CN118056834A

CN118056834A - Condensed ring pyridone derivatives and preparation methods and uses thereof

Info

Publication number: CN118056834A
Application number: CN202311548214.8A
Authority: CN
Inventors: 许勤龙; 林高峰; 邵莉; 莫佳佳; 储昭兴; 何广卫; 赵炎
Original assignee: Hefei Amvite Pharmaceutical Co ltd; Hefei Industrial Pharmaceutical Institute Co ltd
Current assignee: Hefei Amvite Pharmaceutical Co ltd; Hefei Industrial Pharmaceutical Institute Co ltd
Priority date: 2022-11-21
Filing date: 2023-11-20
Publication date: 2024-05-21
Also published as: WO2024109707A1

Abstract

The invention provides a condensed ring pyridone derivative, a preparation method and application thereof. Specifically, the invention provides a compound with a structure shown as a formula (I), or stereoisomers, tautomers, solvates, prodrugs, isotopic labels, pharmaceutically acceptable salts thereof and a pharmaceutical composition containing the compound. The invention also provides application of the compound and/or the pharmaceutical composition in preparing medicines for preventing and/or treating influenza virus infection diseases. The compound and/or the pharmaceutical composition of the invention have the beneficial effects of good anti-influenza virus activity, low toxicity and high bioavailability.

Description

Fused ring pyridone derivatives, preparation method and application thereof

Technical Field

The invention relates to the field of pharmaceutical chemistry, in particular to a fused ring pyridone derivative, a preparation method and medical application thereof.

Background

The RNA polymerase of influenza virus contains a cap-dependent endonuclease (cap-DEPENDENT ENDONUCLEASE) domain that cleaves host mRNA to produce a capped RNA fragment that serves as a primer to initiate viral mRNA synthesis. Translation of viral mRNA by the host ribosome requires the 5 'cap end of the mRNA, which can be accomplished in cells infected with influenza by a cap-on mechanism (cap-snatching) that cleaves the 5' cap end from the host mRNA by a cap-dependent endonuclease, which then serves as a transcription primer (10 to 13 nucleotides), which capped RNA primers are used to synthesize mRNA encoding viral proteins.

Inhibition of the activity of cap-dependent endonucleases can lead to inhibition of viral proliferation, and therefore cap-dependent endonucleases are considered as important biological targets for effective anti-influenza drugs. Different heterocyclic compounds have been used as cap-dependent endonuclease inhibitors. Wherein baluo Sha Weizhi is the first marketed cap-dependent endonuclease inhibitor, and was approved by the FDA in 2020 for use in the treatment of influenza virus infected patients. Balo Sha Wei has reached 17.96nM[Omoto S,Speranzini V,Hashimoto T,et al.Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil.Sci Rep.2018Jun25;8(1):9633.]. for the median EC ₅₀ of a/H1N1 virus but balo Sha Weizhi is a substrate for Pgp, is easily excreted, has low bioavailability, and has clinically emerged in influenza virus patients resistant to balo Sha Weizhi. In addition, chinese patent CN201680081836.6 discloses a class of cap endonuclease inhibitors, wherein cen_ic ₅₀ of reference 583/584 (racemate) is up to 43.4nM.

However, these pharmaceutical compounds have not only low in vivo bioavailability but also no small cytotoxicity to normal cells, resulting in limited clinical safety. Therefore, there is an urgent need to develop new cap-dependent endonuclease inhibitors capable of overcoming the above drawbacks.

Disclosure of Invention

In order to overcome the deficiencies of the prior art, in one aspect, the present invention provides a compound having the following formula (I),

Or stereoisomers, tautomers, solvates, prodrugs, isotopic labels, and pharmaceutically acceptable salts thereof, wherein

Ring a is selected from a C ₃-C₈ carbocycle or a 3-to 8-membered heterocycle optionally substituted with one or more groups selected from: halo, oxo, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy;

r ₁ is selected from:

Wherein X ₁ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂;

X ₂ is selected from CH, N;

Each R ₃、R₃'、R₄ is independently selected from hydrogen, halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy; or R ₃、R₃' together with the carbon atom to which it is attached form a C ₃-C₈ carbocyclic ring;

Ring B is phenyl or 6 membered heteroaryl, optionally substituted with one or more groups selected from: halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy;

Ring C is a C ₆-C₁₀ aryl or a 6 to 10 membered heteroaryl, optionally substituted with one or more groups selected from: halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy;

R ₂ is selected from:

a)H；

b)-C(＝O)-P^R0；

c)-C(＝O)-P^R1；

d)-C(＝O)-L-P^R1；

e)-C(＝O)-L-O-P^R1；

f)-C(＝O)-L-O-L-O-P^R1；

g)-C(＝O)-L-O-C(＝O)-P^R1；

h)-C(＝O)-O-P^R2；

i)-C(＝O)-N(-K)(P^R2)；

j)-C(＝O)-O-L-O-P^R2；

k)-C(＝O)-O-L-N(-K)(P^R2)；

l)-C(P^R3)₂-O-P^R4；

m)-C(P^R3)₂-O-L-O-P^R4；

n)-C(P^R3)₂-O-C(＝O)-P^R4；

o)-C(P^R3)₂-O-C(＝O)-O-P^R4；

p)-C(P^R3)₂-O-C(＝O)-N(-K)-P^R4；

q)-C(P^R3)₂-O-C(＝O)-O-L-O-P^R4；

r)-C(P^R3)₂-O-C(＝O)-O-L-N(P^R4)₂；

s)-C(P^R3)₂-O-C(＝O)-N(-K)-L-O-P^R4；

t)-C(P^R3)₂-O-C(＝O)-N(-K)-L-N(P^R4)₂；

u)-C(P^R3)₂-O-C(＝O)-O-L-O-L-O-P^R4；

v)-C(P^R3)₂-O-C(＝O)-O-L-N(-K)-C(＝O)-P^R4；

w)-C(P^R3)₂-O-P(＝O)(-P^R5)₂；

x)-(C(P^R3)₂)_p-P^R6；

y)-C(＝N⁺(P^R7)₂)(-N(P^R7)₂)；

z)-(C(P^R3)₂)_q-C(＝O)-O-P^R2；

aa)-(C(P^R3)₂)_q-C(＝O)-N(-K)-P^R4；

bb)-(C(P^R3)₂)_q-C(＝O)-P^R1；

cc)-C(P^R3)₂-N(-K)-C(＝O)-O-P^R2；

dd)-P(＝O)(-P^R8)(-P^R9)；

ee)-S(＝O)₂-P^R10；

ff)-P^R11；

gg) - (C (P ^R3)₂)_r-O-P^R12; or

hh)-(C(P^R3)₂)_t-N(-K)-P^R13；

Wherein L is a linear or branched C ₁-C₂₀ alkylene or C ₁-C₂₀ alkenylene group optionally substituted with any one of substituent groups B,

K is a hydrogen atom, or a C ₁-C₂₀ alkyl group optionally substituted by any one of substituent groups A,

P ^R0 is C ₁-C₂₀ alkyl or C ₁-C₂₀ alkenyl optionally substituted by any of the substituents A,

P ^R1 is carbocyclyl, heterocyclyl, C ₁-C₂₀ alkylamino, C ₁-C₂₀ alkylthio optionally substituted by any of substituent groups a,

P ^R2 is C ₁-C₂₀ alkyl optionally substituted by any of substituent groups A, carbocyclyl, heterocyclyl, or tri (C ₁-C₂₀ alkyl) silyl,

P ^R3 is each independently a hydrogen atom, a C ₁-C₂₀ alkyl group or a hydroxyl group, or 2P ^R3 on adjacent carbon atoms optionally together form an alkenylene group or an alkylene group,

P ^R4 is each independently C ₁-C₂₀ alkyl optionally substituted with any of substituent groups a, C ₃-C₈ carbocyclyl, heterocyclyl, C ₁-C₂₀ alkylamino, or tri (C ₁-C₂₀ alkyl) silyl,

P ^R5 are each independently hydroxy or benzyloxy;

P ^R6 is C ₃-C₈ carbocyclyl or heterocyclyl optionally substituted with any one of substituent groups a,

P ^R7 is each independently C ₁-C₂₀ alkyl optionally substituted by any of substituent groups a,

P ^R8 is C ₁-C₂₀ alkoxy optionally substituted by any of the substituents A,

P ^R9 is C ₁-C₂₀ alkoxy optionally substituted with any of substituent groups a, C ₁-C₂₀ alkylamino, C ₃-C₈ carbocyclyloxy, heterocyclyloxy, C ₃-C₈ carbocyclylamino, or heterocyclylamino, and

P ^R8 and P ^R9 optionally form, together with the adjacent phosphorus atom, a heterocyclic ring optionally substituted by any one of the substituent groups A,

P ^R10 is C ₁-C₂₀ alkyl optionally substituted by any of substituent groups A, C ₃-C₈ carbocyclyl, or heterocyclyl,

P ^R11 is C ₁-C₂₀ alkyl optionally substituted with any of substituent groups a, C ₁-C₂₀ alkenyl, C ₁-C₂₀ alkynyl, carbocyclyl, or heterocyclyl,

P ^R12 is each independently a hydrogen atom, or a C ₁-C₂₀ alkyl group optionally substituted with any one of the substituent groups A,

P ^R13 is C ₁-C₂₀ alkylsulfonyl optionally substituted by any of the substituents A,

P is an integer of 2 to 3,

Q is an integer of 1 to 2,

R is an integer of 2 to 4,

T is an integer of 2 to 4,

Substituent group a includes: oxo, C ₁-C₂₀ alkyl, C ₁-C₂₀ alkenyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ hydroxyalkyl, amino, C ₁-C₂₀ alkylamino, C ₃-C₈ carbocyclyl, heterocyclyl, carbocyclylalkyl, C ₃-C₈ spiro, C ₁-C₂₀ alkylcarbonyl, halogen, hydroxy, carboxyl, C ₁-C₂₀ alkylcarbonylamino, C ₁-C₂₀ alkylcarbonylamino C ₁-C₂₀ alkyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkoxycarbonyl C ₁-C₂₀ alkyl, C ₁-C₂₀ alkoxycarbonyloxy, C ₁-C₂₀ alkylaminocarbonyloxy, C ₁-C₂₀ alkylaminoC ₁-C₂₀ alkyl, C ₁-C₂₀ alkoxy, cyano, nitro, azido, C ₁-C₂₀ alkylsulfonyl, tri (C ₁-C₂₀ alkyl) silyl, phosphoryl,

The substituent group B includes: c ₃-C₈ spiro and halogen.

In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In yet another aspect, the present invention provides the use of a compound of formula (I) or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for the prevention and/or treatment of a disease caused by a virus having a cap-dependent endonuclease.

The beneficial effects are that: compared with the prior art, the compound, particularly the compound with the formula (XIV) and the optical activity, has the advantages of remarkably better anti-influenza virus activity, remarkably reduced cytotoxicity, higher bioavailability and better treatment effect on influenza virus resistant to the existing medicines.

Drawings

FIG. 1 shows a single crystal structure of the compound of example 20.

Figure 2 shows the unit cell packing diagram of the compound of example 20.

Detailed Description

Definition of the definition

As used in this specification, the following words and phrases are generally intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

As used herein, the term "alkyl" refers to a monovalent group of a straight or branched saturated hydrocarbon chain having from 1 to 20 carbon atoms (more typically from 1 to 10 carbon atoms, from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms). The term is illustratively a group such as methyl, ethyl, 1-propyl (n-propyl), 2-propyl (isopropyl), 1-butyl (n-butyl), 2-methyl-1-propyl (isobutyl), 2-butyl (sec-butyl), 2-methyl-2-propyl (tert-butyl), 1-pentyl (n-pentyl), 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3-dimethyl-2-butyl, 1-heptyl, 1-octyl, 1-nonyl, 1-decyl, and the like.

As used herein, the term "alkylene" refers to a divalent group of a straight or branched saturated hydrocarbon chain having from 1 to 20 carbon atoms (more typically from 1 to 10 carbon atoms, from 1 to 8 carbon atoms, or from 1 to 6 carbon atoms). The term is illustratively a group such as methylene, ethylene, propylene, butylene, pentylene, hexylene, and the like.

As used herein, the term "alkenyl" refers to a straight or branched unsaturated hydrocarbon chain monovalent group having 2 to 20 carbon atoms (more typically 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms) and having a carbon-carbon double bond (e.g., 1,2, or 3 carbon-carbon double bonds). The term is illustratively a group such as vinyl (i.e., -ch=ch ₂), propen-1-yl (i.e., -ch=chch ₃), propen-3-yl (or allyl, i.e., -CH ₂CH＝CH₂), propen-2-yl (i.e., -C (CH ₃)＝CH₂), butadienyl (including 1, 2-butadienyl and 1, 3-butadienyl), and the like.

As used herein, the term "alkenylene" refers to a divalent group of a straight or branched unsaturated hydrocarbon chain having 1 to 20 carbon atoms (more typically 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 6 carbon atoms) and having a carbon-carbon double bond (e.g., 1, 2, or 3 carbon-carbon double bonds). The term is illustratively a group such as ethenylene, propenylene, butenylene, pentenylene, hexenylene, and the like.

As used herein, the term "alkynyl" refers to a straight or branched unsaturated hydrocarbon chain monovalent group having 2 to 20 carbon atoms (more typically 2 to 10 carbon atoms, 2 to 8 carbon atoms, or 2 to 6 carbon atoms) and having a carbon-carbon triple bond (e.g., 1, 2, or 3 carbon-carbon triple bonds). The term is illustratively a group such as ethynyl (i.e., -C.ident.CH), propargyl (i.e., -CH ₂ C.ident.CH), propynyl (i.e., -C.ident.CCH ₃), and the like.

As used herein, the term "aryl" refers to an aromatic carbocyclic group of 6 to 14 carbon atoms (more typically 6 to 10 carbon atoms, or 6 carbon atoms) having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl) or multiple condensed (fused) rings (e.g., naphthyl, fluorenyl, and anthracenyl). The term is illustratively a group such as phenyl, fluorenyl, naphthyl, anthracenyl, 1,2,3, 4-tetrahydronaphthalene (if the point of attachment is through an aryl group), and the like.

As used herein, the term "halogen" refers to fluorine, chlorine, bromine and iodine.

As used herein, the term "alkoxy" refers to an "alkyl-O-" group, wherein alkyl is as defined herein. The term is illustratively a group such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy and the like.

As used herein, the term "haloalkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced with a halogen, wherein alkyl is as defined herein. The term is illustratively the radicals trifluoromethyl, difluoromethyl, monofluoromethyl, 2-trifluoroethyl, 1, -difluoroethyl and the like.

As used herein, the term "carbocycle", "carbocyclyl" refers to a 3 to 8 membered monocyclic or multiple fused (fused) or bridged or spiro mono-or partially unsaturated group having 3 to 14 carbon atoms as ring atoms. Carbocycles or carbocyclyls may be saturated or partially unsaturated and may be fused to another saturated, partially unsaturated or aromatic ring, provided that the ring atom attached to the target molecule is not an aromatic carbon. Examples of carbocycles or carbocyclyls include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclopentadiene, and the like.

As used herein, the terms "heteroaryl" and "heteroaryl" refer to an aromatic ring group that comprises a single ring or multiple condensed (fused) rings (e.g., comprising 2 or 3 rings) of 5 to 14 ring atoms in the ring, wherein the ring atoms comprise at least one or more heteroatoms selected from oxygen, nitrogen, and/or sulfur in addition to carbon atoms. If the ring is aromatic, the sulfur and nitrogen atoms may also be present in oxidized form. Multiple fused (fused) ring heteroaryl groups are fused from a monocyclic heteroaryl group as defined above with one or more rings selected from the group consisting of: heteroaryl (to form, for example, naphthyridinyl, such as 1, 8-naphthyridinyl), heterocycle (to form, for example, 1,2,3, 4-tetrahydronaphthyridinyl, such as 1,2,3, 4-tetrahydro-1, 8-naphthyridinyl), carbocycle (to form, for example, 5,6,7, 8-tetrahydroquinolinyl), and aryl (to form, for example, indazolyl). Such multiple fused ring systems may be optionally substituted with one or more (e.g., 1,2,3, or 4) oxo groups on the carbocyclic or heterocyclic moiety of the fused ring. Where valence requirements allow, the rings of multiple fused ring systems may be interconnected by fused, spiro, and bridged linkages. It will be appreciated that the individual rings of the multiple fused ring system may be linked relative to one another in any order. It is also understood that the point of attachment of the multiple fused ring systems may be at any position of the multiple fused ring systems, including heteroaryl, heterocyclic, aryl, or carbocyclic moieties of the multiple fused systems. It is also understood that the point of attachment of the heteroaryl group may be on any suitable atom of the heteroaryl group, including carbon atoms and heteroatoms (e.g., nitrogen). Exemplary heteroaryl groups include, but are not limited to: pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, furanyl, oxadiazolyl, thiadiazolyl, quinolinyl, isoquinolinyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalinyl, quinazolinyl, 5,6,7, 8-tetrahydroisoquinolinyl, benzofuranyl, benzimidazolyl, thiaindenyl, pyrrolo [2,3-b ] pyridyl, quinazolinyl-4 (3H) -one, triazolyl, 4,5,6, 7-tetrahydro-1H-indazolyl and 3b, 4a, 5-tetrahydro-1H-cyclopropan [3,4] cyclopentane [1,2-c ] pyrazolyl.

As used herein, the term "heterocycle", "heterocyclyl" refers to a mono-radical saturated or partially unsaturated group having a 3 to 8 membered single ring or multiple fused (condensed) or bridged rings having 3 to 14 ring atoms in the ring, wherein the ring atoms contain, in addition to carbon atoms, at least one more heteroatom selected from oxygen, nitrogen and/or sulfur. Examples of heterocyclyl groups include, but are not limited to, aziridine ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, azepane ring, azacyclooctane ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, oxepane ring, thietane ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, thietane ring, tetrahydroimidazole ring, tetrahydropyrazole ring, tetrahydroisoxazole ring, tetrahydrothiazole ring, tetrahydroisothiazole ring, piperazine ring, morpholine ring, dioxane ring, thiaxane ring, dithiane ring, dihydropyridine group, 4,5,6, 7-tetrahydro-1H-benzo [ d ] imidazole, 4,5,6, 7-tetrahydro-1H-imidazo [4,5-c ] pyridine, and the like.

As used herein, the term "therapeutically effective amount" refers to an amount sufficient to affect treatment, as defined below, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary with the subject and disease condition being treated, the weight and age of the subject, the severity of the disease condition, the manner of administration, and the like, which can readily be determined by one of ordinary skill in the art.

As used herein, the term "stereoisomer" refers to a compound that has the same chemical composition and connectivity, but whose atoms have different orientations in space, which cannot be exchanged by single bond rotation. "stereoisomers" include "diastereomers" and "enantiomers. "diastereoisomers" refers to stereoisomers which have two or more chiral centers and whose molecules are not mirror images of each other. Diastereomers have different physical properties, such as melting point, boiling point, spectral characteristics, and reactivity. Diastereomeric mixtures can be separated under high resolution analytical procedures such as crystallization, electrophoresis and chromatography. "enantiomer" refers to two stereoisomers of a compound that are non-overlapping mirror images of each other.

As used herein, the term "tautomer" refers to the coexistence of two (or more) compounds, the difference between which is only in the position and electron distribution of one (or more) mobile atoms, such as keto-enol tautomers.

As used herein, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness and properties of a given compound, and which is not biologically or otherwise undesirable. The pharmaceutically acceptable salt may be an acid addition salt and/or a base addition salt. Acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloride, hydrobromide, sulfate, nitrate, phosphate, carbonate, bisulfate, hydrogen phosphate, dihydrogen phosphate, bicarbonate, and the like; salts derived from organic acids include formate, acetate, propionate, glycolate, pyruvate, oxalate, malate, malonate, succinate, maleate, fumarate, tartrate, citrate, benzoate, cinnamate, mandelate, mesylate, ethanesulfonate, p-toluenesulfonate, salicylate, lactate, nicotinate, lauryl sulfate, naphthalenesulfonate, camphorsulfonate, gluconate, glucuronate, oleate, palmitate, stearate, pamoate, trifluoroacetate, and the like. The base addition salts may be formed with inorganic or organic bases. Salts derived from inorganic bases include sodium, potassium, ammonium, calcium, magnesium, iron, zinc, copper, lithium, barium, aluminum salts, and the like; salts derived from organic bases include salts with various primary, secondary, and tertiary amines, such as ethylamine, diethylamine, n-propylamine, isopropylamine, diethanolamine, meglumine, lysine, piperazine, piperidine, morpholine, tromethamine, choline, and the like.

As used herein, the term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with other ingredients comprising the formulation and/or the mammal with which it is to be treated.

As used herein, the term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, and ethanolamine. The term "hydrate" refers to a complex in which the solvent molecule is water.

As used herein, the term "prodrugs" refers to those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention. Alternatively, prodrugs can be converted to the compounds of the present invention by chemical or biochemical methods in an ex vivo environment. For example, when the prodrug is placed in a transdermal patch reservoir with a suitable enzyme or chemical agent, the prodrug may be slowly converted to the compound of the invention.

Any formula or structure given herein, including formula I or any formula disclosed herein, is also intended to represent unlabeled as well as isotopically-labeled forms of the compounds. These forms of the compound may also be referred to as "isotopically labeled" or "isotopically enriched analogs". Isotopically-labeled compounds have the structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, such as, but not limited to ² H (deuterium, D), ³ H (tritium )、¹¹C、¹³C、¹⁴C、¹³N、¹⁵N、¹⁵O、¹⁷O、¹⁸O、³¹P、³²P、³⁵S、¹⁸F、³⁶Cl、¹²³I and ¹²⁵ i. Various isotopically labeled compounds of the invention, such as those into which a radioisotope (e.g., ³H、¹³ C and ¹⁴ C) is incorporated.

Compounds of formula (I)

In one embodiment, the compounds of the present invention are compounds of formula (I) or stereoisomers, tautomers, solvates, prodrugs, isotopic labels, pharmaceutically acceptable salts thereof, wherein ring A is selected from

X ₃、X₄、X₅ is each independently CR ₅R₅'、S、O、SO、SO₂ or NR ₆, wherein R ₅、R₅' and R ₆ are each independently selected from H, halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy;

n is an integer selected from 0,1, 2, 3, 4.

In one embodiment, the compounds of the invention are compounds of formula (I) or stereoisomers, tautomers, solvates, prodrugs, isotopic labels, pharmaceutically acceptable salts thereof, wherein ring a is selected from the group consisting of cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, aziridine ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, azepane ring, aziridine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, oxetane ring, thietane ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, thietane ring, tetrahydroimidazole ring, tetrahydropyrazole ring, tetrahydrooxazole ring, tetrahydrothiazole ring, tetrahydroisothiazol ring, piperazine ring, morpholine ring, dioxane ring, thiaoxane ring, dithiane ring, optionally substituted with one or more groups selected from the group consisting of: halogen, oxo, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.

In one embodiment, the compounds of the present invention are compounds of formula (I) or stereoisomers, tautomers, solvates, prodrugs, isotopic labels, pharmaceutically acceptable salts thereof, wherein ring A is selected from Optionally substituted with one or more groups selected from: halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.

In one embodiment, the compounds of the present invention are compounds of formula (I) or stereoisomers, tautomers, solvates, prodrugs, isotopic labels, pharmaceutically acceptable salts thereof, wherein R ₁ is selected from:

R ₇ is halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, m is an integer selected from 0, 1, 2, 3, 4, and X ₁、X₂、R₃、R₃'、R₄ is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (II),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein m, n, X ₁、X₃、X₄、X₅、R₂ and R ₇ are as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (III),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein m, n, X ₂、X₃、X₄、X₅、R₂ and R ₇ are as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (IV),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein m, n, X ₃、X₄、X₅、R₂ and R ₇ are as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (II '), (III ') or (IV '),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein n, X ₃、X₄、X₅ and R ₂ are as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (V),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₆ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₁、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (VI) or (VI'),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₇ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₁、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (VII), (VII ') or (VII'),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₈ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₁、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (VIII),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₆ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₂、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (IX) or (IX'),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₇ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₂、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (X), (X ') or (X'),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₈ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₂、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XI),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₆ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XII) or (XII'),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₇ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XIII), (XIII') or (XIII "),

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₈ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (I) or stereoisomers, tautomers, solvates, prodrugs, isotopic labels, pharmaceutically acceptable salts thereof, wherein R ₂ is selected from:

a)H；

b)-C(＝O)-P^R0；

c)-C(＝O)-P^R1；

h)-C(＝O)-O-P^R2；

i)-C(＝O)-N(-K)(P^R2)；

j)-C(＝O)-O-L-O-P^R2；

k)-C(＝O)-O-L-N(-K)(P^R2)；

n)-C(P^R3)₂-O-C(＝O)-P^R4；

o)-C(P^R3)₂-O-C(＝O)-O-P^R4；

q)-C(P^R3)₂-O-C(＝O)-O-L-O-P^R4；

v)-C(P^R3)₂-O-C(＝O)-O-L-N(-K)-C(＝O)-P^R4；

x)-(C(P^R3)₂)_p-P^R6；

z)-(C(P^R3)₂)_q-C(＝O)-O-P^R2；

aa)-(C(P^R3)₂)_q-C(＝O)-N(-K)-P^R4；

bb)-(C(P^R3)₂)_q-C(＝O)-P^R1；

cc)-C(P^R3)₂-N(-K)-C(＝O)-O-P^R2；

dd)-P(＝O)(-P^R8)(-P^R9)；

ee)-S(＝O)₂-P^R10；

ff)-P^R11；

gg) - (C (P ^R3)₂)_r-O-P^R12; see below)

hh)-(C(P^R3)₂)_t-N(-K)-P^R13；

Wherein L is a linear or branched C ₁-C₂₀ alkylene group optionally substituted with any one of substituent groups B,

P ^R0 is C ₁-C₂₀ alkyl optionally substituted by any of the substituents A,

P ^R1 is C ₃-C₈ carbocyclyl or heterocyclyl optionally substituted with any one of substituent groups a,

P ^R2 is alkyl optionally substituted by any of substituent groups A, C ₃-C₈ carbocyclyl, heterocyclyl,

P ^R3 is each independently a hydrogen atom, C ₁-C₂₀ alkyl or hydroxy, or

2P ^R3 on adjacent carbon atoms optionally together form a C ₁-C₂₀ alkenylene group or a C ₁-C₂₀ alkylene group,

P ^R4 is C ₁-C₂₀ alkyl optionally substituted by any of substituent groups A, C ₃-C₈ carbocyclyl, or heterocyclyl,

P ^R9 is C ₁-C₂₀ alkoxy optionally substituted with any of substituent groups a, C ₁-C₂₀ alkylamino, C ₃-C₈ carbocyclyloxy, heterocyclyloxy, C ₃-C₈ carbocyclylamino, or heterocyclylamino, or

P ^R10 is C ₁-C₂₀ alkyl optionally substituted by any of the substituents A or C ₃-C₈ carbocyclyl,

P ^R11 is C ₁-C₂₀ alkyl optionally substituted by any of substituent groups A, C ₁-C₂₀ alkenyl, C ₁-C₂₀ alkynyl, C ₃-C₈ carbocyclyl, or heterocyclyl,

P is an integer of 2 to 3,

Q is an integer of 1 to 2,

R is an integer of 2 to 4,

T is an integer of 2 to 4,

The substituent group B includes: c ₃-C₈ spiro and halogen.

