Influenza virus inhibitors and uses thereof

Abstract

Provided are compounds of Formula (I), Formula (II), Formula (III), and Formula (IV) as influenza virus replication inhibitors and their use in the manufacture of a medicament for the prevention or treatment of influenza.

Description

Technical Field

[0001] This invention relates to a class of novel compounds that act as inhibitors of influenza virus replication and their use in the treatment of influenza, specifically as cap-dependent endonuclease inhibitors of influenza virus. Background Technology

[0002] Influenza (flu) is an acute respiratory infectious disease caused by the influenza virus that seriously endangers human health. Human infection with influenza is caused by influenza subtypes A and B. Based on the hemagglutinin (H or HA) and neuraminidase (N) antigen types, influenza A virus can be further classified, such as the already identified subtypes H1N1, H1N2, H2N2, and H3N1.

[0003] The influenza virus RNA polymerase is responsible for viral RNA replication and transcription, and is a heterotrimer composed of three subunits: polymerase acid (PA), polymerase base 1 (PB1), and polymerase base 2 (PB2). Influenza virus RNA transcription employs a unique "cap-snap" mechanism. The PB2 subunit is responsible for recognizing and binding to the "cap structure" of the host precursor mRNA. The PA subunit cleaves the host mRNA, which acts as a primer to initiate the transcription process. The cleaved mRNA primer is then used in the PB1 subunit for viral mRNA synthesis. Because the cap-dependent endonuclease of the PA subunit is highly conserved during influenza mutations and is essential for viral life processes, and because its binding site is specific, this binding domain is highly suitable as a target site for developing novel anti-influenza drugs.

[0004] Baloxavir, a novel anti-influenza agent with this mechanism of action, has been marketed. It inhibits viral mRNA synthesis by suppressing cap-dependent endonucleases, ultimately inhibiting viral replication. However, the development of other compounds with higher activity, fewer side effects, and easier administration through this mechanism for treating influenza remains urgently needed. Summary of the Invention

[0005] This invention provides a compound of Formula I, or a deuterated compound thereof, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:

[0006]

[0007] in,

[0008] R 1 R 2 R 3 R 4 R 5 R 6 Each group is independently selected from hydrogen, -OH, -SH, -NH2, halogen, cyano, or -C that is optionally substituted with a halogen. 1～6Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene-OR 1a -C 0～4 Alkylene-OC(O)R 1a -C 0～4 Alkylene-SR 1a -C 0～4 Alkylene-C(O)R 1a -C 0～4 Alkylene-C(O)OR 1a -C 0～4 Alkylene-C(O)NR 1a R 1b -C 0～4 Alkylene-NR 1a R 1b -C 0～4 Alkylene-NR 1a C(O)R 1b -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group), -C 0～4 Alkylene-S(O)2R 1a -C 0～4 Alkylene-S(O)R 1a -C 0～4 Alkylene-S(O)2NR 1a R 1b -C 0～4 Alkylene-S(O)NR 1a R 1b ; wherein the alkylene group, carbocyclic group, heterocyclic group, aryl group, and aromatic heterocyclic group may be further divided by one, two, three, four, or five independent R groups. 1c Replace; and R 1 R 2 R 3 R 4 R 5 R 6 They are not both selected from hydrogen;

[0009] R 1a R 1b Each of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C optionally substituted with a halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 Alkylene (5-10 membered aromatic heterocyclic group); wherein the alkyl, alkenyl, alkynyl, alkylene, carbocyclic, heterocyclic alkyl, aromatic cyclic, or aromatic heterocyclic group may be further influenced by one, two, or three independent R groups. 1c Replace; or, R 1a R 1b Together with the attached atoms, they form saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups;

[0010] Each R 1c Each of the following is independently selected from hydrogen and -C atoms optionally substituted with halogens. 1～6 Straight-chain or branched alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 Alkyne, halogen, cyano, -OH, -SH, -OC 1～6 Alkyl, -O (halogen-substituted C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～4 Alkylene-S(O)2R 1d -C 0～4 Alkylene-S(O)R 1d -C 0～4 Alkylene-S(O)2NR 1d R 1e -C 0～4 Alkylene-S(O)NR 1d R 1e ;

[0011] R 1d R 1e Each of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C optionally substituted with a halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C0～4 alkylene-(5-10 membered aromatic heterocyclic group);

[0012] or,

[0013] R 1 With R 2 R 3 With R 4 R 5 With R 6 Formed together with the adjacent atoms Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups; wherein the carbocyclic group or heterocyclic alkyl group may be further divided by one, two, three, four, five, six, or seven independent R groups. 1d replace;

[0014] Each R 1d Each group is independently selected from hydrogen, -OH, -SH, -NH2, halogen, cyano, or -C that is optionally substituted with a halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene-OR 1e -C 0～4 Alkylene-OC(O)R 1e -C 0～4 Alkylene-C(O)R 1e -C 0～4 Alkylene-C(O)OR 1e -C 0～4 Alkylene-C(O)NR 1e R 1f -C 0～4 Alkylene-NR 1e R 1f -C 0～4 Alkylene-NR 1e C(O)R 1f -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 Alkylene (5- to 10-membered aromatic heterocyclic group); wherein the alkylene group, carbocyclic group, heterocyclic alkyl group, aromatic cyclic group, or aromatic heterocyclic group may be further converted by one, two, or three independent R groups. 1g replace;

[0015] R 1e R 1fEach of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C arbitrarily substituted with a halogen: 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 Alkyne- and halogen-substituted C 1～6 Alkyl, -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 Alkylene (5-10 membered aromatic heterocyclic group); wherein the alkyl, alkenyl, alkynyl, carbocyclic, heterocyclic alkyl, aromatic cyclic, or aromatic heterocyclic group may be further influenced by one, two, or three independent R groups. 1g Replace; or, R 1e R 1f Together with the attached atoms, they form saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups;

[0016] Each R 1g Each of the following is independently selected from hydrogen and -C atoms optionally substituted with halogens. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 Alkyne, halogen, cyano, -SH, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl);

[0017] or,

[0018] Two independent R 1d Formed together with the adjacent atoms Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups, 6- to 10-membered aromatic cyclic groups, and 5- to 10-membered aromatic heterocyclic groups; wherein the carbocyclic group, heterocyclic alkyl group, aromatic cyclic group, and aromatic heterocyclic group may be further converted by one, two, three, four, or five R groups. 1h replace;

[0019] Each R 1h Each group is independently selected from hydrogen, -OH, -SH, -NH2, halogen, cyano, or -C that is optionally substituted with a halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4Alkylene-OR 1i -C 0～4 Alkylene-OC(O)R 1i -C 0～4 Alkylene-C(O)R 1i -C 0～4 Alkylene-C(O)OR 1i -C 0～4 Alkylene-C(O)NR 1i R 1j -C 0～4 Alkylene-NR 1i R 1j -C 0～4 Alkylene-NR 1i C(O)R 1j -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group); or, two independent R groups. 1h Formed together with the adjacent atoms

[0020] R 1i R 1j Each of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C arbitrarily substituted with a halogen: 1～6 Alkyl group, -C- group optionally substituted with halogen 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group);

[0021] A is selected from saturated or unsaturated carbocyclic groups, saturated or unsaturated heterocyclic alkyl groups, aryl groups, or aromatic heterocyclic groups consisting of monocyclic, bicyclic, tricyclic, tetracyclic, pentacyclic, or hexacyclic rings composed of 5 to 30 atoms; wherein the carbocyclic group, heterocyclic alkyl group, aryl group, or aromatic heterocyclic group may be further surrounded by one, two, three, four, five, six, or seven R groups. A1 replace;

[0022] Each R A1Each group is independently selected from hydrogen, -OH, -SH, -NH2, halogen, cyano, or -C that is optionally substituted with a halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene-OR A2 -C 0～4 Alkylene-OC(O)R A2 -C 0～4 Alkylene-C(O)R A2 -C 0～4 Alkylene-C(O)OR A2 -C 0～4 Alkylene-C(O)NR A2 R A3 -C 0～4 Alkylene-NR A2 R A3 -C 0～4 Alkylene-NR A2 C(O)R A3 -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group), -C 0～4 Alkylene-S(O)2R A2 -C 0～4 Alkylene-S(O)R A2 -C 0～4 Alkylene-S(O)2NR A2 R A3 -C 0～4 Alkylene-S(O)NR A2 R A3 ; wherein the alkylene group, carbocyclic group, heterocyclic group, aryl group, and aromatic heterocyclic group may be further converted by one, two, or three independent R groups. A4 replace;

[0023] R A2 R A3 Each of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C arbitrarily substituted with a halogen: 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group); or, R A2 R A3 Together with the attached atoms, they form saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups;

[0024] Each R A4 Each of the following is independently selected from hydrogen and -C atoms optionally substituted with halogens. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 Alkyne, halogen, cyano, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group);

[0025] or,

[0026] Two independent R A1 Formed together with the adjacent atoms Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 3- to 10-membered heterocyclic alkyl groups; wherein the carbocyclic group or heterocyclic alkyl group may be further converted by one, two, or three R groups. A5 replace;

[0027] Each R A5 Each of the following is independently selected from hydrogen and -C atoms optionally substituted with halogens. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 Alkyne, halogen, cyano, -SH, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6 Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 Alkyl), -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group); or, two independent R groups. A5 Formed together with the adjacent atoms

[0028] The heteroatoms in the saturated or unsaturated heterocyclic alkyl groups and aromatic heterocyclic groups are each independently selected from one or more of O, S, B or N. The unsaturated carbocyclic group does not include aryl groups, and the unsaturated heterocyclic alkyl group does not include aromatic heterocyclic groups.

[0029] Furthermore,

[0030] The compounds represented by Formula I are as shown in Formulas Ia, Ib, and Ic:

[0031]

[0032] in,

[0033] Ring B is selected from saturated or unsaturated 3- to 10-membered carbocyclic groups and saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups; wherein the saturated or unsaturated carbocyclic group and the saturated or unsaturated heterocyclic alkyl group may be further separated by one, two, three, four, or five independent R groups. 1d replace;

[0034] Each R 1d Each group is independently selected from hydrogen, -OH, -SH, -NH2, halogen, cyano, or -C that is optionally substituted with a halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene-OR 1e -C 0～4 Alkylene-OC(O)R 1e -C 0～4 Alkylene-C(O)R 1e -C 0～4 Alkylene-C(O)OR 1e -C 0～4 Alkylene-C(O)NR 1e R 1f -C 0～4 Alkylene-NR 1e R 1f -C 0～4 Alkylene-NR 1e C(O)R 1f -C 0～4Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 Alkylene (5- to 10-membered aromatic heterocyclic group); wherein the alkylene group, carbocyclic group, heterocyclic alkyl group, aromatic cyclic group, or aromatic heterocyclic group may be further converted by one, two, or three independent R groups. 1g Replace; two independent R 1d Formed together with the adjacent atoms Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups, 6- to 10-membered aromatic cyclic groups, and 5- to 10-membered aromatic heterocyclic groups; wherein the carbocyclic group, heterocyclic alkyl group, aromatic cyclic group, and aromatic heterocyclic group may be further converted by one, two, or three R groups. 1h replace.

[0035] Furthermore,

[0036] Ring B is selected from saturated or unsaturated 3-membered carbocyclic groups, saturated or unsaturated 4-membered carbocyclic groups, saturated or unsaturated 5-membered carbocyclic groups, saturated or unsaturated 6-membered carbocyclic groups, saturated or unsaturated 4-membered heterocyclic alkyl groups, saturated or unsaturated 5-membered heterocyclic alkyl groups, and saturated or unsaturated 6-membered heterocyclic alkyl groups; wherein the heteroatom of the heterocyclic alkyl group is selected from N, O, and S; wherein the carbocyclic group and heterocyclic alkyl group may be further separated by one, two, three, four, or five independent R groups. 1d replace.

[0037] To be more specific,

[0038] The B ring is selected from The B ring may be further divided into one, two, or three independent R rings. 1d replace;

[0039] Each R 1d Each group is independently selected from hydrogen, -OH, -SH, -NH2, halogen, cyano, or -C that is optionally substituted with a halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene-OR 1e -C 0～4 Alkylene-OC(O)R 1e -C 0～4 Alkylene-C(O)R 1e -C 0～4 Alkylene-C(O)OR1e -C 0～4 Alkylene-C(O)NR 1e R 1f -C 0～4 Alkylene-NR 1e R 1f -C 0～4 Alkylene-NR 1e C(O)R 1f -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 Alkylene (5- to 10-membered aromatic heterocyclic group); wherein the alkylene group, carbocyclic group, heterocyclic alkyl group, aromatic cyclic group, or aromatic heterocyclic group may be further converted by one, two, or three independent R groups. 1g Replace; or, two independent Rs 1d Formed together with the adjacent atoms Saturated or unsaturated 3- to 10-membered carbocyclic groups, saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups, 6- to 10-membered aromatic cyclic groups, and 5- to 10-membered aromatic heterocyclic groups;

[0040] R 1e R 1f Each of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C arbitrarily substituted with a halogen: 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group); or, R 1e R 1f Together with the attached atoms, they form saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups;

[0041] Each R 1g Each of the following is independently selected from hydrogen and -C atoms optionally substituted with halogens. 1～6 Alkyl group, -C- group optionally substituted with halogen 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 Alkyne, halogen, cyano, -SH, -OH, -O(C) 1～6 Alkyl), -O (halogenated C) 1～6Alkyl groups, -NH2, -NH(C) 1～6 alkyl), -N(C) 1～6 Alkyl)(C 1～6 alkyl).

[0042] To be more specific,

[0043] Two independent R 1d Linked together to form saturated or unsaturated 3-membered carbocyclic groups, saturated or unsaturated 4-membered carbocyclic groups, saturated or unsaturated 5-membered carbocyclic groups, saturated or unsaturated 6-membered carbocyclic groups, saturated or unsaturated 4-membered heterocyclic alkyl groups, saturated or unsaturated 5-membered heterocyclic alkyl groups, or saturated or unsaturated 6-membered heterocyclic alkyl groups; wherein the carbocyclic group or heterocyclic alkyl group may be further linked by one, two, or three R groups. 1h replace.

[0044] To be more specific,

[0045] The B ring is selected from The B ring may be further divided by one, two or three R rings. 1h replace;

[0046] R 1h Selected from hydrogen, -OH, -SH, -NH2, halogen, cyano, and -C optionally substituted with halogen. 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene-OR 1i -C 0～4 Alkylene-OC(O)R 1i -C 0～4 Alkylene-C(O)R 1i -C 0～4 Alkylene-C(O)OR 1i -C 0～4 Alkylene-C(O)NR 1i R 1j -C 0～4 Alkylene-NR 1i R 1j -C 0～4 Alkylene-NR 1i C(O)R 1j -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4alkylene-(5-10 membered aromatic heterocyclic group);

[0047] R 1i R 1j Each of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C arbitrarily substituted with a halogen: 1～6 Alkyl groups, optionally halogenated -C 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, -C 0～4 Alkylene-(3- to 10-membered carbon cycloyl), -C 0～4 Alkylene (4- to 10-membered heterocyclic alkyl), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 Alkylene-(5-10 membered aromatic heterocyclic alkyl).

[0048] Furthermore,

[0049] R 1 R 2 R 3 R 4 R 5 R 6 Each group is independently selected from hydrogen, methyl, halogen, cyano, -OH, -SH, -C(O)NH2, -NHC(O)CH3, -OCH3, And R 1 R 2 R 3 R 4 R 5 R 6 They are not both selected from hydrogen.

[0050] Furthermore,

[0051] A is selected from Each X is independently selected from CH2, NH, O, or S; the ring selected from A can be further divided by one, two, three, four, or five R. A1 replace.

[0052] Furthermore,

[0053] A is selected from

[0054] Furthermore,

[0055] Two independent R A1Together with the atoms attached thereto, they form saturated or unsaturated 3-membered carbon cycloalkyl groups, saturated or unsaturated 4-membered carbon cycloalkyl groups, saturated or unsaturated 5-membered carbon cycloalkyl groups, saturated or unsaturated 6-membered carbon cycloalkyl groups, saturated or unsaturated 4-membered heterocyclic alkyl groups, saturated or unsaturated 5-membered heterocyclic alkyl groups, and saturated or unsaturated 6-membered heterocyclic alkyl groups.

[0056] To be more specific,

[0057] A is selected from Where X is selected from CH2, NH, O, or S; the ring selected from A can be further divided by one, two, three, four, or five R. A1 replace.

[0058] Furthermore,

[0059] A is selected from Where X is selected from CH2, NH, O, or S; the ring selected from A can be further divided by one, two, three, or four R. A1 replace.

[0060] The present invention also provides compounds represented by Formulas II and III, or their deuterated compounds, or their stereoisomers, or their pharmaceutically acceptable salts:

[0061]

[0062] in,

[0063] R D1 R D2 R D3 Each of the following can be independently selected from hydrogen, -OH, -SH, -NH2, or -C arbitrarily substituted with a halogen: 1～6 Alkyl group, -C- group optionally substituted with halogen 2～6 Alkenyl groups, or -C groups optionally substituted with halogens 2～6 alkynyl group, C 1～6 Alkyloxy, -C 0～4 Alkylene (saturated or unsaturated 3- to 10-membered carbon cycloalloys), -C 0～4 Alkylene (saturated or unsaturated 4- to 10-membered heterocyclic alkyl groups), -C 0～4 alkylene-(6-10 aryl ring group), -C 0～4 alkylene-(5-10 membered aromatic heterocyclic group);

[0064] The A ring is selected from Each X is independently selected from CH2, NH, O, or S; the ring selected from A can be further divided by one, two, three, four, or five R. A1 replace.

[0065] The present invention also provides compounds of Formula IV, or deuterated compounds thereof, or stereoisomers thereof, or pharmaceutically acceptable salts thereof:

[0066]

[0067] The A ring is selected from Each X is independently selected from CH2, NH, O, or S; the ring selected from A can be further divided by one, two, three, four, or five R. A1 replace.

[0068] In some specific embodiments of the present invention, the compounds of formulas I, II, III, and IV are specifically:

[0069]

[0070]

[0071]

[0072]

[0073] The present invention also provides the use of any of the compounds described above, or their deuterated compounds, stereoisomers, or pharmaceutically acceptable salts thereof, in the preparation of medicaments for the prevention or treatment of viral infectious diseases.

[0074] Furthermore, the viral infection is an influenza virus infection.

[0075] The present invention also provides a pharmaceutical composition comprising any of the compounds described above, or their deuterated compounds, stereoisomers, or pharmaceutically acceptable salts thereof, as preparations thereof.

[0076] Furthermore, it also includes pharmaceutically acceptable carriers, excipients, and mediators.

[0077] The compounds and derivatives provided in this invention can be named according to the IUPAC (International Union of Pure and Applied Chemistry) or CAS (Chemical Abstracts Service, Columbus, OH) nomenclature system.

[0078] Regarding the definition of terms used in this invention: Unless otherwise stated, the initial definitions provided for groups or terms herein apply to the groups or terms used throughout this specification; for terms not specifically defined herein, the meanings that a person skilled in the art would give them should be given based on the disclosure and context.

[0079] "Substitution" refers to the replacement of hydrogen atoms in a molecule by other different atoms or groups; or the replacement of lone pairs of electrons in an atom by other atoms or groups, for example, the lone pair of electrons on a sulfur atom can be replaced by an oxygen atom to form a hydrogen atom.

[0080] "Optional substitution" means that substitution may or may not occur, that is, hydrogen atoms in molecules or groups are replaced by other identical or different atoms or groups.

[0081] "Can be further replaced" means that "replacement" can but does not have to happen, and this statement includes situations where it may or may not happen.

[0082] The minimum and maximum carbon atom content in hydrocarbon groups are indicated by a prefix, for example, the prefix C. a～b Alkyl groups indicate any alkyl group containing "a" to "b" carbon atoms. Therefore, for example, C 1～6 Alkyl groups are alkyl groups containing 1 to 6 carbon atoms.

[0083] "alkyl" refers to a saturated hydrocarbon chain having a specified number of member atoms. Alkyl groups can be straight-chain or branched. Representative branched alkyl groups have one, two, or three branches. Alkyl groups may optionally be substituted with one or more substituents as defined herein. Alkyl groups include methyl, ethyl, propyl (n-propyl and isopropyl), butyl (n-butyl, isobutyl, and tert-butyl), pentyl (n-pentyl, isopentyl, and neopentyl), and hexyl. Alkyl groups may also be part of other groups, such as -O(C) 1～6 alkyl).

[0084] In this invention, "carbocyclic," "cycloalkyl," and "cycloalkanes" refer to saturated or partially saturated cyclic groups having multiple carbon atoms and no heterocyclic atoms, and having a single ring or multiple rings (fused or bridged). For polycyclic systems having aromatic and non-aromatic rings without heteroatoms, the term "carbocyclic" (e.g., 5,6,7,8-tetrahydronaphthalene-5-yl) is used when the connecting point is located on a non-aromatic carbon atom. The term "carbocyclic" includes cycloalkenyl groups, such as cyclohexenyl. Examples of carbocyclic groups include, for example, adamantyl, cyclopropyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclooctyl, cyclopentenyl, and cyclohexenyl. Examples of carbocyclic groups including polycyclic dicycloalkyl ring systems are dicyclohexyl, dicyclopentyl, dicyclooctyl, etc. Two such dicycloalkyl polycyclic structures are illustrated and named below: Dicyclohexyl and Bicyclohexyl. The saturated or unsaturated 3-10 member carbon cyclic groups of this invention refer to 3, 4, 5, 6, 7, 8, 9, or 10 member saturated or unsaturated carbon cyclic groups. The unsaturated 3-10 member carbon cyclic groups are preferably 5-10 member unsaturated carbon cyclic groups, or 6-10 member unsaturated carbon cyclic groups, or 7-10 member unsaturated carbon cyclic groups, or 8-10 member unsaturated carbon cyclic groups, or 9-10 member unsaturated carbon cyclic groups.

[0085] Furthermore, in this invention, "heterocyclic alkyl," "heterocyclic," and "heterocyclic alkane" refer to a saturated ring or a non-aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to nitrogen, oxygen, sulfur, etc. Generally, it represents a monocyclic or bicyclic ring system with multiple ring atoms, consisting of 1, 2, or 3 cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon. A bicyclic ring represents two rings sharing two ring atoms, i.e., the bridge separating the two rings is a single bond or a chain of one or two ring atoms. Examples of monocyclic saturated heterocyclic alkyl groups are oxo-heterobutyl, azirrobutyl, pyrrolidinyl, 2-oxo-pyrrolidin-3-yl, tetrahydrofuranyl, tetrahydro-thiophenyl, pyrazolyl, imidazoalkyl, thiazoalkyl, piperidinyl, tetrahydropyranyl, tetrahydrothiaranyl, piperazineyl, morpholinyl, etc. Thiomorpholinyl, 1,1-dioxo-thiomorpholin-4-yl, azirmonyl, diazarmonyl, periperazinyl, or oxazarmonyl. Examples of bicyclic saturated heterocyclic alkyl groups are 8-aza-bicyclo[3.2.1]octyl, quininecycloyl, 8-oxa-3-aza-bicyclo[3.2.1]octyl, and 9-aza-bicyclo[3.3.1]nonyl. Examples of partially unsaturated heterocyclic alkyl groups are dihydrofuranyl, imidazolinyl, tetrahydropyridyl, or dihydropyranyl.

