Five-membered heterocyclic compounds, methods of making and using the same

Abstract

The application discloses a five-heterocycle compound, a preparation method and application thereof. Specifically disclosed are a compound as shown in formula I, a pharmaceutically acceptable salt or solvate thereof, a composition containing the compound, and a pharmaceutical use of the compound for preparing a drug for treating a disease or disorder related to the mechanism of action of KRAS G12C mutant protein. The five-heterocycle compound in the application has the activity of inhibiting the proliferation of Ba / F3 KRAS-G12C cells, NCI-H358 cells and MIA PaCa-2 cells expressing KRAS G12C mutant protein, and has a good inhibitory effect on the growth of a subcutaneous transplanted tumor of a NCI-H358 nude mouse.

Description

[0001] This application claims priority to Chinese patent application 202110138250.1, filed on February 1, 2021. The entire contents of the aforementioned Chinese patent application are incorporated herein by reference. Technical Field

[0002] This invention relates to a pentacyclic heterocyclic compound, its preparation method, and its application. Background Technology

[0003] RAS protein is a 21 kDa guanine trinucleotide phosphate (GTP)-binding protein located on the cell membrane, composed of 188 or 189 amino acids. The activity state of RAS protein influences cell growth, differentiation, cytoskeleton, protein transport, and secretion, and its activity is regulated by binding to GTP or guanine dinucleotide phosphate (GDP). When RAS protein binds to GDP, it is in an "inactive" state; when stimulated by specific upstream cell growth factors, guanine nucleotide exchange factor (GEF) catalyzes the release of GDP from RAS protein, which then binds to GTP, placing it in an "activated" state. GTP-bound RAS protein can activate downstream proteins and downstream signaling pathways. RAS protein itself possesses weak GTPase activity, capable of hydrolyzing GTP to GDP, thus achieving the transition from an activated to an inactive state. This hydrolysis process also requires the participation of GTPase activator protein (GAP), which interacts with RAS protein and significantly enhances its ability to hydrolyze GTP to GDP. Any mutation in the RAS protein that affects its own GTPase activity, its interaction with GAP, or its ability to hydrolyze GTP to GDP will result in the RAS protein being in a prolonged activated state. The prolonged activated RAS protein continues to give growth signals to downstream proteins, leading to continuous cell growth and differentiation, which may eventually lead to cancer.

[0004] Approximately 30% of human tumors carry some form of mutated RAS gene. Among members of the RAS family, oncogenic mutations are most common in the V-Ki-Ras2 Kirsten rat sarcoma virus oncogene homolog (KRAS) (85%), while those in the neuroblastoma RAS virus oncogene homolog (NRAS) (12%) and the V-Ha-Ras rat Harvey sarcoma virus oncogene homolog (HRAS) (3%) are less common. For KRAS mutations, the most common mutations occur at glycine residues 12 (G12), 13 (G13), and 61 (Q61), with G12 mutations accounting for 83%. The G12C mutation is one of the most common KRAS mutations, specifically a mutation at position 12 of the KRAS sequence where glycine is replaced by cysteine. This mutation is present in approximately 14% of non-small cell lung cancer (NSCLC), 4% of colorectal cancer, and 2% of pancreatic cancer. Other common KRAS mutations include G12D and G12V, which are highly expressed in colorectal and pancreatic cancers.

[0005] In 2013, the feasibility of using small molecules to covalently bind to the KRAS G12C mutant was first reported in the literature (Nature, 2013, 503(7477): 548-551). In recent years, ARAXES PHARMA has filed multiple patents for KRAS G12C inhibitors, such as WO2014152588A1, WO2015054572A1, and WO2018064510A1. AMGEN's patent application WO2018217651A1 discloses a series of KRAS G12C inhibitors, such as AMG510, whose structure is shown below. In May 2021, AMG510 was approved by the FDA for the treatment of patients with KRAS G12C-mutant non-small cell lung cancer who have received at least one prior systemic therapy. MIRATI THERAPEUTICS INC and ARRAY BIOPHARMA jointly filed a patent application WO2019099524A1, which discloses a series of compounds that irreversibly inhibit the activity of KRAS G12C, such as MRTX849, whose structure is shown below. It is currently in Phase III clinical trials.

[0006]

[0007] Although some progress has been made in this field, there is still a need to continue developing effective, stable, and safe small-molecule KRAS G12C inhibitors for the treatment of diseases mediated by KRAS G12C mutations, such as cancer. Summary of the Invention

[0008] The technical problem to be solved by this invention is the lack of structural diversity in existing KRAS G12C inhibitors. This invention provides a pentacyclic heterocyclic compound, its preparation method, and its applications. The pentacyclic heterocyclic compound of this application exhibits activity in inhibiting the proliferation of Ba / F3 KRAS-G12C cells, NCI-H358 cells, and MIA PaCa-2 cells expressing the KRAS G12C mutant protein, and also shows good inhibitory effects on the growth of subcutaneous xenograft tumors in the NCI-H358 nude mouse cell line.

[0009] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0010] This invention provides a compound as shown in Formula I, a pharmaceutically acceptable salt thereof, or a solvate thereof;

[0011]

[0012] X is O, S, SO, SO2 or NR8;

[0013] Y is CH or does not exist;

[0014] Z is 0 or does not exist;

[0015] X1 is CH, CR7, or N;

[0016] Y1 is CH, CR7, or N;

[0017] A is Or -SO2-(CH2) q NR 11 R 12 ;

[0018] Each R1 is independently for deuterium and C. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy groups, C substituted with one or more deuterium groups 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocycloalkyl, 3-7 membered heterocycloalkenyl, C substituted with one or more cyano groups 1-6 Alkyl, oxo (=O), cyano, halogen, C 2-6 alkenyl, C 2-6 alkynyl group, -C(O)NR 11 R 12 -NR 11 R 12 -C(O)OR 13 -C(O)R 13Or, the two R1 atoms together with the attached atoms form a 3-6 membered cycloalkyl, a 3-6 membered cycloalkenyl, a 3-7 membered heterocycloalkyl, or a 3-7 membered heterocycloalkenyl;

[0019] R2 and R3 are each independently C 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, H, deuterium, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl, 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, or R2, R3 together with the attached atoms to form a 3-7-membered heterocyclic alkyl, 3-7-membered heterocyclic alkenyl, or 5-6-membered heteroaryl; wherein the 3-12-membered heterocyclic alkyl, 3-12-membered heterocyclic alkenyl, 3-7-membered heterocyclic alkyl, 3-7-membered heterocyclic alkenyl, or 5-6-membered heteroaryl is optionally composed of 1-3 (e.g., 1, 2, or 3) atoms, each independently selected from halogens, C 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12 -OH, C substituted with one or more hydroxyl groups 1-6 Alkyl and -C 1-6 Substituents of alkylene-NH2, wherein the substituents are the same or different when there are 2 or 3 substituents;

[0020] Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C atoms substituted with one or more deuterium atoms 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups or 3-7 membered heterocyclic alkenyl groups;

[0021] R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) selected from C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12-OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Alkyne group, C substituted with one or more hydroxyl groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 Substitution with 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, 3-7 membered heterocycloalkyl and 3-7 membered heterocycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0022] Each R5 is independently H, deuterium, halogen, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0023] Each R6 is independently H, deuterium, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 -NR 11 R 12 3-7 membered heterocyclic alkyl, 3-7 membered heterocyclic alkenyl, 3-7 membered heterocyclic alkyl-substituted C 1-6 C-substituted alkyl or 3-7 membered heterocyclic alkenyl groups 1-6 Alkyl; wherein the 3-7 membered heterocyclic alkyl or 3-7 membered heterocyclic alkenyl group is optionally halogenated or C 1-6 Alkyl substitution;

[0024] Each R7 is independently halogen, -CN, C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group or C group substituted with one or more halogens 1-6 Alkoxy;

[0025] R 7A H, halogen, -CN, C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group or C group substituted with one or more halogens 1-6 Alkoxy;

[0026] R8 represents H and C. 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0027] Each R 13 H and C independently 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group or C group substituted with one or more halogens 1-6 alkyl;

[0028] n is 0, 1, 2, 3, 4, 5, 6 or 7;

[0029] q can be 0, 1, 2, or 3;

[0030] When the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0031] In the compounds of Formula I, their pharmaceutically acceptable salts, or their solvates, when Y is absent, R2 bonded to Y is also absent, and simultaneously, the two adjacent cyclic atoms bonded to Y (X and Direct bonding.

[0032] The absence of Z in the compounds represented by Formula I, their pharmaceutically acceptable salts, or their solvates means... It is a methylene group.

[0033] In a preferred embodiment of the present invention, certain groups in the compound represented by Formula I, its pharmaceutically acceptable salt or its solvate are defined as follows, and the definitions of groups not mentioned are the same as those in any other embodiment of this application (hereinafter referred to as "in a preferred embodiment of the present invention"): X is O, S, SO or SO2, preferably O, SO or SO2, more preferably O.

[0034] In a preferred embodiment of the present invention: Y is CH.

[0035] In a preferred embodiment of the present invention: Z is 0.

[0036] In a preferred embodiment of the present invention: X1 is CR7 or N.

[0037] In a preferred embodiment of the present invention: X1 is CH or CR7, preferably CR7; when X1 is CR7, R7 is preferably halogen, more preferably chlorine or fluorine, more preferably chlorine.

[0038] In a preferred embodiment of the present invention: Y1 is CR7 or N.

[0039] In a preferred embodiment of the present invention: Y1 is CH or CR7, preferably CR7; when Y1 is CR7, R7 is preferably halogen, more preferably chlorine or fluorine, more preferably fluorine.

[0040] In a preferred embodiment of the invention: each R7 is independently halogen or -CN.

[0041] In a preferred embodiment of the present invention: R 7A For H.

[0042] In a preferred embodiment of the present invention: the heteroatoms in the heterocyclic alkyl, heterocyclic alkenyl or heteroaryl groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4.

[0043] In a preferred embodiment of the present invention: A is Preferred

[0044] In a preferred embodiment of the invention: each R5 is independently H, deuterium or halogen, preferably H or halogen, more preferably H or fluorine.

[0045] In a preferred embodiment of the present invention: each R6 is independently H, deuterium, halogen, or C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 Alkyl groups, preferably H or C substituted with one or more halogens. 1-6 Alkyl, more preferably H or monofluoromethyl.

[0046] In a preferred embodiment of the present invention: each R1 is independently C 1-6 Alkyl group, preferably methyl group.

[0047] In a preferred embodiment of the present invention: R2 or R3 are each independently H, deuterium, and C. 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl, 3-12-membered heterocyclic alkyl, or 3-12-membered heterocyclic alkenyl; wherein the 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl is optionally composed of 1-3 (e.g., 1, 2, or 3) individuals, each independently selected from C10. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different.

[0048] In a preferred embodiment of the present invention: R2 or R3 are each independently H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 3-12 membered heterocyclic alkyl groups, surrounded by one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl.

[0049] In a preferred embodiment of the present invention: R2 or R3 are each independently H and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 , by one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl.

[0050] In a preferred embodiment of the present invention: R2 or R3 are each independently H and C. 1-6 Alkyl group, with one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or -C 1-6 Alkylene-NR 11 R 12 .

[0051] In a preferred embodiment of the present invention: R2 is H, deuterium, or C. 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl, 3-12-membered heterocyclic alkyl, or 3-12-membered heterocyclic alkenyl; wherein the 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl is optionally composed of 1-3 (e.g., 1, 2, or 3) individuals, each independently selected from C10. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different.

[0052] In a preferred embodiment of the present invention: R3 is H, deuterium, or C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 Or by one or more (e.g., 2 or 3) C1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups.

[0053] In a preferred embodiment of the present invention: R3 is H, deuterium, or -C. 1-6 Alkylene-NR 11 R 12 .

[0054] In a preferred embodiment of the present invention: R3 is H or deuterium.

[0055] In a preferred embodiment of the present invention: R2 or R3 are each independently H and C. 1-6 Alkyl, deuterium, C substituted with one or more deuterium atoms 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 3-12 membered heterocyclic alkyl groups, surrounded by one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, preferably H or C 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 , by one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 Alkyl groups, more preferably H or C 1-6 Alkyl group, with one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or -C 1-6 Alkylene-NR 11 R 12 Preferably, R2 or R3 is independently H, methyl,

[0056] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, it forms a 3-7 membered heterocyclic alkyl group, preferably H, methyl, CD3, or R. 11 R 12 Formed together with the adjacent atoms

[0057] In a preferred embodiment of the present invention: R4 is a 6-10 aryl group or a 5-10 heteroaryl group; the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) elements selected from C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-7-membered heterocyclic alkyl, 3-7-membered heterocyclic alkenyl, 3-6-membered cycloalkyl, and 3-6-membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution.

[0058] In a preferred embodiment of the present invention: R4 is a 6-10 aryl group or a 5-10 heteroaryl group; the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) elements selected from C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution.

[0059] In a preferred embodiment of the present invention: R4 is a 6-10 aryl or a 5-10 heteroaryl; the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R12 -OH, halogen, C 2-6 alkenyl, C 2-6 Substitution of alkynyl and 3-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution.

[0060] In a preferred embodiment of the present invention: R4 is a 6-10 aryl or a 5-10 heteroaryl; the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl, amino, -OH, C 2-6 Alkyne and halogen substituents; wherein the C 1-6 Alkyl groups are optionally -CN or C 2-6 Alkyne substitution.

[0061] In a preferred embodiment of the present invention: R4 is a 6-10 aryl group or a 5-10 heteroaryl group, wherein the aryl or heteroaryl group is optionally surrounded by 1-5 groups selected from amino, -OH, fluorine, chlorine, methyl, difluoromethyl, etc. Ethyl, trifluoromethyl, Substitution with methoxy groups.

[0062] In a preferred embodiment of the present invention: R4 is a 6-10 aryl or a 5-10 heteroaryl, wherein the aryl or heteroaryl is optionally substituted by 1-5 substituents selected from amino, -OH, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl and methoxy.

[0063] In a preferred embodiment of the present invention: R4 is a 10-membered aryl or a 9-10-membered heteroaryl; the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) elements selected from C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C2-6 Alkyne substitution.

[0064] In a preferred embodiment of the present invention: R4 is a 6-10 aryl or a 5-10 heteroaryl; the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl, C 2-6 Substituents of the alkynyl group and 3-7 membered heterocyclic alkyl groups, preferably optionally 1-5 selected from C10 and C20. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Substitution with alkyl, amino, -OH and halogen substituents, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; preferably, the aryl or heteroaryl group is optionally replaced by 1-5 groups selected from amino, hydroxyl, fluorine, chlorine, methyl, difluoromethyl, ... Ethyl, trifluoromethyl, The methoxy group is substituted, preferably optionally substituted with 1 to 5 substituents selected from amino, hydroxy, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl and methoxy.

[0065] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl; the aryl or heteroaryl group is optionally selected from -NR by 1-5 of them. 11 R 12 When the substituent is replaced, the R 11 Preferably, H, wherein R 12 H is preferred.

[0066] In a preferred embodiment of the present invention: R4 is preferred.

[0067] In a preferred embodiment of the present invention, n is 0, 1 or 2, preferably 0 or 1.

[0068] In a preferred embodiment of the present invention: when R1 is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being preferred.

[0069] In a preferred embodiment of the present invention: when R2 or R3 is independently C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0070] In a preferred embodiment of the present invention: when R2 or R3 is independently C 1-6 When alkyl, the C 1-6 The alkyl group is methyl.

[0071] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, the C mentioned 1-6 The alkylene group is methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, sec-butylene, or tert-butylene, and may be methylene, ethylene, propylene, isopropylene, butylene, isobutylene, or tert-butylene, more preferably methylene.

[0072] In a preferred embodiment of the present invention: when R 11 Or R 12 Each independently is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being preferred.

[0073] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each independently is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being preferred.

[0074] In a preferred embodiment of the present invention: when R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl groups are used, the plurality of groups is preferably two or three.

[0075] In a preferred embodiment of the present invention: when R 11 Or R 12Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being more preferred.

[0076] In a preferred embodiment of the present invention: when R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 Alkyl groups, preferably two or three, wherein the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being a more preferred choice. The C group is substituted with a plurality of deuterium groups. 1-6 The alkyl group is CD3.

[0077] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl groups are used, the plurality of groups is preferably two or three.

[0078] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being more preferred.

[0079] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the plurality is preferably two or three, and the C 1-6The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, more preferably methyl, wherein the C group is substituted with a plurality of deuterium groups. 1-6 Alkyl groups are preferably CD3.

[0080] In a preferred embodiment of the present invention: when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the 3-7 membered heterocyclic alkyl group is a monocyclic, bicyclic, or tricyclic alkyl group.

[0081] In a preferred embodiment of the present invention: when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the 3-7 membered heterocyclic alkyl group is a spirocyclic or bridged ring.

[0082] In a preferred embodiment of the present invention: when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atom, the 3-7 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group.

[0083] In a preferred embodiment of the present invention: when R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atom, the heteroatom in the 3-7 membered heterocyclic alkyl group is N.

[0084] In a preferred embodiment of the present invention: when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the number of heteroatoms in the 3-7 membered heterocyclic alkyl group is 1 or 2.

[0085] In a preferred embodiment of the present invention: when R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atom, the 3-7 membered heterocyclic alkyl group is preferably a tetrahydropyrrole group.

[0086] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the 3-7 membered heterocyclic alkyl group is a monocyclic, bicyclic, or tricyclic alkyl group.

[0087] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6Alkylene-NR 11 R 12 R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the 3-7 membered heterocyclic alkyl group is a spirocyclic or bridged ring.

[0088] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atom, the 3-7 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group.

[0089] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atom, the heteroatom in the 3-7 membered heterocyclic alkyl group is N.

[0090] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the number of heteroatoms in the 3-7 membered heterocyclic alkyl group is 1 or 2.

[0091] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atom, the 3-7 membered heterocyclic alkyl group is preferably a tetrahydropyrrole group.

[0092] In a preferred embodiment of the present invention: when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, the C mentioned 1-6 The alkylene group is methylene, ethylene, propylene, isopropylene, butylene, isobutylene, or tert-butylene, preferably methylene, wherein the -C 1-6 Alkylene-NR 11 R 12 Preferred

[0093] In a preferred embodiment of the invention: when R2 or R3 is independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl groups are used, the plurality of groups is preferably two or three.

[0094] In a preferred embodiment of the invention: when R2 or R3 is independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being preferred.

[0095] In a preferred embodiment of the invention: when R2 or R3 is independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl, the plurality of preferred compounds are two or three, and the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and is also preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl.

[0096] In a preferred embodiment of the invention: when R2 or R3 is independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl, the plurality of preferred compounds are two or three, and the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being preferred.

