chloride solution (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a white solid (240 mg, 47.69%) .

¹H NMR (600 MHz, DMSO) δ (ppm) 7.29 (dd, J = 16.9, 8.4 Hz, 1H) , 7.24 (m, 1H) , 7.08 (d, J = 7.0 Hz, 1H) , 6.68 (dd, J = 8.1, 1.8 Hz, 1H) , 6.31 (dd, J = 3.2, 2.1 Hz, 1H) , 6.02 (s, 1H) , 5.98 (dd, J = 5.5, 0.7 Hz, 2H) , 4.78 (d, J = 12.7 Hz, 1H) , 4.48 (d, J = 13.8 Hz, 1H) .

Step 6) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4 -c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the microwave tube were added 9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-ol (90 mg, 0.2919 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (108 mg, 0.3300 mmol) , then ethyl acetate (4 mL) was added. 1-propylphosphoric anhydride (0.55 mL, 0.92 mmol) was added dropwise and the mixture was reacted under microwave at 110℃for 30 min. The reaction solution was added to water (5 mL) and the resulting mixture was extracted with ethyl acetate (5 mL × 3) . The organic phases were combined and washed with saturated saline (10 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 25/1) to give the title compound as a light yellow solid (60 mg, 33.28%) .

MS (ESI, pos. ion) m/z: 618.2 [M+H] ⁺

Step 7) : synthesis of (12aR) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4 -c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the single-necked flask were added (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [5', 6'] thieno [2', 3': 3, 4] benzo [1, 2-d] [1, 3] d ioxol-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (100 mg, 0.1619 mmol) and lithium chloride (72 mg, 1.6474 mmol) , then N, N-diethylacetamide (2 mL) was added. The reaction solution was heated to 100℃ and reacted overnight under nitrogen protection. The resulting solution was added with water (5 mL) , adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with ethyl acetate (10 mL×3) . The combined organic phases were washed with saturated saline (20 mL × 3) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by a LUNA preparative column (eluent was acetonitrile /0.1%aqueous trifluoroacetic acid (v/v) = 12/13) to give the title compound as a light yellow solid (80mg, 93.66%) .

MS (ESI, pos. ion) m/z: 528.2 [M+H] ⁺;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.29 (s, 1H) , 7.25 –7.10 (m, 1H) , 7.07 –6.93 (m, 1H) , 6.91 –6.65 (m, 1H) , 6.36 (d, J = 8.0 Hz, 1H) , 6.22 (d, J = 8.1 Hz, 1H) , 6.20 –6.09 (m, 2H) , 6.02 (d, J = 35.7 Hz, 1H) , 5.42 –5.12 (m, 2H) , 4.65 (dd, J = 21.9, 12.0 Hz, 2H) , 4.19 (dd, J = 14.1, 3.8 Hz, 1H) , 4.11 –3.97 (m, 1H) , 3.90 –3.80 (m, 1H) , 3.76 –3.61 (m, 1H) , 3.52 (dd, J = 21.6, 9.9 Hz, 1H) , 2.98 (dt, J = 53.3, 11.3 Hz, 1H) .

Example 7 (R) -12- ( (S) -6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (7-1) and (R) -12- ( (R) -6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (7-2)

Step 1) : synthesis of ethyl 2-methylbenzoate

To the double-necked flask were added 2-methylbenzoic acid (5 g, 36.724 mmol) and ethanol (60 mL) . The reaction solution was cooled to 0℃ under nitrogen protection and dichlorosulfoxide (4.2 mL, 57 mmol) was added slowly dropwise. Then the reaction solution was heated to 80℃ and reacted overnight. The resulting solution was concentrated in vacuo to remove ethanol, then water (100 mL) was added. The solution was extracted with ethyl acetate (50 mL × 2) and the organic phases were combined. The combined organic phases were washed with saturated sodium bicarbonate solution (50 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as yellow oil (6g, 99.5%) .

MS (ESI, pos. ion) m/z: 165.3 [M+H] ⁺

Step 2) : synthesis of ethyl 2- (bromomethyl) -benzoate

To the single-necked flask were added ethyl 2-methylbenzoate (6.06 g, 36.9 mmol) , carbon tetrachloride (100 mL) , N-bromosuccinimide (7.02 g, 38.7 mmol) and benzoyl peroxide (0.9 g, 2 mmol) . The reaction mixture was heated to 80℃ under nitrogen protection and reacted overnight. The reaction was filtered by suction. The filter cake was washed with DCM (10 mL ) , then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as yellow oil (7g, 78%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.97 (d, J = 7.8 Hz, 1H) , 7.52 –7.43 (m, 2H) , 7.40 –7.34 (m, 1H) , 4.96 (s, 2H) , 4.41 (q, J = 7.1 Hz, 2H) , 1.43 (t, J = 7.1 Hz, 3H) .

Step 3) : synthesis of ethyl 2- ( (benzo [b] thiophen-7-yl-thio) methyl) benzoate

To the single-necked flask were added benzothiophene-7-thiol (409 mg, 2.459 mmol) , potassium carbonate (450 mg, 3.22350 mmol) and alumina (328 mg, 3.217 mmol) . Then DMF (8 mL) and ethyl 2- (bromomethyl) benzoate (604 mg, 2.4846 mmol) were added in turn. The resulting mixture was reacted for 3 h at rt. The reaction solution was filtered and the filter cake was washed with ethyl acetate (5 mL) . The filtrate was added with water (20 mL) and extracted with ethyl acetate (20mL × 2) . The organic phases were combined and washed with saturated brine (20mL × 2) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a light yellow solid (600mg, 74.29%) .

MS (ESI, pos. ion) m/z: 351.0 [M+Na] ⁺ ;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.90 (dd, J = 5.9, 3.3 Hz, 1H) , 7.71 (d, J = 7.6 Hz, 1H) , 7.44 (d, J = 5.4 Hz, 1H) , 7.35 (d, J = 5.5 Hz, 1H) , 7.22 (m, 4H) , 6.97 (dd, J = 5.5, 3.3 Hz, 1H) , 4.59 (s, 2H) , 4.32 (q, J = 7.1 Hz, 2H) , 1.38 (t, J = 7.1 Hz, 3H) .

Step 4) : synthesis of 2- ( (benzo [b] thiophen-7-ylthio) methyl) benzoic acid

To the single-necked flask were added ethyl 2- ( (benzo [b] thiophen-7-ylthio) methyl) benzoate (2.8 g, 8.5 mmol) , methanol (15 mL) and tetrahydrofuran (15 mL) in turn. Then sodium hydroxide (1.43 g, 35.4 mmol) in water (10 mL) was added at rt. After the addition is completed, the mixture was heated to 50℃ and reacted for 4.5 h, then concentrated in vacuo to remove organic solvent. Water (20 mL) was added. The reaction solution was adjusted with 4N hydrochloric acid to pH about 4, and extracted with EA (50mL × 2) . The organic phases were combined. The organic phase was washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a light yellow solid (2.5g, 98%) .

MS (ESI, neg. ion) m/z: 299.0 [M-H] ^-

Step 5) : synthesis of benzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6- (11H) -one

To the double-necked flask A were added 2- ( (Benzo [b] thiophen-7-ylthio) methyl) benzoic acid (500 mg, 1.664 mmol) , dichloromethane (8 mL) and DMF (0.05 mL) . Oxalyl chloride (0.6 mL, 7 mmol) was added slowly under nitrogen protection. After the addition was completed, the mixture was reacted for 3 h at rt for backup.

To the double-necked flask were added aluminum chloride (680 mg, 5.04871 mmol) and DCM (10 mL) . The reaction solution was cooled to 0℃ under nitrogen protection and was added slowly dropwise with the solution in double-necked flask A. After the addition was completed, the resulting mixture was reacted at rt for 50 min. Then the reaction solution was added with water (20mL) and extratced with DCM (20mL × 2) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 15/1) to give the title compound as a white solid (325 mg, 69.14%) .

MS (ESI, pos. ion) m/z: 283.2 [M+H] ⁺;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 8.27 (d, J = 8.6 Hz, 1H) , 7.70 (d, J = 8.6 Hz, 1H) , 7.65 (d, J = 7.7 Hz, 1H) , 7.60 (d, J = 5.4 Hz, 1H) , 7.47 (t, J = 7.5 Hz, 1H) , 7.40 –7.33 (m, 2H) , 7.26 (d, J = 7.4 Hz, 1H) , 4.23 (s, 2H) .

Step 6) : synthesis of 6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol

To the single-necked flask were added benzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6- (11H) -one (315 mg, 1.115 mmol) , tetrahydrofuran (4 mL) and methanol (0.4 mL) . Then sodium borohydride (135 mg, 3.42562 mmol) was added slowly and the reaction solution was reacted for 10 min at rt. The reaction was quenched with saturated ammonium chloride solution (5mL) , water (10 mL) was added, then the reaction solution was extracted with EA (15mL × 2) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a white solid (310 mg, 97.72%) .

MS (ESI, pos. ion) m/z: 307.1 [M+Na] ⁺

Step 7) : synthesis of (12aR) -7 - (benzyloxy) -12 - (6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H - [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the single-necked flask were added 6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol (700 mg, 2.461 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-di one (889 mg, 2.716 mmol) , then isopropyl acetate (30 mL) and 1-propylphosphoric anhydride (4.4 mL, 7.4 mmol, 50%ethyl acetate solution) were added. The reaction solution was heated to 90 ℃ and reacted for 1.5 h; the reaction solution was added with water (20 mL) and extracted with DCM (20 mL× 2) . The organic phases were combined and washed with saturated sodium bicarbonate aqueous solution (50 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (1.1g, 75%) .

MS (ESI, pos. ion) m/z: 594.2 [M+H] ⁺

Step 8) : synthesis of (R) -12- ( (S) -6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy 3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (7-1) and (R) -12- ( (R) -6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy 3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (7-2)

To the single-necked flask were added (12aR) -7- (benzyloxy) -12- (6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.7g, 2.9 mmol) and lithium chloride (1.21g, 28.3 mmol) . Then N, N-diethylacetamide (15 mL) was added, the mixture was heated to 100℃, reacted for 3 h under nitrogen, added with water (30 mL) , adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with DCM (30 mL × 3) . The organic phases were combined and washed with saturated saline (30 mL × 3) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound as an orange solid (555mg, 93.66%) .

MS (ESI, pos. ion) m/z: 504.0 [M+H] ⁺;

(R) -12- ( (S) -6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy 3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (7-1) :

¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) 7.74 (d, J = 5.4 Hz, 1H) , 7.53 (d, J = 7.4 Hz, 2H) , 7.45 (t, J = 7.3 Hz, 1H) , 7.42 –7.30 (m, 3H) , 7.08 (d, J = 7.7 Hz, 1H) , 7.02 (d, J = 8.2 Hz, 1H) , 5.82 (s, 1H) , 5.72 (d, J = 13.5 Hz, 1H) , 5.40 (d, J = 7.7 Hz, 1H) , 4.47 (m, 2H) , 4.10 (d, J = 13.6 Hz, 1H) , 4.02 –3.93 (m, 1H) , 3.68 (t, J = 10.2 Hz, 2H) , 3.46 (m, 2H) , 2.98 (t, J = 11.1 Hz, 1H) .

(R) -12- ( (R) -6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy 3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (7-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.63 (d, J = 8.1 Hz, 1H) , 7.54 (d, J = 5.3 Hz, 1H) , 7.34 (d, J = 8.3 Hz, 4H) , 7.12 (t, J = 6.0 Hz, 1H) , 6.83 (d, J = 7.5 Hz, 1H) , 6.73 (d, J = 7.5 Hz, 1H) , 5.98 (d, J = 7.4 Hz, 1H) , 5.79 (d, J = 13.8 Hz, 1H) , 5.32 (s, 1H) , 4.68 –4.46 (m, 2H) , 4.01 (dd, J = 10.8, 2.5 Hz, 1H) , 3.83 (d, J = 13.8 Hz, 1H) , 3.76 (dd, J = 11.8, 2.7 Hz, 1H) , 3.60 (t, J = 10.5 Hz, 1H) , 3.46 (t, J = 10.8 Hz, 1H) , 2.85 (t, J = 11.0 Hz, 1H)

Example 8-1 (R) -12- ( (S) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (8-1)

Step 1) : synthesis of ethyl 3-fluoro-2-methylbenzoate

To the reaction flask were added 3-fluoro-2-methylbenzoic acid (5.0 g, 32 mmol) and EtOH (30 mL) . The mixture was cooled to 0℃ and dichlorosulfoxide (2.8 mL, 38 mmol) was added dropwise. After completion of the dropwise addition, the reaction solution was heated to 80℃ and stirred for 20 h. After the reaction was completed, the reaction solution was cooled to rt, and concentrated in vacuo to remove solvent and remaining dichlorosulfoxide. The residue was added with ethyl acetate (150 mL) and saturated sodium bicarbonate solution (80 mL) , and partitioned. The aqueous phase was extracted with EtOAc (100 mL × 3) and the organic phases were combined. The combined organic phases were washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound as light yellow oil (5.1 g, 86%)

Step 2) : synthesis of ethyl 2- (bromomethyl) -3-fluorobenzoate

To the reaction flask were added ethyl 3-fluoro-2-methylbenzoate (5.1 g, 28 mmol) , N-bromosuccinimide (5.6 g, 31 mmol) , benzoyl peroxide (0.34 g, 1.4 mmol) and CCl ₄ (30 mL) . The reaction solution was heated to 82℃ and stirred for 17 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to rt and filtered. The filter cake was washed with EtOAc (50 mL) , the filtrate was washed with saturated sodium thiosulfate solution (100 mL × 2) , citric acid solution (50 mL) and saturated saline (50 mL) in turn, then dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to give the title compound as light yellow oil (6.17 g, 84%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.77 (d, J = 7.8 Hz, 1H) , 7.35 (td, J = 8.0, 5.6 Hz, 1H) , 7.24 (t, J = 8.9 Hz, 1H) , 5.00 (d, J = 1.6 Hz, 2H) , 4.42 (q, J = 7.2 Hz, 2H) , 1.43 (t, J = 7.1 Hz, 3H)

Step 3) : synthesis of ethyl 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -3-fluorobenzoate

To the reaction flask were added ethyl 2- (bromomethyl) -3-fluorobenzoate (5.5 g, 21 mmol) , benzo [b] thiophene-7-thiol (3.2 g, 19 mmol) , neutral alumina (2.6 g, 26 mmol) , potassium carbonate (3.5 g, 25 mmol) and DMF (50 mL) . The reaction solution was stirred for 24 h at rt. After the reaction was completed, the reaction solution was added with water (150 mL) and EtOAc (150 mL) , then partitioned. The aqueous phase was washed with EtOAc (80 mL × 3) and saturated brine (80 mL × 3) in turn and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as light yellow oil (6.7 g, 100%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.74 (dd, J = 6.0, 2.9 Hz, 1H) , 7.64 (d, J = 7.8 Hz, 1H) , 7.45 (d, J = 5.4 Hz, 1H) , 7.36 (d, J = 5.4 Hz, 1H) , 7.25 (dd, J = 6.8, 3.9 Hz, 3H) , 7.10 (t, J = 8.9 Hz, 1H) , 4.66 (s, 2H) , 4.18 (q, J = 7.1 Hz, 2H) , 1.33 (t, J = 7.1 Hz, 3H) ;

MS (ESI, pos. ion) m/z: 347.1 [M+H] ⁺

Step 4) : synthesis of 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -3-fluorobenzoic acid

To the reaction flask were added ethyl 2- ( (benzo [b] thiophen-7-ylthio) methyl) -3-fluorobenzoate (6.7 g, 19 mmol) , THF (30 mL) and MeOH (30 mL) , then sodium hydroxide (1.6 g, 40 mmol) in water (10 mL) was added, the reaction solution was heated to 70℃ and kept stirring for 20 h. After the reaction was completed, the reaction solution was cooled to rt, concentrated to remove organic solvent, added with water (80 mL) , adjusted by 2N hydrochloric acid to pH 5-6, extracted with EtOAc (100 mL × 3) and the organic phases were combined. The combined organic phases were washed with saturated saline (100 mL) and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound as a light yellow solid (6.1 g, 99%) which was used for next step without further purification. filtered, and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (6.1 g, 99%) directly used for next step.

Step 5) : synthesis of 10-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6- (11H) -one

To the reaction flask were added 2- ( (Benzo [b] thiophen-7-ylthio) methyl) -3-fluorobenzoic acid (6.0 g, 19 mmol) , polyphosphoric acid (30 mL) and PhCl (80 mL) . The reaction solution was heated to 130℃ under nitrogen protection and stirred for 20 h. After the reaction was completed, the reaction solution was cooled to rt, added with ice water (80 g) and DCM (150 mL) , stirred at rt until all PPA was dissolved, then partitioned. The aqueous phase was extracted with DCM (100 mL × 3) , and the combined organic phases were washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo to give the title compound as a light yellow solid (5.7 g, 100%) directly used for next step.

Step 6) : synthesis of 10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol

To the reaction flask were added 10-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6- (11H) -one (5.7 g, 19 mmol) , THF (80 mL) and MeOH (20 mL) . The reaction solution was cooled to 0℃ and added with sodium borohydride (1.1 g, 28 mmol) in batches. After the addition was completed, the reaction solution was stirred for 1 h at rt. After the reaction was completed, a saturated ammonium chloride solution (30 mL) was added dropwise to the reaction solution to quench the reaction. Then water (100 mL) and EtOAc (150 mL) were added. The solution was partitioned, the aqueous phase was extracted with EtOAc (100 mL × 3) , and the combined organic phase was washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to give the title compound as a light yellow solid (4.2 g, 73%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.64 (d, J = 8.2 Hz, 1H) , 7.56 (d, J = 8.2 Hz, 1H) , 7.42 (d, J = 5.4 Hz, 1H) , 7.30 (d, J = 5.4 Hz, 1H) , 7.27 (s, 1H) , 7.22 (td, J = 7.9, 5.6 Hz, 1H) , 7.04 (t, J = 8.6 Hz, 1H) , 6.32 (d, J = 2.5 Hz, 1H) , 4.96 (d, J = 14.2 Hz, 1H) , 4.39 (d, J = 14.2 Hz, 1H) , 2.72 (d, J = 3.1 Hz, 1H) ;

MS (ESI, pos. ion) m/z: 325.1 [M+Na] ⁺

Step 7) : synthesis of (R) -7- (benzyloxy) -12- ( (S) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (8A) and (R) -7- (benzyloxy) -12- ( (R) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (8B)

To the reaction flask were added 10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol (2.8 g, 9.3 mmol) , (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-di one (2.5 g, 7.6 mmol) , T3P (30 mL, 50%ethyl acetate solution) and iPrOAc (30 mL) . The reaction solution was heated to 90℃ and stirred for 24 h. After the reaction was completed, the reaction solution was cooled to rt, to the reaction solution were added saturated sodium bicarbonate solution (100 mL) and EtOAc (150 mL) . After separation, the aqueous phase was extracted with EtOAc (100 mL × 3) . The organic phase was combined. The combined organic phase was washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (PE/EA (v/v) = 2/3) to give the title compound (8A) as a light yellow solid (0.61 g, 13%) and the title compound (8B) as a light yellow solid (1.01 g, 22%) .

(R) -7- (benzyloxy) -12- ( (R) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (8B) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.65-7.63 (m, 3H) , 7.55 (d, J = 5.4 Hz, 1H) , 7.42-7.29 (m, 5H) , 7.10 (t, J = 8.7 Hz, 1H) , 7.01-6.96 (m, 1H) , 6.69 (d, J = 7.8 Hz, 1H) , 6.30 (d, J = 7.5 Hz, 1H) , 5.82 (d, J = 7.7 Hz, 1H) , 5.67 (d, J = 10.8 Hz, 1H) , 5.53-5.48 (m, 2H) , 5.30 (d, J = 14.1 Hz, 1H) , 4.64 (d, J = 11.7 Hz, 1H) , 4.39 (dd, J = 9.9, 2.8 Hz, 1H) , 4.26 (d, J = 14.1 Hz, 1H) , 3.92 (dd, J = 10.7, 2.8 Hz, 1H) , 3.69 (dd, J = 11.8, 3.0 Hz, 1H) , 3.40-3.24 (m, 2H) , 2.82-2.67 (m, 1H) .