[0086] The saturated or unsaturated 4-10 member heterocyclic alkyl groups of the present invention refer to 4, 5, 6, 7, 8, 9 or 10 member saturated or unsaturated heterocyclic alkyl groups, preferably 5-10 member unsaturated heterocyclic alkyl groups, or 6-10 member unsaturated heterocyclic alkyl groups, or 7-10 member unsaturated heterocyclic alkyl groups, or 8-10 member unsaturated heterocyclic alkyl groups, or 9-10 member unsaturated heterocyclic alkyl groups.

[0087] In this invention, unsaturation refers to the presence of carbon-carbon double bonds, carbon-carbon triple bonds, carbon-oxygen double bonds, carbon-sulfur double bonds, carbon-nitrogen triple bonds, etc., in the group or molecule. The unsaturated carbocyclic group of this invention may or may not include aromatic ring groups, and the unsaturated heterocyclic group may or may not include heteroaryl groups. Those skilled in the art can freely choose the appropriate group.

[0088] In this invention, "aryl group" and "aryl ring" refer to an aromatic hydrocarbon group having multiple carbon atoms. Aryl groups are typically monocyclic, bicyclic, or tricyclic aryl groups having multiple carbon atoms. Furthermore, the term "aryl" as used herein refers to an aromatic substituent that can be a single aromatic ring or multiple aromatic rings fused together. Non-limiting examples include phenyl, naphthyl, or tetrahydronaphthyl.

[0089] In this invention, "aromatic heterocyclic group" and "aromatic heterocycle" refer to an aromatic unsaturated ring containing at least one heteroatom; wherein the heteroatom refers to a nitrogen atom, oxygen atom, sulfur atom, etc. Typically, it refers to an aromatic monocyclic or bicyclic hydrocarbon containing multiple ring atoms, one or more of which are selected from O, N, and S heteroatoms. Preferably, it has one to three heteroatoms. Examples of heterocyclic aryl groups include: pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzothiopheneyl, benzofuranyl, benzothiopheneyl, benzopyranyl, benzothiapyranyl, furanyl, pyrroleyl, thiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazoleyl, thiopheneyl, oxadiazolyl, benzimidazoleyl, benzothiazolyl, and benzoxazolyl.

[0090] Furthermore, the present invention is related to R 1a R 1b R 1c R1 d R 1e R 1f R 1f R 1g R 1h R 1i R 1j R A1 R A2 R A3 R A4 R A5 When the connected atoms are O, S, or N, the R... 1a R 1b R 1c R1 d R 1e R 1f R 1f R 1g R 1h R 1i R 1j R A1 R A2 R A3 R A4 R A5 It is not necessary to select -OH, -SH, or -NH2.

[0091] In this invention, "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0092] In this invention, "halogen-substituted alkyl" refers to an alkyl group in which one or more hydrogen atoms are replaced by a halogen; for example, trifluoromethyl, difluoromethyl, monofluoromethyl, etc.

[0093] In this invention, "-OR", "-NRR", etc., refer to the R group being connected to an oxygen atom or a nitrogen atom by a single bond.

[0094] In this invention, the oxygen atom in “-C(O)R”, “-S(O)2R”, etc., is connected to a carbon atom or a sulfur atom by a double bond.

[0095] The invention described "=O" and "=S" refer to oxygen and sulfur atoms being connected to the substitution positions via double bonds.

[0096] The "---" in the description of the functional groups of this invention It is used to describe the position of the substituent group.

[0097] The "deuterated compound" of this invention refers to a molecule or group in which one or more hydrogen atoms are replaced by deuterium atoms, wherein the proportion of deuterium atoms is greater than the abundance of deuterium in nature.

[0098] The term "pharmaceutically acceptable" means that a carrier, delivery substance, diluent, excipient, and / or the salt formed therefrom is generally chemically or physically compatible with other components constituting a drug dosage form and physiologically compatible with receptors.

[0099] The terms "salt" and "pharmaceutical salt" refer to acidic and / or basic salts formed by the above-described compounds or their stereoisomers with inorganic and / or organic acids and bases, including zwitterionic salts (internal salts) and quaternary ammonium salts, such as alkylammonium salts. These salts can be obtained directly during the final separation and purification of the compounds. Alternatively, they can be obtained by mixing the above-described compounds or their stereoisomers with an appropriate amount (e.g., equimolar amounts) of an acid or base. These salts may be obtained by precipitating in solution and collecting by filtration, by recovery after solvent evaporation, or by freeze-drying after reaction in an aqueous medium. The salts described in this invention can be hydrochlorides, sulfates, citrates, benzenesulfonates, hydrobromides, hydrofluoric acids, phosphates, acetates, propionates, succinates, oxalates, malates, succinates, fumarates, maleates, tartrates, or trifluoroacetates of the compounds.

[0100] In some embodiments, one or more compounds of the present invention may be used in combination with each other. Alternatively, the compounds of the present invention may be used in combination with any other active agent to prepare a medicament or pharmaceutical composition for regulating cell function or treating disease. If a group of compounds is used, these compounds may be administered to the test subject simultaneously, separately, or sequentially.

[0101] Obviously, based on the above description of the present invention, and according to common technical knowledge and conventional methods in the field, various other modifications, substitutions or alterations can be made without departing from the basic technical concept of the present invention.

[0102] The following detailed embodiments further illustrate the above-described content of the present invention. However, this should not be construed as limiting the scope of the present invention to the following examples. All technologies implemented based on the above-described content of the present invention fall within the scope of the present invention. Detailed Implementation

[0103] The structure of the compound was determined by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR shifts (δ) are given in units of 10⁻⁶ (ppm). NMR measurements were performed using a Bruker Avance III 400 and a Bruker Avance 300 NMR spectrometer, with deuterated dimethyl sulfoxide (DMSO-d₆), deuterated chloroform (CDCl₃), and deuterated methanol (CD₃OD) as solvents, and tetramethylsilane (TMS) as the internal standard.

[0104] LC-MS was performed using a Shimadzu LC-MS 2020 (ESI) system. HPLC was performed using a Shimadzu LC-20A system. MPLC (medium-pressure preparative chromatography) was performed using a Gilson GX-281 reversed-phase preparative chromatograph. Thin-layer chromatography (TLC) used Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plates, with a thickness of 0.4 mm to 0.5 mm for product separation and purification. Column chromatography generally used Yantai Huanghai 200–300 mesh silica gel as the support.

[0105] The known starting materials of this invention can be synthesized using or according to methods known in the art, or can be purchased from companies such as Anaiji Chemical, Chengdu Kelong Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0106] Unless otherwise specified in the examples, the reaction is carried out under a nitrogen atmosphere. Unless otherwise specified in the examples, the solution refers to an aqueous solution. Unless otherwise specified in the examples, the reaction temperature is room temperature. Unless otherwise specified in the examples, M is moles per liter.

[0107] Synthesis of intermediate compounds

[0108]

[0109] Step 1: Synthesis of compound M1-2

[0110] 12.3 g (50 mmol) of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid M1-1 was dissolved in dimethylformamide (60 mL). After thorough stirring, 1,8-diazabicycloundec-7-ene (11.4 g, 75 mmol) was added to the reaction system at room temperature and stirred for 10 minutes. Iodoethane (14.0 g, 90 mmol) was then added to the reaction system, and the mixture was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was extracted with ethyl acetate and water. The organic phase was washed three times each with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product, ethyl 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid M1-2 (13.4 g), was also obtained. LC-MS: m / z 275 [M+H]. +

[0111] Step 2, Synthesis of Compound M1-3

[0112] Ethyl 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylate M1-2 (13.4 g, 49 mmol) was dissolved in dimethylacetamide (130 mL). After thorough stirring, pyridine p-toluenesulfonate (36.8 g, 147 mmol) and tert-butyl hydrazinoate (9.7 g, 73.5 mmol) were added to the reaction system at room temperature. The mixture was stirred at 60°C for 12 hours, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was extracted with ethyl acetate and water. The organic phase was washed three times each with water and saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give ethyl 3-(benzyloxy)-1-((tert-butyloxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-2-carboxylate M1-3 (12.2 g). LC-MS: m / z 389 [M+H] +

[0113] Step 3, Synthesis of Compound M1

[0114] Ethyl 3-(benzyloxy)-1-((tert-butyloxycarbonyl)amino)-4-oxo-1,4-dihydropyridine-2-carboxylate M1-3 (7.8 g, 20 mmol) was dissolved in dichloromethane (30 mL). After thorough stirring, trifluoroacetic acid (30 mL) was added to the reaction system at room temperature, and the mixture was stirred for 1 hour at room temperature. The reaction was monitored by LC-MS. After the reaction was completed, the dichloromethane and trifluoroacetic acid were removed by concentration under reduced pressure. The pH of the system was adjusted to 7-8 by adding saturated sodium bicarbonate aqueous solution. The mixture was extracted with dichloromethane and water. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. Crude product: Ethyl 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylate M1 (5.4 g). LC-MS: m / z 289 [M+H]+

[0115]

[0116] Step 4: Synthesis of compound M2-2

[0117] 3,4-Difluoro-2-methylbenzoic acid M2-1 (8.6 g, 50 mmol), N-bromosuccinimide (8.9 g, 60 mmol), and azobisisobutyronitrile (164 mg, 1 mmol) were dissolved in carbon tetrachloride (200 mL). The reaction system was purged three times with nitrogen and then purged with nitrogen at one atmosphere. The mixture was stirred at 80 °C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 2-(bromomethyl)-3,4-difluorobenzoic acid M2-2 (12.0 g).

[0118] Step 5: Synthesis of compound M2-4

[0119] Diphenyl disulfide M2-3 (5.5 g, 25 mmol), sodium hydroxide (2.9 g, 72 mmol), and sodium borohydride (1.7 g, 46 mmol) were dissolved in tetrahydrofuran (80 mL) and water (80 mL). The reaction system was purged three times with nitrogen and then purged with nitrogen at one atmosphere. The mixture was stirred at 70°C for 12 hours, and monitored by LC-MS. The reaction solution was used directly for the next step. 2-(bromomethyl)-3,4-difluorobenzoic acid M2-2 (12.0 g, 48 mmol) was added to the above solution and stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction was completed, 1N dilute hydrochloric acid was added to the reaction system to adjust the pH to 5-6. The mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain product 3,4-difluoro-2-((phenylthio)methyl)benzoic acid M2-4 (12.6 g). LC-MS: m / z 281 [M+H] +

[0120] Step 6: Synthesis of compound M2-5

[0121] 12.6 g (45 mmol) of 3,4-difluoro-2-((phenylthio)methyl)benzoic acid M2-4 was dissolved in polyphosphoric acid (300 mL) and stirred at 120 °C for 12 hours, monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, and the reaction solution was poured into 2 kg of crushed ice. Extraction was performed with ethyl acetate and water. The organic phase was washed three times with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 10.1 g (7,8-difluorodiphenyl[b,e]thiahepta-11(6H)-one). LC-MS: m / z 263 [M+H]+

[0122] Step 7, Synthesis of Compound M2

[0123] 10.1 g (38.5 mmol) of 7,8-difluorodiphenyl[b,e]thiahepta-11(6H)-one M2-5 was dissolved in methanol (200 mL). The system was cooled to 0°C, and sodium borohydride (2.9 g, 77 mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-ol M2 (9.8 g). LC-MS: m / z 247 [M+H-18] +

[0124] M2 can be broken down into:

[0125]

[0126] Example 1: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione (compound 1)

[0127]

[0128] Step 1: Synthesis of Compounds 1-3

[0129] Under nitrogen protection, the substrate 8-oxa-2-azaspiro[4,5]dec-3-one 1-1 (1.6 g, 10.0 mmol) was dissolved in tetrahydrofuran (40 mL). The reaction system was cooled to -30°C, and n-butyllithium (2.5 M, 12.0 mmol, 4.8 mL) was slowly added dropwise. The reaction was maintained at -30°C for 1 hour. Allyl chloroformate 1-2 (1.5 g, 12.0 mmol) was added dropwise to the reaction system, and the reaction was maintained at -30°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give the product allyl 3-oxa-8-oxa-2-azaspiro[4.5]decane-2-carbonate 1-3 (2.4 g). LC-MS: m / z 240 [M+H] +

[0130] Step 2, Synthesis of Compounds 1-4

[0131] 3-O-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 1-3 (2.38 g, 10.0 mmol) was dissolved in 25 mL of tetrahydrofuran. The reaction system was cooled to -78°C, and diisobutylaluminum hydride (1.3 M, 12.0 mmol, 9.2 mL) was slowly added dropwise. The reaction was maintained at -78°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product can be used directly in the next reaction without purification. The crude product is 3-hydroxy-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 1-4. LC-MS: m / z 224 [M+H-18] +

[0132] Step 3: Synthesis of compounds 1-5

[0133] The crude products 3-hydroxy-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl esters 1-4 were dissolved in methanol (20 mL). After thorough stirring, p-toluenesulfonic acid monohydrate (153 mg, 0.8 mmol) was added to the reaction system at room temperature, and the mixture was stirred at room temperature for 12 hours. LC-MS was used for monitoring. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-methoxy-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl esters 1-5. LC-MS: m / z 224 [M+H-32] + Step 4: Synthesis of compounds 1-6

[0134] The crude products 3-methoxy-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 1-5 and 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1 (1.8 g, 6.2 mmol) were dissolved in acetonitrile (60 mL). The reaction system was cooled to -30°C, and tin tetrachloride (2.4 g, 9.4 mmol) was slowly added to the reaction system. The mixture was stirred at -30°C for 1 hour, and monitored by LC-MS. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was concentrated under reduced pressure. It was then extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 1-6. LC-MS: m / z 512 [M+H] +

[0135] Step 5: Synthesis of compounds 1-7

[0136] The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 1-6, tetra-triphenylphosphine palladium (285 mg, 0.3 mmol), and morpholine (4.3 g, 50 mmol) were dissolved in tetrahydrofuran (40 mL). The reaction system was purged with nitrogen three times and then purged with nitrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour and monitored by TLC and LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the product 9'-(benzyloxy)-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 1-7 (1.5 g). LC-MS: m / z 382 [M+H] +

[0137] Compounds 1-7 can be separated into:

[0138]

[0139] Step 6: Synthesis of compounds 1-8

[0140] 9'-(benzyloxy)-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 1-7 (38.2 mg, 0.1 mmol) and 7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-ol M2 (39.6 mg, 0.2 mmol) were dissolved in 1-propylphosphonic anhydride (50 wt.% ethyl acetate solution, 400 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction, the product was concentrated under reduced pressure to give the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 1-8. LC-MS: m / z 628 [M+H] +

[0141] Step 7, Synthesis of Compound 1

[0142] The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 1-8 was dissolved in methanol (5 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified using a medium-pressure reversed-phase preparative column to obtain compound 1 (24.2 mg) of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone. LC-MS: m / z 538 [M+H] +

[0143] 1 H NMR (400MHz, DMSO-d6) δ7.58-7.45(m,2H),7.39-7.30(m,1H),7.13-7.07(m,1H),7.03(d,J=7.8Hz,1H),6.94-6.82(m,2H),5.78-5 .54(m,4H),4.15(d,J=13.8Hz,1H),3.90(d,J=12.0Hz,1H),3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H).

[0144] Compound 1 can produce the following 6 isomers:

[0145]

[0146] Isomer 1-1 corresponding NMR: 1H NMR (400MHz, DMSO-d6) δ7.58-7.45(m,2H),7.39-7.30(m,1H),7.13-7.07(m,1H),7.03(d,J=7.8Hz,1H),6.94-6.82(m,2H),5.78-5 .54(m,4H),4.15(d,J=13.8Hz,1H),3.90(d,J=12.0Hz,1H),3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H).

[0147] Isomer 1-2 corresponding NMR: 1 H NMR (400MHz, DMSO-d6) δ7.58-7.45(m,2H),7.39-7.30(m,1H),7.13-7.07(m,1H),7.03(d,J=7.8Hz,1H),6.94-6.82(m,2H),5.78-5 .54(m,4H),4.15(d,J=13.8Hz,1H),3.90(d,J=12.0Hz,1H),3.42-3.40(m,3H),2.36(s,1H),2.07-1.94(m,1H),1.55-1.24(m,6H).

[0148] Example 2: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione (compound 2)

[0149]

[0150] Step 1: Synthesis of Compounds 2-3

[0151] Under nitrogen protection, sodium hydride (1.9 g, 48 mmol) and anhydrous tetrahydrofuran (200 mL) were added to a 250 mL three-necked flask. The mixture was cooled completely to 0°C, and a solution of triethyl phosphoroacetate 2-2 (10.8 g, 48 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at 0°C for 0.5 h, followed by a reaction at room temperature for 1 h. The reaction system was then cooled completely to 0°C, and 4,4-difluorocyclohexanone 2-1 (5.4 g, 40 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at room temperature for 2 h, and the reaction was monitored by TLC and LC-MS. After the reaction was complete, 50 mL of saturated ammonium chloride aqueous solution was added to the system, and the mixture was concentrated under reduced pressure. The solution was extracted with ethyl acetate and water, and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 2-3 (8.0 g) of ethyl acetate 2-(4,4-difluorocyclohexyldiene). LC-MS: m / z 205 [M+H] + .

[0152] Step 2, Synthesis of Compounds 2-4

[0153] Add 2-(4,4-difluorocyclohexyldiene)ethyl acetate 2-3 (8.0 g, 39 mmol), potassium carbonate (11 g, 80 mmol), dimethyl sulfoxide (80 mL), and nitromethane (4.9 g, 80 mmol) to a 250 mL reaction flask. Stir the mixture at 80 °C for 2 hours, monitoring the reaction by TLC and LC-MS. After the reaction is complete, add water (200 mL) to the system, extract with ethyl acetate, wash the organic phase twice with saturated aqueous brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude 2-(4,4-difluoro-1-(nitromethyl)cyclohexyl)ethyl acetate 2-4, which can be used directly in the next reaction. LC-MS: m / z 266 [M+H] +

[0154] Step 3, Synthesis of Compounds 2-5

[0155] Add 2-(4,4-difluoro-1-(nitromethyl)cyclohexyl)ethyl acetate 2-4, methanol (80 mL), and Raney nickel to a 250 mL reaction flask. Purge the reaction system three times with nitrogen, then purge with hydrogen at one atmosphere. Stir the mixture at room temperature for 12 hours. Monitor the reaction by LC-MS. After the reaction is complete, concentrate under reduced pressure, extract with ethyl acetate and water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography to obtain the product 8,8-difluoro-2-azaspiro[4.5]dec-3-one 2-5 (3.8 g). LC-MS: m / z 190 [M+H] +

[0156] Step 4: Synthesis of compounds 2-6

[0157] The substrate 8,8-difluoro-2-azaspiro[4,5]dec-3-one 2-5 (3.8 g, 20.1 mmol) was dissolved in tetrahydrofuran (50 mL). The reaction system was cooled to -30°C, and n-butyllithium (2.5 M, 24.1 mmol, 9.6 mL) was slowly added dropwise. The reaction was maintained at -30°C for 1 hour. Allyl chloroformate 1-2 (2.6 g, 21.4 mmol) was added dropwise to the reaction system, and the reaction was maintained at -30°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give the product allyl 3-oxo-8,8-difluoro-2-azaspiro[4,5]decane-2-carbonate 2-6 (4.3 g). LC-MS: m / z 274 [M+H] +

[0158] Step 5, Synthesis of Compounds 2-7

[0159] 3-O-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 2-6 (4.3 g, 15.8 mmol) was dissolved in tetrahydrofuran (40 mL). The reaction system was cooled to -78°C, and diisobutylaluminum hydride (1.3 M, 19.0 mmol, 14.6 mL) was slowly added dropwise. The reaction was maintained at -78°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. It was used directly in the next reaction without purification. The crude product was 3-hydroxy-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 2-7. LC-MS: m / z 258 [M+H-18] +

[0160] Step 6, Synthesis of Compounds 2-8

[0161] The crude product, 3-hydroxy-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 2-7, was dissolved in methanol (32 mL). After thorough stirring, p-toluenesulfonic acid monohydrate (241 mg, 1.3 mmol) was added to the reaction system at room temperature, and the mixture was stirred for 12 hours at room temperature. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-methoxy-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 2-8. LC-MS: m / z 258 [M+H-32] +

[0162] Step 7, Synthesis of Compounds 2-9

[0163] The crude product 3-methoxy-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 2-8 and 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1 (3.2 g, 11.1 mmol) were dissolved in acetonitrile (110 mL). The reaction system was cooled to -30°C, and tin tetrachloride (7.5 g, 16.6 mmol) was slowly added to the reaction system. The mixture was stirred at -30°C for 1 hour, and monitored by LC-MS. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was concentrated under reduced pressure. It was then extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 2-9. LC-MS: m / z 546 [M+H] +

[0164] Step 8, Synthesis of Compounds 2-10

[0165] The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8,8-difluoro-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 2-9, tetra-triphenylphosphine palladium (480 mg, 0.4 mmol), and morpholine (7.2 g, 83 mmol) were dissolved in tetrahydrofuran (66 mL). The reaction system was purged with nitrogen three times and then purged with nitrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour and monitored by TLC and LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the product 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-10 (2.2 g). LC-MS: m / z 416 [M+H] +

[0166] Step 9, Synthesis of Compound 2-11

[0167] 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-10 (41.5 mg, 0.1 mmol) and 7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-ol M2 (39.6 mg, 0.2 mmol) were dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction, the product was concentrated under reduced pressure to give the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-11. LC-MS: m / z 662 [M+H] +

[0168] Step 10, Synthesis of Compound 2

[0169] The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-11 was dissolved in methanol (5 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by medium-pressure reversed-phase preparative column chromatography to obtain compound 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone 2 (24.5 mg). LC-MS: m / z 572 [M+H] +

[0170] 1H NMR(400MHz,DMSO-d6)δ7.44-7.35(m,2H),7.32-7.05(m,4H),7.05-6.96(m,1H),5.75-5.51(m,1H),5.45-5.31(m,1H),5.24-5 .04(m,1H),4.38-4.25(m,1H),3.93-3.81(m,1H),3.58-3.53(m,2H),2.41-2.22(m,1H),2.04-1.84(m,4H),1.77-1.41(m,5H).

[0171] Example 3: Synthesis of 4-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9-hydroxy-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine-2,4'-thiaran]-8,10(1H,3H)-dione (compound 3)

[0172]

[0173] Step 1: Synthesis of Compound 3-2

[0174] Under nitrogen protection, sodium hydroxide (2.2 g, 55 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. The mixture was cooled to 0°C, and a solution of triethyl phosphoroacetate 2-2 (12.3 g, 55 mmol) in tetrahydrofuran (40 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at 0°C for 0.5 h, followed by 1 h at room temperature. The reaction system was then cooled to 0°C, and tetrahydrothiaran-4-one 3-1 (5.8 g, 50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at room temperature for 2 h, and the reaction was monitored by TLC and LC-MS. After the reaction was complete, a saturated ammonium chloride aqueous solution (50 mL) was added to the system, and the mixture was concentrated under reduced pressure. The solution was extracted with ethyl acetate and water, and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product 2-tetrahydrothiaran-4-ethylene ethyl acetate 3-2 (8.6 g). LC-MS: m / z 187 [M+H] + .