In one embodiment, the compounds of the present invention are compounds of formula (XIV)

Or a tautomer, solvate, prodrug, isotopic label, or pharmaceutically acceptable salt thereof, wherein

r ₁ is selected from:

Wherein X ₁ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂;

X ₂ is selected from CH, N;

R ₂ is selected from:

a)H；

b)-C(＝O)-P^R0；

c)-C(＝O)-P^R1；

d)-C(＝O)-L-P^R1；

e)-C(＝O)-L-O-P^R1；

f)-C(＝O)-L-O-L-O-P^R1；

g)-C(＝O)-L-O-C(＝O)-P^R1；

h)-C(＝O)-O-P^R2；

i)-C(＝O)-N(-K)(P^R2)；

j)-C(＝O)-O-L-O-P^R2；

k)-C(＝O)-O-L-N(-K)(P^R2)；

l)-C(P^R3)₂-O-P^R4；

m)-C(P^R3)₂-O-L-O-P^R4；

n)-C(P^R3)₂-O-C(＝O)-P^R4；

o)-C(P^R3)₂-O-C(＝O)-O-P^R4；

p)-C(P^R3)₂-O-C(＝O)-N(-K)-P^R4；

q)-C(P^R3)₂-O-C(＝O)-O-L-O-P^R4；

r)-C(P^R3)₂-O-C(＝O)-O-L-N(P^R4)₂；

s)-C(P^R3)₂-O-C(＝O)-N(-K)-L-O-P^R4；

t)-C(P^R3)₂-O-C(＝O)-N(-K)-L-N(P^R4)₂；

u)-C(P^R3)₂-O-C(＝O)-O-L-O-L-O-P^R4；

v)-C(P^R3)₂-O-C(＝O)-O-L-N(-K)-C(＝O)-P^R4；

w)-C(P^R3)₂-O-P(＝O)(-P^R5)₂；

x)-(C(P^R3)₂)_p-P^R6；

y)-C(＝N⁺(P^R7)₂)(-N(P^R7)₂)；

z)-(C(P^R3)₂)_q-C(＝O)-O-P^R2；

aa)-(C(P^R3)₂)_q-C(＝O)-N(-K)-P^R4；

bb)-(C(P^R3)₂)_q-C(＝O)-P^R1；

cc)-C(P^R3)₂-N(-K)-C(＝O)-O-P^R2；

dd)-P(＝O)(-P^R8)(-P^R9)；

ee)-S(＝O)₂-P^R10；

ff)-P^R11；

gg) - (C (P ^R3)₂)_r-O-P^R12; or

hh)-(C(P^R3)₂)_t-N(-K)-P^R13；

P ^R5 are each independently hydroxy or benzyloxy;

P is an integer of 2 to 3,

Q is an integer of 1 to 2,

R is an integer of 2 to 4,

T is an integer of 2 to 4,

The substituent group B includes: c ₃-C₈ spiro and halogen.

In one embodiment, the compounds of the present invention are compounds of formula (XIV) or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein ring A is selected from

n is an integer selected from 0,1, 2, 3, 4.

In one embodiment, the compounds of the invention are compounds of formula (XIV) or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of cyclopropane ring, cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, cyclooctane ring, aziridine ring, azetidine ring, tetrahydropyrrole ring, piperidine ring, azepane ring, aziridine ring, oxetane ring, tetrahydrofuran ring, tetrahydropyran ring, oxetane ring, oxaoctane ring, thietane ring, tetrahydrothiophene ring, tetrahydrothiopyran ring, thietane ring, tetrahydroimidazole ring, tetrahydropyrazole ring, tetrahydrooxazole ring, tetrahydrothiazole ring, tetrahydroisothiazol ring, piperazine ring, morpholine ring, dioxane ring, thiaoxane ring, dithiane ring, optionally substituted with one or more groups selected from the following: halogen, oxo, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.

In one embodiment, the compounds of the present invention are compounds of formula (XIV) or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein ring A is selected from Optionally substituted with one or more groups selected from: halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.

In one embodiment, the compounds of the invention are compounds of formula (XIV) or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein R ₁ is selected from:

in one embodiment, the compounds of the present invention are compounds of formula (XV),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein m, n, X ₁、X₃、X₄、X₅、R₂ and R ₇ are as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XVI),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein m, n, X ₂、X₃、X₄、X₅、R₂ and R ₇ are as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XVII),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein m, n, X ₃、X₄、X₅、R₂ and R ₇ are as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XV '), (XVI ') or (XVII '),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein n, X ₃、X₄、X₅ and R ₂ are as defined herein.

In one embodiment, the compound of the present invention is a compound of formula (XVIII),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₆ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₁、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XIX) or formula (XIX'),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₇ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₁、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XX), (XX') or (XX "),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₈ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₁、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XXI),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₆ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₂、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XXII) or (XXII'),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₇ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₂、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XXIII), (XXIII ') or (XXIII'),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₈ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₂、R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XXIV),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₆ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XXV) or formula (XXV'),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₇ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the present invention are compounds of formula (XXVI), (XXVI ') or (XXVI'),

Or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein X ₈ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,R₂、R₇ and m is as defined herein.

In one embodiment, the compounds of the invention are compounds of formula (XIV) or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, wherein R ₂ is selected from:

a)H；

b)-C(＝O)-P^R0；

c)-C(＝O)-P^R1；

h)-C(＝O)-O-P^R2；

i)-C(＝O)-N(-K)(P^R2)；

j)-C(＝O)-O-L-O-P^R2；

k)-C(＝O)-O-L-N(-K)(P^R2)；

n)-C(P^R3)₂-O-C(＝O)-P^R4；

o)-C(P^R3)₂-O-C(＝O)-O-P^R4；

q)-C(P^R3)₂-O-C(＝O)-O-L-O-P^R4；

v)-C(P^R3)₂-O-C(＝O)-O-L-N(-K)-C(＝O)-P^R4；

x)-(C(P^R3)₂)_p-P^R6；

z)-(C(P^R3)₂)_q-C(＝O)-O-P^R2；

aa)-(C(P^R3)₂)_q-C(＝O)-N(-K)-P^R4；

bb)-(C(P^R3)₂)_q-C(＝O)-P^R1；

cc)-C(P^R3)₂-N(-K)-C(＝O)-O-P^R2；

dd)-P(＝O)(-P^R8)(-P^R9)；

ee)-S(＝O)₂-P^R10；

ff)-P^R11；

gg) - (C (P ^R3)₂)_r-O-P^R12; see below)

hh)-(C(P^R3)₂)_t-N(-K)-P^R13；

P ^R3 is each independently a hydrogen atom, C ₁-C₂₀ alkyl or hydroxy, or

P is an integer of 2 to 3,

Q is an integer of 1 to 2,

R is an integer of 2 to 4,

T is an integer of 2 to 4,

The substituent group B includes: c ₃-C₈ spiro and halogen.

In one embodiment, the compounds of the present invention include, but are not limited to, the following:

Or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof.

Pharmaceutical composition and administration

The invention provides pharmaceutical compositions comprising a compound of the invention, or a stereoisomer, tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are known to those skilled in the art and include diluents, lubricants, disintegrants, binders, buffers, preservatives, stabilizers, wetting agents, glidants, emulsifiers, coloring agents, flavoring agents, sweeteners, and the like. Depending on the route of administration of the drug, such as oral, parenteral, rectal, etc., the pharmaceutical compositions of the present invention may be formulated in solid form (including but not limited to tablets, capsules, pills, granules, powders, dusts, suppositories) or in liquid form (including but not limited to solutions, suspensions, emulsions, tinctures, syrups). When the pharmaceutical composition of the present invention is in solid form, the pharmaceutically acceptable carrier typically comprises one or more of the following: a) Diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and the like; b) Lubricants, such as silica, talc, stearic acid, polyethylene glycol, and the like; c) Binders such as magnesium aluminosilicate, gelatinized starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, microcrystalline cellulose, polyvinylpyrrolidone, and the like; d) Disintegrants, for example starch, alginic acid, agar, corn starch; e) Stabilizers, for example antioxidants such as ascorbic acid; f) Glidants, such as silicon dioxide; g) Flavoring agents, such as peppermint, methyl salicylate; sweeteners, such as sucrose, saccharin. When the pharmaceutical composition of the present invention is in liquid form, the pharmaceutically acceptable carrier typically comprises one or more of the following: a) Diluents such as water for injection, physiological saline, ringer's solution, polyethylene glycol, glycerin, propylene glycol, etc.; b) Antioxidants, such as ascorbic acid or sodium bisulfite; c) Buffers such as acetates, phosphates, and the like.

The effective dosage of the compounds of the present invention will depend at least on the nature, extent, method of delivery and pharmaceutical dosage form of the condition being treated and will be ultimately determined by the clinician. About 0.0001 to about 100mg per kg body weight per day is contemplated; typically about 0.01 to about 10mg per kg of body weight per day; more typically, about 0.01 to about 5mg per kilogram of body weight per day; most typically about 0.05 to about 0.5mg per kg of body weight per day. For example, a daily candidate dose for an adult human of about 70kg body weight will be in the range of 1mg to 1000mg, preferably 5mg to 500mg, and may be administered in single or multiple doses.

Indication of disease

The compounds of the present invention have inhibitory activity against viral RNA polymerase, particularly cap-dependent endonucleases, and are useful for the prevention and/or treatment of diseases caused by viruses having cap-dependent endonucleases, including influenza virus infection diseases, such as influenza a virus infection, influenza b virus infection, influenza c virus infection, influenza delta virus infection, avian influenza virus infection, swine influenza virus infection, and the like.

The compound and/or the pharmaceutical composition of the invention can be used for preventing, alleviating, relieving and/or curing symptoms and/or diseases caused by various influenza viruses, such as common cold symptoms including fever, chill, headache, myalgia and the like, respiratory inflammation symptoms including pharyngalgia, runny nose, nasal obstruction, cough and the like, gastrointestinal tract symptoms including abdominal pain, vomiting, diarrhea and the like.

Combination drug

The compounds of the invention may be administered simultaneously or sequentially in combination with one or more additional agents. The compounds of the invention and the additional agent may be administered separately by the same or different routes of administration, or simultaneously in one pharmaceutical composition as a combined agent. Additional agents suitable for use in the present invention may be various antiviral agents having inhibitory activity against influenza virus including, but not limited to, neuraminidase inhibitors (e.g., oseltamivir, peramivir, zanami Weila nimavir), M2 protein inhibitors (e.g., amantadine, rimantadine), RNA polymerase inhibitors (e.g., fapira Weili bavirin), PB1/PB2 inhibitors (e.g., VX-787), and antiviral vaccines, among others.

General synthetic method

The compounds of the present invention may be prepared using the methods disclosed herein and modifications thereof, as well as methods well known in the art. Typical embodiments of compounds according to the present invention can be synthesized using the following general reaction scheme. It is apparent from the description herein that a correspondingly different product can be obtained by using other materials having similar structures instead of the reaction raw materials. The reaction starting materials are typically obtained from commercial sources or synthesized using published methods.

Reaction scheme I

Step 1 intermediate 1 is reacted with intermediate 2 in the presence of a catalyst, such as a lewis acid including, but not limited to, tin tetrachloride, in a suitable organic solvent such as acetonitrile, tetrahydrofuran, and the like to afford intermediate 3; wherein PG represents an amino protecting group, particularly one which is readily removable under alkaline conditions, including, but not limited to, allyloxycarbonyl, benzyloxycarbonyl, fluorenylmethoxycarbonyl, and the like.

Step 2 intermediate 3 undergoes a ring closure reaction in the presence of a catalyst, particularly a metal catalyst such as palladium catalyst, including tetrakis triphenylphosphine palladium and the like, under basic conditions to afford intermediate 4;

Step 3, intermediate 4 is subjected to substitution reaction with R ₁ X under alkaline conditions (such as carbonate, bicarbonate and the like of alkali metal, alkaline earth metal and the like) to obtain intermediate 5; wherein R ₁ is as defined herein, X represents halogen chlorine, bromine, iodine;

Step 4, intermediate 5 is subjected to chiral resolution and then reacts in the presence of LiCl to remove benzyl protecting groups to obtain a compound of a formula (I) (R ₂ is H);

Step 5 substitution reaction of a compound of formula (I) (R ₂ is H) with R ₂ X under basic conditions (e.g. inorganic or organic base) in a suitable organic solvent to give a compound of formula (XIV) wherein R ₂ is a group other than H as defined herein.

Reaction scheme II

Step 1, the raw material and ethyl acetate are subjected to addition reaction under alkaline conditions (such as lithium diisopropylamide, butyl lithium, sodium hydrogen, sodium tert-butoxide and the like) to obtain an intermediate 1-a;

step 2, reacting the intermediate 1-a with TMSCN in the presence of TMSOTF to generate an intermediate 1-b;

Step 3 intermediate 1-b is hydrogenated in the presence of a catalyst such as palladium on carbon to provide intermediate 1-c;

step 4, the intermediate 1-c undergoes a ring closure reaction under alkaline conditions to obtain an intermediate 1-d;

Step 5, reacting the intermediate 1-d with a protecting group reagent (e.g., allyl chloroformate, benzyl chloroformate, fluorenylmethyl chloroformate) to produce an intermediate 1-e;

Step 6, the intermediate 1-e undergoes a reduction reaction in the presence of a reducing agent to obtain an intermediate 1-f; the reducing agent comprises diisobutylaluminum hydride and the like;

step 7, intermediate 1-f reacts with methanol under acidic conditions to form ether, thus obtaining intermediate 1.

Example 1 4- (7 ',8' -difluoro-6 ',11' -dihydrodibenzo [ b, e ] thiazepinePreparation of (E) -11' -yl) -9-hydroxy-3 a, 4-dihydro-1H, 3H-spiro [ cyclohexane-1, 2-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8, 10-dione

Step 13 preparation of allyl-oxo-2-azaspiro [4.5] decane-2-carboxylate (intermediate 1)

To a 500mL three-necked flask, 2-azaspiro [4.5] decan-3-one (10.0 g,65.3 mmol) and anhydrous tetrahydrofuran (200 mL) were sequentially added and magnetically stirred under nitrogen. N-BuLi (2.5N N-hexane solution, 26mL,65.3 mmol) was added dropwise to the reaction system at-78deg.C. After the dripping, the reaction is kept warm and stirred for 1.5h. A solution of allyl chloroformate (8.03 g,65.3 mmol) in anhydrous tetrahydrofuran (50 mL) was then added dropwise to the reaction system. After the completion of the dropping, the reaction was stirred at-78℃for 1 hour. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting material. The reaction was quenched by adding saturated aqueous ammonium chloride (50 mL) at-78deg.C, a large amount of white solid was precipitated, filtered, the filtrate was separated, and the aqueous phase was extracted with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated brine (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 16.92g of a colorless oil, which was used in the next reaction without purification.

¹H NMR(600MHz,DMSO-d₆ ) Delta (ppm) 5.93-5.86 (m, 1H, alkenylhydrogen), 5.34 (dq, J ₁＝17.2Hz,J₂ = 1.7Hz,1H, alkenylhydrogen), 5.19 (dd, J ₁＝10.6Hz,J₂ = 1.6Hz,1H, alkenylhydrogen ),4.61(dt,J₁＝5.2Hz,J₂＝1.6Hz,2H,OCH₂),3.45(s,2H,NCH₂),2.32(s,2H,OCCH₂),1.43-1.29(m,10H,(CH₂)₅).)

Step 2 3-hydroxy-2-azaspiro [4.5] decane-2-carboxylic acid allyl ester (intermediate 2)

To a 500mL three-necked flask, intermediate 1 (16.92 g,71.3 mmol) and anhydrous tetrahydrofuran (200 mL) were sequentially added, and after the addition, the mixture was magnetically stirred under nitrogen. DIBAL-H (71 mL,71.3 mmol) was added dropwise to the reaction at-78deg.C. After the dripping, the reaction is kept warm and stirred for 1h. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 4:1) monitored complete reaction of starting material. Acetone (50 mL) and an aqueous potassium sodium tartrate solution (prepared by dissolving 100g of potassium sodium tartrate in 120mL of water) were added to the reaction system at-78℃and stirred for 10min. The mixture was separated, and 1M aqueous HCl was added dropwise to the aqueous phase to adjust the pH to 7, followed by extraction with ethyl acetate (100 mL. Times.3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 15.36g of a colorless oil, which was used in the next reaction without purification.

¹H NMR(600MHz,DMSO-d₆ ) Delta (ppm) 5.95-5.82 (m, 1H, olefine hydrogen), 5.37-5.19 (m, 2H, olefine hydrogen, CHOH), 5.19-5.09 (m, 1H, olefine hydrogen ),4.55-4.41(m,2H,OCH₂),3.22-3.01(m,2H,NCH₂),1.55-1.46(m,2H,CH₂),1.43-1.18(m,10H,(CH₂)₅).)

Step 3 3-methoxy-2-azaspiro [4.5] decane-2-carboxylic acid allyl ester (intermediate 3)

To a 250mL three-necked flask, intermediate 2 (15.36 g,64.2 mmol), p-toluenesulfonic acid monohydrate (1.22 g,6.42 mmol) and methanol (150 mL) were sequentially added, and the mixture was reacted at room temperature under nitrogen protection for 2 hours. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting material. The reaction was quenched by addition of saturated aqueous sodium bicarbonate (50 mL), the mixture was concentrated, the remaining solution was extracted with ethyl acetate (100 ml×3), the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by flash chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} =10:1) to give 6.23g of a colorless oil in 38% yield.

¹H NMR(600MHz,DMSO-d₆ ) Delta (ppm): 5.93-5.84 (m, 1H, alkenylhydrogen), 5.25 (t, J=16.7 Hz,1H, OCH), 5.17-5.13 (m, 1H, alkenylhydrogen), 5.06-5.01 (m, 1H, alkenylhydrogen ),4.56-4.45(m,2H,OCH₂),3.22-3.08(m,5H,NCH₂,OCH₃),1.83-1.66(m,2H,CH₂),1.55-1.44(m,2H,CH₂),1.43-1.22(m,8H,(CH₂)₄). step 4 3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxo-1, 4-dihydropyridin-1-yl) amino) -2-azaspiro [4.5] decane-2-carboxylic acid allyl ester (intermediate 4)

To a 100mL three-necked flask, 3 (2.53 g,10.0 mmol) intermediate, ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (2.40 g,8.3 mmol) and acetonitrile (30 mL) were added in this order, and the mixture was stirred at room temperature under nitrogen protection after complete dissolution, cooled to-20℃and tin tetrachloride (3.47 g,13.3 mmol) was added dropwise, and the mixture was reacted at room temperature for 1h under heat preservation. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material. To the reaction system was added dropwise saturated aqueous sodium hydrogencarbonate solution (30 mL) at-20℃to quench the reaction, methylene chloride (50 mL) was added, and after stirring at room temperature for 10min, the mixture was filtered through celite, and the cake was washed with methylene chloride (50 mL). The filtrate was separated, the organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) to give 2.17g of a reddish brown oil in 43% yield.

Step 59 '- (benzyloxy) -3a',4 '-dihydro-1' H,3 'H-spiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (intermediate 5)

To a 100mL three-necked flask were successively added intermediate 4 (2.17 g,4.26 mmol), anhydrous tetrahydrofuran (30 mL), morpholine (3.71 g,42.6 mmol) and tetrakis triphenylphosphine palladium (0.50 g,0.43 mmol). After the addition, stirring for 1h at room temperature under the protection of nitrogen, and a large amount of solid is precipitated. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material. Isopropyl ether (50 mL) was added to the reaction system, stirred for 30min, filtered, the filter cake was washed with isopropyl ether (50 mL), and the filter cake was purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) to give 1.05g of a white solid in 65% yield.

¹ H NMR (600 MHz, chloroform -d)δ(ppm):7.51-7.46(m,2H,ArH),7.36(d,J＝7.6Hz,1H,ArH),7.30-7.26(m,2H,ArH),7.24-7.22(m,1H,ArH),6.28(d,J＝7.7Hz,1H,ArH),5.85(d,J＝13.1Hz,1H,NH),5.24(d,J＝10.4Hz,1H,OCH₂),5.18(d,J＝10.5Hz,1H,OCH₂),4.69-4.62(m,1H,NCH),3.35(d,J＝11.9Hz,1H,NCH₂),3.11(d,J＝12.0Hz,1H,NCH₂),2.08-2.01(m,1H,CH₂),1.54-1.42(m,7H,CH₂),1.40-1.29(m,4H,CH₂))

Step 69 '- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -3a ',4' -dihydro-1 ' H,3' H-spiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (intermediate 6)

To a 100mL single vial was added sequentially intermediate 5 (0.83 g,2.19 mmol), 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine(1.24 G,4.38 mmol), cesium carbonate (2.14 g,6.57 mmol) and acetonitrile (20 mL), after the addition, under nitrogen, at 50deg.C overnight. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material. The reaction was quenched by addition of water (30 mL), the mixture was extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) to give 502mg of a yellow solid in 37% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.55(d,J＝7.8Hz,0.5H,ArH),7.52-7.49(m,2H,ArH),7.78-7.44(m,0.5H,ArH),7.35-7.30(m,3H,ArH),7.30-7.23(m,2.5H,ArH),7.22-7.18(m,0.5H,ArH),7.17-7.15(m,1H,ArH),7.15-7.11(m,0.5H,ArH),7.07-7.03(m,0.5H,ArH),7.01-6.98(m,0.5H,ArH),6.85-6.81(m,1H,ArH),6.81-6.77(m,0.5H,ArH),5.74-5.69(m,1H,NCH),5.68-5.63(m,0.5H,OCH₂),5.46-5.51(m,0.5H,OCH₂),5.44(dd,J₁＝10.3Hz,J₂＝6.9Hz,0.5H,OCH₂),5.35-5.32(m,0.5H,OCH₂),5.15(d,J＝2.2Hz,1H,SCH₂),5.07-5.01(m,1H,NH),4.09(dd,J₁＝14.2Hz,J₂＝11.2Hz,1H,SCH₂),3.66(d,J＝11.8Hz,0.5H,NCH₂),3.50(d,J＝11.8Hz,0.5H,NCH₂),3.37(d,J＝11.7Hz,0.5H,NCH₂),2.98(d,J＝11.8Hz,0.5H,NCH₂),1.86-1.77(m,1H,CH₂),1.40-1.26(m,5H,CH₂),1.25-1.16(m,5H,CH₂),0.88-0.74(m,1H,CH₂).

Step 7 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -9 '-hydroxy-3 a',4 '-dihydro-1' H,3 'H-spiro [ cyclohexane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (example 1)

To a 50mL single vial was added sequentially intermediate 6 (502 mg,0.80 mmol), lithium chloride (399 mg,8.00 mmol), and anhydrous DMA (10 mL). After the addition, the reaction was carried out at 80℃overnight under nitrogen protection. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material. The reaction was quenched by adding water (20 mL), the mixture was extracted with ethyl acetate (50 ml×3), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrate was purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =15:1) to give a crude product, which was slurried with diethyl ether (10 mL) and chloroform (1 mL) for 2 hours. Filtration and washing of the filter cake with diethyl ether (5 mL) followed by vacuum drying gave 194mg of a yellow solid in 70% yield.

¹H NMR(600MHz,DMSO-d₆):δ(ppm):7.73(d,J＝7.6Hz,1H,ArH),7.52(d,J＝7.4Hz,2H,ArH),7.35(t,J＝7.4Hz,2H,ArH),7.30(t,J＝7.2Hz,1H,ArH),7.18(d,J＝12.6Hz,1H,ArH),6.20(d,J＝7.6Hz,1H,ArH),5.19(d,J＝10.4Hz,1H,SCH₂),5.02(d,J＝10.4Hz,1H,SCH₂),4.99-4.93(m,1H,NCH),3.43(d,J＝11.8Hz,1H,NCH₂),3.22(d,J＝11.8Hz,1H,NCH₂),2.23-2.16(m,1H,NCH),1.53-1.35(m,12H,CH₂).HRMS(ESI):m/z[M+H]⁺C₂₉H₂₇F₂N₃O₃S Theoretical value 536.1819; actual measurement value 536.1837.

Example 2 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepinePreparation of (E) -11-yl) -9 '-hydroxy-2, 3a',4',5, 6-hexahydro-1' H,3 'H-azaspiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione

Step 13 Synthesis of allyl-8-oxa-2-azaspiro [4.5] decane-2-carboxylate (intermediate 2)

To a 250mL single-necked flask, 1 (9.00 g,58 mmol) and tetrahydrofuran (200 mL) were sequentially added, and the mixture was allowed to react under nitrogen at-78deg.C by dropwise addition of n-BuLi (23.2 mL,58mmol,2.5N in n-hexane) and then allowed to react for 2h. A solution of Alloc-Cl (7.00 g,58 mmol) in tetrahydrofuran (40 mL) was then added dropwise and the reaction was continued for 2h at constant temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched by addition of saturated aqueous ammonium chloride (200 mL) at low temperature, extracted with ethyl acetate (200 mL x 3), combined with organic phases washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give 12.75g of yellow oil in 91.9% yield.