MS (ESI, pos. ion) m/z: 612.3 [M+H] ⁺

(R) -7- (benzyloxy) -12- ( (S) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (8A) :

¹H NMR (400 MHz, CDCl ₃) : δ (ppm) 7.65 (d, J = 7.0 Hz, 2H) , 7.45-7.33 (m, 4H) , 7.28-7.17 (m, 4H) , 7.04 (d, J = 7.3 Hz, 1H) , 6.97 (d, J = 7.7 Hz, 1H) , 6.47 (d, J = 8.2 Hz, 1H) , 5.71-5.60 (m, 2H) , 5.48 (d, J = 12.1 Hz, 2H) , 5.42-5.35 (m, 1H) , 4.75-4.65 (m, 1H) , 4.53 (dd, J = 9.9, 2.8 Hz, 1H) , 4.27 (d, J = 13.7 Hz, 1H) , 3.92 (dd, J = 10.8, 2.8 Hz, 1H) , 3.74 (dd, J = 11.8, 3.0 Hz, 1H) , 3.47-3.29 (m, 2H) , 2.97-2.84 (m, 1H) .

MS (ESI, pos. ion) m/z: 612.3 [M+H] ⁺

Step 8) : synthesis of (R) -12- ( (S) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the reaction flask were added (R) -7- (benzyloxy) -12- ( (S) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.0 g, 1.6 mmol) , lithium chloride (0.70 g, 16 mmol) and DMAc (10 mL) , and the reaction solution was warmed to 100℃ under protection of nitrogen and stirred for 15 h. After the reaction was completed, the reaction solution was cooled to rt, EtOAc (100 mL) and water (100 mL) were added. After separation, the aqueous phase was extracted with EtOAc (80 mL× 4) . The combined organic phases were washed with saturated saline (80 mL× 4) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The obtained crude product was purified by preparative HPLC (Column packing: LUNA; Mobile phase: phase A: 1‰aqueous solution of trifluoroacetic acid; phase B: acetonitrile, isocratic elution 45%B-60%A) to give the title compound as an orange solid (0.6 g, 70%)

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.44 (d, J = 5.4 Hz, 1H) , 7.34 (d, J = 8.1 Hz, 1H) , 7.29-7.26 (m, 1H) , 7.24-7.20 (m, 2H) , 7.08 (d, J = 7.3 Hz, 1H) , 6.97 (d, J = 7.7 Hz, 1H) , 6.71 (d, J = 8.2 Hz, 1H) , 5.61 (d, J = 7.7 Hz, 1H) , 5.50 (s, 1H) , 5.41 (d, J = 13.7 Hz, 1H) , 5.30 (s, 1H) , 4.70-4.63 (m, 2H) , 4.29 (d, J = 13.8 Hz, 1H) , 4.00 (dd, J = 11.1, 2.9 Hz, 1H) , 3.82 (dd, J = 12.0, 3.1 Hz, 1H) , 3.62 (t, J = 10.6 Hz, 1H) , 3.48 (dd, J = 11.8, 9.6 Hz, 1H) , 3.08-2.96 (m, 1H) .

HRMS (ESI, pos. ion) m/z: 522.0952 [M+H] +

Example 8-2: (R) -12- ( (R) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (8-2)

To the reaction flask were added (R) -7- (benzyloxy) -12- ( (R) -10-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl ) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.8 g, 2.9 mmol) , lithium chloride (1.3 g, 30 mmol) and DMAc (10 mL) , and the reaction solution was warmed to 100℃ under protection of nitrogen and stirred for 15 h. After the reaction was completed, the reaction solution was cooled to rt, EtOAc (150 mL) and water (100 mL) were added. After separation, the aqueous phase was extracted with EtOAc (80 mL× 4) . The combined organic phases were washed with saturated saline (50 mL× 5) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The obtained crude product was purified by preparative HPLC (Column packing: LUNA; Mobile phase: phase A: 1‰aqueous solution of trifluoroacetic acid; phase B: acetonitrile, isocratic elution 45%B-60%A) to give the title compound as an orange solid (0.7 g, 50%)

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.66 (d, J = 8.2 Hz, 1H) , 7.57 (d, J = 5.4 Hz, 1H) , 7.36 (dd, J = 10.2, 6.8 Hz, 2H) , 7.19-7.07 (m, 2H) , 6.71 (t, J = 7.3 Hz, 2H) , 5.84 (d, J = 7.7 Hz, 1H) , 5.55 (d, J = 14.0 Hz, 1H) , 5.36 (d, J = 33.5 Hz, 2H) , 4.70-4.59 (m, 1H) , 4.54 (dd, J = 9.9, 2.9 Hz, 1H) , 4.32 (d, J = 14.1 Hz, 1H) , 4.03 (dd, J = 10.9, 2.9 Hz, 1H) , 3.77 (dd, J = 11.9, 3.1 Hz, 1H) , 3.58 (t, J = 10.4 Hz, 1H) , 3.52-3.39 (m, 1H) , 2.92-2.78 (m, 1H) ;

HRMS (ESI, pos. ion) m/z: 522.0957 [M+H] ⁺

Example 9 (R) -12- ( (S) -9-fluoro-6, 11-dihydrobenzo [e] thieno [3, 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (9-1) and (R) -12- ( (R) -9-fluoro-6, 11-dihydrobenzo [e] thieno [3, 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (9-2)

Step 1) : synthesis of ethyl 4-fluoro-2-methylbenzoate

4-Fluoro-2-methylbenzoic acid (10g, 64.8 mmol) was mixed in ethanol (30 mL) . The mixture was stirred at rt and then thionyl chloride (5.7 mL, 78 mmol) was added slowly dropwise. The reaction solution was reacted at 78℃ for 8 h. After the reaction was completed, the reaction solution was adjusted with saturated sodium bicarbonate solution to pH about 6, extracted with ethyl acetate (10 mL× 3) . The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a white solid (11.2g, 94%) .

MS (ESI, pos. ion) m/z: 183.1 [M+H] ⁺

Step 2) : synthesis of ethyl 2- (bromomethyl) -4-fluorobenzoate

Ethyl 4-fluoro-2-methylbenzoate (11.0g, 60.3 mmol) , NBS (11.8 g, 66.3 mmol) and BPO (731mg, 3.0mmol) were dissolved in carbon tetrachloride (30 mL) . The mixture was reacted at 78℃ for 23 h under nitrogen protection. After the reaction was completed, the reaction solution was filtered and extracted with ethyl acetate (100 mL × 3) . The organic phases were combined and washed with saturated brine (100 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as yellow liquid (6.0 g, 38.4%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 8.02 (dd, J = 8.7, 5.9 Hz, 1H) , 7.19 (dd, J = 9.2, 2.5 Hz, 1H) , 7.05 (td, J = 8.4, 2.6 Hz, 1H) , 4.94 (s, 2H) , 4.40 (q, J = 7.1 Hz, 2H) , 1.42 (t, J = 7.1 Hz, 3H)

Step 3) : synthesis of ethyl 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -4-fluorobenzoate

Benzo [b] thiophene-7-thiol (0.9 g, 5 mmol) , ethyl 2- (bromomethyl) -4-fluorobenzoate (2.0g, 7.6 mmol) , potassium carbonate (1 g, 7.1 mmol) and alumina (0.7 g, 6.8 mmol) were mixed in DMF (10 mL) . The mixture was stirred for 4 h at rt. After the reaction was completed, the reaction was added with water (20 mL) and extracted with ethyl acetate (10 mL × 3) . The organic phases were combined and washed with saturated brine (10 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a yellow solid (1.3g, 70%) .

¹H NMR (400 MHz, CDCl3) δ (ppm) 7.97 (dd, J = 8.7, 6.0 Hz, 1H) , 7.76 (d, J = 7.7 Hz, 1H) , 7.47 (d, J = 5.5 Hz, 1H) , 7.39 (s, 1H) , 7.30 –7.25 (m, 1H) , 7.22 (d, J = 7.2 Hz, 1H) , 4.59 (s, 2H) , 4.34 (q, J = 7.1 Hz, 2H) , 1.41 (d, J = 7.1 Hz, 3H)

Step 4) : synthesis of 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -4-fluorobenzoic acid

Ethyl 2- ( (benzo [b] thiophen-7-ylthio) methyl) -4-fluorobenzoate (3.1g, 8.9 mmol) was dissolved in tetrahydrofuran (6 mL) and ethanol (6 mL) . The mixture was stirred at rt, then sodium hydroxide (1.4 mg, 35 mmol) in water (3 mL) was added. The reaction solution was reacted at 60℃for 4 h. After the reaction was completed, the reaction solution was adjusted with 2N hydrochloric acid to pH 5, extracted with ethyl acetate (10 mL× 3) . The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (2.8g, 98%) .

MS (ESI, pos. ion) m/z: 371.1 [M+H] ⁺

Step 5) : synthesis of 9-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6- (11H) -one

2- ( (Benzo [b] thiophen-7-ylthio) methyl) -4-fluorobenzoic acid (5.9 g, 19mmol) was mixed in polyphosphoric acid (10 mL) . The mixture was reacted at 130℃ for 6 h. After the reaction was completed, the reaction solution was added with ice water (20 mL) for dissolution, extracted with dichloromethane (10 mL × 3) . The organic phases were combined and washed with saturated saline (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a black solid (5.33g, 96%) .

MS (ESI, pos. ion) m/z: 301.1 [M+H] +

Step 6) : synthesis of 9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol

9-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one (5.3 g, 18 mmol) was dissolved in THF (5 mL) and methanol (5 mL) , and the mixture was stirred at rt. Sodium borohydride (2.8g, 71mmol) was added slowly, and the resulting mixture was reacted at rt for 20 minutes. After the reaction was completed, the reaction solution was added with saturated ammonium chloride solution (10 mL) for dissolution and extracted with ethyl acetate (5 mL × 3) . The combined organic phases were washed with saturated saline solution (10 mL) and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (PE/EA (v/v) = 5/1) to give the title compound as a yellow solid (4.61g, 86%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.63 (d, J = 8.2 Hz, 1H) , 7.53 (d, J = 8.2 Hz, 1H) , 7.42 (t, J = 5.7 Hz, 2H) , 7.31 –7.28 (m, 1H) , 7.01 –6.91 (m, 2H) , 6.22 (d, J = 2.2 Hz, 1H) , 4.93 (d, J = 13.8 Hz, 1H) , 4.21 (d, J = 13.8 Hz, 1H) .

Step 7) : synthesis of (12aR) -7- (benzyloxy) -12- (9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol (1.5g, 5.0 mmol) and(R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.8g, 5.5 mmol) were mixtured in isopropyl acetate (16 mL) , and 1-propylphosphoric anhydride (8.9 mL, 15 mmol) was added, the reaction system was reacted at 90 ℃ for 2 h. After the reaction was completed, the reaction solution was added with water (10 mL) and extracted with ethyl acetate (5 mL × 3) . The organic phases were combined and washed with saturated brine (10 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (DCM/methanol (v/v) = 15/1) to give the title compound as a light brown solid (2.73mg, 90%) .

MS (ESI, pos. ion) m/z: 612.0 [M+H] ⁺

Step 8) : synthesis of (R) -12- ( (S) -9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (9-1) and (R) -12- ( (R) -9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (9-2)

(12aR) -7- (benzyloxy) -12- (9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiep in-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2.73g, 4.4 mmol) was dissolved in DMF (30 mL) , anhydrous lithium chloride (1.95g, 44.6 mmol) was added, and the reaction solution was warmed to 100℃ under protection of nitrogen and reacted overnight.. After the reaction was completed, the reaction solution was adjusted with 2N diluted hydrochloric acid to pH about 6, and extracted with ethyl acetate (10 mL × 3) . The organic phases were combined and washed with saturated brine (20 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 42/3) to give the title compound (9-1) as a light orange solid (795mg, 34%) and the title compound (9-2) as a light orange solid (666mg, 28%) , respectively.

MS (ESI, pos. ion) m/z: 522.3 [M+H] ⁺

(R) -12- ( (S) -9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (9-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.42 (d, J = 5.3 Hz, 1H) , 7.32 (d, J = 8.1 Hz, 1H) , 7.27 –7.24 (m, 1H) , 7.21 (d, J = 5.3 Hz, 1H) , 7.12 (dd, J = 8.4, 1.9 Hz, 1H) , 7.02 –6.90 (m, 2H) , 6.71 (d, J = 8.1 Hz, 1H) , 5.71 (d, J = 13.5 Hz, 1H) , 5.56 (d, J = 7.7 Hz, 1H) , 5.46 (s, 1H) , 5.30 (s, 1H) , 4.65 (dd, J = 17.8, 7.9 Hz, 2H) , 3.98 (dd, J = 11.0, 2.4 Hz, 1H) , 3.81 (dd, J = 11.7, 2.4 Hz, 1H) , 3.74 (d, J = 13.5 Hz, 1H) , 3.65 (t, J = 10.6 Hz, 1H) , 3.49 (t, J = 10.9 Hz, 1H) , 3.01 (dd, J = 17.9, 7.1 Hz, 1H) ;

(R) -12- ( (R) -9-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (9-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.65 (d, J = 8.2 Hz, 1H) , 7.55 (d, J = 5.4 Hz, 1H) , 7.39 –7.32 (m, 2H) , 7.11 –7.06 (m, 1H) , 6.84 (dt, J = 19.2, 8.3 Hz, 2H) , 6.67 (d, J = 7.7 Hz, 1H) , 5.82 (dd, J = 10.7, 5.9 Hz, 2H) , 5.33 (d, J = 17.0 Hz, 2H) , 4.62 (d, J = 12.4 Hz, 1H) , 4.51 (dd, J = 9.8, 2.7 Hz, 1H) , 4.00 (dd, J = 10.8, 2.6 Hz, 1H) , 3.76 (dd, J = 13.9, 8.3 Hz, 2H) , 3.58 (t, J = 10.4 Hz, 1H) , 3.45 (dd, J = 11.8, 9.8 Hz, 1H) , 2.89 –2.78 (m, 1H) .

Example 10-1 (R) -12- ( (S) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (10-1)

Step 1) : synthesis of methyl 2- (bromomethyl) -5-fluorobenzoate

To the reaction flask were added methyl 5-fluoro-2-methylbenzoate (5.0 g, 30 mmol) , N-bromosuccinimide (5.9 g, 32 mmol) , benzoyl peroxide (0.36 g, 1.5 mmol) and CCl4 (50 mL) The reaction solution was heated to 82℃ and stirred for 20 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to rt, and concentrated in vacuo to remove solvent. The residue was added with EtOAc (150 mL) and saturated ammonium chloride solution (100 mL) , and partitioned. The aqueous phase was extracted with EtOAc (80 mL × 3) and the organic phases were combined. The combined organic phases were washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The obtained crude product was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to give the title compound as light yellow oil (4.6 g, 63%)

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.62 (dd, J = 9.3, 1.4 Hz, 1H) , 7.41 (dd, J = 8.5, 5.5 Hz, 1H) , 7.15 (ddd, J = 8.6, 2.6, 1.4 Hz, 1H) , 4.90 (s, 2H) , 3.91 (s, 3H)

Step 2) : synthesis of methyl 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -5-fluorobenzoate

To the reaction flask were added methyl 2- (bromomethyl) -5-fluorobenzoate (4.6 g, 19 mmol) , benzo [b] thiophen-7-thiol (2.8 g, 17 mmol) , potassium carbonate (3.1 g, 22 mmol) , neutral alumina (2.2 g, 22 mmol) and DMF (40 mL) . The reaction solution was stirred for 24 h at rt. After the reaction was completed, EtOAc (150 mL) and water (100 mL) were added to the reaction solution. After separation, the aqueous phase was extracted with EtOAc (100 mL× 3) . The combined organic phases were washed with saturated saline (100 mL× 3) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound as light yellow oil (5.6 g, 100%) directly used for next step.

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.74 (d, J = 7.8 Hz, 1H) , 7.61 (dd, J = 9.4, 2.6 Hz, 1H) , 7.46 (d, J = 5.5 Hz, 1H) , 7.37 (d, J = 5.5 Hz, 1H) , 7.26 (dd, J = 12.8, 5.4 Hz, 1H) , 7.19 (d, J = 7.3 Hz, 1H) , 7.02-6.88 (m, 2H) , 4.56 (s, 2H) , 3.86 (s, 3H) ;

MS: (ESI, pos. ion) m/z: 333.1 [M+H] ⁺

Step 3) : synthesis of 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -5-fluorobenzoic acid

To the reaction flask were added methyl 2- ( (benzo [b] thiophen-7-ylthio) methyl) -5-fluorobenzoate (5.6 g, 17 mmol) , THF (40 mL) and MeOH (40 mL, 100 mass%) . Then Sodium hydroxide (1.4 g, 35 mmol) in water (10 mL) was added. The reaction solution was heated to 70℃ and stirred and refluxed overnight. After the reaction was completed, the reaction solution was cooled to rt, and concentrated under reduced pressure to remove organic solvent. The residue was added with water (100 mL) , adjusted with 2N hydrochloric acid to pH 5, then EtOAc (150 mL) was added. After separation, the aqueous phase was extracted with EtOAc (100 mL × 3) . The organic phases were combined. The combined organic phases were washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound (5.3 g, 99%)

Step 4) : synthesis of 8-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one

To the reaction flask were added 2- ( (benzo [b] thiophen-7-ylthio) methyl) -5-fluorobenzoic acid (5.0 g, 16 mmol) , PPA (40 mL) and PhCl (100 mL) . The reaction solution was heated to 130℃ and stirred for 24 h under nitrogen protection. After the reaction was completed, the reaction solution was cooled to rt, and ice water (150 g) and DCM (100 mL) were added to dissolve all PPA. After separation, the aqueous phase was extracted with DCM (100 mL × 3) . The organic phases were combined. The combined organic phase was washed with saturated saline (100mL) , collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo to give the title compound as a yellow solid (4.7 g, 100%) directly used for next step.

Step 5) : synthesis of 8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol

To the reaction flask were added 8-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6- (11H) -one (4.7 g, 16 mmol) , THF (80 mL) and MeOH (20 mL) . The reaction solution was cooled to 0℃, and sodium borohydride (1.5 g, 38 mmol) was added in batches. The reaction solution was stirred at rt for 2 h. After the reaction was completed, a saturated ammonium chloride solution (50 mL) was slowly added dropwise to the reaction mixture to quench the reaction. Water (100 mL) and EtOAc (150 mL) were added. After separation, the aqueous phase was extracted with EtOAc (100 mL× 3) . The combined organic phases were washed with saturated saline (100 mL× 3) , collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to give the title compound as a light yellow solid (4.0 g, 85%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.62 (q, J = 8.2 Hz, 2H) , 7.40 (d, J = 5.4 Hz, 1H) , 7.30 (s, 1H) , 7.27-7.18 (m, 2H) , 6.93 (td, J = 8.3, 2.5 Hz, 1H) , 6.37 (s, 1H) , 4.63 (d, J = 13.7 Hz, 1H) , 4.46 (d, J = 13.7 Hz, 1H) , 2.61 (s, 1H) ;

MS (ESI, pos. ion) m/z: 325.0 [M+H] ⁺

Step 6) : synthesis of (R) -7- (benzyloxy) -12- ( (S) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (10A) and (R) -7- (benzyloxy) -12- ( (R) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (10B)

To the reaction flask were added 8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol (2.8 g, 9.3 mmol) , (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2.5 g, 7.6 mmol) , iPrOAc (30 mL) and T3P (30 mL, 50 %ethyl acetate solution) . The reaction solution was warmed to 90℃ under protection of nitrogen and stirred for 10 h. After the reaction was completed, the reaction solution was cooled to rt. EtOAc (150 mL) and saturated sodium bicarbonate solution (100 mL) were added (gas generation) . The reaction solution was partitioned and the aqueous was extracted with EtOAc (100 mL × 3) . The combined organic phases were washed with saturated saline (100 mL) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The crude product was purified by silica gel column chromatography (eluent: EA) to give the title compound (10A) as a light yellow solid (2.0 g, 43%) and the title compound (10B) as a light yellow solid (1.0 g, 21%) .