[0175] Step 2, Synthesis of Compound 3-3

[0176] Ethyl 2-tetrahydrothiaran-4-ethylene 3-2 (8.6 g, 46 mmol), potassium carbonate (12.7 g, 92 mmol), dimethyl sulfoxide (100 mL), and nitromethane (5.6 g, 92 mmol) were added to a 250 mL reaction flask. The mixture was stirred at 80 °C for 2 hours, and the reaction was monitored by TLC and LC-MS. After the reaction was complete, water (200 mL) was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude 2-[4-(nitromethyl)tetrahydrothiaran-4-yl]ethyl acetate 3-3, which was directly used in the next step of the reaction. LC-MS: m / z 248 [M+H] +

[0177] Step 3, Synthesis of Compounds 3-4

[0178] Add ethyl 2-[4-(nitromethyl)tetrahydrothiaran-4-yl]acetate 3-3, methanol (80 mL), and Raney nickel to a 250 mL reaction flask. Purge the reaction system three times with nitrogen, then purge with hydrogen at one atmosphere. Stir the mixture at room temperature for 12 hours. Monitor the reaction by LC-MS. After the reaction is complete, concentrate under reduced pressure, extract with ethyl acetate and water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography to obtain the product 8-thia-2-azaspiro[4.5]decane-3-one 3-4 (2.3 g). LC-MS: m / z 172 [M+H] +

[0179] Step 4: Synthesis of compounds 3-5

[0180] The substrate 8-thia-2-azaspiro[4.5]decane-3-one 3-4 (1.0 g, 5.9 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction system was cooled to -30°C, and n-butyllithium (2.5 M, 5.9 mmol, 2.3 mL) was slowly added dropwise. The reaction was maintained at -30°C for 1 hour. Allyl chloroformate 1-2 (0.7 g, 5.9 mmol) was added dropwise to the reaction system, and the reaction was maintained at -30°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product 3-oxo-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-5. LC-MS: m / z 256 [M+H] +

[0181] Step 5, Synthesis of Compounds 3-6

[0182] 3-O-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-5 was dissolved in tetrahydrofuran (25 mL). The reaction system was cooled thoroughly to -78°C, and diisobutylaluminum hydride (1.3 M, 7.9 mmol, 6.1 mL) was slowly added dropwise. The reaction was maintained at -78°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product can be used directly in the next reaction without purification. The crude product is 3-hydroxy-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-6. LC-MS: m / z 240 [M+H-18] +

[0183] Step 6, Synthesis of Compounds 3-7

[0184] The crude product 3-hydroxy-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-6 was dissolved in methanol (20 mL). After thorough stirring, p-toluenesulfonic acid monohydrate (114 mg, 0.6 mmol) was added to the reaction system at room temperature, and the mixture was stirred at room temperature for 12 hours. LC-MS was used for monitoring. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-methoxy-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-7. LC-MS: m / z 240 [M+H-32] +

[0185] Step 7, Synthesis of Compounds 3-8

[0186] The crude products 3-methoxy-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-7 and 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1 (1.6 g, 5.5 mmol) were dissolved in acetonitrile (60 mL). The reaction system was cooled to -30°C, and tin tetrachloride (2.2 g, 8.3 mmol) was slowly added to the reaction system. The mixture was stirred at -30°C for 1 hour, and monitored by LC-MS. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was concentrated under reduced pressure. It was then extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-8. LC-MS: m / z 528 [M+H] +

[0187] Step 8, Synthesis of Compounds 3-9

[0188] The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 3-8, tetra-triphenylphosphine palladium (263 mg, 0.2 mmol), and morpholine (4.0 g, 46 mmol) were dissolved in tetrahydrofuran (40 mL). The reaction system was purged with nitrogen three times and then purged with nitrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour and monitored by TLC and LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the product 9-(benzyloxy)-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine-2,4'-thiaran]-8,10(1H,3H)-dione 3-9 (275 mg). LC-MS: m / z 398 [M+H] +

[0189] Step 9, Synthesis of Compounds 3-10

[0190] 9-(benzyloxy)-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrolopyrrolidone[2,1-c][1,2,4]triazine-2,4'-thiaran]-8,10(1H,3H)-dione 3-9 (30.0 mg, 0.08 mmol) and 7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-ol M2 (29.9 mg, 0.1 mmol) were dissolved in 1-propylphosphonic anhydride (50 wt.% ethyl acetate solution, 300 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction was complete, the sample was extracted with ethyl acetate and water. The organic phase was dried and filtered. The filtrate was concentrated under reduced pressure to give the crude product 9-(benzyloxy)-4-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahept-11-yl)-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine-2,4'-thiaran]-8,10(1H,3H)-dione 3-10. LC-MS: m / z 644 [M+H] +

[0191] Step 10, Synthesis of Compound 3

[0192] The crude product 9-(benzyloxy)-4-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahept-11-yl)-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine-2,4'-thiaran]-8,10(1H,3H)-dione 3-10 was dissolved in methanol (5 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction was completed, the solution was filtered with diatomaceous earth, and the filtrate was concentrated under reduced pressure to prepare and purify 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1' H,3'H)-diketone 4-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahept-11-yl)-9-hydroxy-2',3a,3',4,5',6'-hexahydrospiro[pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine-2,4'-thiaran]-8,10(1H,3H)-diketone compound 3 (12 mg). LC-MS: m / z 554 [M+H] +

[0193] 1 H NMR (400MHz, DMSO-d6) δ7.56-7.46(m,2H),7.41-7.30(m,1H),7.15-7.04(m,1H),7.03(d,J=7.8Hz,1H),6.92-6.85(m,2H),5.65-5.40(m ,3H),4.15(d,J=13.8Hz,1H),4.01(d,J=12.0Hz,1H),2.84-2.62(m,2H),2.53-2.41(m,2H),2.36(m,1H),2.00(m,1H),1.78-1.41(m,6H).

[0194] Example 4: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahept-11-yl)-9'-hydroxy-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione (compound 4)

[0195]

[0196] Step 1: Synthesis of Compound 4-2

[0197] Under nitrogen protection, sodium hydroxide (2.2 g, 55 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. The mixture was cooled to 0°C, and a solution of triethyl phosphoroacetate 2-2 (12.3 g, 55 mmol) in tetrahydrofuran (40 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at 0°C for 0.5 h, followed by 1 h at room temperature. The reaction system was then cooled to 0°C, and cyclobutanone 4-1 (3.5 g, 50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at room temperature for 2 h, monitored by TLC and LC-MS. After the reaction was complete, saturated ammonium chloride aqueous solution (50 mL) was added to the system, and the mixture was concentrated under reduced pressure. The extract was extracted with ethyl acetate and water, and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product 2-cyclobutenylethyl acetate 4-2 (6.8 g). LC-MS: m / z 141 [M+H] + .

[0198] Step 2, Synthesis of Compound 4-3

[0199] Add ethyl 2-cyclobutenyl acetate 4-2 (6.8 g, 49 mmol), potassium carbonate (13.4 g, 97 mmol), dimethyl sulfoxide (100 mL), and nitromethane (6.0 g, 97 mmol) to a 250 mL reaction flask. Stir the mixture at 80 °C for 2 hours, monitoring the reaction by TLC and LC-MS. After the reaction is complete, add water (200 mL) to the system, extract with ethyl acetate, wash the organic phase twice with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude ethyl 2-[1-(nitromethyl)cyclobutyl]ethyl acetate 4-3, which was directly used in the next step of the reaction. LC-MS: m / z 202 [M+H] +

[0200] Step 3, Synthesis of Compound 4-4

[0201] Add 4-3 ethyl 2-[1-(nitromethyl)cyclobutyl]acetate, 80 mL methanol, and Raney nickel to a 250 mL reaction flask. Purge the reaction system three times with nitrogen, then purge with hydrogen at one atmosphere. Stir the mixture at room temperature for 12 hours. Monitor the reaction by LC-MS. After the reaction is complete, concentrate under reduced pressure, extract with ethyl acetate and water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography to obtain the product 1.7 g of 6-azaspiro[3.4]octane-7-one. LC-MS: m / z 126 [M+H] +

[0202] Step 4, Synthesis of Compounds 4-5

[0203] The substrate 6-azaspiro[3.4]octane-7-one 4-4 (1.0 g, 13.6 mmol) was dissolved in tetrahydrofuran (20 mL). The reaction system was cooled to -30°C, and n-butyllithium (2.5 M, 15.0 mmol, 6.0 mL) was slowly added dropwise. The reaction was maintained at -30°C for 1 hour. Allyl chloroformate 1-2 (1.8 g, 15.0 mmol) was added dropwise to the reaction system, and the reaction was maintained at -30°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product 7-oxo-6-azaspiro[3.4]octane-6-carboxylic acid allyl ester 4-5. LC-MS: m / z 210 [M+H] +

[0204] Step 5, Synthesis of Compounds 4-6

[0205] 7-Oxy-6-azaspiro[3.4]octane-6-carboxylic acid allyl ester 4-5 was dissolved in tetrahydrofuran (25 mL). The reaction system was cooled to -78°C, and diisobutylaluminum hydride (1.3 M, 3.3 mmol, 2.5 mL) was slowly added dropwise. The reaction was maintained at -78°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 7-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid allyl ester 4-6. LC-MS: m / z 194 [M+H-18] +

[0206] Step 6, Synthesis of Compounds 4-7

[0207] The crude product, 7-hydroxy-6-azaspiro[3.4]octane-6-carboxylic acid allyl ester 4-6, was dissolved in methanol (10 mL). After thorough stirring, p-toluenesulfonic acid monohydrate (38 mg, 0.2 mmol) was added to the reaction system at room temperature, and the mixture was stirred for 12 hours at room temperature. LC-MS was used for monitoring. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 7-methoxy-6-azaspiro[3.4]octane-6-carboxylic acid allyl ester 4-7. LC-MS: m / z 194 [M+H-32] +

[0208] Step 7, Synthesis of Compounds 4-8

[0209] The crude products 3-methoxy-8-thia-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 4-7 and 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1 (610 mg, 2.1 mmol) were dissolved in acetonitrile (20 mL). The reaction system was cooled to -30°C, and tin tetrachloride (830 mg, 3.2 mmol) was slowly added to the reaction system. The mixture was stirred at -30°C for 1 hour, and monitored by LC-MS. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was concentrated under reduced pressure. It was then extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 7-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-6-azaspiro[3.4]octane-6-carboxylic acid allyl ester 4-8. LC-MS: m / z 482 [M+H] +

[0210] Step 8, Synthesis of Compounds 4-9

[0211] The crude product 7-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-6-azaspiro[3.4]octane-6-carboxylic acid allyl ester 4-8, tetra-triphenylphosphine palladium (89 mg, 0.08 mmol), and morpholine (1.34 g, 15.4 mmol) were dissolved in tetrahydrofuran (10 mL). The reaction system was purged with nitrogen three times and then purged with nitrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour, and the reaction was monitored by TLC and LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 9'-(benzyloxy)-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 4-9 (106 mg). LC-MS: m / z 352 [M+H] +

[0212] Step 9, Synthesis of Compounds 4-10

[0213] 9'-(benzyloxy)-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 4-9 (30.0 mg, 0.09 mmol) and 7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-ol M2 (33.8 mg, 0.1 mmol) were dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 300 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction was complete, the sample was extracted with ethyl acetate and water. The organic phase was dried and filtered. The filtrate was concentrated under reduced pressure to give the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 4-10 (45 mg). LC-MS: m / z 598 [M+H] +

[0214] Step 10, Synthesis of Compound 4

[0215] The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 4-10 (45 mg, 0.08 mmol) was dissolved in methanol (5 mL), and palladium hydroxide on carbon (15 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction, the solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure to prepare and purify compound 4 (14 mg): 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-3a',4'-dihydrospiro[cyclobutane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone. LC-MS: m / z 508 [M+H] +

[0216] 1H NMR (400MHz, CDCl3) δ7.59(d,J=7.6Hz,1H),7.11-7.06(m,3H),6.83(d,J=7.6Hz,1H),6.63(d,J=7.8Hz,1H),6.10(d,J=7.6Hz,1H),5.55(d,J=13. 6Hz,1H),5.41-5.30(m,1H),5.14(s,1H),4.14(d,J=13.6Hz,1H),4.09-4 .02(m,2H),3.42(d,J=12.2Hz,1H),2.11-2.97(m,3H),1.95-1.64(m,5H).

[0217] Example 5: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione (compound 5)

[0218]

[0219] Step 1: Synthesis of Compound 5-2

[0220] Under nitrogen protection, sodium hydroxide (2.4 g, 60 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. The mixture was cooled completely to 0°C, and a solution of triethyl phosphoroacetate 2-2 (10.8 g, 60 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at 0°C for 0.5 h, followed by a reaction at room temperature for 1 h. The reaction system was then cooled completely to 0°C, and a solution of 4,4-dimethylcyclohexanone 5-1 (6.3 g, 50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at room temperature for 2 h, and the reaction was monitored by TLC and LC-MS. After the reaction was complete, 50 mL of saturated ammonium chloride aqueous solution was added to the system, and the mixture was concentrated under reduced pressure. The solution was extracted with ethyl acetate and water, and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 5-2 (9.4 g) of ethyl 2-(4,4-dimethylcyclohexyldiene). LC-MS: m / z 197 [M+H] + .

[0221] Step 2, Synthesis of Compound 5-3

[0222] Add ethyl 2-(4,4-dimethylcyclohexyldiene)acetate 5-2 (9.4 g, 48 mmol), potassium carbonate (13.8 g, 100 mmol), dimethyl sulfoxide (100 mL), and nitromethane (6.1 g, 100 mmol) to a 250 mL reaction flask. Stir the mixture at 80 °C for 2 hours, monitoring the reaction by TLC and LC-MS. After the reaction, add water (200 mL) to the system, extract with ethyl acetate, wash the organic phase twice with saturated aqueous brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude ethyl 2-(4,4-dimethyl-1-(nitromethyl)cyclohexyl)acetate 5-3, which was directly used in the next reaction. LC-MS: m / z 258 [M+H] +

[0223] Step 3, Synthesis of Compounds 5-4

[0224] Add 5-3g of 2-(4,4-dimethyl-1-(nitromethyl)cyclohexyl)ethyl acetate, 80mL of methanol, and Raney nickel to a 250mL reaction flask. The reaction system was purged three times with hydrogen gas, and then purged with hydrogen gas at one atmosphere. The mixture was stirred at room temperature for 12 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give 5-4g (4.4g) of 8,8-dimethyl-2-azaspiro[4.5]dec-3-one. LC-MS: m / z 182 [M+H] +

[0225] Step 4, Synthesis of Compound 5-5

[0226] 5-4 (1.8 g, 10.0 mmol) of the substrate 8,8-dimethyl-2-azaspiro[4,5]dec-3-one was dissolved in tetrahydrofuran (40 mL). The reaction system was cooled to -30°C, and n-butyllithium (2.5 M, 12.0 mmol, 4.8 mL) was slowly added dropwise. The reaction was maintained at -30°C for 1 hour. 1-2 (1.5 g, 12.0 mmol) of allyl chloroformate was added dropwise to the reaction system, and the reaction was maintained at -30°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to give the product allyl 3-oxo-8,8-dimethyl-2-azaspiro[4,5]decane-2-carbonate 5-5 (2.6 g). LC-MS: m / z 266 [M+H] +

[0227] Step 5, Synthesis of Compounds 5-6

[0228] 3-O-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 5-5 (2.6 g, 9.9 mmol) was dissolved in tetrahydrofuran (25 mL). The reaction system was cooled to -78°C, and diisobutylaluminum hydride (1.3 M, 12.0 mmol, 9.2 mL) was slowly added dropwise. The reaction was maintained at -78°C for 1 hour. The reaction was quenched with saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-hydroxy-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 5-6. LC-MS: m / z 250 [M+H-18] +

[0229] Step 6, Synthesis of Compounds 5-7

[0230] The crude product 3-hydroxy-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 5-6 was dissolved in methanol (20 mL). After thorough stirring, p-toluenesulfonic acid monohydrate (153 mg, 0.8 mmol) was added to the reaction system at room temperature, and the mixture was stirred at room temperature for 12 hours. LC-MS was used for monitoring. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-methoxy-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 5-7. LC-MS: m / z 250 [M+H-32] +

[0231] Step 7, Synthesis of Compounds 5-8

[0232] The crude products 3-methoxy-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 5-7 and 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1 (1.8 g, 6.3 mmol) were dissolved in acetonitrile (60 mL). The reaction system was cooled to -30°C, and tin tetrachloride (2.4 g, 9.4 mmol) was slowly added to the reaction system. The mixture was stirred at -30°C for 1 hour, and monitored by LC-MS. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was concentrated under reduced pressure. It was then extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 5-8. LC-MS: m / z 538 [M+H] +

[0233] Step 8, Synthesis of Compounds 5-9

[0234] The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 5-8, tetra-triphenylphosphine palladium (285 mg, 0.3 mmol), and morpholine (4.3 g, 50 mmol) were dissolved in tetrahydrofuran (40 mL). The reaction system was purged with nitrogen three times and then purged with nitrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour and monitored by TLC and LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the product 9'-(benzyloxy)-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 5-9 (1.5 g). LC-MS: m / z 408 [M+H] +

[0235] Step 9, Synthesis of Compounds 5-10

[0236] 9'-(benzyloxy)-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 5-9 (40.7 mg, 0.1 mmol) and 7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-ol M2 (39.6 mg, 0.2 mmol) were dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction was completed, the product was concentrated under reduced pressure to give the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepten-11-yl)-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 5-10. LC-MS: m / z 654 [M+H] +

[0237] Step 10, Synthesis of Compound 5

[0238] The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 5-10 was dissolved in methanol (5 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 4 hours and monitored by LC-MS. After the reaction, the solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by medium-pressure reversed-phase preparative column chromatography to obtain compound 5 (23.1 mg) of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-4,4-dimethyl-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone. LC-MS: m / z 564 [M+H] +

[0239] 1 H NMR(400MHz,DMSO-d6)δ7.55-7.43(m,2H),7.41-7.30(m,1H),7.12-7.05(m,1H),7.02( d,J=7.8Hz,1H),6.94-6.78(m,2H),5.71(d,J=13.8Hz,1H),5.60(s,1H),5.56(d,J=7.8H z,1H),4.16(t,J=14.6Hz,1H),3.78(d,J=12.4Hz,1H),3.32-3.03(m,2H),1.92-1.80(m, 1H),1.44-1.27(m,3H),1.23-1.14(m,4H),1.13-1.04(m,2H),0.86(s,3H),0.81(s,3H).

[0240] Example 6: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione (compound 6)

[0241]

[0242] Step 1: Synthesis of Compound 6-2

[0243] Under nitrogen protection, sodium hydroxide (2.4 g, 60 mmol) and anhydrous tetrahydrofuran (100 mL) were added to a 250 mL three-necked flask. The mixture was thoroughly cooled to 0°C, and a solution of triethyl phosphoroacetate 2-2 (10.8 g, 60 mmol) in tetrahydrofuran (50 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at 0°C for 0.5 h, followed by a reaction at room temperature for 1 h. The reaction system was then thoroughly cooled to 0°C, and a solution of 2,6-dimethyltetrahydropyranone 6-1 (6.4 g, 50 mmol) in tetrahydrofuran (30 mL) was slowly added dropwise. After the addition was complete, the reaction was maintained at room temperature for 2 h, and the reaction was monitored by TLC and LC-MS. After the reaction was complete, 50 mL of saturated ammonium chloride aqueous solution was added to the system, and the mixture was concentrated under reduced pressure. The solution was extracted with ethyl acetate and water, and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give 6-2 (9.5 g) of ethyl acetate 2-(3,5-dimethyl-4-oxacyclohexyldiene). LC-MS: m / z 199 [M+H] + .

[0244] Step 2, Synthesis of Compound 6-3

[0245] Add 9.5 g (48 mmol) of ethyl 2-(3,5-dimethyl-4-oxacyclohexyldiene) 6-2, 13.8 g (100 mmol) of potassium carbonate, 100 mL of dimethyl sulfoxide, and 6.1 g (100 mmol) of nitromethane to a 250 mL reaction flask. Stir the mixture at 80 °C for 2 hours, monitoring the reaction by TLC and LC-MS. After the reaction, add 200 mL of water to the system, extract with ethyl acetate, wash the organic phase twice with saturated aqueous brine, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure to obtain crude ethyl 2-(3,5-dimethyl-4-oxa-1-(nitromethyl)cyclohexyl) 6-3, which was directly used in the next reaction. LC-MS: m / z 260 [M+H] +

[0246] Step 3, Synthesis of Compound 6-4

[0247] Add 6-3 ethyl acetate (4,4-dimethyl-1-(nitromethyl)cyclohexyl) 6-3, methanol (80 mL), and Raney nickel to a 250 mL reaction flask. Purge the reaction system three times with nitrogen, then purge with hydrogen at one atmosphere. Stir the mixture at room temperature for 12 hours. Monitor the reaction by LC-MS. After the reaction is complete, concentrate under reduced pressure, extract with ethyl acetate and water, dry the organic phase with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the residue by column chromatography to obtain 7,9-dimethyl-8-oxa-2-azaspiro[4,5]dec-3-one 6-4 (4.5 g). LC-MS: m / z 184 [M+H] +

[0248] Step 4, Synthesis of Compounds 6-5

[0249] The substrate 7,9-dimethyl-8-oxa-2-azaspiro[4.5]dec-3-one 6-4 (1.8 g, 10.0 mmol) was dissolved in tetrahydrofuran (40 mL). The reaction system was cooled to -30°C, and n-butyllithium (2.5 M, 12.0 mmol, 4.8 mL) was slowly added dropwise. The reaction was maintained at -30°C for 1 hour. Allyl chloroformate 1-2 (1.5 g, 12.0 mmol) was added dropwise to the reaction system. The reaction was maintained at -30°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to obtain the product allyl 3-oxo-7,9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carbonate 6-5 (2.6 g). LC-MS: m / z 268 [M+H] +

[0250] Step 5, Synthesis of Compound 6-6

[0251] 2.6 g (9.9 mmol) of 3-oxo-7,9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 6-5 was dissolved in tetrahydrofuran (25 mL). The reaction system was cooled to -78°C, and diisobutylaluminum hydride (1.3 M, 12.0 mmol, 9.2 mL) was slowly added dropwise. The reaction was maintained at -78°C for 1 hour. The reaction was quenched by adding saturated ammonium chloride solution, concentrated under reduced pressure, and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-hydroxy-7,9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 6-6. LC-MS: m / z 252 [M+H-18] +

[0252] Step 6, Synthesis of Compounds 6-7

[0253] The crude product, 3-hydroxy-7,9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 6-6, was dissolved in methanol (20 mL). After thorough stirring, p-toluenesulfonic acid monohydrate (153 mg, 0.8 mmol) was added to the reaction system at room temperature, and the mixture was stirred for 12 hours at room temperature. The reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure and extracted with ethyl acetate and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-methoxy-7,9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 6-7. LC-MS: m / z 252 [M+H-32] +

[0254] Step 7, Synthesis of Compounds 6-8

[0255] The crude products 3-methoxy-7,9-dimethyl-8-oxa-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 6-7 and 1-amino-3-(benzyloxy)-4-oxo-1,4-dihydropyridine-2-carboxylic acid ethyl ester M1 (1.8 g, 6.3 mmol) were dissolved in acetonitrile (60 mL). The reaction system was cooled to -30°C, and tin tetrachloride (2.4 g, 9.4 mmol) was slowly added to the reaction system. The mixture was stirred at -30°C for 1 hour, and monitored by LC-MS. After the reaction was completed, a saturated sodium bicarbonate aqueous solution was added to quench the reaction, and the mixture was concentrated under reduced pressure. It was then extracted with dichloromethane and water. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product could be used directly in the next reaction without purification. The crude product was 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-7,9-dimethyl-8-oxa-2-azaspiro[4,5]decane-2-carboxylic acid allyl ester 6-8. LC-MS: m / z 540 [M+H] +

[0256] Step 8, Synthesis of Compounds 6-9

[0257] The crude product 3-((3-(benzyloxy)-2-(ethoxycarbonyl)-4-oxopyridin-1(4H)-yl)amino)-8,8-dimethyl-2-azaspiro[4.5]decane-2-carboxylic acid allyl ester 6-8, tetra-triphenylphosphine palladium (285 mg, 0.3 mmol), and morpholine (4.3 g, 50 mmol) were dissolved in tetrahydrofuran (40 mL). The reaction system was purged with nitrogen three times and then purged with nitrogen at one atmosphere. The mixture was stirred at room temperature for 1 hour and monitored by TLC and LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography to give the product 9'-(benzyloxy)-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 6-9 (1.6 g). LC-MS: m / z 410 [M+H] +

[0258] Compounds 6-9 can be separated into:

[0259]

[0260] Step 9, Synthesis of Compounds 6-10

[0261] 9'-(benzyloxy)-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 6-9 (40.9 mg, 0.1 mmol) and 7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-ol M2 (39.6 mg, 0.2 mmol) were dissolved in 1-propylphosphonic anhydride (50 wt.% ethyl acetate solution, 400 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction was completed, the product was concentrated under reduced pressure to give the crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 6-10. LC-MS: m / z 656 [M+H] +

[0262] Step 10, Synthesis of Compound 6

[0263] The crude product 9'-(benzyloxy)-4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 6-10 was dissolved in methanol (5 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 4 hours, and monitored by LC-MS. After the reaction, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified using a medium-pressure reversed-phase preparative column to obtain compound 6 (23.1 mg) of 4'-(7,8-difluoro-6,11-dihydrodiphenyl[b,e]thiahepta-11-yl)-9'-hydroxy-2,6-dimethyl-2,3,3a',4',5,6-hexahydrospiro[pyran-4,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone. LC-MS: m / z 566 [M+H] +

[0264] 1 H NMR(400MHz, CDCl3)δ7.61(s,1H),7.10-7.04(m,2H),6.89(s,1H),6.81(s,1H),6. 62(s,1H),6.18(s,1H),5.59(s,1H),5.51(d,J=13.6Hz,1H),5.13(s,1H),4.14(d,J =13.6Hz,2H),3.73-3.60(m,1H),3.48-3.35(m,1H),3.36-3.25(m,1H),3.24-3.10( m,1H),2.25-2.17(m,1H),1.40-1.31(m,2H),1.22-1.16(m,3H),1.11-1.00(m,6H).