[0097] In a preferred embodiment of the invention: when R2 or R3 is each independently a C substituted with a hydroxyl group. 1-6 When alkyl, the C substituted with one hydroxyl group 1-6 Alkyl is

[0098] In a preferred embodiment of the present invention: when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is a monocyclic, bicyclic or tricyclic.

[0099] In a preferred embodiment of the present invention: when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is a spirocyclic or bridged ring.

[0100] In a preferred embodiment of the present invention: when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group.

[0101] In a preferred embodiment of the present invention: when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the heteroatom in the 3-12 membered heterocyclic alkyl group is N.

[0102] In a preferred embodiment of the present invention: when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the number of heteroatoms in the 3-12 membered heterocyclic alkyl group is 1 or 2.

[0103] In a preferred embodiment of the present invention: when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group, preferably tetrahydropyrrole, more preferably tetrahydropyrrole. (For example ).

[0104] In a preferred embodiment of the present invention: when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, C 1-6 The number of alkyl groups is preferably one, two, or three.

[0105] In a preferred embodiment of the present invention: when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and even more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being the most preferred.

[0106] In a preferred embodiment of the present invention: when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, C 1-6 The number of alkyl groups is preferably one, two, or three, wherein the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being a more preferred choice. The 3-12 membered heterocyclic alkyl group is preferably a 3-6 membered heterocyclic alkyl group, with tetrahydropyrrole being a more preferred choice. C 1-6 Alkyl-substituted 3-12 membered heterocyclic alkyl groups are preferred.

[0107] In a preferred embodiment of the present invention: R2 or R3 is each independently hydrogen, methyl,

[0108] In a preferred embodiment of the present invention: R2 is hydrogen, methyl, R3 is hydrogen or

[0109] In a preferred embodiment of the present invention: R2 is hydrogen, methyl, R3 is hydrogen.

[0110] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl group, the 6-10 aryl group is phenyl or naphthyl, preferably phenyl. Phenyl or More preferably, phenyl.

[0111] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl group, the 6-10 aryl group does not fuse with cycloalkyl or heterocyclic groups.

[0112] In a preferred embodiment of the present invention: when R4 is a 5-10 member heteroaryl group, the 5-10 member heteroaryl group is a monocyclic or bicyclic group.

[0113] In a preferred embodiment of the present invention: when R4 is a 5-10 member heteroaryl group, the 5-10 member heteroaryl group does not fuse with cycloalkyl or heterocyclic groups.

[0114] In a preferred embodiment of the present invention: when R4 is a 5-10 heteroaryl group, the 5-10 heteroaryl group is a 9-10 heteroaryl group.

[0115] In a preferred embodiment of the present invention: when R4 is a 5-10 member heteroaryl group, the heteroatom in the 5-10 member heteroaryl group is one or more of N, O and S.

[0116] In a preferred embodiment of the present invention: when R4 is a 5-10 member heteroaryl group, the number of heteroatoms in the 5-10 member heteroaryl group is 1 or 2.

[0117] In a preferred embodiment of the present invention: when R4 is a 5-10 member heteroaryl group, the 5-10 member heteroaryl group is pyridyl, pyrazolyl, benzothiazolyl, indazole, benzoxazolyl, indolyl, benzimidazolyl, benzofuranyl, or quinolinyl, and may also be pyridyl, pyrazolyl, benzothiazolyl, indazole, benzoxazolyl, indolyl, benzimidazolyl, or quinolinyl, preferably.

[0118] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from C 1-6 When the alkyl group is substituted, the C 1-6The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and may be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl or ethyl being preferred.

[0119] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from C 1-6 When the alkoxy group is substituted, the C 1-6 The alkoxy group can be methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, or it can also be methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, with methoxy being preferred.

[0120] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine.

[0121] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the plurality of groups is preferably two or three.

[0122] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and even more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being the most preferred.

[0123] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine; the plurality of halogens is preferably two or three; and the C... 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and even more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being a more preferred alkyl group. The C group is substituted with multiple halogens. 1-6 The alkyl group is preferably difluoromethyl or trifluoromethyl.

[0124] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkoxy groups are used as substituents, the halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine.

[0125] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkoxy groups are substituents, two or three are preferred.

[0126] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkoxy groups are substituents, the C 1-6 The alkoxy group is preferably methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, and even more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, and more preferably methoxy or ethoxy.

[0127] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkoxy groups are substituents, the halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine; the plurality of halogens is preferably two or three; and the C... 1-6 The alkoxy group is preferably methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy, more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy, and even more preferably methoxy or ethoxy. The C group is substituted with multiple halogens. 1-6 The alkoxy group is preferably difluoromethoxy, trifluoromethoxy, or trifluoroethoxy.

[0128] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from -NR. 11 R 12 When the substituent is replaced, the R 11 Or R 12 H is preferred.

[0129] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, and the aryl or heteroaryl is substituted by a substituent selected from halogens, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0130] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from C 2-6 When the alkenyl group is substituted, the C 2-6 The alkenyl group is vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-isobutenyl or 2-isobutenyl, preferably vinyl.

[0131] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from C 2-6 When the alkynyl group is substituted, the C 2-6 The alkynyl group is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl, or 2-isobutynyl.

[0132] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from C 2-6 When the alkynyl group is substituted, the C 2-6 The alkynyl group is an acetylenic group.

[0133] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more hydroxyl groups. 1-6 When alkyl groups are used, the plurality of groups can be two or three.

[0134] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more hydroxyl groups. 1-6 When alkyl, the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and even more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being the most preferred.

[0135] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more hydroxyl groups. 1-6 When alkyl, the plurality is two or three, and the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and even more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being the most preferred.

[0136] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more hydroxyl groups. 1-6 When alkyl, the C substituted with one or more hydroxyl groups1-6 The alkyl group is hydroxymethyl.

[0137] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl substituent substitution, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are -CN or C 2-6 When alkynyl is substituted, the C 2-6 The alkynyl group is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl or 2-isobutynyl, preferably ethynyl.

[0138] In a preferred embodiment of the present invention: when R4 is a 6-10 aryl or a 5-10 heteroaryl, the aryl or heteroaryl is selected from C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl substituent substitution, C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are -CN or C 2-6 When alkynyl is substituted, the C 2-6 The alkynyl group is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl, or 2-isobutynyl, preferably ethynyl, with the C group substituted by -CN. 1-6 Alkyl preferred C replaced by -CN 2-6 Alkenyl preferred C 2-6 alkynyl-substituted C 1-6 Alkoxy groups are preferred. C replaced by -CN 1-6 Alkoxy groups are preferred.

[0139] In a preferred embodiment of the present invention: R4 is

[0140] In a preferred embodiment of the present invention: when R5 is a halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0141] In a preferred embodiment of the present invention: when R6 is a halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0142] In a preferred embodiment of the present invention: when R6 is a C substituted with one or more halogens... 1-6When alkyl groups are used, the plurality of groups is preferably two or three.

[0143] In a preferred embodiment of the present invention: when R6 is a C substituted with one or more halogens... 1-6 When the halogen is alkyl, the halogen is preferably fluorine, chlorine, bromine or iodine, more preferably fluorine.

[0144] In a preferred embodiment of the present invention: when R6 is a C substituted with one or more halogens... 1-6 When alkyl, the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and even more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl, with methyl being the most preferred.

[0145] In a preferred embodiment of the present invention: when R6 is a C substituted with one or more halogens... 1-6 When alkyl, the plurality of alkyl groups is preferably two or three; the halogen is preferably fluorine, chlorine, bromine, or iodine, more preferably fluorine; the C 1-6 The alkyl group is preferably methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl, and more preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; the C group is substituted with one halogen. 1-6 Alkyl groups are preferably monofluoromethyl groups.

[0146] In a preferred embodiment of the present invention: when R7 is a halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0147] In a preferred embodiment of the present invention: when R7 in X1 is a halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

[0148] In a preferred embodiment of the present invention: when R7 in Y1 is a halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine.

[0149] In a preferred embodiment of the present invention: when R 7A When the halogen is halogen, the halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine, and even more preferably fluorine.

[0150] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-6 membered cycloalkyl group is a monocyclic ring.

[0151] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R12 and R 13 In this context, the 3-6 membered cyclic alkenyl group is a monocyclic ring.

[0152] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-6 membered cycloalkenyl group contains only one or two double bonds.

[0153] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-7 membered heterocyclic alkyl group is a monocyclic, bicyclic, or tricyclic alkyl group.

[0154] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-7 membered heterocyclic alkyl group is a monocyclic alkyl group.

[0155] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-7 membered heterocyclic alkyl group is a spirocyclic or bridged ring.

[0156] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-12 membered heterocyclic alkyl group is a monocyclic, bicyclic, or tricyclic alkyl group.

[0157] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-12 membered heterocyclic alkyl group is a monocyclic alkyl group.

[0158] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12and R 13 In this context, the 3-12 membered heterocyclic alkyl group is a spirocyclic or bridged ring.

[0159] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-7 membered heterocyclic alkenyl group is a monocyclic, bicyclic, or tricyclic ring.

[0160] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-7 membered heterocyclic alkenyl group is a monocyclic compound.

[0161] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-7 membered heterocyclic alkenyl group is a spirocyclic or bridged ring.

[0162] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-7 membered heterocyclic alkenyl group contains only one or two double bonds.

[0163] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-12 membered heterocyclic alkenyl group is a monocyclic, bicyclic, or tricyclic ring.

[0164] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-12 membered heterocyclic alkenyl group is a monocyclic compound.

[0165] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R13 In this context, the 3-12 membered heterocyclic alkenyl group is a spirocyclic or bridged ring.

[0166] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 3-12 membered heterocyclic alkenyl group contains only one or two double bonds.

[0167] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 6-10 aryl group is either monocyclic or bicyclic.

[0168] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 6-10 aryl groups do not fuse with cycloalkyl or heterocyclic groups.

[0169] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 5-6 membered heteroaryl group is a monocyclic compound.

[0170] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 5-6 membered heteroaryl group does not fuse with cycloalkyl or heterocyclic groups.

[0171] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R 13 In this context, the 5-10 member heteroaryl group is either monocyclic or bicyclic.

[0172] In a preferred embodiment of the present invention: R1, R2, R3, R4, R5, R6, R7, R 7A R8, R 11 R 12 and R13 In this context, the 5-10 membered heteroaryl groups do not fuse with cycloalkyl or heterocyclic groups.

[0173] In a preferred embodiment of the present invention: except for specially indicated isotopic atoms (such as deuterium), all atoms are atoms of the element at their natural abundance, that is, a mixture of isotopes at their natural abundance.

[0174] In a preferred embodiment of the present invention, the compound represented by Formula I is any of the following:

[0175] Option 1:

[0176] X is O, S, SO or SO2;

[0177] Z is O;

[0178] A is

[0179] R1 is C 1-6 alkyl;

[0180] R2 or R3 are independently H and C. 1-6 Alkyl, deuterium, C substituted with one or more deuterium atoms 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 3-12 membered heterocyclic alkyl groups, surrounded by one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl;

[0181] When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups;

[0182] R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl, C2-6 Substitution of alkynyl and 3-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0183] R5 is H, deuterium, or halogen;

[0184] R6 is H, deuterium, halogen, or C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0185] X1 is CH or CR7, and R7 is a halogen;

[0186] Y1 is CH or CR7, and R7 is a halogen;

[0187] R 7A For H;

[0188] n is 0 or 1;

[0189] Option 2:

[0190] X is O, SO, or SO2;

[0191] Z is O;

[0192] A is

[0193] R1 is C 1-6 alkyl;

[0194] R2 or R3 are independently H and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 , by one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl;

[0195] When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups;

[0196] R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl, C 2-6 Substitution of alkynyl and 3-7 membered heterocyclic alkyl groups, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0197] R5 is H or halogen;

[0198] R6 is H or C substituted with one or more halogens. 1-6 alkyl;

[0199] X1 is CR7, and R7 is halogen;

[0200] Y1 is CR7, and R7 is halogen;

[0201] n is 0 or 1;

[0202] Option 3:

[0203] X is O;

[0204] Y represents CH;

[0205] Z is O;

[0206] A is

[0207] R1 is C 1-6 alkyl;

[0208] R2 or R3 are independently H and C. 1-6 Alkyl group, with one or more (e.g., 2 or 3) C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or -C 1-6 Alkylene-NR 11 R 12 ;

[0209] When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups;

[0210] R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Substitution with alkyl, amino, -OH and halogen groups; wherein the C 1-6 Alkyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0211] R5 is H or halogen;

[0212] R6 is H or C substituted with one or more halogens. 1-6 alkyl;

[0213] X1 is CR7, and R7 is halogen;

[0214] Y1 is CR7, and R7 is halogen;

[0215] n is 0 or 1;

[0216] Option 4:

[0217] X is O, SO, or SO2;

[0218] Z is O;

[0219] A is

[0220] R1 is a methyl group;

[0221] R2 or R3 are each independently H, methyl,

[0222] R4 is a 6-10 aryl group or a 5-10 heteroaryl group, wherein the aryl or heteroaryl group is optionally surrounded by 1-5 groups selected from amino, hydroxyl, fluorine, chloro, methyl, difluoromethyl, etc. Ethyl, trifluoromethyl, Substitution with methoxy groups;

[0223] R5 is H or fluorine;

[0224] R6 is H or a monofluoromethyl group;

[0225] X1 is CR7, and R7 is chlorine;

[0226] Y1 is CR7, and R7 is fluorine;

[0227] n is 0 or 1;

[0228] Option 5:

[0229] X is O, SO, or SO2;

[0230] Z is O;

[0231] A is

[0232] R1 is a methyl group;

[0233] R2 or R3 are each independently H, methyl,

[0234] R4 is

[0235] R5 is H or fluorine;

[0236] R6 is H or a monofluoromethyl group;

[0237] X1 is CR7, and R7 is chlorine;

[0238] Y1 is CR7, and R7 is fluorine;

[0239] n is 0 or 1;

[0240] Option Six:

[0241] X is O;

[0242] Y represents CH;

[0243] Z is O;

[0244] A is

[0245] R1 is a methyl group;

[0246] R2 or R3 are each independently H, methyl,

[0247] R4 is

[0248] R5 is H or fluorine;

[0249] R6 is H or a monofluoromethyl group;

[0250] X1 is CR7, and R7 is chlorine;

[0251] Y1 is CR7, and R7 is fluorine;

[0252] n is 0 or 1;

[0253] Option Seven:

[0254] X is O, S, SO or SO2;

[0255] Y is CH or does not exist;

[0256] Z is O;

[0257] X1 is CH, CR7, or N;

[0258] Y1 is CH, CR7, or N;

[0259] A is

[0260] Each R1 is independently C 1-6 alkyl;

[0261] R2 and R3 are independently H, deuterium, and C, respectively. 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl, 3-12-membered heterocyclic alkyl, or 3-12-membered heterocyclic alkenyl; wherein the 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl is optionally composed of 1-3 (e.g., 1, 2, or 3) individuals, each independently selected from C10. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different;

[0262] Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups or 3-7 membered heterocyclic alkenyl groups;

[0263] R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) selected from C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-7-membered heterocyclic alkyl, 3-7-membered heterocyclic alkenyl, 3-6-membered cycloalkyl, and 3-6-membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0264] Each R5 is independently H, deuterium, halogen, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0265] Each R6 is independently H, deuterium, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0266] Each R7 is independently either halogenated or -CN;

[0267] R 7A For H;

[0268] n is 0, 1, or 2;

[0269] Option 8:

[0270] X is O, S, SO or SO2;

[0271] Y represents CH;

[0272] Z is O;

[0273] X1 is either CR7 or N;

[0274] Y1 is either CR7 or N;

[0275] A is

[0276] Each R1 is independently C 1-6 alkyl;

[0277] R2 is H, deuterium, a 3-12-membered heterocyclic alkyl group, or a 3-12-membered heterocyclic alkenyl group; wherein the 3-12-membered heterocyclic alkyl group or the 3-12-membered heterocyclic alkenyl group is optionally selected by 1-3 (e.g., 1, 2, or 3) individuals, each independently selected from C. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different;

[0278] R3 is H, deuterium, a 3-12 membered heterocyclic alkyl group, or a 3-12 membered heterocyclic alkenyl group; wherein the 3-12 membered heterocyclic alkyl group or the 3-12 membered heterocyclic alkenyl group is optionally selected by 1-3 (e.g., 1, 2, or 3) individuals, each independently selected from C. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different;

[0279] Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups or 3-7 membered heterocyclic alkenyl groups;

[0280] R4 is a 10-membered aryl or a 9-10-membered heteroaryl; the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) elements selected from C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0281] Each R5 is independently H, deuterium, halogen, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0282] Each R6 is independently H, deuterium, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0283] Each R7 is independently either halogenated or -CN;

[0284] R 7A For H;

[0285] n is 0, 1, or 2;

[0286] Option Nine:

[0287] X is O, S, SO or SO2;

[0288] Y is CH or does not exist;

[0289] Z is O;

[0290] X1 is either CR7 or N;

[0291] Y1 is either CR7 or N;

[0292] A is

[0293] Each R1 is independently C 1-6 alkyl;

[0294] R2 and R3 are independently H, deuterium, and C, respectively. 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl, 3-12-membered heterocyclic alkyl, or 3-12-membered heterocyclic alkenyl; wherein the 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl is optionally composed of 1-3 (e.g., 1, 2, or 3) individuals, each independently selected from C10. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different;

[0295] Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups or 3-7 membered heterocyclic alkenyl groups;

[0296] R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) selected from C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0297] Each R5 is independently H, deuterium, halogen, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0298] Each R6 is independently H, deuterium, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0299] Each R7 is independently either halogenated or -CN;

[0300] R 7A For H;

[0301] n is 0, 1, or 2;

[0302] Option 10:

[0303] X is O, S, SO or SO2;

[0304] Y is CH or does not exist;

[0305] Z is O;

[0306] X1 is either CR7 or N;

[0307] Y1 is either CR7 or N;

[0308] A is

[0309] Each R1 is independently C 1-6 alkyl;

[0310] R2 represents H, deuterium, and C. 1-6 Alkyl, 3-6 membered cycloalkyl, 3-6 membered cycloalkenyl, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6Alkyl, 3-12-membered heterocyclic alkyl, or 3-12-membered heterocyclic alkenyl; wherein the 3-12-membered heterocyclic alkyl or 3-12-membered heterocyclic alkenyl is optionally composed of 1-3 (e.g., 1, 2, or 3) individuals, each independently selected from C10. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different;

[0311] R3 is H, deuterium, or -C. 1-6 Alkylene-NR 11 R 12 ;

[0312] Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups or 3-7 membered heterocyclic alkenyl groups;

[0313] R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) selected from C 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0314] Each R5 is independently H, deuterium, halogen, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0315] Each R6 is independently H, deuterium, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0316] Each R7 is independently either halogenated or -CN;

[0317] R 7A For H;

[0318] n is 0, 1, or 2;

[0319] Option 11:

[0320] X is O, S, SO or SO2;

[0321] Y represents CH;

[0322] Z is O;

[0323] X1 is either CR7 or N;

[0324] Y1 is either CR7 or N;

[0325] A is

[0326] Each R1 is independently C 1-6 alkyl;

[0327] R2 is a 3-12-membered heterocyclic alkyl group or a 3-12-membered heterocyclic alkenyl group; wherein the 3-12-membered heterocyclic alkyl group or the 3-12-membered heterocyclic alkenyl group is optionally composed of 1-3 (e.g., 1, 2 or 3) individuals, each independently selected from C10. 1-6 Alkyl groups and C groups substituted with one or more deuterium atoms 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different;

[0328] R3 is H, deuterium, or -C. 1-6 Alkylene-NR 11 R 12 ;

[0329] Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups or 3-7 membered heterocyclic alkenyl groups;

[0330] R4 is a 10-membered aryl or a 9-10-membered heteroaryl; the aryl or heteroaryl group is optionally composed of 1-5 (e.g., 1, 2, 3, 4 or 5) elements selected from C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl groups, C substituted with one or more halogens1-6 Alkoxy, -NR 11 R 12 -OH, halogens, -CN, C 2-6 alkenyl, C 2-6 Substitution of alkynyl, 3-6 membered cycloalkyl and 3-6 membered cycloalkenyl groups, wherein the number of substituents is 2-5, and the substituents may be the same or different; wherein the C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution;

[0331] Each R5 is independently H, deuterium, halogen, C 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0332] Each R6 is independently H, deuterium, halogen, C 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl;

[0333] Each R7 is independently either halogenated or -CN;

[0334] R 7A For H;

[0335] n is 0, 1, or 2.