(R) -7- (benzyloxy) -12- ( (S) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (10A) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.65 (d, J = 7.0 Hz, 2H) , 7.44-7.36 (m, 5H) , 7.21 (dd, J = 9.1, 6.8 Hz, 2H) , 7.12 (td, J = 8.2, 2.5 Hz, 1H) , 7.00-6.97 (m, 2H) , 6.46 (d, J = 8.2 Hz, 1H) , 5.64 (d, J = 7.6 Hz, 3H) , 5.50 (s, 1H) , 5.35 (s, 1H) , 4.78-4.46 (m, 2H) , 3.92 (dd, J = 10.9, 2.8 Hz, 1H) , 3.83-3.72 (m, 2H) , 3.47-3.29 (m, 2H) , 3.01-2.88 (m, 1H) ;

MS (ESI, pos. ion) m/z: 612.2 [M+H] ⁺

(R) -7- (benzyloxy) -12- ( (R) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (10B) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.64 (d, J = 6.6 Hz, 3H) , 7.54 (d, J = 5.4 Hz, 1H) , 7.42-7.34 (m, 4H) , 7.33-7.29 (m, 1H) , 7.28-7.26 (m, 1H) , 7.02 (td, J = 8.2, 2.5 Hz, 1H) , 6.68 (d, J = 7.8 Hz, 1H) , 6.26 (dd, J = 8.6, 2.5 Hz, 1H) , 5.84 (d, J = 7.7 Hz, 1H) , 5.77 (d, J = 13.8 Hz, 1H) , 5.68 (d, J = 10.8 Hz, 1H) , 5.54 (d, J = 10.8 Hz, 1H) , 5.11 (s, 1H) , 4.62 (dd, J = 13.4, 1.7 Hz, 1H) , 4.36 (dd, J = 9.9, 2.8 Hz, 1H) , 3.93 (dd, J = 10.6, 2.8 Hz, 1H) , 3.79 (d, J = 13.8 Hz, 1H) , 3.68 (dd, J = 11.8, 3.1 Hz, 1H) , 3.39-3.27 (m, 2H) , 2.74-2.67 (m, 1H) ;

MS (ESI, pos. ion) m/z: 612.2 [M+H] ⁺

Step 7) : synthesis of (R) -12- ( (S) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the reaction flask were added (R) -7- (benzyloxy) -12- ( (S) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.8 g, 2.9 mmol) , lithium chloride (1.3 g, 30 mmol) and DMAc (10 mL, 100 mass%) , and the reaction solution was warmed to 100℃ and stirred for 5 h. After the reaction was completed, the reaction solution was cooled to rt, added with EtOAc (100 mL) and water (100 mL) , and adjusted with 2N to pH about 6. After separation, the aqueous phase was extracted with EtOAc (80 mL× 3) . The combined organic phases were washed with saturated saline (60 mL× 5) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The obtained crude product was purified by preparative chromatography (Column packing: LUNA; Mobile phase: phase A: 1‰aqueous solution of trifluoroacetic acid; phase B: acetonitrile, isocratic elution 40%B-60%A) to give the title compound as a light solid (0.9 g, 60%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.42 (d, J = 5.4 Hz, 1H) , 7.39 (dd, J = 8.4, 5.5 Hz, 1H) , 7.34 (d, J = 8.1 Hz, 1H) , 7.23 (d, J = 5.4 Hz, 1H) , 7.12 (td, J = 8.2, 2.5 Hz, 1H) , 7.01 (dd, J = 8.7, 2.5 Hz, 1H) , 6.98 (d, J = 7.7 Hz, 1H) , 6.72 (d, J = 8.2 Hz, 1H) , 5.64 (d, J = 13.5 Hz, 1H) , 5.57 (d, J = 7.7 Hz, 1H) , 5.39 (s, 1H) , 4.76-4.67 (m, 1H) , 4.64 (dd, J = 10.0, 2.9 Hz, 1H) , 4.00 (dd, J = 11.1, 2.8 Hz, 1H) , 3.88-3.77 (m, 2H) , 3.63 (t, J = 10.6 Hz, 1H) , 3.49 (td, J = 11.8, 2.4 Hz, 1H) , 3.12-2.98 (m, 1H) ;

HRMS (ESI, pos. ion) m/z: 522.0951 [M+H] ⁺

Example 10-2 (R) -12- ( (R) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (10-2)

To the reaction flask were added (R) -7- (benzyloxy) -12- ( (R) -8-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2.5 g, 4.1 mmol) , lithium chloride (1.7 g, 40 mmol) and DMAc (10 mL) , and the reaction solution was warmed to 100℃ and stirred for 6 h. After the reaction was completed, the reaction solution was cooled to rt, EtOAc (100 mL) and water (100 mL) were added. After separation, the aqueous phase was extracted with EtOAc (80 mL× 3) . The combined organic phases were washed with saturated saline (80 mL× 4) , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. The obtained crude product was separated by preparative chromatography to give the title compound as a light yellow solid (1.5 g, 70%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.65 (d, J = 8.2 Hz, 1H) , 7.55 (d, J = 5.4 Hz, 1H) , 7.38-7.33 (m, 3H) , 7.06 (td, J = 8.2, 2.5 Hz, 1H) , 6.72 (d, J = 7.7 Hz, 1H) , 6.66 (dd, J = 8.5, 2.4 Hz, 1H) , 5.88-5.79 (m, 2H) , 5.31 (d, J = 8.4 Hz, 2H) , 4.67-4.57 (m, 1H) , 4.52 (dd, J = 9.9, 2.9 Hz, 1H) , 4.03 (dd, J = 10.9, 2.8 Hz, 1H) , 3.85 (d, J = 13.8 Hz, 1H) , 3.76 (dd, J = 11.9, 3.1 Hz, 1H) , 3.59 (t, J = 10.4 Hz, 1H) , 3.45 (td, J = 11.8, 2.4 Hz, 1H) , 2.82 (td, J = 13.4, 3.4 Hz, 1H) ;

HRMS (ESI, pos. ion) m/z: 522.0954 [M+H] ⁺

Example 11 (R) -12- ( (S) -7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (11-1) and (R) -12- ( (R) -7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (11-2)

Step 1) : synthesis of ethyl 6-fluoro-2-methylbenzoate

6-Fluoro-2-methylbenzoic acid (10g, 64.8 mmol) was dissolved in ethanol (30 mL) . The mixture was stirred at rt and then thionyl chloride (5.7 mL, 78 mmol) was added dropwise slowly. The reaction solution was reacted at 78℃ for 29 h. The reaction was stopped, and the reaction solution was adjusted with saturated sodium bicarbonate solution to pH about 6, extracted with ethyl acetate (10 mL× 3) . The combined organic phases were washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as colorless transparent liquid (8.86g, 75%) .

MS (ESI, pos. ion) m/z: 183.2 [M+H] +

Step 2) : synthesis of ethyl 2- (bromomethyl) -6-fluorobenzoate

Ethyl 6-fluoro-2-methylbenzoate (8.86g, 48.6 mmol) , NBS (9.52g, 53.5mmol) and BPO (589mg, 2.4mmol) were dissolved in carbon tetrachloride (30 mL) . The mixture was reacted at 78℃ for 32 h under nitrogen. After the reaction was completed, the reaction solution was filtered and extracted with ethyl acetate (100 mL × 3) . The organic phases were combined and washed with saturated brine (100 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 10/1) to give the title compound as yellow oil (6.31g, 49.7%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.35 (td, J = 8.0, 5.6 Hz, 1H) , 7.19 (d, J = 7.7 Hz, 1H) , 7.05 (t, J = 8.9 Hz, 1H) , 4.64 (s, 2H) , 4.44 (q, J= 7.1 Hz, 2H) , 1.40 (t, J = 7.1 Hz, 3H)

Step 3) : synthesis of ethyl 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -6-fluorobenzoate

Benzo [b] thiophene-7-thiol (4.0 g, 24.0 mmol) , ethyl 2- (bromomethyl) -6-fluorobenzoate (6.9g, 26.4 mmol) , potassium carbonate (4.36 g, 31.2 mmol) and alumina (3.19 g, 31.3 mmol) were mixed in DMF (10 mL) . The mixture was stirred for 17 h at rt. After the reaction was completed, the reaction solution was added with water (20 mL) and extracted with ethyl acetate (10 mL × 3) . The organic phases were combined and washed with saturated brine (10 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EtOAc (v/v) = 20/1) to give the title compound as a yellow solid (6.39g, 76%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.74 (dd, J = 5.4, 3.6 Hz, 1H) , 7.47 (d, J = 5.5 Hz, 1H) , 7.37 (d, J = 5.5 Hz, 1H) , 7.28 –7.23 (m, 2H) , 7.15 (td, J = 8.0, 5.7 Hz, 1H) , 6.97 (t, J = 9.0 Hz, 1H) , 6.78 (d, J = 7.7 Hz, 1H) , 4.41 (dd, J = 14.1, 6.9 Hz, 4H) , 1.42 (t, J = 7.1 Hz, 3H)

Step 4) : synthesis of 2- ( (benzo [b] thiophen-7-yl-thio) methyl) -6-fluorobenzoic acid

Ethyl 2- ( (benzo [b] thiophen-7-ylthio) methyl) -6-fluorobenzoate (4.8g, 14 mmol) was dissolved in tetrahydrofuran (10 mL) and ethanol (10 mL) , The mixture was stirred at rt, then sodium hydroxide (2.2 mg, 54 mmol) in water (3 mL) was added. After the addition was completed, the reaction solution was reacted at 60℃ for 2 h. After the reaction was completed, the reaction solution was adjusted with 2N hydrochloric acid to pH 5, extracted with ethyl acetate (10 mL× 3) . The combined organic phases were washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (4.18g, 95%) .

MS (ESI, pos. ion) m/z: 371.1 [M+H] ⁺

Step 5) : synthesis of 7-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one

2- ( (Benzo [b] thiophen-7-ylthio) methyl) -6-fluorobenzoic acid (4.1g, 13 mmol) was mixed in polyphosphoric acid (10 mL) . The mixture was reacted at 130℃ for 24 h. After the reaction was completed, the reaction solution was added with ice water (20 mL) for dissolving, extracted with ethyl acetate (10 mL × 3) . The organic phases were combined and washed with saturated saline (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a black solid (3.9g, 100%) .

MS (ESI, pos. ion) m/z: 301.1 [M+H] +

Step 6) : synthesis of 7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol

7-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one (3.9g, 13 mmol) was dissolved in tetrahydrofuran (10 mL) and methanol (10 mL) . The mixture was stirred at rt. Sodium borohydride (2.0g, 51 mmol) was added slowly, and the mixture was reacted at rt for 1 h. After the reaction was completed, saturated ammonium chloride solution was added (10 mL) , and the reaction solution was extracted with ethyl acetate (5 mL × 3) . The organic phases were combined and washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 5/1) to give the title compound as a yellow solid (2.3g, 59%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.61 (d, J = 8.1 Hz, 1H) , 7.47 –7.41 (m, 2H) , 7.32 (d, J = 5.4 Hz, 1H) , 7.29 –7.21 (m, 1H) , 7.07 (d, J = 7.5 Hz, 1H) , 6.98 (t, J = 9.2 Hz, 1H) , 6.43 (s, 1H) , 5.74 (d, J = 13.8 Hz, 1H) , 3.79 (d, J = 13.8 Hz, 1H) .

Step 7) : synthesis of (12aR) -7- (benzyloxy) -12- (7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiophene-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol (1.5g, 5.0 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.8g, 5.5 mmol) were mixed in isopropyl acetate (16 mL) , and 1-propylphosphoric anhydride (8.9 mL, 15 mmol) was added, the reaction system was reacted at 90 ℃ for 2 h. After the reaction was completed, the reaction solution was added with water (10 mL) and extracted with ethyl acetate (10 mL × 3) . The organic phases were combined and washed with saturated brine (10 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EtOAc (v/v) = 15/1) to give the title compound as a light brown solid (600mg, 20%) .

MS (ESI, pos. ion) m/z: 612.3 [M+H] ⁺

Step 8) : synthesis of (R) -12- ( (S) -7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (11-1) and (R) -12- ( (R) -7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (11-2)

(12aR) -7- (benzyloxy) -12- (7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiophene-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.5g, 2.5 mmol) was dissolved in DMF (30 mL) , anhydrous lithium chloride (1.1g, 25 mmol) was added, and the reaction solution was warmed to 100℃ under protection of nitrogen and reacted for 5 h. After the reaction was completed, the reaction solution was adjusted with 2N diluted hydrochloric acid to pH about 6, and extracted with ethyl acetate (10 mL × 3) . The organic phases were combined and washed with saturated brine (20 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 42/3) to give the title compound (11-1) as a light brown solid (795 mg, 34%) and the title compound (11-2) as a light brown solid (666 mg, 28%) .

MS (ESI, pos. ion) m/z: 522.3 [M+H] ⁺

(R) -12- ( (S) -7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (11-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.46 (d, J = 5.4 Hz, 1H) , 7.42 (d, J = 5.9 Hz, 1H) , 7.37 (d, J = 8.1 Hz, 1H) , 7.28 –7.20 (m, 2H) , 7.11 (dd, J = 12.6, 8.6 Hz, 2H) , 6.79 (d, J = 8.1 Hz, 1H) , 6.11 (s, 1H) , 5.74 (dd, J = 10.3, 6.9 Hz, 2H) , 5.32 (s, 1H) , 4.72 (dd, J = 17.6, 11.6 Hz, 2H) , 4.01 (d, J = 9.0 Hz, 1H) , 3.85 (d, J = 13.6 Hz, 2H) , 3.65 (t, J = 10.5 Hz, 1H) , 3.52 (t, J = 10.7 Hz, 1H) , 3.11 (t, J = 11.1 Hz, 1H) .

(R) -12- ( (R) -7-fluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (11-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.67 (d, J = 7.9 Hz, 1H) , 7.56 (d, J = 4.8 Hz, 1H) , 7.42 (d, J = 8.1 Hz, 1H) , 7.38 (d, J = 4.6 Hz, 1H) , 7.33 (d, J = 5.9 Hz, 1H) , 7.15 (d, J = 7.2 Hz, 1H) , 6.92 (t, J = 8.6 Hz, 1H) , 6.69 (d, J = 7.2 Hz, 1H) , 6.01 (s, 1H) , 5.86 (dd, J = 20.1, 10.8 Hz, 2H) , 4.63 (d, J = 13.4 Hz, 1H) , 4.54 (d, J = 8.2 Hz, 1H) , 4.02 (d, J = 9.4 Hz, 1H) , 3.86 (d, J = 13.6 Hz, 1H) , 3.76 (d, J = 10.3 Hz, 1H) , 3.59 (t, J = 10.3 Hz, 1H) , 3.45 (t, J = 11.3 Hz, 1H) , 2.84 (t, J = 11.1 Hz, 1H) .

Example 12 (R) -12- ( (S) -9, 10-difluoro-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy -3,4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (12-1) and (R) -12- ( (R) -9, 10-difluoro-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (12-2)

Step 1) : synthesis of 4-bromo-2, 3-dihydro-1H-indene

To a single-necked flask were added 4-bromo-1-indanone (5 g, 23.690 mmol) and trifluoroacetic acid (20 mL, 216.8 mmol) in turn. The mixture was cooled to 0℃, and triethylsilane (12 mL, 73 mmol) was added dropwise. After the addition is completed, the mixture was warmed to 50℃ and reacted overnight. The reaction solution was added with saturated ammonium chloride solution (20 mL) and extracted with dichloromethane (50 mL × 2) . The organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL× 2) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as colorless oil (3.944g, 84.48%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.27 (d, J = 7.9 Hz, 1H) , 7.13 (d, J = 7.4 Hz, 1H) , 6.98 (t, J = 7.6 Hz, 1H) , 3.00 (t, J = 7.5 Hz, 2H) , 2.94 (t, J = 7.5 Hz, 2H) , 2.07 (p, J = 7.5 Hz, 2H) .

Step 2) : synthesis of 1, 2-bis (2, 3-dihydro-1H-indene-4-yl) disulfide

To the double-necked flask A were added magnesium (2.48 g, 102 mmol) and iodine (1.29 g, 5.08 mmol) , tetrahydrofuran (30 mL) was added to, and the mixture was heated to 60℃ under nitrogen. A solution of 4-bromo-2, 3-dihydro-1H-indene (10 g, 50.744 mmol) in THF (20 mL) was added, and the reaction solution was reacted for 2 h at 60℃ for backup.

To a two-necked flask was added sublimed sulfur (3.254 g, 101.5 mmol) , and tetrahydrofuran (20 mL) was added, the reaction solution was cooled to 0℃ under nitrogen. The solution in double-necked flask A was added slowly dropwise, then the resulting mixture was reacted overnight at rt. The reaction was quenched with saturated ammonium chloride solution (30 mL) . The reaction mixture was extracted with EA (50 mL × 2) . The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as yellow oil (4.47g, 59%) .

Step 3) : synthesis of ethyl 2- ( ( (2, 3-dihydro-1H-indene-4-yl) thio) methyl) -3, 4-difluorobenzoate

To a single-necked flask were added 1, 2-bis (2, 3-dihydro-1H-indene-4-yl) disulfide (4.46 g, 14.9 mmol) , THF (50 mL) and sodium borohydride (707 mg, 17.9401 mmol) . The mixture was heated to 50℃ and reacted for 3 h. Then the reaction solution was cooled to rt, ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (8.34 g, 29.9 mmol) was added, and the solution was reacted overnight. The reaction was quenched with saturated ammonium chloride solution (20 mL) . The reaction mixture was extracted with EA (20 mL × 2) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1) to give the title compound as colorless oil (6.1g, 59%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.67 (ddd, J = 8.3, 5.0, 1.5 Hz, 1H) , 7.07 (ddd, J = 12.6, 10.5, 6.3 Hz, 4H) , 4.53 (d, J = 1.4 Hz, 2H) , 4.27 (q, J = 7.1 Hz, 2H) , 2.91 (t, J = 7.4 Hz, 2H) , 2.81 (t, J = 7.4 Hz, 2H) , 2.05 –1.93 (m, 2H) , 1.35 (t, J = 7.1 Hz, 3H) .

Step 4) : synthesis of 2- ( ( (2, 3-dihydro-1H-indene-4-yl) thio) methyl) -3, 4-difluorobenzoic acid

To a single-necked flask were added ethyl 2- ( ( (2, 3-dihydro-1H-indene-4-yl) thio) methyl) -3, 4-difluorobenzoate (4.4 g, 13 mmol) , THF (25 mL) and methanol (25 mL) , then a solution of sodium hydroxide (2 g, 50.00 mmol) in water (10 mL) was added dropwise at rt. After the addition is completed, the mixture was heated to 50℃ and reacted for 3 h. The reaction solution was concentrated in vacuo to remove organic solvent. The reaction solution was added with ice water (20 mL) , adjusted with 4N hydrochloric acid to pH about 4, then extracted with ethyl acetate (30 mL × 2) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (3.77g, 93%) .

MS (ESI, neg. ion) m/z: 318.9 [M+H] +

Step 5) : synthesis of 9, 10-difluoro-2, 3-dihydro-1H-benzo [e] indeno [4, 5-b] thiepin-6- (11H) -one

To a single-necked flask was added 2- ( ( (2, 3-dihydro-1H-indene-4-yl) thio) methyl) -3, 4-difluorobenzoic acid (100 mg, 0.3121 mmol) , then PPA (5 mL) was added. The mixture was heated to 130℃ and reacted for 3 h. The reaction solution was cooled to rt, added with ice water (10 mL) , then extracted with dichloromethane (10 mL × 3) . The organic phases were combined and washed with saturated sodium bicarbonate solution (15 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a brown solid (94.3mg, 99.9%) .