[0265] Compound 6 can produce the following four isomers:

[0266]

[0267] Example 7: Synthesis of 4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloen-5-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione (compound 7)

[0268]

[0269] Step 1: Synthesis of Compound 7-2

[0270] Dibenzo[a,d]cyclohepten-5-one 7-1 (412 mg, 2 mmol) was dissolved in methanol (10 mL), and platinum dioxide (11.5 mg, 0.05 mmol) was added. The reaction system was purged three times with nitrogen, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 12 hours, and monitored by LC-MS. After the reaction was complete, the mixture was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, extracted with ethyl acetate and water, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give product 10,11-dihydro-5H-dibenzo[a,d][7]cycloen-5-ol 7-2. LC-MS: m / z 193 [M+H-18] +

[0271] Step 2, Synthesis of Compound 7-3

[0272] 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-10 (41.5 mg, 0.1 mmol) and 10,11-dihydro-5H-dibenzo[a,d][7]cycloen-5-ol 7-2 (31.5 mg, 0.2 mmol) were dissolved in 1-propylphosphonic anhydride (50 wt.% ethyl acetate solution, 400 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction was completed, the product was concentrated under reduced pressure to give the crude product 9'-(benzyloxy)-4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloen-5-yl)-4,4-difluoro-3a',4'-dihydrospiro[1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone 7-3. LC-MS: m / z 608 [M+H] +

[0273] Step 3, Synthesis of Compound 7

[0274] The crude product 9'-(benzyloxy)-4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloen-5-yl)-4,4-difluoro-3a',4'-dihydrospiro[1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 7-3 was dissolved in methanol (5 mL), and palladium hydroxide carbon (14 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 4 hours and monitored by LC-MS. After the reaction, the solution was filtered through diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by medium-pressure reversed-phase preparative column chromatography to obtain compound 4'-(10,11-dihydro-5H-diphenyl[a,d][7]cycloen-5-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone 7 (22.4 mg). LC-MS: m / z 518 [M+H] +1

[0275] 1 H NMR (400MHz, DMSO-d6) δ7.45 (d, J=7.4Hz, 1H), 7.29 (s, 1H), 7.22-7.10 (m, 4H), 7.06 (d, J= 7.6Hz,1H),6.89-6.81(m,1H),6.68(d,J=7.8Hz,1H),5.61-5.51(m,1H),5.50-5.37(m,1H ),5.35-5.22(m,1H),4.45-4.39(m,1H),3.86(d,J=12.2Hz,1H),3.65-3.62(m,1H),3.27- 3.24(m,1H),2.99-2.92(m,1H),2.82-2.77(m,1H),1.98-1.76(m,4H),1.71-1.26(m,6H).

[0276] Example 8: Synthesis of 4'-(6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrroleium[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione (compound 8)

[0277]

[0278] Step 1: Synthesis of Compound 8-2

[0279] Diphenyl disulfide M2-3 (2.2 g, 10 mmol), sodium hydroxide (1.2 g, 28.8 mmol), and sodium borohydride (700 mg, 18.4 mmol) were dissolved in tetrahydrofuran (30 mL) and water (30 mL). The reaction system was purged three times with nitrogen, and then purged with nitrogen at one atmosphere. The mixture was stirred at 70°C for 12 hours, and monitored by LC-MS. The reaction solution was used directly for the next reaction. 2-Bromomethylbenzoic acid 8-1 (4.3 g, 20 mmol) was added to the above solution, and the mixture was stirred at room temperature for 1 hour, and monitored by LC-MS. After the reaction was complete, 1N dilute hydrochloric acid was added to the reaction system to adjust the pH to 5-6. The mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residue was purified by column chromatography to obtain the product 2-(phenylthio)methylbenzoic acid 8-2 (1.9 g). LC-MS: m / z 245 [M+H] +

[0280] Step 2, Synthesis of Compound 8-3

[0281] 2-(phenylthio)methylbenzoic acid 8-2 (1.9 g, 8.1 mmol) was dissolved in polyphosphoric acid (60 mL) and stirred at 120 °C for 12 hours, monitored by LC-MS. After the reaction was completed, the reaction system was cooled to room temperature, and the reaction solution was poured into 0.5 kg of crushed ice. Extraction was performed with ethyl acetate and water. The organic phase was washed three times with saturated sodium bicarbonate aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product diphenyl[b,e]thiahepta-11(6H)-one 8-3 (1.6 g). LC-MS: m / z 227 [M+H] +

[0282] Step 3, Synthesis of Compound 8-4

[0283] Diphenyl[b,e]thiohepta-11(6H)-one 8-3 (1.6 g, 7.3 mmol) was dissolved in methanol (35 mL). The system was cooled to 0°C, and sodium borohydride (557 mg, 14.6 mmol) was slowly added at 0°C. The mixture was stirred at 0°C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was completed, the mixture was concentrated under reduced pressure, extracted with ethyl acetate and water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography to give the product 6,11-dihydrodiphenyl[b,e]thiohepta-11-ol 8-4 (1.5 g). LC-MS: m / z 211 [M+H-18] +

[0284] Step 4, Synthesis of Compound 8-5

[0285] 9'-(benzyloxy)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 2-10 (41.5 mg, 0.1 mmol) and 6,11-dihydrodiphenyl[b,e]thiahepta-11-ol 8-4 (34.2 mg, 0.2 mmol) were dissolved in 1-propylphosphoric anhydride (50 wt.% ethyl acetate solution, 400 μL), and stirred in a microwave at 110 °C for 3 hours. The mixture was monitored by LC-MS. After the reaction, the product was concentrated under reduced pressure to give the crude product 9'-(benzyloxy)-4'-(6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 8-5. LC-MS: m / z 626 [M+H] +

[0286] Step 5, Synthesis of Compound 8

[0287] The crude product 9'-(benzyloxy)-4'-(6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-dione 8-5 was dissolved in methanol (5 mL), and palladium hydroxide on carbon (14 mg, 0.1 mmol) was added. The reaction system was purged with nitrogen three times, and then purged with hydrogen at one atmosphere. The mixture was stirred at room temperature for 4 hours and monitored by LC-MS. After the reaction, the solution was filtered through diatomaceous earth, and the filtrate was concentrated under reduced pressure and purified by medium-pressure reversed-phase preparative column chromatography to obtain compound 8 (24.6 mg): 4'-(6,11-dihydrodiphenyl[b,e]thiophene-11-yl)-4,4-difluoro-9'-hydroxy-3a',4'-dihydrospiro[cyclohexane-1,2'-pyridinium[2,1-f]pyrrolopyridine[2,1-c][1,2,4]triazine]-8',10'(1'H,3'H)-diketone. LC-MS: m / z 536 [M+H] +

[0288] 1H NMR(400MHz,DMSO-d6)δ7.59-7.46(m,2H),7.45-7.29(m,2H),7.28-7.09(m,2H),7.08-6.77(m,3H ),5.83-5.24(m,3H),3.91-3.85(m,2H),3.46-3.42(m,2H),1.98-1.74(m,4H),1.73-1.23(m,6H).

[0289] Example 9: Synthesis of ((4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-2,6-dimethyl-8',10'-dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 9)

[0290]

[0291] Step 1: Synthesis of Compound 9

[0292] Dissolve 6 in DMA (2 mL) in a dry round-bottom flask, add KI (36.7 mg, 0.2 mmol), dimethyl chloromethyl carbonate (55.0 mg, 0.4 mmol, 42.2 μL) and cesium carbonate (144.0 mg, 0.4 mmol), heat to 50 degrees Celsius, stir for 1 hour, and monitor by LC-MS. After the reaction was complete, the solution was concentrated under reduced pressure, and the residual impurities were purified by medium-pressure reversed-phase preparative column chromatography to obtain 9 (26 mg) of ((4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-2,6-dimethyl-8',10'-dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrido[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate. LC-MS: m / z 654.4 [M+H] +

[0293] 1H NMR(600MHz,DMSO-d6)δ7.65(d,1H),7.55-7.49(m,1H),7.39-7.32(m,1H),7.13-7.06(m,1H),7.04(d ,J=8.0Hz,1H),6.92-6.87(m,2H),5.83(d,J=7.8Hz,1H),5.72-5.66(m,2H),5.65-5.59(m,1H),5.54(d ,J=6.6Hz,1H),5.38(s,1H),4.16(d,J=14.0Hz,1H),3.76(s,3H),3.57-3.42(m,3H),3.20-3.11(m,1H ),2.30-2.24(m,1H),1.61(d,J=13.4Hz,1H),1.32-1.24(m,1H),1.25-1.17(m,1H),1.05-0.86(m,8H).

[0294] Compound 9 can produce the following four isomers:

[0295]

[0296] Examples 10 and 11, (3a'R)-4'-(6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'hydroxy-2,3,3a',4',5,6-hexahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 10) and (((3a) Synthesis of 'R)-4'-(6,11-dihydrodibenzo[b,e]thiophene-11-yl)-8',10'-dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 11)

[0297]

[0298] Step 1: Synthesis of Compound 10-1

[0299] 10-1 is obtained by splitting 1-7.

[0300] Step 2, Synthesis of Compound 10-2

[0301] Following the synthesis method in step 4 of Example 8, 2-10 in step 4 was replaced with 10-1, and the synthesis method remained the same, yielding product 10-2 (56 mg). LC-MS: m / z 592 [M+H] +.

[0302] Step 3, Synthesis of Compound 10

[0303] Following the synthesis method in step 5 of Example 8, 8-5 in step 5 was replaced with 10-2, and the synthesis method remained the same, yielding product 10 (24 mg). LC-MS: m / z 502 [M+H] + .

[0304] 1 H NMR (600MHz, DMSO-d6) δ11.08(s,1H),7.56(d,J=7.8Hz,1H),7.52(d,J=7.6Hz,1H),7.42(d,J=7.4Hz, 1H),7.39-7.34(m,1H),7.27-7.21(m,1H),7.11-7.01(m,1H),7.00(d,J=7.8Hz,1H),6.90-6.85(m,1H) ,6.85-6.79(m,1H),5.83-5.78(m,1H),5.66-5.59(m,2H),5.46(s,1H),3.93-3.87(m,2H),3.58-3.47( m,2H),3.45-3.29(m,3H),1.90-1.84(m,1H),1.53-1.46(m,1H),1.43-1.25(m,3H),1.17-1.10(m,1H).

[0305] Step 4, Synthesis of Compound 11

[0306] Following the synthesis method in step 1 of Example 9, 6 was replaced with 10 in step 1, and the synthesis method remained the same, yielding product 11 (18 mg). LC-MS: m / z 590.3 [M+H] + .

[0307] 1H NMR(600MHz,DMSO-d6)δ7.64(d,J=7.8Hz,1H),7.50-7.42(m,2H),7.41-7.35(m,1H),7.28-7.22(m,1H),7.11 -7.03(m,1H),7.01(d,J=8.0Hz,1H),6.86(d,J=3.0Hz,2H),5.84-5.77(m,2H),5.71(d,J=6.6Hz,1H),5.62-5. 54(m,2H),5.19(s,1H),3.91(d,J=13.2Hz,1H),3.82(d,J=11.8Hz,1H),3.77(s,3H),3.55-3.50(m,2H),3.44 -3.36(m,2H),3.35-3.28(m,1H),1.92-1.85(m,1H),1.46-1.35(m,2H),1.34-1.26(m,2H),1.15-1.08(m,1H).

[0308] Example 12: Synthesis of 6-((R)-9'-hydroxy-8',10'-dioxo-2,3,3',3a',5,6,8',10'-octahydro-1'H,4'H-spirocyclic[pyran-4,2'-pyridine[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-4'-yl)-N-methyl-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropane[c][7]cycloen-1-carboxamide (compound 12)

[0309]

[0310] Step 1: Synthesis of Compound 12-2

[0311] CuSO4 (15.0 mg, 0.06 mmol) was added to a dry 50 mL three-necked flask. The flask was heated with a hot air gun, and the air in the flask was purged with nitrogen. 7-1 (206 mg, 1 mmol) and ultra-dry toluene (5 mL) were added to the flask, and the mixture was heated to 75°C and stirred for 5 minutes. 12-1 (284.9 mg, 2.5 mmol) was added while stirring, and the reaction was continued at 75°C for 18 hours, monitored by LC-MS. After the reaction was complete, the solvent was concentrated under reduced pressure. No purification was required, and the product could be directly used in the next reaction. 12-2 (200 mg, crude) was a yellow oil. LC-MS: m / z 293 [M+H] + .

[0312] Step 2, Synthesis of Compound 12-3

[0313] The crude product 12-2 (200 mg) was dissolved in methanol (2 mL), and sodium hydroxide (273.7 mg, 6.8 mmol) and water (2 mL) were added. The mixture was heated to 50 °C and stirred for 18 hours, monitored by LC-MS. After the reaction, the organic solvent was concentrated under reduced pressure, the pH was adjusted to 3 with 1 M HCl, and the mixture was extracted three times with ethyl acetate. The organic phase was collected, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed using a medium-pressure preparative column to obtain 12-3 (40 mg). LC-MS: m / z 265 [M+H] +

[0314] Step 3, Synthesis of Compound 12-4

[0315] Add 12-3 (40 mg, 0.2 mmol) to a dry round-bottom flask, dissolve in ultradry DMF (2 mL), and cool the system to 0°C. Add DIPEA (117.4 mg, 0.9 mmol, 158.2 μL), stir for 5 minutes, then add HATU (115.0 mg, 0.3 mmol) and continue stirring for another 5 minutes. Add methylamine hydrochloride (30.7 mg, 0.5 mmol), and continue stirring at 0°C for 20 minutes, monitoring the reaction by LC-MS. After the reaction is complete, concentrate the solvent under reduced pressure, and purify by MPLC to obtain product 12-4 (40 mg) as a white solid. LC-MS: m / z 278 [M+H] + .

[0316] Step 4, Synthesis of Compound 12-5

[0317] In a dry round-bottom flask, 12-4 (40 mg, 0.1 mmol) was dissolved in methanol (3 mL), and the system was cooled to 0°C. NaBH4 (54.6 mg, 1.4 mmol) was added, and the mixture was heated to 50°C and stirred for 18 hours, monitored by LC-MS. After the reaction was complete, the solvent was concentrated under reduced pressure, and residual impurities were removed by MPLC purification to obtain product 12-5 (20 mg) as a white solid. LC-MS: m / z 280 [M+H] + .

[0318] Step 5, Synthesis of Compound 12

[0319] In a dry round-bottom flask, 12-5 (10 mg, 0.04 mmol) and 10-1 (16.4 mg, 0.4 mmol) were dissolved in T3P (200 μL), and the system was heated to 110°C. After microwave reaction for 1 hour, methanesulfonic acid (7.1 mg, 0.1 mmol, 10 μL) was added, and the reaction was continued at 110°C for another hour, monitored by LC-MS. After the reaction was completed, the solvent was concentrated under reduced pressure, and residual impurities were removed by Prep-HPLC purification to obtain product 12 (3.7 mg) as a white solid. LC-MS: m / z 553.3 [M+H] + .

[0320] Example 13: Synthesis of (((3a'R)-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-8',10'-dioxo-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrrolo[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 13)

[0321]

[0322] Step 1: Synthesis of Compound 13

[0323] Following the synthesis method in step 1 of Example 9, 6 in step 1 was replaced with Isomer 1-2, and the synthesis method remained the same, yielding product 13 (7 mg). LC-MS: m / z 626.3 [M+H] + .

[0324] 1 H NMR(400MHz,DMSO-d6)δ7.64(d,J=7.8Hz,1H),7.56-7.48(m,1H),7.40-7.28(m,1H),7.15-7.06(m,1H),7 .07-7.00(m,1H),6.94-6.84(m,2H),5.82(d,J=7.8Hz,1H),5.74-5.66(m,2H),5.62-5.57(m,1H),5.55(d, J=6.6Hz,1H),5.37(s,1H),4.16(d,J=13.8Hz,1H),3.81(d,J=11.8Hz,1H),3.76(s,3H),3.52( d,J=17.4Hz,3H),3.44-3.38(m,2H),2.04-1.94(m,1H),1.49-1.28(m,4H),1.26-1.18(m,1H).

[0325] Compound 13 can produce one of the following isomers:

[0326]

[0327] Isomer 13-1 NMR data:

[0328] 1 H NMR(400MHz, DMSO-d6)δ7.65(d,J=7.8Hz,1H),7.56-7.48(m,1H),7.40-7.28(m,1H),7.14-7.07(m ,1H),7.04(d,J=7.8Hz,1H),6.93-6.86(m,2H),5.82(d,J=7.8Hz,1H),5.70(d,J=6.6Hz,2H),5.63 -5.57(m,1H),5.55(d,J=6.4Hz,1H),5.37(s,1H),4.16(d,J=13.9Hz,1H),3.81(d,J=12.0Hz,1H), 3.76(s,3H),3.52(d,J=16.8Hz,3H),3.40(d,J=5.4Hz,2H),2.05-1.93(m,1H),1.51-1.12(m,5H).

[0329] Example 14: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spirocyclic[oxetane-3,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 14)

[0330]

[0331] Step 1: Synthesis of Compound 14-3

[0332] In a dry round-bottom flask, 14-1 (1 g, 7.9 mmol) was dissolved in THF (20 mL), and n-BuLi (2.5 M, 3.8 mL) was slowly added dropwise. The system was cooled to -30°C and stirred for 1 hour. Then, 14-2 (1.1 g, 9.4 mmol, 1.0 mL) was added dropwise, and the reaction was continued at -30°C for another hour, monitored by LC-MS. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the combined organic phases were dried over saturated brine and anhydrous sodium sulfate, respectively. The organic phase was concentrated under reduced pressure to obtain product 14-3 (1.5 g, crude) as a yellow oil. LC-MS: m / z 212 [M+H] + .

[0333] Step 2, Synthesis of Compound 14-4

[0334] In a dry round-bottom flask, 14-3 (1.5 g, 7.1 mmol) was dissolved in THF (20 mL), and DIBAL-H (1.5 M, 7.1 mL) was added dropwise. The system was cooled to -78°C and reacted for 1 hour, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature and then quenched with saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain product 14-4 (1.2 g, crude) as a yellow oil. LC-MS: m / z 214 [M+H] + .

[0335] Step 3, Synthesis of Compounds 14-5

[0336] 14-4 (1.2 g, 5.4 mmol) was dissolved in THF (15 mL) in a dry round-bottom flask. NaH (155.3 mg, 6.5 mmol) was added under ice bath conditions. After reacting at 0°C for 1 hour, methyl iodide (918.6 mg, 6.5 mmol, 402.9 μL) was added dropwise, and the reaction was stirred for 15 hours, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature and then quenched with saturated ammonium chloride solution. The mixture was extracted three times with ethyl acetate, and the combined organic phases were dried over saturated brine and anhydrous sodium sulfate, respectively. The organic phase was concentrated under reduced pressure to obtain product 14-5 (1.1 g, crude) as a yellow oil. LC-MS: m / z 228 [M+H] + .

[0337] Step 4: Synthesis of Compounds 14-7

[0338] In a dry round-bottom flask, 14-5 (1.1 g, 4.7 mmol) and 14-6 (1.1 g, 3.9 mmol) were dissolved in toluene (30 mL), and SnCl4 (1.0 g, 3.9 mmol, 454.9 μL) was added dropwise. The system was cooled to -30°C and reacted for 1 hour, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature and then quenched with saturated sodium bicarbonate solution. The mixture was extracted three times with DCM, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain product 14-7 (2.4 g, crude) as a brown oil. LC-MS: m / z 484 [M+H] + .

[0339] Step 5: Synthesis of Compounds 14-8

[0340] In a dry round-bottom flask, 14-7 (2.4 g, 5.1 mmol) and morpholine (4.4 g, 50.5 mmol) were dissolved in THF (20 mL), followed by the addition of Pd(PPh3)4 (291.6 mg, 0.3 mmol). The reaction was carried out at room temperature for 2 hours under nitrogen protection, monitored by LC-MS. After the reaction was complete, the mixture was filtered, and the filter cake was washed three times with THF and concentrated under reduced pressure to obtain product 14-8 (1.6 g, crude) as a white solid. LC-MS: m / z 354 [M+H] + .

[0341] Compound 14-8 can be resolved into:

[0342]

[0343] Step 6, Synthesis of Compound 14

[0344] In a dry round-bottom flask 1, 14-8 (35 mg, 0.1 mmol) was dissolved in DMF (1 mL), and NaH (5.9 mg, 0.3 mmol) was added at 0°C, followed by stirring for 1 hour. In another round-bottom flask 2, M2 (39.3 mg, 0.2 mmol) and SOCl2 (1.6 g, 13.8 mmol, 1 mL) were added and stirred at 0°C for 1 hour. This mixture was then added to round-bottom flask 1, and the reaction was continued at 0°C for another hour, monitored by LC-MS. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residual impurities were removed by MPLC to obtain product 14 (10 mg) as a white solid. LC-MS: m / z 510.5 [M+H] + .