Step 23 Synthesis of allyl hydroxy-8-oxa-2-azaspiro [4.5] decane-2-carboxylate (intermediate 3)

To a 250mL single-necked flask, 2 (12.75 g,53.3 mmol) and tetrahydrofuran (200 mL) were sequentially added, the temperature was lowered to-78℃under nitrogen protection, DIBAL-H (69.3 mL,69.3mmol,1N n-hexane solution) was added dropwise, and the reaction was continued for 2 hours. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:1) monitored complete reaction of the starting materials, quenched by addition of 50wt% potassium sodium tartrate solution (200 mL) at low temperature, stirred at room temperature for 20min, gummy, addition of 1N diluted hydrochloric acid (50 mL), extraction with ethyl acetate (200 mL x 3), combined organic phases, washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 2:1) to give 7.80g of yellow oil in 60.2% yield.

Step 33 Synthesis of allyl-8-oxa-2-azaspiro [4.5] decane-2-carboxylate (intermediate 4)

To a 250mL single-necked flask, 3 (7.80 g,32.3 mmol), methanol (50 mL), and p-toluenesulfonic acid monohydrate (616 mg,3.2 mmol) were sequentially added, and the mixture was reacted overnight at room temperature under nitrogen. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 2:1) monitored complete reaction of starting materials, addition of saturated aqueous sodium bicarbonate (50 mL), concentration to remove methanol, extraction with ethyl acetate (70 mL x 3), combined organic phases, washing with saturated brine (100 mL), drying over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 3:1) gave 5.34g of colorless oil in 64.7% yield.

Step 43 Synthesis of allyl 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8-oxa-2-azaspiro [4.5] decane-2-carboxylate (intermediate 5)

To a 250mL single-necked flask, 4 (5.34 g,20.9 mmol), ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (5.13 g,17.7 mmol) and acetonitrile (100 mL) were added sequentially, the temperature was lowered to-25℃under nitrogen protection, snCl ₄ (8.71 g,33.4 mmol) was added dropwise, and the reaction was continued for 1.5h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched with saturated aqueous sodium bicarbonate (200 mL) at low temperature, extracted with dichloromethane (100 mL x 3), combined organic phases washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 6.67g of yellow oil in 62.3% yield.

Step 59 '- (benzyloxy) -2, 3a',4',5, 6-hexahydro-1' H,3 'H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (intermediate 6)

To a 250mL single-port flask, 5 (3.00 g,5.9 mmol) and morpholine (30 mL) were added sequentially, and the mixture was dissolved with stirring, pd (PPh ₃)₄ (678 mg,0.59 mmol), nitrogen-protected, room temperature reaction for 1h.TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) was monitored to complete the reaction, isopropyl ether (250 mL) was added, slurried for 30min, filtered, and the filter cake purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =15:1) to give 1.90g of yellow solid in 85.0% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.74(d,J＝7.8Hz,1H,ArH),7.54-7.51(m,2H,ArH),7.36-7.33(m,2H,ArH),7.31-7.28(m,1H,ArH),7.18(d,J＝12.6Hz,1H,ArH),6.21(d,J＝7.8Hz,1H,NH),5.19(d,J＝10.2Hz,1H,CH),5.03-4.98(m,2H,CH₂),3.67-3.49(m,6H,CH₂),2.33-2.30(m,1H,CH₂),1.59-1.57(m,2H,CH₂),1.53-1.49(m,3H,CH₂).

Step 69 '- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-azaspiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (intermediate 7)

To a 100mL single vial was added sequentially intermediate 6 (0.80 g,2.1 mmol), 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine(1.50 G,5.3 mmol), acetonitrile (100 mL) and cesium carbonate (2.73 g,8.4 mmol), nitrogen-protected, and reacted overnight at room temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched with water (100 mL), extracted with dichloromethane (50 mL x 6), combined with organic phases, washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 100:1) to give 510mg of a yellow solid in 38.7% yield.

Step 7 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -9 '-hydroxy-2, 3a',4',5, 6-hexahydro-1' H,3 'H-azaspiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione

To a 25mL single vial was added sequentially intermediate 7 (430 mg,0.69 mmol), DMA (5 mL), and LiCl (290 mg,6.9 mmol), nitrogen blanketed, and reacted overnight at 80 ℃. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, cooled to room temperature, added 0.5N diluted hydrochloric acid dropwise, pH adjusted to 3, diluted with water (25 mL), extracted with ethyl acetate (25 mL x 3), combined organic phases, washed with brine (40 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash preparative chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 120mg of brown solid in 48.4% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.55-7.46(m,1H,ArH),7.46-7.08(m,5H,ArH),7.10-6.79(m,2H,ArH),5.74-5.59(m,2H,CH),5.58-5.44(m,1H,CH₂),4.16-4.11(m,1H,CH₂),3.90-3.81(m,1H,CH₂),3.65-3.43(m,4H,CH₂),2.19-1.95(m,1H,CH₂),1.38-1.28(m,3H,CH₂),1.26-1.19(m,3H,CH₂).¹³C NMR(150MHz,DMSO-d₆)δ(ppm):171.11,160.53,151.53,147.96,146.33,137.95,135.86,133.00,130.85,129.83,129.22,128.68,125.26,123.88,117.13,116.15,110.15,76.58,69.90,64.78,64.01,38.40,37.84,35.91,34.13,31.63,30.33,29.50,23.30,15.65.

HRMS (ESI) M/z [ M+H ] ⁺C₂₈H₂₅F₂N₃O₄ S theory 538.1612; actual measurement value: 538.1631.HPLC:99.94%.

Example 3 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine-11-Yl) -9 '-hydroxy-8', 10 '-dioxo-3 a',4',8',10 '-tetrahydro-1' H,3 'H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -1-carboxylic acid benzyl ester

Referring to the synthetic procedure of example 2, substituting 3-oxo-8-oxa-2-azaspiro [4.5] decane with 3-oxo-2, 8-diazaspiro [4.5] decane benzyl ester, the above intermediate compound was prepared to finally give 140mg of the compound of example 3 as a brown solid in a yield of 81.8%.

¹H NMR(600MHz,CD₃OD)δ(ppm):7.74-7.43(m,0.2H,ArH),7.42-7.19(m,9H,ArH),7.11-7.02(m,1.8H,ArH),6.94-6.87(m,1H,CH＝CH),6.80-6.70(m,1H,CH＝CH),5.85-5.71(m,1H,ArCH₂),5.66-5.63(m,1H,ArCH₂),5.54-5.42(m,1H,CH),5.30-5.20(m,0.8H,CHCH₂),5.06-5.05(m,2.2H,CHCH₂,SCH₂),4.13-4.11(m,1H,NCH₂),3.99-3.85(m,1H,NCH₂),3.48-3.39(m,3H,NCH₂CH₂),3.22-3.16(m,1H,NCH₂CH₂),2.07-1.96(m,1H,CHCH₂),1.48(br,3H,NCH₂CH₂,CHCH₂),1.21-1.01(m,2H,NCH₂CH₂).HRMS(ESI):m/z[M+H]+C₃₆H₃₂F₂N₄O₅S Theoretical value 671.2134; actual measurement value 671.2131

Example 49 '-hydroxy-4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -3,3a ', 4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-2, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione

Step 12 Synthesis of Ethyl- (2-hydroxytetrahydro-2H-pyran-2-yl) acetate (2)

To a 500mL three-necked flask, anhydrous ethyl acetate (17.6 g,200 mmol) and tetrahydrofuran (200 mL) were sequentially added, the temperature was reduced to-78℃under nitrogen protection, LDA (105 mL,210mmol,2N n-hexane solution) was added dropwise, and the reaction was continued for 1h. 1 (20 g,200 mmol) was added dropwise thereto, and the reaction was continued for 2 hours at a constant temperature. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 50:1) monitored complete reaction of starting material, quenched by addition of ethanol (50 mL) at low temperature, further added water (10 mL), extracted with ethyl acetate (200 mL x 3), combined organic phases washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 5:1) to give 23g of a pale yellow oil in 62% yield.

Step 2 2- (2-cyanotetrahydro-2H-pyran-2-yl) acetic acid ethyl ester (3)

To a 500mL three-necked flask, compound 2 (23 g,122.34 mmol), acetonitrile (200 mL), TMSCN (60.55 g,611.7 mmol) and TMSOTF (81.47 g,367.02 mmol) were added sequentially, and the mixture was reacted overnight at room temperature under nitrogen. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 3:1) monitored the end of the reaction, the pH of the reaction solution was adjusted to 8 by addition of saturated aqueous sodium bicarbonate, extracted with ethyl acetate (200 mL x 3), the organic phases were combined, washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) to give 11.5g of a colorless transparent oil in 47% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm):4.22(q,J＝7.2Hz,2H,COOCH₂CH₃),3.97-3.93(m,1H,CH₂CH₂),3.88-3.82(m,1H,CH₂CH₃),2.82-2.71(m,2H,COCH₂),2.08-2.03(m,1H,OCH₂CH₂),1.86-1.81(m,2H,CH₂CH₂),1.70-1.64(m,1H,CH₂CH₂),1.62-1.56(m,2H,OCH₂CH₂),1.29(t,J＝7.2Hz,3H,CH₃).

Step 32 Synthesis of Ethyl- (2- (aminomethyl) tetrahydro-2H-pyran-2-yl) acetate (4)

To a 1L single port flask, compound 3 (8 g,40.16 mmol), methanol (1L), concentrated hydrochloric acid (2 mL) and 10% palladium on carbon (800 mg,10% wt) were sequentially added, hydrogenation (15 Psi) was performed at room temperature overnight, TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} =10:1) monitored for completion of the reaction, the reaction solution was filtered, concentrated, and the concentrate was purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1) to give 6.8g of a white solid in 83% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.81(s,2H,NH₂),4.05-4.01(m,2H,CH₂CH₃),3.64-3.56(m,2H,CH₂CH₂),3.05-2.97(m,2H,NH₂CH₂),2.77(d,J＝9.6Hz,1H,COCH₂),2.67(d,J＝10.0Hz,1H,COCH₂),1.60-1.53(m,3H,CH₂),1.48-1.46(m,1H,CH₂CH₂),1.43-1.39(m,2H,CH₂CH₂),1.16(t,J＝4.8Hz,3H,CH₃).

Step 4 6 Synthesis of oxa-2-azaspiro [4.5] decan-3-one (5)

To a 500mL single vial was added compound 4 (8.8 g,43.78 mmol), ethanol (200 mL) and sodium tert-butoxide (4.2 g,43.78 mmol), and the mixture was reacted at 60℃for 1h under nitrogen atmosphere. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, concentrated to dryness and purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 40:1) to give 6.4g of a colorless transparent oil in 94% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm):6.57(s,1H,NH),3.70-3.62(m,2H,CH₂CH₃),3.46(d,J＝6.8Hz,1H,OCH₂),3.30(d,J＝6.8Hz,1H,OCH₂),2.58(d,J＝11.2Hz,1H,COCH₂),2.33(d,J＝11.2Hz,1H,COCH₂),1.68-1.60(m,4H,CH₂CH₂),1.56-1.52(m,2H,CH₂CH₂).

Step 53 Synthesis of allyl-oxo-6-oxa-2-azaspiro [4.5] decane-2-carboxylate (6)

To a 500mL three-necked flask, compound 5 (6.4 g,41.29 mmol) and tetrahydrofuran (100 mL) were added, the temperature was lowered to-78℃under the protection of nitrogen, and n-BuLi (18 mL,45.42mmol,2.5N n-hexane solution) was added dropwise thereto for reaction at a constant temperature for 1h. Then, alloc-Cl (5.47 g,45.42 mmol) was added dropwise thereto, and the reaction was continued for 1 hour with heat preservation. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quench with saturated aqueous ammonium chloride (200 mL) at low temperature, extract with ethyl acetate (150 mL x 3), combine organic phases, wash with saturated brine (200 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate, purify by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) to give 8.4g of a pale yellow oil in 85% yield.

Step 6 3 Synthesis of allyl-hydroxy-6-oxa-2-azaspiro [4.5] decane-2-carboxylate (7)

To a 250mL three-necked flask, compound 6 (8.4 g,35.11 mmol) and tetrahydrofuran (120 mL) were added, the temperature was lowered to-78℃under the protection of nitrogen, DIBAl-H (46 mL,45.6mmol,1N n-hexane solution) was added dropwise, and the reaction was continued for 1.5H. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored completion of the reaction, quenched by addition of saturated potassium sodium tartrate solution (30 mL) at low temperature, extracted with ethyl acetate (300 mL x 3), combined with organic phases washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated to give 6.5g of a brown oil in 77% yield.

Step 73 Synthesis of allyl-6-oxa-2-azaspiro [4.5] decane-2-carboxylate (8)

To a 250mL single-necked flask, compound 7 (6.28 g,26.06 mmol), methanol (100 mL) and p-toluenesulfonic acid monohydrate (284 mg,2.6 mmol) were sequentially added, and the mixture was reacted at room temperature under nitrogen atmosphere for 1h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, addition of saturated sodium bicarbonate solution (100 mL), extraction with ethyl acetate (200 mL x 3), combined organic phases, washing of the organic phase with saturated brine (100 mL), drying over anhydrous sodium sulfate, filtration, concentration, purification by flash chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) afforded 3.31g of a colorless transparent oil in 46% yield.

Step 8 3 Synthesis of allyl 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -6-oxa-2-azaspiro [4.5] decane-2-carboxylate (9)

To a 100mL three-necked flask, compound 8 (2.6 g,10.25 mmol), ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (2.95 g,10.25 mmol) and acetonitrile (60 mL) were added sequentially, the temperature was reduced to-25℃under nitrogen protection, snCl ₄ (4.26 g,16.4 mmol) was added dropwise, and the reaction was continued for 3.5h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored the end of the reaction, quenched by addition of saturated aqueous sodium bicarbonate (40 mL) at low temperature, extracted with ethyl acetate (200 mL x 3), combined with the organic phases, washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 1.84g of a yellow solid in 34% yield.

Step 9 9'- (benzyloxy) -3,3a', 4',5, 6-hexahydro-1' H,3 'H-spiro [ pyran-2, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (10)

To a 50mL single vial was added compound 9 (1.84 g,3.6 mmol) and morpholine (10 mL) in sequence, and the mixture was dissolved with stirring, then Pd (PPh ₃)₄ (418 mg,0.36 mmol), nitrogen, and the reaction at room temperature was monitored for completion of the reaction for 1h.TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1), isopropyl ether (150 mL) was added, the solid was precipitated, filtered, and the filter cake was purified by flash chromatography (40 g, V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) to give 1.1g of a yellow solid in 80% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm):7.56-7.55(m,2H,ArH),7.46(d,J＝4.8Hz,1H,ArH),7.34-7.32(m,2H,ArH),7.31-7.28(m,1H,ArH),6.35(d,J＝5.2Hz,1H,ArH),6.06(d,J＝8.8Hz,1H,NH),5.39(d,J＝6.8Hz,1H,ArCH₂),4.98(d,J＝6.8Hz,1H,BnCH₂),4.84-4.79(m,1H,NCH),3.63-3.55(m,3H,CH₂),3.08(d,J＝8.4Hz,1H,CH₂CH₂),2.26-2.23(m,1H,CH₂)1.72-1.68(m,1H,CH₂),1.65-1.52(m,5H,CH₂),1.46-1.42(m,1H,CH₂).

Step 109 '- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -3,3a ',4', 5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-2, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (11)

Into a 100mL single vial was added compound 10 (1.1 g,2.89 mmol), 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine in sequence(2.3 G,7.21 mmol), acetonitrile (340 mL) and cesium carbonate (3.69 g,11.56 mmol), nitrogen-protected, and reacted overnight at room temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched with water (40 mL), extracted with ethyl acetate (150 mL x 3), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (40 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) to give 350mg of brown solid in 21% yield.

Step 119 '-hydroxy-4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -3,3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-2, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (example 4)

To a 25mL single-necked flask, compound 11 (330 mg,0.53 mmol), DMA (5 mL), and lithium chloride (223 mg,5.3 mmol) were sequentially added, and the mixture was reacted at 80℃under nitrogen atmosphere for 4 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, cooled to room temperature, quenched with water (40 mL), extracted with dichloromethane (30 mL x 3), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 170mg of a yellow solid in 60% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.48-7.44(m,1H,ArH),7.37-7.24(m,2H,ArH),7.18-7.12(m,1.5H,ArH),7.10(d,J＝5.2Hz,0.5H,ArH),7.06-7.04(m,1H,ArH),6.99(d,J＝4.8Hz,0.5H,ArH),6.94-6.92(m,0.5H,ArH),6.87-6.81(m,1H,ArH),5.71-5.67(m,0.6H,CH,SCH₂),5.63-5.60(m,0.6H,CH,SCH₂),5.55-5.52(m,0.8H,CH,SCH₂),5.49-5.47(m,0.5H,CH),5.43-5.41(m,0.5H,CH),4.12-4.07(m,1H,CH₂CH₂),3.93(t,J＝8.8Hz,0.6H,OCH₂),3.57-3.52(m,2.8H,OCH₂),2.30-2.26(m,0.6H,CH₂CH₂),1.47-1.26(m,5.5H,OCH₂),1.24-1.12(m,2H,CH₂CH₂),1.02-0.99(m,1H,CH₂CH₂),0.97-0.91(m,0.5H,CH₂CH₂),0.83-0.79(m,0.5H,CH₂CH₂).

Example 5 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -9 '-hydroxy-3 a',4',5, 6-tetrahydro-1' H,2H,3'H, 4H-spiro [ pyran-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione

Step 1 Synthesis of methyl (E) -2- (dihydro-2H-pyran-3 (4H) -methylene) acetate (2)

To a 1L single-necked flask, compound 1 (20 g,200 mmol), methyl 2- (triphenyl ⁵ -phosphinidene) acetate (73.47 g,220 mmol) and toluene (300 mL) were sequentially added, and the mixture was reacted overnight at 110℃under nitrogen atmosphere. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} =5:1) monitored complete reaction of starting material, dilution with ethyl acetate (300 mL), washing with saturated brine (200 ml×3), drying over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} =5:1) gave 30g of colorless transparent oil in 97% yield.

Synthesis of methyl 2 2- (3- (nitromethyl) tetrahydro-2H-pyran-3-yl) acetate (3)

To a 500mL single vial was added compound 2 (37 g,237.18 mmol), tetrahydrofuran (300 mL), nitromethane (28.95 g,474.36 mmol) and TBAF (1N tetrahydrofuran solution, 356mL,355.77 mmol) in sequence, nitrogen blanket, and reacted overnight at 70 ℃. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 5:1) monitored complete reaction of starting material, dilution with ethyl acetate (600 mL), washing with 1N hydrochloric acid (100 mL x 2), then with saturated brine (200 mL x 3), drying over anhydrous sodium sulfate, filtration, concentration, and purification by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) gave 37g of colorless transparent oil in 73% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm):4.83-4.78(m,2H,CH₂CH₂),3.79-3.74(m,2H,CH₂CH₂),3.69(s,3H,OCH₃),3.60-3.56(m,1H,OCH₂),3.49(d,J＝7.6Hz,1H,CH₂),2.60(d,J＝8.4Hz,1H,CH₂CH₂),2.45(d,J＝8.4Hz,1H,CH₂CH₂),1.81-1.73(m,2H,OCH₂),1.65-1.60(m,2H,CH₂CH₂). Step 37 Synthesis of oxa-2-azaspiro [4.5] decan-3-one (4)

To a 1L jar was added compound 3 (37 g,170.50 mmol), ethanol (500 mL), water (50 mL), ammonium chloride (45.60 g,852.53 mmol) and iron powder (47.74 g,852.53 mmol) in this order, and the mixture was reacted at 80℃for 2 hours under nitrogen. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1) monitored complete reaction of starting material, the reaction was filtered, concentrated and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =40:1) to give 25g of a colorless transparent oil in 95% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.50(s,1H,NH),3.58-3.53(m,1H,CH₂CH₂),3.50-3.46(m,1H,CH₂),3.37(d,J＝7.2Hz,1H,CH₂CH₂),3.28(d,J＝7.2Hz,1H,CH₂CH₂),3.07(d,J＝6.8Hz,1H,CH₂CH₂),2.96(d,J＝6.4Hz,1H,CH₂),1.97(s,2H,CH₂CH₂),1.65-1.57(m,2H,CH₂CH₂),1.52-1.47(m,2H,CH₂).

Step 43 Synthesis of allyl-7-oxa-2-azaspiro [4.5] decane-2-carboxylate (5)

To a 500mL three-necked flask, compound 4 (25 g,161.29 mmol) and tetrahydrofuran (300 mL) were added, the temperature was lowered to-78℃under nitrogen protection, n-BuLi (71 mL,177.42mmol,2.5N in n-hexane) was added dropwise, and the reaction was continued for 2 hours. Then, alloc-Cl (21.38 g,177.42 mmol) was added dropwise thereto, and the reaction was continued for 1 hour with heat preservation. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) monitored complete reaction of starting material, quenched by addition of saturated aqueous ammonium chloride (200 mL) at low temperature, extracted with ethyl acetate (200 mL x 3), combined organic phases washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) to give 25g of yellow oil in 65% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):5.93-5.87(m,1H,CH＝CH₂),5.36-5.33(m,1H,CH＝CH₂),5.21-5.19(m,1H,CH＝CH₂),4.62-4.60(m,2H,OCH₂),3.58(d,J＝6.8Hz,1H,OCH₂CH₂),3.55-3.51(m,1H,CH₂CH₂),3.46-3.37(m,4H,CH₂CH₂),2.36-2.28(m,2H,CH₂),1.64-1.60(m,1H,CH₂),1.58-1.54(m,1H,CH₂CH₂),1.50-1.45(m,2H,CH₂CH₂).

Step 53 Synthesis of allyl-hydroxy-7-oxa-2-azaspiro [4.5] decane-2-carboxylate (6)

To a 500mL single flask were added compound 5 (15 g,62.69 mmol) and tetrahydrofuran (150 mL), nitrogen was purged, cooled to-78deg.C, and DIBAl-H (82 mL,81.49mmol,1N in hexane) was added dropwise thereto, followed by a reaction at a constant temperature for 4 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) monitored complete reaction of starting material, quenched by addition of saturated potassium sodium tartrate solution (100 mL) at low temperature, stirred at room temperature for 20min, extracted with ethyl acetate (200 mL x 3), combined organic phases washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated to give 15.12g of yellow oil which was used directly in the next step without purification.

Step 63 Synthesis of allyl-7-methoxy-7-oxa-2-azaspiro [4.5] decane-2-carboxylate

To a 1L single flask was added compound 6 (15.12 g,62.7 mmol), methanol (200 mL) and p-toluenesulfonic acid monohydrate (1.19 g,6.27 mmol), nitrogen blanket, and reacted at room temperature for 1h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) monitored complete reaction of starting materials, addition of saturated sodium bicarbonate solution (50 mL), extraction with ethyl acetate (200 mL x 3), combined organic phases, washing of the organic phases with saturated brine (100 mL), drying over anhydrous sodium sulfate, filtration, concentration, and purification by flash chromatography (120 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) gave 11g of a colorless transparent oil in 65% yield.

Step 73 Synthesis of allyl 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -7-oxa-2-azaspiro [4.5] decane-2-carboxylate (8)

To a 250mL three-necked flask were added compound 7 (6.46 g,25.32 mmol), ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (7.3 g,25.32 mmol) and acetonitrile (150 mL), and the mixture was cooled to-25℃under nitrogen protection, snCl ₄ (10.55 g,40.51 mmol) was added dropwise, and the reaction was continued for 1.5h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) monitored complete reaction of starting material, quenched by addition of saturated sodium bicarbonate solution (200 mL) at low temperature, extracted with dichloromethane (200 mL. Times.3),

The organic phases were combined, washed with saturated brine (150 ml×2), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography (120 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) to give 6.5g of a yellow solid in 50% yield.

Step 8 9'- (benzyloxy) -3a',4',5, 6-tetrahydro-1' H,2H,3'H, 4H-spiro [ pyran-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (9)

To a 250mL single vial was added compound 8 (6.5 g,12.76 mmol) and morpholine (100 mL) in sequence, and the mixture was dissolved with stirring, pd (PPh ₃)₄ (1.47 g,1.28 mmol), nitrogen, and the reaction at room temperature was monitored for complete reaction for 1h.TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1), isopropyl ether (600 mL) was added, solids were precipitated, filtered, and the filter cake was purified by flash chromatography (80 g, V _{dichloromethane (dichloromethane)}：V_Methanol =30:1) to give 3.7g of a yellow solid in 77% yield.

Step 9 Synthesis of tert-butyl 9' - (benzyloxy) -8',10' -dioxo-3 ',3a ',5,6,8',10' -hexahydro-1 ' H,2H, 4' H-spiro [ pyran-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -4' -carboxylate (10)

To a 250mL single-necked flask, compound 9 (3.7 g,9.71 mmol) and methylene chloride (60 mL) were successively added, and the mixture was dissolved by stirring, and triethylamine (1.96 g,19.42 mmol), DMAP (120 mg,0.97 mmol) and (Boc) ₂ O (4.23 g,19.42 mmol) were further added thereto and reacted at room temperature under nitrogen atmosphere overnight. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, dilution with dichloromethane (100 mL), washing with saturated brine (60 mL x 3), drying over anhydrous sodium sulfate, filtration, concentration, and purification by flash chromatography (80 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) afforded compound 10 (2.00 g, 42.8% yield).

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.85-7.83(m,1H,ArH),7.53-7.51(m,2H,ArH),7.36-7.33(m,2H,ArH),7.31-7.28(m,1H,ArH),6.27-6.24(m,1H,ArH),5.55(t,J＝6.4Hz,1H,ArCH₂),5.16(d,J＝7.2Hz,1H,ArCH₂),5.07(d,J＝7.2Hz,1H,CH),3.67-3.60(m,1H,CH₂),3.53-3.43(m,4H,CH₂CH₂),3.34-3.33(m,1H,CH₂),2.89(dd,J₁＝8.4Hz,J₂＝6.0Hz,1H,OCH₂),2.23(dd,J₁＝8.8Hz,J₂＝5.2Hz,1H,OCH₂),1.71-1.56(m,4H,CH₂CH₂),1.36(s,9H,O(CH₂)₃).