[0336] In a preferred embodiment of the present invention, the compound represented by Formula I has any of the following structures:

[0337]

[0338]

[0339] Among them, X, Y, Z, X1, Y1, R1, R2, R3, R4, R5, R6, A, n and R 7A As defined above, when a carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0340] In a preferred embodiment of the present invention, the compound represented by Formula I is any of the following compounds:

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356] (In the above compounds, with For example, for (mixture)

[0357] In a preferred embodiment of the present invention, the compound represented by Formula I is any of the following compounds:

[0358] The retention time is 2.758 min or 3.990 min under the following conditions.

[0359] Column: Chiralcel OD-3 100*4.6mm ID, 3μm; Mobile phase: A: CO2 B: Ethanol (0.05% DEA), isocratic elution: 40% B; Flow rate: 2.8mL / min; Column temperature: 35℃; ABPR: 1500psi;

[0360] The retention time is 0.916 min or 1.260 min under the following conditions.

[0361] Column: Chiralcel OD-3 50*4.6mm ID, 3μm; Mobile phase: A: CO2 B: Methanol (0.05% DEA), isocratic elution: 40% B; Flow rate: 4mL / min; Column temperature: 35℃; ABPR: 1500psi;

[0362] The retention time is 4.997 min or 2.350 min under the following conditions. Column: DAIICEL CHIRALPAK IG (250mm*30mm, 10μm); Mobile phase A: 0.1% NH3H2O, Mobile phase B: Ethanol; Mobile phase B%: 60%-60%;

[0363] The retention time is 7.281 min or 6.252 min under the following conditions.

[0364] Column: Chiralpak AD-3 150*4.6mm ID, 3μm; Mobile phase: A: CO2, B: Isopropanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 5 minutes), then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0365] The retention time is 2.761 min or 2.201 min under the following conditions.

[0366] Column: Diamonsil C18 150*30mm*5μm; Mobile phase A: Water (0.05% ammonia hydroxide v / v), Mobile phase B: ACN; Mobile phase B %: 26%-66%, 9min;

[0367] The retention time is 6.323 min or 3.391 min under the following conditions.

[0368] Column: Chiralpak AD-3 150*4.6mm ID, 3μm; Mobile phase: 40% of ethanol (0.05% DEA) in CO2; Flow rate: 2.5mL / min; Column temperature: 35℃; ABPR: 1500psi;

[0369] The retention time is 2.152 min or 3.090 min under the following conditions.

[0370] Column: DAIICEL CHIRALPAK AD (250mm*30mm, 10μm); Mobile phase A: 0.1% NH3H2O, Mobile phase B: IPA;

[0371] Mobile phase B%: 50%-50%;

[0372] The retention time is 1.848 min or 3.799 min under the following conditions.

[0373] Column: ChiralPak AD-3 150×4.6mm ID, 3μm; Mobile phase: 40% of ethanol (0.05% DEA) in CO2; Flow rate: 2.5 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0374] The retention time is 0.660 min or 1.016 min under the following conditions.

[0375] Column: Chiralpak AD-3 50*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA), isocratic elution: 40% B; Column temperature: 35℃; ABPR: 1500psi;

[0376] The retention time is 1.979 min or 2.457 min under the following conditions.

[0377] Column: Phenomenex Gemini-NX 80*40mm*3μm; Mobile phase A: Water (0.05% ammoniahydroxide v / v), Mobile phase B: ACN; Mobile phase B %: 36%-76%, 9min;

[0378] The retention time is 1.489 min or 0.706 min under the following conditions.

[0379] Column: Chiralpak AD-3 150*4.6mm ID, 3μm; Mobile phase: A: CO2 B: ethanol (0.05% DEA) isocratic elution: 40% B; Flow rate: 4mL / min; Column temperature: 35℃; ABPR: 1500psi;

[0380] The proton spectrum data are shown below. 1H NMR (400MHz, CDCl3) δ7.86(s,1H),7.37-7.28(m,1H),6.99(br dd,J=10.8,16.7Hz,1H),6.87(br d,J=8.1Hz,1H),6.78(br t,J=8.4Hz,1H),6.36(br d,J=17.0Hz,1H),5.81(br d,J=11.1Hz,1H),4.95(br s,1H),4.85-4.68(m,2H),4.24(br s,1H),3.89-3.77(m,1H),3.74(br s,1H),3.37-2.85(m,5H),2.67-2.32(m,4H),2.16-1.75(m,4H),1.68-1.61(m,3H);

[0381] The proton spectrum data are shown below. 1 H NMR (400MHz, CDCl3) δ7.79(s,1H),7.33-7.27(m,1H),7.06-6.83(m,2H),6.75(br t,J=8.6Hz,1H),6.34(br d,J=16.6Hz,1H),5.78(br d,J =10.9Hz,1H),5.48-4.87(m,1H),4.77(br t,J=12.4Hz,2H),4.28(br s,1H),3.86-3.61(m,2H),3.41-2.85(m,5H),2.70-2.40(m,4H),2.16-1.78(m,4H),1.63(br d,J=6.5Hz,3H);

[0382] The retention time is 1.238 min or 0.927 min under the following conditions.

[0383] Column: Chiralpak IG-3 50*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Isocratic elution: 40% B; Flow rate: 4mL / min; Column temperature: 35℃; ABPR: 1500psi;

[0384] The retention time is 6.729 min or 6.169 min under the following conditions.

[0385] Column: ChiralPak AD-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (over 5.5 min), then hold at 40% mobile phase B for 3 min, then hold at 5% mobile phase B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40℃; ABPR: 100 bar;

[0386] The retention time is 5.082 min or 3.099 min under the following conditions.

[0387] Column: ChiralPak AD-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2 B: ethanol (0.05% DEA) isocratic elution: 40% B; Flow rate: 2.5mL / min; Column temperature: 40℃; ABPR: 100bar;

[0388] The retention time is 5.279 min or 6.689 min under the following conditions.

[0389] Column: Phenomenex Gemini-NX 80*40mm*3μm; Mobile phase A: Water (0.05% ammoniahydroxide v / v), Mobile phase B: ACN; Mobile phase B %: 50%-90%, 9min;

[0390] The retention time is 2.463 min or 2.780 min under the following conditions.

[0391] Column: Diamonsil C18 150*30mm*5μm; Mobile phase A: Water (0.05% ammonia hydroxide v / v), Mobile phase B: ACN; Mobile phase B %: 40%-80%, 9min;

[0392] The retention time is 1.214 min or 0.744 min under the following conditions.

[0393] Column: Phenomenex Gemini 150*25mm*10μm; Mobile phase A: Water (0.05% ammoniahydroxide v / v), Mobile phase B: ACN; Mobile phase B %: 45%-85%, 9min;

[0394] The retention time is 6.803 min or 5.848 min under the following conditions.

[0395] Column: Chiralpak AD-3 150*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 5 minutes), then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0396] The retention time is 3.701 min or 3.222 min under the following conditions.

[0397] Column: Chiralcel OJ-3 100×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 4 min), then hold at 40% mobile phase B for 2.5 min, then hold at 5% mobile phase B for 1.5 min; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0398] The retention time is 1.437 min or 0.736 min under the following conditions.

[0399] Column: Chiralpak AD-3 50*4.6mm ID, 3μm; Mobile phase: A:CO2 B:ethanol (0.05% DEA); Gradient: 40% B; Flow rate: 4mL / min; Column temperature: 35℃; ABPR: 1500psi;

[0400] The retention time is 4.975 min or 5.600 min under the following conditions.

[0401] Column: Chiralcel OJ-3 100*4.6mm ID, 3μm; Mobile phase: A: CO2, B: Isopropanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 4 minutes), then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0402] The retention time is 3.456 min or 3.337 min under the following conditions.

[0403] Column: Chiralcel OJ-3 100*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 4 minutes), then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0404] The retention time is 3.645 min or 5.527 min under the following conditions.

[0405] Column: Chiralpak AS-3 100*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Flow rate: 2.8mL / min; Column temperature: 35℃; ABPR: 1500psi;

[0406] The retention time is 3.826 min or 1.706 min under the following conditions.

[0407] Column: Chiralpak AS-3 100*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 4 min), then hold at 40% mobile phase B for 2.5 min, then hold at 5% mobile phase B for 1.5 min; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 Psi;

[0408] The retention time is 4.032 min or 2.090 min under the following conditions.

[0409] Column: Chiralcel OD-3 100*4.6mm ID, 3μm; Mobile phase: A: CO2 B: Ethanol (0.05% DEA); Flow rate: 2.8mL / min; Column temperature: 35℃; ABPR: 1500Psi;

[0410] The retention time is 2.052 min or 2.580 min under the following conditions.

[0411] Column: Chiralpak AD-3 50*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 2 min), then hold at 40% mobile phase B for 1.2 min, then hold at 5% mobile phase B for 0.8 min; Flow rate: 4 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0412] The retention time is 3.536 min or 3.573 min under the following conditions.

[0413] Column: Chiralpak AS-3 100*4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol (0.05% DEA); Elution program: from 5% to 40% mobile phase B (within 4 minutes), then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35℃; ABPR: 1500 psi;

[0414] The retention time is 0.477 min or 1.927 min under the following conditions.

[0415] Column: Chiralpak AD-3 50*4.6mm ID, 3μm; Mobile phase: A: CO2 B: Ethanol (0.05% DEA) isocratic elution: 40% B; Flow rate: 4mL / min; Column temperature: 35℃; ABPR: 1500psi.

[0416] In a preferred embodiment of the present invention: the pharmaceutically acceptable salt of the compound represented by Formula I has any of the following structures:

[0417]

[0418]

[0419] The present invention also provides a method for preparing the compound shown in formula (I), comprising the following steps:

[0420] The compound shown in formula (II) is subjected to an acylation reaction with A-OH or A-Cl as shown below to give the compound shown in formula (I).

[0421]

[0422] Among them, R1, R2, R3, R4, A, Z, X1, Y1, X, Y, R 7AAs defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0423] The present invention also provides a method for preparing the compound shown in formula (II), comprising the following steps:

[0424] In the presence of an acid, the compound of formula (III) is subjected to the following deprotection reaction to give the compound of formula (II).

[0425]

[0426] Among them, R1, R2, R3, R4, Z, X1, Y1, X, Y, R 7A As defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0427] In the deprotection reaction described above, the acid can be any acid commonly used in this type of reaction in the art, preferably hydrochloric acid or trifluoroacetic acid.

[0428] The present invention also provides a method for preparing the compound shown in formula (III), comprising the following steps:

[0429] The compound shown in formula (IV) and R4-B(OH)2 are subjected to the Suzuki coupling reaction shown below to obtain the compound shown in formula (III);

[0430]

[0431] Among them, R1, R2, R3, R4, Z, X1, Y1, X, Y, R 7A As defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0432] The present invention also provides a method for preparing the compound shown in formula (IV), comprising the following steps:

[0433] When Z is 0, the compound shown in formula (IV) is

[0434] The compound shown in formula (V) was subjected to the following cyclization reaction to give the compound shown in formula (IV).

[0435]

[0436] Among them, R1, R2, R3, X1, Y1, X, Y, R 7AAs defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0437] The cyclization reaction is preferably carried out in the presence of triphenylphosphine or tributylphosphine and diisopropyl azodicarbonate or diethyl azodicarbonate.

[0438] The present invention also provides a method for preparing the compound shown in formula (V), comprising the following steps:

[0439] In the presence of an acid (a conventional acid in the art, such as hydrochloric acid) and HF, TBAF (tetrabutylammonium fluoride) or KF, the compound shown in formula (VI) undergoes the following deprotection reaction to give the compound shown in formula (V).

[0440]

[0441] Among them, R1, R2, R3, X1, Y1, X, Y, R 7A As defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0442] The present invention also provides a method for preparing the compound shown in formula (VI), comprising the following steps:

[0443] In the presence of a base, the compound shown in formula (VII) undergoes a substitution reaction with the compound shown in formula (VIII) as shown below to give the compound shown in formula (VI).

[0444]

[0445] Among them, R1, R2, R3, X1, Y1, X, Y, R 7A As defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0446] The present invention also provides a method for preparing the compound shown in formula (VII), comprising the following steps:

[0447] In the presence of a reducing agent, the compound shown in formula (IX) undergoes a reductive cyclization reaction as shown below to give the compound shown in formula (VII).

[0448]

[0449] Among them, R1, X1, Y1, R 7A As defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0450] In the reductive cyclization reaction shown, the reducing agent is preferably iron powder, zinc powder, sodium hydrosulfite, or H2 (when reducing with H2, it must be carried out in the presence of a catalyst, which is selected from palladium / carbon and Pd(OH)2 / carbon).

[0451] The method for preparing the compound as shown in formula (VII) may further include the following steps:

[0452] In the presence of a base (a conventional organic or inorganic base), the compound shown in formula (X) is subjected to the substitution reaction shown below with the compound shown in formula (XI) to give the compound shown in formula (IX).

[0453]

[0454] Among them, R1, X1, Y1, R 7A As defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0455] The method for preparing the compound as shown in formula (VII) may further include the following steps:

[0456] The compound shown in formula (XII) was subjected to the chlorination reaction shown below to give the compound shown in formula (X).

[0457]

[0458] Among them, X1, Y1 and R 7A The definition is as described above.

[0459] The method for preparing the compound as shown in formula (VII) may further include the following steps:

[0460] The compound shown in formula (XIII) was subjected to the nitration reaction shown below to give the compound shown in formula (XII).

[0461]

[0462] Among them, X1, Y1 and R 7A The definition is as described above.

[0463] The method for preparing the compound as shown in formula (VII) may further include the following steps:

[0464] In the presence of a catalyst (e.g., polyphosphoric acid, phosphorus pentoxide, or aluminum trichloride), the compound shown in formula (XIV) undergoes the following cyclization reaction to yield the compound shown in formula (XIII).

[0465]

[0466] Among them, X1, Y1 and R 7A The definition is as described above.

[0467] The method for preparing the compound as shown in formula (VII) may further include the following steps:

[0468] The compound shown in formula (XV) was subjected to an acylation reaction with isopropyl malonate as shown below to give the compound shown in formula (XIV).

[0469]

[0470] Among them, X1, Y1 and R 7A The definition is as described above.

[0471] The present invention also provides a method for preparing the compound shown in formula (I), which is route 1 or 2;

[0472] Route 1 includes the following steps:

[0473]

[0474] Where Z is O;

[0475] The reaction parameters for step 1 are as follows: Curtius rearrangement reaction;

[0476] The reaction parameters for step 2 are as follows: deprotection reaction, acidic conditions (in the presence of a conventional acid for this type of reaction in the art, such as dilute hydrochloric acid or TFA, etc.);

[0477] The reaction parameters for step 3 are as follows: iodination reaction, acidic conditions (in the presence of an acid conventional to this type of reaction in the art, such as glacial acetic acid), and iodination reaction with N-iodosuccinimide;

[0478] The reaction parameters for step 4 are as follows: carbonyl insertion reaction, palladium catalysis, alkaline conditions (in the presence of conventional organic and inorganic bases for this type of reaction in the art), carbonyl insertion reaction with CO / ethanol;

[0479] The reaction parameters for step 5 are as follows: acylation reaction, acylation reaction with monoethyl malonate chloride;

[0480] The reaction parameters for step 6 are as follows: cyclization reaction, under alkaline conditions (in the presence of conventional organic and inorganic bases for this type of reaction in this field);

[0481] The reaction parameters for step 7 are as follows: decarboxylation reaction, acidic conditions (in the presence of acids that are conventional for this type of reaction in the art);

[0482] The reaction parameters for step 8 are as follows: nitration reaction, acidic conditions (in the presence of acids that are conventional for this type of reaction in the art);

[0483] The reaction parameters for step 9 are as follows: chlorination reaction, involving chlorination with POCl3, phosphorus pentachloride, or thionyl chloride;

[0484] The reaction parameters for step 10 are as follows: substitution reaction, basic conditions (in the presence of conventional organic and inorganic bases for this type of reaction in the art);

[0485] The reaction parameters for step 11 are as follows: reduction cyclization, reducing agent (iron powder, zinc powder, sodium hydrosulfite, H2 (in the presence of catalysts palladium / carbon, Pd(OH)2 / carbon));

[0486] The reaction parameters for step 12 are as follows: esterification reaction, alkaline conditions (in the presence of conventional organic or inorganic bases for this type of reaction in the art), esterification reaction with trifluoromethanesulfonic anhydride;

[0487] The reaction parameters for step 13 are as follows: substitution reaction, under acidic conditions, with bromide (sodium bromide or potassium bromide) for substitution reaction;

[0488] The reaction parameters for step 14 are as follows: substitution reaction, basic conditions (in the presence of conventional organic and inorganic bases for this type of reaction in the art);

[0489] The reaction parameters for step 15 are as follows: deprotection, acidic conditions (in the presence of an acid conventional to this type of reaction in the art, such as dilute hydrochloric acid), and the presence of HF, TBAF (tetrabutylammonium fluoride) or KF.