[0345] Compound 14 can be resolved into the following four isomers:

[0346]

[0347] Examples 15 and 16, (2R,3a'R,6S)-4'-((R)-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-2,6-dimethyl-2,3,3a',4',5,6-hexahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound) Synthesis of (15) and (2R,3a'R,6S)-4'-((S)-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-2,6-dimethyl-2,3,3a',4',5,6-hexahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrrolo[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-8',10'-dione (compound 16)

[0348]

[0349] Step 1: Synthesis of Compound 15-1

[0350] Compound 15-1 was obtained by resolving compound 6-9.

[0351] Step 2, Synthesis of Compound 15-2

[0352] Following the synthesis method in step 4 of Example 8, 2-10 was replaced with 15-1, and 8-4 was replaced with the two fractionated products of 8-4. The synthesis method remained the same, yielding products 15-2 (60 mg) and 16-1 (30 mg). LC-MS: m / z 620 [M+H] + .

[0353] Step 3, Synthesis of Compound 15

[0354] In a dry round-bottom flask, 15-2 (60 mg, 0.1 mmol) and LiCl (41.0 mg, 1 mmol) were dissolved in DMA (1.5 mL), and the mixture was heated to 110 °C and reacted for 3 hours. Then, under ice bath conditions, 0.5 M HCl (1.5 mL) and acetone (1.5 mL) were added, and the reaction was continued at 0 °C to room temperature for 1 hour, monitored by LC-MS. After the reaction was complete, the organic phase was concentrated under reduced pressure, and residual impurities were removed by prep-HPLC to obtain product 15 (1.2 mg) as a yellow solid. LC-MS: m / z 530.2 [M+H] +

[0355] 1H NMR (600MHz, DMSO-d6) δ7.53-7.51(m,2H),7.42(d,J=7.6Hz,1H),7.39-7.36(m,1H),7.26-7.24(m,1H),7.07-7.05(m,1H),7.01(d,J=7.8Hz ,1H),6.87(d,J=7.8Hz,1H),6.83-6.81(m,1H),5.80(d,J=13.2Hz,1H),5.65(dd,J=10.8,6.4Hz,1H),5.59(d,J=7.6Hz,1H),5.43(s,1H),3. 89(d,J=13.2Hz,1H),3.58(d,J=13.2Hz,1H),3.45-3.43(m,1H),2.98(dd,J=11.8,6.2Hz,1H),2.15(dd,J=12.8,6.6Hz,1H),1.66(d,J=13.6 Hz,1H),1.27-1.22(m,2H),1.17(t,J=11.8Hz,1H),0.97(d,J=6.0Hz,3H),0.96-0.94(m,1H),0.92(d,J=6.0Hz,3H),0.84(d,J=13.2Hz,1H).

[0356] Step 4, Synthesis of Compound 16

[0357] Following the synthesis method in step 3 of Example 15, 15-2 in step 3 was replaced with 16-1, and the synthesis method remained the same, yielding product 16 (1.0 mg). LC-MS: m / z 530.2 [M+H] + .

[0358] 1H NMR (600MHz, DMSO-d6) δ7.53-7.51(m,2H),7.42(d,J=7.6Hz,1H),7.39-7.36(m,1H),7.26-7.24(m,1H),7.07-7.05(m,1H),7.01(d,J=7.8Hz ,1H),6.87(d,J=7.8Hz,1H),6.83-6.81(m,1H),5.80(d,J=13.2Hz,1H),5.65(dd,J=10.8,6.4Hz,1H),5.59(d,J=7.6Hz,1H),5.43(s,1H),3. 89(d,J=13.2Hz,1H),3.58(d,J=13.2Hz,1H),3.45-3.43(m,1H),2.98(dd,J=11.8,6.2Hz,1H),2.15(dd,J=12.8,6.6Hz,1H),1.66(d,J=13.6 Hz,1H),1.27-1.22(m,2H),1.17(t,J=11.8Hz,1H),0.97(d,J=6.0Hz,3H),0.96-0.94(m,1H),0.92(d,J=6.0Hz,3H),0.84(d,J=13.2Hz,1H).

[0359] Example 17: Synthesis of (((2R,3a'R,6S)-4'-((R)-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-2,6-dimethyl-8',10'-dioxy-2,3,3a',4',5,6,8',10'-octahydro-1'H,3'H-spirocyclic[pyran-4,2'-pyrrolo[2,1-f]pyrrolo[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 17)

[0360]

[0361] Step 1: Synthesis of Compound 17

[0362] Following the synthesis method in step 1 of Example 9, 6 in step 1 was replaced with 16-1, and the synthesis method remained the same, yielding product 17 (2.1 mg). LC-MS: m / z 618.2 [M+H] + .

[0363] 1H NMR (600MHz, DMSO-d6) δ7.62(d,J=7.8Hz,1H),7.48(d,J=7.6Hz,1H),7.44(d,J=7.6Hz,1H),7.40-7.38(m,1H),7.28-7.25(m,1H),7. 09-7.06(m,1H),7.02(d,J=8.0Hz,1H),6.86(d,J=4.2Hz,2H),5.81(dd,J=16.0,10.6Hz,2H),5.72(d,J=6.6Hz,1H),5.61(dd,J=10.0 ,7.2Hz,1H),5.55(d,J=6.4Hz,1H),5.18(s,1H),3.91(d,J=13.4Hz,1H),3.76(s,3H),3.51-3.41(m,3H),3.03-2.97(m,1H),2.16(dd ,J=13.2,7.0Hz,1H),1.59(d,J=13.6Hz,1H),1.26-1.22(m,3H),1.15(t,J=11.6Hz,1H),0.98(d,J=6.0Hz,3H),0.92(d,J=6.2Hz,3H).

[0364] Example 18: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spirocyclic[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 18)

[0365]

[0366] Step 1: Synthesis of Compound 18-3

[0367] In a dry round-bottom flask, 18-1 (12.5 g, 71.7 mmol), 18-2 (11.4 g, 93.2 mmol), and CEMTPP (32.5 g, 93.2 mmol) were dissolved in toluene (150 mL). The mixture was substituted with N2 three times, and the reaction was carried out at 80°C for 16 hours, monitored by LC-MS. After the reaction was completed, the solvent was concentrated under reduced pressure, and residual impurities were removed by column chromatography to obtain product 18-3 (7.5 g) as a pale yellow oil. LC-MS: m / z 127 [M+H] +

[0368] Step 2, Synthesis of Compound 18-4

[0369] In a dry round-bottom flask, 18-3 (7.5 g, 59.5 mmol), nitromethane (7.3 g, 118.9 mmol, 6.4 mL), and potassium carbonate (16.4 g, 118.9 mmol) were dissolved in DMSO (120 mL). The mixture was heated to 80°C and reacted for 3 hours, monitored by LC-MS. After the reaction was complete, water (400 mL) was added, and the mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. No further purification was required; the crude product could be used directly in the next reaction to obtain product 18-4 (7.5 g, crude), a brown oily substance. LC-MS: m / z 188 [M+H] +

[0370] Step 3, Synthesis of Compound 18-5

[0371] In a dry round-bottom flask, 18-4 (7.5 g, 40.1 mmol) and Raney Ni (2 g, 40.1 mmol) were dissolved in methanol (50 mL). The reaction was carried out at room temperature for 12 hours, monitored by LC-MS. After the reaction was complete, the mixture was filtered, and the filtrate was distilled under reduced pressure. The remaining impurities were removed by column chromatography to obtain product 18-5 (1.5 g) as a white solid. LC-MS: m / z 112 [M+H] +

[0372] Step 4: Synthesis of Compound 18-7

[0373] In a dry round-bottom flask, 18-5 (1.5 g, 13.5 mmol) was dissolved in THF (25 mL), and n-BuLi (2.5 M, 6.5 mL) was added dropwise. The system was cooled to -30°C and reacted for 1 hour. Then, 18-6 (2 g, 16.2 mmol, 1.7 mL) was added dropwise at -30°C, and the reaction continued for another hour, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, quenched with saturated ammonium chloride solution, and extracted three times with ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 18-7 (2.2 g, crude) was obtained and could be used directly in the next reaction without further purification. LC-MS: m / z 196 [M+H] +

[0374] Step 5: Synthesis of Compound 18-8

[0375] In a dry round-bottom flask, 18-7 (2.2 g, 11.3 mmol) was dissolved in THF (25 mL), and DIBAL-H (1.5 M, 11.3 mL) was added dropwise. The system was cooled to -78°C and reacted for 1 hour, monitored by LC-MS. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 18-8 (2 g, crude) was obtained and could be used directly in the next reaction without further purification. LC-MS: m / z 198 [M+H] +

[0376] Step 6, Synthesis of Compounds 18-9

[0377] In a dry round-bottom flask, 18-8 (2 g, 9.9 mmol) was dissolved in methanol (15 mL), and PTSA·H₂O (939.3 mg, 4.9 mmol) was added. The reaction was carried out at room temperature for 16 hours, monitored by LC-MS. After the reaction was complete, the solvent was suspended, and the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 18-9 (1.6 g, crude) was obtained and could be used directly in the next reaction without further purification. LC-MS: m / z 212 [M+H] +

[0378] Step 7, Synthesis of Compound 18-10

[0379] In a dry round-bottom flask, 18-9 (1.6 g, 7.7 mmol) and M1 (1.8 g, 6.4 mmol) were dissolved in MeCN (40 mL). The system was cooled to -30°C, and SnCl4 (1.7 g, 6.4 mmol, 747.9 μL) was added dropwise. The reaction was allowed to proceed for 1 hour, monitored by LC-MS. After the reaction was complete, saturated sodium bicarbonate solution was added, and the mixture was extracted three times with DCM. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 18-10 (2.2 g, crude) was obtained and could be used directly in the next reaction without further purification. LC-MS: m / z 468 [M+H] +

[0380] Step 8, Synthesis of Compounds 18-11

[0381] Following the synthesis method in step 5 of Example 14, 14-7 was replaced with 18-10 in step 5, and the synthesis method remained the same, yielding product 18-11 (0.6 g, crude) as a white solid. LC-MS: m / z 338 [M+H]+ .

[0382] Compound 18-11 can be resolved into:

[0383]

[0384] Step 9, Synthesis of Compounds 18-12

[0385] Following the synthesis method in step 9 of Example 5, 5-9 was replaced with 18-11 in step 9, and the synthesis method remained the same, yielding product 18-12 (55.6 mg, crude) as a white solid. LC-MS: m / z 584 [M+H] + .

[0386] Step 10, Synthesis of Compound 18

[0387] Following the synthesis method in step 3 of Example 15, 15-2 was replaced with 18-12 in step 3, and the synthesis method remained the same, yielding product 18 (8 mg) as a white solid. LC-MS: m / z 494.2 [M+H] + .

[0388] 1 H NMR(600MHz,DMSO-d6)δ11.29(s,1H),7.56(d,J=7.8Hz,1H),7.54-7.49(m,1H),7.42-7.34(m,1H),7.12- 7.05(m,1H),7.03(d,J=8.0Hz,1H),6.94(d,J=7.8Hz,1H),6.89-6.84(m,1H),5.76(s,1H),5.72-5.66(m, 2H),5.61(d,J=7.8Hz,1H),4.14(d,J=13.8Hz,1H),3.88(d,J=11.6Hz,1H),3.36(d,J=11.6Hz,1H ),1.88-1.81(m,1H),1.51-1.45(m,1H),0.67-0.61(m,1H),0.55-0.49(m,1H),0.47-0.37(m,2H).

[0389] Compound 18 can be resolved into the following four isomers:

[0390]

[0391] Example 19: Synthesis of ((4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-8',10'-dioxo-3a',4',8',10'-tetrahydro-1'H,3'H-spirocyclic[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 19)

[0392]

[0393] Step 1: Synthesis of Compound 19

[0394] Following the synthesis method in step 1 of Example 9, 6 was replaced with 18 in step 1, and the synthesis method remained the same, yielding product 19 (2.1 mg). LC-MS: m / z 582.5 [M+H] + .

[0395] 1 H NMR(600MHz,DMSO-d6)δ7.67(d,J=7.8Hz,1H),7.57-7.51(m,1H),7.42-7.34(m,1H),7.14-7.08(m,1H), 7.06-7.01(m,1H),6.97-6.92(m,1H),6.91-6.87(m,1H),5.82(d,J=7.8Hz,1H),5.72-5.62(m,3H),5.56- 5.50(m,2H),4.15(d,J=13.8Hz,1H),3.95(d,J=11.6Hz,1H),3.74(s,3H),3.28-3.19(m,1H),1.84(dd,J= 12.8,9.7Hz,1H),1.52(dd,J=12.8,6.8Hz,1H),0.67-0.61(m,1H),0.53-0.47(m,1H),0.44-0.36(m,2H).

[0396] Example 20: Synthesis of (((R)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-8',10'-dioxo-3a',4',8',10'-tetrahydro-1'H,3'H-spirocyclic[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 20)

[0397]

[0398] Step 1: Synthesis of Compound 20

[0399] Following the synthesis method in step 1 of Example 9, 6 in step 1 was replaced with Isomer 18-3, and the synthesis method remained the same, yielding product 20 (2.5 mg). LC-MS: m / z 582.5 [M+H] + .

[0400] 1 H NMR(600MHz,DMSO-d6)δ7.69-7.65(m,1H),7.57-7.52(m,1H),7.42-7.35(m,1H),7.13-7.08(m,1H),7.05- 7.02(m,1H),6.95-6.92(m,1H),6.91-6.87(m,1H),5.84-5.80(m,1H),5.72-5.67(m,2H),5.67-5.63(m,1H ),5.56-5.50(m,2H),4.15(d,J=13.8Hz,1H),3.95(d,J=11.6Hz,1H),3.74(s,3H),3.22(d,J=11.6Hz,1H), 1.87-1.81(m,1H),1.55-1.48(m,1H),0.64(d,J=9.8Hz,1H),0.50(d,J=9.5Hz,1H),0.40(d,J=2.6Hz,2H).

[0401] Example 21: Synthesis of (((S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-8',10'-dioxo-3a',4',8',10'-tetrahydro-1'H,3'H-spirocyclo[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-9'-yl)oxy)methyl carbonate (compound 21)

[0402]

[0403] Step 1, Synthesis of Compound 21

[0404] Following the synthesis method in step 1 of Example 9, 6 in step 1 was replaced with Isomer 18-1, and the synthesis method remained the same, yielding product 21 (3 mg). LC-MS: m / z 582.5 [M+H] + .

[0405] 1H NMR (600MHz, DMSO-d6) δ7.70-7.64(m,1H),7.58-7.50(m,1H),7.43-7.34(m,1H),7.14-7.08(m,1H),7. 06-7.01(m,1H),6.97-6.92(m,1H),6.91-6.86(m,1H),5.83-5.80(m,1H),5.72-5.67(m,2H),5.67-5.62 (m,1H),5.56-5.50(m,2H),4.15(d,J=13.8Hz,1H),3.95(d,J=11.6Hz,1H),3.74(s,3H),3.22(d,J=11.6 Hz,1H),1.87-1.79(m,1H),1.55-1.47(m,1H),0.67-0.62(m,1H),0.53-0.48(m,1H),0.43-0.37(m,2H).

[0406] Example 22: Synthesis of 4'-(6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spirocyclic[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 22)

[0407]

[0408] Step 1: Synthesis of Compound 22-1

[0409] Following the synthesis method in step 4 of Example 8, 2-10 in step 4 was replaced with 18-11, and the synthesis method remained the same, yielding product 22-1 (53.6 mg). LC-MS: m / z 548 [M+H] + .

[0410] Step 2, Synthesis of Compound 22

[0411] Following the synthesis method in step 5 of Example 8, 8-5 in step 5 was replaced with 22-1, and the synthesis method remained the same, yielding product 22 (5 mg). LC-MS: m / z 458.2 [M+H] + .

[0412] Example 23: Synthesis of 4'-(2-chloro-5,11-dihydrodibenzo[6,7]thiazolyl[3,4-b]pyridin-5-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spirocyclic[cyclopropane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 23)

[0413]

[0414] Step 1: Synthesis of Compound 23-2

[0415] In a dry round-bottom flask, 23-1 (12.3 g, 100 mmol), AIBN (820.0 mg, 5 mmol), and NBS (17.8 g, 100 mmol) were dissolved in CCl4 (200 mL). Under nitrogen protection, the system was heated to 80°C and reacted for 18 hours, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and the organic solvent was concentrated under reduced pressure to obtain product 23-2 (20 g, crude), which could be directly used in the next reaction without further purification. LC-MS: m / z 203 [M+H] +

[0416] Step 2, Synthesis of Compounds 23-4

[0417] In a dry round-bottom flask, 23-2 (30 g, 148.5 mmol), 23-3 (25 g, 148.5 mmol), and potassium carbonate (41 g, 296.0 mmol) were dissolved in DMF (150 mL). The mixture was stirred at 0°C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and then extracted three times with water and ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 23-4 (40 g). LC-MS: m / z 290 [M+H] +

[0418] Step 3, Synthesis of Compound 23-5

[0419] In a dry round-bottom flask, 23-4 (40 g, 138.2 mmol) and sodium hydroxide (2.2 g, 55.3 mmol) were dissolved in methanol (150 mL). The mixture was stirred at 80 °C for 18 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and the pH was adjusted to 3 by adding 1 N HCl solution at 0 °C. The mixture was extracted three times with ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a medium-pressure reversed-phase preparative column to obtain product 23-5 (35 g). LC-MS: m / z 276 [M+H] +

[0420] Step 4, Synthesis of Compounds 23-6

[0421] In a dry round-bottom flask, 23-5 (13 g, 47.2 mmol), LiCl (12 g, 283.3 mmol), and TsOH (14.8 g, 283.3 mmol) were dissolved in DMF (150 mL). The mixture was stirred at 120 °C for 12 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and the mixture was extracted three times with water and ethyl acetate. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a medium-pressure reversed-phase preparative column to obtain product 23-6 (10.8 g). LC-MS: m / z 262 [M+H] +

[0422] Step 5, Synthesis of Compounds 23-7

[0423] 23-6 (5.4 g, 20.7 mmol) was dissolved in PPA (100 mL) in a dry round-bottom flask and reacted with the mixture at 120 °C for 18 hours, monitored by LC-MS. After the reaction was complete, the system was cooled to 0 °C, extracted three times with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by medium-pressure reversed-phase preparative column chromatography to obtain product 23-7 (2.8 g). LC-MS: m / z 248 [M+H] +

[0424] Step 6, Synthesis of Compounds 23-8

[0425] Add 23-7 (520 mg, 2.1 mmol) to a dry round-bottom flask, dissolve in DMF (5 mL), add PCl3 (577.5 mg, 4.2 mmol, 366.9 μL) at 0°C, and stir at 110°C for 2 hours, monitoring with LC-MS. After the reaction is complete, allow the system to return to room temperature, extract three times with ice water and ethyl acetate, combine the organic phases, wash with saturated brine, dry with anhydrous sodium sulfate, concentrate under reduced pressure, and purify using a medium-pressure reversed-phase preparative column to obtain product 23-8 (130 mg). LC-MS: m / z 266 [M+H] +

[0426] Step 7, Synthesis of Compounds 23-9

[0427] 23-8 (130 mg, 489.2 μmol) was added to a dry round-bottom flask and dissolved in methanol (3 mL). Sodium borohydride (92.5 mg, 2.5 mmol) was added at 0°C, and the mixture was stirred at 110°C for 2 hours, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and extracted three times with ice water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a medium-pressure reversed-phase preparative column to obtain product 23-9 (120 mg). LC-MS: m / z 268 [M+H] +

[0428] Step 8, Synthesis of Compounds 23-10

[0429] 23-9 (20 mg, 74.7 μmol) was added to a dry round-bottom flask and dissolved in T3P (0.5 mL). 18-11 (92.5 mg, 2.5 mmol) was then added, and the mixture was stirred at 110 °C for 2 hours, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and extracted three times with ice water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified using a medium-pressure reversed-phase preparative column to obtain product 23-10 (20 mg). LC-MS: m / z 588 [M+H] +

[0430] Step 9, Synthesis of Compound 23

[0431] 23-10 (40 mg, 68.1 μmol) was added to a dry round-bottom flask and dissolved in DMA (1 mL). LiCl (2.9 mg, 68.1 μmol) was added, and the mixture was stirred at 80°C for 3 hours. After the reaction was complete, the system was cooled to 0°C, and acetone (1 mL) and 1 N HCl were added. The mixture was stirred at 0°C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was concentrated under reduced pressure and purified using a medium-pressure reversed-phase preparative column to obtain product 23 (5 mg). LC-MS: m / z 493.2 [M+H] +

[0432] 1H NMR(600MHz,DMSO-d6)δ7.54(d,J=8.4Hz,1H),7.51(d,J=8.4Hz,1H),7.12-7.09 (m,1H),7.05-7.04(m,1H),6.96-6.94(m,1H),6.89-6.85(m,1H),6.53(s,1H),5 .92(d,J=12.0Hz,1H),5.69-5.67(m,1H),5.56(d,J=7.8Hz,1H),3.94(d,J=12.0 Hz,,1H),2.99(s,2H),1.76(t,J=11.4Hz,1H),1.49-1.47(m,1H),0.66-0.63(m, 1H), 0.53-0.41(m,4H).

[0433] Example 24: Synthesis of 4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9-hydroxy-2,2-dimethyl-2,3,3a,4-tetrahydro-1H-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine-8,10-dione (compound 24)

[0434]

[0435] Step 1: Synthesis of Compound 24-3

[0436] Following the synthesis method in step 1 of Example 14, 14-1 in step 1 was replaced with 24-1, and the synthesis method remained the same, yielding product 24-3 (3.9 g). LC-MS: m / z 198 [M+H] + .

[0437] Step 2, Synthesis of Compound 24-4

[0438] Following the synthesis method in step 2 of Example 14, 14-3 in step 2 was replaced with 24-3, and the synthesis method remained the same, yielding product 24-4 (2.7 g). LC-MS: m / z 200 [M+H] + .

[0439] Step 3, Synthesis of Compound 24-5

[0440] Following the synthesis method in step 3 of Example 14, 14-4 in step 3 was replaced with 24-4, and the synthesis method remained the same, yielding product 24-5 (2.6 g). LC-MS: m / z 214 [M+H] + .

[0441] Step 4, Synthesis of Compound 24-6

[0442] Following the synthesis method in step 4 of Example 14, 14-5 in step 4 was replaced with 24-5, and the synthesis method remained the same, yielding product 24-6 (4.3 g). LC-MS: m / z 470 [M+H] + .

[0443] Step 5, Synthesis of Compound 24-7

[0444] Following the synthesis method in step 5 of Example 14, 14-7 in step 5 was replaced with 24-6, and the synthesis method remained the same, yielding product 24-7 (4.3 g). LC-MS: m / z 340 [M+H] + .

[0445] Step 6, Synthesis of Compound 24-8

[0446] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 24-7, and the synthesis method remained the same, yielding product 24-8 (54.2 mg). LC-MS: m / z 586 [M+H] + .

[0447] Step 7, Synthesis of Compound 24

[0448] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 24-8, and the synthesis method remained the same, yielding product 24 (8 mg) as a white solid. LC-MS: m / z 496.3 [M+H] + .