Step 10 Synthesis of 9'- (benzyloxy) -3a',4',5, 6-tetrahydro-1' H,2H,3'H, 4H-spiro [ pyran-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (11)

To a 100mL jar was added compound 10 (2 g,4.16 mmol) and HCl/ethyl acetate (3N, 20 mL) and reacted at 60℃for 2h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, concentrated to dryness, added water (10 mL), saturated sodium bicarbonate to adjust pH to 7, extracted with dichloromethane (60 mL x 5), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography (40 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 1.1g of white solid in 70% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.69(d,J＝7.6Hz,1H,ArH),7.50-7.48(m,2H,ArH),7.33-7.23(m,3H,ArH),7.13(d,J＝12.4Hz,1H,ArH),6.15(d,J＝7.6Hz,1H,ArCH₂),5.13(d,J＝10.8Hz,1H,ArCH₂),5.01-4.91(m,2H,CH,CH₂),3.58-3.45(m,3H,NH,CH₂),3.37-3.25(m,2H,CH₂CH₂),3.18(d,J＝12.0Hz,1H,CH₂CH₂),2.20(dd,J₁＝12.8Hz,J₂＝6.4Hz,1H,OCH₂),1.65-1.58(m,2H,CH₂CH₂),1.51-1.41(m,3H,CH₂CH₂).

Step 11 9'- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -3a ',4',5, 6-tetrahydro-1 ' H,2H,3' H, 4H-spiro [ pyran-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (12)

Into a 100mL single vial was added compound 11 (600 mg,1.57 mmol), 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine in sequence(1.3 G,3.9 mmol), acetonitrile (15 mL) and cesium carbonate (2.05 g,6.28 mmol), nitrogen blanket, and reacted overnight at room temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quenched with water (100 mL), extracted with dichloromethane (50 mL x 6), combined organic phases washed with brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (40 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to yield 439mg of yellow solid in 45% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.56-7.47(m,3H,ArH),7.36-7.22(m,6H,ArH),7.18-7.11(m,2H,ArH),7.08-6.99(m,1H,ArH),6.83-6.77(m,2H,ArH),5.74-5.64(m,1H,ArCH₂),5.52-5.42(m,1H,ArCH₂),5.42-5.35(m,1H,SCH₂),5.19-5.13(m,2H,CH₂CH₂),5.10-5.01(m,1H,SCH₂),4.08(dd,J₁＝14Hz,J₂＝5.2Hz,1H,CH₂),3.78-3.42(m,3H,CH₂),3.13-3.01(m,1H,CH₂),1.93-1.86(m,1H,CH₂),1.44-1.15(m,4H,CH₂CH₂),1.04-0.92(m,1H,CH₂).

Step 12 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -9 '-hydroxy-3 a',4',5, 6-tetrahydro-1' H,2H,3'H, 4H-spiro [ pyran-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (example 5)

To a 25mL single vial was added compound 12 (230 mg,0.37 mmol), DMAc (5 mL) and lithium chloride (156 mg,3.7 mmol) in sequence, nitrogen-blanketed, and reacted at 80℃for 5h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, cooled to room temperature, diluted with ethyl acetate (40 mL), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 90mg of a brownish red solid in 45% yield.

¹H NMR(400MHz,CD₃OD)δ(ppm):7.73-7.37(m,1H,ArH),7.29-6.97(m,3H,ArH),6.85-6.41(m,2H),5.78-5.46(m,2H,ArH),5.42-5.10(m,1H,SCH₂),4.28-4.00(m,2H,SCH₂,CH),3.78-3.53(br,2H,CH₂),3.50-3.32(m,2H,CH₂),3.26-3.16(m,1H,CH₂),2.11-1.93(m,1H,CH₂),1.65-1.35(br,3.5H,CH₂),1.33-1.07(m,4H,CH₂CH₂),0.90-0.81(m,0.5H,CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₂₈H₂₅F₂N₃O₄ S theory 538.1612; found 538.162.HPLC:97.174%.

Example 6 9-hydroxy-4- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of methyl 12- (tetrahydro-4H-thiopyran-4-propylene) acetate (2) as step 12- (tetrahydro-4H-thiopyran-4-ylene) acetate (2) for synthesis of-11-yl) -2',3a,3',4,5',6' -hexahydro-1H, 3H-spiro [ pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-2, 4' - (1 ',1' -dioxothiopyran) ] -8, 10-dione

To a 500mL single-necked flask, compound 1 (11.6 g,100 mmol), methoxyformyl methylene triphenylphosphine (36.78 g,110 mmol) and toluene (200 mL) were sequentially added and reacted overnight at 110℃under nitrogen. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} =10:1) monitored completion of the reaction, concentrated to dryness and purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} =10:1) to give 17g of compound 2 as a colorless transparent oil in 98.9% yield.

Synthesis of methyl 2 2- (4- (nitromethyl) tetrahydro-2H-thiopyran-4 yl) acetate (3)

To a 500mL single vial was added compound 2 (17 g,98.8 mmol), tetrahydrofuran (120 mL), nitromethane (12.05 g,197.6 mmol) and TBAF (1N tetrahydrofuran solution, 148mL,148.25 mmol) in sequence, nitrogen blanket, and reacted overnight at 70 ℃. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 50:1) monitored completion of reaction, diluted with ethyl acetate (400 mL), washed with 1N hydrochloric acid (100 mL x 2), then with saturated brine (200 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) to give 18g of compound 3 as a white solid in 74% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):4.71(s,2H,NO₂CH₂),3.57(s,3H,OCH₃),2.61(t,J＝6.0Hz,4H,CH₂CH₂),2.48-2.46(m,2H,CH₂),1.85-1.71(m,4H,CH₂CH₂).

Step 38 Synthesis of thia-2-azaspiro [4.5] decan-3-one (4)

To a 1L single-necked flask, intermediate 3 (18 g,77.25 mmol), ethanol (200 mL), water (20 mL), ammonium chloride (20.66 g,386.27 mmol) and iron powder (21.63 g,386.27 mmol) were sequentially added, and reacted at 80℃for 2 hours under nitrogen protection. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored completion of the reaction, the reaction was filtered, concentrated, and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 11.35g of intermediate 4 as a white solid in 86% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.45(s,1H,NH),2.95(s,2H,NCH₂),2.55-2.48(m,4H,CH₂CH₂),1.97(s,2H,COCH₂),1.72-1.65(m,4H,CH₂CH₂).

Step 43 Synthesis of allyl-8-thia-2-azaspiro [4.5] decane-2-carboxylate (5)

To a 500mL three-necked flask, intermediate 4 (11.35 g,161.29 mmol) and tetrahydrofuran (150 mL), nitrogen were added, the temperature was lowered to-78℃and n-BuLi (29 mL,72.90mmol,2.5N hexane solution) was added dropwise thereto, followed by thermal insulation for 1 hour. Then, alloc-Cl (8.77 g,72.90 mmol) was added dropwise thereto, and the reaction was continued for 1 hour with heat preservation. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) monitored complete reaction of starting material, quenched by addition of saturated ammonium chloride solution (200 mL) at low temperature, extracted with ethyl acetate (100 mL x 3), combined organic phases, washed with saturated brine (300 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) to give 9.5g of intermediate 5 as a white solid in 56% yield.

Step 53 Synthesis of allyl-8-thia-2-azaspiro [4.5] decane-2-carboxylate (6)

To a 250mL three-necked flask, intermediate 5 (9.5 g,37 mmol) and tetrahydrofuran (100 mL) were added, the temperature was lowered to-78℃under nitrogen protection, DIBAl-H (48 mL,48mmol,1N hexane solution) was added dropwise, and the reaction was continued for 2H. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) monitored that the reaction was no longer changing, quenched by addition of saturated ammonium chloride solution (200 mL) at low temperature, extracted with ethyl acetate (100 mL x 3), the organic phases combined, washed with saturated brine (300 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated to give 10g of colorless transparent oily intermediate 6 which was used directly in the next step without purification.

Step 63 Synthesis of allyl-8-thia-2-azaspiro [4.5] decane-2-carboxylate (7)

To a 500mL single-necked flask, intermediate 6 (10 g,38.86 mmol), methanol (150 mL) and p-toluenesulfonic acid monohydrate (0.71 g,3.9 mmol) were successively added, and the mixture was reacted at room temperature under nitrogen atmosphere for 1h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) monitored complete reaction of starting material, addition of saturated potassium sodium tartrate solution (100 mL), extraction with ethyl acetate (200 mL x 3), washing of the combined organic phases with saturated brine (100 mL), drying over anhydrous sodium sulfate, filtration, concentration, column chromatography purification (V _{dichloromethane (dichloromethane)}：V_Methanol = 40:1) afforded 3.39g of intermediate 7 as a colorless transparent oil in a two-step yield of 32.2%.

Step 73 Synthesis of allyl 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -8-thia-2-azaspiro [4.5] decane-2-carboxylate (8)

To a 100mL three-necked flask, intermediate 7 (3.39 g,12.5 mmol), ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (3.6 g,12.5 mmol) and acetonitrile (40 mL) were added sequentially, the mixture was cooled to-25℃under nitrogen protection, snCl ₄ (5.2 g,20 mmol) was added dropwise, and the reaction was continued for 2h under thermal insulation. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quenched by addition of saturated sodium bicarbonate solution (200 mL) at low temperature, extracted with dichloromethane (100 mL x 3), combined organic phases washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 2.43g of yellow solid intermediate 8 in 37% yield.

Step 8 9- (benzyloxy) -2',3a,3',4,5',6' -hexahydro-1H, 3H-spiro [ pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-2, 4' -thiopyran ] -8, 10-dione (9) Synthesis

To a 100mL single-necked flask, intermediate 8 (2.43 g,4.6 mmol) and morpholine (30 mL) were added sequentially, and the mixture was stirred and dissolved, pd (PPh ₃)₄ (284 mg,0.46 mmol), nitrogen-protected, and reacted at room temperature for 1h.TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) to monitor complete reaction, isopropyl ether (100 mL) was added to precipitate a solid, which was filtered, and the filter cake was dried under vacuum at 40℃for 1h to give 1.8g of yellow solid intermediate 9 in 98% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.74(d,J＝5.2Hz,1H,ArH),7.53-7.52(m,2H,ArH),7.36-7.34(m,2H,ArH),7.31-7.28(m,1H,ArH),7.18(d,J＝8.4Hz,1H,ArH),6.21(d,J＝8.4Hz,1H,NH),5.20(d,J＝6.8Hz,1H,ArCH₂),5.03(d,J＝6.8Hz,1H,ArCH₂),5.00-4.96(m,1H,CH),3.49-3.47(m,1H,CH₂CH₂),3.23(d,J＝8.0Hz,1H,CH₂CH₂),2.66-2.55(m,4H,CH₂CH₂),2.32(dd,J₁＝8.4Hz,J₂＝4.0Hz,1H,CH₂),1.82-1.68(m,4H,CH₂CH₂),1.47-1.43(m,1H,CH₂).

Step 9 9- (benzyloxy) -2',3a,3',4,5',6' -hexahydro-1H, 3H-spiro [ pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-2, 4' - (1 ',1' -dioxothiopyran) ] -8, 10-dione (10) synthesis

To a 100mL single-necked flask, intermediate 9 (1 g,2.5 mmol), t-butanol (10 mL) and water (10 mL) were sequentially added, and the mixture was dissolved by stirring, followed by addition of potassium peroxymonosulfonate (1.86 g,3.02 mmol), nitrogen protection, and reaction at room temperature overnight. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, addition of water (10 mL), extraction with dichloromethane (40 mL x 5), combined organic phases, washing with saturated brine (150 mL x 2), drying over anhydrous sodium sulfate, filtration, concentration, purification by flash chromatography (20 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) afforded 1g of off-white solid intermediate 10 in 93% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.76(d,J＝4.8Hz,1H,ArH),7.53-7.52(m,2H,ArH),7.36-7.34(m,2H,ArH),7.31-7.29(m,1H,ArH),7.18(d,J＝8.4Hz,1H,ArH),6.21(d,J＝4.8Hz,1H,NH),5.20(d,J＝7.2Hz,1H,ArCH₂),5.03-4.98(m,3H,ArCH₂,CH),3.63(d,J＝8.0Hz,1H,CH₂),3.35-3.33(m,1H,CH₂),3.18-3.16(m,2H,CH₂),3.11-3.09(m,2H,CH₂CH₂),2.48-2.47(m,1H,CH₂CH₂),2.09-1.93(m,4H,CH₂CH₂),1.59-1.56(m,1H,CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₂₁H₂₃N₃O₅ S theory 430.1436; actual measurement value 430.1413.

Step 10 9- (benzyloxy) -4- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis/> -11-yl) -2',3a,3',4,5',6' -hexahydro-1H, 3H-spiro [ pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-2, 4' - (1 ',1' -dioxothiopyran) ] -8, 10-dione (11)

To a 100mL single vial was added sequentially intermediate 10 (800 mg,1.86 mmol), 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine(1.6 G,4.66 mmol), acetonitrile (35 mL) and cesium carbonate (2.42 g,7.46 mmol), nitrogen-protected, and reacted overnight at room temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched with water (40 mL), extracted with dichloromethane (50 mL x 6), combined organic phases dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (40 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to yield 420mg of yellow solid intermediate 11 in 34% yield.

Step 11 9-hydroxy-4- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -2',3a,3',4,5',6' -hexahydro-1H, 3H-spiro [ pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-2, 4' - (1 ',1' -dioxothiopyran) ] -8, 10-dione (example 6)

To a 50mL single-necked flask, intermediate 11 (420 mg,0.62 mmol), DMAc (10 mL) and LiCl (262 mg,6.2 mmol) were sequentially added, and the mixture was reacted at 80℃for 5 hours under N ₂ protection. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, cooled to room temperature, quenched with water (40 mL), extracted with dichloromethane (50 mL x 6), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to afford 208mg of example 6 as a yellow solid in 70% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.48-7.44(m,1H,ArH),7.36-7.22(m,2.5H,ArH),7.19-7.12(m,1.5H,ArH),7.07-7.04(m,1H,ArH),7.00-6.91(m,1H,ArH),6.86-6.78(m,1H,ArH),5.71-5.52(m,3H,NH,CH),4.21-4.09(m,1.5H,CH₂),3.90(t,J＝8.4Hz,0.5H,CH₂),3.13-2.71(m,4.5H,CH₂CH₂,CH),1.94-1.81(m,3H,CH₂CH₂),1.61-1.41(m,1H,CH₂),1.37-1.29(m,1H,CH₂),1.26-1.18(m,1H,CH₂),1.03-0.80(m,0.5H,CH₂CH₂).

Example 7

Step 13 Synthesis of methyltetrahydro-4H-pyran-4-one (2)

To a 500mL single-necked flask was added LDA (198mL, 2N tetrahydrofuran solution, 396 mmol) and tetrahydrofuran (100 mL) in this order, and Compound 1 (33.00 g,330 mmol) and HMPA (58 mL,330 mmol) were added dropwise at-78℃under nitrogen. Preserving the heat for 10min, dropwise adding methyl iodide (83 mL,1.32 mol), heating to 0 ℃ after the addition, and reacting for 3h. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting material, quenched with saturated aqueous ammonium chloride (200 mL), extracted with ethyl acetate (100 mL x 3), combined organic phases, washed with saturated aqueous sodium chloride (200 mL), dried over anhydrous sodium sulfate, filtered off with suction, concentrated, purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 30:1) to give 10.00g of intermediate 2 as colourless oil in 26.6% yield.

Step 2 Synthesis of methyl (E) -2- (3-methyltetrahydro-4H-pyran-4-ylmethylene) acetate (3)

To a 250mL single-necked flask, intermediate 2 (15.00 g,131 mmol), toluene (100 mL), and methoxyformyl methylene triphenylphosphine (48.33 g,145 mmol) were added sequentially, and reacted overnight at 110℃under nitrogen. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} =10:1) monitored complete reaction of starting material, cooling to 0 ℃, precipitation of solid, filtration, collection of filtrate, concentration, column chromatography purification (V _{Petroleum ether}：V_{acetic acid ethyl ester} =30:1) gave 6.50g of intermediate 3 as colourless oil in 29.6% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):5.68-5.63(m,1H,CH),3.85-3.89(m,2H,CH₂CH₂),3.69-3.68(m,3H,CH₃),3.60-3.56(m,1H,CH₂CH₂),3.48-3.43(m,1H,CH₂CH₂),3.28-3.24(m,1H,CH₂CH₂),2.66-2.56(m,1H,CH₂CH₂),2.49-2.39(m,1H,CH₂CH₂),1.06-1.04(m,3H,CHCH₃). Step 32 Synthesis of methyl- (3-methyl-4- (nitromethyl) tetrahydro-2H-pyran-4-yl) acetate (4)

To a 250mL single-necked flask, intermediate 3 (6.50 g,38.2 mL), tetrahydrofuran (600 mL), TBAF (57.3mL,57.3mmol,1N in THF) and nitromethane (4.1 mL,76.3 mmol) were sequentially added, and the mixture was reacted overnight at 70℃under nitrogen. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting materials, cooled to room temperature, diluted with ethyl acetate (300 mL) and washed with 2N diluted hydrochloric acid (200 mL x 3), saturated sodium chloride solution (200 mL x 3), dried over anhydrous sodium sulfate, suction filtered, concentrated, purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) to give 4.60g of intermediate 4 as colourless oil in 52.1% yield.

¹H NMR(400MHz,CDCl₃)δ(ppm):4.92-4.89(m,1H,CH₂CH₂),4.77-4.74(m,1H,CH₂CH₂),3.81-3.74(m,1H,CH₂CH₂),3.72-3.70(m,4H,CH₂CH₂,CHCH₃),3.69-3.66(m,1H,CH₂CH₂),3.41-3.36(m,1H,CH₂CH₂),2.75-3.72(m,1H,CH₂CH₂),2.42-2.38(m,1H,CH₂CH₂),1.97-1.89(m,1H,CH),1.76-1.73(m,2H,CH₂CH₂),0.92-0.90(m,3H,CH₃).

Step 46 Synthesis of methyl-8-oxa-2-azaspiro [4.5] decan-3-one (5)

To a 250mL single-necked flask, intermediate 4 (6.50 g,38.2 mmol), ethanol (50 mL), water (5 mL), ammonium chloride (4.63 g,86.5 mmol) and iron powder (4.85 g,86.5 mmol) were sequentially added, and the mixture was reacted at 80℃for 2 hours under nitrogen protection. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting materials, cooled to room temperature, filtered through celite, concentrated, and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 2.70g of intermediate 5 as a yellow oil in 92.2% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):6.37(s,1H,NH),3.83-3.79(m,1H,CH₂CH₂),3.63-3.61(m,1H,CH₂CH₂),3.53-3.49(m,1H,CH₂CH₂),3.29-3.27(m,1H,CH₂CH₂),3.20-3.15(m,2H,CH₂CH₂),2.39-2.36(m,1H,CH₂CH₂),2.10-2.07(m,1H,CH₂CH₂),1.77-1.71(m,1H,CH),1.69-1.67(m,2H,CH₂CH₂),0.86-0.85(m,3H,CH₃)

Step 5 6 Synthesis of allyl-3-oxo-8-oxa-2-azaspiro [4.5] decane-2-carboxylate (6)

To a 500mL single-necked flask, intermediate 5 (11.00 g,65 mmol) and tetrahydrofuran (200 mL) were sequentially added, nitrogen was used for protection, n-BuLi (26 mL,65mmol,2.5N tetrahydrofuran solution) was sequentially added dropwise at-78deg.C, the temperature was kept for 10min, and then an Alloc-Cl (7.83 g,65 mmol) solution of tetrahydrofuran (10 mL) was added dropwise, and the reaction was continued for 1h at the end of the addition. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quenched with saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (100 mL x 3), combined organic phases, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered off with suction, concentrated, purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:1) to give 14.50g of intermediate 6 as colourless oil in 88.1% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):6.08-5.98(m,1H,CHCH₂),5.43-5.40(m,1H,CHCH₂),5.30-5.27(m,1H,CHCH₂),4.74-4.73(m,2H,CH₂),3.84-3.80(m,1H,CH₂CH₂),3.78-3.63(m,3H,CH₂CH₂),3.54-3.50(m,1H,CCH₂),3.21-3.18(m,1H,CCH₂),2.62-2.59(m,1H,CH₂CH₂),2.35-2.32(m,1H,CH₂CH₂),1.78-1.75(m,1H,CH),1.70-1.62(m,2H,CH₂CH₂),0.87-0.86(m,3H,CH₃). Step 6 6 Synthesis of allyl-3-hydroxy-8-oxa-2-azaspiro [4.5] decane-2-carboxylate (7)

To a 500mL single-necked flask, intermediate 6 (14.50 g,57.2 mmol) and tetrahydrofuran (200 mL) were sequentially added, followed by dropwise addition of DIBAl-H (86 mL,86mmol,1N tetrahydrofuran solution) at-78deg.C under nitrogen protection, and the reaction was continued for 3H at the temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) monitored complete reaction of starting material, quenched by addition of saturated potassium sodium tartrate solution (200 mL), extracted with ethyl acetate (200 mL x 3), combined organic phases washed with 0.5N dilute hydrochloric acid (200 mL x 3), washed with saturated sodium chloride solution (300 mL), dried over anhydrous sodium sulfate, filtered off with suction, concentrated to give 9.00g of intermediate 7 as colourless oil in 61.4% yield.

Step 76 Synthesis of allyl-3-methoxy-8-oxa-2-azaspiro [4.5] decane-2-carboxylate (8)

To a 250mL single-necked flask, intermediate 7 (9.00 g,35.1 mmol), methanol (50 mL), and p-toluenesulfonic acid monohydrate (0.67 g,3.5 mmol) were added sequentially, and the mixture was reacted overnight at room temperature under nitrogen. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =50:1) monitored complete reaction of starting material, quenched with saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (150 ml×3), combined organic phases dried over anhydrous sodium sulfate, filtered off with suction, concentrated, purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =50:1) to give 7.90g of intermediate 8 as colourless oil in 83.2% yield.

Step 8 3 Synthesis of allyl 3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -6-methyl-8-oxa-2-azaspiro [4.5] decane-2-carboxylate (10)

To a 250mL three-necked flask were successively added intermediate 8 (5.90 g,21.9 mmL), ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (compound 9) (6.32 g,21.9 mmol) and acetonitrile (120 mL), followed by dropwise addition of tin tetrachloride (4.1 mL,35.0 mmol) at-25℃under nitrogen protection, and the reaction was continued for 2.5h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting materials, addition of saturated sodium bicarbonate solution, adjustment of pH to 7, extraction with dichloromethane (100 mL x 3), combined organic phases, washing with saturated sodium chloride solution (200 mL), drying over anhydrous sodium sulfate, suction filtration, concentration, column chromatography purification (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) afforded 4.7g yellow oily intermediate 10 in 40.8% yield.

Step 99 '- (benzyloxy) -3-methyl-2, 3a',4',5, 6-hexahydro-1' H,3 'H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (11)

To a 250mL single-necked flask, intermediate 10 (4.70 g,8.9 mmol), morpholine (40 mL) and tetrakis triphenylphosphine palladium (1.03 g,0.89 mmol) were added in sequence and reacted at room temperature under nitrogen for 2.5h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) monitored complete reaction of starting material, addition of isopropyl ether (400 mL), precipitation of solids, suction filtration, collection of filter cake, column chromatography purification (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1) gave 3.50g of white solid intermediate 11 in 99.4% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.75-7.72(m,1H,ArH),7.53-7.52(m,2H,ArH),7.37-7.33(m,2H,ArH),7.32-7.27(m,1H,ArH),7.21-7.14(m,1H,ArH),6.21-6.20(m,1H,ArH),5.23-5.18(m,1H,CH),5.05-4.88(m,2H,ArCH₂),3.67-3.57(m,2H,CH₂),3.55-3.38(m,3H,CH₂),3.27-3.25(m,1H,CH₂),2.20-2.09(m,1H,CH₂),1.70-1.58(m,2H,CH₂),1.56-1.53(m,1H,CH₂),1.46-1.37(m,1H,CH),0.92-0.81(m,3H,CH₃).

Step 10 Synthesis of tert-butyl 10' - (benzyloxy) -3-methyl-8 ',10' -dione-2, 3',3a ',5,6,8',10' -octahydro-1 ' H,4' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -4' -carboxylate (12)

To a 250mL three-necked flask, intermediate 11 (3.50 g,8.85 mmol), methylene chloride (100 mL), di-tert-butyl dicarbonate (3.86 g,17.7 mmol), triethylamine (1.79 g,17.7 mmol) and DMAP (108 mg,0.89 mmol) were successively added, and the mixture was reacted at room temperature under nitrogen for 1.5 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1) monitored complete reaction of starting material, dilution with dichloromethane (200 mL), washing with saturated sodium chloride solution (200 ml×3), drying over anhydrous sodium sulfate, suction filtration, concentration, column chromatography purification (V _{dichloromethane (dichloromethane)}：V_Methanol =200:1) afforded 3.67g of intermediate 12 as a white solid in 83.7% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.84-7.83(m,1H,ArH),7.54-7.48(m,2H,ArH),7.35-7.33(m,2H,ArH),7.31-7.27(m,1H,ArH),6.26-6.24(m,1H,ArH),5.48(t,J＝8.4Hz,1H,CH),5.22(d,J＝10.8Hz,1H,ArCH₂),5.07(d,J＝10.8Hz,1H,ArCH₂),3.71-3.54(m,3H,CH₂),3.48-3.45(m,1H,CH₂),3.30-3.21(m,2H,CH₂),2.89-2.85(m,1H,CCH₂),2.55-2.51(m,1H,CCH₂),1.75-1.67(m,1H,CH),1.63-1.58(m,2H,CCH₂),1.35(s,9H,C(CH₃)₃),0.78(d,J＝7.2Hz,3H,CH₃).