[0490] The reaction parameters for step 16 are as follows: cyclization reaction, carried out in the presence of DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate) and PPh3 or PBu3;

[0491] The reaction parameters for step 17 are as follows: coupling reaction, Suzuki coupling reaction;

[0492] The reaction parameters for step 18 are as follows: deprotection, acidic conditions (in the presence of an acid commonly used in this type of reaction in the art, such as dilute hydrochloric acid or TFA, etc.);

[0493] The reaction parameters for step 19 are as follows: acylation reaction, acylation reaction with A-OH or A-Cl;

[0494] Route 2 includes the following steps:

[0495]

[0496] Where Z is O;

[0497] The reaction parameters for step 1 are as follows: coupling reaction, palladium catalysis, alkaline conditions, coupling reaction with methanol;

[0498] The reaction parameters for step 2 are as follows: chlorination reaction, involving chlorination with POCl3, phosphorus pentachloride, or thionyl chloride;

[0499] The reaction parameters for step 3 are as follows: substitution and fluorination reactions are carried out under alkaline conditions;

[0500] The reaction parameters for step 4 are as follows: reduction cyclization, reducing agent (iron powder, zinc powder, sodium hydrosulfite, H2 (in the presence of catalysts palladium / carbon, Pd(OH)2 / carbon));

[0501] The reaction parameters for step 5 are as follows: substitution reaction, basic conditions (in the presence of conventional organic and inorganic bases for this type of reaction in the art);

[0502] The reaction parameters for step 6 are as follows: deprotection, acidic conditions (in the presence of an acid conventional to this type of reaction in the art, such as dilute hydrochloric acid), and the presence of HF, TBAF (tetrabutylammonium fluoride) or KF.

[0503] The reaction parameters for step 7 are as follows: cyclization reaction, carried out in the presence of DEAD (diethyl azodicarboxylate) or DIAD (diisopropyl azodicarboxylate) and PPh3 or PBu3;

[0504] The reaction parameters for step 8 are as follows: demethylation reaction, with HI undergoing a demethylation reaction;

[0505] The reaction parameters for step 9 are as follows: esterification reaction, alkaline conditions (in the presence of conventional organic or inorganic bases for this type of reaction in the art), esterification reaction with trifluoromethanesulfonic anhydride;

[0506] The reaction parameters for step 10 are as follows: substitution reaction, under acidic conditions, with bromides (sodium bromide, potassium bromide) undergoing substitution reaction;

[0507] The reaction parameters for step 11 are as follows: coupling reaction, Suzuki coupling reaction;

[0508] The reaction parameters for step 12 are as follows: deprotection, acidic conditions (in the presence of acids commonly used in this type of reaction in the art, such as dilute hydrochloric acid or TFA, etc.);

[0509] The reaction parameters for step 13 are as follows: acylation reaction, with A-OH or A-Cl.

[0510] The present invention also provides the following compounds:

[0511]

[0512]

[0513] Among them, R1, R2, R3, R4, Z, X1, Y1, X, Y, R 7A As defined above, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0514] The present invention also provides the following compounds:

[0515]

[0516]

[0517]

[0518]

[0519]

[0520]

[0521]

[0522]

[0523]

[0524]

[0525]

[0526]

[0527]

[0528]

[0529]

[0530]

[0531]

[0532]

[0533]

[0534]

[0535]

[0536]

[0537]

[0538]

[0539]

[0540]

[0541] The present invention also provides a pharmaceutical composition comprising a compound as shown in Formula I as described above, a pharmaceutically acceptable salt thereof or a solvate thereof, and a pharmaceutically acceptable excipient.

[0542] The present invention also provides the use of the above-described "compound as shown in Formula I, its pharmaceutically acceptable salt or solvate thereof" or the above-described pharmaceutical composition as an inhibitor of KRAS G12C mutant protein.

[0543] The present invention also provides the use of the above-described "compound of Formula I, its pharmaceutically acceptable salt or solvate thereof" or the above-described pharmaceutical composition as a cell proliferation inhibitor, wherein the cells are preferably Ba / F3 KRAS-G12C cells expressing KRAS G12C mutant protein, NCI-H358 cells expressing KRAS G12C mutant protein, or MIAPaCa-2 cells expressing KRAS G12C mutant protein.

[0544] The present invention also provides the use of the above-described "compound of Formula I, its pharmaceutically acceptable salt or solvate thereof" or the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is preferably cancer associated with the KRAS G12C mutant protein, more preferably non-small cell lung cancer, pancreatic cancer, leukemia, esophageal cancer, breast cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, sarcoma, osteoma, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine fibroids, thyroid tumors, colon cancer, brain cancer, cervical cancer, testicular cancer, head or neck cancer, bone cancer, rectal cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, esophageal cancer, thyroid cancer, lymphoma, glioma, glioblastoma, gastrointestinal stromal tumor, bile duct cancer, endometrial cancer or multiple myeloma.

[0545] The present invention also provides the use of the above-described "compound as shown in Formula I, its pharmaceutically acceptable salt or solvate thereof" or the above-described pharmaceutical composition in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is non-small cell lung cancer, pancreatic cancer, leukemia, esophageal cancer, breast cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, sarcoma, osteoma, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine fibroids, thyroid tumors, colon cancer, brain cancer, cervical cancer, testicular cancer, head or neck cancer, bone cancer, rectal cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, esophageal cancer, thyroid cancer, lymphoma, glioma, glioblastoma, gastrointestinal stromal tumor, bile duct cancer, endometrial cancer or multiple myeloma.

[0546] Except as otherwise specified, when used in the specification and claims of this application, the following terms shall have the following meanings.

[0547] In this application, the term "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0548] In this application, when the carbon atom marked with "*" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

[0549] In this application, "multiple" means two, three, four, or five.

[0550] In this application, "hydroxyl group" refers to the -OH group.

[0551] In this application, "amino" refers to -NH2.

[0552] In this application, as a group or part of other groups (e.g., in halogen-substituted alkyl groups), the term "alkyl" refers to a fully saturated straight-chain or branched hydrocarbon chain group consisting only of carbon and hydrogen atoms, having, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, even more preferably 1 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, nonyl, and decyl.

[0553] In this application, as part of a group or other group, the term "alkylene" refers to an alkyl group in which one hydrogen atom is substituted, and the definition of an alkyl group is as described above.

[0554] In this application, as part of a group or other group, the term "alkoxy" refers to -O-alkyl, and the definition of alkyl is as described above.

[0555] In this application, as part of a group or other group, the term "alkenyl" refers to a straight-chain or branched hydrocarbon chain group having at least one double bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, even more preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to vinyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, sec-butenyl, tert-butenyl, n-pentenyl, 2-methylbutenyl, 2,2-dimethylpropenyl, n-hexenyl, heptenyl, 2-methylhexenyl, 3-methylhexenyl, octenyl, nonenyl, and decenyl.

[0556] In this application, as part of a group or other group, the term "alkynyl" refers to a straight-chain or branched hydrocarbon chain group having at least one triple bond, consisting only of carbon and hydrogen atoms, having, for example, 2 to 12 (preferably 2 to 8, more preferably 2 to 6, even more preferably 2 to 4) carbon atoms, and connected to the rest of the molecule by single bonds, such as including but not limited to ethynyl, n-propynyl, isopropynyl, n-butynyl, isobutynyl, sec-butynyl, tert-butynyl, n-pentynyl, 2-methylbutynyl, 2,2-dimethylpropynyl, n-hexynyl, heptynyl, 2-methylhexynyl, 3-methylhexynyl, octyynyl, nonynyl, and decynyl.

[0557] In this application, as part of a group or other group, the term "cycloalkyl" means a saturated monocyclic or polycyclic cycloalkyl group having 3 to 15 carbon atoms, preferably 3 to 10 carbon atoms, more preferably 3 to 6 carbon atoms, such as including but not limited to cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0558] In this application, as part of a group or other group, the term "cycloalkenyl" means a monocyclic or polycyclic cycloalkenyl group having at least one double bond (such as a carbon-carbon double bond), having 3 to 15 carbon atoms, preferably having 3 to 10 carbon atoms, more preferably having 3 to 6 carbon atoms, such as including but not limited to cyclopentenyl, cyclohexenyl, or cyclohexadienyl.

[0559] In this application, as part of a group or other group, the term "heterocyclic alkyl" means a stable cyclic system having 2 to 14 (preferably 2 to 6) carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, consisting of monocyclic, bicyclic, tricyclic or more rings, such as including but not limited to pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, thiaranyl, tetrahydropyranyl or tetrahydrofuranyl.

[0560] In this application, as part of a group or other group, the term "heterocyclic alkenyl" means a stable 3- to 20-membered (preferably 3- to 12-membered, more preferably 3- to 7-membered) non-aromatic ring system comprising at least one double bond, consisting of 2 to 14 (preferably 2 to 6) carbon atoms and 1 to 6 heteroatoms selected from nitrogen, oxygen and sulfur, such as including but not limited to pyranyl, 2,3-dihydropyrroleyl, 2,3-dihydrofuranyl, 1,2,3,4-tetrahydropyridyl or 3,4-dihydro-2H-pyran.

[0561] In this application, as a group or part of other groups, the term "aryl" refers to a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms (preferably 6 to 10 carbon atoms). For the purposes of this invention, the aryl group can be a monocyclic, bicyclic, tricyclic, or more cyclic system, and can be fused with cycloalkyl or heterocyclic groups as defined above, provided that the aryl group is connected to the rest of the molecule via single bonds through atoms on the aromatic ring. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthracene, phenanthryl, or fluorene.

[0562] In this application, as a group or part of other groups, the term "heteroaryl" means a 5- to 16-membered conjugated cyclic group having 1 to 15 carbon atoms (preferably 1 to 10 carbon atoms) and 1 to 6 heteroatoms selected from nitrogen, oxygen, and sulfur. Unless otherwise specifically indicated in this specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic, or more cyclic system, and may be fused with a cycloalkyl or heterocyclic group as defined above, provided that the heteroaryl group is connected to the rest of the molecule via a single bond from an atom on the aromatic ring. For the purposes of this invention, the heteroaryl group preferably comprises 1 to 5 stable 5- to 12-membered aromatic groups selected from nitrogen, oxygen and sulfur heteroatoms, more preferably 1 to 4 stable 5- to 10-membered aromatic groups selected from nitrogen, oxygen and sulfur heteroatoms, or 1 to 3 5- to 6-membered aromatic groups selected from nitrogen, oxygen and sulfur heteroatoms (e.g., heteroaryl groups of C1-C5, wherein the heteroatoms are selected from N, O and S, and the number of heteroatoms is 1, 2, 3 or 4). Examples of heteroaryl groups include, but are not limited to, thiophene, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrazinyl, pyridazinyl, benzimidazolyl, benzopyrazolyl, indole, furanyl, pyrroleyl, triazolyl, tetrazolyl, triazinyl, indazinyl, isoindoleyl, indazole, isoindazoleyl, purine, quinolinyl, isoquinolinyl, and diazonaphthyl. Naphthyl, naphthinyl, quinoxalinyl, pteridinyl, carbazolyl, carbazolyl, phenanthrynyl, phenanthrolinyl, acridineyl, phenazinyl, isothiazolyl, benzothiazolyl, benzothiophene, oxtriazolyl, cinolinyl, quinazolinyl, phenylthiol, indene, o-diazaphenanthyl, isoxazolyl, phenoxazinyl, phenthiazolyl, benzoxazolyl, indolyl, benzimidazolyl, benzofuranyl, or quinolinyl.

[0563] Any structural formulas given herein are also intended to represent both the unlabeled and isotopically labeled forms of the compounds. Isotopically labeled compounds have the structures described by the formulas given herein, except that one or more atoms are replaced by atoms having a selected atomic weight or mass number. Examples of isotopes that can be incorporated into the compounds of this invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, […]. 2 H, 3 H, 11 C 13 C 14 C 15 N、 18 O、 17 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 125 I, preferred 2 H.

[0564] As used herein, compounds of Formula I may contain one or more chiral centers and exist in different optically active forms. When a compound contains one chiral center, the compound comprises enantiomers. This invention includes both isomers and mixtures of isomers, such as racemic mixtures. Enantiomers can be resolved by methods known in the art, such as crystallization and chiral chromatography. When a compound of Formula I contains more than one chiral center, diastereomers may be present. This invention includes resolved optically pure specific isomers and mixtures of diastereomers. Diastereomers can be resolved by methods known in the art, such as crystallization and preparative chromatography. The term "stereoisomer" includes conformational isomers and configurational isomers, wherein configurational isomers primarily include cis-trans isomers and optical isomers. The compounds of this invention can exist in stereoisomers, and therefore encompass all possible stereoisomeric forms, including but not limited to cis-trans isomers, tautomers, enantiomers, diastereomers, and trans-isomers. The compounds of this invention can also exist in any combination or mixture of the aforementioned stereoisomers, such as meso compounds, racemic mixtures, and equal mixtures of trans-isomers. Examples include a single enantiomer, a single diastereomer or a mixture of several diastereomers, or a single trans-isomer or a mixture thereof. When the compounds of this invention contain an olefinic double bond, unless otherwise specified, they include cis and trans isomers, and any combination thereof. The trans-isomers of this invention are stereoisomers with axial or planar chirality resulting from restricted intramolecular rotation. The compounds of the present invention have two transisomers originating from axial asymmetry. These transisomers arise because rotation is hindered by steric hindrance between the substituted quinoline ring and the substituted ring when the substituent R4 is a 6-10 aryl, 5-10 heteroaryl, or other cyclic group (especially when there are substituents at the two ends of the linking bond or a group with a large spatial structure at the adjacent position of the linking bond). Regarding the transisomers of the present invention, the compound having the structure of Formula I, or the Formula I compound having an isomer derived from an asymmetric carbon, indicates any one of a pair of transisomers present in each isomer compound. Furthermore, transisomers with excellent activity are preferred as pharmaceuticals. The Formula I compound has an optical isomer derived from an asymmetric carbon, axial asymmetry, etc., and if necessary, a single isomer can be obtained by methods known in the art, such as crystallization or chromatography (e.g., chiral chromatography).

[0565] As previously stated, the present invention provides compounds with the structures shown above, or tautomers, cis-trans isomers, meso compounds, racemates, enantiomers, diastereomers, septate isomers, or mixtures thereof, wherein “mixtures thereof” includes any form of mixing between any of the aforementioned stereoisomers (e.g., tautomers, cis-trans isomers, enantiomers, diastereomers, septate isomers) and / or mixtures (meso compounds, racemates), such as mixtures of cis-trans isomers, mixtures of enantiomers and diastereomers, mixtures of diastereomers, mixtures of septate isomers, or mixtures of cis-trans isomers and racemates, mixtures of enantiomers and diastereomers, mixtures of septate isomers and diastereomers, etc.

[0566] In this application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.

[0567] "Pharmaceutically acceptable acid addition salts" refer to salts formed with inorganic or organic acids that retain the bioavailability of the free base without other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobroms, sulfates, nitrates, and phosphates; organic acid salts include, but are not limited to, formates, acetates, 2,2-dichloroacetate, trifluoroacetate, propionates, hexanoates, octanoates, decanoates, undecenoates, glycolates, gluconates, lactates, sebates, adipates, glutarate, malonates, oxalates, maleates, succinates, fumarates, tartrates, citrates, palmitates, stearates, oleates, cinnamates, laurates, malates, glutamates, pyroglutamates, aspartate, benzoates, methanesulfonates, benzenesulfonates, p-toluenesulfonates, alginates, ascorbic acid salts, salicylates, 4-aminosalicylic acid salts, and naphthalene disulfonates. These salts can be prepared using methods known in this field.

[0568] "Pharmaceutically acceptable base addition salts" refer to salts formed with inorganic or organic bases that retain the bioavailability of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum salts. Preferred inorganic salts are ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, the following: primary amine salts, secondary amine salts, and tertiary amine salts; substituted amine salts, including naturally occurring substituted amine salts, cyclic amine salts, and basic ion exchange resins, such as ammonium salts, isopropylamine salts, trimethylamine salts, diethylamine salts, triethylamine salts, tripropylamine salts, ethanolamine salts, diethanolamine salts, triethanolamine salts, dimethylethanolamine salts, 2-dimethylaminoethanol salts, 2-diethylaminoethanol salts, dicyclohexylamine salts, lysine salts, arginine salts, histidine salts, caffeine salts, procaine salts, choline salts, betaine salts, ethylenediamine salts, glucosamine salts, methylglucosamine salts, theobromine salts, purine salts, piperazine salts, piperidine salts, N-ethylpiperidine salts, polyamine resins, etc. Preferred organic base salts include isopropylamine salts, diethylamine salts, ethanolamine salts, trimethylamine salts, dicyclohexylamine salts, choline salts, and caffeine salts. These salts can be prepared using methods known in this field.

[0569] In this application, "pharmaceutical composition" refers to a formulation of the compounds of the present invention with a medium generally accepted in the art for delivering bioactive compounds to mammals (e.g., humans). This medium includes pharmaceutically acceptable carriers. The purpose of the pharmaceutical composition is to facilitate administration to the organism, thereby promoting the absorption of the active ingredient and the exertion of its bioactivity.

[0570] In this application, "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0571] In this application, "pharmaceuticalally acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, flow aids, sweeteners, diluents, preservatives, dyes / colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, or emulsifiers that are permitted by the relevant government regulatory authorities to be acceptable for human or livestock use.

[0572] In this application, "solvent" refers to the physical association of the compound of the present invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In some cases, the solvate can be segregated, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvent" includes solution phases and segregable solvates. Non-limiting examples of solvates include ethanol compounds, methanol compounds, hydrates, etc. A "hydrate" is a solvate in which the solvent molecule is water.

[0573] The term “treatment” refers to a therapeutic approach or a remission measure. When a specific condition is involved, treatment means: (1) alleviating one or more biological manifestations of the disease or condition; (2) interfering with (a) one or more points in a biological cascade that causes or precipitates the condition or (b) one or more biological manifestations of the condition; (3) improving one or more symptoms, effects, or side effects associated with the condition, or one or more symptoms, effects, or side effects associated with the condition or its treatment; or (4) slowing the progression of the disease or one or more biological manifestations of the condition. “Treatment” can also mean prolonging survival compared to expected survival without treatment.

[0574] The term "prevention" refers to the reduction of the risk of acquiring or developing a disease or disorder.

[0575] Those skilled in the art will understand that, according to the conventions used in the art, the structural formulas of the descriptive groups described in this application... and This refers to the fact that the corresponding group R is linked to other fragments or groups in the compound through this site.

[0576] The term "multiple" refers to 2, 3, 4, or 5.