[0449] 1 H NMR (400MHz, DMSO-d6) δ7.56-7.47(m,2H),7.43-7.31(m,1H),7.14-7.05(m,1H),7.03(d,J=7.8Hz,1H),6.94-6.81(m,2H),5.74-5.56(m,4 H),4.14(d,J=13.8Hz,1H),3.58(d,J=11.8Hz,1H),3.45(d,J=11.8Hz,1H),1.73-1.62(m,1H),1.45-1.32(m,1H),0.98(s,3H),0.91(s,3H).

[0450] Example 25: Synthesis of ((4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-2,2-dimethyl-8,10-dioxo-2,3,3a,4,8,10-hexahydro-1H-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine-9-yl)oxy)methyl carbonate (compound 25)

[0451]

[0452] Step 1: Synthesis of Compound 25

[0453] Following the synthesis method in step 1 of Example 9, 6 was replaced with 24 in step 1, and the synthesis method remained the same, yielding product 25 (3.2 mg). LC-MS: m / z 584.5 [M+H] + .

[0454] 1 H NMR(400MHz,DMSO-d6)δ7.63(d,J=7.8Hz,1H),7.57-7.48(m,1H),7.43-7.31(m,1H),7.15- 7.05(m,1H),7.04(d,J=7.6Hz,1H),6.94-6.84(m,2H),5.82(d,J=7.8Hz,1H),5.79-5.64(m ,2H),5.65-5.54(m,1H),5.54(d,J=6.6Hz,1H),5.37(s,1H),4.15(d,J=13.8Hz,1H),3.75( s,3H),3.53-3.41(m,2H),1.73-1.63(m,1H),1.44-1.33(m,1H),0.96(s,3H),0.90(s,3H).

[0455] Example 26: Synthesis of 1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-5-hydroxy-1H-pyrido[1,2-b]pyridazine-2,4,6(3H)-trione (compound 26)

[0456]

[0457] Step 1: Synthesis of Compound 26-3

[0458] In a dry round-bottom flask, 26-1 (10 g, 40.6 mmol) was dissolved in THF (150 mL). Under nitrogen protection at 0°C, CDI (7.9 g, 48.7 mmol) was added. After reacting at 10°C for 1 hour, 26-2 (13.8 g, 81.2 mmol) and MgCl2 (9.7 g, 101.5 mmol) were added, and the reaction was monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and the organic solvent was concentrated under reduced pressure. Residual impurities were purified using a medium-pressure reversed-phase preparative column to obtain product 26-3 (5.1 g), a yellow oily substance. LC-MS: m / z 317 [M+H] +

[0459] Step 2, Synthesis of Compound 26-4

[0460] In a dry round-bottom flask, 26-3 (1.1 g, 3.6 mmol), NH2NHBoc (570.9 mg, 4.3 mmol), and PTSA.Py (2.7 g, 10.8 mmol) were dissolved in DMA (15 mL). The mixture was heated to 60°C under nitrogen protection and reacted for 1 hour, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and the organic solvent was concentrated under reduced pressure. Residual impurities were purified using a medium-pressure reverse-phase preparative column to obtain product 26-4 (1.2 g), a pale yellow oil. LC-MS: m / z 431 [M+H] +

[0461] Step 3, Synthesis of Compound 26-5

[0462] In a dry round-bottom flask, 26-4 (300 mg, 0.7 mmol) was dissolved in DCM (2 mL), followed by the addition of TFA (2 mL). The mixture was stirred at room temperature for 0.5 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the organic solvent was concentrated under reduced pressure. No further purification was required, and the product could be used directly in the next reaction to give product 26-5 (230 mg, crude), which was a yellow oil. LC-MS: m / z 331 [M+H] +

[0463] Step 4: Synthesis of compounds 26-6 and 26

[0464] In a dry round-bottom flask, 26-5 (230 mg, 0.7 mmol) and M2 (220.8 mg, 0.8 mmol) were dissolved in ClCH2CH2Cl (3.1 mL), followed by the addition of Cl2HCCOOH (269.5 mg, 2.1 mmol, 172.4 μL). The mixture was heated to 85°C and reacted for 1 hour, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and the organic solvent was concentrated under reduced pressure. Residual impurities were purified using a medium-pressure reversed-phase preparative column to obtain product 26-6 (10 mg). LC-MS: m / z 531 [M+H] + ;26(6.2mg), LC-MS: m / z441.1[M+H] +

[0465] 1H NMR (400MHz, DMSO-d6) δ12.17(s,1H),9.83(s,1H),9.47(s,1H),7.85(d,J=5.6Hz,1H),7.35(d,J=7.4Hz,1H),7.32-7.24(m,1H),7.19-7 .13(m,1H),7.00-6.93(m,2H),6.88(d,J=7.4Hz,1H),6.25(d,J=5.6Hz,1H),5.50(s,1H),4.40(d,J=14.4Hz,1H),3.92(d,J=14.4Hz,1H).

[0466] Examples 27 and 28: Synthesis of 1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-5-hydroxy-4-methoxy-1H-pyrido[1,2-b]pyridazine-2,6-dione (compound 27) and 1-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-4,5-dihydroxy-3-methyl-1H-pyrido[1,2-b]pyridazine-2,6-dione (compound 28)

[0467]

[0468] Step 1: Synthesis of compounds 27-1 and 28-1

[0469] In a dry round-bottom flask, 26-6 (780 mg, 1.5 mmol) was dissolved in THF (1.7 mL). TBAF (1 M, 2.9 mL) was added dropwise at 0°C, and after stirring for 5 minutes, MeI (835.1 mg, 5.9 mmol, 366.3 μL) was added. The reaction was carried out at room temperature for 18 hours, monitored by LC-MS. After the reaction was complete, the system was allowed to return to room temperature, and the organic solvent was concentrated under reduced pressure. Residual impurities were purified using a medium-pressure reversed-phase preparative column to obtain product 27-1 (40 mg), a yellow oily substance. LC-MS: m / z 545 [M+H] + ; 28-1 (60 mg), a yellow oily substance, LC-MS: m / z 545 [M+H] +

[0470] Step 2, Synthesis of Compound 27

[0471] In a dry round-bottom flask, 27-1 (40 mg, 0.07 mmol) and Pd(OH)2 (10 mg, 0.07 mmol) were added and dissolved in MeOH (1 mL). The mixture was substituted with H2 three times and reacted at room temperature for 18 hours, monitored by LC-MS. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Residual impurities were purified by Prep-HPLC to obtain product 27 (1.7 mg), a white solid. LC-MS: m / z 455.2 [M+H] +

[0472] 1 H NMR (400MHz, DMSO-d6) δ12.49(s,1H),9.53(s,1H),7.83(d,J=5.6Hz,1H),7.31(d,J=7.4Hz,1H),7.28-7.15(m,2H),7.02-6.92 (m,2H),6.89(d,J=7.6Hz,1H),6.24(d,J=5.4Hz,1H),5.49(s,1H),4.33(d,J=14.4Hz,1H),3.88(d,J=14.4Hz,2H),3.64(s,4H).

[0473] Step 3, Synthesis of Compound 28

[0474] In a dry round-bottom flask, 28-1 (60 mg, 0.1 mmol) and Pd(OH)2 (10 mg, 0.07 mmol) were added and dissolved in MeOH (1 mL). The mixture was substituted with H2 three times and reacted at room temperature for 18 hours, monitored by LC-MS. After the reaction was complete, the mixture was filtered, and the filtrate was concentrated under reduced pressure. Residual impurities were purified by Prep-HPLC to obtain product 28 (1.4 mg), a white solid. LC-MS: m / z 455.2 [M+H] +

[0475] 1 H NMR (400MHz, DMSO-d6) δ9.84(s,1H),9.59(s,1H),7.80(s,1H),7.32(d,J=7.6Hz,1H),7.22-7.13(m,2H),7.00-6.92(m,2H ), 6.86 (d, J = 7.6Hz, 1H), 6.23 (d, J = 5.6Hz, 1H), 5.35 (s, 1H), 4.45 (d, J = 14.4Hz, 1H), 3.82 (d, J = 14.4Hz, 1H), 3.45 (s, 3H).

[0476] Example 29: Synthesis of 4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9-hydroxy-3a,4-dihydro-1H,3H-spirocyclic [pyridino[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,3'-pyrrolidine]-8,10-dione (compound 29)

[0477]

[0478] Step 1: Synthesis of Compound 29-2

[0479] Following the synthesis method in step 1 of Example 5, 5-1 in step 1 was replaced with 29-1, and the synthesis method remained the same, yielding product 29-2 (12.8 g). LC-MS: m / z 256 [M+H] + .

[0480] Step 2, Synthesis of Compound 29-3

[0481] Following the synthesis method in step 2 of Example 5, 5-2 in step 2 was replaced with 29-2, and the synthesis method remained the same, yielding product 29-3 (13g). LC-MS: m / z 317 [M+H] + .

[0482] Step 3, Synthesis of Compound 29-4

[0483] Following the synthesis method in step 3 of Example 5, 5-3 in step 3 was replaced with 29-3, and the synthesis method remained the same, yielding product 29-4 (11.5 g). LC-MS: m / z 287 [M+H] + .

[0484] Step 4, Synthesis of Compound 29-5

[0485] In a dry round-bottom flask, 29-4 (11.5 g, 40 mmol) and NaOH (1.8 g, 44.0 mmol) were added and dissolved in EtOH (100 mL) and H2O (100 mL). The mixture was heated to 50 °C and reacted overnight, monitored by LC-MS. After the reaction was complete, the organic solvent was concentrated under reduced pressure. Residual impurities were purified by medium-pressure reverse-phase preparative column chromatography to obtain product 29-5 (7.2 g), a pale yellow oil. LC-MS: m / z 241 [M+H] +

[0486] Step 5, Synthesis of Compounds 29-6

[0487] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 29-5, and the synthesis method remained the same, yielding product 29-6 (9.7 g). LC-MS: m / z 325 [M+H] + .

[0488] Step 6, Synthesis of Compounds 29-7

[0489] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 29-6, and the synthesis method remained the same, yielding product 29-7 (7.9 g). LC-MS: m / z 327 [M+H] + .

[0490] Step 7, Synthesis of Compounds 29-8

[0491] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 29-7, and the synthesis method remained the same, yielding product 29-8 (5.1 g). LC-MS: m / z 341 [M+H] + .

[0492] Step 8, Synthesis of Compounds 29-9

[0493] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 29-8, and the synthesis method remained the same, yielding product 29-9 (2g). LC-MS: m / z 597 [M+H] + .

[0494] Step 9, Synthesis of Compounds 29-10

[0495] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 29-9, and the synthesis method remained the same, yielding product 29-10 (1.1 g). LC-MS: m / z 467 [M+H] + .

[0496] Step 10, Synthesis of Compounds 29-11

[0497] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 29-10, and the synthesis method remained the same, yielding product 29-11 (100 mg). LC-MS: m / z 613 [M+H] + .

[0498] Step 11, Synthesis of Compound 29

[0499] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 29-11, and the synthesis method remained the same, yielding product 29 (10.8 mg). LC-MS: m / z 523.3 [M+H]+ .

[0500] 1 H NMR (400MHz, DMSO-d6) δ9.27 (s, 2H), 7.70 (ddt, J = 8.8, 5.4, 3.0Hz, 1H), 7.6 1–7.45(m,2H),7.36(q,J=8.8Hz,1H),7.15–6.99(m,2H),6.95–6.80(m,1H) ,5.69(d,J=16.8Hz,2H),5.60(d,J=7.6Hz,1H),4.22–4.10(m,2H),3.17(s, 2H),2.12–1.87(m,2H),1.63(s,2H),1.41–1.20(m,2H),0.97–0.80(m,2H).

[0501] Example 30: Synthesis of 1'-acetyl-4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9-hydroxy-3a,4-dihydro-1H,3H-spirocyclic [pyridino[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,3'-pyrrolidine]-8,10-dione (compound 30)

[0502]

[0503] Step 1: Synthesis of Compound 30-1

[0504] In a dry round-bottom flask, 29-11 (11.5 g, 40 mmol), NaHCO3 (0.2 mmol), and Ac2O (13.3 mg, 0.1 mmol) were added and dissolved in THF (1 mL) and H2O (0.5 mL). The reaction was carried out at room temperature for 1 hour, and monitored by LC-MS. After the reaction was completed, the organic solvent was concentrated under reduced pressure, extracted three times with ethyl acetate, and the organic phase was washed twice with saturated brine. After drying with anhydrous sodium sulfate, the solution was concentrated under reduced pressure. The residual impurities were purified by Prep-HPLC to obtain product 30-1 (20 mg), which was a yellow oily substance. LC-MS: m / z 655 [M+H] +

[0505] Step 2, Synthesis of Compound 30

[0506] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 30-1, and the synthesis method remained the same, yielding product 30 (14.8 mg). LC-MS: m / z 565.3 [M+H] + .

[0507] 1H NMR(400MHz, DMSO-d6)δ9.14(s,1H),7.52(t,J=8.4Hz,1H),7.44–7.25(m,2H),7.22–7.06(m,2H),7.03(d,J=7.6Hz ,1H),6.87(t,J=7.4Hz,1H),5.67(d,J=5.6Hz,1H),5.61(d,J=12.6Hz,1H),5.57(d,J=7.6Hz,1H),4.14(d,J=14.0Hz ,1H),3.74(d,J=11.8Hz,1H),3.62(d,J=12.2Hz,1H),2.87(d,J=64.2Hz,1H),2.67(q,J=1.8Hz,1H),2.42(s,1H),2. 33(p,J=1.8Hz,2H),1.96(s,1H),1.89(d,J=4.0Hz,1H),1.85(d,J=5.4Hz,2H),1.51(d,J=11.6Hz,1H),1.24(s,2H).

[0508] Example 31: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spirocyclic[piperidine-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 31)

[0509]

[0510] Step 1: Synthesis of Compound 31-3

[0511] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 31-1, and the synthesis method remained the same, yielding product 31-3 (1.5 g). LC-MS: m / z 339 [M+H] + .

[0512] Step 2, Synthesis of Compound 31-4

[0513] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 31-3, and the synthesis method remained the same, yielding product 31-4 (736 mg). LC-MS: m / z 341 [M+H] + .

[0514] Step 3, Synthesis of Compound 31-5

[0515] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 31-4, and the synthesis method remained the same, yielding product 31-5 (590 mg). LC-MS: m / z 355 [M+H] + .

[0516] Step 4, Synthesis of Compounds 31-6

[0517] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 31-5, and the synthesis method remained the same, yielding product 31-6 (1g). LC-MS: m / z 611 [M+H] + .

[0518] Step 5, Synthesis of Compounds 31-7

[0519] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 31-6, and the synthesis method remained the same, yielding product 31-7 (300 mg). LC-MS: m / z 481 [M+H] + .

[0520] Compound 31-7 can be resolved into:

[0521]

[0522] Step 6, Synthesis of Compounds 31-8

[0523] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 31-7, and the synthesis method remained the same, yielding product 31-8 (30 mg). LC-MS: m / z 627 [M+H] + .

[0524] Step 7, Synthesis of Compound 31

[0525] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 31-8, and the synthesis method remained the same, yielding product 31 (1.6 mg). LC-MS: m / z 537.3 [M+H] + .

[0526] 1H NMR (400MHz, DMSO-d6) δ7.66(d,J=7.6Hz,1H),7.41(t,J=6.8Hz,1H),7.31(q,J=8.8Hz,1H),7.13(td,J=7.2,6.0, 2.2Hz,1H),7.06(d,J=7.8Hz,1H),6.92–6.84(m,2H),5.78–5.67(m,1H),5.64(dd,J=11.0,6.0Hz,1H),5.54(s,1H ),4.17(d,J=13.8Hz,1H),3.90(s,1H),3.55(d,J=12.4Hz,1H),3.14–3.04(m,2H),2.95(d,J=8.2Hz,2H),2.08–1. 96(m,1H),1.73(d,J=14.2Hz,1H),1.60(dd,J=14.4,6.4Hz,2H),1.44(q,J=12.4,10.0Hz,2H),1.28–1.15(m,1H).

[0527] Example 32: Synthesis of 1-acetyl-4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spirocyclic[piperidine-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 32)

[0528]

[0529] Step 1: Synthesis of Compound 32-1

[0530] Following the synthesis method in step 1 of Example 29, 29-11 in step 1 was replaced with 31-8, and the synthesis method remained the same, yielding product 32-1 (20 mg). LC-MS: m / z 669 [M+H] + .

[0531] Step 2, Synthesis of Compound 32

[0532] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 32-1, and the synthesis method remained the same, yielding product 32 (1.6 mg). LC-MS: m / z 579.3 [M+H] + .

[0533] 1H NMR (400MHz, DMSO-d6) δ7.66(dd,J=7.6,3.6Hz,1H),7.38(s,1H),7.33(t,J=8.8Hz,1H),7.13(t,J=7.0Hz,1H), 7.06(d,J=7.8Hz,1H),6.87(d,J=7.6Hz,2H),5.70(t,J=11.0Hz,2H),5.66–5.60(m,1H),5.52(s,1H),4.18(s,1H ),4.14(s,1H),3.90(s,1H),3.87(s,1H),3.50(d,J=12.8Hz,1H),3.38(s,0H),3.27(d,J=7.2Hz,2H),2.02(s,0H ),1.99(d,J=6.0Hz,3H),1.96(d,J=7.2Hz,2H),1.49–1.39(m,1H),1.35(t,J=7.2Hz,1H),1.03(t,J=7.2Hz,1H).

[0534] Compound 32 can produce one of the following isomers:

[0535]

[0536] Example 33: Synthesis of (12aR)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]octahydro[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 33)

[0537]

[0538] Step 1: Synthesis of Compound 33-3

[0539] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 33-1, and the synthesis method remained the same, yielding product 33-3 (8.3 g). LC-MS: m / z 186 [M+H] + .

[0540] Step 2, Synthesis of Compound 33-4

[0541] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 33-3, and the synthesis method remained the same, yielding product 33-4 (7.7 g). LC-MS: m / z 188 [M+H] + .

[0542] Step 3, Synthesis of Compound 33-5

[0543] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 33-4, and the synthesis method remained the same, yielding product 33-5 (590 mg). LC-MS: m / z 202 [M+H] + .

[0544] Step 4, Synthesis of Compound 33-6

[0545] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 33-5, and the synthesis method remained the same, yielding product 33-6 (4.2 g). LC-MS: m / z 458 [M+H] + .

[0546] Step 5, Synthesis of Compound 33-7

[0547] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 33-6, and the synthesis method remained the same, yielding product 33-7 (1.6 g). LC-MS: m / z 328 [M+H] + .

[0548] Step 6, Synthesis of Compound 33-8

[0549] Compound 33-8 was obtained by resolving 33-7.

[0550] Step 7, Synthesis of Compounds 33-9

[0551] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 33-8, and the synthesis method remained the same, yielding product 33-9 (35 mg). LC-MS: m / z 574 [M+H] + .

[0552] Step 8, Synthesis of Compound 33

[0553] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 33-9, and the synthesis method remained the same, yielding product 33 (10 mg). LC-MS: m / z 484.0 [M+H] + .

[0554] 1H NMR(400MHz,DMSO-d6)δ7.68-7.50(m,1H),7.46-7.30(m,2H),7.26-7.20(m,1H),7 .18-7.12(m,1H),7.10(d,J=8.2Hz,1H),7.02-6.76(m,1H),5.73(d,J=25.6Hz,1H) ,5.60(dd,J=29.0,7.6Hz,1H),5.52-5.35(m,1H),4.58-4.35(m,2H),4.24-4.02(m ,2H),3.98(ddd,J=9.6,6.4,3.0Hz,1H),3.74-3.56(m,2H),3.04(t,J=12.4Hz,1H).

[0555] Example 34: Synthesis of (12aS)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-7-qiangji-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrrolo[2,1-f][1,2,4]triazine-6,8-dione (compound 34)

[0556]

[0557] Step 1: Synthesis of Compound 34-1

[0558] Compound 34-1 was obtained by resolving 33-7.

[0559] Step 2, Synthesis of Compound 34-2

[0560] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 34-1, and the synthesis method remained the same, yielding product 34-2 (5 mg). LC-MS: m / z 574 [M+H] + .

[0561] Step 3, Synthesis of Compound 34

[0562] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 34-2, and the synthesis method remained the same, yielding product 34 (2 mg). LC-MS: m / z 484.0 [M+H] + .

[0563] 1H NMR(400MHz,DMSO-d6)δ7.66–7.48(m,1H),7.46–7.30(m,2H),7.27–7.20(m,1H),7 .18–7.12(m,1H),7.09(d,J=8.2Hz,1H),7.00–6.77(m,1H),5.72(d,J=25.6Hz,1H) ,5.59(dd,J=29.0,7.6Hz,1H),5.52–5.35(m,1H),4.57–4.36(m,2H),4.23–4.03(m ,2H),3.96(ddd,J=9.6,6.4,3.0Hz,1H),3.73–3.57(m,2H),3.03(t,J=12.4Hz,1H).

[0564] Example 35: Synthesis of (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-7-yl)oxy)methyl carbonate (compound 35)

[0565]

[0566] Step 1: Synthesis of Compound 35-1

[0567] Following the synthesis method in step 1 of Example 9, 6 was replaced with 33 in step 1, and the synthesis method remained the same, yielding product 35-1 (3.2 mg). LC-MS: m / z 572.3 [M+H] + .

[0568] Step 2, Synthesis of Compound 35

[0569] Compound 35 was obtained by resolving 35-1.

[0570] 1H NMR (400MHz, DMSO-d6) δ7.47-7.34(m,2H),7.23(d,J=7.8Hz,1H),7.20-7.11(m,1H ),7.13-7.06(m,1H),7.05-6.97(m,1H),6.90-6.81(m,1H),5.76-5.71(m,3H),5.6 7(d,J=6.6Hz,1H),5.47-5.38(m,1H),4.50-4.36(m,2H),4.10-3.96(m,2H),3.73( s,3H),3.71-3.65(m,1H),3.50-3.40(m,1H),3.34-3.23(m,1H),3.01-2.89(m,1H).

[0571] Example 36: Synthesis of 6-((R)-7-hydroxy-6,8-dioxo-1,3,4,6,8,12a-hexahydro-12H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-12-yl)-N-methyl-1,1a,6,10b-tetrahydrodibenzo[a,e]cyclopropaneformyl chloride[c][7]cycloargen-1-carboxamide (compound 36)

[0572]

[0573] Step 1: Synthesis of Compound 36

[0574] Following the synthesis method in step 5 of Example 12, 10-1 in step 5 was replaced with 33-8, and the synthesis method remained the same, yielding product 36 (4.3 mg). LC-MS: m / z 499.5 [M+H] + .

[0575] 1H NMR (400MHz, DMSO-d6) δ8.22-8.18(m,1H),7.45-7.30(m,5H),7.26-7.22(m,,2H),7.17(d,J=7 .6Hz,1H),6.98-6.92(m,2H),5.50(d,J=7.6Hz,1H),5.32(s,1H),4.43(dd,J=13.4,2.4Hz,1H), 4.37(dd,J=10.0,3.2Hz,1H),3.89(dd,J=10.8,3.2Hz,1H),3.67-3.64(m,2H),3.17-3.13(m,1H ),2.97(dd,J=9.6,4.8Hz,1H),2.85-2.78(m,1H),2.74(d,J=4.4Hz,3H),1.76(t,J=4.8Hz,1H).