Step 11 Synthesis of 9'- (benzyloxy) -3-methyl-2, 3a',4',5, 6-hexahydro-1' H,3 'H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (13)

To the jar was added intermediate 12 (640 mg,1.33 mmol) and HCl/ethyl acetate (15 mL, 3N), sealed and reacted at 60℃for 2.5h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, cooled to room temperature, concentrated to remove ethyl acetate, added water (10 mL), added dropwise with saturated sodium bicarbonate solution, pH adjusted to 7, dichloromethane (30 mL x 3) extracted, combined organic phases, dried over anhydrous sodium sulfate, suction filtered, concentrated, column chromatography purified (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to afford 350mg of intermediate 13 as a white solid in 66.4% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.73(d,J＝7.8Hz,1H,NH),7.56-7.50(m,2H,ArH),7.37-7.33(m,2H,ArH),7.31-7.27(m,1H,ArH),7.15(d,J＝12.6Hz,1H,ArH),6.20(d,J＝7.8Hz,1H,ArH),5.22(d,J＝10.8Hz,1H,ArCH₂),5.02(d,J＝10.8Hz,1H,ArCH₂),4.94-4.90(m,1H,CH),3.63-3.57(m,2H,CH₂),3.50-3.43(m,3H,CH₂),3.30-3.25(m,1H,CH₂),2.49-2.45(m,1H,CH₂),1.65-1.58(m,3H,CH₂),1.45-1.42(m,1H,CH),0.82(d,J＝7.2Hz,3H,CH₃).

Step 12 9- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis/>, of-11-yl) -3-methyl-2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (14)

To a 50mL single vial were added sequentially intermediate 13 (350 mg,0.89 mmol), acetonitrile (10 mL), 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine(751 Mg,2.66 mmol) and cesium carbonate (1.44 g,4.43 mmol), under nitrogen, at room temperature overnight. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quenching with water (25 mL), extraction with dichloromethane (25 mL x 4), combined organic phases, washing with saturated sodium chloride solution (50 mL), drying over anhydrous sodium sulfate, suction filtration, concentration, column chromatography purification (V _{dichloromethane (dichloromethane)}：V_Methanol = 200:1) afforded 220mg of yellow solid intermediate 14 in 38.7% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.60(d,J＝7.8Hz,1H,ArH),7.57-7.50(m,2.5H,ArH),7.43-7.34(m,3H,ArH),7.33-7.29(m,2H,ArH),7.25-7.22(m,1H,ArH),7.21-7.17(m,1H,ArH),7.11-7.07(m,0.5H,ArH),7.05-7.02(m,0.5H,ArH),6.89-6.83(m,1.5H,ArH),5.77-5.75(m,1H,CH),5.74-5.71(m,0.5H,CH),5.54-4.52(m,0.5H,CH),5.46-4.44(m,0.5H,CH₂),5.39-5.33(m,1H,CH₂),5.25-5.23(m,0.5H,CH₂),5.20-5.16(m,1H,CH₂),5.13-5.07(m,1H,CH₂),4.18-4.14(m,1H,CH₂),3.86-3.84(m,0.5H,CH₂),3.68-3.66(m,0.5H,CH₂),3.61-3.59(m,1H,CH₂),3.55-3.49(m,0.5H,CH₂),3.45-3.39(m,0.5H,CH₂),3.34-3.33(m,0.5H,CH₂),3.20-3.18(m,2H,CH₂),3.13-3.03(m,0.5H,CH₂),2.27-2.25(m,0.5H,CH₂),2.16-2.13(m,0.5H,CH₂),1.56-1.53(m,1H,CH₂),1.50-1.48(m,1H,CH₂),1.17-1.13(m,0.5H,CH),1.01-0.95(m,0.5H,CH),0.74(d,J＝7.2Hz,1.5H,CH₃),0.71(d,J＝7.2Hz,1.5H,CH₃).

Step 13 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -9 '-hydroxy-3-methyl-2', 3a ',4,5, 6-hexahydro-1' H,3 'H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (example 7)

To a 50mL single-necked flask, intermediate 14 (210 mg,0.33 mmol), DMAc (3 mL) and lithium chloride (139 mg,3.27 mmol) were sequentially added, and the mixture was reacted at 80℃for 4.5 hours under nitrogen atmosphere. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, cooling to room temperature, quenching with water (15 mL), extraction with dichloromethane (25 mL x 4), washing with saturated sodium chloride solution (50 mL), drying over anhydrous sodium sulfate, suction filtration, concentration, column chromatography purification (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) gave 119mg of example 7 as a yellow-red solid in 65.9% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.67-7.49(m,1.5H,ArH),7.48-7.31(m,2H,ArH),7.29-7.06(m,3H,ArH),7.04-7.64(m,1.5H,ArH),5.85-5.3(m,3H,CH,CH₂),5.46-5.32(m,1H,CH),4.25-4.13(m,1H,CH₂),4.01-3.75(m,1H,CH₂),3.57-3.50(m,1H,CH₂),3.17-3.13(m,1H,CH₂),2.25-2.11(m,1H,CH₂),1.67-1.51(m,1H,CH₂),1.42-1.31(m,1H,CH),1.29-1.17(m,3H,CH₂),0.87-0.64(m,3H,CH₃).

Example 8 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -9 '-hydroxy-1' H,3 'H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] -triazine ] -8',10' -dione

Step 12 Synthesis of allyl-8-tert-butyl-3-hydroxy-2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylic acid ester (2)

To a 250mL three-necked flask, compound 1 (12.0 g,35.5 mmol) and anhydrous tetrahydrofuran (75 mL) were sequentially added, and the mixture was cooled to-78℃under nitrogen. To the reaction system, diisobutylaluminum hydride (1N tetrahydrofuran solution, 70.9mL,70.9 mmol) was slowly added dropwise thereto, and the reaction was continued for 1 hour with a constant temperature. After the completion of the reaction, monitored by TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 2:1), saturated potassium sodium tartrate solution (200L) was quenched, ethyl acetate (200 mL) was added and stirred at room temperature for 15min. The mixture was filtered under celite pad, and the filtrate was extracted with ethyl acetate (100 mL. Times.2), and the organic phase was collected and washed with saturated sodium chloride solution (100 mL. Times.2). Drying over anhydrous sodium sulfate, filtration and concentration gave 12.10g of colorless oily intermediate 2, which was used in the next step without purification.

Step 22 Synthesis of allyl-8-tert-butyl-3-methoxy-2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylic acid ester (3)

To a 500mL single-necked flask, intermediate 2 (12.10 g,35.5 mmol), methanol (120 mL), and p-toluenesulfonic acid monohydrate (6755 mg,3.55 mmol) were sequentially added and reacted at room temperature for 1h. After TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 2:1) monitoring the end of the reaction, saturated sodium bicarbonate solution was adjusted to pH = 7 and concentrated. The residue was extracted with ethyl acetate (20 mL. Times.3), and the organic phase was collected. Dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash chromatography (80 g, v _{Petroleum ether}：V_{acetic acid ethyl ester} = 4:1) to afford 9.24g of intermediate 3 as a colorless oil in 73.4% two-step yield.

Step 32 Synthesis of allyl-8-tert-butyl-3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylic acid ester (4)

To a 500mL single-necked flask were successively added intermediate 3 (9.24 g,26.1 mmol), ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (7.52 g,26.1 mmol) and anhydrous acetonitrile (370 mL), followed by cooling to-35℃under nitrogen. Tin tetrachloride (8.16 g,31.3 mmol) was slowly added dropwise to the reaction system, and the reaction was continued for 1h with a constant temperature. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitoring the end of the reaction, the reaction was poured into saturated sodium bicarbonate solution (800 mL). The mixture was extracted with ethyl acetate (100 mL. Times.3), and the organic phase was collected and washed with a saturated sodium chloride solution (100 mL. Times.3). Drying over anhydrous sodium sulfate, filtration, concentration and purification by flash chromatography (80 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 97:3) afforded 12.9g of yellow solid intermediate 4 in 81.1% yield.

Step 4 9'- (benzyloxy) -8',10 '-dioxo-3 a',4',8',10 '-tetrahydro-1' H,3 'H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -1-carboxylic acid tert-butyl ester (5)

To a 500mL single-necked flask, intermediate 4 (12.9 g,21.1 mmol), tetrahydrofuran (150 mL), morpholine (18.4 g,211 mmol) and palladium tetraphenylphosphine (2.43 mg,2.11 mmol) were successively added, and the mixture was reacted at room temperature under nitrogen atmosphere for 1 hour. After completion of the reaction by TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1), isopropyl ether (100 mL) was added and filtered to give 9.40g of intermediate 5 as a white solid in 90.6% yield.

Step 5 tert-butyl-9 '- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -8',10' -dioxo-3 a ',4',8',10' -tetrahydro-1 ' H,3' H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] -triazine ] -1-carboxylic acid ester (6)

Into a 50mL single-necked flask, 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine was sequentially introduced(3.34 G,6.96 mmol), acetonitrile (100 mL), cesium carbonate (9.07 g,27.8 mmol) and intermediate 5 (4.92 g,17.4 mmol) were reacted overnight at room temperature under nitrogen. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 15:1) monitoring the end of the reaction, filtration over celite pad, concentration of the filtrate and purification by flash chromatography (80 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) gave 3.20g of yellow solid intermediate 6 in 28.8% yield.

Step 69 '- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -3a ',4' -dihydro-1 ' H,3' H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] -triazine ] -8',10' -dione (7)

To a 50mL two-necked flask, intermediate 6 (600 mg,0.83 mmol) and methylene chloride (12 mL) were successively added, and the mixture was cooled to 0℃under nitrogen. Trifluoroacetic acid (0.6 mL) was added to the reaction mixture, and the mixture was incubated for 30min and then reacted at room temperature for 4 hours. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored the end of the reaction, the reaction was poured into a rapidly stirred saturated sodium bicarbonate solution (100 mL). Dichloromethane (50 mL. Times.3) was extracted and the organic phase was collected and washed with saturated sodium chloride solution (20 mL. Times.3). Drying over anhydrous sodium sulfate, filtration, concentration and purification by flash chromatography (12 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) afforded 293mg of yellow solid intermediate 7 in 56.4% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.61-7.58(m,2.27H,ArH),7.43(d,J＝7.8Hz,0.72H,ArH),7.35-7.32(m,2.29H,ArH),7.30-7.27(m,1.07H,ArH),7.23-7.20(m,0.38H,ArH),7.17-7.09(m,1.19H,ArH),7.03-6.99(m,2.22H,ArH),6.84-6.81(m,1.04H,ArH),6.73-6.70(m,1.01H,ArH),6.64-6.62(m,0.55H,ArH),6.34-6.33(m,0.26H,ArH),5.88-5.84(m,0.9H,CH),5.48-5.44(m,1.12H,NH),5.42-5.29(m,2.08H,CH₂),5.26 -5.15(m,0.90H,CH₂),4.98-4.88(m,0.74H,CH₂),4.08-3.92(m,1.60H,CH₂),3.72-3.63(m,0.40H,CH₂),3.24-3.12(m,1.11H,CH₂),2.93(br,0.9H,NH),2.88-2.81(m,1.80H,CH₂),2.73-2.62(m,1.72H,CH₂),1.87-1.75(m,1.40H,CH₂),1.55-1.48(m,1.31H,CH₂),1.43-1.39(m,3.02H,CH₂).

Step 7 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -9 '-hydroxy-1' H,3 'H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] -triazine ] -8',10' -dione (example 8)

To the thumb flask were successively added intermediate 7 (597 mg,0.95 mmol), N-dimethylacetamide (1.5 mL) and lithium chloride (201 mg,4.77 mmol), and reacted at 80℃for 3 hours under nitrogen protection. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitoring the reaction was completed, the reaction was cooled to room temperature, water (5 mL) was added, stirred, filtered, and the filter cake was slurried with dichloromethane (15 mL) to give 80mg of a white solid in 15.6% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.45-7.43(m,1.43H,ArH),7.34-7.30(m,1.41H,ArH),7.25-7.21(m,0.45H,ArH),7.06-7.03(m,1.35H,ArH),7.06-7.03(m,1.18H,ArH),6.99-6.98(m,0.75H,ArH),6.87-6.80(m,1.43H,ArH),5.68-5.60(m,1.64H,CH,CH₂),5.55-5.50(m,2.89H,CH₂),5.38(br,0.60H,CH₂),4.11-4.07(m,1.43H,CH₂),3.77-3.67(m,1.44H,CH₂),2.98-2.96(m,0.41H,CH₂),2.60-2.54(m,2.55H,NH,CH₂),2.37-2.34(m,0.42H,CH₂),1.90-1.84(m,0.90H,CH₂),1.37-1.08(m,4.72H,CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₂₈H₂₆F₂N₄O₃ S theory 537.1767; actual measurement value 537.1768

Example 9 4' - (5H-dibenzo [ a, d ] [7] cyclohex-5-yl) -9' -hydroxy-2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione Synthesis procedure 1 referring to example 2, 9' - (hexyloxy) -2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione was prepared with ethyl 1-amino-3- (hexyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate instead of ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate.

Step 24 ' - (5H-dibenzo [ a, d ] [7] cyclohex-5-yl) -9' - (hexyloxy) -2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (3) synthesis

To a 10mL single port flask, compound 1 (325 mg,1.56 mmol), ethyl acetate (6 mL), and SM2 (200 mg,0.53 mmol) were added in this order, methanesulfonic acid (77 mg,0.81 mmol) and T ₃ P (50 wt% ethyl acetate solution, 1.11g,1.72 mmol) were added with stirring at room temperature, and stirring was continued overnight at 65℃under nitrogen. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, cooled to room temperature, quenched with water (10 mL), extracted with dichloromethane (20 mL x 3), washed with saturated brine (10 mL x 3), dried, filtered, concentrated and purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 200mg of pale red solid intermediate 2 in 78.6% yield

¹H NMR(600MHz,CD₃OD)δ(ppm):7.65(d,J＝7.6Hz,1H,ArH),7.53(d,J＝7.6Hz,1H,ArH),7.36-7.31(m,3H,ArH),7.27-7.25(m,2H,ArH),7.24-7.21(m,2H,ArH),7.14(s,1H,ArH),6.89(d,J＝2.1Hz,2H,ArH),5.71(d,J＝13.2Hz,1H,CH),4.71-4.66(m,1H,CH),4.16-4.12(m,1H,CH),3.87-3.83(m,1H,CH₂),3.63-3.59(m,1H,CH₂),3.54-3.49(m,2H,CH₂),3.25(t,J＝11.4Hz,1H,CH₂),3.09(d,J＝12.4Hz,1H,CH₂),2.54(d,J＝12.4Hz,1H),2.13(dd,J₁＝12.7Hz,J₂＝5.6Hz,1H,CH₂),1.72-1.67(m,2H,CH₂),1.51(dd,J₁＝12.6Hz,J₂＝9.6Hz,1H,CH₂),1.44-1.38(m,2H,CH₂),1.37-1.32(m,3H,CH₂),1.29-1.23(m,5H,CH₂),0.88(t,J＝6.9Hz,3H,CH₂).

Step 24 ' - (5H-dibenzo [ a, d ] [7] cyclohen-5-yl) -9' -hydroxy-2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (example 9)

To a 10mL thumb flask were added sequentially intermediate 2 (150 mg,0.27 mmol), lithium chloride (103 mg,2.39 mmol) and NMP (0.5 mL) and stirred under nitrogen at 100deg.C for 16h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of the starting materials, the reaction was cooled to room temperature and stirred directly, concentrated, and purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give crude product, which was slurried with EA (10 mL) at room temperature for 3h, filtered, the filter cake collected and dried overnight at 42 ℃ in a vacuum oven to give 75mg of pink solid example 9 in 11.2% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.66-7.53(m,2H,ArH),7.45-7.27(m,7H,ArH),7.15-6.89(m,3H,ArH),5.68-5.60(m,1H,CH₂),5.02-4.90(m,1H,CH₂),3.69-3.41(m,6H,CH₂OCH₂,NCH₂),2.33-2.22(m,1H,H of NCHCH₂),1.69-1.48(m,5H,CH₂CCH₂,H of NCHCH₂).

Example 10 Synthesis of 4' - ((3, 4-difluorophenyl) benzyl) -9' -hydroxy-2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione

Step1 Synthesis of (3, 4-difluorophenyl) benzyl alcohol (2)

To a 250mL single vial was added compound 1 (5.00 g,22.9 mmol) followed by MeOH (40 mL), sodium borohydride (520 mg,1.38 mmol) in portions under an ice bath, and stirred at room temperature under nitrogen for 2h. TLC (V _{acetic acid ethyl ester}：V_{Petroleum ether} = 1:5) monitored complete reaction of starting material, quenched with water (100 mL), extracted with ethyl acetate (120 mL x 3), washed with saturated aqueous sodium chloride (50 mL x 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash preparative chromatography (80 g, V _{acetic acid ethyl ester}：V_{Petroleum ether} = 1:5) to give 5.0g of intermediate 2 as a colourless oil in 99.2% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.41-7.33(m,4H,ArH),7.32-7.29(m,2H,ArH),7.23-7.19(m,2H,ArH),6.06(br,1H,OH),5.71(s,1H,CH).

Step 24 ' - ((3, 4-difluorophenyl) benzyl) -9' - (hexyloxy) -2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (3) Synthesis

To a 10mL jar was added in order intermediate 2 (200 mg,0.82 mmol), ethyl acetate (0.5 mL), SM2 (200 mg,0.53 mmol), methanesulfonic acid (77 mg,0.81 mmol) and T ₃ P (50 wt% ethyl acetate solution, 1.11g,1.72 mmol) and stirred overnight at 100deg.C. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting materials, the reaction was cooled to room temperature, quenched with water (10 mL), extracted with dichloromethane (20 mL x 3), washed with saturated brine (10 mL x 3), dried, filtered, concentrated and purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to afford 190mg of intermediate 3 as a white solid in 37.2% yield

¹H NMR(600MHz,CD₃OD)δ(ppm):7.93-7.80(m,1.5H,ArH),7.70(d,J＝7.7Hz,1H,ArH),7.51-7.39(m,2H,ArH),7.33-7.31(m,0.5H,ArH),7.25-7.20(m,0.5H,ArH),7.15-7.09(m,2H,ArH),7.09-6.89(m,2H,ArH),5.78(d,J＝7.2Hz,0.5H,ArH),5.68-5.65(m,1H,CH),5.63(s,0.5H,CH₂),5.56-5.51(m,1H,CH),3.94-3.90(m,0.5H,CH₂),3.89-3.84(m,1.5H,CH₂),3.78(d,J＝11.6Hz,1H,CH₂),3.62-3.51(m,3H,CH₂),3.50-3.46(m,0.5H,CH₂),3.44-3.41(m,1H,CH₂),1.92-1.82(m,1H,CH₂),1.64-1.57(m,2H,CH₂),1.50-1.42(m,4H,CH₂),1.38-1.33(m,2H,CH₂),1.31-1.27(m,3H,CH₂),1.23(s,2H,CH₂),0.89(t,J＝6.6Hz,3H,CH₃).

Step 3

Synthesis of 4' - ((3, 4-difluorophenyl) benzyl) -9' -hydroxy-2, 3a ',4',5, 6-hexahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (example 10)

To a 10mL thumb bottle were added, in order, intermediate 3 (190 mg,0.33 mmol), lithium chloride (128 mg,2.97 mmol), and NMP (0.5 mL), and the mixture was stirred under nitrogen at 100deg.C for 16h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of the starting materials, the reaction was cooled to room temperature, directly stirred, concentrated, and purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give crude product, which was slurried with ethyl acetate (10 mL) at room temperature for 3h, filtered, the filter cake collected and dried overnight at 42 ℃ in a vacuum oven to give 100mg of pink solid example 10 in 37.2% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):8.04-7.63(m,2.5H,ArH),7.60-7.23(m,2.5H,ArH),7.20-6.85(m,4H,ArH),5.79(s,1H,ArH),5.65-5.56(m,2H,CH₂),3.76(d,J＝11.8Hz,1H,CH₂),3.62-3.49(m,5H,CH₂),1.90-1.68(m,1H,CH₂),1.48-1.31(m,5H,CH₂).

EXAMPLE 11 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -9 '-hydroxy-3 a',4 '-dihydro-1' H,3 'H-spiro [ octane-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-8 ',10' -dione

Step 17 Synthesis of allyl-2-oxo-2-oxa-6-azaspiro [3,4] octane-6-carboxylate (2)

To a 150mL three-necked flask, compound 1 (2.00 g,15.7 mmol) and anhydrous tetrahydrofuran (35 mL) were sequentially added, and the mixture was cooled to-78℃under nitrogen. N-butyllithium (2.5N hexane solution, 6.3mL,15.7 mmol) was slowly added dropwise to the reaction system, and the reaction was continued for 45min at the end of 20 min. Then, an anhydrous tetrahydrofuran solution (5 mL) of allyl chloroformate (1.89 g,15.7 mmol) was slowly added dropwise thereto, and the reaction was continued for 1h at the end of 15 minutes. After TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:2) monitored the reaction was completed, the reaction was transferred to room temperature, quenched with saturated aqueous ammonium chloride (25 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was collected and washed with saturated aqueous sodium chloride (10 mL x 2). Drying over anhydrous sodium sulfate, filtration, concentration and purification by flash chromatography (40 g, v _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:1) afforded 1.38g of intermediate 2 as a colourless oil in 41.5% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):5.93-5.87(m,1H,CH₂＝CH),5.37-5.34(m,1H,CH₂＝CH),5.21-5.19(m,1H,CH₂＝CH),4.62-4.60(m,2H,CH₂＝CHCH₂),4.52-4.51(m,2H,OCH₂),4.48-4.47(m,2H,OCH₂),3.94(s,2H,NCH₂),2.82(s,2H,COCH₂).

Step 27 Synthesis of allyl hydroxy-2-oxa-6-azaspiro [3,4] octane-6-carboxylate (3)

To a 50mL single-necked flask, intermediate 2 (1.38 g,6.53 mmol) and anhydrous tetrahydrofuran (15 mL) were sequentially added, and the mixture was cooled to-78℃under nitrogen. To the reaction system, diisobutylaluminum hydride (1N hexane solution, 8.5mL,8.49 mmol) was slowly added dropwise thereto, and the reaction was continued for 2 hours. After completion of the reaction, monitored by TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1), the reaction was quenched with saturated potassium sodium tartrate solution (30 mL), ethyl acetate (25 mL) was added and stirred at room temperature for 15min. The mixture was filtered through celite pad, and the filtrate was extracted with ethyl acetate (20 mL. Times.2), and the organic phase was collected and washed with saturated sodium chloride solution (5 mL. Times.2). Drying over anhydrous sodium sulfate, filtration and concentration gave 1.23g of colorless oily intermediate 3, which was used in the next step without purification.

Step 37 Synthesis of allyl-2-oxa-6-azaspiro [3,4] octane-6-carboxylate (4)

To a 50mL single-necked flask, intermediate 3 (1.23 g,5.77 mmol), methanol (5 mL) and p-toluenesulfonic acid monohydrate (0.11 g,0.58 mmol) were sequentially added and reacted at room temperature for 1h. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitoring the end of the reaction, saturated sodium bicarbonate solution was adjusted to pH around 7 and concentrated. The residue was extracted with ethyl acetate (25 mL. Times.3), and the organic phase was collected. Drying over anhydrous sodium sulfate, filtration, concentration and purification by flash chromatography (20 g, v _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:1) afforded 1.18g of intermediate 4 as a colourless oil in 92.9% two-step yield.

Step 47 Synthesis of allyl 2- (ethoxycarbonyl) -3- (hexyloxy) -4-oxopyridin-1 (4H) -yl) amino) -2-oxa-6-azaspiro [3.4] octane-6-carboxylate (5)

To a 50mL single-necked flask were successively added intermediate 4 (1.00 g,4.40 mmol), ethyl 1-amino-3- (hexyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (1.13 g,4.00 mmol) and anhydrous acetonitrile (28 mL), followed by cooling to-30℃under nitrogen. Tin tetrachloride (1.67 g,6.40 mmol) was slowly added dropwise to the reaction system, and the reaction was continued for 1.5 hours. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 15:1) monitoring the end of the reaction, the reaction was poured into saturated sodium bicarbonate solution (50 mL). The mixture was extracted with ethyl acetate (20 mL. Times.3), and the organic phase was collected and washed with a saturated sodium chloride solution (10 mL. Times.3). Drying over anhydrous sodium sulfate, filtration, concentration and purification by flash chromatography (20 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) afforded 1.88g of intermediate 5 as a white solid in 98.5% yield.

Step 5 9'- (hexyloxy) -3a',4 '-dihydro-1' H,3 'H-spiro [ oxetane-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (6) Synthesis

To a 50mL single-necked flask, intermediate 5 (1.80 g,3.77 mmol), tetrahydrofuran (1.6 mL), morpholine (8 mL) and tetrakis triphenylphosphine palladium (348 mg,3.02 mmol) were sequentially added and reacted at room temperature under nitrogen for 1h. After completion of the reaction by TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1), isopropyl ether (30 mL) was added and filtered to give 1.17g of intermediate 6 as a white solid in 89.0% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.41(d,J＝7.7Hz,1H,CH＝CH),6.24(d,J＝7.7Hz,1H,CH＝CH),6.09(d,J＝13.2Hz,1H,NH),4.82-4.78(m,1H,NHCH),4.76-4.74(m,1H,OCH₂),4.71-4.70(m,1H,OCH₂),4.60-4.59(m,1H,OCH₂CH₂),4.55-4.54(m,1H,OCH₂CH₂),4.28-4.24(m,1H,NCH₂),3.92-3.88(m,1H,NCH₂),3.75(d,J＝12.5Hz,1H,CHCH₂),3.50(d,J＝12.5Hz,1H,CHCH₂),2.74-2.71(m,1H,CH₂),2.15-2.12(m,1H,CH₂),1.73-1.68(m,2H,CH₂),1.40-1.35(m,2H,CH₂),1.32-1.28(m,4H,CH₂),0.88(t,J＝7.1Hz,3H,CH₃).