[0577] When arbitrary variables (e.g., group C) 1-6 When alkyl groups appear multiple times in the definition of a compound, their definitions are independent and do not affect each other. For example, alkyl groups formed by three carbon atoms... 1-6 Alkyl-substituted 6-10 aryl groups refer to 6-10 aryl groups that are replaced by 3 carbon atoms. 1-6 Alkyl substitution, 3 carbons 1-6 The definitions of alkyl groups are independent of each other and do not affect each other.

[0578] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0579] The reagents and raw materials used in this invention are all commercially available.

[0580] The positive and progressive effects of this invention are as follows: the compounds in this application can effectively inhibit the proliferation of Ba / F3 KRAS-G12C, NCI-H358 and MIA PaCa-2 cells containing KRAS G12C mutation, and some compounds or their salts have a good inhibitory effect on the growth of subcutaneous xenograft tumors in the NCI-H358 cell line in nude mice. Detailed Implementation

[0581] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0582] DMSO: Dimethyl sulfoxide; Boc: tert-butyloxycarbonyl; TBS: tert-butyldimethylsilyl; CDCl3: deuterated chloroform; DEA: diethylamine; IPA: isopropanol; ACN: acetonitrile; PMB: p-methoxybenzyl; THP: 2-tetrahydropyranyl; Ms: methanesulfonyl; FA: formic acid; TIPS: triisopropylsilyl; MOM: methoxymethyl (CH3OCH2-); Tf: trifluoromethanesulfonyl.

[0583] Intermediate 1: (2R,4aR)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0584]

[0585] Step 1: 3-Bromo-4-chloro-2-fluoroaniline

[0586]

[0587] 3-Bromo-2-fluoroaniline (210 g, 1.11 mol, 1 eq) was dissolved in N,N-dimethylformamide (2000 mL), and N-chlorosuccinimide (154.96 g, 1.16 mol, 1.05 eq) was added. The reaction was carried out overnight at 70 °C. The reaction was confirmed to be complete by LC-MS. After the reaction was cooled to room temperature, the solution was poured into ice water, and water and ethyl acetate were added for extraction. The organic phase was washed three times each with saturated sodium bicarbonate aqueous solution, anhydrous sodium sulfite aqueous solution, and saturated brine. The solution was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product (240 g).

[0588] MS m / z: 223.9 / 225.9 [M+H] + .

[0589] Step 2: 3-((3-bromo-4-chloro-2-fluorophenyl)amino)-3-carbonylpropionic acid

[0590]

[0591] 240 g of 3-bromo-4-chloro-2-fluoroaniline was dissolved in 2400 mL of toluene, and 184.93 g of isopropyl malonate (1.28 mol, 1.2 eq) was added. The reaction was carried out overnight at 90 °C. The reaction was confirmed to be complete by LC-MS. After cooling to room temperature, the mixture was filtered, and the filter cake was the product, yielding 175 g of crude 3-((3-bromo-4-chloro-2-fluorophenyl)amino)-3-carbonylpropionic acid, a white product.

[0592] MS m / z: 309.9 / 311.9 [M+H] + .

[0593] Step 3: 7-Bromo-6-chloro-8-fluoroquinoline-2,4-diphenol

[0594]

[0595] 3-((3-bromo-4-chloro-2-fluorophenyl)amino)-3-carbonylpropionic acid (174 g, 560.38 mmol, 1 eq) was mixed with polyphosphoric acid (1.89 kg, 5.60 mol, 10 eq) and reacted at 135 °C for 16 h. The reaction was monitored by LCMS until complete. The reaction solution was poured into ice (1.9 kg), sodium hydroxide was added to adjust the pH of the reaction solution to 4, and the mixture was filtered. The filter cake was successively beaten with water, acetonitrile, and ethyl acetate to obtain 7-bromo-6-chloro-8-fluoroquinoline-2,4-diol (130 g, yield 79.31%), a yellow solid.

[0596] MS m / z:292.0 / 294.0[M+H] + .

[0597] 1 H NMR (400MHz, DMSO-d6) δ7.74 (d, J = 1.63Hz, 1H), 5.81 (s, 1H).

[0598] Step 4: 7-Bromo-6-chloro-8-fluoro-3-nitroquinoline-2,4-diphenol

[0599]

[0600] 129 g (441.03 mmol, 1 eq) of 7-bromo-6-chloro-8-fluoroquinoline-2,4-diol was dissolved in concentrated nitric acid (430 mL) and reacted at 75 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was poured into ice (1.3 kg), filtered, and the filter cake was washed with water to obtain crude 7-bromo-6-chloro-8-fluoro-3-nitroquinoline-2,4-diol (106 g), a yellow solid.

[0601] MS m / z:337.0 / 339.0[M+H] + .

[0602] 1 H NMR (400MHz, DMSO-d6) δ11.82 (br s, 1H), 7.96 (d, J = 1.83Hz, 1H).

[0603] Step 5: 7-Bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline

[0604]

[0605] 7-Bromo-6-chloro-8-fluoro-3-nitroquinoline-2,4-diol (25 g, 74.08 mmol, 1 eq) was added to phosphorus oxychloride (340.75 g, 2.22 mol, 30 eq), and N,N-diisopropylethylamine (28.72 g, 222.23 mmol, 3 eq) was slowly added dropwise at room temperature. The reaction was carried out at 100 °C for 10 hours. LC-MS analysis confirmed the reaction was complete. The residue was distilled under reduced pressure and purified by silica gel column chromatography (ethyl acetate / petroleum ether: 0-10%) to give the product (25 g, yield: 72.12%) as a yellow solid. This product was used directly in the next step.

[0606] Step 6: (3R,6R)-1-tert-butyl-3-methyl-4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester

[0607]

[0608] 7-Bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline (10.2 g, 27.25 mmol, 1 eq) and (3R,6R)-1-tert-butyl-3-methyl-6-methylpiperazine-1,3-dicarboxylic acid ester (7.74 g, 29.97 mmol, 1.1 eq) were dissolved in N,N-dimethylacetamide (125 mL), and then N,N-diisopropylethylamine (7.04 g, 54.49 mmol, 9.49 mL, 2 eq) was added. The mixture was reacted at room temperature for 3 days. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) until complete. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried with anhydrous sodium sulfate. The mixture was filtered and concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate: petroleum ether = 0-10%) to give (3R,6R)-1-tert-butyl-3-methyl-4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (5.47 g, yield: 16.84%), a yellow solid.

[0609] 1 H NMR (400MHz, CDCl3) δ8.37(br s,1H),6.99(s,1H),5.02(s,1H),4.54(br d,J=13.9Hz,1H),4.44(br s,1H),4.30(br d,J=3.1Hz,1H),4.17(br s,1H),3.79-3.70(m,1H),3.75(s,2H),3.58-3.41(m,1H),3.15(br d,J=11.8Hz,1H),2.63(s,1H),2.28(s,1H),1.49(s,9H),1.26(br d,J=6.8Hz,3H).

[0610] Step 7: (2R,4aR)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0611]

[0612] (3R,6R)-1-tert-butyl-3-methyl-4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (29.89 g, 50.13 mmol, 1 eq) was dissolved in acetic acid (250 mL), and iron powder (11.20 g, 200.53 mmol, 4 eq) was added. The reaction was carried out at 80 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was concentrated, and the residue was dissolved in dichloromethane. The pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was filtered. The filtrate was extracted, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was pulped at room temperature (petroleum ether: methyl tert-butyl ether = 3:1). The mixture was filtered, and the filter cake was collected to give the product (22 g, yield: 82.15%), a yellow solid.

[0613] MS m / z:533.0 / 535.0[M+H] + .

[0614] 1 H NMR (400MHz, CDCl3) δ8.02(br s,1H),7.94(d,J=1.76Hz,1H),4.95(br d,J=13.30Hz,1H),4.55(br s,1H),3.75-3.41(m,2H),3.13-2.94(m,2H),1.60(s,9H),1.57-1.55(m,3H).

[0615] Intermediate 2: (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0616]

[0617] Step 1: (R)-3-azidopropane-1,2-diol

[0618]

[0619] Sodium azide (17.7 g, 272 mmol, 1.5 eq) was dissolved in water (200 mL), and (S)-3-chloro-1,2-propanediol (20.0 g, 181 mmol, 1.0 eq) was added. The mixture was reacted at 80 °C for 48 hours. After the reaction was complete, the pH of the reaction solution was adjusted to 8 with saturated sodium carbonate solution. The solution was extracted with 2-methyltetrahydrofuran, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain crude (R)-3-azidopropane-1,2-diol (21.0 g), a colorless liquid.

[0620] 1 H NMR (400MHz, CDCl3) δ3.87-3.82(m,1H),3.70-3.63(m,1H),3.60-3.53(m,1H),3.40-3.30(m,2H).

[0621] Step 2: (R)-1-azido-3-((tert-butyldimethylsilyl)oxo)propane-2-ol

[0622]

[0623] (R)-3-azidopropane-1,2-diol (21.0 g, 179 mmol, 1.0 eq) was dissolved in tetrahydrofuran (300 mL), and imidazole (18.31 g, 268.99 mmol, 1.5 eq) and dimethyl tert-butylchlorosilane (25.68 g, 170.36 mmol, 0.95 eq) were added. The reaction mixture was reacted overnight at room temperature. Complete consumption of the starting material was confirmed by TLC (petroleum ether: ethyl acetate = 5:1). The reaction mixture was filtered and concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether: 0-5%) to give (R)-1-azido-3-((tert-butyldimethylsilyl)oxo)propane-2-ol (31.0 g, yield: 74.7%), a colorless liquid.

[0624] 1 H NMR (400MHz, CDCl3) δ3.89-3.80 (m, 1H), 3.71-3.60 (m, 2H), 3.38 (d, J = 5.5Hz, 2H), 0.93 (s, 9H), 0.12-0.07 (m, 6H).

[0625] Step 3: (2R,4aR)-tert-butyl-7-(((R)-1-azido-3-((tert-butyldimethylsilyl)oxo)propane-2-yl)oxo)-10-bromo-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0626]

[0627] Sodium hydride (2.25 g, 56.16 mmol, 60% purity, 3 eq) was dissolved in toluene (210 mL). (R)-1-azido-3-((tert-butyldimethylsilyl)oxo)propane-2-ol (6.10 g, 28.08 mmol, 1.5 eq) was added dropwise at 0 °C and stirred for 30 minutes. Then (2R,4aR)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (10 g, 18.72 mmol, 1 eq) was added and the reaction was carried out at 50 °C for 4.5 hours. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 5:1) until complete. The reaction solution was quenched with saturated ammonium chloride solution at 0°C, extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was subjected to silica gel column chromatography (petroleum ether / ethyl acetate: 0-5%) to give (2R,4aR)-tert-butyl-7-(((R)-1-azido-3-((tert-butyldimethylsilyl)oxo)propane-2-yl)oxo)-10-bromo-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (6.2 g, yield: 45.42%), a yellow solid.

[0628] 1 H NMR (400MHz, DMSO-d6) δ10.70-10.48(m,1H),7.84-7.71(m,1H),5.60-5.49(m,1H),4.69-4.54(m,1H),4.32-4.1 0(m,1H),3.97-3.67(m,6H),3.43-3.36(m,1H),3.29-3.20(m,1H),3.03-2.90(m,1H),2.85-2.73(m,1H),1.44(br d,J=10.4Hz,12H),0.75(s,9H),0.00(d,J=2.0Hz,6H).

[0629] Step 4: (2R,4aR)-tert-butyl-7-(((R)-1-azido-3-hydroxypropane-2-yl)oxo)-10-bromo-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0630]

[0631] (2R,4aR)-tert-butyl-7-(((R)-1-azido-3-((tert-butyldimethylsilyl)oxo)propane-2-yl)oxo)-10-bromo-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (16.2 g, 22.22 mmol, 1 eq) was dissolved in tetrahydrofuran (200 mL), and tetrabutylammonium fluoride (1 M, 33.33 mL, 1.5 eq) was added. The mixture was reacted overnight at room temperature. The reaction was monitored by LCMS until complete. The reaction solution was diluted with water, extracted with ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate. After filtration and concentration, crude product (13 g) of (2R,4aR)-tert-butyl-7-(((R)-1-azido-3-hydroxypropane-2-yl)oxo)-10-bromo-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester was obtained. This crude product was directly used in the next step.

[0632] MS m / z:558.0 / 560.0[M+H-56] + .

[0633] Step 5: (2R,4aR,7S)-tert-butyl-7-(azidomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0634]

[0635] Triphenylphosphine (16.64 g, 63.43 mmol, 3 eq) was dissolved in tetrahydrofuran (400 mL), and diisopropyl azodicarbonate (12.83 g, 63.43 mmol, 3 eq) was added at 0 °C. The mixture was stirred for 30 minutes, and then (2R,4aR)-tert-butyl-7-(((R)-1-azido-3-hydroxypropane-2-yl)oxo)-10-bromo-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (13 g, 21.14 mmol, 1 eq) was added dropwise. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LCMS until complete. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine, filtered and concentrated, and the residue was subjected to silica gel column chromatography (ethyl acetate / petroleum ether: 0-45%) to give (2R,4aR,7S)-tert-butyl-7-(azidomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (9 g, yield: 71.32%), as a yellow solid.

[0636] MS m / z: 595.9 / 597.9 [M+H] + .

[0637] 1 H NMR (400MHz, CDCl3) δ7.84(d,J=1.8Hz,1H),4.96(d,J=13.8Hz,1H),4.79-4.68(m,1H),4.52(br s,1H),4.31(dd,J=5.1,13.9Hz,1H),3.87(dd,J=3.1,13.8Hz,1H),3.77-3.62(m,3H),3.51(br d,J=5.6Hz,1H),3.03(br s,2H),1.58(br d,J=6.8Hz,3H),1.54(br s,9H).

[0638] Step 6: (2R,4aR,7R)-tert-butyl-7-(aminomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0639]

[0640] (2R,4aR,7S)-tert-butyl-7-(azidomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (9 g, 15.08 mmol, 1 eq) was dissolved in tetrahydrofuran (120 mL) and water (15 mL), and trimethylphosphine (1 M, 22.62 mL, 1.5 eq) was added. The mixture was reacted at room temperature for 1 hour. TLC (petroleum ether: ethyl acetate = 1:1) monitored the reaction until complete. The reaction solution was concentrated to obtain crude residue (2R,4aR,7R)-tert-butyl-7-(aminomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (8.8 g), a yellow solid. This crude product was directly used in the next step.

[0641] Step 7: (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0642]

[0643] (2R,4aR,7R)-tert-butyl-7-(aminomethyl)-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (8.61 g, 15.08 mmol, 1 eq) was dissolved in methanol (100 mL), and triethylamine (3.05 g, 30.17 mmol, 2 eq), paraformaldehyde (1.36 g, 45.25 mmol, 3 eq), and sodium cyanoborohydride (2.37 g, 37.71 mmol, 2.5 eq) were added. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (tetrahydrofuran (containing 0.1% ammonia) / petroleum ether: 0-30%) to give (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (4.5 g, yield: 49.82%), a yellow solid.

[0644] MS m / z: 598.1 / 600.2 [M+H] + .

[0645] 1 H NMR (400MHz, CDCl3) δ7.82(d,J=1.8Hz,1H),4.96(d,J=13.8Hz,1H),4.80-4.68(m,1H),4.51(br s,1H),4.35-4.22(m,1H),3.88(dd,J=3.2,13.6Hz,1H),3.76-3.45(m,3H),3.08-2.99(m,2H),2.77-2.58(m,3H),2.35(s,6H),1.58(br d,J=6.7Hz,3H),1.54(br s,9H).

[0646] Intermediate 3: (R)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0647]

[0648] Step 1: (R)-1-tert-butyl-3-methyl-4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinoline-4-yl)piperazine-1,3-dicarboxylic acid ester

[0649]

[0650] 7-Bromo-2,4,6-trichloro-8-fluoro-3-nitroquinoline (7 g, 14.7 mmol, 1 eq) and 3-methylpiperazine(R)-1-tert-butyl-1,3-dicarboxylic acid ester (5.3 g, 22 mmol, 1.5 eq) were dissolved in N,N-dimethylacetamide (70 mL), and then N,N-diisopropylethylamine (5.6 g, 44.1 mmol, 3 eq) was added. The mixture was reacted at 25 degrees Celsius for 7 days. The reaction was monitored by TLC (petroleum ether: ethyl acetate = 8:1) until complete. The reaction solution was diluted with water and extracted three times with ethyl acetate. The organic phase was washed three times with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration and concentration, the solution was separated by column chromatography (ethyl acetate: petroleum ether = 1:60) to give (R)-1-tert-butyl-3-methyl-4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperazine-1,3-dicarboxylic acid ester (1.2 g, yield 16%), a yellow solid.

[0651] MS m / z:581.0 / 583.0[M+H] + .

[0652] 1 H NMR(400MHz,DMSO-d6)δ8.26(s,1H),4.41(s,1H),4.25-4.22(m,1H),3.90-3.86(m,1H),3.63-3 .61(m,1H),3.62(s,3H),3.48-3.44(m,1H),3.33-3.31(m,1H),3.17-3.15(m,1H),1.42(s,9H).

[0653] Step 2: (R)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0654]

[0655] (R)-1-tert-butyl-3-methyl-4-(7-bromo-2,6-dichloro-8-fluoro-3-nitroquinolin-4-yl)piperazine-1,3-dicarboxylic acid ester (11.8 g, 20.3 mmol, 1 eq) was dissolved in acetic acid (100 mL), and iron powder (5.7 g, 101.5 mmol, 5 eq) was added. The reaction was carried out at 80°C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was concentrated, and the residue was dissolved in 200 mL of dichloromethane. The pH was adjusted to 8 with saturated sodium bicarbonate solution and then filtered. The filtrate was extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the residue was pulped at room temperature (petroleum ether: ethyl acetate = 10:1) overnight. Filter and dry to give (R)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2':4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylic acid ester (10 g, 95% yield), a yellow solid.

[0656] MS m / z:519.0 / 521.0[M+H] + .

[0657] Intermediate 4: (4aR,7S)-11-bromo-12-chloro-10-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid tert-butyl ester

[0658]

[0659] Step 1: (R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxazolidine

[0660]

[0661] (R)-(-)-glycerol acetal (4.8 g, 36.3 mmol, 1 eq) was dissolved in anhydrous N,N-dimethylformamide (50 mL), cooled to 0°C, and sodium hydroxide (2.9 g, 72.7 mmol, 2.0 eq, 60% purity) was added. The mixture was stirred at 0°C for 1 hour. 4-Methoxybenzyl chloride (8.54 g, 54.5 mmol, 1.5 eq) was added to the reaction solution, the mixture was heated to room temperature and stirred for 2 hours, filtered, and the reaction was monitored by LCMS until completion. The mixture was cooled to 0°C and quenched with ammonium chloride aqueous solution. It was extracted with ethyl acetate, the organic phases were combined and washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrated residue was purified by thin-layer chromatography (dichloromethane / methanol = 50 / 1, v / v) to give (R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxazolidine (8.2 g, 90% yield), a yellow liquid.