MS (ESI, pos. ion) m/z: 302.9 [M+H] ⁺

Step 6) : synthesis of 9, 10-difluoro2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-ol

To a single-necked flask were added 9, 10-difluoro2, 3-dihydro-1H-benzo [e] indeno [4, 5-b] thiepin-6- (11H) -one (94.3 mg, 0.3121 mmol) , THF (4 mL) and methanol (0.4 mL) , then sodium borohydride (49 mg, 1.24337 mmol) was added slowly. The resulting mixture was reacted at rt for 10 min. The reaction was quenched with saturated ammonium chloride solution (5 mL) . The reaction mixture was added with water (10 mL) , then extracted with EA (15 mL × 2) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the title compound as a white solid (49mg, 51.58%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.24 (d, J = 7.7 Hz, 1H) , 7.14 –7.05 (m, 1H) , 7.03 –6.94 (m, 2H) , 5.97 (s, 1H) , 4.93 (d, J = 14.1 Hz, 1H) , 4.19 (d, J = 14.2 Hz, 1H) , 2.86 (t, J = 7.5 Hz, 2H) , 2.75 (ddt, J = 23.6, 16.1, 7.9 Hz, 2H) , 2.11 –1.99 (m, 2H) .

Step 7) : synthesis of (12aR) -7 - (benzyloxy) -12 - (9, 10-difluoro-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To a single-necked flask were added 9, 10-difluoro2, 3, 6, 11-tetraydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-ol (2.2 g, 7.2 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-di one (2.6 g, 7.9 mmol) , then isopropyl acetate (90 mL) and T3P (13 mL, 21.84 mmol) were added, the reaction system was reacted at 90 ℃ for 3 h. The reaction was added with water (30 mL) . After separation, the aqueous phase was extracted with ethyl acetate (20 mL × 2) . Organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (1.478g, 33%) .

MS (ESI, pos. ion) m/z: 614.0 [M+H] ⁺

Step 8) : synthesis of (R) -12- ( (S) -9, 10-difluoro2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (12-1) and (R) -12- ( (R) -9, 10-difluoro2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (12-2)

To a single-necked flask were added (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.6g, 2.6 mmol) and lithium chloride (1.2g, 27 mmol) . N, N-Diethylacetamide (15 mL) then was added, and the mixture was heated to 100℃ and reacted for 3 h under nitrogen. The reaction solution was added with water (30 mL) , adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with DCM (30 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (12-1) as an orange solid (254mg, 19%) and the title compound (12-2) as an orange solid (250mg, 19%) .

MS (ESI, pos. ion) m/z: 524.1 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hyd roxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (12-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.16 –7.04 (m, 2H) , 7.04 –6.97 (m, 1H) , 6.72 (d, J = 7.6 Hz, 1H) , 6.43 (d, J = 7.6 Hz, 1H) , 6.02 (d, J = 7.5 Hz, 1H) , 5.28 (d, J = 15.1 Hz, 2H) , 4.70 –4.59 (m, 2H) , 4.13 (d, J = 13.8 Hz, 1H) , 3.98 (dd, J = 11.0, 2.4 Hz, 1H) , 3.83 (dd, J = 11.9, 2.8 Hz, 1H) , 3.63 (t, J = 10.6 Hz, 1H) , 3.49 (td, J = 11.8, 1.8 Hz, 1H) , 3.02 (td, J = 13.6, 3.4 Hz, 1H) , 2.94 –2.58 (m, 4H) , 2.16 –1.93 (m, 2H) .

HRMS (ESI, pos. ion) m/z: 524.1474 [M+H] +;

(R) -12- ( (R) -9, 10-difluoro2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hyd roxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (12-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.11 (d, J = 7.7 Hz, 1H) , 7.02 (d, J = 7.7 Hz, 1H) , 6.91 (dd, J = 16.9, 8.4 Hz, 1H) , 6.81 (d, J = 7.3 Hz, 1H) , 6.57 (dd, J = 7.5, 3.8 Hz, 1H) , 6.14 (d, J = 7.3 Hz, 1H) , 5.38 (d, J = 14.1 Hz, 1H) , 5.17 (s, 1H) , 4.60 (d, J = 9.4 Hz, 2H) , 4.14 (d, J = 14.1 Hz, 1H) , 4.04 (d, J = 8.7 Hz, 1H) , 3.86 –3.74 (m, 1H) , 3.63 (dd, J = 17.9, 7.4 Hz, 1H) , 3.49 (t, J = 11.0 Hz, 1H) , 3.02 –2.77 (m, 4H) , 2.77 –2.64 (m, 1H) , 2.25 –2.03 (m, 2H) ;

HRMS (ESI, pos. ion) m/z: 524.1451 [M+H] +

Example 13 (R) -12- ( (S) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (13-1) and (R) -12- ( (R) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6 -yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (13-2)

Step 1) : synthesis of 2-methyl-7-bromobenzothiophene

7-bromobenzothiophene (5.00 g, 23.50 mmol) was dissolved in THF (30 mL) , and the mixture was stirred at -78℃ under nitrogen, then LDA (12.90 mL, 25.80 mmol, 2 mol/L) was added slowly, and the mixture was stirred for 5 min, then transferred to 0℃ and stirred for 30 min, then transferred to -78℃ and continuously stirred. Potassium iodide (2.95 mL, 46.90mmol) was added, the mixture was stirred for 20 min at -78℃ and heated to rt and then reacted overnight. The stirring was stopped and the reaction mixture was added with saturated ammonium chloride (20 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as light yellow oil (5.21 g, 97.8%) .

¹H NMR (600 MHz, CDCl ₃) δ (ppm) 7.62 (d, J = 7.9 Hz, 1H) , 7.45 (d, J = 7.7 Hz, 1H) , 7.22 (t, J = 7.8 Hz, 1H) , 7.08 (d, J = 1.0 Hz, 1H) , 2.63 (d, J = 1.0 Hz, 3H) .

Step 2) : synthesis of 1, 2-bis (2-methylbenzo [b] thiophene-7-yl) disulfide

The solution of magnesium strip (607 mg, 25.29 mmol) and iodine (292 mg, 1.15 mmol) dissolved in THF (80 mL) was added in the two-necked flask A. Then 7-bromo-2-methylbenzothiophene (2.61 g, 11.50 mmol) in THF (80 mL) was added dropwise under nitrogen. The mixture was reacted at reflux at 65℃. Sulfur powder (1.47 g, 45.90mmol) in THF (80 mL) was added to two-necked flask B. The mixture was stirred in an ice bath under nitrogen. The reaction solution in flask A was added to flask B slowly. Flask B was transferred to rt and the solution was reacted overnight. The stirring was stopped and the reaction mixture was added with saturated ammonium chloride (30 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EA/PE (v/v) =1/10) to give the title compound as light yellow oil (3.75 g, 91%) .

Step 3) : synthesis of ethyl 3, 4-difluoro-2 ( ( (2-methylbenzo [b] thiophen-7-yl) thio) methyl) benzoate

1, 2-bis (2-methylbenzo [b] thiophen-7-yl) disulfide (3.75 g, 10.50 mmol) was dissolved in THF(100 mL) . The mixture was stirred at rt, added with NaBH ₄ (412mg, 10.46 mmol) , transferred to 50℃ and reacted for 30 min. Ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (5.84 g, 20.90mmol) was added before the reaction solution was cooled. Then the mixture was transferred to rt and stirred at rt for 30 min. The reaction was stopped and the reaction solution was added with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/PE (v/v) = 50/1) to give the title compound as a yellow solid (5.96g, 75%) .

MS (ESI, pos. ion) m/z: 379.0 [M+H] +

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.68 (ddd, J = 8.5, 5.1, 1.6 Hz, 1H) , 7.58 (d, J = 7.7 Hz, 1H) , 7.20 (dd, J = 14.1, 6.6 Hz, 1H) , 7.13 (d, J = 7.1 Hz, 1H) , 7.05 (dt, J = 13.3, 6.7 Hz, 1H) , 7.00 (s, 1H) , 4.65 (d, J = 1.5 Hz, 2H) , 4.26 –4.13 (m, 2H) , 2.58 (s, 3H) , 1.34 (t, J = 7.1 Hz, 3H) .

Step 4) : synthesis of 3, 4-difluoro-2- ( ( (2-methylbenzo [b] thiophen-7-yl) thio) methyl) benzoic acid

Ethyl 3, 4-difluoro-2- ( ( (2-methylbenzo [b] thiophen-7-yl) thio) methyl) benzoate (2.85 g, 7.53 mmol) was dissolved in THF (20 mL) and methanol (20 mL) , then sodium hydroxide (602 mg, 15.05 mmol) in water (5 mL) was added. The resulting solution was reacted at 50℃ for 15 min. After the reaction was completed, the reaction solution was added with saturated saline (50 mL) , adjusted with diluted hydrochloric acid to pH about 6, and partitioned. The aqueous phase was extracted with ethyl acetate (50 mL× 2) . The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a milky white solid (2.50g, 95%) .

MS (ESI, neg. ion) m/z: 349.0 [M+H] +

Step 5) : synthesis of 9, 10-fluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one

3, 4-difluoro-2- ( ( (2-methylbenzo [b] thiophen-7-yl) thio) methyl) benzoic acid (500 mg, 1.34 mmol) was dissolved in PPA (20 mL) . The mixture was reacted under nitrogen at 140℃ for about 2.5 h. The reaction was stopped, water (30 mL) was added slowly, and the reaction mixture was extracted with dichloromethane (20 mL× 3) . The organic phases were combined, washed with saturated saline (25mL) , dried over anhydrous sodium sulfate, filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a white solid (1.91 g, 100%) . It was used directly in the next reaction without purification.

Step 6) : synthesis of 9, 10-difluoro-2-methyl-6, 11-benzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol

9, 10-Difluoro-2-methylbenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiophene-6- (11H) -one (1.91g, 5.75 mmol) was dissolved in methanol (15 mL) and THF (15 mL) . Sodium borohydride (453mg, 11.50mmol) was added, and the mixture was stirred at rt for about 30 min. The reaction was stopped and the reaction solution was added with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL × 3) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/PE (v/v) = 3/1) to give the title compound as a yellow solid (1.03g, 54%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.44 (q, J = 8.1 Hz, 2H) , 7.22 –7.11 (m, 1H) , 7.02 (dd, J = 17.6, 8.5 Hz, 1H) , 6.94 (s, 1H) , 6.16 (s, 1H) , 5.00 (d, J = 14.3 Hz, 1H) , 4.30 (d, J = 14.4 Hz, 1H) , 2.58 (s, 3H) .

Step 7) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

9, 10-Difluoro-2-methyl-6, 11-benzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol (865 mg, 2.59mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (930 mg, 2.84mmol) were mixed in isopropyl acetate (20 mL) solution of T3P (6.20 mL, 10.40mmol, 50 %ethyl acetate solution) . The reaction system was reacted at 90 ℃ overnight. The reaction was stopped and the reaction solution was added to water (15 mL) and the solution was extracted with ethyl acetate (20 mL × 3) . The organic phases were combined and washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) = 1/2) to give the title compound as a white solid (1.50 g, 90%) .

MS (ESI, pos. ion) m/z: 644.0 [M+H] +

Step 8) : synthesis of (R) -12- ( (S) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (13-1) and (R) -12- ( (R) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (13-2)

(12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] be nzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.50g, 2.33 mmol) and lithium chloride (988mg, 23.30mmol) were mixed in DMAc (30 mL) , and the reaction solution was reacted at 100℃ overnight under protection of nitrogen. The reaction was quenched by adding reaction solution to water (10 mL) , the reaction solution was adjusted with 2N hydrochloric acid to being weakly acidic, stirred for 10 min and extracted with ethyl acetate (20 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and concentrated under reduced pressure, and the residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (13-1) as a light yellow solid (277 mg, 22%) and the title compound (13-2) as a light yellow solid (270 mg, 21%) .

MS (ESI, pos. ion) m/z: 554.0 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (13-1) :

HRMS (ESI, pos. ion) 554.1016 [M+H] ⁺;

¹H NMR (600 MHz, CDCl ₃-d ₆) δ (ppm) 7.10 (ddd, J = 18.7, 17.8, 8.2 Hz, 3H) , 6.96 (d, J = 7.7 Hz, 1H) , 6.88 (s, 1H) , 6.64 (d, J = 8.1 Hz, 1H) , 5.64 (d, J = 7.6 Hz, 1H) , 5.45 (d, J = 13.2 Hz, 2H) , 4.76 –4.58 (m, 2H) , 4.26 (d, J = 13.8 Hz, 1H) , 4.00 (dd, J = 11.0, 2.6 Hz, 1H) , 3.84 (d, J = 9.4 Hz, 1H) , 3.64 (t, J = 10.5 Hz, 1H) , 3.50 (t, J = 10.9 Hz, 1H) , 3.03 (t, J = 11.1 Hz, 1H) , 2.57 (s, 3H) .

(R) -12- ( (R) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (13-2) :

HRMS (ESI, pos. ion) 554.1020 [M+H] ⁺;

¹H NMR (600 MHz, CDCl ₃-d ₆) δ (ppm) 7.47 (d, J = 8.1 Hz, 1H) , 7.27 (d, J = 8.5 Hz, 1H) , 7.00 (s, 1H) , 6.90 (dd, J = 17.0, 8.5 Hz, 1H) , 6.76 (d, J = 7.7 Hz, 1H) , 6.63 (dd, J = 7.8, 4.2 Hz, 1H) , 5.90 (d, J = 7.6 Hz, 1H) , 5.54 (d, J = 15.0 Hz, 1H) , 5.33 (s, 1H) , 4.60 (d, J = 12.4 Hz, 1H) , 4.51 (dd, J = 9.8, 2.7 Hz, 1H) , 4.25 (d, J = 14.2 Hz, 1H) , 4.00 (dd, J = 10.8, 2.5 Hz, 1H) , 3.74 (dd, J = 11.7, 2.6 Hz, 1H) , 3.62 (t, J = 10.5 Hz, 1H) , 3.46 (dd, J = 11.7, 10.0 Hz, 1H) , 2.90 –2.74 (m, 1H) , 2.61 (s, 3H) .

Example 14 (R) -7-hydroxy-12- ( (S) -2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (14-1) and (R) -7-hydroxy-12- ( (R) -2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (14-2)

Step 1) : synthesis of 2-fluoro-7-bromobenzothiophene

7-bromobenzothiophene (5.00 g, 23.50 mmol) was dissolved in THF (30 mL) , and the mixture was stirred at -78℃ under nitrogen, then LDA (12.90 mL, 25.80 mmol, 2 mol/L) was added slowly, and the mixture was stirred for 5 min, then transferred to 0℃ and stirred for 30 min, then transferred to -78℃ and stirred continuously. NFSI (14.80 g, 46.94 mmol) was added, the mixture was stirred for 5 min at -78℃ and heated to rt and then reacted overnight. After the reaction was stopped and the reaction mixture was added with saturated ammonium chloride (20 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: PE) to give the title compound as light yellow oil (1.01 g, 18.6%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.60 (d, J = 7.9 Hz, 1H) , 7.47 (d, J = 7.8 Hz, 1H) , 7.26 (t, J = 7.9 Hz, 1H) , 6.83 (d, J = 2.2 Hz, 1H) .

Step 2) : synthesis of 1, 2-bis (2-fluorobenzo [b] thiophen-7-yl) disulfide

Asolution of magnesium strip (731 mg, 30.45 mmol) and iodine (351 mg, 1.38 mmol) dissolved in THF (80 mL) was added to two-necked flask A. 7-Bromo-2-fluorobenzothiophene (3.20 g, 13.80 mmol) in THF (80 mL) was added. The mixture was reacted at reflux at 65℃. Sulfur powder (1.77 g, 55.30mmol) in THF (80 mL) was added to two-necked flask B. The solution was stirred in an ice bath under nitrogen. The reaction solution in flask A was added dropwise to flask B slowly. Flask B was transferred to rt and the solution was reacted overnight. The reaction was stopped and the reaction mixture was added with saturated ammonium chloride (30 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: EA/PE (v/v) =50/1) to give the title compound as light yellow oil (5.14 g, 101%) .

Step 3) : synthesis of ethyl 3, 4-difluoro-2- ( ( (2-fluorobenzo [b] thiophen-7-yl) thio) methyl) benzoate

1, 2-bis (2-fluorobenzo [b] thiophen-7-yl) disulfide (5.10 g, 13.90 mmol) was dissolved in THF (100 mL) . The mixture was stirred at rt, NaBH ₄ (1.10 g, 27.90 mmol) was added, then the mixture was reacted at 50℃ for 30 min. Ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (7.80 g, 27.90mmol) was added before the reaction solution was cooled. Then the mixture was transferred to rt and stirred at rt for 30 min. The reaction was stopped and the reaction solution was added with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (EA/PE (v/v) = 10/1) to give the title compound as a yellow solid (4.84g, 45%) .

Step 4) : synthesis of 3, 4-difluoro-2- ( ( (2-fluorobenzo [b] thiophen-7-yl) thio) methyl) benzoic acid

Ethyl 3, 4-difluoro-2- ( ( (2-fluorobenzo [b] thiophen-7-yl) thio) methyl) benzoate (2.42 g, 6.33 mmol) was dissolved in THF (20 mL) and methanol (20 mL) , then sodium hydroxide (2.02 g, 50.60 mmol) in water (5 mL) was added. The resulting solution was reacted at 50℃ for about 15 min. The reaction solution was added with saturated saline (50 mL) , adjusted with 2N diluted hydrochloric acid to pH about 6, and partitioned. The aqueous phase was extracted with ethyl acetate (50 mL× 2) . The combined organic phases were washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure to give the title compound as a milky white solid (2.19g, 98%) .

MS (ESI, pos. ion) m/z: 352.9 [M+H] +

Step 5) : synthesis of 2, 9, 10-trifluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one

3, 4-difluoro-2- ( ( (2-fluorobenzo [b] thiophen-7-yl) thio) methyl) benzoic acid (500 mg, 1.34 mmol) was dissolved in dichloromethane (20 mL) , N, N-dimethylformamide (20 mg, 0.27 mmol) was added, and the solution was stirred at rt under nitrogen for 0.5 h. Oxalyl chloride (1.10 mL, 13.00 mmol) was added. The resulting solution was reacted at 46℃ for about 30 min, then concentrated in vacuo. Dichloromethane (20 mL) was added, aluminum chloride (720 mg, 5.40mmol) was then added under nitrogen. After the addition was completed, the mixture was reacted at rt for about 5 min. The reaction was stopped, water (30 mL) was added, and the reaction mixture was extracted with dichloromethane (20 mL× 3) . The organic phases were combined, washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound as a light yellow solid (475 mg, 99.85%) . It was used directly in the next reaction without purification.

Step 6) : synthesis of 2, 9, 10-trifluoro-6, 11-dihydro-benzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-ol

2, 9, 10-trifluorobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one (1.95g, 5.80 mmol) was dissolved in methanol (20 mL) and THF (20 mL) . Sodium borohydride (865mg, 22.00 mmol) was added, and the mixture was stirred at rt for about 30 min. The reaction was stopped and the reaction solution was added with saturated ammonium chloride solution (10 mL) and extracted with ethyl acetate (20 mL × 3) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) = 3/1) to give the title compound as a light yellow solid (1.73g, 93%) .

Step 7) : synthesis of (12aR) -7- (benzyloxy) -12- (2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6-dione

2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol (50 mg, 0.15mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (106 mg, 0.33mmol) were mixed in isopropyl acetate (20 mL) solution of T3P (0.50 mL, 0.84mmol, 50 %) , the reaction system was reacted at 90 ℃ overnight. The reaction was stopped and the reaction solution was added with water (15 mL) and extracted with ethyl acetate (20 mL ×3) . The organic phases were combined and washed with saturated brine (15 mL) and dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) = 1/2) to give the title compound as a white solid (30 mg, 31 %) .