Step 6 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of (E) -11-yl) -9'- (hexyloxy) -3a',4 '-dihydro-1' H,3 'H-spiro [ octane-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-8 ',10' -dione methanesulfonate (8)

To a 100mL single vial was added sequentially intermediate 6 (1.00 g,2.88 mmol), ethyl acetate (20 mL), 7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine11-Alcohol (989 mg,3.74 mmol), propylphosphoric anhydride (50 wt% ethyl acetate solution, 2.75g,4.32 mmol) and methanesulfonic acid (554 mg,5.76 mmol) were reacted at 60℃for 1.5h under nitrogen. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 15:1) monitoring the end of the reaction, the reaction was cooled to room temperature. The organic phase was collected by washing with water (10 mL. Times.3). Drying over anhydrous sodium sulfate, filtration, concentration and purification by flash chromatography (80 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) afforded 529mg of intermediate 8 as a white solid in 19.0% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.43(d,J＝7.7Hz,1H,ArH),7.39-7.29(m,1H,ArH),7.12-7.11(m,2H,ArH,CH＝CH),7.10-7.04(m,2H,ArH),7.03-7.00(m,1H,ArH),6.19(d,J＝7.8Hz,1H,CH＝CH),6.11-6.09(m,1H,CH),5.00-4.95(m,1H,CH),4.34-4.30(m,1H,CH₂),4.24-4.16(m,2H,CH₂),3.94-3.89(m,1H,CH₂),3.64-3.58(m,2H,CH₂),3.34-3.31(m,1H,CH₂),3.23-3.16(m,1H,CH₂),3.00-2.96(m,3H,CH₃SO₃H),2.39-2.34(m,1H,CH₂),1.84-1.79(m,1H,CH₂),1.75-1.69(m,2H,CH₂),1.37-1.34(m,2H,CH₂),1.28-1.24(m,5H,CH₂),0.87-0.84(m,3H,CH₃).

Step 7 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -9 '-hydroxy-3 a',4 '-dihydro-1' H,3 'H-spiro [ octane-3, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine-8 ',10' -dione (example 11)

To the tube was added, in order, intermediate 8 (320 mg,0.46 mmol), lithium chloride (177 mg,4.18 mmol) and N-methylpyrrolidone (1 mL), and the mixture was reacted at 100℃for 20 hours. After the completion of the reaction, monitored by TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1), the reaction mixture was cooled to 40 ℃, acetonitrile (0.5 mL) and water (8.5 mL) were added in this order, cooled to 30 ℃ and stirred for 30min. Filtration and beating of the filter cake with (V _Acetonitrile：V_{acetic acid ethyl ester} = 1:1,3 ml) mixed solvent for 1h gave 70mg of white solid example 11 in 29.9% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.48(br,1H,ArH),7.29(br,2H,ArH),7.20(br,1H,ArH),7.10(br,2H,ArH),7.05-6.92(m,1H,ArH),5.71(br,1.5H,CH＝CH,CH),4.95(br,1.5H,CH＝CH,CH),4.46(br,1H,CH₂),3.82(br,2H,CH₂),3.53(br,5H,CH₂),2.25(br,1H,CH₂),1.77(br,1H,CH₂).

Example 12

Step 12 Synthesis of methyl cyclobutylacetate (2)

To a 500mL single-necked flask, compound 1 (5.00 g,71.3 mmol) and tetrahydrofuran (150 mL) were sequentially added, and 60% sodium hydrogen (3.71 g,92.7 mmol) was added in portions under nitrogen protection in an ice-water bath, followed by dropwise addition of a solution of trimethyl phosphate (18.2 g,99.9 mmol) in tetrahydrofuran (150 mL) after incubation for 1h, and after addition, room temperature was maintained overnight. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting materials, quenched with water (100 mL), extracted with n-hexane (150 mL x 3), combined organic phases, washed with saturated sodium chloride solution (200 mL), dried over anhydrous sodium sulfate, filtered off with suction, concentrated to give 9.00g of intermediate 2 as a yellow oil, which was used in the next step without purification.

Step 22 Synthesis of methyl- (1- (nitromethyl) cyclobutyl) acetate (3)

To a 250mL single-necked flask, intermediate 2 (9.00 g,71.3 mml), nitromethane (90 mL) and DBU (10.90 g,71.3 mmol) were sequentially added and reacted at room temperature under nitrogen for 2h. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting material, direct concentration, column chromatography purification (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) gave 9.50g of intermediate 3 as a yellow oil in 71.1% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):(s,2H,CH₂NO₂),3.69(s,3H,CH₃),2.73(s,2H,CH₂),2.19-2.06(m,2H,(CH₂)₃),2.06-1.96(m,4H,(CH₂)₃).

Step 36 Synthesis of azaspiro [3,4] octan-7-one (4)

To a 250mL autoclave were added, in order, intermediate 3 (4.00 g,21.4 mmol), methanol (50 mL), sodium methoxide (1.33g,30%wt in MeOH), and Raney Nickel (400 mg), and the mixture was reacted overnight at 60℃under hydrogen pressure to 60 psi. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, cooled to room temperature, filtered through celite, concentrated, and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 40:1) to give 2.30g of intermediate 4 as a white solid in 86.0% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):6.06(s,1H,NH),3.37(d,J＝0.9Hz,2H,CH₂),2.38(s,2H,CH₂),2.09-2.00(m,4H,(CH₂)₃),1.94-1.85(m,2H,(CH₂)₃).

Step 47 Synthesis of allyl-oxo-6-azaspiro [3,4] octane-6-carboxylate (5)

To a 100mL single-necked flask, intermediate 4 (1.00 g,8.0 mmol) and tetrahydrofuran (20 mL) were sequentially added, and n-BuLi (3.2 mL,8.0mmol,2.5N tetrahydrofuran solution) was added dropwise at-78deg.C under nitrogen protection, followed by heat preservation for 1h, and then Alloc-Cl (0.84 mL,8.0 mmol) was added dropwise, followed by heat preservation for 1h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quenched with saturated ammonium chloride solution (20 mL), extracted with ethyl acetate (30 mL x 3), combined organic phases, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered off with suction, concentrated, purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 100:1) to give 1.55g of intermediate 6 as colourless oil in 92.7% yield.

Step 5 7 Synthesis of allyl hydroxy-6-azaspiro [3,4] octane-6-carboxylate (6)

To a 100mL single-necked flask, intermediate 5 (1.55 g,7.4 mmol) and THF (30 mL) were sequentially added, followed by dropwise addition of DIBAl-H (9.6 mL,9.66mmol,1N tetrahydrofuran solution) at-78deg.C under nitrogen, and the reaction was continued for 2H at the temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) monitored complete reaction of starting material, quenched by addition of 0.5N diluted hydrochloric acid (30 mL), extracted with ethyl acetate (30 mL x 3), combined organic phases, dried over anhydrous sodium sulfate, filtered off with suction, concentrated to give 1.50g of intermediate 6 as colourless oil, which was used directly in the next step without purification.

Step 67 Synthesis of methoxy-6-azaspiro [3,4] octane-6-carboxylic acid allyl ester 7)

To a 100mL single-necked flask, intermediate 6 (1.50 g,7.1 mmol), methanol (20 mL), and p-toluenesulfonic acid monohydrate (135 mg,0.71 mmol) were sequentially added, and the mixture was reacted at room temperature under nitrogen for 1h. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 3:1) monitored complete reaction of starting materials, quenched with saturated sodium bicarbonate solution (40 mL), extracted with ethyl acetate (40 mL x 3), combined organic phases dried over anhydrous sodium sulfate, filtered off with suction, concentrated, purified by column chromatography (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) to give 1.22g of intermediate 7 as colourless oil in 76.3% yield.

Synthesis of allyl ester of 77- ((2- (ethoxycarbonyl) -3- (acetoxy) -4-oxopyridin-1 (4H) -yl) amino) -6-azaspiro [3.4] octane-6-carboxylate (8)

To a 100mL three-necked flask were successively added intermediate 7 (1.20 g,5.3 mml), ethyl 1-amino-3- (hexyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (1.50 g,5.3 mmol) and acetonitrile (30 mL), followed by dropwise addition of tin tetrachloride (1.0 mL,8.5 mmol) at-25℃under nitrogen protection, and the reaction was continued for 2 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting materials, addition of saturated sodium bicarbonate solution, adjustment of pH to 7, extraction with dichloromethane (50 mL x 3), combined organic phases, washing with saturated sodium chloride solution (50 mL), drying over anhydrous sodium sulfate, suction filtration, concentration, column chromatography purification (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) afforded 2.45g of intermediate 8 as a yellow oil in 92.4% yield.

Step 8 8',10' -Dioxo-3 a ',4',8',10' -tetrahydro-1 'H,3' H-spiro [ cyclobutane-1, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -9' -caproyl ester (9) Synthesis

To a 100mL single-necked flask, intermediate 8 (2.45 g,5.15 mmol), morpholine (20 mL) and tetrakis triphenylphosphine palladium (300 mg,0.26 mmol) were added sequentially and reacted at room temperature under nitrogen for 1h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, addition of isopropyl ether (400 mL), precipitation of solids, suction filtration and collection of filter cake gave 1.45g of intermediate 9 as a white solid in 80.6% yield.

Step 9 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis/> -11-yl) -8',10' -dioxo-3 a ',4',8',10' -tetrahydro-1 'H,3' H-spiro [ cyclobutane-1, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -9' -caproate (10)

To a 50mL single vial was added sequentially intermediate 9 (500 mg,1.45 mmol), ethyl acetate (20 mL), (S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine11-Alcohol (514 mg,2.17 mmol), propylphosphoric anhydride (50 wt% ethyl acetate solution, 2.76g,4.34 mmol) and methanesulfonic acid (278 mg,2.89 mmol), nitrogen blanket, were reacted overnight at 75 ℃. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =15:1) monitored complete reaction of starting material, cooled, diluted with ethyl acetate (50 mL), washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, suction filtered, concentrated, purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =200:1) to afford 370mg of yellow solid intermediate 10 in 42.3% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.48(d,J＝7.8Hz,1H,ArH),7.06-7.00(m,3H,ArH),6.82-6.75(m,3H,ArH),5.84(d,J＝7.8Hz,1H,ArH),5.61-5.58(m,1H,CH),5.30-5.26(m,1H,CH),5.08(s,1H,CH₂),4.29-4.20(m,2H,CH₂),4.10(d,J＝13.2Hz,1H,CH₂),3.98(d,J＝12.0Hz,1H,CH₂),3.42(d,J＝12.0Hz,1H,CH₂),2.03-1.99(m,2H,CH₂),1.96-1.84(m,5H,CH₂),1.83-1.80(m,1H,CH₂),1.73-1.70(m,1H,CH₂),1.59-1.55(m,1H,CH₂),1.47-1.43(m,2H,CH₂),1.38-1.34(m,4H,CH₂),0.92-0.89(m,3H,CH₃).

Step 10 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of-11-yl) -9 '-hydroxy-3 a',4 '-dihydro-1' H,3 'H-spiro [ cyclobutane-1, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (example 12)

To a 5mL thumb flask was added intermediate 10 (280 mg,0.47 mmol), N-methylpyrrolidone (0.6 mL), and lithium chloride (181 mg,4.26 mmol) in sequence, nitrogen-protected, and reacted overnight at 100 ℃. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of the starting material, cooled to room temperature, quenched with water (20 mL), solid precipitated, filtered, the filter cake collected, slurried with methanol (10 mL) and dried to give 100mg of white solid in 42.6% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.39-7.25(m,3H,ArH),7.08-6.97(m,2H,ArH),6.95-6.69(m,2H,ArH),5.82-5.70(m,1H,ArH),5.49-5.34(m,1H,CH),5.30-4.92(m,1.7H,CH,CH₂),4.21-4.07(m,1H,CH₂),3.86-3.74(m,0.8H,CH₂),3.48-3.41(m,1.5H,CH₂),2.08-1.92(m,2H,CH₂),1.88-1.72(m,4H,CH₂),1.65-1.54(m,1H,CH₂),1.41-1.29(m,1H,CH₂).

HRMS (ESI) M/z [ M+Na ] ⁺C₂₇H₂₃F₂N₃O₃ S theory 530.1326; actual measurement 530.1345.

Examples 13 to 16

SFC separation conditions:

Analysis conditions: method A: instrument: waters UPC2 analysis SFC (SFC-H), chromatographic column: CHIRALPAK AD, 150X 4.6mm I.D.,3 μm. Mobile phase: a represents CO ₂, and B represents isopropanol (0.05% DEA). Gradient: b50%. Flow rate: 2.5mL/min. Column pressure: 100bar. Column temperature: 35 ℃. Detector wavelength: 220nm. Method B: instrument: waters UPC2 analysis SFC (SFC-H). Chromatographic column: CHIRALPAK IG, 150X 4.6mm I.D.,3 μm. Mobile phase: a represents CO ₂, and B represents isopropanol (0.05% DEA). Gradient: b50%. Flow rate: 2.5mL/min. Column pressure: 100bar. Column temperature: 35 ℃. Detector wavelength: 220nm.

The preparation conditions are as follows: method A: instrument: SFC (SFC-14) was prepared. Chromatographic column: CHIRALPAK AD, 250X 30mm I.D.,10 μm. Mobile phase: a represents CO ₂, and B represents isopropanol (0.1% NH ₃H₂ O). Gradient: b45%. Flow rate: 80mL/min. Column pressure: 100bar. Column temperature: 38 ℃. Detector wavelength: 220nm. The preparation method of the sample comprises the following steps: the sample was dissolved in a mixed solvent (methanol/dichloromethane, 38 ml). Sample injection mode: sample introduction was performed every 9min, 2mL each time. The post-treatment method comprises the following steps: concentrating under reduced pressure to obtain the desired isomer. Method B: instrument: /(I) SFC (SFC-14) was prepared. Chromatographic column: CHIRALPAK IG, 250X 30mm I.D.,10 μm. Mobile phase: a represents CO ₂ and B represents methanol. Gradient: b50%. Flow rate: 80mL/min. Column pressure: 100bar. Column temperature: 38 ℃. Detector wavelength: 220nm. The preparation method of the sample comprises the following steps: the sample was dissolved in a mixed solvent (methanol/dichloromethane, 40 ml). Sample injection mode: sample injection is carried out every 8.3min, and the sample injection is carried out every 4mL. The post-treatment method comprises the following steps: concentrating under reduced pressure to obtain the desired isomer.

Intermediate 7 of example 2 (1.50 g) was resolved by SFC to give 262mg of example 13 as a pale yellow solid in 17.5% yield, ee=100%; 234mg of pale yellow solid example 14, yield 15.6%, ee=100%; 260mg of pale yellow solid example 15, yield 17.3%, ee=99.98%; 237mg of example 16 as a pale yellow solid, yield 15.8%, ee=99.94%.

Examples 13:¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.57-7.54(m,2H,ArH),7.39-7.35(m,2H,ArH),7.33-7.28(m,3H,ArH),7.25-7.17(m,4H,ArH),6.86-6.83(m,1H,ArH),5.75(d,J＝7.8Hz,1H,ArH),5.55-5.52(m,1H,CH),5.46-5.43(m,1H,CH),5.22(s,1H,CH₂),5.19(s,2H,CH₂),4.13(d,J＝14.4Hz,1H,CH₂),3.69(d,J＝12.0Hz,1H,CH₂),3.57-3.47(m,2H,CH₂),3.35-3.33(m,2H,CH₂),3.09(d,J＝12.0Hz,1H,CH₂),2.03-2.00(m,1H,CH₂),1.46-1.39(m,1H,CH₂),1.38-1.33(m,1H,CH₂),1.04-1.01(m,1H,CH₂),1.00-0.95(m,1H,CH₂),0.93-0.91(m,1H,CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₃₅H₃₁F₂N₃O₄ S theory 628.2082; actual measurement 628.2086.

Examples 14:¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.61(d,J＝7.8Hz,1H,ArH),7.56-7.53(m,2H,ArH),7.52-7.50(m,1H,ArH),7.39-7.31(m,4H,ArH),7.11-7.08(m,1H,ArH),7.04-7.03(m,1H,ArH),6.89-6.84(m,2H,ArH),5.77(d,J＝7.8Hz,1H,ArH),5.72-5.69(m,1H,CH),5.54-5.51(m,1H,CH),5.40(s,1H,CH₂),5.12-5.04(m,2H,CH₂),4.15(d,J＝13.8Hz,1H,CH₂),3.85(d,J＝12.0Hz,1H,CH₂),3.56-3.51(m,2H,CH₂),3.48(d,J＝12.0Hz,1H,CH₂),3.42-3.39(m,2H,CH₂),1.99-1.96(m,1H,CH₂),1.47-1.43(m,1H,CH₂),1.39-1.35(m,1H,CH₂),1.33-1.30(m,2H,CH₂),1.24-1.20(m,1H,CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₃₅H₃₁F₂N₃O₄ S theory 628.2082; actual measurement 628.2084.

Examples 15:¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.57-7.54(m,2H,ArH),7.39-7.35(m,2H,ArH),7.34-7.28(m,3H,ArH),7.26-7.16(m,4H,ArH),6.86-6.73(m,1H,ArH),5.75(d,J＝7.8Hz,1H,ArH),5.55-5.52(m,1H,CH),5.46-5.43(m,1H,CH),5.22(s,1H,CH₂),5.19(s,2H,CH₂),4.13(d,J＝14.4Hz,1H,CH₂),3.69(d,J＝12.0Hz,1H,CH₂),3.58-3.47(m,2H,CH₂),3.35-3.33(m,2H,CH₂),3.09(d,J＝12.0Hz,1H,CH₂),2.03-2.00(m,1H,CH₂),1.44-1.39(m,1H,CH₂),1.38-1.34(m,1H,CH₂),1.04-1.02(m,1H,CH₂),0.98-0.94(m,1H,CH₂),0.93-0.60(m,1H,CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₃₅H₃₁F₂N₃O₄ S theory 628.2082; actual measurement 628.2079.

Examples 16:¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.61(d,J＝7.8Hz,1H,ArH),7.58-7.54(m,2H,ArH),7.52-7.50(m,1H,ArH),7.39-7.30(m,4H,ArH),7.11-7.08(m,1H,ArH),7.05-7.02(m,1H,ArH),6.0-6.85(m,2H,ArH),5.77(d,J＝7.8Hz,1H,ArH),5.72-5.69(m,1H,CH),5.54-5.51(m,1H,CH),5.40(s,1H,CH₂),5.11-5.05(m,2H,CH₂),4.15(d,J＝13.8Hz,1H,CH₂),3.85(d,J＝12.0Hz,1H,CH₂),3.56-3.54(m,2H,CH₂),3.48(d,J＝12.0Hz,1H,CH₂),3.43-3.39(m,2H,CH₂),1.99-1.96(m,1H,CH₂),1.46-1.43(m,1H,CH₂),1.39-1.35(m,1H,CH₂),1.33-1.30(m,2H,CH₂),1.24-1.21(m,1H,CH₂).

Examples 17 to 20

To a thumb flask were added example 13 (250 mg,0.40 mmol), N-dimethylacetamide (4 mL), and lithium chloride (169 mg,4.0 mmol) in sequence, nitrogen-protected, and reacted for 5h at 80 ℃. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, the reaction cooled to room temperature, quenched by addition of water (10 mL) to the reaction, filtered and the filter cake purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 145mg of example 17 as a reddish brown solid in 67.7% yield, ee = 98.882%.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.63-7.36(m,2H,ArH),7.35-7.25(m,2H,ArH),7.24-7.09(m,3H,ArH),7.09-6.66(m,1H,ArH),5.80-5.46(m,3H,CH,CH₂),5.40-5.20(m,1H,CH₂),4.22-4.11(m,1H,CH₂),3.82-3.80(m,1H,CH₂),3.68-3.51(m,2H,CH₂),3.24-2.99(m,2H,CH₂),2.22-1.95(m,1H,CH₂),1.58-1.33(m,2H,CH₂),1.29-1.11(m,2H,CH₂),1.03-0.89(m,2H,CH₂).

Example 18

Referring to the preparation method of example 17, using example 14 as a raw material, the compound of example 18 was prepared in 127mg of a reddish brown solid, yield 64.5％,ee＝99.314％;¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.52-7.48(m,2H,ArH),7.44-7.31(m,2H,ArH),7.10-7.00(m,2H,ArH),6.98-6.85(m,2H,ArH),5.75-5.68(m,1.5H,CH,CH₂),5.63-5.58(m,2.5H,CH,CH₂),4.24-4.13(m,1H,CH₂),3.92-3.88(m,1H,CH₂),3.57-3.46(m,4H,CH₂),2.07-1.93(m,1H,CH₂),1.53-1.31(m,4H,CH₂),1.25-1.21(m,2H,CH₂).

Example 19

Referring to the procedure for the preparation of example 17, starting from example 15, the compound of example 19 was prepared in 130mg of a reddish brown solid, yield 60.7％,ee＝100％;¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.63-7.37(m,2H,ArH),7.37-7.13(m,5H,ArH),7.13-6.75(m,1H,ArH),5.80-5.52(m,3H,CH,CH₂),5.50-5.40(m,1H,CH₂),4.18-4.11(m,1H,CH₂),3.83-3.80(m,1H,CH₂),3.65-3.52(m,3H,CH₂),3.16-3.06(m,1H,CH₂),2.13-1.90(m,1H,CH₂),1.56-1.33(m,2H,CH₂),1.27-1.16(m,1H,CH₂),1.06-0.79(m,3H,CH₂).

Example 20

Referring to the procedure for the preparation of example 17, starting from example 16, the compound of example 20 was prepared in 130mg of a reddish brown solid, yield 66.0％,ee＝100％.¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.52-7.48(m,2H,ArH),7.40-7.30(m,2H,ArH),7.10-7.01(m,2H,ArH),6.97-6.80(m,2H,ArH),5.76-5.68(m,1.5H,CH,CH₂),5.65-5.56(m,2.5H,CH,CH₂),4.21-4.14(m,1H,CH₂),3.90-3.88(m,1H,CH₂),3.58-3.48(m,4H,CH₂),2.00-1.95(m,1H,CH₂),1.53-1.40(m,2H,CH₂),1.37-1.30(m,2H,CH₂),1.26-1.20(m,2H,CH₂)

10Mg of the compound of example 20 was weighed and dissolved in 1.0ml of methanol, and the solvent was evaporated at room temperature to obtain colorless bulk crystals, i.e., a single crystal of the compound of example 20. The results of single crystal structure analysis of the compound of example 20 are shown below.

TABLE 1 crystallographic data

TABLE 2 atomic coordinates (x 10 ⁴) and equivalent isotropic displacement parameters

FIGS. 1 and 2 show a single crystal structure and a single crystal stacking diagram, respectively, of the compound of example 20.

Examples 21 to 24

SFC separation conditions: analysis conditions: method A: instrument: waters UPC2 analysis SFC (SFC-H). Chromatographic column: CHIRALCEL OJ, 150X 4.6mm I.D.,3 μm. Mobile phase: a represents CO ₂, and B represents isopropanol (0.05% DEA). Gradient: b40%. Flow rate: 2.5mL/min. Column pressure: 100bar. Column temperature: 35 ℃. Detector wavelength: 220nm. Method B: instrument: waters UPC2 analysis SFC (SFC-H). Chromatographic column: CHIRALPAK AS, 150X 4.6mm I.D.,3 μm. Mobile phase: a represents CO ₂, and B represents isopropanol (0.05% DEA). Gradient: b40%. Flow rate: 2.5mL/min. Column pressure: 100bar. Column temperature: 35 ℃. Detector wavelength: 220nm.

The preparation conditions are as follows: method A: instrument: MG II produced SFC (SFC-14). Chromatographic column: CHIRALCEL OJ, 250X 30mm I.D.,10 μm. Mobile phase: a represents CO ₂, and B represents isopropanol (0.1% NH ₃H₂ O). Gradient: b30%. Flow rate: 70mL/min. Column pressure: 100bar. Column temperature: 38 ℃. Detector wavelength: 220nm. The preparation method of the sample comprises the following steps: the sample was dissolved in a mixed solvent (methanol/dichloromethane, 60 ml). Sample injection mode: samples were taken every 23min, 2mL each time. The post-treatment method comprises the following steps: concentrating under reduced pressure to obtain the desired isomer. Method B: instrument: MG II produced SFC (SFC-14). Chromatographic column: CHIRALPAK AS, 250X 30mm I.D.,10 μm. Mobile phase: a represents CO ₂ and B represents methanol. Gradient: b10%. Flow rate: 60mL/min. Column pressure: 100bar. Column temperature: 38 ℃. Detector wavelength: 220nm. The preparation method of the sample comprises the following steps: the sample was dissolved in a mixed solvent (methanol/dichloromethane, 15 ml). Sample injection mode: sample injection is carried out every 20min, and the sample injection is 4mL each time. The post-treatment method comprises the following steps: concentrating under reduced pressure to obtain desired isomer

The intermediate compound of example 3 (1.40 g,1.84 mmol) was resolved by SFC to give 270mg of example 21 as a pale yellow solid in 19% yield, ee >99%;230mg of pale yellow solid example 22, yield 16%, ee >99%;260mg of pale yellow solid example 23, yield 19%, ee=98.8%; 230mg of pale yellow solid example 24, yield 16%, ee=98.8%;

examples 25 to 28

To a thumb flask were added example 21 (100 mg,0.13 mmol), N-dimethylacetamide (3 mL) and lithium chloride (28 mg,0.66 mmol) in sequence, and reacted at 80℃for 5h under nitrogen protection. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitoring the end of the reaction, the reaction was cooled to room temperature, quenched by addition of water (10 mL), filtered and the filter cake purified by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 60mg of example 25 as a reddish brown solid in 69%.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.81-7.51(m,1H,ArH),7.52-7.41(m,1H,ArH),7.41-7.35(m,1.5H,ArH),7.34-7.29(m,1H,ArH),7.28-7.22(m,1H,ArH),7.17-7.02(m,1.5H,ArH),7.00-6.87(m,0.5H,ArH),6.85-6.70(m,1H,ArH),5.84-5.66(m,1H,SCH₂),5.65-5.55(m,1H,SCH₂),5.54-5.40(m,1H,NCH),5.39-5.23(m,1H,NCH),5.07-4.93(m,2H,OCH₂),4.26-4.03(m,1H,NCH₂),3.93-3.69(m,1H,NCH₂),3.64-3.48(m,1H,NCH₂),3.47-3.34(m,2H,NCH₂),3.23-3.06(m,1H,NCH₂),2.19-1.94(m,1H,CH₂),1.53-1.29(m,3H,CH₃),1.17-0.78(m,2H,CH₂).