[0662] MS m / z: 275.0 [M+Na] + .

[0663] Step 2: (S)-3-((4-methoxybenzyl)oxy)propane-1,2-diol

[0664]

[0665] (R)-4-(((4-methoxybenzyl)oxy)methyl)-2,2-dimethyl-1,3-dioxazolidine (31.6 g, 125.4 mmol, 1 eq) was dissolved in tetrahydrofuran (350 mL), and dilute hydrochloric acid (1 M, 351.1 mL, 351.1 mmol, 2.8 eq) was added dropwise at 0°C. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The pH was adjusted to 6-7 with sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The concentrate was subjected to column chromatography (dichloromethane / methanol = 20 / 1, v / v) to give (S)-3-((4-methoxybenzyl)oxy)propane-1,2-diol (22.6 g, 85% yield), a yellow liquid.

[0666] MS m / z: 235.0 [M+Na] + .

[0667] Step 3: (R)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)propane-2-ol

[0668]

[0669] (S)-3-((4-methoxybenzyl)oxy)propane-1,2-diol (15.3 g, 72.1 mmol, 1 eq), triethylamine (21.9 g, 216.4 mmol, 3.0 eq), and 4-dimethylaminopyridine (1.76 g, 14.4 mmol, 0.2 eq) were dissolved in anhydrous dichloromethane (300 mL). Tert-butyldimethylchlorosilane (13 g, 86.6 mmol, 1.2 eq) was added at 0°C, and the reaction was carried out at room temperature for 16 hours under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 10 / 1, v / v) to give (R)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)propane-2-ol (23 g, 98% yield). A yellow liquid was obtained.

[0670] 1 H NMR (400MHz, DMSO-d6) δ7.27(d,J=10.8Hz,2H),6.90(d,J=11.2Hz,2H),4.74(d,J=6.4Hz,1H),4.42(s,2H),3.77( s,3H),3.66-3.59(m,1H),3.54(d,J=7.2Hz,2H),3.47-3.42(m,1H),3.35-3.34(m,1H),0.88(s,9H),0.05(s,6H).

[0671] MS m / z: 349.2 [M+Na] + .

[0672] Step 4: (R)-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)prop-2-yl)oxy)-11-chloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline-3(2H)-tert-butyl formate

[0673]

[0674] Sodium hydride (769 mg, 19.22 mmol, 2.0 eq) was added to a toluene solution (100 mL) of (R)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)propane-2-ol (6.3 g, 19.22 mmol, 2.0 eq). The mixture was stirred at 0°C for 30 minutes, and then (R)-10-bromo-7,11-dichloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylic acid tert-butyl ester (5.0 g, 9.61 mmol, 1.0 eq) was added. The mixture was heated to 50°C and reacted for 3 hours. A saturated aqueous solution of ammonium chloride was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The concentrated residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1, v / v) to give crude (R)-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)prop-2-yl)oxy)-11-chloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylic acid tert-butyl ester (4.6 g), a yellow solid.

[0675] 1 H NMR (400MHz, DMSO-d6) δ10.46(s,1H),7.93(s,1H),7.20(d,J=8.8Hz,2H),6.83(d,J=8.8Hz,2H),5.64-5.61(m,1H),4.71(d,J=12.8Hz,1H),4 .47(s,2H),3.87-3.82(m,4H),3.77-3.75(m,2H),3.70(s,3H),3.22-3 .13(m,3H),2.62-2.57(m,1H),1.44(s,9H),0.73(s,9H),0.01(s,6H).

[0676] MS m / z:809.1 / 811.1[M+H] + .

[0677] Step 5: (R)-10-bromo-11-chloro-9-fluoro-7-(((S)-1-hydroxy-3-((4-methoxybenzyl)oxy)propane-2-yl)oxy)-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline-3(2H)-tert-butyl formate

[0678]

[0679] At room temperature, tetrabutylammonium fluoride (2.9 g, 11.35 mmol, 2 eq) was added to a solution of (R)-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxy)-3-((4-methoxybenzyl)oxy)propyl-2-yl)oxy)-11-chloro-9-fluoro-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylic acid tert-butyl ester (4.6 g, 5.68 mmol, 1.0 eq) in tetrahydrofuran (40 mL). The reaction was stirred at room temperature for 2 hours. The mixture was washed with ethyl acetate, a mixture of saturated brine and saturated ammonium chloride (v / v = 1 / 1, 20 mL × 3), and the organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The concentrated residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to (R)-10-bromo-11-chloro-9-fluoro-7-(((S)-1-hydroxy-3-((4-methoxybenzyl)oxy)propane-2-yl)oxy)-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylic acid tert-butyl ester (2.9 g, yield 73%), as a yellow solid.

[0680] 1 H NMR (400MHz, DMSO-d6) δ10.47(s,1H),7.94(s,1H),7.17(d,J=8.4Hz,2H),6.80(d,J=8.4Hz,2H),5.46-5.44(m,1H),4.93-4.8 9(m,1H),4.73-4.69(m,1H),4.46(s,2H),3.90-3.71(m,6H),3.69(s,3H),3.22-3.16(m,3H),2.65-2.60(m,1H),1.44(s,9H).

[0681] MS m / z: 695.2 / 697.2 [M+H] + .

[0682] Step 6: (4aR,7S)-11-bromo-12-chloro-10-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-tert-butyl formate

[0683]

[0684] At room temperature, a tetrahydrofuran solution (20 mL) of (R)-10-bromo-11-chloro-9-fluoro-7-(((S)-1-hydroxy-3-((4-methoxybenzyl)oxy)propane-2-yl)oxy)-5-oxo-4,4a,5,6-tetrahydro-1H-pyrazino[1',2',4,5]pyrazino[2,3-c]quinoline-3(2H)-carboxylic acid tert-butyl ester (5.9 g, 8.48 mmol, 1 eq) was added to a tetrahydrofuran solution (50 mL) of triphenylphosphine (4.4 g, 16.95 mmol, 2.0 eq) and diisopropyl azodicarbonate (3.4 g, 16.95 mmol, 2.0 eq). The mixture was stirred overnight at room temperature. Water was added, and the mixture was extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness. The concentrated residue was purified by column chromatography (petroleum ether / ethyl acetate = 2 / 1, v / v) to (4aR,7S)-11-bromo-12-chloro-10-fluoro-7-(((4-methoxybenzyl)oxy)methyl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid tert-butyl ester (4.7 g, yield 82%). A yellow solid.

[0685] 1 H NMR (400MHz, DMSO-d6) δ7.97(s,1H),7.12(d,J=8.4Hz,2H),6.80(d,J=8.4Hz,2H),4.94-4.91(m,1H),4.69( d,J=13.6Hz,1H),4.41-4.26(m,3H),3.89-3.62(m,8H),3.24-3.17(m,3H),2.76-2.70(m,1H),1.44(s,9H).

[0686] MS m / z: 677.2 / 679.2 [M+H] + .

[0687] Intermediate 5: (R)-2-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-1-ol

[0688]

[0689] Step 1: (R)-3-(dimethylamino)propane-1,2-diol

[0690]

[0691] In a 500 mL three-necked flask, (S)-3-chloropropane-1,2-diol (10 mL, 133.8 mmol, 1 eq) and dimethylamine hydrochloride (64.6 g, 792 mmol, 5.9 eq) were added, followed by sodium hydroxide solution (40 g dissolved in 100 mL of water). The mixture was stirred at room temperature for 24 hours, then water was added, and the mixture was extracted with chloroform. The solution was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude (R)-3-(dimethylamino)propane-1,2-diol (6.5 g), which was used directly in the next reaction.

[0692] MS m / z: 120.2 [M+H] + .

[0693] Step 2: (R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-ol

[0694]

[0695] In a 500 mL three-necked flask, (R)-3-(dimethylamino)propane-1,2-diol (6.5 g, 54.57 mmol, 1 eq) was added and dissolved in dichloromethane (150 mL). Imidazole (3.71 g, 54.57 mmol, 1 eq) was added, and the mixture was cooled to 0 °C. Tert-butyldimethylsilyl chloride (8.24 g, 54.57 mmol, 1 eq) was added, and the mixture was reacted at room temperature until the reactants were completely reacted. The mixture was diluted with dichloromethane, washed with water, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain (R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-ol (6.1 g), which was used directly in the next reaction.

[0696] MS m / z: 234.2 [M+H] + .

[0697] Step 3: (R)-2,3-Di((tert-butyldimethylsilyl)oxo)-N,N-dimethylpropane-1-amine

[0698]

[0699] In a 500 mL three-necked flask, (R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-ol (6 g, 25.75 mmol, 1 eq) was added, dissolved in dichloromethane (330 mL), and 2,6-dimethylpyridine (7.5 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and tert-butyldimethylsilyltrifluoromethanesulfonate (11.9 mL) was slowly added. The mixture was stirred at 0 °C until the reactants were completely reacted. A saturated ammonium chloride solution was slowly added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give (R)-2,3-bis((tert-butyldimethylsilyl)oxo)-N,N-dimethylpropane-1-amine (6.5 g, yield 72.7%).

[0700] MS m / z: 348.3 [M+H] + .

[0701] Step 4: (R)-2-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-1-ol

[0702]

[0703] In a 1000 mL three-necked flask, (R)-2,3-di((tert-butyldimethylsilyl)oxo)-N,N-dimethylpropane-1-amine (6.1 g, 17.6 mmol, 1 eq) was added and dissolved in anhydrous tetrahydrofuran (310 mL). Under nitrogen protection, pyridine (24.6 mL) was added, the temperature was lowered to 0 °C, and pyridine hydrofluoric acid salt (20.3 mL) was added dropwise. The mixture was stirred at 0 °C until the reactants were completely reacted. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give (R)-2-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-1-ol (2.3 g, yield 56%).

[0704] MS m / z: 234.1 [M+H] + .

[0705] 1 H NMR(400MHz,CDCl3)δ4.31(br s,1H),3.88-3.82(m,1H),3.70-3.66(m,1H),3.62-3.58(m,1H),2.59-2.54(m ,1H),2.49-2.44(m,1H),2.34(s,1H),2.29(s,5H),0.87(s,9H),0.06(br,6H).

[0706] Intermediate 6: (R)-1-((tert-butyldimethylsilyl)oxo)-3-(pyrrolidone-1-yl)propane-2-ol

[0707]

[0708] Step 1: (R)-3-(pyrrolidone-1-yl)propane-1,2-diol

[0709]

[0710] In a 250 mL three-necked flask, tetrahydropyrrole (20.6 g, 289.5 mmol, 3.2 eq) and anhydrous methanol (26 mL) were added. Under nitrogen protection, the mixture was heated to 70 °C, and (S)-3-chloropropane-1,2-diol (10 g, 90.46 mmol, 1 eq) was slowly added. The mixture was reacted at 70 °C for 4 hours until the starting material was completely reacted. The mixture was then cooled to room temperature, and 48% sodium hydroxide solution (3.98 g, 99.51 mmol, 1.1 eq) was added. The mixture was stirred for 0.5 hours, and a white solid precipitated. The solid was filtered, and the mother liquor was concentrated to dryness to obtain crude (R)-3-(pyrrolidine-1-yl)propane-1,2-diol (13.4 g), which was used directly in the next reaction.

[0711] MS m / z: 146.2 [M+H] + .

[0712] Step 2: (R)-1-((tert-butyldimethylsilyl)oxo)-3-(pyrrolidone-1-yl)propane-2-ol

[0713]

[0714] In a 500 mL three-necked flask, (13.4 g, 90.46 mmol, 1 eq) was added and dissolved in dichloromethane (120 mL). Under nitrogen protection, imidazole (9.24 g, 135.69 mmol, 1.5 eq) was added, and the mixture was cooled to 0 °C. Tert-butyldimethylsilyl chloride (12.95 g, 85.94 mmol, 0.95 eq) was added at 0 °C, and the mixture was allowed to rise naturally to room temperature until the reactants were almost completely reacted. Water was added, and the mixture was separated. The organic phase was washed twice with water, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude (R)-1-((tert-butyldimethylsilyl)oxo)-3-(pyrrolidine-1-yl)propane-2-ol (19.8 g).

[0715] MS m / z: 260.1 [M+H] + .

[0716] 1H NMR(400MHz,DMSO-d6)δ4.34(br s,1H),3.55-3.52(m,1H),3.47-3.45(m,2H),2.48-2.39(m, 5H),2.30-2.26(m,1H),1.64-1.60(m,4H),0.84(s,9H),0.00(s,6H).

[0717] Intermediate 7: (2R,4aR,7R)-tert-butyl-11-bromo-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidone-2-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0718]

[0719] Step 1: 8-Fluoro-7-methoxy-3-nitro-1,6-naphthidine-2,4-diol

[0720]

[0721] 8-Fluoro-7-chloro-3-nitro-1,6-naphthidine-2,4-diol (26.4 g, 101.70 mmol, 1 eq), palladium acetate (1.83 g, 8.14 mmol, 0.08 eq), 2-di-tert-butylphosphine-2′,4′,6′-triisopropylbiphenyl (6.91 g, 16.27 mmol, 0.16 eq), and cesium carbonate (99.41 g, 305.11 mmol, 3 eq) were dissolved in N,N-dimethylformamide (1000 mL) and methanol (500 mL). After nitrogen purging, the reaction was carried out at 100 °C for two hours. The reaction was monitored by LC-MS until complete. The reaction solution was filtered, the pH of the filtrate was adjusted to 2 with concentrated hydrochloric acid and then concentrated. The residue was slurried with water, filtered, and the filter cake was washed with ethyl acetate to obtain 20 g of crude 8-fluoro-7-methoxy-3-nitro-1,6-naphthidine-2,4-diol.

[0722] MS m / z: 256.1 [M+H] +

[0723] Step 2: 2,4-Dichloro-8-fluoro-7-methoxy-3-nitro-1,6-naphthidine

[0724]

[0725] 8-Fluoro-7-methoxy-3-nitro-1,6-naphthidine-2,4-diol (40 g, 156.76 mmol, 1 eq) was dissolved in phosphorus oxychloride (400 mL), and N,N-diisopropylethylamine (60.78 g, 470.29 mmol, 3 eq) was slowly added. The reaction was carried out at 110 °C for 2 hours. The reaction was monitored by LC-MS until complete. The reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-15%) to give 2,4-dichloro-8-fluoro-7-methoxy-3-nitro-1,6-naphthidine (8 g, yield: 17.5%).

[0726] MS m / z: 292.0 [M+H] +

[0727] 1 H NMR (400MHz, DMSO-d6) δ9.28 (s, 1H), 4.18 (s, 3H).

[0728] Step 3: (3R,6R)-1-tert-butyl-3-methyl-4-(2,8-difluoro-7-methoxy-3-nitro-1,6-naphthid-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester

[0729]

[0730] 2,4-Dichloro-8-fluoro-7-methoxy-3-nitro-1,6-naphthidine (5.2 g, 17.81 mmol, 1 eq) and cesium fluoride (27.05 g, 178.05 mmol, 10 eq) were dissolved in N,N-dimethylformamide (150 mL), purged with nitrogen, and reacted at room temperature for 5 minutes. TLC (petroleum ether:ethyl acetate = 3:1) showed no starting material remaining. (3R,6R)-1-tert-butyl-3-methyl-6-methylpiperazine-1,3-dicarboxylic acid ester (6.90 g, 26.71 mmol, 1.5 eq) was added under nitrogen, and the reaction was continued at room temperature for 5 minutes. TLC (petroleum ether:ethyl acetate = 3:1) showed a small amount of intermediate remaining, and a new spot formed below the starting material. The reaction mixture was slowly poured into water at room temperature to quench the reaction, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-20%) to give (3R,6R)-1-tert-butyl-3-methyl-4-(2,8-difluoro-7-methoxy-3-nitro-1,6-naphthid-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (7.0 g, yield: 79.0%), a yellow solid.

[0731] MS m / z: 498.2 [M+H] +

[0732] Step 4: (8aR,11R)-tert-butyl-4,6-difluoro-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyrano[1',2':4,5]pyrano[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester

[0733]

[0734] (3R,6R)-1-tert-butyl-3-methyl-4-(2,8-difluoro-7-methoxy-3-nitro-1,6-naphthid-4-yl)-6-methylpiperazine-1,3-dicarboxylic acid ester (4.5 g, 9.05 mmol, 1 eq) was dissolved in a mixture of ethanol (30 mL) and water (8 mL), and sodium hyposulfite (7.88 g, 45.23 mmol, 5 eq) was added. The reaction was carried out at room temperature for 1 hour. LCMS showed no starting material remaining. The reaction solution was concentrated, and the residue was extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated to give an orange solid. Ethyl acetate (170 mL) was added, and the reaction was carried out at 50 °C for 2 hours. LCMS showed the reaction was complete. The reaction solution was concentrated, and the residue was purified by column chromatography (tetrahydrofuran / petroleum ether: 0-20%) to give (8aR,11R)-tert-butyl-4,6-difluoro-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyrano[1',2':4,5]pyrano[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester (2.9 g, yield: 74.1%), as an orange solid.

[0735] MS m / z: 436.2 [M+H] +

[0736] Step 5: (8aR,11R)-tert-butyl-6-((S)-2-((tert-butyldimethylsilyl)oxo)-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-4-fluoro-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyrano[1',2':4,5]pyrano[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester

[0737]

[0738] Sodium hydrogen (620.0 mg, 15.50 mmol, 60% purity, 3 eq) was dissolved in tetrahydrofuran (40 mL), purged with nitrogen, and (S)-2-((tert-butyldimethylsilyl)oxo)-1-((S)-1-methylpyrrolidone-2-yl)ethanol (1.61 g, 6.20 mmol, 1.2 eq) was added at 0 °C. After stirring at 0 °C for half an hour, (8aR,11R)-tert-butyl-4,6-difluoro-3-methoxy-11-methyl-8-oxoylide-8a,9,11,12-tetrahydro-7H-pyranadiazono[1',2':4,5]pyranadiazono[2,3-c][1,6]naphthidine-10(8H)-carboxylic acid ester (2.25 g, 5.17 mmol, 1 eq) was added, and the reaction was carried out at 0 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was quenched in a saturated ammonium chloride aqueous solution at 0°C and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (methanol / dichloromethane: 0-3%) to give (8aR,11R)-tert-butyl-6-((S)-2-((tert-butyldimethylsilyl)oxo)-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-4-fluoro-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyrano[1',2':4,5]pyrano[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester (2.56 g, yield: 73.41%).