[0576] Example 37: Synthesis of (12aS)-12-(1-bromo-3-methyl-6,12-dihydro-3H-benzo[6,7]thiophene[4,3-e]indazol-12-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 37)

[0577]

[0578] Step 1: Synthesis of Compound 37-2

[0579] In a dry round-bottom flask, 37-1 (1.6 g, 8.2 mmol), NBS (1.5 g, 8.2 mmol), and AIBN (1.3 g, 8.2 mmol) were added and dissolved in 50 mL of CCl4. The system was heated to 80°C and reacted under nitrogen protection for 16 hours, monitored by LC-MS. After the reaction was complete, the solvent was concentrated under reduced pressure. No further purification was required, and the product could be used directly for the next reaction, yielding product 37-2 (3 g, crude) as a white solid. LC-MS: m / z 348 [M+H] + .

[0580] Step 2, Synthesis of Compound 37-3

[0581] 37-2 (3 g, 8.6 mmol) was added to a dry round-bottom flask, followed by 20 mL of H₂O and 20 mL of a THF solution containing sodium thiophene (0.5 M, 17.24 mL). The reaction was carried out at 15°C for 0.5 h, monitored by LC-MS. After the reaction was complete, 200 mL of water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with saturated hydrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual impurities were purified by column chromatography to obtain product 37-3 (700 mg) as a yellow solid. LC-MS: m / z 378 [M+H] + .

[0582] Step 3, Synthesis of Compound 37-4

[0583] In a dry round-bottom flask, 37-3 (700 mg, 1.9 mmol), methyl iodide (316.2 mg, 2.2 mmol, 138.7 μL), and cesium carbonate (1.2 g, 3.7 mmol) were added and dissolved in 10 mL of DMF solution. The mixture was reacted at 60 °C for 18 hours, monitored by LC-MS. After the reaction was complete, water (100 mL) was added to the system, and the mixture was extracted three times with ethyl acetate. The organic phase was washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. No further purification was required, and the product 37-4 (700 mg, crude) was obtained as a yellow oil. LC-MS: m / z 392 [M+H] + .

[0584] Step 4, Synthesis of Compound 37-5

[0585] Following the synthesis method in step 4 of Example 29, 29-4 was replaced with 37-4 in step 4, and the synthesis method remained the same, yielding product 37-5 (500 mg). LC-MS: m / z 378 [M+H] + .

[0586] Step 5, Synthesis of Compound 37-6

[0587] 37-5 (500 mg, 1.3 mmol) was dissolved in 15 mL of PPA solution and added to a dry round-bottom flask. The mixture was reacted overnight at 100°C, monitored by LC-MS. After the reaction was complete, ice water was added to the system, and the mixture was extracted with ethyl acetate. The organic phase was washed twice with saturated hydrated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were purified by column chromatography to give product 37-6 (220 mg) as a white solid. LC-MS: m / z 360 [M+H] + .

[0588] Step 6, Synthesis of Compound 37-7

[0589] In a dry round-bottom flask, 37-6 (220 mg, 0.6 mmol) was dissolved in methanol (5 mL), and then NaBH4 (231.7 mg, 6.1 mmol) was added. The reaction was carried out at 15°C for 18 hours under ice bath monitoring. After the reaction was complete, the organic phase was concentrated under reduced pressure, and the residual impurities were purified by column chromatography to obtain product 37-7 (150 mg). LC-MS: m / z 362 [M+H] + .

[0590] Step 7, Synthesis of Compounds 37-8

[0591] Following the synthesis method in step 9 of Example 5, 5-9 was replaced with 34-1, and M2 was replaced with 37-7. The synthesis method remained the same, yielding product 37-8 (20 mg). LC-MS: m / z 671 [M+H] + .

[0592] Step 8, Synthesis of Compound 37

[0593] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 37-8, and the synthesis method remained the same, yielding product 37 (14.7 mg). LC-MS: m / z 582.1 [M+H] + .

[0594] 1 H NMR (400MHz, DMSO-d6) δ7.83(d,J=8.6Hz,0.59H),7.75(d,J=8.6Hz,0.47H),7.64(d,J=8.6Hz,0.62H),7.58(d,J=8.6Hz,0.51H),7.50(d ,J=7.6Hz,0.5H),7.35-7.30(m,0.53H),7.25-7.22(m,1.26H),7.17-7.08(m,1.42H),7.03(d,J=7.6Hz,0.67H),6.94-6.92(m,1H),6.88- 6.84(m,1H),5.92(d,J=14.2Hz,0.49H),5.77(d,J=13.8Hz,0.55H),5.62(d,J=7.6Hz,0.57H),5.41(d,J=7.6Hz,0.47H),4.50-4.46(m,1. 06H),4.43-4.40(m,0.64H),4.34(dd,J=9.8,3.0Hz,0.50H),4.04-3.94(m,5H),3.76-3.67(m,1H),3.63-3.60(m,1H),2.91-2.77(m,1H).

[0595] Example 38: Synthesis of (12aR)-7-hydroxy-12-(3-methyl-6,12-dihydro-3H-benzo[6,7]thiophene[4,3-e]indazol-12-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 38)

[0596]

[0597] Step 1: Synthesis of Compound 38-3

[0598] In a dry round-bottom flask, 50 mL of a THF solution containing 630.9 mg NaH (15.8 mmol, 60% purity) was added. Under ice bath and nitrogen protection, 5 mL of a THF solution containing 2 g of 38-1 (10.5 mmol) was added. The mixture was stirred at 0°C for 0.5 hours. Then, benzenesulfonyl chloride (2.8 g, 15.8 mmol) was slowly added dropwise at 0°C, and the reaction was stirred at 20°C for 3 hours. The reaction was monitored by LC-MS. After the reaction was complete, the mixture was quenched with saturated ammonium chloride solution, extracted three times with ethyl acetate, and the combined organic phases were washed with saturated brine and dehydrated with anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure without further purification. The crude product could be used directly in the next reaction to obtain product 38-3 (3.5 g, crude) as a yellow solid. LC-MS: m / z 331 [M+H] + .

[0599] Step 2, Synthesis of Compound 38-4

[0600] Following the synthesis method in step 1 of Example 37, 37-1 in step 1 was replaced with 38-3, and the synthesis method remained the same, yielding product 38-4 (4.2 g). LC-MS: m / z 410 [M+H] + .

[0601] Step 3, Synthesis of Compound 38-5

[0602] Following the synthesis method in step 2 of Example 37, 37-2 was replaced with 38-4 in step 2, and the synthesis method remained the same, yielding product 38-5 (3g). LC-MS: m / z 439 [M+H] + .

[0603] Step 4: Synthesis of compound 38-6

[0604] In a dry round-bottom flask, 38-5 (6 g, 13.7 mmol) and NaOH (2.7 g, 68.4 mmol) were added and dissolved in methanol (40 mL) and H₂O (40 mL). The mixture was stirred at 90 °C for 18 hours, and monitored by LC-MS. After the reaction was complete, the organic solvent was concentrated under reduced pressure, the pH was adjusted to 3 with 1 M HCl solution, and the mixture was extracted three times with ethyl acetate. The organic phase was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. No further purification was required; the crude product could be used directly in the next reaction to obtain product 38-6 (4.1 g, crude) as a yellow solid. LC-MS: m / z 285 [M+H] + .

[0605] Step 5: Synthesis of compound 38-7

[0606] Following the synthesis method in step 3 of Example 37, 37-3 was replaced with 38-6 in step 3, and the synthesis method remained the same, yielding product 38-7 (2.2 g). LC-MS: m / z 313 [M+H] + .

[0607] Step 6, Synthesis of Compound 38-8

[0608] Following the synthesis method in step 4 of Example 29, 29-4 in step 4 was replaced with 38-7, and the synthesis method remained the same, yielding product 38-8 (2g, crude). LC-MS: m / z 299 [M+H] + .

[0609] Step 7, Synthesis of Compounds 38-9

[0610] Following the synthesis method in step 5 of Example 37, 37-5 was replaced with 38-8 in step 5, and the synthesis method remained the same, yielding product 38-9 (350 mg). LC-MS: m / z 281 [M+H] + .

[0611] Step 8, Synthesis of Compound 38-10

[0612] Following the synthesis method in step 6 of Example 37, 37-6 was replaced with 38-9 in step 6, and the synthesis method remained the same, yielding product 38-10 (220 mg). LC-MS: m / z 283 [M+H] + .

[0613] Step 9, Synthesis of Compound 38-11

[0614] Following the synthesis method in step 9 of Example 5, 5-9 was replaced with 33-8, and M2 was replaced with 38-10. The synthesis method remained the same, yielding product 38-11 (50 mg). LC-MS: m / z 592 [M+H] + .

[0615] Step 10, Synthesis of Compound 38

[0616] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 38-10, and the synthesis method remained the same, yielding product 38 (4.3 mg). LC-MS: m / z 502.2 [M+H] + .

[0617] 1 H NMR (400MHz, DMSO-d6) δ8.61(s,1H),7.71(d,J=8.4Hz,1H),7.52(d,J=8.4Hz,1H),7.31(d,J=7. 6Hz,1H),7.18(d,J=7.6Hz,1H),7.14-7.10(m,1H),7.06(d,J=7.6Hz,1H),6.83-6.80(m,1H),6. 08(s,1H),5.65(d,J=13.6Hz,1H),5.59(d,J=7.6Hz,1H),4.46-4.32(m,2H),4.03(s,3H),3.98( d,J=13.8Hz,1H),3.92(dd,J=11.0,3.2Hz,1H),3.66(t,J=10.6Hz,2H),3.58(d,J=13.8Hz,2H).

[0618] Example 39: Synthesis of (12aR)-12-(6,12-dihydrodibenzo[6,7]thiophene[3,4-g]benzofuran-12-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 39)

[0619]

[0620] Step 1: Synthesis of Compound 39-3

[0621] In a dry round-bottom flask, 39-1 (10 g, 53.5 mmol), 39-2 (15.8 g, 7.66 mL), and KOH (4.5 g, 80.2 mmol) were added and dissolved in 27 mL of DMSO solution. The mixture was stirred at 160 °C for 0.5 h, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed by column chromatography to obtain product 39-3 (14.2 g) as a yellow solid. LC-MS: m / z 303 [M+H] + .

[0622] Step 2, Synthesis of Compound 39-4

[0623] In a dry round-bottom flask, 39-3 (14.2 g, 46.9 mmol) and PPA (15 g, 93.7 mmol) were dissolved in toluene solution (120 mL). The mixture was stirred at 110 °C for 1 hour, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed by column chromatography to give product 39-4 (11.6 g). LC-MS: m / z 211 [M+H] + .

[0624] Step 3, Synthesis of Compound 39-5

[0625] In a dry round-bottom flask, 39-4 (4.4 g, 20.8 mmol), diethyl oxalate (3.6 g, 25 mmol, 3.35 mL), DMAP (3.1 g, 25.0 mmol), and Pd(PPh3)2Cl2 (500 mg, 0.7 mmol) were dissolved in ethanol solution (3.7 mL). The mixture was stirred at 150 °C for 18 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed by column chromatography to give product 39-5 (3 g). LC-MS: m / z 205 [M+H] + .

[0626] Step 4, Synthesis of Compound 39-6

[0627] Following the synthesis method in step 1 of Example 37, 37-1 in step 1 was replaced with 39-5, and the synthesis method remained the same, yielding product 39-6 (2g, crude). LC-MS: m / z 284 [M+H] + .

[0628] Step 5, Synthesis of Compound 39-7

[0629] Following the synthesis method in step 1 of Example 38, 38-1 in step 1 was replaced with 39-6, and the synthesis method remained the same, yielding product 39-7 (1g, crude). LC-MS: m / z 313 [M+H] + .

[0630] Step 6, Synthesis of Compound 39-8

[0631] Following the synthesis method in step 4 of Example 29, 29-4 in step 4 was replaced with 39-7, and the synthesis method remained the same, yielding product 39-8 (300 mg). LC-MS: m / z 285 [M+H] + .

[0632] Step 7, Synthesis of Compound 39-9

[0633] Following the synthesis method in step 2 of Example 39, 39-3 was replaced with 39-8 in step 2, and the synthesis method remained the same, yielding product 39-9 (48 mg). LC-MS: m / z 267 [M+H] + .

[0634] Step 8, Synthesis of Compounds 39-10

[0635] Following the synthesis method in step 6 of Example 37, 37-6 was replaced with 39-9 in step 6, and the synthesis method remained the same, yielding product 39-10 (23 mg). LC-MS: m / z 269 [M+H] + .

[0636] Step 9, Synthesis of Compounds 39-11

[0637] Following the synthesis method in step 9 of Example 5, 5-9 was replaced with 33-8, and M2 was replaced with 39-10. The synthesis method remained the same, yielding product 39-11 (54.2 mg). LC-MS: m / z 578 [M+H] + .

[0638] Step 10, Synthesis of Compound 39

[0639] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 39-10, and the synthesis method remained the same, yielding product 39 (3 mg). LC-MS: m / z 488.1 [M+H] + .

[0640] Example 40: Synthesis of 7-hydroxy-12-(5-(trifluoromethyl)-10,11-dihydro-5H-dibenzo[a,d][7]cyclo-5-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazine[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (compound 40)

[0641]

[0642] Step 1: Synthesis of Compound 40-1

[0643] In a dry round-bottom flask, 7-1 (10.4 g, 5 mmol) was dissolved in TMS-CF3 (10.6 g, 1.2 mL). The mixture was stirred for 5 minutes at 0°C under nitrogen protection. Then, TBAF (13 mg, 0.05 mmol) was added, and the mixture was heated to 40°C and reacted for 3 hours, monitored by LC-MS. After the reaction, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed by column chromatography to give product 40-1 (5 g). LC-MS: m / z 261 [M+H] + (The score shows 261.)

[0644] Step 2, Synthesis of Compound 40-2

[0645] 40-1 (1 g, 3.6 mmol) was dissolved in THF (5 mL) in a dry round-bottom flask, and 1 N HCl (5 mL) was added. The reaction was carried out overnight at room temperature, monitored by LC-MS. After the reaction was complete, the organic phase was concentrated under reduced pressure, extracted three times with water and ethyl acetate, and the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the residual impurities were removed by column chromatography to give product 40-2 (200 mg). LC-MS: m / z 279 [M+H] + .

[0646] Step 3, Synthesis of Compound 40-3

[0647] Following the synthesis method in step 9 of Example 5, 5-9 was replaced with 33-7, and M2 was replaced with 40-2. The synthesis method remained the same, yielding product 40-3 (55.6 mg). LC-MS: m / z 588 [M+H] + .

[0648] Step 4, Synthesis of Compound 40

[0649] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 40-3, and the synthesis method remained the same, yielding product 40 (4.7 mg). LC-MS: m / z 498.4 [M+H] + .

[0650] Example 41: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4,4',5-tetrahydro-1'H,2H,3'H-spirocyclic[furan-3,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 41)

[0651]

[0652] Step 1: Synthesis of Compound 41-3

[0653] Following the synthesis method in step 1 of Example 5, 5-1 in step 1 was replaced with 41-1, and the synthesis method remained the same, yielding product 41-3 (12 g). LC-MS: m / z 157 [M+H] + .

[0654] Step 2, Synthesis of Compound 41-4

[0655] Following the synthesis method in step 2 of Example 5, 5-2 in step 2 was replaced with 41-3, and the synthesis method remained the same, yielding product 41-4 (12 g). LC-MS: m / z 218 [M+H] + .

[0656] Step 3, Synthesis of Compounds 41-5

[0657] Following the synthesis method in step 3 of Example 5, 5-3 in step 3 was replaced with 41-4, and the synthesis method remained the same, yielding product 41-5 (5g). LC-MS: m / z 188 [M+H] + .

[0658] Step 4, Synthesis of Compounds 41-6

[0659] Following the synthesis method in step 4 of Example 29, 29-4 in step 4 was replaced with 41-5, and the synthesis method remained the same, yielding product 41-6 (3.8 g). LC-MS: m / z 142 [M+H] + .

[0660] Step 5: Synthesis of Compounds 41-8

[0661] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 41-6, and the synthesis method remained the same, yielding product 41-8 (4g). LC-MS: m / z 226 [M+H] + .

[0662] Step 6, Synthesis of Compounds 41-9

[0663] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 41-8, and the synthesis method remained the same, yielding product 41-9 (1g). LC-MS: m / z 228 [M+H] + .

[0664] Step 7, Synthesis of Compounds 41-10

[0665] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 41-9, and the synthesis method remained the same, yielding product 41-10 (1g). LC-MS: m / z 242 [M+H] + .

[0666] Step 8, Synthesis of Compounds 41-11

[0667] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 41-10, and the synthesis method remained the same, yielding product 41-11 (328 mg). LC-MS: m / z 498 [M+H] + .

[0668] Step 9, Synthesis of Compounds 41-12

[0669] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 41-11, and the synthesis method remained the same, yielding product 41-12 (200 mg). LC-MS: m / z 368 [M+H] + .

[0670] Step 10, Synthesis of Compounds 41-13

[0671] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 41-12, and the synthesis method remained the same, yielding product 41-13 (30 mg). LC-MS: m / z 614 [M+H] + .

[0672] Step 11, Synthesis of Compound 41

[0673] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 41-13, and the synthesis method remained the same, yielding product 41 (3.6 mg). LC-MS: m / z 524.3 [M+H] + .

[0674] Example 42: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-3a',4'-dihydro-1'H,3'H-spirocyclic[cyclopentane-1,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 42)

[0675]

[0676] Step 1: Synthesis of Compound 42-2

[0677] Following the synthesis method in step 1 of Example 5, 5-1 in step 1 was replaced with 42-1, and the synthesis method remained the same, yielding product 42-2 (7.3 g). LC-MS: m / z 155 [M+H] + .

[0678] Step 2, Synthesis of Compound 42-3

[0679] Following the synthesis method in step 2 of Example 5, 5-2 in step 2 was replaced with 42-2, and the synthesis method remained the same, yielding product 42-3 (8.7 g). LC-MS: m / z 216 [M+H] + .

[0680] Step 3, Synthesis of Compound 42-4

[0681] Following the synthesis method in step 3 of Example 5, 5-3 in step 3 was replaced with 42-3, and the synthesis method remained the same, yielding product 42-4 (6.1 g). LC-MS: m / z 186 [M+H] + .

[0682] Step 4, Synthesis of Compound 42-5

[0683] Following the synthesis method in step 4 of Example 29, 29-4 in step 4 was replaced with 42-4, and the synthesis method remained the same, yielding product 42-5 (4.3 g). LC-MS: m / z 140 [M+H] + .

[0684] Step 5, Synthesis of Compounds 42-6

[0685] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 42-5, and the synthesis method remained the same, yielding product 42-6 (3.2 g). LC-MS: m / z 224 [M+H] + .

[0686] Step 6, Synthesis of Compounds 42-7

[0687] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 42-6, and the synthesis method remained the same, yielding product 42-7 (2.3 g). LC-MS: m / z 226 [M+H] + .

[0688] Step 7, synthesis of compounds 42-8

[0689] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 42-7, and the synthesis method remained the same, yielding product 42-8 (1.6 g). LC-MS: m / z 240 [M+H] + .

[0690] Step 8, Synthesis of Compounds 42-9

[0691] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 42-8, and the synthesis method remained the same, yielding product 42-9 (1.9 g). LC-MS: m / z 496 [M+H] + .

[0692] Step 9, Synthesis of Compounds 42-10

[0693] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 42-9, and the synthesis method remained the same, yielding product 42-10 (230 mg). LC-MS: m / z 366 [M+H] + .

[0694] Step 10, Synthesis of Compounds 42-11

[0695] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 42-10, and the synthesis method remained the same, yielding product 42-11 (30 mg). LC-MS: m / z 612 [M+H] + .

[0696] Step 11, Synthesis of Compound 42

[0697] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 42-11, and the synthesis method remained the same, yielding product 42 (1.9 mg). LC-MS: m / z 522.2 [M+H]+ .

[0698] 1 H NMR(600MHz,DMSO-d6)δ9.47(s,1H),7.60-7.46(m,2H),7.36-7.31(m,1H),7.12- 7.01(m,2H),6.93-6.83(m,2H),5.75-5.58(m,4H),4.22-3.84(m,3H),3.45(d,J=1 2.4Hz,1H),3.19-3.06(m,1H),3.02-2.88(m,1H),2.77-2.66(m,3H),1.99-1.88(m ,1H),1.87-1.78(m,1H),1.66-1.54(m,1H),1.51-1.32(m,2H),1.32-1.22(m,2H).

[0699] Example 43: Synthesis of 1'-(7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiophene-11-yl)-5'-hydroxy-spirocyclic [cyclopropane-1,3'-pyrido[1,2-b]pyridazine]-2',4',6'-trione (compound 43)

[0700]

[0701] Step 1: Synthesis of Compound 43-2

[0702] In a dry round-bottom flask, 43-1 (20 g, 158.6 mmol), BnBr (32.6 g, 190.7 mmol, 22.8 mL), and potassium carbonate (43.8 g, 317.4 mmol) were dissolved in 200 mL of DMF solution. The mixture was stirred at 80°C for 2 hours, and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. No further purification was required; the crude product could be used directly in the next reaction to obtain product 43-2 (34 g, crude), which was a yellow oil. LC-MS: m / z 217 [M+H] + .

[0703] Step 2, Synthesis of Compound 43-3

[0704] In a dry round-bottom flask, 43-2 (10 g, 46.3 mmol) and SeO2 (10.4 g, 92.5 mmol) were added, followed by 50 mL of brominated benzene solution. The mixture was stirred at 160 °C for 18 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed by column chromatography to obtain product 43-3 (6 g) as a yellow oil. LC-MS: m / z 231 [M+H] + .

[0705] Step 3, Synthesis of Compound 43-4

[0706] In a dry round-bottom flask, 43-3 (2.8 g, 9.3 mmol) was dissolved in 40 mL of THF solution. Then, 20 mL of 2-methyl-2-butene and 3.2 g (28.0 mmol, 80% purity) of NaH2PO4 (aq) solution (40 mL) were added. The mixture was stirred at 25°C for 18 hours, and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed by column chromatography to obtain product 43-4 (2.5 g) as a yellow oil. LC-MS: m / z 317 [M+H] + .

[0707] Step 4, Synthesis of Compounds 43-5

[0708] 43-4 (2.5 g, 7.9 mmol) was dissolved in 15 mL of methanol solution in a dry round-bottom flask, followed by the addition of 15 mL of NH3H2O. The mixture was stirred at 25°C for 18 hours, and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed using a medium-pressure reverse-phase preparative column to obtain product 43-5 (2 g) as a yellow oil. LC-MS: m / z 316 [M+H] + .

[0709] Step 5, Synthesis of Compounds 43-6

[0710] 43-5 (2 g, 6.3 mmol) was dissolved in 30 mL of acetone solution in a dry round-bottom flask. Jones' reagent (6 mL) was slowly added dropwise at 0°C, and the mixture was stirred at 25°C for 18 hours, monitored by LC-MS. After the reaction was complete, isopropanol was added to quench the reaction, and stirring was continued for 30 minutes. The pH of the system was adjusted to 7 by adding saturated sodium bicarbonate solution. The mixture was filtered, and the filtrate was concentrated under reduced pressure. Residual impurities were removed using a medium-pressure reverse-phase preparative column to obtain product 43-6 (1.5 g) as a yellow oil. LC-MS: m / z 314 [M+H] + .