Example 26

With reference to the preparation method of example 25, using example 22 as a raw material, 135mg of a reddish brown solid was obtained in 100% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.85-7.48(m,1H,ArH),7.47-7.40(m,1H,ArH),7.39-7.35(m,1H,ArH),7.34-7.27(m,5H,ArH),7.26-7.19(m,1.5H,ArH),7.16-7.01(m,1H,ArH),7.00-6.88(m,1.5H,ArH),6.87-6.71(m,1H,ArH),5.92-5.63(m,1H,SCH₂),5.63-5.51(m,1H,SCH₂),5.51-5.34(m,1H,NCH),5.34-5.25(m,1H,NCH),5.05-4.92(m,1H,OCH₂),4.24-4.02(m,1H,NCH₂),3.94-3.65(m,1H,NCH₂),3.64-3.39(m,3H,NCH₂),3.18-3.12(m,1H,NCH₂),2.15-1.83(m,1H,CH₂),1.54-1.23(m,3H,CH₂),1.21-0.84(m,2H,CH₂).

Example 27

With reference to the preparation method of example 25, starting from example 23, 106mg of a reddish brown solid were obtained in 79% yield.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.53-7.36(m,1H,ArH),7.36-7.32(m,2H,ArH),7.32-7.25(m,5H,ArH),7.25-7.20(m,2H,ArH),7.20-6.97(m,2H,ArH),6.96-6.44(m,1H,ArH),5.83-5.62(m,1H,SCH₂),5.61-5.51(m,1H,SCH₂),5.51-5.24(m,1H,NCH),5.24-5.06(m,1H,NCH),5.05-4.92(m,2H,OCH₂),4.20-4.10(m,1H,NCH₂),4.09-3.93(m,1H,NCH₂),3.85-3.50(m,1H,NCH₂),3.45-3.35(m,2H,NCH₂),3.15-3.09(m,1H,NCH₂),2.18-1.87(m,1H,CH₂),1.58-1.23(m,3H,CH₂),1.02-0.77(m,2H,CH₂).

Example 28

With reference to the preparation method of example 25, 100mg of a reddish brown solid was obtained in 75% yield using example 24 as a starting material.

¹H NMR(400MHz,DMSO-d₆)δ(ppm):7.60-7.36(m,1H,ArH),7.36-7.31(m,2H,ArH),7.31-7.26(m,5H,ArH),7.25-7.18(m,2H,ArH),7.18-6.89(m,2H,ArH),6.88-6.37(m,1H,ArH),5.84-5.62(m,1H,SCH₂),5.61-5.52(m,1H,SCH₂),5.51-5.25(m,1H,NCH),5.24-5.04(m,1H,NCH),5.05-4.92(m,2H,OCH₂),4.25-3.96(m,1H,NCH₂),3.91-3.52(m,1H,NCH₂),3.46-3.36(m,1H,NCH₂),3.22-2.87(m,3H,NCH₂),2.30-1.76(m,1H,CH₂),1.62-1.31(m,2H,CH₂),1.13-0.73(m,3H,CH₂)

EXAMPLE 29 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)Synthesis of (E) -11-yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin-9' -yl) oxy) methyl (t-butoxycarbonyl) -L-valine ester

Step 1 Synthesis of chloromethyl (t-butoxycarbonyl) -L-valine (2)

To a 100mL single-necked flask, compound 1 (2.0 g,9.21 mmol), sodium bicarbonate (3.09 g,36.84 mmol), tetrabutylammonium bisulfate (312 mg,0.92 mmol), methylene chloride (20 mL) and water (20 mL) were sequentially added, and after the addition was completed, chloromethyl chlorosulfonate (1.82 g,11.05 mmol) was added after stirring at room temperature for 10min, and the reaction was completed at room temperature overnight. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting material. The aqueous phase was separated, extracted with dichloromethane (50 ml×3), the organic phases combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, concentrated, and purified by flash preparative chromatography (20 g, v _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) to give 1.95g of colorless oily intermediate 2 in 79.7% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):5.87(d,J＝6.1Hz,1H,CH₂Cl),5.62(d,J＝6.1Hz,1H,CH₂Cl),4.97(d,J＝9.0Hz,1H,NH),4.27(dd,J₁＝9.0Hz,J₂＝4.9Hz,1H,NHCH),2.23-2.13(m,1H,CH(CH₃)₂),1.45(s,9H,C(CH₃)₃),1.00(d,J＝6.8Hz,3H,CH₃),0.92(d,J＝6.9Hz,3H,CH₃).

Step 2 Synthesis of iodomethyl (t-butoxycarbonyl) -L-valine (3)

To a Schlenk reaction tube were added intermediate 2 (500 mg,1.88 mmol), sodium iodide (1.41 g,9.41 mmol) and acetone (5 mL), and the mixture was reacted at 60℃for 2 hours in the absence of light. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 10:1) monitored complete reaction of starting material. The reaction solution was filtered through celite, the filtrate was concentrated, and the residue was dissolved in ethyl acetate (20 mL), washed with a saturated aqueous sodium thiosulfate solution (50 mL) and a saturated saline solution (50 mL) in this order, dried over anhydrous sodium sulfate, filtered, and concentrated to give 600mg of crude intermediate 3 as a yellow oil, which was directly subjected to the next reaction.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):6.86(d,J＝8.5Hz,1H,NH),4.63(d,J＝6.2Hz,1H,CH₂I),3.76-3.71(m,1H,CH₂I),1.99-1.91(m,1H,CH(CH₃)₂),1.34(s,9H,C(CH₃)₃),0.85-0.79(m,6H,CH(CH₃)₂).

Step 3 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)Synthesis of-11-yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl (t-butoxycarbonyl) -L-valine ester (example 29)

To a thumb flask were added example 20 (140 mg,0.26 mmol), intermediate 3 (279 mg,0.78 mmol), cesium carbonate (254 mg,0.78 mmol) and acetonitrile (5 mL), and the addition was completed and reacted overnight at 80℃under nitrogen. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored the starting material for a significant amount remaining. The reaction solution was filtered through celite, and the filtrate was concentrated and purified by flash chromatography (4 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 30mg of a yellow solid in 15.0% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.57(d,J＝7.8Hz,1H,ArH),7.43(dd,J₁＝8.9Hz,J₂＝4.6Hz,1H,ArH),7.34-7.27(m,1H,ArH),7.08-7.03(m,1H,ArH),7.02-6.97(m,2H,ArH),6.89-6.84(m,1H,ArH),6.84-6.79(m,1H,ArH),5.75(d,J＝7.8Hz,1H,NH),5.71-5.66(m,2H,SCH₂),5.66-5.61(m,1H,NHCH),5.52(dd,J₁＝10.3Hz,J₂＝6.8Hz,1H,NCH),5.31(s,1H,NCH),4.12(d,J＝13.9Hz,1H,OCH₂),3.97(dd,J₁＝8.8Hz,J₂＝5.4Hz,1H,OCH₂),3.84(d,J＝11.9Hz,1H,NCH₂),3.55-3.49(m,2H,OCH₂),3.40(d,J＝11.9Hz,1H,NCH₂),3.38-3.34(m,2H,OCH₂),2.07-2.00(m,1H,CH₂),1.99-1.94(m,1H,CH₂),1.47-1.38(m,1H,CH₂),1.37-1.33(m,1H,CH₂),1.31(s,9H,C(CH₃)₃),1.30-1.25(m,2H,CH₂),1.22-1.13(m,1H,CH(CH₃)),0.82(d,J＝6.9Hz,3H,CH(CH₃)),0.76(d,J＝6.9Hz,3H,CH(CH₃)).

EXAMPLE 30 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11-Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl carbonate synthesis/>

To a 25mL single-port flask, compound example 20 (P4) (130 mg,0.24 mmol), acetonitrile (4 mL), potassium carbonate (67 mg,0.48 mmol), chloromethyl dimethyl carbonate (45 mg,0.36 mmol) and potassium iodide (40 mg,0.24 mmol) were successively added, and the mixture was reacted at 80℃for 6 hours under nitrogen atmosphere. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1) monitored complete reaction of starting material, cooled to room temperature, filtered through celite, concentrated, and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =50:1) to give 45mg of white solid example 30 in 30.9% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.64(d,J＝7.8Hz,1H,ArH),7.54-7.49(m,1H,ArH),7.36-7.31(m,1H,ArH),7.12-7.09(m,1H,ArH),7.06-7.01(m,1H,ArH),6.92-6.86(m,2H,ArH),5.82(d,J＝7.8Hz,1H,ArH),5.73-5.67(m,2H,CH₂),5.61-5.59(m,1H,CH),5.55(d,J＝6.8Hz,1H,CH),5.37(s,1H,CH₂),4.16(d,J＝13.8Hz,1H,CH₂),3.81(d,J＝12.0Hz,1H,CH₂),3.76(s,3H,CH₃),3.57-3.51(m,2H,CH₂),3.49(d,J＝12.0Hz,1H,CH₂),3.41(t,J＝5.4Hz,2H,CH₂),2.01-1.97(m,1H,CH₂),1.49-1.38(m,2H,CH₂),1.36-1.30(m,2H,CH₂),1.25-1.21(m,1H,CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₃₁H₂₉F₂N₃O₇ S theory 626.1773; actual measurement value: 626.1766.

EXAMPLE 31 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) butanoic acid methyl ester

To a 50mL single port flask was added compound example 20 (P4) ((100 mg,0.19 mmol), methyl bromobutyrate (51 mg,0.28 mmol), cesium carbonate (309 mg,0.95 mmol), potassium iodide (32 mg,0.19 mmol) and DMF (4 mL), nitrogen-protected, reacted overnight at 100 ℃ C. TLC (_{dichloromethane (dichloromethane)}：V_Methanol =10:1) monitored the reaction was complete, the reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL×3), the organic phases were combined, washed with saturated brine (30 mL×3), dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1) to give 80mg of a reddish brown solid example 31 in 67.2% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.61(d,J＝7.8Hz,1H,ArH),7.53-7.51(m,1H,ArH),7.36-7.33(m,1H,ArH),7.11-7.08(m,1H,ArH),7.04-7.02(m,1H,ArH),6.89-6.86(m,2H,ArH),5.72-5.70(m,2H,ArH,CH₂),5.61-5.58(m,1H,CH₂),5.40(s,1H,CH),4.16(d,J＝14.4Hz,1H,CH₂),4.05(t,J＝6.0Hz,2H,CH₂),3.86(d,J＝12.0Hz,1H,CH₂),3.62(s,3H,CH₃),3.54(t,J＝5.4Hz,2H,CH₂),3.50(d,J＝12.0Hz,1H,CH₂),3.41(t,J＝5.4Hz,2H,CH₂),2.58(t,J＝7.2Hz,2H,CH₂),2.00-1.96(m,1H,CH₂),1.95-1.87(m,2H,CH₂),1.50-1.46(m,1H,CH₂CH₃),1.41-1.38(m,1H,CH₂CH₂),1.36-1.32(m,2H,CH₂CH₂),1.22-1.20(m,1H,CH₂).

EXAMPLE 32 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) butanoic acid synthesis

To a 50mL single vial was added compound example 31 (80 mg,0.13 mmol), lithium hydroxide monohydrate (11 mg,0.25 mmol), methanol (4 mL), and water (0.8 mL), nitrogen blanket, and reacted overnight at room temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored the reaction was complete, the reaction was concentrated to remove methanol, the aqueous phase was washed with ethyl acetate (2 mL x 3), 1N hydrochloric acid adjusted to pH 5, the solid precipitated, filtered, washed with water (1 mL x 3), dried in vacuo at room temperature for 3h to give 55mg of off-white solid example 32 in 70.3% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):11.99(s,1H,COOH),7.57(d,J＝7.8Hz,1H,ArH),7.49-7.46(m,1H,ArH),7.32-7.27(m,1H,ArH),7.07-7.04(m,1H,ArH),6.99-6.98(m,1H,ArH),6.85-6.83(m,2H,ArH),5.68-5.66(m,2H,ArH,CH₂),5.57-5.54(m,1H,CH₂),5.36(s,1H,CH),4.12(d,J＝13.8Hz,1H,CH₂),4.01(t,J＝6.6Hz,2H,CH₂),3.83(d,J＝12.0Hz,1H,CH₂),3.51(d,J＝4.8Hz,2H,CH₂),3.46(d,J＝12.0Hz,1H,CH₂),3.36(t,J＝4.8Hz,2H,CH₂),2.44-2.42(m,2H,CH₂),1.96-1.92(m,1H,CH₂),1.90-1.80(m,2H,CH₂),1.45-1.43(m,1H,CH₂CH₃),1.37-1.28(m,3H,CH₂CH₂),1.19-1.15(m,1H,CH₂CH₂).

EXAMPLE 33 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) butanoic acid sodium salt synthesis

To a 25mL single vial was added compound example 32 (32 mg,0.05 mmol) and methanol (1 mL), followed by a solution of sodium hydroxide (2 mg,0.05 mmol) in water (0.1 mL), nitrogen-blanketed, and reacted at room temperature for 1h. The reaction mixture was concentrated to dryness, distilled over methanol (1 mL), and dried under vacuum at room temperature for 4h to give 33mg of yellow-brown solid example 33 in 100% yield.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.54(d,J＝7.8Hz,1H,ArH),7.48-7.46(m,1H,ArH),7.31-7.27(m,1H,ArH),7.06-7.03(m,1H,ArH),6.99-6.97(m,1H,ArH),6.91-6.88(m,1H,ArH),6.86-6.84(m,1H,ArH),5.68-5.64(m,2H,ArH,CH₂),5.56(dd,J₁＝10.2Hz,J₂＝7.2Hz,1H,CH₂),5.35(s,1H,CH),4.12(d,J＝14.4Hz,1H,CH₂),3.95(t,J＝6.6Hz,2H,CH₂),3.84(d,J＝12.0Hz,1H,CH₂),3.50(d,J＝6.0Hz,2H,CH₂),3.45(d,J＝12.0Hz,1H,CH₂),3.36-3.35(m,2H,CH₂),1.95-1.90(m,3H,CH₂,CH₂),1.85-1.76(m,2H,CH₂),1.46-1.42(m,1H,CH₂),1.37-1.32(m,1H,CH₂CH₃),1.30-1.27(m,2H,CH₂CH₂),1.19-1.14(m,1H,CH₂CH₂).

EXAMPLE 34 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl 2-morpholinoacetate Synthesis step 1 (((R) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiaSynthesis of (E) -11-yl) -9 '-chloromethyloxy-2, 3a',4',5, 6-hexahydro-1' H,3 'H-azaspiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione (2)

To a 50mL single-necked flask was added sequentially example 20 (500 mg,0.93 mmol), DCM (10 mL), tetrabutylammonium bisulfate (32 mg,0.09 mmol), water (10 mL) and sodium bicarbonate (313 mg,3.72 mmol), followed by stirring at room temperature for 20min and then dropwise chloromethylchlorosulfonate (307 mg,1.86 mmol) and stirring at room temperature under nitrogen overnight. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched with water (20 mL), extracted with dichloromethane (30 mL x 3), washed with saturated brine (10 mL x 3), dried, filtered, concentrated and purified by flash chromatography (24 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 240mg of intermediate 2 as a white solid in 44.1% yield.

HRMS (ESI) M/z [ M+H ] ⁺C₂₉H₂₆ClF₂N₃O₄ S theory 586.1374; actual measurement value 586.1388.

Step 2 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)Synthesis/>, of-11-yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl 2-morpholinoacetate (example 34)

To a 10mL thumb flask were added in order intermediate 2 (120 mg,0.21 mmol), DMF (2 mL), potassium carbonate (58 mg,0.42 mmol) and morpholin-4-ylacetic acid (53 mg,0.32 mmol) and stirred at room temperature under nitrogen for 3h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenching with water (10 mL), extraction with dichloromethane (20 mL x 3), washing with saturated brine (10 mL x 3), drying, filtration, concentration and purification by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) gave crude product which was slurried with low boiling petroleum ether (10 mL) at room temperature for 3h, filtration, collection of the filter cake and oven drying overnight at 42 ℃ in a vacuum oven gave 75mg of pink solid example 34 in 51.4% yield.

HRMS (ESI) M/z [ M+H ] ⁺C₃₅H₃₆F₂N₄O₇ S theory 695.2346; actual measurement value 695.2355

EXAMPLE 35 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)Synthesis of-11 yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl-2- (4-methylpiperazin-1-yl) acetate

To a 10mL thumb flask was added compound 2 (120 mg,0.21 mmol), DMF (2 mL), potassium carbonate (58 mg,0.42 mmol) and 4-methyl-1-piperazineacetic acid (60 mg,0.32 mmol) in this order, and stirred at room temperature under nitrogen for 3h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenching with water (10 mL), extraction with dichloromethane (20 mL x 3), washing with saturated brine (10 mL x 3), drying, filtration, concentration and purification by flash chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) gave crude product which was slurried with low boiling petroleum ether (10 mL) at room temperature for 3h, filtration, collection of the filter cake and oven drying overnight at 42 ℃ in a vacuum oven gave 70mg of pink solid example 35 in 47.1% yield.

HRMS (ESI) M/z [ M+H ] ⁺C₃₆H₃₉F₂N₅O₆ S theory 708.2662; actual measurement value 708.2654.

EXAMPLE 36 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11-Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methylmorpholine-4-carboxylate synthesis/>

To a 25mL single vial was added example 20 (100 mg,0.20 mmol), chloromethylmorpholine-4-carboxylate (42.0 mg,0.24 mmol), potassium carbonate (60 mg,0.40 mmol), potassium iodide (40.0 mg,0.20 mmol) and N, N-dimethylformamide (4 mL), and the addition was completed and reacted overnight at 65℃under nitrogen. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored the starting material remaining 50%. The reaction was cooled to room temperature, quenched with water (20 mL), the reaction was extracted with dichloromethane (30 mL. Times.3), and the organic phase was collected. Saturated sodium chloride solution (50 ml×3) was washed, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (4 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give example 36 as a yellow solid 44mg in 32.3% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):7.41(d,J＝7.8Hz,1H,CH＝CH),7.07-7.01(m,3H,ArH),6.89-6.82(m,2H,ArH),6.78(d,J＝7.7Hz,1H,ArH),5.97(d,J＝6.3Hz,1H,CH＝CH),5.87-5.80(m,2H,CH₂),5.53(d,J＝11.1Hz,1H,CH₂),5.41-5.38(m,1H,CH),5.02(s,1H,CH),4.11-4.07(m,1H,CH₂),4.03(d,J＝11.9Hz,1H,CH₂),3.74-3.70(m,4H,CH₂CH₂),3.70-3.66(m,1H,CH₂),3.59-3.579(m,4H,CH₂),3.56-3.52(m,2H,CH₂),3.48-3.43(m,1H,CH₂),3.26(d,J＝11.9Hz,1H,CH₂),1.93-1.88(m,1H,CH₂),1.48-1.44(m,3H,CH₂CH₂),1.38-1.34(m,1H,CH₂),1.32-1.30(m,1H,CH₂).

HRMS (ESI) M/z [ M+Na ] ⁺C₃₄H₃₄F₂N₄O₇ S theory 703.2014; actual measurement value 703.1985.

EXAMPLE 37 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl carbamate synthesis

Step 1 Synthesis of chloromethyl methyl carbamate (2)

To a 100mL three-necked flask, compound 1 (2.15 g,16.7 mmol) and methylene chloride (20 mL) were successively added, and a methylamine solution (3.14 g,33.3mmol,33wt% ethanol solution) was added dropwise thereto at-30℃under nitrogen, followed by reaction at Bi Huanman liters to room temperature for 2 hours. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 3:1) monitored complete reaction of starting materials, cooled to room temperature, quenched with water (30 mL), extracted with dichloromethane (20 mL x 3), combined organic phases, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, concentrated to give 1.60g of yellow oil 2 which was used directly in the next step without purification.

Step 2 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11-Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl carbamate synthesis/>

To a 25mL single-port flask, the compound of example 20 (200 mg,0.37 mmol), acetonitrile (4 mL), potassium carbonate (103 mg,0.74 mmol), intermediate 2 (55 mg,0.44 mmol), potassium iodide (62 mg,0.37 mmol), nitrogen protection, and reaction at 80℃were sequentially added for 6 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =20:1) monitored complete reaction of starting material, cooled to room temperature, filtered through celite, concentrated, and purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol =50:1) to give 50mg of white solid, example 37, 21.5% yield.

HRMS (ESI) M/z [ M+H ] ⁺C₃₁H₃₀F₂N₄O₆ S theory 625.1932; actual measurement value: 625.1344.

EXAMPLE 38 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl carbamate Synthesis step 1 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiaSynthesis of (E) -11-yl) -9 '-azidomethoxy-2, 3a',4',5, 6-hexahydro-1' H,3 'H-azaspiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione

To a 25mL single-necked flask was added intermediate 2 (500 mg,0.85 mmol) of example 34 and N, N-dimethylformamide (5 mL) in this order, and an aqueous solution (2 mL) of sodium azide (83 mg,1.28 mmol) was slowly added dropwise and the mixture was reacted overnight at room temperature under nitrogen. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored the end of the reaction, the reaction was quenched with saturated sodium bicarbonate solution (3 mL), extracted with dichloromethane (5 mL x 3) and the organic phase was collected. Saturated sodium chloride solution (4 ml×3) was washed, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (4 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 176mg of a white solid in 35.0% yield.

Step 2 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)Synthesis/>, of-11-yl) -9 '-aminomethoxy-2, 3a',4',5, 6-hexahydro-1' H,3 'H-azaspiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -8',10' -dione

To a 25mL single-port flask, compound 2 (160 mg,0.27 mmol), tetrahydrofuran (4 mL), water (0.4 mL), and triphenylphosphine (106 mg,0.41 mmol) were sequentially added, and the mixture was reacted overnight at room temperature under nitrogen. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored the reaction was completed, the reaction was quenched with water (5 mL), extracted with dichloromethane (5 mL x 3) and the organic phase was collected. Saturated sodium chloride solution (4 ml×3) was washed, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (4 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 105mg of a white solid in 68.6% yield.

Step 3 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl carbamate synthesis

To a 25mL single-necked flask, compound 3 (100 mg,0.18 mmol), N-dimethylformamide (1 mL), methyl chloroformate (20 mg,0.21 mmol) and N, N-diisopropylethylamine (35 mg,0.27 mmol) were successively added, and the mixture was reacted at room temperature under nitrogen atmosphere for 2 hours. After TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored the reaction was completed, the reaction was quenched with water (4 mL), extracted with dichloromethane (5 mL x 3) and the organic phase was collected. Saturated sodium chloride solution (5 ml×3) was washed, dried over anhydrous sodium sulfate, filtered, concentrated and purified by flash chromatography (4 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 80mg of a white solid in 71.4% yield.

HRMS (ESI) M/z [ M+H ] ⁺C₃₁H₃₀F₂N₄O₆S₃ theory: 625.1932; actual measurement value: 625.1922.

EXAMPLE 39 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11 Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 ' H,3' H-spiro [ pyran-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl (S) -2- ((S) -2, 6-diaminohexanoyl) amino-3, 3-dimethylbutyrate synthesis step 1 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiaSynthesis/> -11-yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl (S) -2-t-butoxycarbonylamino-3, 3-dimethylbutyrate (2)

Example 34 intermediate 2 (500 mg,0.85 mmol), DMF (10 mL), potassium carbonate (236 mg,1.71 mmol) and N-Boc-L-tert-leucine (295 mg,1.28 mmol) were added sequentially to a bottle at port 2 for L-intermediate monomer in example 2354m and stirred at room temperature under nitrogen for 3h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched with water (20 mL), extracted with dichloromethane (35 mL x 3), washed with saturated brine (20 mL x 3), dried, filtered, concentrated and purified by flash chromatography (24 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 500mg of white solid in 75.4% yield.

Step 2 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)-11-Yl) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl (S) -2-amino-3, 3-dimethylbutyrate hydrochloride (3) synthesis

To a 25mL single-necked flask, compound 2 (500 mg,0.64 mmol), ethyl acetate (5 mL) and 4 NHCl/ethyl acetate (5 mL) were sequentially added, and the mixture was reacted at room temperature under nitrogen atmosphere for 2 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material. Concentration directly gave 400mg of white solid 3 which was used directly in the next step without purification.

Step 3 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)Synthesis/>

To a 25mL single vial was added compound 3 (400 mg,0.56 mmol), DMF (8 mL), (S) -2, 6-di-tert-butoxycarbonylaminohexanoic acid (29 mg,0.84 mmol), HATU (425 mg,1.12 mmol) and DIPEA (433 mg,3.36 mmol) in sequence, and the reaction was continued at room temperature under nitrogen for 16h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material. Quench with water (20 mL), extract with dichloromethane (40 ml×3), wash with saturated brine (20 ml×4), dry, filter, concentrate and purify by flash chromatography (24 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) to give 380mg of white solid 4 in 58.8% two steps.

Step 4 (((S) -4' - ((S) -7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine)Synthesis of (11) -8',10' -dioxo-2, 3a ',4',5,6,8',10' -octahydro-1 'H,3' H-spiro [ pyran-4, 2 '-pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazin ] -9' -yl) oxy) methyl (S) -2- ((S) -2, 6-diaminohexanoyl) amino-3, 3-dimethylbutyrate (example 39)

To a 25mL single-necked flask, compound 4 (380 mg,0.38 mmol), ethyl acetate (5 mL) and 4 NHCl/ethyl acetate (5 mL) were sequentially added, and the mixture was reacted at room temperature under nitrogen atmosphere for 2 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material. Saturated sodium bicarbonate solution was added to adjust the pH to 8, extracted with dichloromethane (30 ml×3), the organic phases combined, saturated sodium chloride solution (20 ml×3), dried over anhydrous sodium sulfate, filtered off with suction, concentrated and purified by flash chromatography (24 g, v _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 150mg of the compound as a white solid, example 39 in a two-step yield of 48.8%.