[0739] MS m / z: 675.5 [M+H] +

[0740] Step 6: (8aR,11R)-tert-butyl-4-fluoro-6-((S)-2-hydroxy-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyrano[1',2':4,5]pyrano[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester

[0741]

[0742] (8aR,11R)-tert-butyl-6-((S)-2-((tert-butyldimethylsilyl)oxo)-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-4-fluoro-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyrano[1',2':4,5]pyrano[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester (2.5 g, 3.70 mmol, 1 eq) was dissolved in a mixture of tetrahydrofuran (7.5 mL), acetic acid (32.5 mL), and water (17.5 mL), and reacted overnight at 40 °C. The reaction was monitored by LCMS until complete. The reaction solution was diluted with water, the pH was adjusted to 7-8 with sodium bicarbonate, and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was filtered, concentrated, and purified by column chromatography (methanol / dichloromethane: 0-5%) to give (8aR,11R)-tert-butyl-4-fluoro-6-((S)-2-hydroxy-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyrano[1',2':4,5]pyrano[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester (1.15 g, yield: 55.4%), an orange oil.

[0743] MS m / z: 561.3 [M+H] + .

[0744] Step 7: (2R,4aR,7R)-tert-butyl-10-fluoro-11-methoxy-2-methyl-7-((S)-1-methylpyrrolidone-2-yl)-5-oxoylide-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-formate

[0745]

[0746] Triphenylphosphine (1.54 g, 5.89 mmol, 3 eq) was dissolved in tetrahydrofuran (20 mL). Diisopropyl azodicarbonate (1.19 g, 5.89 mmol, 1.14 mL, 3 eq) was added at 0 °C. After reacting at 0 °C for 30 min, (8aR,11R)-tert-butyl-4-fluoro-6-((S)-2-hydroxy-1-((S)-1-methylpyrrolidone-2-yl)ethoxy)-3-methoxy-11-methyl-8-carbonyl-8a,9,11,12-tetrahydro-7H-pyranadiazono[1',2':4,5]pyranadiazono[2,3-c][1,6]diazanaphthalene-10(8H)-carboxylic acid ester (1.1 g, 1.96 mmol, 1 eq) was added, and the reaction was allowed to proceed overnight at room temperature. The reaction was monitored by LCMS until complete. The reaction solution was quenched with water, extracted with ethyl acetate, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the filtrate was concentrated. The residue was purified by column chromatography (methanol / dichloromethane: 0-5%) to give (2R,4aR,7R)-tert-butyl-10-fluoro-11-methoxy-2-methyl-7-((S)-1-methylpyrrolidine-2-yl)-5-oxoylide-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (700 mg, yield: 65.8%), a yellow solid.

[0747] MS m / z: 543.2 [M+H] +

[0748] Step 8: (2R,4aR,7R)-tert-butyl-10-fluoro-11-hydroxy-2-methyl-7-((S)-1-methylpyrrolidone-2-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0749]

[0750] (2R,4aR,7R)-tert-butyl-10-fluoro-11-methoxy-2-methyl-7-((S)-1-methylpyrrolidone-2-yl)-5-oxoylide-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (300 mg, 0.553 mmol, 1 eq) was dissolved in hydroiodic acid (2 mL, 45% purity) and water (5 mL), and reacted at 80 °C for 1 h. The reaction was monitored by LCMS until complete. The pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate. Tetrahydrofuran (4 mL) and Boc anhydride (295.4 mg, 1.35 mmol, 2 eq) were added to the reaction solution, and the reaction was carried out at room temperature for 3 h. The reaction was monitored by LCMS until complete. The reaction solution was filtered and concentrated. The crude product was prepared by HPLC to obtain (2R,4aR,7R)-tert-butyl-10-fluoro-11-hydroxy-2-methyl-7-((S)-1-methylpyrrolidine-2-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (0.1 g, yield: 28.0%), a yellow solid.

[0751] MS m / z: 529.3 [M+H] +

[0752] HPLC separation conditions:

[0753] Column: Reverse-phase C18, imported spherical silica gel, 40-60μm, 120g, 28g

[0754] Mobile phase A: Water

[0755] Mobile phase B: ACN

[0756] Mobile phase B%: 0%-30%.

[0757] Step 9: (2R,4aR,7R)-tert-butyl-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidone-2-yl)-5-carbonyl-11-(((trifluoromethyl)sulfonyl)oxo)-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0758]

[0759] (2R,4aR,7R)-tert-butyl-10-fluoro-11-hydroxy-2-methyl-7-((S)-1-methylpyrrolidine-2-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (70 mg, 0.132 mmol, 1 eq) and pyridine (31.4 mg, 0.397 mmol, 3 eq) were dissolved in dichloromethane (1 mL). Trifluoromethanesulfonic anhydride (56.1 mg, 0.199 mmol, 1.5 eq) was added at 0 °C, and the reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was quenched with water, extracted with dichloromethane, and the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The residue was filtered, concentrated, and purified by column chromatography (methanol / dichloromethane: 0-5%) to give (2R,4aR,7R)-tert-butyl-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidone-2-yl)-5-carbonyl-11-(((trifluoromethyl)sulfonyl)oxo)-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (87 mg, yield: 99.4%), a yellow solid.

[0760] MS m / z: 661.3 [M+H] +

[0761] Step 10: (2R,4aR,7R)-tert-butyl-11-bromo-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidone-2-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0762]

[0763] (2R,4aR,7R)-tert-butyl-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidin-2-yl)-5-carbonyl-11-(((trifluoromethyl)sulfonyl)oxo)-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (80 mg, 0.121 mmol, 1 eq) and sodium bromide (62.3 mg, 0.605 mmol, 5 eq) were dissolved in acetonitrile (1 mL). Trifluoromethanesulfonic acid (181.7 mg, 1.21 mmol, 10 eq) was slowly added dropwise at 0 °C, and the reaction was carried out at 50 °C for 4 hours. The reaction was monitored by LC-MS to ensure complete reaction. The pH of the reaction solution was adjusted to 7-8 with sodium bicarbonate aqueous solution. Add 5 mL of tetrahydrofuran, 5 mL of water, and 2 eq of Boc anhydride to the reaction mixture and react overnight at room temperature. Monitor the reaction for completeness using LC-MS. Extract the reaction mixture with ethyl acetate, wash the organic phase with saturated brine, and dry it over anhydrous sodium sulfate. The residue was filtered, concentrated, and separated by TLC (petroleum ether: tetrahydrofuran + 0.5% ammonia = 1:1) to give (2R,4aR,7R)-tert-butyl-11-bromo-10-fluoro-2-methyl-7-((S)-1-methylpyrrolidine-2-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,12,13c-pentazonaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (40 mg, yield: 56.3%), a yellow oil.

[0764] MS m / z:591.2 / 593.2[M+H] +

[0765] Intermediate 8: 4,7-Dichloro-8-fluoro-3-nitro-1,6-naphthidine-2-ol

[0766]

[0767] Step 1: tert-butyl (2-chloro-3-fluoropyridin-4-yl)carbamate

[0768]

[0769] 2-Chloro-3-fluoroisonicotinic acid (100.0 g, 0.571 mol, 1 eq), 4A molecular sieve (300.0 g), and triethylamine (173.1 g, 1.714 mol, 3 eq) were dissolved in toluene (1 L) and tert-butanol (1 L). The mixture was stirred at 110 °C for 1 hour, cooled to room temperature, and diphenyl azidophosphate (236.0 g, 0.857 mol, 1.5 eq) was added. The mixture was stirred at 110 °C for 16 hours. The reaction was monitored by LCMS until complete. The reaction mixture was filtered, the filtrate was concentrated, and the residue was extracted with water and ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The solution was passed through a silica gel column (ethyl acetate / petroleum ether = 1 / 10, v / v) to give tert-butyl(2-chloro-3-fluoropyridin-4-yl)carbamate (124.0 g, 88% yield) as a pale yellow solid.

[0770] MS m / z: 190.9 / 192.9 [M+H-56] + .

[0771] 1 H NMR (400MHz, DMSO-d6) δ9.95 (s, 1H), 8.10 (d, J = 5.6Hz, 1H), 7.96 (t, J = 5.6Hz, 1H), 1.50 (s, 9H).

[0772] Step 2: 2-Chloro-3-Fluoropyridine-4-amine

[0773]

[0774] 124.0 g (0.504 mol, 1 eq) of tert-butyl(2-chloro-3-fluoropyridin-4-yl)carbamate was dissolved in 1,4-dioxane / hydrochloric acid (1.3 L, 4 M). The mixture was stirred at room temperature for 16 hours, and the reaction was monitored by LC-MS until complete. The solid was filtered, washed with ethyl acetate, and dried under reduced pressure to give 110.0 g (crude) of 2-chloro-3-fluoropyridin-4-amine hydrochloride as a white solid. 2-chloro-3-fluoropyridin-4-amine hydrochloride (110.0 g, 0.504 mol, 1 eq) was dissolved in water (2 L). Sodium bicarbonate (423.4 g, 5.04 mol, 10 eq) was added while stirring. The mixture was stirred at room temperature for two hours, and the reaction was monitored by TLC until complete. The mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 65.0 g (88% yield) of 2-chloro-3-fluoropyridin-4-amine as a white solid.

[0775] MS m / z: 146.9 / 148.8 [M+H] + .

[0776] 1H NMR (400MHz, DMSO-d6) δ7.68 (d, 5.6Hz, 1H), 6.69 (t, J = 6.4Hz, 1H), 6.58 (s, 2H).

[0777] Step 3: 2-Chloro-3-fluoro-5-iodopyridine-4-amine

[0778]

[0779] 2-Chloro-3-fluoropyridin-4-amine (65.0 g, 0.445 mol, 1 eq) was dissolved in glacial acetic acid (650 mL), and N-iodosuccinimide (104.7 g, 0.467 mol, 1.05 eq) was added. The mixture was stirred at 120 °C for 16 hours. The reaction was monitored by LCMS until complete. The mixture was concentrated under reduced pressure and passed through a silica gel column (ethyl acetate / petroleum ether = 1 / 5, v / v) to give 2-chloro-3-fluoro-5-iodopyridin-4-amine (101.0 g, yield 83%) as a yellow solid.

[0780] MS m / z: 272.9 / 274.9 [M+H] + .

[0781] 1 H NMR (400MHz, DMSO-d6) δ8.10 (s, 1H), 6.67 (s, 2H).

[0782] Step 4: Ethyl 4-amino-6-chloro-5-fluoronicotinic acid

[0783]

[0784] 4-Amino-2-chloro-3-fluoro-5-iodopyridine (30 g, 110.3 mmol, 1.0 eq), triethylamine (33.4 g, 330.9 mmol, 3.0 eq), and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (8.07 g, 11.03 mmol, 0.1 eq) were dissolved in ethanol (750 mL). The mixture was purged twice with carbon monoxide gas and reacted overnight at 80°C under carbon monoxide protection. The reaction solution was cooled to room temperature and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 5 / 1 / 1, v / v) to give ethyl 4-amino-6-chloro-5-fluoronicotinic acid (19.6 g, yield 81%), an off-white solid.

[0785] MS m / z: 218.9 / 220.8 [M+H] + .

[0786] 1H NMR (400MHz, DMSO-d6) δ8.38 (s, 1H), 7.59 (s, 2H), 4.35-4.29 (m, 2H), 1.32 (t, J = 7.2Hz, 3H).

[0787] Step 5: Ethyl 6-chloro-4-(3-ethoxy-3-oxypropionamide)-5-fluoronicotinic acid

[0788]

[0789] Ethyl 4-amino-6-chloro-5-fluoronicotinic acid (31.5 g, 144.5 mmol, 1.0 eq) was dissolved in 1,2-dichloroethane (630 mL), and then monoethyl malonate chloride (43.5 g, 289 mmol, 2.0 eq) was slowly added. The mixture was purged twice with nitrogen gas and reacted overnight at 80°C under nitrogen protection. The reaction solution was cooled to room temperature and concentrated. The concentrate residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate / dichloromethane = 3 / 1 / 1, v / v) to give ethyl 6-chloro-4-(3-ethoxy-3-oxypropionamide)-5-fluoronicotinic acid (39.4 g, yield 82.1%), a white solid.

[0790] MS m / z: 332.9 / 334.8 [M+H] + .

[0791] 1 H NMR (400MHz, DMSO-d6) δ10.80(s,1H),8.52(s,1H),4.27-4.22(m,2H),4.15-4.09(m,2H),3.59(s,2H),1.27(t,J=7.2Hz,3H),1.20(t,J=7.2Hz,3H).

[0792] Step 6: Ethyl 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthyl-3-carboxylate

[0793]

[0794] Ethyl 6-chloro-4-(3-ethoxy-3-oxypropionamide)-5-fluoronicotinic acid (17.5 g, 52.59 mmol, 1.0 eq) was dissolved in tetrahydrofuran solution (300 mL), and potassium tert-butoxide (1.8 g, 105.19 mmol, 2.0 eq) was added at 0°C. The reaction was carried out at room temperature for 1 hour. The pH was adjusted to 5 with 2 M hydrochloric acid, filtered, and dried to give ethyl 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthidine-3-carboxylic acid (14.5 g, 96% yield) as a white solid.

[0795] MS m / z: 287.1 [M+H] +.

[0796] 1 H NMR (400MHz, DMSO-d6) δ12.27(br s,1H),8.71(s,1H),4.31(q,J=7.2Hz,2H),1.29(t,J=7.2Hz,3H).

[0797] Step 7: 7-Chloro-8-fluoro-1,6-naphthidine-2,4-diol

[0798]

[0799] Ethyl 7-chloro-8-fluoro-2,4-dihydroxy-1,6-naphthidine-3-carboxylic acid (14.5 g, 50.58 mmol, 1.0 eq) was dissolved in dioxane (100 mL) and concentrated hydrochloric acid (100 mL) and reacted overnight at 90°C. The dioxane was removed by rotary evaporation, the mixture was filtered, the solid was washed with a small amount of water, and dried to give a white solid 7-chloro-8-fluoro-1,6-naphthidine-2,4-diol (11.2 g, 90% yield).

[0800] MS m / z: 215.0 [M+H] + .

[0801] 1 H NMR (400MHz, DMSO-d6) δ12.09(br s,1H),11.97(br s,1H),8.54(s,1H),5.81(s,1H).

[0802] Step 8: 7-Chloro-8-fluoro-3-nitro-1,6-naphthidine-2,4-diol

[0803]

[0804] 7-Chloro-8-fluoro-1,6-naphthidine-2,4-diol (8 g, 37.3 mmol, 1 eq) was dissolved in concentrated sulfuric acid (32 mL) at 0°C. Concentrated nitric acid (8 mL) was slowly added dropwise while stirring for 20 minutes, followed by stirring at room temperature for approximately 2 hours. After the reaction was monitored by LCMS until complete, the reaction solution was poured into an appropriate amount of ice water and stirred. The solution was filtered, washed with an appropriate amount of water, and dried to obtain 7-chloro-8-fluoro-3-nitro-1,6-naphthidine-2,4-diol (8.2 g, 80% yield), a yellow solid.

[0805] MS m / z: 259.9 [M+H] + .

[0806] 1 H NMR(400MHz,DMSO-d6)δ11.72(br s,1H),8.71(s,1H).

[0807] Step 9: 4,7-Dichloro-8-fluoro-3-nitro-1,6-naphthidine-2-ol

[0808]

[0809] 7-Chloro-8-fluoro-3-nitro-1,6-naphthidine-2,4-diol (3.0 g, 11.56 mmol, 1.0 eq) was dissolved in phosphorus oxychloride solution (20 mL), and N,N-diisopropylethylamine (3.0 g, 23.12 mmol, 2.0 eq) was added dropwise at 0°C. The reaction was carried out at 50°C for 1 hour. The mixture was concentrated, and ethyl acetate (60 mL) was added. The mixture was washed with sodium bicarbonate solution, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1, v / v) to give a yellow solid 4,7-dichloro-8-fluoro-3-nitro-1,6-naphthidine-2-ol (2.5 g, 78% yield).

[0810] MS m / z: 276.0 [MH] - .

[0811] Example 1: Compound 1-P1 methanesulfonate and Compound 1-P2 methanesulfonate

[0812] (2R,4aR,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one methanesulfonate and (2R,4aR,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one methanesulfonate

[0813]

[0814] Step 1: (2R,4aR)-tert-butyl-10-bromo-7-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0815]

[0816] In a 250 mL three-necked flask, 2-((tert-butyldimethylsilyl)oxo)ethanol (2.9 g, 16.478 mmol, 2.2 eq) was added and dissolved in toluene (75 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and sodium hydroxide (749 mg, 18.725 mmol, 2.5 eq) was added. The mixture was stirred at 0 °C for 0.5 hours, and then (2R,4aR)-tert-butyl-10-bromo-7,11-dichloro- 9-Fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (4 g, 7.49 mmol, 1 eq) was added and allowed to rise naturally to room temperature. The mixture was stirred at room temperature until the reactants were completely reacted. Saturated brine was slowly added, and the mixture was extracted three times with ethyl acetate. The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give (2R,4aR)-tert-butyl-10-bromo-7-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.6 g, yield 51.5%).

[0817] MS m / z: 673.2 / 675.2 [M+H] + .

[0818] 1 H NMR (400MHz, DMSO-d6) δ10.48(s,1H),7.77(d,J=1.6Hz,1H),4.60-4.54(m,3H),4.21(d,J=52.4Hz,1H),4.02(t,J=6.0Hz,2H),3.8 (d,J=28.8Hz,1H),3.42-3.38(m,1H),2.95(t,J=13.2Hz,1H),2.82-2.75(m,1H),1.44(d,J=9.6Hz,12H),0.81(s,9H),0.04(s,6H).

[0819] Step 2: (2R,4aR)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-(2-hydroxyethoxy)-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0820]

[0821] In a 250 mL single-necked flask, add (2R,4aR)-tert-butyl-10-bromo-7-(2-((tert-butyldimethylsilyl)oxo)ethoxy)-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.6 g, 3.86 mmol, 1 eq), dissolve in anhydrous tetrahydrofuran (85 mL), under nitrogen protection, and add tetrabutylammonium fluoride tetrahydrofuran solution. The solution (10 mL) was stirred at room temperature until the reactants reacted completely. The solvent was evaporated to dryness, and the product was dissolved in ethyl acetate. The organic phase was then washed several times with brine, and the sodium sulfate was dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness to obtain crude (2.3 g) (2R,4aR)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-(2-hydroxyethoxy)-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester, a yellow solid. This was used directly in the next reaction.

[0822] MS m / z:559.1 / 561.1[M+H] + .

[0823] 1 H NMR (400MHz, DMSO-d6) δ10.54(s,1H),7.78(d,J=1.6Hz,1H),5.02(t,J=6.8Hz,1H),4.65-4.56(m,1H),4.44-4.39(m,2H),4.2 9-4.14(m,1H),3.89-3.76(m,3H),3.44-3.40(m,1H),2.97(t,J=13.2Hz,1H),2.83(t,J=11.6Hz,1H),1.44(d,J=9.6Hz,12H).