MS (ESI, pos. ion) m/z: 648.2 [M+H] +

Step 8) : synthesis of (R) -7-hydroxy-12- ( (S) -2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (14-1) and (R) -7-hydroxy-12- ( (R) -2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (14-2)

(12aR) -7- (benzyloxy) -12- (2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.04g, 1.61 mmol) and lithium chloride (1.83g, 16.10mmol) were mixed in DMAc (40 mL) , and the reaction solution was warmed to 110℃ under protection of nitrogen and reacted overnight. The reaction was quenched by adding reaction solution to water (10mL) , then the reaction solution was adjusted with 2N diluted hydrochloric acid to being weakly acidic, stirred for 10 min, and extracted with ethyl acetate (20 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (14-1) as a light yellow solid (98 mg, 11%) and the title compound (14-2) as a light yellow solid (101 mg, 11%) .

MS (ESI, pos. ion) m/z: 557.9 [M+H] +;

(R) -7-hydroxy-12- ( (S) -2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (14-1) :

HRMS (ESI, pos. ion) m/z: 558.0767 [M+H] +;

¹H NMR (600 MHz, CDCl ₃-d ₆) δ (ppm) 7.23 –7.01 (m, 4H) , 6.76 –6.58 (m, 2H) , 5.93 (d, J = 7.5 Hz, 1H) , 5.42 (d, J = 7.0 Hz, 2H) , 4.79 –4.59 (m, 2H) , 4.31 (d, J = 13.9 Hz, 1H) , 4.03 (dd, J = 11.1, 2.4 Hz, 1H) , 3.91 –3.71 (m, 2H) , 3.56 (t, J = 10.9 Hz, 1H) , 3.08 (dd, J = 17.8, 7.3 Hz, 1H) .

(R) -7-hydroxy-12- ( (R) -2, 9, 10-trifluoro-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (14-2) :

HRMS (ESI, pos. ion) m/z: 558.0767 [M+H] +;

¹H NMR (600 MHz, CDCl ₃-d ₆) δ (ppm) 7.50 (d, J = 8.2 Hz, 1H) , 7.35 (d, J = 8.2 Hz, 1H) , 6.99 –6.85 (m, 2H) , 6.77 (d, J = 1.6 Hz, 1H) , 6.66 (dd, J = 7.9, 4.1 Hz, 1H) , 6.13 (d, J = 7.5 Hz, 1H) , 5.50 (d, J = 14.3 Hz, 1H) , 5.33 (s, 1H) , 4.71 –4.50 (m, 2H) , 4.30 (d, J = 14.4 Hz, 1H) , 4.05 (dd, J = 11.0, 2.7 Hz, 1H) , 3.83 –3.64 (m, 2H) , 3.52 (dd, J = 11.8, 9.8 Hz, 1H) , 2.96 –2.76 (m, 1H) .

Example 15 (R) -12- ( (S) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (15-1) and (R) -12- ( (R) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (15-2)

Step 1) : synthesis of 2- (7-bromobenzo [b] thiophen-2-yl) propan-2-ol

To a two-necked flask were added 7-bromobenzothiophene (5 g, 23.464 mmol) , then THF (50 mL) under nitrogen. The solution was cooled to -78℃, then lithium diisopropylamide (12.9 mL, 25.8 mmol) was added dropwise slowly. The mixture was reacted for 1 h, and then slowly added with acetone (2.6 mL, 35 mmol) diluted in THF (5 mL) , reacted at -78℃ for 1 h, and heated to rt and reacted overnight. The reaction was quenched with saturated ammonium chloride solution (50 mL) . The reaction mixture was extracted with EA (30 mL × 2) . The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the title compound as yellow oil (5.1g, 80%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.63 (d, J = 7.9 Hz, 1H) , 7.43 (d, J = 7.6 Hz, 1H) , 7.25 (s, 1H) , 7.20 (t, J = 7.8 Hz, 1H) , 1.72 (s, 6H) .

Step 2) : synthesis of 7-bromo-2-isopropylbenzo [b] thiophene

To a single-necked flask were added 2- (7-bromobenzo [b] thiophen-2-yl) propan-2-ol (3.8 g, 14 mmol) and dichloromethane (80 mL) in turn. The mixture was cooled to -40℃, and triethylsilane (9.5 mL, 57 mmol) and trifluoroacetate (4.9 mL, 63 mmol) were added. The mixture was reacted at -40℃ for 1 h. The reaction was quenched with saturated sodium bicarbonate solution (30 mL) . The reaction mixture was extracted with DCM (30 mL × 2) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as colorless oil (3.5g, 98%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.60 (d, J = 7.8 Hz, 1H) , 7.39 (d, J = 7.6 Hz, 1H) , 7.17 (t, J = 7.8 Hz, 1H) , 7.11 (s, 1H) , 3.36 –3.11 (m, 1H) , 1.40 (d, J = 6.9 Hz, 6H) .

Step 3) : synthesis of 1, 2-bis (2-isopropylbenzo [b] thiophen-7-yl) disulfide

To the double-necked flask A were added magnesium (0.82 g, 33 mmol) and iodine (0.43 g, 1.6 mmol) , tetrahydrofuran (30 mL) was added, and the mixture was heated to 60℃ under nitrogen. 7-bromo-2-isopropylbenzo [b] thiophene (4.2 g, 16.4 mmol) in THF (20 mL) was added, and the reaction solution was reacted for 2 h at 60℃ for backup.

To a two-necked flask was added sublimed sulfur (1.1 g, 34 mmol) , and tetrahydrofuran (20 mL) was added, then the reaction solution was cooled to 0℃ under nitrogen. The solution in double-necked flask A was added dropwise slowly, then the resulting mixture was reacted overnight at rt. The reaction was quenched with saturated ammonium chloride solution (30 mL) . The reaction mixture was extracted with EA (50 mL × 2) . The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as light yellow oil (2.75g, 81%) .

Step 4) : synthesis of ethyl 3, 4-difluoro-2- ( ( (2-isopropylbenzo [b] thiophen-7-yl) thio) methyl) benzoate

To the single-necked flask was added 1, 2-bis (2-isopropylbenzo [b] thiophen-7-yl) disulfide (2.75 g, 6.63 mmol) , then THF (30 mL) was added to dissolve the raw material, then sodium borohydride (0.64 g, 17 mmol) was added. The mixture was heated to 50℃ and reacted for 5 h. The reaction solution was cooled to rt, added with ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (3.7g, 13.3mmol) , and reacted overnight. The reaction was quenched with saturated ammonium chloride solution (20 mL) . The reaction mixture was extracted with EA (40 mL × 2) . The organic phases were combined and washed with saturated brine (240 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1) to give the title compound as colorless oil (3.4g, 63%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.65 (dd, J = 6.8, 5.2 Hz, 1H) , 7.58 (d, J = 7.5 Hz, 1H) , 7.22 –7.10 (m, 2H) , 7.07 –6.97 (m, 2H) , 4.63 (s, 2H) , 4.17 (dd, J = 14.2, 7.1 Hz, 2H) , 3.21 (dt, J = 13.3, 6.7 Hz, 1H) , 1.38 (d, J = 6.8 Hz, 6H) , 1.32 (t, J = 7.1 Hz, 3H) .

Step 5) : synthesis of 3, 4-difluoro-2- ( ( (2-isopropylbenzo [b] thiophen-7-yl) thio) methyl) benzoic acid

To a single-necked flask were added ethyl 3, 4-difluoro-2- ( ( (2-isopropylbenzo [b] thiophen-7-yl) thio) methyl) benzoate (3.35 g, 8.24 mmol) , THF (25 mL) and methanol (8 mL) , then sodium hydroxide solution (8.3 mL, 2 mol/L) was added dropwise. The mixture was heated to 50℃ and reacted for 3 h. The reaction solution was concentrated in vacuo to remove organic solvent. The reaction solution was added with water (20 mL) , adjusted with 4N hydrochloric acid to pH 4, then extracted with ethyl acetate (30 mL × 2) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (2.96g, 94.9%) .

MS (ESI, neg. ion) m/z: 377.0 [M+H] +

Step 6) : synthesis of 9, 10-difluoro-2-isopropylbenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one

To the double-necked flask A were added 3, 4-difluoro-2- ( ( (2-isopropylbenzo [b] thiophen-7-yl) thio) methyl) benzoic acid (2.15 g, 5.68 mmol) , dichloromethane (20 mL) and DMF (0.05 mL) in turn. Oxalyl chloride (1 mL, 11 mmol) was added dropwise, and the mixture was reacted for 1 h at rt, then concentrated in vacuo, and added with DCM (20 mL) for backup.

To a two-necked flask was added aluminum chloride (2.22 g, 15.8 mmol) , and DCM (40 mL) was added. The reaction solution in flask A was added dropwise under nitrogen, then the resulting mixture was reacted for 0.5 h at rt. The reaction solution was added with water (10 mL) , extracted with DCM (20 mL × 2) . The organic phases were combined and washed with saturated saline (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (2 g, 97.7%) .

MS (ESI, pos. ion) m/z: 361.0 [M+H] +;

Step 7) : synthesis of 9, 10-difluoro-2--isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol

To a single-necked flask were added 9, 10-difluoro-2-isopropylbenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one (2 g, 5.549 mmol) , THF (20 mL) and MeOH (2 mL) , then sodium borohydride (0.42 g, 11 mmol) was added dropwise. The resulting mixture was reacted at rt for 15min. The reaction was quenched with saturated ammonium chloride solution (10 mL) . The reaction mixture was extracted with EA (20 mL × 2) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the title compound as a white solid (1.96g, 97.63%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.43 (dd, J = 20.3, 8.1 Hz, 2H) , 7.15 (dd, J = 7.2, 4.9 Hz, 1H) , 7.04 –6.92 (m, 2H) , 6.15 (d, J = 1.6 Hz, 1H) , 4.96 (d, J = 14.3 Hz, 1H) , 4.29 (d, J = 14.3 Hz, 1H) , 3.28 –3.14 (m, 1H) , 2.72 (d, J = 2.7 Hz, 1H) , 1.37 (d, J = 6.8 Hz, 6H) .

Step 8) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To a single-necked flask were added 9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-ol (1.84 g, 5.08 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-di one (1.83 g, 5.59 mmol) , then isopropyl acetate (74 mL) and1-propylphosphoric anhydride (9 mL, 15.3 mmol) were added. The reaction system was reacted at 90 ℃ for 3 h. The reaction was added with water (30 mL) . After separation, the aqueous phase was extracted with ethyl acetate (20 mL ×2) . Organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (2.68g, 78.6%) .

MS (ESI, pos. ion) m/z: 672.0 [M+H] +

Step 9) : synthesis of (R) -12- ( (S) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (15-1) and (R) -12- ( (R) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (15-2)

To a single-necked flask were added (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2.7g, 4.0 mmol) and lithium chloride (1.7g, 40 mmol) . N, N-Diethylacetamide (20 mL) then was added, and the mixture was heated to 100℃ and reacted under nitrogen for 3 h. The reaction solution was added with water (50 mL) , adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with DCM (30 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound as an orange solid (945 mg, 40%) .

MS (ESI, pos. ion) m/z: 582.1 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (15-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.18 (d, J = 8.1 Hz, 1H) , 7.10 (dd, J = 16.5, 8.5 Hz, 1H) , 7.06 –6.98 (m, 2H) , 6.91 (s, 1H) , 6.60 (d, J = 8.1 Hz, 1H) , 5.73 (d, J = 7.6Hz, 1H) , 5.43 (dd, J = 9.6, 3.8 Hz, 2H) , 4.66 (dd, J = 17.7, 7.7 Hz, 2H) , 4.26 (d, J = 13.8 Hz, 1H) , 4.00 (dd, J = 11.1, 2.8 Hz, 1H) , 3.83 (dd, J = 11.9, 2.9 Hz, 1H) , 3.64 (t, J = 10.6 Hz, 1H) , 3.50 (dd, J = 11.8, 9.7 Hz, 1H) , 3.21 (dt, J = 13.6, 6.9 Hz, 1H) , 3.08 –2.97 (m, 1H) , 1.37 (d, J = 6.8 Hz, 6H) ;

HRMS (ESI, pos. ion) m/z: 582.1323 [M+H] +;

(R) -12- ( (R) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [e] thieno [3', 2': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (15-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.50 (d, J = 8.2 Hz, 1H) , 7.25 (d, J = 8.2 Hz, 1H) , 7.04 (s, 1H) , 6.92 (dd, J = 17.0, 8.5 Hz, 1H) , 6.76 (d, J = 7.6 Hz, 1H) , 6.63 (dd, J = 7.7, 4.4 Hz, 1H) , 6.01 (d, J = 7.6 Hz, 1H) , 5.51 (d, J = 14.0 Hz, 1H) , 5.31 (s, 1H) , 4.60 (d, J = 12.3 Hz, 1H) , 4.52 (dd, J = 9.9, 2.8 Hz, 1H) , 4.27 (d, J = 14.2 Hz, 1H) , 4.04 –3.95 (m, 1H) , 3.75 (dd, J = 11.8, 2.8 Hz, 1H) , 3.58 (t, J = 10.4 Hz, 1H) , 3.44 (dd, J = 11.7, 9.7 Hz, 1H) , 3.27 (dt, J = 13.6, 6.8 Hz, 1H) , 2.83 (dd, J = 17.6, 7.4 Hz, 1H) , 1.48 –1.35 (m, 6H) ;

HRMS (ESI, pos. ion) m/z: 582.1331 [M+H] +

Example 16 (R) -12- ( (S) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (16-1) and (R) -12- ( (R) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (16-2)

Step 1) : synthesis of 2- (7-bromobenzofuran-2-yl) propan-2-ol

To a two-necked flask were added 7-bromobenzothiophene (8 g, 40.603 mmol) , then THF (50 mL) under nitrogen. The solution was cooled to -78℃, then lithium diisopropylamide (22 mL, 44 mmol) was added dropwise slowly. The mixture was reacted for 1.5 h, and then slowly added with acetone (4.5 mL, 61 mmol) diluted in THF (5 mL) , reacted at -78℃ for 1 h, and heated to rt and reacted overnight. The reaction was quenched with saturated ammonium chloride solution (50 mL) . The reaction mixture was extracted with EA (30 mL × 3) . The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the title compound as yellow oil (8.64g, 83.4%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.45 (d, J = 7.7 Hz, 1H) , 7.41 (d, J = 7.8 Hz, 1H) , 7.08 (t, J = 7.8 Hz, 1H) , 6.64 (s, 1H) , 2.36 (s, 1H) , 1.70 (s, 6H) .

Step 2) : synthesis of 7-bromo-2-isopropylbenzofuran

To a single-necked flask were added 2- (7-bromobenzofuran-2-yl) propan-2-ol (8.4 g, 33 mmol) and dichloromethane (150 mL) in turn. The mixture was cooled to -40℃, and triethylsilane (17 mL, 100 mmol) and trifluoroacetate (13 mL, 166.27 mmol) were added. The mixture was reacted at -40℃ for 1 h. The reaction was quenched with saturated ammonium chloride solution (30 mL) . After standing for stratification, the reaction mixture was extracted with DCM (50 mL × 2) . The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as colourless oil (7.6g, 98%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.44 (d, J = 7.7 Hz, 1H) , 7.39 (d, J = 7.8 Hz, 1H) , 7.07 (t, J = 7.8 Hz, 1H) , 6.45 (s, 1H) , 3.21 –3.09 (m, 1H) , 1.40 (d, J = 6.9 Hz, 6H) .

Step 3) : synthesis of 1, 2-bis (2-isopropylbenzofuran-7-yl) disulfide

To the double-necked flask A were added magnesium (1.6 g, 66 mmol) and iodine (0.83 g, 3.2 mmol) , tetrahydrofuran (30 mL) was added, and the mixture was heated to 60℃ under nitrogen. A solution of 7-bromo-2-isopropylbenzofuran (7.6 g, 32 mmol) in THF (20 mL) was added dropwise, and the reaction solution was reacted for 2 h at 60℃ for backup.

To a two-necked flask was added sublimed sulfur (2.1 g, 64 mmol) , and tetrahydrofuran (20 mL) was added. The reaction solution was cooled to 0℃ under nitrogen. The solution in double-necked flask A was added dropwise slowly, then the resulting mixture was reacted overnight at rt. The reaction was quenched with saturated ammonium chloride solution (30 mL) . The reaction mixture was extracted with EA (50 mL × 2) . The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as light yellow oil (5.5g, 90%) .

Step 4) : synthesis of ethyl 3, 4-difluoro-2- ( ( (2-isopropylbenzofuran-7-yl) ) thio) methyl) benzoate

To the single-necked flask was added 1, 2-bis (2-isopropylbenzofuran-7-yl) disulfide (5.16 g, 13.5 mmol) , then THF (40 mL) was added to dissolve the raw material, then sodium borohydride (1 g, 25.9 mmol) was added. The mixture was heated 50℃ to and reacted for 5 h. The reaction solution was cooled to rt, added with ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (7.5 g, 27 mmol) , and reacted overnight. The reaction was quenched with saturated ammonium chloride solution (30 mL) . The reaction mixture was extracted with EA (40 mL × 2) . The organic phases were combined and washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1) to give the title compound as colorless oil (7.8g, 74%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.65 (ddd, J = 8.6, 5.1, 1.7 Hz, 1H) , 7.40 (dd, J = 7.6, 1.0 Hz, 1H) , 7.11 –7.07 (m, 1H) , 7.05 –6.97 (m, 2H) , 6.36 (s, 1H) , 4.67 (d, J = 1.6 Hz, 2H) , 4.24 (q, J = 7.1 Hz, 2H) , 3.16 –2.99 (m, 1H) , 1.34 (m, 9H) .

Step 5) : synthesis of 3, 4-difluoro-2- ( ( (2-isopropylbenzofuran-7-yl) ) thio) methyl) benzoic acid

To a single-necked flask was added ethyl 3, 4-difluoro-2- ( ( (2-isopropylbenzofuran-7-yl) ) thio) methyl) benzoate (6.67 g, 17.1 mmol) , THF (45 mL) and methanol (15 mL) , then sodium hydroxide (17 mL, 2 mol/L) solution was added dropwise at rt. The mixture was heated to 50℃ and reacted for 3 h. The reaction solution was concentrated in vacuo to remove organic solvent. The reaction solution was added with water (20 mL) , adjusted with 4N hydrochloric acid to pH about 4, extracted with ethyl acetate (30 mL × 2) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a white solid (5.94g, 95.9%) .

MS (ESI, neg. ion) m/z: 361.0 [M+H] +

Step 6) : synthesis of 9, 10-difluoro-2-isopropylbenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one

To the double-necked flask A were added 3, 4-difluoro-2- ( ( (2-isopropylbenzofuran-7-yl) thio) methyl) benzoic acid (5 g, 13.8 mmol) , dichloromethane (30 mL) and DMF (0.1 mL) in turn. Oxalyl chloride (2.45 mL, 27.8 mmol) was added dropwise slowly under nitrogen protection. After the addition is complete, the mixture was reacted for 2 h at rt, then concentrated, and added with DCM (30 mL) for backup.

To a two-necked flask was added aluminum chloride (5.52 g, 41.4 mmol) , and DCM (60 mL) was added. The reaction solution in flask A was added dropwise under nitrogen, then the resulting mixture was reacted for 0.5 h at rt. The reaction solution was added with water (20 mL) . After separation, the aqueous phase was extracted with DCM (20 mL × 2) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a light yellow solid (4.69 g, 98.7%) .