HRMS (ESI) M/z [ M+H ] ⁺C₄₁H₅₀F₂N₆O₇ S theory 809.3503; actual measurement value 809.3492

EXAMPLE 40 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of ethyl-11-yl) -9 '-hydroxy-8', 10 '-dioxo-3 a',4',8',10 '-tetrahydro-1' H,3 'H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -1-carboxylate step 12 Synthesis of allyl-8-tert-butyl-3-oxo-2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylate (2)/>

To a 500mL three-necked flask, compound 1 (15 g,58.98 mmol) and THF (200 mL), nitrogen protection, cooling to-78deg.C, dropwise adding n-BuLi (41 mL,64.88mmol,1.6N hexane solution), and reacting for 1h under heat. Allyl chloride Alloc-Cl (7.82 g,64.88 mmol) was then added dropwise and the reaction was continued for 1h with heat preservation. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quench with saturated ammonium chloride solution (200 mL) at low temperature, extract with ethyl acetate (100 mL x 3), combine the organic phases, wash with saturated brine (300 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate, purify by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) to afford 19.6g of compound 2 as colorless transparent oil in 98.0% yield.

Step 22 Synthesis of allyl-3-oxo-2, 8-diazaspiro [4.5] decane-2-carboxylate trifluoroacetate salt (3)

To a 50mL single vial was added compound 2 (2 g,5.91 mmol), dichloromethane (20 mL) and trifluoroacetic acid (4 mL), nitrogen blanketing, and the reaction was performed at room temperature for 2h. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:1) monitored complete reaction of starting materials, concentrated reaction, toluene was evaporated once (5 mL) to give 3.0g of compound 3 as a yellow oil, which was used directly in the next step.

Step 32 Synthesis of allyl-8-ethyl-3-oxo-2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylic acid ester (4)

To a 100mL single-necked flask, compound 3 (2.5 g,7.43 mmol), methylene chloride (40 mL), methanol (4 mL), potassium carbonate (3.08 g,22.29 mmol) and ethyl chloroformate (1.61 g,14.87 mmol) were added and the mixture was reacted at room temperature under nitrogen for 1h. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:1) monitored complete reaction of starting materials, quench of the reaction with water (100 mL), extraction with dichloromethane (100 mL x 3), wash of the combined organic phases with saturated brine (100 mL x 2), drying over anhydrous sodium sulfate, filtration, concentration, purification by flash preparative chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) afforded 1.35g of colorless transparent oil 4 in 61.3% yield.

¹H NMR(600MHz,CDCl₃)δ(ppm):6.00-5.93(m,1H,CH＝CH₂),5.44-5.40(m,1H,CH＝CH₂),5.31-5.28(m,1H,CH＝CH₂),4.75-4.73(m,2H,CH₂),4.15-4.12(m,2H,CH₂CH₃),3.63(s,2H,CH₂),3.59-3.55(m,2H,CH₂CH₂),3.39-3.35(m,2H,CH₂CH₂)2.46(s,2H,CH₂),1.63-1.59(m,4H,CH₂CH₂),1.27(t,J＝7.2Hz,3H,CH₂CH₃)

Step 42 Synthesis of allyl-8-ethyl-3-hydroxy-2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylic acid ester (5)

To a 100mL single-necked flask, compound 4 (1.62 g,5.47 mmol) and THF (20 mL), nitrogen protection, cooling to-78deg.C, dropwise adding DIBAl-H (11 mL,10.94mmol,1N hexane solution), and reacting for 1H under heat preservation. TLC (V _{Petroleum ether}：V_{acetic acid ethyl ester} = 1:1) monitored completion of the reaction, quenched by addition of saturated sodium potassium tartrate (60 mL) solution at low temperature, extracted with ethyl acetate (100 mL x 3), combined organic phases, dried over anhydrous sodium sulfate, filtered and concentrated to give 2.2g of compound 5 as a white foamy solid which was used directly in the next step without purification.

Step 52 Synthesis of allyl-8-ethyl-3-methoxy-2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylic acid ester (6)

To a 150mL single-necked flask, compound 5 (2.2 g,5.47 mmol), methanol (50 mL) and p-toluenesulfonic acid monohydrate (105 mg,0.55 mmol) were successively added, and the mixture was reacted at room temperature under nitrogen atmosphere for 1h. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 30:1) monitored complete reaction of starting material, addition of saturated sodium bicarbonate (100 mL) solution, extraction with ethyl acetate (100 mL x 3), combined organic phases, washing with saturated brine (100 mL), drying over anhydrous sodium sulfate, filtration, concentration, purification by flash chromatography (40 g, V _{Petroleum ether}：V_{acetic acid ethyl ester} = 3:1) afforded 0.69g of colorless transparent oil in 40.5% yield over 2 steps.

Step 62 Synthesis of allyl-8-ethyl-3- ((3- (benzyloxy) -2- (ethoxycarbonyl) -4-oxopyridin-1 (4H) -yl) amino) -2, 8-diazaspiro [4.5] decane-2, 8-dicarboxylic acid ester (7)

To a 100mL three-necked flask, compound 6 (690 mg,2.21 mmol), ethyl 1-amino-3- (benzyloxy) -4-oxo-1, 4-dihydropyridine-2-carboxylate (637 mg,2.21 mmol) and acetonitrile (15 mL) were sequentially added, and the mixture was cooled to-25℃under nitrogen protection, snCl ₄ (921 mg,3.54 mmol) was added dropwise, and the reaction was continued for 2 hours. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 20:1) monitored complete reaction of starting material, quenched by addition of saturated sodium bicarbonate solution (20 mL) at low temperature, extracted with dichloromethane (100 mL x 3), combined organic phases washed with saturated brine (150 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, purified by column chromatography (V _{dichloromethane (dichloromethane)}：V_Methanol = 50:1) to give 360mg of compound 7 as a yellow solid in 28.6% yield.

Step 7 9'- (benzyloxy) -8',10 '-dioxo-3 a',4',8',10 '-tetrahydro-1' H,3 'H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -1-carboxylic acid ethyl ester (8) synthesis

To a 50mL single-port flask, compound 7 (360 mg,0.63 mmol) and morpholine (5 mL) were added sequentially, and the mixture was dissolved with stirring, pd (PPh ₃)₄ (37 mg,0.03 mmol) was added, and the reaction was monitored by room temperature 1h.TLC (V _{dichloromethane (dichloromethane)}：V_Methanol =10:1) to complete the reaction, isopropyl ether (100 mL) was added, solids were precipitated, filtered, and the filter cake was dried under vacuum at 40℃for 2h to give 322mg of compound 8 as a brown solid, which was used in the next step without purification.

Step 89 '- (benzyloxy) -4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of ethyl-11-yl) -8',10' -dioxo-3 a ',4',8',10' -tetrahydro-1 ' H,3' H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] -triazine ] -1-carboxylate (9)

Into a 50mL single vial was added compound 8 (322 mg,0.63 mmol), 11-chloro-7, 8-difluoro-dihydrodibenzo [ b, e ] thiazepine in sequence(635 Mg,1.58 mmol), acetonitrile (10 mL) and cesium carbonate (823 g,2.52 mmol), nitrogen protection, and reacted overnight at room temperature. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, quenched with water (20 mL), extracted with dichloromethane (50 mL x 6), combined organic phases, dried over anhydrous sodium sulfate, filtered, concentrated, purified by flash preparative chromatography (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 100:1) to give 152mg of compound 9 as a yellow solid in 35.2% two-step yield.

Step 9 4' - (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepineSynthesis of ethyl-11-yl) -9 '-hydroxy-8', 10 '-dioxo-3 a',4',8',10 '-tetrahydro-1' H,3 'H-spiro [ piperidine-4, 2' -pyrido [2,1-f ] pyrrolo [2,1-c ] [1,2,4] triazine ] -1-carboxylate (example 40)

To a 25mL single vial was added compound 9 (150 mg,0.21 mmol), DMAc (2 mL), and LiCl (90 mg,2.1 mmol) in order, and the mixture was reacted at 80℃for 5 hours under N ₂ protection. TLC (V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) monitored complete reaction of starting material, cooled to room temperature, sand-making, flash chromatography purification (12 g, V _{dichloromethane (dichloromethane)}：V_Methanol = 10:1) to give 75mg crude product, methanol band distilled (2 mL x 2), petroleum ether (5 mL) slurried overnight, filtered, air-dried at 40 ℃ for 4h to give 48mg yellow solid example 40, yield 36.6%.

¹H NMR(600MHz,DMSO-d₆)δ(ppm):7.47(br,1H,ArH),7.31(br,2H,ArH),7.21(br,1H,ArH),7.13(br,1H,ArH),7.03(br,1H,ArH),6.84-6.74(m,1H,ArH),5.69-5.62(m,1.4H,ArH,CH₂),5.52(br,1.6H,CH₂,CH),5.41-5.25(m,0.75H,CH),5.16-5.12(m,0.25H,CH),4.19(t,J＝7.2Hz,1H,CH₂),3.96(br,2H,CH₂CH₃),3.44-3.33(m,1H,CH₂CH₂),3.21-3.05(m,2H,CH₂CH₂),2.10-2.01(m,1H,CH₂),1.41(br,2H,CH₂CH₂),1.29-1.23(m,1H,CH₂CH₂),1.22-1.18(m,1H,CH₂CH₂),,1.15-1.01(m,5H,CH₂CH₂),0.93-0.88(m,1H,CH₂CH₂),0.83-0.79(m,1H,CH₂CH₂).

HRMS (ESI) M/z [ M+H ] ⁺C₃₁H₃₀F₂N₄O₅ S theory 609.1983; actual measurement value 609.1974

Biological Activity test

1. In vitro anti-influenza A/WSN/33 (H ₁N₁) Activity of Compounds

1. Experimental materials and methods

The positive control compound baluo Sha Weizhi was supplied by the Shanghai Minkangde New drug development Co. Compounds were prepared as stock solutions in 100% dmso, tested at 8 concentration points, 3-fold gradient dilution, double multiplex wells. Canine kidney cells MDCK were purchased from ATCC under the accession number CCL-34. Cells were cultured using EMEM (Sigma) broth supplemented with 10% fetal bovine serum (Hyclone or Excell Bio), 1% diabody (Hyclone), 1% L-glutamine (Gibco) and 1% non-essential amino acid (Gibco). OptiPRO SFM (Gibco) culture broth with 1% diabody, 1% L-glutamine and 1% nonessential amino acid added was used as experimental culture broth. The experimental broth to which pancreatin (Invitrogen) was added was a virus infection broth. Influenza A/WSN/33 (H1N 1) strain was purchased from Virapur, cat# F1003A.

2. Experimental procedure

MDCK cells were seeded at a density of 2,000 cells per well into 384-well test plates and incubated overnight in a 5% CO ₂, 37 ℃ incubator. The next day, compounds (8 concentration points, 3-fold gradient dilution, double multiplex wells) and virus (moi=0.03) were added to 384 well cell culture plates. The final concentration of DMSO and pancreatin in the culture medium was 0.5% and 2.5. Mu.g/ml, respectively. Cells were incubated in 5% CO ₂, 37℃incubator for 5 days until no compound was present in the virus control wells to 80-95%. Cell viability was measured using Cell counting kit kit (Shanghai plum). The cytotoxicity test is the same as the antiviral test, but no virus infection. The antiviral activity and cytotoxicity of the compounds are represented by the inhibition (%) of the virus-induced cytopathic effect of the compounds at different concentrations and the activation (%) of MDCK cells, respectively. The calculation formula is as follows:

Inhibition (%) = (test well read-virus control mean)/(cell control mean-virus control mean) ×100

Cell viability (%) = (test well read-culture broth control mean)/(cell control mean-culture broth control mean) ×100

Non-linear fitting analysis of inhibition and cell viability of the compounds was performed using GRAPHPAD PRISM software, and half-maximal effective concentration (EC ₅₀) and half-maximal cytotoxic concentration (CC ₅₀) values of the compounds were calculated.

Mode: log (inhibitor) vs. response-variable slope

Formula y=minimum response+ (maximum response-minimum response)/(1+10 ((LogIC ₅₀ -X) gradient of curve))

As can be seen from the results in Table 1, all of the compounds 1 to 28 of the present invention had significant anti-influenza A/WSN/33 (H1N 1) activity, and the activity of the compound was superior to that of the compound of referential example 583, and even superior to that of the positive compound, baluo Sha Wei. CC ₅₀ represents the cytotoxicity of the compounds, and from the results in table 1, it is clear that the cytotoxicity of the compounds of the invention is low, significantly lower than the positive compound balo Sha Weizhi and the compound of reference example 583.

TABLE 1 evaluation of in vitro anti-influenza A/WSN/33 (H1N 1) Activity and cytotoxicity of the Compounds of the invention

++++:EC₅₀<10nM;+++:10nM<EC₅₀<50nM;++:50nM<EC₅₀<100nM;+:EC₅₀>100nM

A:CC₅₀<20μM;B:20μM<CC₅₀<100μM;C:100μM<CC₅₀<200μM;D:CC₅₀>200μM

2. Effect of Compounds on drug resistant strains

1. Experimental materials and methods

The strain of Barlow Sha Weizhi resistant influenza A/PR/8/34 (H ₁N₁) was purchased from Minkangde. Other experimental materials and methods were as above. From the results in Table 2, it is found that the inhibitory activity of the compound of example 20 against drug-resistant strains is superior to that of baluo Sha Weizhi.

TABLE 2 inhibitory Activity of partial Compounds of the invention against Ballon Sha Weizhi resistant influenza A/PR/8/34 (H ₁N₁) strains

3. Compound in vitro cell model transmembrane transport evaluation

3.1 Cell culture

MDCK cells (source ATCC), high-sugar DMEM cell culture broth (including 10% fetal bovine serum, 100U/mL penicillin, and 100. Mu.g/mL streptomycin, 200. Mu.g/mL glutamine). The cells are placed in a 37 ℃ incubator and cultured under the condition of 5% CO ₂ saturated humidity, the liquid is changed every 1-2 days, the cells are observed under a fluorescent inverted microscope, and after the cells grow to be full of monolayers, the cells are digested with 0.25% trypsin for passage.

Transwell chamber inoculation: cells were inoculated to a transwell fluff side (AP side) at a fixed density of 13.0X10 ⁵ cells/cm ² 0.4.4 mL, 1mL of a blank culture solution was added to the basal side (BL side), fresh cell culture solution was changed every two days after inoculation, and after one week, the culture solution was changed every day, 300. Mu.L on the A side, 1mL on the B side, and molding was performed for about 12 days.

3.2 Cell model transmembrane transport experiments

Old culture solution in the culture well and the insert culture dish was aspirated, and Hank' S solution preheated to 37℃was added to both the AP side and BL side, and incubated for 10min at 37℃under 5% CO ₂.

Absorption (ap→bl) osmotic transport: 0.3mL of Hank 'S solution of the compound to be tested at a concentration of 20. Mu.M was added to the AP side as a supply solution, while 1mL of blank Hank' S was added to the BL side as a receiving solution. After incubation of the plates at 37℃in a 5% CO ₂ incubator for 30min, 60min and 90min, respectively, 200. Mu.L of BL-side samples were taken for measurement (n=5), followed by addition of 200. Mu.L of blank Hank' S solution to supplement hydrostatic pressure.

Efflux (BL→AP) osmotic transport: 1mL of Hank 'S solution of the test compound at a concentration of 20. Mu.M was added to the BL side as a supply solution, while 0.3mL of blank Hank' S was added to the A side as a receiving solution. After incubation of the plates at 37℃in a 5% CO ₂ incubator for 30min, 60min and 90min, 200. Mu.L of AP side samples were taken for measurement (n=5), followed by addition of 200. Mu.L of blank Hank' S solution to supplement hydrostatic pressure.

3.3 Data analysis method

The apparent permeability coefficient Papp is calculated as follows:

The apparent permeability coefficient Papp (cm/sec) reflects the drug's permeability in cells; VR (mL) represents the volume of solution in the receiving chamber; a represents the area of the membrane (in this case, A is 0.3cm ²);C₀(μg·mL^-1) and represents the initial concentration of the drug in the test solution; dC/dt (μg.mL ^-1·sec^-1) represents the drug concentration obtained in the receiving chamber per unit time.

Papp (AP. Fwdarw.BL) for AP-side transport and Papp (BL. Fwdarw.AP) for BL-side transport were calculated, respectively, and the efflux capacity with transporter participation was expressed as the Ratio of Papp (BL. Fwdarw.AP) to Papp (AP. Fwdarw.BL). The formula is as follows:

Ratio B/A＝Papp(BL→AP)/Papp(AP→BL)

3.4 results

Some of the compounds of the present invention were tested for permeability and drug delivery characteristics in an in vitro Caco-2 (purchased from ATCC) monolayer cell model and the results are shown in Table 3. The partial compounds of the invention have higher cell membrane permeability and lower efflux relative to balo Sha Weizhi.

TABLE 3 evaluation of in vitro cell model transmembrane transport of the compounds of the invention

Papp value: 1X 10 ^-6～2×10^-6 cm/s, low permeability; 2X 10 ^-6～20×10^-6 cm/s, medium permeation; 20X 10 ^-6 cm/s, high permeability.

The efflux rate >20 suggests a stronger efflux effect.

4. In vivo pharmacokinetic parameter study of Compounds in dogs

4.1 Experimental methods

6 Beagle dogs were selected, which were male, and were randomly divided into 2 groups according to body weight, i.e., intravenous injection group and oral gavage group, each group having 3 animals. Intravenous administration of 0.5mg/kg and oral gavage of 2mg/kg, both groups were pre-dosed, blood was collected from the anterior limb at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8, 24h post-dosing time points, each sample was taken at about 1.0ml, edta-K2 was anticoagulated, placed on wet ice after collection and plasma was centrifuged within 1 hour (centrifugation conditions: 6000g,3 min, 2-8 ℃). The plasma samples were stored in a-80 ℃ freezer prior to analysis.

1. Sample pretreatment: 50.0. Mu.L of plasma sample was removed to a 96-well plate and 500. Mu.L of 50% methanolic acetonitrile solution containing an internal standard (tolbutamide, 100 ng/mL) was added. After swirling the sample for 5 minutes, centrifuging at 14000rpm and 4℃for 5 minutes, transferring 80. Mu.L to 80. Mu.L of water, mixing well, and performing LC-MS/MS analysis

2. Chromatographic conditions chromatographic column: synergi 4 μm Fusion-RP 80ALC Column 50*2mm; flow rate: 0.5ml/min; sample injection volume: 2 μl; column temperature: 40 ℃; mobile phase: phase A: 0.1% formic acid aqueous solution, phase B: acetonitrile; gradient elution: 0 to 1.9min,5 percent of phase A; 1.91-2.5 min,80% phase A.

3. Mass spectrometry conditional ionization mode: electrospray ionization, positive ion mode (esi+); mass spectrometry scanning mode: multiple Reaction Monitoring (MRM); example 20 and example 30 feature ion pairs 538.20/247.20, 626.20/247.10, respectively; the internal standard is tolbutamide, and the characteristic ion pair is 271.10/155.00; the capillary voltage is 4.0kV; the desolvation temperature is 400 ℃;

4.2 experimental results

The results are shown in tables 4 and 5, and the compound of example 30 has a certain absorption in dogs, and can reach the maximum blood concentration after oral administration for 0.3h, the half-life of oral administration for 3.015h and the bioavailability for 5.87%.

Table 4: single intravenous administration of example 20 following beagle plasma PK data

Table 5: beagle plasma PK data after single intragastric administration of compound of example 30

All references mentioned herein are incorporated herein by reference. It will be understood that many variations and modifications may be made to the disclosed solution without departing from the spirit and scope of the disclosure.

Claims

1. Compounds of formula (XIV)

r ₁ is selected from:

Wherein X ₁ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂;

X ₂ is selected from CH, N;

R ₂ is selected from:

a)H；

b)-C(＝O)-P^R0；

c)-C(＝O)-P^R1；

d)-C(＝O)-L-P^R1；

e)-C(＝O)-L-O-P^R1；

f)-C(＝O)-L-O-L-O-P^R1；

g)-C(＝O)-L-O-C(＝O)-P^R1；

h)-C(＝O)-O-P^R2；

i)-C(＝O)-N(-K)(P^R2)；

j)-C(＝O)-O-L-O-P^R2；

k)-C(＝O)-O-L-N(-K)(P^R2)；

l)-C(P^R3)₂-O-P^R4；

m)-C(P^R3)₂-O-L-O-P^R4；

n)-C(P^R3)₂-O-C(＝O)-P^R4；

o)-C(P^R3)₂-O-C(＝O)-O-P^R4；

p)-C(P^R3)₂-O-C(＝O)-N(-K)-P^R4；

q)-C(P^R3)₂-O-C(＝O)-O-L-O-P^R4；

r)-C(P^R3)₂-O-C(＝O)-O-L-N(P^R4)₂；

s)-C(P^R3)₂-O-C(＝O)-N(-K)-L-O-P^R4；

t)-C(P^R3)₂-O-C(＝O)-N(-K)-L-N(P^R4)₂；

u)-C(P^R3)₂-O-C(＝O)-O-L-O-L-O-P^R4；

v)-C(P^R3)₂-O-C(＝O)-O-L-N(-K)-C(＝O)-P^R4；

w)-C(P^R3)₂-O-P(＝O)(-P^R5)₂；

x)-(C(P^R3)₂)_p-P^R6；

y)-C(＝N⁺(P^R7)₂)(-N(P^R7)₂)；

z)-(C(P^R3)₂)_q-C(＝O)-O-P^R2；

aa)-(C(P^R3)₂)_q-C(＝O)-N(-K)-P^R4；

bb)-(C(P^R3)₂)_q-C(＝O)-P^R1；

cc)-C(P^R3)₂-N(-K)-C(＝O)-O-P^R2；

dd)-P(＝O)(-P^R8)(-P^R9)；

ee)-S(＝O)₂-P^R10；

ff)-P^R11；

gg) - (C (P ^R3)₂)_r-O-P^R12; or

hh)-(C(P^R3)₂)_t-N(-K)-P^R13；

P ^R1 is C ₃-C₈ carbocyclyl, heterocyclyl, C ₁-C₂₀ alkylamino, C ₁-C₂₀ alkylthio optionally substituted by any of substituent groups A,

P ^R2 is C ₁-C₂₀ alkyl optionally substituted by any of substituent groups A, C ₃-C₈ carbocyclyl, heterocyclyl, or tri (C ₁-C₂₀ alkyl) silyl,

P ^R5 are each independently hydroxy or benzyloxy;

P is an integer of 2 to 3,

Q is an integer of 1 to 2,

R is an integer of 2 to 4,

T is an integer of 2 to 4,

The substituent group B includes: c ₃-C₈ spiro and halogen.

2. The compound of claim 1, or a tautomer, solvate, prodrug, isotopic label, and pharmaceutically acceptable salt thereof, wherein ring a is selected from the group consisting of

n is an integer selected from 0,1, 2, 3, 4.

3. The compound of claim 1, or a tautomer, solvate, prodrug, isotopic label, and pharmaceutically acceptable salt thereof, wherein

Ring a is selected from the group consisting of a cyclopropane ring, a cyclobutane ring, a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, a cyclooctane ring, an aziridine ring, an azetidine ring, a tetrahydropyrrole ring, a piperidine ring, an azepane ring, an oxetane ring, a tetrahydrofuran ring, a tetrahydropyran ring, an oxetane ring, a thietane ring, a tetrahydrothiophene ring, a tetrahydrothiopyran ring, a thietane ring, a tetrahydroimidazole ring, a tetrahydropyrazole ring, a tetrahydroisoxazole ring, a tetrahydrothiazole ring, a tetrahydroisothiazole ring, a piperazine ring, a morpholine ring, a dioxane ring, a thiaoxane ring, a dithiane ring, optionally substituted with one or more groups selected from the group consisting of: halogen, oxo, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.

4. The compound of claim 1, or a tautomer, solvate, prodrug, isotopic label, and pharmaceutically acceptable salt thereof, wherein

Ring A is selected from Optionally substituted with one or more groups selected from: halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, C ₁-C₂₀ alkylcarbonyl, C ₁-C₂₀ alkoxycarbonyl, C ₁-C₂₀ alkylcarbonyloxy, C ₁-C₂₀ alkoxycarbonyloxy, benzyloxycarbonyl, benzyloxycarbonyloxy.

5. The compound of claim 1, or a tautomer, solvate, prodrug, isotopic label, and pharmaceutically acceptable salt thereof, wherein

R ₁ is selected from:

R ₇ is halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, m is an integer selected from 0, 1,2, 3,4, and X ₁、X₂、R₃、R₃'、R₄ is as defined in claim 1.

6. The compound of claim 1, or a tautomer, solvate, prodrug, isotopic label, and pharmaceutically acceptable salt thereof, wherein

R ₁ is selected from:

7. The compound according to claim 1, which is a compound represented by the formula (XV), (XVI) or (XVII),

R ₇ is halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, m, n are integers selected from 0,1, 2, 3, 4, X ₁、X₂、R₂ is as defined in claim 1.

8. The compound according to claim 1, which is a compound represented by the following formula,

Or a tautomer, solvate, prodrug, isotopic label, and pharmaceutically acceptable salt thereof, wherein X ₁、X₆、X₇、X₈ is selected from CH ₂、O、S、NH、S＝O、S(＝O)₂,X₂ is selected from CH or N, R ₇ is selected from halogen, C ₁-C₂₀ alkyl, C ₁-C₂₀ haloalkyl, C ₁-C₂₀ alkoxy, m is an integer selected from 0, 1,2, 3, 4, and R ₂ is as defined in claim 1.

9. The compound according to claim 1, which is:

or a tautomer, solvate, prodrug, isotopic label, or pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to any one of claims 1-9, or a tautomer, solvate, prodrug, isotopic label, pharmaceutically acceptable salt, and pharmaceutically acceptable carrier thereof.

11. The pharmaceutical composition of claim 10, optionally further comprising one or more additional therapeutic agents, wherein the additional therapeutic agents are selected from an anti-influenza virus agent or vaccine.

12. Use of a compound according to any one of claims 1-9 or a tautomer, solvate, prodrug, isotopic label, and pharmaceutically acceptable salt thereof and/or a pharmaceutical composition according to claim 10 or 11 for the manufacture of a medicament for the prevention and/or treatment of a disease caused by a virus having a cap dependent endonuclease.

13. The use according to claim 12, wherein the disease is selected from diseases caused by influenza virus infection.

14. The use of claim 13, wherein the influenza virus infection comprises an influenza a virus infection, an influenza b virus infection, an influenza c virus infection, an influenza delta virus infection, an avian influenza virus infection, a swine influenza virus infection.