[0711] Step 6, Synthesis of Compounds 43-7

[0712] In a dry round-bottom flask, 43-6 (1.5 g, 4.8 mmol) was dissolved in 20 mL of DMF solution. Then, 2,4-dinitrophenylhydroxylamine (1.14 g, 5.8 mmol) and potassium carbonate (3.3 g, 24.0 mmol) were added, and the mixture was stirred at 30°C for 18 hours, monitored by LC-MS. After the reaction was complete, the pH was adjusted to 3 with 1 M HCl solution. The mixture was extracted three times with ethyl acetate, and the organic phase was collected, washed twice with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Residual impurities were removed using a medium-pressure reverse-phase preparative column to obtain product 43-7 (1.3 g) as a brown solid. LC-MS: m / z 329 [M+H] + .

[0713] Step 7, Synthesis of Compounds 43-8

[0714] In a dry round-bottom flask, 43-7 (1.3 g, 4.0 mmol) was dissolved in 30 mL of DMF solution. DMAP (967.5 mg, 7.9 mmol) and DIPEA (10.2 g, 79.2 mmol) were added, and the mixture was stirred for 5 minutes. Then, EDCI (7.6 g, 39.6 mmol) was added, and the mixture was stirred at 30°C for 18 hours. The reaction was monitored by LC-MS. After the reaction was complete, the organic phase was concentrated under reduced pressure, and residual impurities were removed using a medium-pressure reverse-phase preparative column to obtain product 43-8 (100 mg) as a yellow solid. LC-MS: m / z 311 [M+H] + .

[0715] Step 8, Synthesis of Compound 43

[0716] In a dry round-bottom flask, 43-8 (5 mg, 0.02 mmol) and M2 (8.5 mg, 0.03 mmol) were dissolved in 1-propylphosphonic anhydride (50 wt.% ethyl acetate solution, 200 μL). The mixture was stirred at 110 °C for 18 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the organic phase was concentrated under reduced pressure, and residual impurities were removed using a medium-pressure reversed-phase preparative column to give product 43 (1.7 mg). LC-MS: m / z 467.2 [M+H] +

[0717] 1 H NMR(600MHz,DMSO-d6)δ11.42(s,1H),7.52-7.48(m,2H),7.37-7.33(m,1H),7.29-7.26(m,1H),7.24-7.2 2(m,1H),7.17-7.15(m,1H),7.01(s,1H),5.89(s,1H),4.59-4.52(m,2H),3.83(s,2H),3.06-2.95(m,2H).

[0718] Example 44: Synthesis of 4-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9-hydroxy-2',3a,3',4,5',6'-hexahydro-1H,3H-spirocyclic [pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine-2,4'-thiaran]-8,10-dione 1',1'-dioxide (compound 44)

[0719]

[0720] Step 1: Synthesis of Compound 44-2

[0721] Following the synthesis method in step 1 of Example 5, 5-1 in step 1 was replaced with 44-1, and the synthesis method remained the same, yielding product 44-2 (7.8 g). LC-MS: m / z 187 [M+H] + .

[0722] Step 2, Synthesis of Compound 44-3

[0723] Following the synthesis method in step 2 of Example 5, 5-2 in step 2 was replaced with 44-2, and the synthesis method remained the same, yielding product 44-3 (9.0 g). LC-MS: m / z 248 [M+H] + .

[0724] Step 3, Synthesis of Compound 44-4

[0725] Following the synthesis method in step 3 of Example 5, 5-3 in step 3 was replaced with 44-3, and the synthesis method remained the same, yielding product 44-4 (8.5 g). LC-MS: m / z 218 [M+H] + .

[0726] Step 4, Synthesis of Compound 44-5

[0727] Following the synthesis method in step 4 of Example 29, 29-4 in step 4 was replaced with 44-4, and the synthesis method remained the same, yielding product 44-5 (4.0 g). LC-MS: m / z 172 [M+H] + .

[0728] Step 5, Synthesis of Compounds 44-6

[0729] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 44-5, and the synthesis method remained the same, yielding product 44-6 (6g). LC-MS: m / z 256 [M+H] + .

[0730] Step 6, Synthesis of Compounds 44-7

[0731] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 44-6, and the synthesis method remained the same, yielding product 44-7 (4.1 g). LC-MS: m / z 258 [M+H] + .

[0732] Step 7, Synthesis of Compounds 44-8

[0733] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 44-7, and the synthesis method remained the same, yielding product 44-8 (4.1 g). LC-MS: m / z 271 [M+H] + .

[0734] Step 8, Synthesis of Compounds 44-9

[0735] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 44-8, and the synthesis method remained the same, yielding product 44-9 (2.6 g). LC-MS: m / z 528 [M+H] + .

[0736] Step 9, Synthesis of Compounds 44-10

[0737] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 44-9, and the synthesis method remained the same, yielding product 44-10 (1.9 g). LC-MS: m / z 397 [M+H]+ .

[0738] Step 10, Synthesis of Compound 44-11

[0739] 44-10 (500 mg, 1.3 mmol) was dissolved in 50 mL of DCM solution in a dry round-bottom flask. m-CPBA (651.2 mg, 3.8 mmol) was added at 0°C, and the mixture was stirred at 0°C for 3 hours, monitored by LC-MS. After the reaction was complete, the organic phase was concentrated under reduced pressure, and residual impurities were removed using a medium-pressure reverse-phase preparative column to obtain product 44-11 (75 mg). LC-MS: m / z 314 [M+H] + .

[0740] Step 11, Synthesis of Compound 44-12

[0741] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 44-11, and the synthesis method remained the same, yielding product 44-12 (19 mg). LC-MS: m / z 430.1 [M+H] + .

[0742] Step 11, Synthesis of Compound 44

[0743] Following the synthesis method in step 6 of Example 14, 14-8 in step 6 was replaced with 44-12, and the synthesis method remained the same, yielding product 44 (7 mg). LC-MS: m / z 586 [M+H] + .

[0744] 1 H NMR (400MHz, DMSO-d6) δ7.39 (d, J=7.4Hz, 2H), 7.32-7.11 (m, 5H), 7.06 (d, J= 12.6Hz,1H),5.38(s,1H),5.23-5.01(m,1H),4.30(dd,J=15.0,8.0Hz,1H),3 .90(d,J=13.8Hz,1H),3.63(d,J=12.4Hz,1H),3.43(dd,J=12.6,8.0Hz,1H), 3.25-3.04(m,4H),2.46-2.31(m,1H),2.13-1.94(m,4H),1.70-1.59(m,1H).

[0745] Example 45: Synthesis of 4'-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-2',3',3a',4'-tetrahydrospirocyclic[cyclopropane-1,1'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 45)

[0746]

[0747] Step 1: Synthesis of Compound 45-3

[0748] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 45-1, and the synthesis method remained the same, yielding product 45-3 (1.3 g). LC-MS: m / z 196 [M+H] + .

[0749] Step 2, Synthesis of Compound 45-4

[0750] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 45-3, and the synthesis method remained the same, yielding product 45-4 (1.3 g). LC-MS: m / z 198 [M+H] + .

[0751] Step 3, Synthesis of Compound 45-5

[0752] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 45-4, and the synthesis method remained the same, yielding product 45-5 (1.2 g). LC-MS: m / z 212 [M+H] + .

[0753] Step 4, Synthesis of Compounds 45-6

[0754] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 45-5, and the synthesis method remained the same, yielding product 45-6 (2.3 g). LC-MS: m / z 468 [M+H] + .

[0755] Step 5, Synthesis of Compound 45-8

[0756] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 45-6, and the synthesis method remained the same, yielding product 45-8 (400 mg). LC-MS: m / z 338 [M+H] + .

[0757] Step 6, Synthesis of Compounds 45-9

[0758] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 45-8, and the synthesis method remained the same, yielding product 45-9 (32 mg). LC-MS: m / z 584 [M+H] + .

[0759] Step 7, Synthesis of Compound 45

[0760] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 45-9, and the synthesis method remained the same, yielding product 45 (5 mg). LC-MS: m / z 494.3 [M+H] + .

[0761] Example 46: Synthesis of 1'-acetyl-2-(7,8-difluoro-6,11-dihydrobenzo[c][1]benzothiophene-11-yl)-10-hydroxy-spirocyclic [1,2,7-triazatricyclo[7.4.0.03,7]tetrazol-9,12-diene-5,3'-azacyclobutane]-8,11-dione (compound 46)

[0762]

[0763] Step 1: Synthesis of Compound 46-3

[0764] Following the synthesis method in step 4 of Example 5, 5-4 in step 4 was replaced with 46-1, and the synthesis method remained the same, yielding product 46-3 (16.2 g). LC-MS: m / z 311 [M+H] + .

[0765] Step 2, Synthesis of Compound 46-4

[0766] Following the synthesis method in step 5 of Example 5, 5-5 in step 5 was replaced with 46-3, and the synthesis method remained the same, yielding product 46-4 (6 g). LC-MS: m / z 313 [M+H] + .

[0767] Step 3, Synthesis of Compound 46-5

[0768] Following the synthesis method in step 6 of Example 5, 5-6 in step 6 was replaced with 46-4, and the synthesis method remained the same, yielding product 46-5 (620 mg). LC-MS: m / z 327 [M+H] + .

[0769] Step 4, Synthesis of Compound 46-6

[0770] Following the synthesis method in step 7 of Example 5, 5-7 in step 7 was replaced with 46-5, and the synthesis method remained the same, yielding product 46-6 (970 mg). LC-MS: m / z 583 [M+H] + .

[0771] Step 5, Synthesis of Compounds 46-7

[0772] Following the synthesis method in step 8 of Example 5, 5-8 in step 8 was replaced with 46-6, and the synthesis method remained the same, yielding product 46-7 (430 mg). LC-MS: m / z 453 [M+H] + .

[0773] Step 6, Synthesis of Compound 46-8

[0774] 46-7 (45.2 mg, 99.9 μmol) was added to a dry round-bottom flask, dissolved in EA (2 mL), and then 1 N HCl (2 mL) was added. The mixture was stirred at 25°C for 1 hour, and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 46-8 (35.2 mg). LC-MS: m / z 353 [M+H] +

[0775] Step 7, Synthesis of Compounds 46-9

[0776] 46-8 (35.2 mg, 99.9 μmol) was added to a dry round-bottom flask and dissolved in water (0.5 mL) and THF (0.5 mL). NaHCO3 (16.8 mg, 199.8 μmol) and acetic anhydride (0.5 mL) were then added. The mixture was stirred at 25°C for 0.5 h and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 46-9 (32 mg) was purified using a medium-pressure reversed-phase preparative column. LC-MS: m / z 395 [M+H] +

[0777] Step 8, Synthesis of Compounds 46-10

[0778] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 46-9, and the synthesis method remained the same, yielding product 46-10 (30 mg). LC-MS: m / z 641 [M+H] + .

[0779] Step 9, Synthesis of Compound 46

[0780] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 45-9, and the synthesis method remained the same, yielding product 46 (6 mg). LC-MS: m / z 551 [M+H] + .

[0781] Example 47: Synthesis of (S)-4'-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophene-11-yl)-9'-hydroxy-1-methyl-3a',4'-dihydro-1'H,3'H-spirocyclic[piperidine-4,2'-pyrido[2,1-f]pyrrole[2,1-c][1,2,4]triazine]-8',10'-dione (compound 47)

[0782]

[0783] Step 1: Synthesis of Compound 47-1

[0784] In a dry round-bottom flask, Isomer 31-7-2 (24 mg, 49.9 μmol) and Isomer M2-2 (19.8 mg, 74.9 μmol) were added and dissolved in T3P (0.2 mL). NaHCO3 (16.8 mg, 199.8 μmol) and acetic anhydride (0.5 mL) were then added. The mixture was stirred at 110 °C for 2 hours, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give crude product 47-1 (35 mg). LC-MS: m / z 395 [M+H] +

[0785] Step 2, Synthesis of Compound 47-2

[0786] 47-1 (35 mg, 55.9 μmol) was dissolved in formaldehyde (1 mL) and methanol (1 mL) in a dry round-bottom flask. NaBH3CN (7.0 mg, 111.7 μmol) was added, and the mixture was stirred at 25°C for 0.5 h, monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and DCM. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude product 47-2 (28 mg). LC-MS: m / z 641 [M+H] +

[0787] Step 3, Synthesis of Compound 47

[0788] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 47-2, and the synthesis method remained the same, yielding product 47 (10 mg). LC-MS: m / z 551.3 [M+H] + .

[0789] 1 H NMR(600MHz,DMSO-d6)δ9.47(s,1H),7.60-7.46(m,2H),7.36-7.31(m,1H),7.12- 7.01(m,2H),6.93-6.83(m,2H),5.75-5.58(m,4H),4.22-3.84(m,3H),3.45(d,J=1 2.4Hz,1H),3.19-3.06(m,1H),3.02-2.88(m,1H),2.77-2.66(m,3H),1.99-1.88(m ,1H),1.87-1.78(m,1H),1.66-1.54(m,1H),1.51-1.32(m,2H),1.32-1.22(m,2H).

[0790] Example 48: Synthesis of (12aS)-11-(7,8-difluoro-4a,6,6a,10a,11,11a-hexahydrodiphenyl[b,e]thiophene-11-yl)-6-hydroxy-1,2,3,11,12,12a-hexahydropyridine[1,2-b]pyrrole[1,2-e][1,2,5]triaza-5,7-dione (compound 48)

[0791]

[0792] Step 1: Synthesis of Compound 48-3

[0793] In a dry round-bottom flask, 48-1 (288 mg, 999 μmol) and 48-2 (238.8 mg, 1.2 mmol) were added and dissolved in methanol (5 mL). The mixture was stirred at 50 °C for 1 h, and the reaction was monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 48-3 (455 mg) was purified using a medium-pressure reversed-phase preparative column. LC-MS: m / z 470 [M+H] +

[0794] Step 2, Synthesis of Compound 48-4

[0795] 48-3 (455 mg, 969.1 μmol) and NaBH4 (73.3 mg, 1.9 mmol) were added to a dry round-bottom flask and dissolved in methanol (5 mL). The mixture was stirred at 0°C for 0.5 h and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 48-4 (448 mg) was purified using a medium-pressure reversed-phase preparative column. LC-MS: m / z 472 [M+H] +

[0796] Step 3, Synthesis of Compound 48-5

[0797] 48-4 (448 mg, 950.1 μmol) was added to a dry round-bottom flask and dissolved in methanol (5 mL) and TFA (5 mL). The mixture was stirred at 25°C for 0.5 h, and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 48-5 (302 mg) was purified using a medium-pressure reversed-phase preparative column. LC-MS: m / z 372 [M+H] +

[0798] Step 4, Synthesis of Compound 48-6

[0799] 48-5 (302 mg, 813.1 μmol) was added to a dry round-bottom flask and dissolved in methanol (3 mL). The mixture was stirred at 0°C for 5 minutes, and then a methanol solution of MeONa (240 μL) was slowly added dropwise. The mixture was stirred at 0°C to room temperature for 1 hour, and monitored by LC-MS. After the reaction was complete, the mixture was extracted three times with water and ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The product 48-6 (230 mg) was purified using a medium-pressure reversed-phase preparative column. LC-MS: m / z 326 [M+H] +

[0800] Step 5: Synthesis of Compound 48-7

[0801] Compound 48-7 was obtained by resolving 48-6.

[0802] Step 6, Synthesis of Compound 48-8

[0803] Following the synthesis method in step 9 of Example 5, 5-9 in step 9 was replaced with 48-7, and the synthesis method remained the same, yielding product 48-9 (33 mg). LC-MS: m / z 576 [M+H] + .

[0804] Step 7, Synthesis of Compound 48

[0805] Following the synthesis method in step 10 of Example 5, 5-10 in step 10 was replaced with 48-9, and the synthesis method remained the same, yielding product 48 (8 mg). LC-MS: m / z 483.3 [M+H] + .

[0806] 1 H NMR (600MHz, DMSO-d6) δ8.15-5.81(m,8H),5.58-4.96(m,2H),4.17-3.75(m,3H),3.58-3.07(m,2H),2.69(s,1H),2.16-1.39(m,5H).

[0807] Experimental Example 1: Enzyme Activity Experiment

[0808] Compound preparation

[0809] 1) Dissolve the compound in DMSO to obtain 10 mM test compound and 10 mM reference compound (Baloxaviracid). Dilute the compound 3- or 4-fold with DMSO to prepare 100-fold DMSO solutions for 10 stoichiometric points. Take 4 μL of the 100-fold diluted compound and add it to 96 μL of a 1-fold buffer solution (20 mM Tris-HCl, 50 mM NaCl, 2 mM MnCl2, 10 mM β-mercaptoethanol, 0.05% Tween-20, pH 8.0) to obtain a 4-fold compound solution. The highest concentrations of the test compound in the enzyme reaction solution were 1 μM in influenza A virus H1N1_WSN_1933PAN (protein series 1-196, del52-72) and 10 μM in influenza B virus Lee_1940PAN (protein series 1-198).

[0810] Enzyme experiment

[0811] 1) Prepare 4x enzyme solution (final concentration 10nM influenza A virus H1N1_WSN_1933 PAN and 250nM influenza B virus Lee_1940 PAN) and 2x substrate solution (single-stranded DNA substrate) (final concentration 0.3uM) (single-stranded DNA substrate series: [6-FAM]AAT CGC AGG CAG CAC TC[BHQ1] (custom-synthesized by Sangon Biotech).

[0812] 2) In a 384-well assay plate (Corning, catalog number: 3575), add 5 μL of 4-fold compound solution and 5 μL of 4-fold enzyme solution to each well. For the blank control, add an equal volume of 1-fold buffer to replace the enzyme solution as a 100% inhibition control (negative control), and add an equal volume of 1-fold buffer to replace the compound solution as a 0% inhibition control (positive control). Centrifuge at 1000 rpm, 25°C for 1 minute. Place the 384 assay plate in a microplate incubator and mix at 220 rpm for 15 minutes at 25°C.

[0813] 3) Add 10 μL of 2-fold substrate solution to the 384 detection plate, centrifuge at 1000 rpm and 25°C for 1 minute. Place the 384 detection plate in a microplate incubator and mix at 37°C and 220 rpm for 120 minutes.

[0814] 4) Fluorescence was detected using a Tecan Spark 20M at an excitation wavelength Ex of 485 nm (10 nm bandwidth) and an emission wavelength Em of 535 nm (10 nm bandwidth). The fluorescence signals from the positive control (maximum signal control) and negative control (minimum signal control) were standardized to determine the inhibition rate of different compound concentrations. The IC50 of the compound's inhibitory effect on enzyme activity was then calculated using GraphPad Prism 6 in log(inhibitor) vs. response-variable slope mode. 50 The fitted equation is: Y = Bottom + (Top - Bottom) / (1 + 10^(LogIC)) 50 -X)*HillSlope)), where Y represents the known percentage of residual enzyme activity, and X represents the known concentration of the compound after logarithmization, calculated as the IC50 of the compound's inhibitory effect on enzyme activity. 50 .

[0815] 5) Experimental results: The compound of this invention exhibits inhibitory IC50 values ​​for the enzyme activity of both 10 nM influenza virus A H1N1_WSN_1933 PAN and influenza virus BLee_1940 PAN. 50 As shown in Table 1.

[0816] Table 1. Inhibitory activity of the compounds of the present invention against influenza virus A / WSN / 33 (H1N1) and influenza virus B / Lee / 40.

[0817]

[0818]

[0819]

[0820] Where “+” represents ≤10, “++” represents >10 and ≤50, “+++” represents >50 and ≤250, and “++++” represents >250; N / A indicates not detected.

[0821] The above experiments show that the compounds of the present invention have a strong inhibitory effect on the enzyme activity of influenza virus A H1N1_WSN_1933 PAN and influenza virus BLee_1940 PAN.

[0822] Experimental Example 2: Cell Viability

[0823] MDCK cells were seeded at a specific density in microplates and cultured overnight in a 5% CO2, 37°C incubator. The next day, serially diluted compounds and viruses were added. Cell controls (cells, no compound treatment or virus infection), virus controls (cells infected with virus, no compound treatment), and culture medium controls (culture medium only) were set up. The final concentration of DMSO in the culture medium was 0.5%. Cells were cultured for 5 days in a 5% CO2, 33-37°C incubator. Cytotoxicity assays were performed under the same conditions as antiviral assays, but without virus infection. Cell viability was assessed using the CCK8 cell viability assay kit. The antiviral activity and cytotoxicity of the compounds were expressed as the inhibition rate (%) of the compound on virus-induced cytopathic effects and the viability (%) of MRC5 cells at different concentrations, respectively. GraphPad Prism was used to perform nonlinear fitting analysis on the inhibition rate and cell viability of the compounds to calculate the half-maximal effective concentration (EC5). 50 ) and half-maximal cytotoxic concentration (CC) 50 )value.

[0824] Table 2 shows the in vitro activity of some compounds against influenza virus (EC). 50 and CC on virus-infected cells 50

[0825]

[0826]

[0827] The above experiments show that the compounds of the present invention have excellent anti-influenza virus activity and / or very low cytotoxicity.

[0828] Experimental Example 3: Pharmacokinetic Evaluation

[0829] To investigate the pharmacokinetic properties of the compound in rats, the compound solution was administered to three male SD rats via intravenous injection / oral gavage at appropriate doses. Anticoagulated whole blood was collected from the rats at 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, and 24 h after administration, and plasma was separated. To investigate the pharmacokinetic properties of the compound in mice, the compound was administered to six male ICR mice via intravenous injection / oral gavage at appropriate doses. Mice administered via each route were divided into two groups, A and B. Anticoagulated whole blood was collected from mice in group A at 5 min, 30 min, 2 h, and 8 h after administration, while anticoagulated whole blood was collected from mice in group B at 15 min, 1 h, 4 h, and 24 h after administration, and plasma was separated.

[0830] Plasma concentrations of the compound were determined using LC-MS with standard curve correction. Winnolin 5.2 software was used to fit the plasma concentration-time data to pharmacokinetic parameters, including elimination half-life (T0). 1 / 2 The area under the plasma drug-time curve at the sampling endpoint (AUC) last Peak concentration (C) max Apparent volume of distribution (Vz), total clearance (Cl), absolute bioavailability (F%), etc.

[0831] Table 3 shows the pharmacokinetic data of some compounds in animals.

[0832]

Claims

1. The compound represented by formula Ib, or its stereoisomer, or its pharmaceutically acceptable salt: Ib R 1 R 2 R 5 R 6 Each is independently selected from hydrogen; A is selected from or ,in, Each X is independently selected from CH2 or S; the ring selected from A can be further divided by one or two R. A1 Replace; each R A1 Each is independently selected from hydrogen or halogen; or, A is selected from Wherein, the ring selected from A can be further divided by an R A1 Replace; the R A1 For C(O)NR A2 R A3 ;R A2 R A3 Each is independently selected from hydrogen or methyl; Ring B is selected from , , , , , , , , , , The B ring can be further divided by one or two independent R rings. 1d replace; Each R 1d Each element is independently selected from hydrogen, halogen, and C. 1~3 Alkyl or acetyl groups.

2. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: A is selected from , , , or .

3. The compound according to claim 1, or its stereoisomer, or its pharmaceutically acceptable salt, characterized in that: The compound is specifically: , , , , , , , , , , , , , , , , , , , , , , , .

4. Use of the compound of any one of claims 1 to 3, or its stereoisomer, or its pharmaceutically acceptable salt, in the preparation of a medicament for the prevention or treatment of viral infectious diseases; The viral infection mentioned is an influenza virus infection.

5. A pharmaceutical composition comprising the compound of any one of claims 1 to 3, or a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.

6. The pharmaceutical composition according to claim 5, further comprising a pharmaceutically acceptable carrier, excipient, or mediator.

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