MS (ESI, pos. ion) m/z: 344.9 [M+H] +

Step 7) : synthesis of 9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol

To a single-necked flask were added 9, 10-difluoro-2-isopropylbenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one (4.69 g, 13.6 mmol) , THF (30 mL) and MeOH (3 mL) in turn, then sodium borohydride (1.08 g, 28.0 mmol) was added slowly. The resulting mixture was reacted at rt for 15min. The reaction solution was quenched with saturated ammonium chloride solution (15 mL) . The reaction mixture was extracted with EA (20 mL × 2) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the title compound as a yellow solid (3.24g, 68.7%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.23 (dd, J = 12.7, 6.4 Hz, 2H) , 7.08 (m, 1H) , 6.98 (dd, J = 17.6, 8.4 Hz, 1H) , 6.29 (s, 1H) , 6.04 (s, 1H) , 5.08 (d, J = 14.1 Hz, 1H) , 4.23 (d, J = 14.1 Hz, 1H) , 3.16 –2.98 (m, 1H) , 2.69 (s, 1H) , 1.31 (dd, J = 6.9, 2.4 Hz, 6H) .

Step 8) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To a single-necked flask were added 9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol (2 g, 5.774 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dio ne (2.08 g, 6.36 mmol) , then isopropyl acetate (80 mL) and1-propylphosphoric anhydride (10.3 mL, 17.3 mmol) were added. The reaction system was reacted at 90 ℃ for 3 h. The reaction solution was added with water (30 mL) . After separation, the aqueous phase was extracted with ethyl acetate (20 mL × 2) . Organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (2.864g, 75.65%) .

MS (ESI, pos. ion) m/z: 656.2 [M+H] +

Step 9) : synthesis of (R) -12- ( (S) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (16-1) and (R) -12- ( (R) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1 -f] [1, 2, 4] triazine-6, 8-dione (16-2)

To a single-necked flask were added (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofu ran-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2.86g, 4.36 mmol) and lithium chloride (1.9g, 44 mmol) . N, N-Diethylacetamide (20 mL) was added. The reaction solution was reacted at 100℃ overnight under nitrogen, then added with water (50 mL) and adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with ethyl acetate (30 mL× 2) . The organic phases were combined. The combined organic phases were washed with saturated saline (30 mL × 3) , dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by LUNA preparation column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (16-1) as an orange solid (863 mg, 35%) and the title compound (16-2) as an orange solid (654mg, 26.5%) .

MS (ESI, pos. ion) m/z: 566.7 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (16-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.10 (dd, J = 16.6, 8.6 Hz, 1H) , 7.03 (d, J = 7.5 Hz, 2H) , 6.97 (d, J = 7.9 Hz, 1H) , 6.46 (d, J = 8.0 Hz, 1H) , 6.26 (s, 1H) , 5.81 (d, J = 7.6 Hz, 1H) , 5.39 (dd, J = 17.5, 3.5 Hz, 2H) , 4.75 –4.60 (m, 2H) , 4.21 (d, J = 13.9 Hz, 1H) , 3.99 (dd, J = 11.1, 2.8 Hz, 1H) , 3.83 (dd, J = 11.9, 3.0 Hz, 1H) , 3.67 (t, J = 10.6 Hz, 1H) , 3.55 –3.45 (m, 1H) , 3.14 –2.97 (m, 2H) , 1.32 (dd, J = 10.1, 6.9 Hz, 6H) ;

HRMS (ESI, pos. ion) m/z: 566.1577 [M+H] +;

(R) -12- ( (R) -9, 10-difluoro-2-isopropyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6 -yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (16-2)

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.28 (d, J = 8.1 Hz, 1H) , 7.13 (d, J = 8.1 Hz, 1H) , 6.91 (dd, J = 17.1, 8.5 Hz, 1H) , 6.76 (d, J = 7.7 Hz, 1H) , 6.61 (dd, J = 7.7, 4.3 Hz, 1H) , 6.37 (s, 1H) , 6.01 (d, J = 7.6 Hz, 1H) , 5.51 –5.43 (m, 1H) , 5.30 (s, 1H) , 4.60 (d, J = 11.8 Hz, 1H) , 4.55 (dd, J = 9.9, 2.9 Hz, 1H) , 4.23 (d, J = 14.1 Hz, 1H) , 4.01 (dd, J = 10.9, 2.8 Hz, 1H) , 3.76 (dd, J = 11.9, 3.1 Hz, 1H) , 3.60 (t, J = 10.5 Hz, 1H) , 3.46 (dd, J = 11.9, 9.6 Hz, 1H) , 3.11 (dt, J = 13.7, 6.9 Hz, 1H) , 2.88 –2.77 (m, 1H) , 1.36 (t, J = 7.1 Hz, 6H) ;

HRMS (ESI, pos. ion) m/z: 566.1701 [M+H] +

Example 17 (R) -12- ( (S) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (17-1) and (R) -12- ( (R) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (17-2)

Step 1) : synthesis of 7-bromo-2-methylbenzofuran

To a two-necked flask were added 7-bromobenzofuran (8 g, 40.603 mmol) , then THF (50 mL) . The solution was cooled to -78℃ under nitrogen, then lithium diisopropylamide (22 mL, 44 mmol) was added dropwise slowly. The mixture was reacted for 2 h at -78℃, and then slowly added with methyl iodide (5.3 mL, 81 mmol) , reacted at -78℃ for 0.5 h, and heated to rt and reacted overnight. The reaction was quenched with saturated ammonium chloride solution (200 mL) . The reaction mixture was extracted with EA (200 mL × 2) . The organic phases were combined and washed with saturated brine (100 mL × 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as light yellow oil (8.11g, 94.6%) .

Step 2) : synthesis of 1, 2-bis (2-methylbenzofuran-7-yl) disulfide

To the double-necked flask A were added magnesium (1.87 g, 76.9 mmol) and iodine (0.98 g, 3.8 mmol) , then tetrahydrofuran (30 mL) was added, and the mixture was heated to 60℃ under nitrogen. A solution of 7-bromo-2-methylbenzofuran (8.1 g, 38.4 mmol) in THF (20 mL) was added dropwsie, and the reaction solution was reacted for 2 h at 60℃ for backup.

To a two-necked flask was added sublimed sulfur (2.51 g, 76.7 mmol) , and tetrahydrofuran (20 mL) was added, then the reaction solution was cooled to 0℃ under nitrogen. The solution in double-necked flask A was added dropwise slowly, then the resulting mixture was reacted overnight at rt. The reaction was quenched with saturated ammonium chloride solution (100 mL) . The reaction mixture was extracted with EA (100 mL × 2) . The organic phases were combined and washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as yellow oil (5.787g, 92.4%) .

Step 3) : synthesis of ethyl 3, 4-difluoro-2- ( ( (2-methylbenzofuran-7-yl) ) thio) methyl) benzoate

To a single-necked flask were added 1, 2-bis (2-methylbenzofuran-7-yl) disulfide (5.75 g, 17.6 mmol) , THF (50 mL) and sodium borohydride (1.36g, 35.2 mmol) . The mixture was heated to 50℃ and reacted for 4 h. Then the reaction solution was cooled to rt, ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (9.83 g, 35.2 mmol) was added, and the solution was reacted overnight. The reaction was quenched with saturated ammonium chloride solution (100 mL) . The reaction mixture was extracted with EA (100 mL × 2) . The organic phases were combined and washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1) to give the title compound as light yellow oil (7.2g, 56%) .

MS (ESI, pos. ion) m/z: 363.2 [M+H] +

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.65 (ddd, J = 8.5, 5.1, 1.7 Hz, 1H) , 7.39 (d, J = 7.5 Hz, 1H) , 7.09 (d, J = 7.5 Hz, 1H) , 7.06 –6.99 (m, 2H) , 6.36 (s, 1H) , 4.64 (d, J = 1.6 Hz, 2H) , 4.21 (q, J = 7.1 Hz, 2H) , 2.43 (s, 3H) , 1.33 (t, J = 7.1 Hz, 3H) .

Step 4) : synthesis of 3, 4-difluoro-2- ( ( (2-methylbenzofuran-7-yl) ) thio) methyl) benzoic acid

To a single-necked flask were added ethyl 3, 4-difluoro-2- ( ( (2-methylbenzofuran-7-yl) ) thio) methyl) benzoate (6 g, 16.56 mmol) , THF (45 mL) and methanol (15 mL) , then sodium hydroxide (16.5 mL, 2mol/L) solution was added dropwise. The mixture was heated to 50℃ and reacted for 3 h. The reaction solution was concentrated in vacuo to remove organic solvent. The reaction solution was added with water (20 mL) , adjusted with 4N hydrochloric acid to pH about 4, then extracted with ethyl acetate (30 mL × 2) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (5.4g, 98%) .

MS (ESI, neg. ion) m/z: 333.1 [M+H] +

Step 5) : synthesis of 9, 10-difluo2-methylbenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one

To the double-necked flask A were added 3, 4-difluoro-2- ( ( (2-methylbenzofuran-7-yl) thio) methyl) benzoic acid (3 g, 8.97 mmol) , dichloromethane (30 mL) and DMF (0.1 mL) in turn. Oxalyl chloride (1.6 mL, 18 mmol) was added dropwise under nitrogen, and the mixture was reacted for 2 h at rt, then concentrated, and added with DCM (30 mL) for backup.

To a two-necked flask was added aluminum chloride (3.6 g, 27 mmol) , and DCM (60 mL) was added, the reaction solution in flask A was added dropwise under nitrogen, then the resulting mixture was reacted for 4 h at rt. The reaction solution was added with water (20 mL) . After separation, the aqueous phase was extracted with DCM (20 mL × 2) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a light yellow solid (2.8 g, 99%) .

MS (ESI, pos. ion) m/z: 317.2 [M+H] +

Step 6) : synthesis of 9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol

To a single-necked flask were added 9, 10-difluoro-2-methylbenzo [5, 6] thiepino [3, 2-g] benzofuran-6- (11H) -one (2.8g, 8.9 mmol) , THF (30 mL) and MeOH (3 mL) in turn, then sodium borohydride (700 mg, 17.76 mmol) was added slowly. The resulting mixture was reacted at rt for 10min. The reaction was quenched with saturated ammonium chloride solution (10 mL) . The reaction mixture was added with water (10mL) , extracted with EA (20 mL × 3) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the title compound as a white solid (1.8g, 64%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.27 (d, J = 7.5 Hz, 1H) , 7.21 (d, J = 8.0 Hz, 1H) , 7.13 –7.06 (m, 1H) , 6.98 (dd, J = 17.7, 8.4 Hz, 1H) , 6.30 (s, 1H) , 6.07 (s, 1H) , 5.06 (d, J = 14.2 Hz, 1H) , 4.24 (d, J = 14.2 Hz, 1H) , 2.44 (s, 3H) .

Step 7) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To a single-necked flask were added 9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-ol (1.87 g, 5.87 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (2.12 g, 6.48 mmol) , then isopropyl acetate (75 mL) and 1-propylphosphoric anhydride (10.5 mL, 21.84 mmol) were added. The resulting mixture was heated to 90℃ and reacted for 3 h. Water (30 mL) was added. After separation, the aqueous phase was extracted with ethyl acetate (20 mL × 2) . The organic phases were combined and washed with saturated sodium bicarbonate aqueous solution (50 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (3.05g, 82.7%) .

MS (ESI, pos. ion) m/z: 628.0 [M+H] ⁺

Step 8) : synthesis of (R) -12- ( (S) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (17-1) and (R) -12- ( (R) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (17-2)

To a single-necked flask were added (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofura n-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (3.15g, 5.02 mmol) and lithium chloride (2.15g, 50.2 mmol) . N, N-Diethylacetamide (20 mL) was added. The reaction solution was reacted at 100℃ for 3 h under nitrogen, then added with water (30 mL) and adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with ethyl acetate (30 mL× 3) . The organic phases were combined. The combined organic phases were washed with saturated saline (30 mL × 3) , dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by LUNA preparation column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (17-1) as an orange solid (779mg, 28.9%) and the title compound (17-2) as an orange solid (781mg, 29%) .

MS (ESI, pos. ion) m/z: 538.3 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl ) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (17-1) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.10 (dd, J = 16.6, 8.6 Hz, 1H) , 7.03 (m, 2H) , 6.96 (d, J = 7.9 Hz, 1H) , 6.47 (d, J = 8.0 Hz, 1H) , 6.27 (s, 1H) , 5.79 (d, J = 7.6 Hz, 1H) , 5.41 (s, 1H) , 5.41 –5.35 (m, 1H) , 4.66 (m, 2H) , 4.36 (s, 1H) , 4.21 (d, J = 13.8 Hz, 1H) , 3.99 (dd, J = 11.1, 2.7 Hz, 1H) , 3.83 (dd, J = 11.9, 2.9 Hz, 1H) , 3.67 (t, J = 10.6 Hz, 1H) , 3.50 (dd, J = 11.9, 9.7 Hz, 1H) , 3.10 –2.96 (m, 1H) , 2.44 (s, 3H) ;

HRMS (ESI, pos. ion) m/z: 538.1245 [M+H] +;

(R) -12- ( (R) -9, 10-difluoro-2-methyl-6, 11-dihydrobenzo [5, 6] thiepino [3, 2-g] benzofuran-6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (17-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.37 (d, J = 7.9 Hz, 1H) , 7.27 (d, J = 6.6 Hz, 1H) , 7.14 (d, J = 8.1 Hz, 1H) , 6.91 (dd, J = 17.1, 8.5 Hz, 1H) , 6.78 (d, J = 7.6 Hz, 1H) , 6.61 (dd, J = 7.8, 4.2 Hz, 1H) , 6.39 (s, 1H) , 6.04 (d, J = 7.6 Hz, 1H) , 5.46 (d, J = 14.1 Hz, 1H) , 4.66 –4.50 (m, 3H) , 4.23 (d, J = 14.1 Hz, 1H) , 4.00 (dd, J = 10.9, 2.6 Hz, 1H) , 3.76 (dd, J = 11.8, 2.9 Hz, 1H) , 3.61 (t, J = 10.5 Hz, 1H) , 3.46 (m, 1H) , 2.90 –2.75 (m, 1H) , 2.50 (s, 3H) ;

HRMS (ESI, pos. ion) m/z: 538.1249 [M+H] +

Example 18 (R) -12- ( (S) -9, 10-difluoro-2, 2-dimethyl-6, 11-dihydro-benzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2, 2-d] [1, 3] dioxolene-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 11-f] [1, 2, 4] triazine-6, 8-dione (18-1) and (R) -12- ( (R) -9, 10-difluoro-2, 2-dimethyl-6, 11-dihydro-benzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2, 2-d] [1, 3] dioxolene-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 11-f] [1, 2, 4] triazine-6, 8-dione (18-2)

Step 1) : synthesis of 4-bromo-2, 2-dimethylbenzo [d] [1, 3] dioxolene

3-Bromobenzene-1, 2-diol (450 mg, 2.38 mmol) was dissolved in toluene (15 mL) , then acetone (276 mg, 4.75 mmol) was added, the mixture was stirred at 75℃, and phosphorus pentoxide (380 mg, 2.62 mmol) divided in three portions was added to the above reaction solution every 30 minutes. Then the mixture was reacted at 75℃ for 6 h. The reaction was stopped, the reaction solution was concentrated in vacuo and the residue was purified by a silica gel column chromatography (eluent: PE) to give the title compound as colorless oil (201 mg, 36.855%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 6.94 (t, J = 4.7 Hz, 1H) , 6.69 (d, J = 4.6 Hz, 2H) , 1.74 (s, 6H) .

Step 2) : synthesis of 1, 2-bis (2, 2-dimethylbenzo [d] [1, 3] dioxol-4-yl) disulfide

Magnesium strip (2.10 g, 87.50 mmol) was added to THF (30 mL) , then iodine (1.11 g, 4.37 mmol) was added. The solution was heated at 60℃under nitrogen protection, added dropwise slowly with 4-bromo-2, 2-dimethylbenzo [d] [1, 3] dioxolene (10.00 g, 43.65 mmol) , and stirred for 2 h. Then the reaction solution was added to THF (30 mL) solution of sulfur powder (2.80 g, 87.50 mmol) . The mixture was stirred overnight. The reaction was stopped and the reaction mixture was added with saturated ammonium chloride (20 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elunt: PE/EA (v/v) =5/1) to give the title compound as a yellow solid (4.70 g, 29.7%) .

Step 3) : synthesis of ethyl 2- ( (2, 2-dimethylbenzo [d] [1, 3] dioxol-4-yl) thio) methyl) -3, 4-difluorobenzoate

1, 2-Bis (2, 2-dimethylbenzo [d] [1, 3] dioxol-4-yl) disulfide (350 mg, 0.97 mmol) was dissolved in THF (100 mL) . The mixture was stirred at rt, NaBH4 (76 mg, 1.93 mmol) was added, then the mixture was reacted at 56℃ for 30 min. Ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (538 mg, 1.93mmol) was added before the reaction solution was cooled. Then the mixture was transferred to rt and stirred at rt overnight. The reaction solution was added with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (20 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elunt: PE/EA (v/v) = 10/1) to give the title compound as a light yellow solid (270 mg, 73.51%) .

MS (ESI, pos. ion) m/z: 381.6 [M+H] +;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.71 (ddd, J = 8.6, 5.1, 1.7 Hz, 1H) , 7.05 (dd, J = 16.7, 8.9 Hz, 1H) , 6.67 (dt, J = 8.0, 4.1 Hz, 1H) , 6.64 –6.58 (m, 2H) , 4.53 (d, J = 1.5 Hz, 2H) , 4.31 (q, J = 7.1 Hz, 2H) , 1.69 (s, 6H) , 1.38 (t, J = 7.1 Hz, 3H) .

Step 4) : synthesis of 2- ( ( (2, 2-dimethylbenzo [d] [1, 3] dioxol-4-yl) thio) methyl) -3, 4-difluorobenzoic acid

Ethyl 2- ( ( (2, 2-dimethylbenzo [d] [1, 3] dioxol-4-yl) thio) methyl) -3, 4-difluorobenzoate (4.92 g, 12.90 mmol) was dissolved in THF (15 mL) and MeOH (15 mL) . The aqueous solution of NaOH (1.55 g, 38.80 mmol) in water (3 mL) was added. The reaction solution was reacted at 50℃ for 20 min. The reaction was stopped and cooled. The reaction solution was adjusted with 2N hydrochloric acid to pH 2-4, and extracted with ethyl acetate (20 mL× 3) . The combined organic phases were washed with saturated brine (20 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound as an off-white solid (4.56 g, 100%) .

MS (ESI, pos. ion) m/z: 353.5 [M+H] +

Step 5) : synthesis of 9, 10-difluo-2, 2-dimethylbenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6- (11H) -one

2- ( ( (2, 2-Dimethylbenzo [d] [1, 3] dioxol-4-yl) thio) methyl) -3, 4-difluorobenzoic acid (100 mg, 0.28 mmol) was dissolved in DCM (20 mL) , then DMF (2 mg, 0.03 mmol) was added, and oxalyl chloride (0.03 mL, 0.40 mmol) was added slowly. The mixture was stirred at rt for 1 h. Aluminum chloride (41 mg, 0.31mmol) was added and the mixture was continued to react at this temperature for about 2 h. The reaction was stopped, water (20 mL) was added, and the reaction mixture was extracted with dichloromethane (20 mL× 3) . The organic phases were combined, washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound as a yellow solid (94 mg, 99.09%) . It was used directly in the next step without purification.

MS (ESI, pos. ion) m/z: 335.0 [M+H] +

Step 6) : synthesis of 9, 10-difluo-2, 2-dimethyl-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-ol

9, 10-Difluoro-2, 2-methylbenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6- (11H) -one (3.98 g, 11.90 mmol) was dissolved in THF (30 mL) and MeOH (30 mL) . Sodium borohydride (704 mg, 17.87 mmol) was added, and the mixture was stirred at rt for 15 min. The reaction was stopped and the reaction mixture was added with saturated ammonium chloride (20 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate and filtered, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) =5/1) to give the title compound as a light yellow solid (710 mg, 17.7%) .

Step 7) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2, 2-dimethyl-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the mixture solution of 1-propylphosphoric anhydride (50%ethyl acetate, 3.79 mL) and isopropyl acetate (15 mL) were added 9, 10-difluoro-2, 2-dimethyl-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-ol (710 mg, 2.11 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dio ne (759 mg, 2.32 mmol) , nitrogen gas was blown in, and the reaction solution was reacted at 90 ℃ for about 5 h. The reaction was completed, the reaction solution was added with ice water (30 mL) and extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 25/1) to give the title compound as a light yellow solid (700 mg, 51%) .

MS (ESI, pos. ion) m/z: 646.2 [M+H] +

Step 8) : synthesis of (R) -12- ( (S) -9, 10-difluoro-2, 2-dimethyl-6, 11-dihydro-benzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2, 2-d] [1, 3] dioxolene-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 11-f] [1, 2, 4] triazine-6, 8-dione (18-1) and (R) -12- ( (R) -9, 10-difluoro-2, 2-dimethyl-6, 11-dihydro-benzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2, 2-d] [1, 3] dioxolene-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4 -c] pyrido [2, 11-f] [1, 2, 4] triazine-6, 8-dione (18-2)

(12aR) -7- (Benzyloxy) -12- (9, 10-difluoro-2, 2-dimethyl-6, 11-dihydrobenzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2-d] [1, 3] dioxol-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.17 g, 1.80 mmol) was dissolved in N, N-dimethylacetamide (20 mL) , and anhydrous lithium chloride (763 mg, 18.00 mmol) was added. The reaction solution was reacted at 100℃ overnight under nitrogen, then added with water (10 mL) and adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with ethyl acetate (10 mL× 3) . The combined organic phases were washed with saturated saline (20 mL × 3) , dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by LUNA preparation column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (18-1) as a light yellow solid (430 mg, 43%) and the title compound (18-2) as a light yellow solid (500 mg, 50%) .

MS (ESI, pos. ion) m/z: 556.25 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro-2, 2-dimethyl-6, 11-dihydro-benzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2, 2-d] [1, 3] dioxolene-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 11-f] [1, 2, 4] triazine-6, 8-dione (18-1) :

MS (ESI, pos. ion) m/z: 556.1349 [M+H] ⁺

¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) : 7.12 (dd, J = 15.1, 8.0 Hz, 2H) , 7.02 (d, J = 3.9 Hz, 1H) , 6.24 (dd, J = 22.2, 8.0 Hz, 2H) , 5.85 (d, J = 7.7 Hz, 1H) , 5.31 (d, J = 13.8 Hz, 1H) , 5.27 (d, J = 21.8 Hz, 1H) , 4.67 (d, J = 13.1 Hz, 1H) , 4.65 –4.52 (m, 1H) , 4.13 (d, J = 13.7 Hz, 1H) , 4.03 –3.91 (m, 1H) , 3.83 (d, J = 9.3 Hz, 1H) , 3.62 (t, J = 10.6 Hz, 1H) , 3.49 (t, J = 11.0 Hz, 1H) , 3.00 (t, J = 12.2 Hz, 1H) , 1.65 (m, 6H) ;

(R) -12- ( (R) -9, 10-difluoro-2, 2-dimethyl-6, 11-dihydro-benzo [5', 6'] thiepino [2', 3': 3, 4] benzo [1, 2, 2-d] [1, 3] dioxolene-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 11-f] [1, 2, 4] triazine-6, 8-dione (18-2) :

¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) : 6.91 (dd, J = 16.7, 8.5 Hz, 1H) , 6.88 –6.79 (m, 1H) , 6.70 –6.51 (m, 3H) , 5.83 (d, J = 7.6 Hz, 1H) , 5.37 (d, J = 14.2 Hz, 1H) , 5.15 (s, 1H) , 4.62 (d, J = 10.3 Hz, 2H) , 4.13 (dd, J = 14.3, 8.0 Hz, 1H) , 4.05 (d, J = 8.9 Hz, 1H) , 3.82 (d, J = 9.8 Hz, 1H) , 3.59 (t, J = 10.4 Hz, 1H) , 3.48 (t, J = 11.1 Hz, 1H) , 2.92 (dd, J = 23.2, 12.1 Hz, 1H) , 1.73 (m, 6H) ;

HRMS (ESI, pos. ion) m/z: 556.1349 [M+H] +

Example 19 (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (19-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (19-2)

Step 1) : synthesis of 1, 2-bis (benzo [b] thiophen-4-yl) disulfide

Magnesium strip (2.87 g, 120.00mmol) was added to THF (20 mL) , then iodine (1.19 g, 4.69mmol) was added. The solution was heated at 60℃ under nitrogen, added with 4-bromobenzothiophene (10.60 g, 49.74mmol) dropwise slowly, and stirred for 2 h. Then the reaction solution was added to THF (30 mL) solution of sulfur powder (3.30 g, 103.20mmol) . The mixture was stirred overnight. The reaction was stopped and the reaction mixture was added with saturated ammonium chloride (20 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) =5/1) to give the title compound as a yellow solid (4.70 g, 29.7%) .

Step 2) : synthesis of methyl 2- ( (benzo [b] thiophen-4-ylthio) methyl) -3, 4-difluorobenzoate

1, 2-bis (benzo [b] thiophen-4-yl) disulfide (1.14 g, 3.45 mmol) was dissolved in THF (30 mL) . The mixture was stirred at rt, NaBH4 (272 mg, 6.90 mmol) was added, then the mixture was reacted at 55℃ for 30 min. Ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (1.93 g, 6.92mmol) was added before the reaction solution was cooled. Then the mixture was transferred to rt and stirred at rt overnight. The reaction solution was added with saturated ammonium chloride solution (30 mL) and extracted with ethyl acetate (20 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (PE/EA (v/v) = 10/1) to give the title compound as a light yellow solid (1.13 g, 90%) .

MS (ESI, pos. ion) m/z: 365.2 [M+H] +;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.81 (d, J = 8.0 Hz, 1H) , 7.65 (ddd, J = 8.4, 5.0, 1.6 Hz, 1H) , 7.52 (d, J = 5.5 Hz, 1H) , 7.43 (d, J = 5.5 Hz, 1H) , 7.35 (d, J = 7.3 Hz, 1H) , 7.23 (t, J = 7.7 Hz, 1H) , 7.04 (dd, J = 16.8, 8.8 Hz, 1H) , 4.62 (t, J = 5.5 Hz, 2H) , 4.19 (q, J = 7.1 Hz, 2H) , 1.33 (t, J = 7.1 Hz, 3H) .

Step 3) : synthesis of 9, 10-difluorobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one

Methyl 2- ( (benzo [b] thiophen-4-ylthio) methyl) -3, 4-difluorobenzoate (5.50 g, 12.40 mmol) was dissolved in THF (30 mL) and MeOH (30 mL) . The aqueous solution of NaOH (1.98 g, 49.50 mmol) in water (3 mL) was added. The reaction solution was reacted at 50℃ for 20 min. The reaction solution was cooled, adjusted with 2N hydrochloric acid to pH 2-4, and extracted with ethyl acetate (20 mL× 3) . The combined organic phases were washed with saturated brine (20 mL) , dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was used directly in next reaction without further purification.

The residue (100 mg) obtained in the previous step was dissolved in DCM (5 mL) , then DMF (7 mg, 0.09 mmol) was added, and oxalyl chloride (0.094 mL, 0.40 mmol) was added slowly. The mixture was stirred at rt for 1 h. Aluminum chloride (270 mg, 2.02mmol) was added. The mixture was continued to react at this temperature for about 4 h. The reaction was stopped, water (20 mL) was added, and the reaction mixture was extracted with dichloromethane (20 mL× 3) . The organic phases were combined, washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, concentrated under reduced pressure to give the title compound as a yellow solid (80 mg, 50%) . It was used directly in the next reaction without purification.

¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) 8.05 (d, J = 8.7 Hz, 1H) , 7.94 (dd, J = 15.5, 7.2 Hz, 2H) , 7.60 (d, J = 5.3 Hz, 1H) , 7.50 –7.35 (m, 2H) , 4.44 (s, 2H) .

Step 4) : synthesis of 9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin -6-ol

9, 10-Difluorobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin-6- (11H) -one (2.50 g, 11.90 mmol) was dissolved in THF (25 mL) and MeOH (25 mL) . The mixture was stirred at rt. Sodium borohydride (619 mg, 15.71 mmol) was added, and the mixture was stirred at rt for 1 h. The reaction was stopped and the reaction mixture was added with saturated ammonium chloride (20 mL) , extracted with ethyl acetate (25 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (PE/EA (v/v) =5/1) to give the title compound as an off-white solid (1.90 g, 76%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.68 (d, J = 8.4 Hz, 1H) , 7.56 (d, J = 5.6 Hz, 1H) , 7.52 –7.43 (m, 2H) , 7.25 –7.18 (m, 1H) , 7.03 (dd, J = 17.8, 8.4 Hz, 1H) , 6.26 (s, 1H) , 4.87 (d, J = 14.5 Hz, 1H) , 4.30 (d, J = 14.4 Hz, 1H) , 2.86 (s, 1H) .

Step 5) : synthesis of (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To the mixture solution of 1-propylphosphoric anhydride (50%ethyl acetate, 9.92 mL) and isopropyl acetate (3 mL) were added 9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin-6-ol (1.77 g, 5.52 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.99 g, 6.08 mmol) , nitrogen gas was blown in, and the reaction solution was reacted at 90 ℃ for 5 h. The reaction solution was added with ice water (30 mL) and extracted with ethyl acetate (30 mL × 3) . The organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 25/1) to give the title compound as a light yellow solid (1.80 g, 52%) .

MS (ESI, pos. ion) m/z: 630.1 [M+H] +

Step 6) : synthesis of (R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (19-1) and (R) -12- ( (R) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (19-2)

(12aR) -7- (benzyloxy) -12- (9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.80 g, 2.86 mmol) was dissolved in N, N-dimethylacetamide (30 mL) , and lithium chloride (1.21 g, 28.60mmol) was added, the reaction solution was reacted at 100℃overnight under nitrogen, then added with water (10 mL) and adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with ethyl acetate (10 mL× 3) . The organic phases were combined. The combined organic phases were washed with saturated saline (20 mL × 3) , dried over anhydrous sodium sulfate, filtered. The filtrate was concentrated under reduced pressure. The residue was purified by LUNA preparation column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (19-1) as a light yellow solid (413mg, 27%) and the title compound (19-2) as a light yellow solid (670mg, 43%) .

MS (ESI, pos. ion) m/z: 540.0 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin -6-yl) -7-hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (19-1) :

¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) : 7.52 (s, 2H) , 7.39 (d, J = 8.1 Hz, 1H) , 7.08 (dd, J = 27.9, 7.5 Hz, 3H) , 6.62 (d, J = 8.1 Hz, 1H) , 5.75 (d, J = 7.2 Hz, 1H) , 5.47 (s, 1H) , 5.41 (d, J = 13.9 Hz, 1H) , 5.31 (s, 1H) , 4.70 (d, J = 10.2 Hz, 2H) , 4.25 (d, J = 13.8 Hz, 1H) , 4.02 (d, J = 10.6 Hz, 1H) , 3.85 (d, J = 10.3 Hz, 1H) , 3.71 (t, J = 10.5 Hz, 1H) , 3.53 (t, J = 11.4 Hz, 1H) , 3.05 (t, J = 11.3 Hz, 1H) ;

(R) -12- ( (S) -9, 10-difluoro-6, 11-dihydrobenzo [e] thieno [2', 3': 5, 6] benzo [1, 2-b] thiepin-6-yl) -7 -hydroxy3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (19-2) : ¹H NMR (400 MHz, DMSO-d ₆) δ (ppm) 7.69 (d, J = 8.3 Hz, 1H) , 7.64 –7.52 (m, 2H) , 7.42 –7.31 (m, 1H) , 7.32 –7.25 (m, 1H) , 6.92 (dd, J = 17.1, 8.5 Hz, 1H) , 6.81 (d, J = 7.6 Hz, 1H) , 6.66 (dd, J = 7.6, 4.3 Hz, 1H) , 5.97 (d, J = 7.6 Hz, 1H) , 5.52 (dd, J = 14.3, 1.6 Hz, 1H) , 5.36 (s, 1H) , 4.62 (d, J = 10.2 Hz, 1H) , 4.57 –4.50 (m, 1H) , 4.25 (d, J = 14.2 Hz, 1H) , 4.03 (dd, J = 10.9, 2.8 Hz, 1H) , 3.76 (dd, J = 11.9, 3.0 Hz, 1H) , 3.66 (t, J = 10.5 Hz, 1H) , 3.49 (td, J = 11.8, 2.3 Hz, 1H) , 2.84 (td, J = 13.4, 3.3 Hz, 1H) .

Example 20 (R) -12- ( (S) -9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (20-1) and (R) -12- ( (R) -9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6 -yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (20-2)

Step 1) : synthesis of 7-bromo-2, 2-dimethyl-2, 3-dihydro-1H-inden-1-one

To a single-necked flask were added 7-bromoindanone (500 mg, 2.37 mmol) DMF (5 mL) , and slowly sodium hydride (209 mg, 5.23mmol) in turn. The mixture was reacted at rt for 1 h, then methyl iodide (0.33 mL, 5.2 mmol) was added dropwise. The mixture was reacted at rt overnight. The reaction was quenched with saturated ammonium chloride solution (20 mL) . The reaction mixture was extracted with EA (30 mL × 2) . The organic phases were combined and washed with saturated brine (30 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =15/1) to give the title compound as light yellow oil (130 mg, 22.9%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.52 (d, J = 7.2 Hz, 1H) , 7.45 –7.34 (m, 2H) , 2.96 (s, 2H) , 1.24 (s, 6H) .

Step 2) : synthesis of 4-bromo-2, 2-dimethyl-2, 3-dihydro-1H-indene

To a single-necked flask was added 7-bromo-2, 2-dimethyl-2, 3-dihydro-1H-1-inden-1-one (100 mg, 0.42 mmol) . Trifluoroacetic acid (2 mL) and triethylsilane (0.3 mL, 2 mmol) were added. The mixture was warmed to 50℃ and reacted for 3 h. The reaction was quenched with saturated sodium bicarbonate solution (20 mL) . The reaction mixture was extracted with ethyl acetate (10 mL × 2) . The organic phases were combined and washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as colorless oil (44 mg, 46.73%) .

¹H NMR (400 MHz, CDCl3) δ (ppm) 7.27 (d, J = 7.9 Hz, 1H) , 7.07 (d, J = 7.3 Hz, 1H) , 6.98 (t, J = 7.6 Hz, 1H) , 2.81 (s, 2H) , 2.76 (s, 2H) , 1.16 (s, 6H) .

Step 3) : synthesis of 1, 2-bis (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) disulfide

To the double-necked flask A were added magnesium (1.05 g, 43.2 mmol) and iodine (555mg, 2.15 mmol) , tetrahydrofuran (30 mL) was added, and the mixture was heated to 60℃under nitrogen. 4-Bromo-2, 2-dimethyl-2, 3-dihydro-1H-indene (4.82 g, 21.4 mmol) in THF (20 mL) was added, and the reaction solution was reacted for 2 h at 60℃ for backup.

To a two-necked flask was added sublimed sulfur (1.38 g, 43.0 mmol) , and tetrahydrofuran (20 mL) was added, the reaction solution was cooled to 0℃ under nitrogen. The solution in double-necked flask A was added dropwise slowly, then the resulting mixture was reacted overnight at rt. The reaction was quenched with saturated ammonium chloride solution (30 mL) . The reaction mixture was extracted with EA (50 mL × 2) . The organic phases were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE) to give the title compound as light yellow oil (1.67g, 43.8%) .

Step 4) : synthesis of ethyl 2- ( ( (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) thio) methyl) -3, 4-difluorobenzoate

To the single-necked flask was added 1, 2-bis (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) disulfide (1.67 g, 4.71 mmol) , then THF (20 mL) was added to dissolve the raw material, then sodium borohydride (364mg, 9.43 mmol) was added. The mixture was heated to 50℃ and reacted for 5 h. The reaction solution was cooled to rt, added with ethyl 2- (bromomethyl) -3, 4-difluorobenzoate (2.63 g, 9.42 mmol) , and reacted overnight. The reaction was quenched with saturated ammonium chloride solution (20 mL) . The reaction mixture was extracted with EA (40 mL × 2) . The organic phases were combined and washed with saturated brine (40 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =10/1) to give the title compound as colorless oil (2.56g, 72.2%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.67 (ddd, J = 8.6, 5.1, 1.7 Hz, 1H) , 7.10 (dd, J = 7.8, 3.7 Hz, 1H) , 7.07 –6.99 (m, 3H) , 4.51 (d, J = 1.6 Hz, 2H) , 4.29 (q, J = 7.1 Hz, 2H) , 2.71 (s, 2H) , 2.62 (s, 2H) , 1.36 (t, J = 7.1 Hz, 3H) , 1.08 (s, 6H) .

Step 5) : synthesis of 2- ( ( (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) thio) methyl) -3, 4-difluorobenzoic acid

To a single-necked flask were added ethyl 2- ( (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) thio) methyl) -3, 4-difluorobenzoate (2.56 g, 6.8 mmol) , THF (25 mL) and methanol (8 mL) in turn, then sodium hydroxide solution (6.8 mL, 2 mol/L) was added. The mixture was heated to 50℃ and reacted for 3 h. The reaction solution was concentrated in vacuo to remove organic solvent. The reaction solution was added with water (20 mL) , adjusted with 4N hydrochloric acid to pH about 4, extracted with ethyl acetate (30 mL × 2) . The organic phases were combined and washed with saturated saline (30 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give the title compound as a light yellow solid (2.16g, 91.1%) .

MS (ESI, neg. ion) m/z: 347.2 [M+H] +

Step 6) : synthesis of 9, 10-difluoro-2, 2-dimethyl-2, 3-dihydro-1H-benzo [e] indeno [4, 5-b] thiepin-6- (11H) -one

To the double-necked flask A were added 2- ( ( (2, 2-dimethyl-2, 3-dihydro-1H-inden-4-yl) thio) methyl) -3, 4-difluorobenzoic acid (2.02 g, 5.8 mmol) , dichloromethane (20 mL) and DMF (0.05 mL) in turn. Oxalyl chloride (1 mL, 12 mmol) was added under nitrogen, and the mixture was reacted for 1 h at rt, then concentrated, and added with DCM (20 mL) for backup.

To a two-necked flask was added aluminum chloride (2.32 g, 17.4 mmol) , and DCM (40 mL) was added. The reaction solution in flask A was added dropwise under nitrogen, then the resulting mixture was reacted for 2.5 h at rt. The reaction solution was added with water (10 mL) and extracted with DCM (20 mL × 2) . The organic phases were combined and washed with saturated saline (20 mL) , dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give a light yellow solid (1.89 g, 98.7%) .

Step 7) : synthesis of 9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-ol

To a single-necked flask were added 9, 10-difluoro-2, 2-dimethyl-2, 3-dihydro-1H-benzo [e] indeno [4, 5-b] thiepin-6- (11H) -one (1.89 g, 5.72 mmol) , THF (20 mL) and MeOH (2 mL) , then sodium borohydride (445mg, 11.53 mmol) was added slowly. The resulting mixture was reacted at rt for 15min. The reaction was quenched with saturated ammonium chloride solution (10 mL) . The reaction mixture was extracted with EA (20 mL × 2) . The organic phases were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (eluent: PE/EA (v/v) =5/1) to give the title compound as a white solid (1.36g, 71.5%) .

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.22 (d, J = 7.7 Hz, 1H) , 7.11 –7.05 (m, 1H) , 6.98 (dd, J = 17.6, 8.4 Hz, 1H) , 6.92 (d, J = 7.7 Hz, 1H) , 5.94 (s, 1H) , 4.94 (d, J = 14.2 Hz, 1H) , 4.16 (d, J = 14.2 Hz, 1H) , 2.67 (s, 2H) , 2.65 –2.50 (m, 3H) , 1.12 (d, J = 8.5 Hz, 6H) .

Step 8) : synthesis of (12aR) -7 - (benzyloxy) -12 - (9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione

To a single-necked flask were added 9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-ol (1.3 g, 3.9 mmol) and (R) -7- (benzyloxy) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.4 g, 4.3 mmol) , then isopropyl acetate (50 mL) and T3P (7 mL, 11.76 mmol) were added, the reaction system was reacted at 90 ℃ for 3.5 h. The reaction was added with water (30 mL) . After separation, the aqueous phase was extracted with ethyl acetate (20 mL × 2) . Organic phases were combined and washed with saturated sodium bicarbonate solution (50 mL) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (dichloromethane/methanol (v/v) = 20/1) to give the title compound as a light yellow solid (1.64g, 65%) .

MS (ESI, pos. ion) m/z: 642.0 [M+H] +

Step 9) : synthesis of (R) -12- ( (S) -9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (20-1) and (R) -12- ( (R) -9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (20-2)

To a single-necked flask were added (12aR) -7- (benzyloxy) -12- (9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b ] thiepin-6-yl) -3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (1.63g, 2.54 mmol) and lithium chloride (1.08g, 25.5 mmol) . N, N-Diethylacetamide (20 mL) then was added, and the mixture was heated to 100℃ and reacted for 3 h under nitrogen. The reaction solution was added with water (50 mL) , adjusted with 1N diluted hydrochloric acid to pH about 6, and extracted with DCM (30 mL × 3) . The organic phases were combined and washed with saturated brine (30 mL× 3) and dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the residue was purified by LUNA preparative column (acetonitrile /0.1%aqueous solution of trifluoroacetic acid (v/v) = 12/13) to give the title compound (20-1) as an orange solid (490 mg, 35.0%) and the title compound (20-2) as an orange solid (400mg, 28.5%) .

MS (ESI, pos. ion) m/z: 552.1 [M+H] +;

(R) -12- ( (S) -9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (20-1) :

HRMS (ESI, pos. ion) m/z: 552.1765;

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.14 –7.05 (m, 2H) , 7.01 (dd, J = 8.3, 4.2 Hz, 1H) , 6.66 (d, J = 7.6 Hz, 1H) , 6.44 (d, J = 7.7 Hz, 1H) , 5.95 (d, J = 7.6 Hz, 1H) , 5.29 (d, J = 9.3 Hz, 2H) , 4.71 –4.59 (m, 2H) , 4.11 (d, J = 13.9 Hz, 1H) , 3.96 (dd, J = 11.1, 2.8 Hz, 1H) , 3.83 (dd, J = 12.0, 3.0 Hz, 1H) , 3.63 (t, J = 10.6 Hz, 1H) , 3.49 (dd, J = 11.9, 9.6 Hz, 1H) , 3.08 –2.98 (m, 1H) , 2.58 (ddd, J = 45.7, 31.6, 16.0 Hz, 4H) , 1.09 (d, J = 7.1 Hz, 6H) ;

(R) -12- ( (R) -9, 10-difluoro-2, 2-dimethyl-2, 3, 6, 11-tetrahydro-1H-benzo [e] indeno [4, 5-b] thiepin-6-yl) -7-hydroxy-3, 4, 12, 12a-tetrahydro-1H- [1, 4] oxazino [3, 4-c] pyrido [2, 1-f] [1, 2, 4] triazine-6, 8-dione (20-2) :

¹H NMR (400 MHz, CDCl ₃) δ (ppm) 7.10 (d, J = 7.8 Hz, 1H) , 6.97 (d, J = 7.7 Hz, 1H) , 6.91 (dd, J = 17.1, 8.5 Hz, 1H) , 6.77 (d, J = 7.6 Hz, 1H) , 6.57 (dd, J = 7.9, 4.2 Hz, 1H) , 6.13 –6.06 (m, 1H) , 5.40 –5.33 (m, 1H) , 5.16 (s, 1H) , 4.87 (s, 1H) , 4.60 (dd, J = 7.9, 4.9 Hz, 2H) , 4.12 (d, J = 14.1 Hz, 1H) , 4.04 (dd, J = 10.9, 2.8 Hz, 1H) , 3.81 (dd, J = 11.9, 3.0 Hz, 1H) , 3.62 (t, J = 10.5 Hz, 1H) , 3.48 (dd, J = 11.9, 9.7 Hz, 1H) , 2.94 –2.84 (m, 1H) , 2.75 (dd, J = 32.9, 12.9 Hz, 2H) , 2.60 (dd, J = 51.2, 13.0 Hz, 2H) , 1.17 (d, J = 59.4 Hz, 6H) ;

HRMS (ESI, pos. ion) m/z: 552.1766;

Examples of Activity test

In the following examples, the inventors examined the antiviral activity and cytotoxicity, pharmacokinetic properties, and stability in liver microparticles of the compounds of the present invention by taking a part of the compounds of the present invention as an example.

Example A: cytopathic effect assay (CPE assay) :

This experiment detected the ability of the compounds to inhibit viral H1N1 A/Weiss/43-induced cytopathic effect (CPE) at the cellular level in vitro.

Experimental steps: MDCK cells (Madin-Darby canine kidney cells, Canine renal epithelial continuous cell line, source: ATCC#CCL-34) MDCK cells were seeded at 2000 cells per well in 384-well plates, which were incubated overnight at 37 ℃ , 5%CO ₂; The culture medium was changed to the fresh culture solution containing different concentrations of the compound on the second day, cells were infected with influenza virus (A/Weiss/43 (H1N1) ) at a multiplicity of infection (MOI ) of 80 ～ 95%cytopathic effect (CPE ) produced. The highest detection concentration of the compound is 100 nM, with 3 times dilution, 8 concentrations in turn: 100 nM, 33.33 nM, 11.11 nM, 3.70 nM, 1.23 nM, 0.41 nM, 0.14 nM, 0.05 nM. At the same time, a non-medicated virus control group and a non-medicated cell control group free of virus were set up. No virus was added in the cytotoxicity test group but medium was added for repalcement. Two duplicate holes were set in both groups. Incubation of the plates at 37 ℃ in 5%CO ₂. The cell activity is measured according to the CCK-8 kit (source: Shanghai Liji Biotechnology Co., Ltd. #D3100L4057) and the data will be used to calculate the antiviral effect and cytotoxicity of the compound. Data were analyzed by GraphPad Prism, CPE inhibition rate and cell viability were calculated, and the EC ₅₀ and CC ₅₀ were obtained according to the fitted curve.

wherein,

CPE inhibition rate = (absorbance of dosing hole-absorbance of virus control well) / (absorbance of cell control well-absorbance of virus control well) × 100%

Cell viability = (absorbance of dosing hole-absorbance of virus control well) / (absorbance of cell control well-absorbance of virus control well) × 100%

Table 1 EC ₅₀ activity data of some compounds of the present invention against influenza virus (A/Weiss/43 (H1N1) ) in vitro

Example number	EC ₅₀ (nM)
Example 1	10.3
Example 2 compound (2-1)	4.27

Example 3 compound (3-1)	6.74
Example 5 compound (5-1)	19.08
Example 6	19.1
Example 12 compound (12-1)	5.48

Table 2 CC ₅₀ data of some compounds of the present invention against viral infected cells

Example number	CC ₅₀ (μM)
Example 2 compound (2-1)	6.02
Example 3 compound (3-1)	40.15
Example 5 compound (5-1)	62.76
Example 6	>100
Example 12 compound (12-1)	6.3

The test results show that the compounds of the present invention have excellent anti-influenza activity and/or low cytotoxicity.

Example B: pharmacokinetic evaluation after intravenous or oral quantification of the compound of the present invention

Pharmacokinetic studies of compounds of the invention in healthy and adult male SD rats, dogs or monkeys were evaluated. The compound of the present invention is administered in 5%DMSO + 5%Kolliphor HS 15 + 90%physiological saline solution. For intravenous (iv) administration, animals were given at a dose of 1 mg/kg and blood was taken at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours (0.3 mL) , and centrifugated at 3,000 or 4,000 rpm for 10 minutes. For oral (po) administration, animals were given at a dose of 5 mg/kg, blood was taken at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours (0.3 mL) and centrifuged at 3,000 or 4,000 rpm for 10 minutes. The plasma solution was collected and stored at -20 ℃ or -70 ℃ until the above LC/MS/MS analysis was performed.

The test results show that the compound of the present invention has a large exposure, good absorption and good pharmacokinetic properties in rats, dogs or monkeys.

Example C: pharmacokinetic evaluation after intravenous or oral quantification of the compound of the present invention

Pharmacokinetic studies of compounds of the invention in healthy and adult male SD rats, dogs or monkeys were evaluated. The compounds of the present invention were administered in 10%DMSO + 10%Kolliphor HS 15 + 80%physiological saline solution. For intravenous (iv) administration, animals were given at a dose of 0.2 or 1 mg/kg and blood was taken at time points of 0.083, 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours (0.3 mL) and centrifugatd for 10 minutes at 3,000 or 4,000 rpm. For oral (po) administration, animals were given at a dose of 1 or 5 mg/kg. Blood was taken at time points of 0.25, 0.5, 1.0, 2.0, 5.0, 7.0, and 24 hours (0.3 mL) and centrifugatd at 3,000 or 4,000 rpm for 10 minutes. The plasma solution was collected and stored at -20 ℃ or -70 ℃ until the above LC/MS/MS analysis was performed.

Table 3 Pharmacokinetic data of some compounds of the present invention in SD rats

Example D: Stability Evaluation in Human Liver Particles

The stability of the compound of the present invention in mixed rat and human liver microparticles were evaluated. The compound of the present invention was incubated with mixed human and rat liver microsomes at 37 ℃, pH = 7.4. By measuring the concentration of the sample at different incubation times, the “incubation time” was plotted as “Log [drug concentration] ” to obtain the rate constant, and the drug half-life and Cl _in vivo (clearance rate in vivo) were calculated. Drug stability in liver microsomes was evaluated by drug half-life and Cl _in vivo (clearance rate in vivo) . The specific experimental system is as follows

The test results show that the compounds of the present invention are stable in both rat and human liver microparticles.

Reference throughout this specification to “an embodiment, ” “some embodiments, ” “one embodiment” , “another example” , “an example” , “a specific examples, ” or “some examples” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the phrases such as “in some embodiments” , “in one embodiment” , “in an embodiment” , “in another example” , “in an example” , “in a specific examples” , or “in some examples” in various places throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.

Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.

Claims

A compound having Formula (I) or a stereoisomer, a tautomer, an N-oxide, a solvate, a metabolite, a pharmaceutically acceptable salt or a prodrug thereof,

wherein,

Y is -O-, -S-, -S (=O) -, -S (=O) ₂-, -CR ⁷R ⁸-or -N (R ⁹) -;

Ring Cy is a C _3-5 carbocyclic ring, a heterocyclic ring consisting of 3 to 8 atoms or a heteroaromatic ring consisting of 5 to 10 atoms;

each of R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

each of R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkoxy, C _1-6 alkylthio, C _1-6 alkylamino, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

R ⁹ is H, deuterium, C _1-6 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6atoms, wherein each of the C _1-6 haloalkyl, C _1-6 alkyl, C _2-6 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OR ^b, -NR ^cR ^d, -C (=O) R ^a, -C (=O) OR ^b, -C (=O) NR ^cR ^d, C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-4 alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5 to 10 atoms or (heteroaryl consisting of 5 to 10 atoms) -C _1-4 alkylene, wherein each of the C _1-6 haloalkyl, C _1-6 haloalkoxy, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-4 alkylene, heterocyclyl consisting of 3 to 8 atoms, (heterocyclyl consisting of 3 to 8 atoms) -C _1-4 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-4 alkylene, heteroaryl consisting of 5 to 10 atoms and (heteroaryl consisting of 5 to 10 atoms) -C _1-4 alkylene is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

each R ^a, R ^b, R ^c and R ^d is independently H, deuterium, C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-6 alkyl, C _2-6 alkenyl, C _2-6 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

or R ^c, R ^d together with the nitrogen atom to which they are attached form a heterocyclic ring consisting of 3 to 6 atoms or a heteroaromatic ring consisting of 5 to 6 atoms, wherein each of the heterocyclic ring consisting of 3 to 6 atoms and heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-6 alkyl, C _1-6 haloalkyl, C _1-6 alkoxy or C _1-6 alkylamino;

m is 0, 1, 2, 3 or 4.
The compound of claim 1, wherein the ring Cy is a C _3-5 carbocyclic ring, a heterocyclic ring consisting of 3 to 6 atoms, a heteroaromatic ring consisting of 5 atoms or a heteroaromatic ring consisting of 6 atoms.
The compound of claim 1 or 2, wherein the ring Cy is cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclopentadiene, ethylene oxide, azetidine, oxetane, thietane, 1, 3-dioxolane, 1, 3-dithiocyclopentane, tetrahydrofuran, dihydrofuran, tetrahydrothiophene, dihydrothiophene, tetrahydropyran, dihydropyran, pyrrolidine, pyrazolidine, imidazolidine, piperidine, morpholine, thiomorpholine, piperazine, pyrrole, pyridine, pyrimidine, thiazole, thiophene, furan, pyrazole, imidazole, triazole, tetrazole, oxazole, isoxazole, oxadiazole, pyrazine, pyridazine or 1, 3, 5-triazine.
The compound of any one of claims 1 to 3, wherein each of the R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl , C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino;

each of R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkoxy, C _1-4 alkylthio, C _1-4 alkylamino, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino;

R ⁹ is H, deuterium, C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 haloalkyl, C _1-4 alkyl, C _2-4 alkenyl, C _3-6 cycloalkyl, heterocyclyl consisting of 5 to 6 atoms, C _6-10 aryl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.
The compound of any one of claims 1 to 4, wherein each of the R ¹, R ², R ³, R ⁴, R ⁵ and R ⁶ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, -CHF ₂, -CF ₃, -CH ₂CF ₃ , -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCF ₃, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;

each R ⁷ and R ⁸ is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, -OH, -NH ₂, -COOH, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCF ₃, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methoxy, ethoxy, -OCHF ₂, -OCHFCH ₂F, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy;

R ⁹ is H, deuterium, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl, pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.
The compound of any one of claims 1 to 5, wherein each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, -NO ₂, oxo (=O) , -OR ^b, -NR ^cR ^d, -C (=O) R ^a, -C (=O) OR ^b, -C (=O) NR ^cR ^d, C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-2 alkylene, heteroaryl consisting of 5 to 6 atoms or (heteroaryl consisting of 5 to 6 atoms) -C _1-2 alkylene, wherein each of the C _1-4 haloalkyl, C _1-4 haloalkoxy, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 carbocyclyl, C _3-6 carbocyclyl-C _1-2 alkylene, heterocyclyl consisting of 5 to 6 atoms, (heterocyclyl consisting of 5 to 6 atoms) -C _1-2 alkylene, C _6-10 aryl, C _6-10 aryl-C _1-2 alkylene, heteroaryl consisting of 5 to 6 atoms and (heteroaryl consisting of 5 to 6 atoms) -C _1-2 alkylene is independently unsubstituted or substituted by 1, 2, 3, or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino;

each R ^a, R ^b, R ^c, and R ^d is independently H, deuterium, C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl consisting of 5 to 6 atoms, wherein each of the C _1-4 alkyl, C _2-4 alkenyl, C _2-4 alkynyl, C _3-6 cycloalkyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino;

or R ^c , R ^d together with the nitrogen atom to which they are attached form a heterocyclic ring consisting of 5 to 6 atoms or a heteroaromatic ring consisting of 5 to 6 atoms, wherein each of the heterocyclic ring consisting of 5 to 6 atoms and heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, C _1-4 alkyl, C _1-4 haloalkyl, C _1-4 alkoxy or C _1-4 alkylamino.
The compound of any one of claims 1 to 6, wherein each R ^x is independently H, deuterium, F, Cl, Br, I, -CN, NO ₂, oxo (=O) , -OH, -OCH ₃, -OCH ₂CH ₃, -NH ₂, -NHCH ₃, -NHCH ₂CH ₃, -N (CH ₃) ₂, -C (=O) OH, -C (=O) OCH ₃, -C (=O) OCH ₂CH ₃, -C (=O) NH ₂, -CHF ₂, -CF ₃, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, -OCHF ₂, -OCF ₃, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl or 1, 3, 5-triazinyl, wherein each of the -CHF ₂, -CH ₂CF ₃, -CHFCH ₂F, -CHFCHF ₂, -OCHF ₂, -OCH ₂CF ₃, methyl, ethyl, n-propyl, isopropyl, tert-butyl, n-butyl, allyl, propenyl, propargyl, 1-propynyl, cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, phenyl, pyrrolyl , pyridyl, pyrimidinyl, thiazolyl, thienyl, furyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazinyl, pyridazinyl and 1, 3, 5-triazinyl is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, =O, -CN, -OH, -NH ₂, -COOH, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy or ethoxy.
The compound of any one of claims 1 to 7, each R ^a, R ^b, R ^c, and R ^d is independently H, deuterium, methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, heterocyclyl consisting of 3 to 6 atoms, phenyl or heteroaryl consisting of 5 to 6 atoms, wherein each of the methyl, ethyl, n-propyl, isopropyl, tert-butyl, cyclopropyl, cyclobutyl, heterocyclyl consisting of 3-6 atoms, phenyl and heteroaryl consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy;

or R ^c, R ^d together with nitrogen atom to which they are attached form a heterocyclic ring consisting of 5 to 6 atoms or a heteroaromatic ring consisting of 5 to 6 atoms, wherein each of the heterocyclic ring consisting of 5 to 6 atoms and heteroaromatic ring consisting of 5 to 6 atoms is independently unsubstituted or substituted by 1, 2, 3 or 4 substituents independently selected from deuterium, F, Cl, Br, I, -CN, -OH, -NH ₂, -NO ₂, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or methoxy.
The compound of any one of claims 1 to 8 having the structure of Formula (II) :
The compound of any one of claims 1 to 9 having one of the following structures:

or stereoisomers, tautomers, N-oxides, solvates, metabolites, pharmaceutically acceptable salts or produgs thereof.
A pharmaceutical composition comprising the compound of any one of claims 1 to 10, and optionally further comprising pharmaceutically acceptable carriers, adjuvants, vehicles or a combination thereof.
The pharmaceutical composition of claim 11, further comprising one or more other therapeutic agents, wherein other therapeutic agents are selected from anti-influenza virus or vaccine; or other therapeutic agents are amantadine, rimantadine, oseltamivir, zanamivir, peramivir, laninamivir, laninamivir octanoate hydrate, favipiravir, arbidol, ribavirin, stachyflin, ingavirin, Fludase, Drug of CAS 1422050-75-6, pimodivir, baloxavir marboxil, influenza vaccines or a combination thereof.
Use of the compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 12 in the manufacture of a medicament for preventing, managing, treating or lessening a viral infectious disease in a patient.
The use of claim 13, wherein the viral infection is an influenza virus infection.
Use of the compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 12 in the manufacture of a medicament for inhibiting influenza virus RNA polymerase.
The use of claim 15, wherein the RNA polymerase is cap-dependent endonuclease.
The compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 12 for use in preventing, managing, treating or lessening a viral infectious disease in a patient.
The compound or the pharmaceutical composition of claim 17, wherein the viral infection is an influenza virus infection.
The compound of any one of claims 1 to 10 or the pharmaceutical composition of any one of claims 11 to 12 for use in inhibiting influenza virus RNA polymerase.
The compound or the pharmaceutical composition of claim 19, wherein the RNA polymerase is cap-dependent endonuclease.
A method of preventing, managing, treating or lessening a viral infectious disease in a patient, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 11 to 12 to the patient.
The method of claim 21, wherein the viral infection is an influenza virus infection.
A method of inhibiting influenza virus RNA polymerase in a patient, comprising administering a therapeutically effective amount of the compound of any one of claims 1 to 10 or the pharmaceutical composition of claim 11 to 12 to the patient.
The method of claim 23, wherein the RNA polymerase is cap-dependent endonuclease.