[0824] Step 3: (2R,4aR)-tert-butyl-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0825]

[0826] In a 500 mL three-necked flask, add (2R,4aR)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-(2-hydroxyethoxy)-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.25 g, 4.018 mmol, 1 eq), triphenylphosphine (4.2 g, 16.072 mmol, 4 eq), tetrahydrofuran (90 mL), and diisopropyl azodicarbonate (3.25 g, 16.072 mmol, 1 eq). Under argon protection, the mixture was stirred at room temperature until the reactants were completely reacted. Saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give (2R,4aR)-tert-butyl-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (2.05 g, yield 98.1%).

[0827] MS m / z:541.3 / 543.3[M+H] + .

[0828] 1 H NMR(400MHz,DMSO-d6)δ7.80(d,J=1.6Hz,1H),4.72-4.59(m,2H),4.43-4.35(m,2H),4.20(d,J=16.4Hz,1 H),3.91(d,J=23.2Hz,1H),3.58-3.45(m,2H),3.04-2.96(m,1H),2.90-2.86(m,1H),1.45-1.43(m,12H).

[0829] Step 4: (2R,4aR)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0830]

[0831] In a 100 mL reaction tube, add (2R,4aR)-tert-butyl-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (660 mg, 1.215 mmol, 1 eq), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)boronic acid (601 mg, 1.8225 mmol, 1.5 eq), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy). The reaction mixture consisted of 2-amino-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (203 mg, 0.243 mmol, 0.2 eq), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (283 mg, 0.6075 mmol, 0.5 eq), potassium phosphate (773 mg, 3.645 mmol, 3 eq), toluene (35 mL), ethanol (17.5 mL), and water (17.5 mL). The reaction was carried out under argon protection at 80 °C for 4 hours. Heating was then stopped, saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (dichloromethane:methanol = 15:1) to give (2R,4aR)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (335 mg, yield 36.9%).

[0832] MS m / z:747.2 / 749.2[M+H] + .

[0833] 1 H NMR (400MHz, DMSO-d6) δ12.20(s,1H),8.86(s,1H),7.84(t,J=1.6Hz,1H),7.53-7.47(m,1H),4.80-4.63(m,3H),4.45-4.36(m,2H),4.29-4 .20(m,1H),3.96(d,J=23.2Hz,1H),3.62-3.57(m,1H),3.56-3.49(m,1H),2.95(d,J=6.0Hz,1H),1.47-1.43(m,15H),1.18(d,J=6.4Hz,6H).

[0834] Step 5: (2R,4aR)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[0835]

[0836] In a 100 mL single-necked flask, add (2R,4aR)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl)-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (335 mg, 0.448 mmol, 1 eq) and dichloromethane (8 mL). L) Dissolve, under nitrogen protection, add trifluoroacetic acid (4 mL), stir at room temperature until the reactants react completely, evaporate the solvent to obtain crude (2R,4aR)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (355 mg), which can be used directly in the next step of the reaction.

[0837] MS m / z: 547.2 / 549.2 [M+H] + .

[0838] Step 6: Compound 1-P1 and Compound 1-P2

[0839] (2R,4aR,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (2R,4aR,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[0840]

[0841] In a 100 mL single-necked flask, add (2R,4aR)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (355 mg, 0.448 mmol, 1 eq), add acetonitrile (6 mL), and reduce... The mixture was heated to 0°C, and N,N-diisopropylethylamine (578 mg, 4.48 mmol, 10 eq), acrylic acid (48 mg, 0.672 mmol, 1.5 eq), and 1-propylphosphoric anhydride (50% ethyl acetate solution) (570 mg, 0.896 mmol, 2 eq) were added. The mixture was stirred at 0°C until the reaction was complete. Saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (ethyl acetate:methanol = 25:1) to give compound 1-P1 (26 mg, yield 9.7%) and compound 1-P2 (29 mg, yield 10.8%).

[0842] Compound 1-P1:

[0843] MS m / z:601.1 / 603.1[M+H] + .

[0844] 1 H NMR (400MHz, DMSO-d6) δ8.10(s,1H),7.83(s,1H),7.16(t,J=9.6Hz,1H),7.05-6.75(m,1H),6.15(d,J=16.4Hz,1H),5.76(d,J=10.8Hz,1H),5 .23-4.65(m,3H),4.41(d,J=12.4Hz,2H),4.06-4.02(m,1H),3.79(d,J =14.4Hz,1H),3.70-3.50(m,1H),3.12-2.92(m,2H),1.56-1.50(m,3H).

[0845] 13 C NMR(101MHz,DMSO-d6)δ169.01,164.66,163.48,157.00,155.67,154.56,153.13,151.66,137.59,130.99,129.85,128 .72,127.29,122.25,118.30,117.66,116.43,112.29,105.90,96.28,65.13,55.22,51.28,43.62,37.68,36.98,14.54.

[0846] 19 F NMR(376MHz,DMSO-d6)δ-109.905(s,1F),-115.399(s,1F),-119.216(s,1F).

[0847] Compound 1-P2:

[0848] MS m / z:601.1 / 603.1[M+H] + .

[0849] 1 H NMR (400MHz, DMSO-d6) δ8.11(s,1H),7.84(d,J=6.0Hz,1H),7.16(t,J=10.0Hz,1H),7 .07-6.76(m,1H),6.15(dd,J=2.4,14.4Hz,1H),5.76(dd,J=2.4,8Hz,1H),5.22-4.65( m,3H),4.44-4.38(m,2H),4.08-4.03(m,1H),3.80(dd,J=4.4,10.0Hz,1H),3.62-3.55 (m,1H),3.19(dd,J=2.4,10.0Hz,1H),2.93(dd,J=4.0,8.4Hz,1H),1.63-1.50(m,3H).

[0850] 13 C NMR(101MHz,DMSO-d6)δ168.99,164.63,163.63,157.09,155.68,154.54,153.14,151.66,137.62,130.96,129.77,128 .75,127.25,122.32,118.26,117.66,116.63,112.76,105.93,96.28,65.11,55.27,51.16,43.73,37.67,37.02,14.50.

[0851] 19 F NMR(376MHz,DMSO-d6)δ-109.919(s,1F),-115.488(s,1F),-118.910(s,1F).

[0852] Step 7: Compound 1-P1 methanesulfonate and Compound 1-P2 methanesulfonate

[0853] (2R,4aR,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one methanesulfonate and (2R,4aR,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one methanesulfonate

[0854]

[0855] Compound 1-P1 (60 mg, 0.1 mmol, 1 eq) was dissolved in acetone (9 mL). A solution of methanesulfonic acid (9 mg, 0.097 mmol, 0.97 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 0.5 h and then reacted at 40 °C for 0.5 h. The reaction solution was concentrated, and the residue was slurried with ethyl acetate to give compound 1-P1 methanesulfonate (46 mg, yield 66%) as a white solid.

[0856] MS m / z:601.1 / 603.1[M+H] + .

[0857] 1 H NMR (400MHz, DMSO-d6) δ8.10(s,2H),7.82(s,1H),7.17(t,J=10.0Hz,1H),7.08-6.75(m,1H),6.14(d,J=16.8Hz,1H),5.76(d,J=10.8Hz,1H),5.20 -4.62(m,3H),4.50-4.34(m,2H),4.06-4.01(m,1H),3.81-3.77(m,1H),3 .57(t,J=12.4Hz,1H),3.11-2.91(m,2H),2.42(s,3H),1.60-1.50(m,3H).

[0858] 13C NMR(101MHz,DMSO-d6)δ169.11,164.75,163.60,157.10,155.78,154.66,153.23,151.79,137.69,131.07,129.91,128 .83,127.40,122.28,118.34,117.78,116.64,112.33,106.00,96.45,65.22,55.31,51.37,43.72,37.78,37.08,14.65.

[0859] 19 F NMR(376MHz, DMSO-d6)δ-109.912(s,1F),-115.425(s,1F),-119.234(s,1F).

[0860] Compound 1-P2 (78 mg, 0.13 mmol, 1 eq) was dissolved in acetone (12 mL), and a solution of methanesulfonic acid (12 mg, 0.126 mmol, 0.97 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate to give compound 1-P2 methanesulfonate (67 mg, yield 73.9%) as a white solid.

[0861] MS m / z:601.1 / 603.1[M+H] + .

[0862] 1 H NMR (400MHz, DMSO-d6) δ8.10 (s, 2H), 7.83 (s, 1H), 7.18 (t, J = 10.0Hz, 1H), 7.06-6.75 (m, 1H), 6.16-6.12 (m, 1H), 5.77-5.74 (m, 1H), 5.15-4.6 4(m,3H),4.42-4.38(m,2H),4.07-4.02(m,1H),3.82-3.77(m,1H),3.5 8(t,J=12.4Hz,1H),3.40-2.85(m,2H),2.39(s,3H),1.60-1.50(m,3H).

[0863] 13C NMR(101MHz,DMSO-d6)δ169.06,164.71,163.71,157.11,155.75,154.62,153.21,151.75,137.71,131.03,129.81,128 .85,127.35,122.30,118.31,117.75,116.74,112.30,106.03,96.42,65.19,55.35,51.25,43.81,37.74,37.10,14.59.

[0864] 19 F NMR(376MHz, DMSO-d6)δ-109.910(s,1F),-115.464(s,1F),-118.935(s,1F).

[0865] Example 2: Compound 2-P1 and Compound 2-P2

[0866] (2R,4aR,11S)-3-Acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (2R,4aR,11R)-3-Acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[0867]

[0868] Step 1: Compounds 2-1-1 and 2-1-2

[0869] (2R,4aR,11S)-tert-butyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester and (2R,4aR,11R)-tert-butyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0870]

[0871] In a 100 mL reaction tube, add (2R,4aR)-tert-butyl-11-bromo-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (400 mg, 0.737 mmol, 1 eq), potassium trifluoro(2-fluoro-6-hydroxyphenyl)borate (321 mg, 1.473 mmol, 2 eq), and methanesulfonic acid (2-bicyclo[2-di ... Hexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (62 mg, 0.0737 mmol, 0.1 eq), potassium carbonate (305 mg, 2.211 mmol, 3 eq), 1,4-dioxane (7.2 mL), and water (2.4 mL) were reacted under argon protection at 85 °C for 4 hours. Heating was then stopped, saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (ethyl acetate:methanol = 25:1) to give compound 2-1-1 (105 mg, yield 24.9%) and compound 2-1-2 (120 mg, yield 28.4%).

[0872] Compound 2-1-1:

[0873] MS m / z: 573.2 / 575.2 [M+H] + .

[0874] 1 H NMR (400MHz, DMSO-d6) δ10.32(s,1H),7.80(d,J=1.6Hz,1H),7.36-7.30(m,1H),6.91(d,J=8.4Hz,1H),6.77(t,J=8.8Hz,1H),4.70-4.64(m,2H ),4.43-4.36(m,2H),4.23(d,J=46.4Hz,1H),3.97-3.91(m,1H),3.60- 3.47(m,2H),3.10-3.01(m,1H),2.94-2.90(m,1H),1.46-1.43(m,12H).

[0875] Compound 2-1-2:

[0876] MS m / z: 573.2 / 575.2 [M+H] + .

[0877] 1H NMR (400MHz, DMSO-d6) δ10.32(s,1H),7.80(s,1H),7.32(q,J=7.6Hz,1H),6.92(d,J=8.4Hz,1H) ,6.77(t,J=8.8Hz,1H),4.70-4.61(m,2H),4.43-4.36(m,2H),4.22(d,J=48.8Hz,1H),3.93(d,J =22.8Hz,1H),3.60-3.47(m,2H),3.11-3.03(m,1H),1.45-1.43(m,12H).

[0878] Step 2: Compounds 2-2-1 and 2-2-2

[0879] (2R,4aR,11S)-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (2R,4aR,11R)-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[0880]

[0881] In a 100 mL single-necked flask, compound 2-1-1 (105 mg, 0.183 mmol, 1 eq) was added and dissolved in dichloromethane (4 mL). Under nitrogen protection, trifluoroacetic acid (2 mL) was added and stirred at room temperature until the reactants were completely reacted. The solvent was then evaporated to obtain crude compound 2-2-1 (115 mg), which was used directly in the next reaction.

[0882] MS m / z: 473.3 / 475.3 [M+H] + .

[0883] The synthesis of compound 2-2-2 was the same as that of compound 2-2-1, crude product (131 mg).

[0884] MS m / z: 473.3 / 475.3 [M+H] + .

[0885] Step 3: Compounds 2-3-1 and 2-3-2

[0886] 2-((2R,4aR,11S)-3-acryloyl-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,3,4,4a,5,6,7-octahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-11-yl)-3-fluorophenylacryloyl ester and 2-((2R,4aR,11R)-3-acryloyl-12-chloro-10-fluoro-2-methyl-5-carbonyl-1,2,3,4,4a,5,6,7-octahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-11-yl)-3-fluorophenylacryloyl ester

[0887]

[0888] In a 100 mL single-necked flask, compound 2-2-1 (115 mg, 0.183 mmol, 1 eq) was added and dissolved in dichloromethane (5 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and triethylamine (185 mg, 1.83 mmol, 10 eq) and acryloyl chloride (38 mg, 0.421 mmol, 2.3 eq) were added. The mixture was stirred at 0 °C until the reactants were completely reacted. Water was added, and the mixture was extracted with dichloromethane. The extract was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude compound 2-3-1 (110 mg). This crude compound was used directly in the next step.

[0889] MS m / z: 581.5 / 583.5 [M+H] + .

[0890] 1 H NMR(400MHz,DMSO-d6)δ7.82(d,J=7.6Hz,1H),7.71-7.65(m,1H),7.41-7.33(m,2H),7.00 (dd,J=6.4,10.4Hz,1H),6.30-6.25(m,1H),6.17-6.07(m,2H),5.99-5.96(m,1H),5.78-5 .74(m,1H),4.75-4.62(m,2H),4.41-4.36(m,2H),4.03-3.97(m,1H),3.78(dd,J=4.4,10. 4Hz,1H),3.60-3.55(m,1H),3.08(d,J=12.4Hz,1H),3.01-2.92(m,2H),1.55-1.47(m,3H).

[0891] The synthesis of compound 2-3-2 was the same as that of compound 2-3-1. The crude product (110 mg) was used directly in the next step.

[0892] MS m / z: 581.5 / 583.5 [M+H] + .

[0893] 1 H NMR (400MHz, DMSO-d6) δ7.82(d,J=7.6Hz,1H),7.71-7.65(m,1H),7.4(t,J=8.8Hz,1H),7.34(d,J=8.4Hz,1H ),7.00(dd,J=6.4,10.4Hz,1H),6.26(dd,J=1.6,15.6Hz,1H),6.16-6.04(m,2H),5.97(dd,J=1.6,8.8Hz,1H) ,5.77-5.74(m,1H),4.70-4.62(m,2H),4.42-4.36(m,2H),4.06-4.01(m,1H),3.78(dd,J=4.4,10.4Hz,1H),3 .58-3.51(m,1H),3.17(d,J=12.0Hz,1H),3.09-2.99(m,1H),2.91(dd,J=4.0,8.4Hz,1H),1.55-1.47(m,3H).

[0894] Step 4: Compound 2-P1 and Compound 2-P2

[0895] (2R,4aR,11S)-3-Acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (2R,4aR,11R)-3-Acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[0896]

[0897] In a 100 mL single-necked flask, compound 2-3-1 (110 mg, 0.183 mmol, 1 eq), dichloromethane (0.5 mL), and ammonia-methanol (3 mL) were added. Under argon protection, the mixture was stirred at room temperature until the reactants were completely reacted. The solvent was evaporated to obtain the crude product. The crude product was purified by preparative plate (ethyl acetate:methanol = 16:1) to obtain compound 2-P1 (29 mg, yield 30%).

[0898] MS m / z: 527.4 / 529.4 [M+H] + .

[0899] 1 H NMR (400MHz, DMSO-d6) δ10.33(s,1H),7.82(s,1H),7.33(q,J=8.0Hz,1H),7 .04-6.90(m,2H),6.82-6.75(m,1H),6.14(d,J=16.8Hz,1H),5.76(d,J=10.8 Hz,1H),5.15-4.63(m,3H),4.40(d,J=12.0Hz,2H),4.05-4.01(m,1H),3.79 (d,J=14.0Hz,1H),3.60-3.51(m,1H),3.25-2.90(m,2H),1.60-1.50(m,3H).

[0900] 13 C NMR(101MHz,DMSO-d6)δ164.64,163.50,161.30,158.89,156.9,155.53,152.99,151.53,137.66,13 0.9,130.08,128.72,127.27,121.97,117.72,116.52,111.69,107.7,105.41,65.09,55.22,51.18, 43.69,37.66,37.0,14.5.

[0901] 19 F NMR(376MHz,DMSO-d6)δ-113.725(s,1F),-119.727(s,1F).

[0902] The synthesis of compound 2-P2 was the same as that of compound 2-P1, with a yield of 32%, and it was a white solid.

[0903] MS m / z: 527.4 / 529.4 [M+H] + .

[0904] 1H NMR (400MHz, DMSO-d6) δ10.28(s,1H),7.84(s,1H),7.33(q,J=8.0Hz,1H),7.01(dd,J=6.0,10.8 Hz,1H),6.90(d,J=8.0Hz,1H),6.81-6.76(m,1H),6.15(dd,J=2.4,14.4Hz,1H),5.76(dd,J=2.4 ,8.0Hz,1H),5.20-4.64(m,3H),4.40(d,J=11.6Hz,2H),4.06-4.01(m,1H),3.79(dd,J=4.0,10. 4Hz,1H),3.61-3.54(m,1H),3.20-3.16(m,1H),2.91(dd,J=4.0,8.4Hz,1H),1.58-1.50(m,3H).

[0905] 13 C NMR(101MHz,DMSO-d6)δ164.64,163.50,161.38,158.97,156.79,155.58,153.05,151.55,137.59,130.97,130.03 ,128.74,127.26,122.01,117.6,116.54,111.68,107.75,105.48,65.10,55.26,51.17,43.7,37.67,37.01,14.49.

[0906] 19 F NMR(376MHz,DMSO-d6)δ-113.715(s,1F),-119.499(s,1F).

[0907] Example 3: Compound 3-P1 methanesulfonate and Compound 3-P2 methanesulfonate

[0908] (4aR,7R,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate

[0909]

[0910] Step 1: (R)-tert-butyl-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-yl)oxo)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0911]

[0912] In a 500 mL three-necked flask, (R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-ol (15 g, 64.62 mmol, 2.4 eq) was added and dissolved in toluene (280 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and sodium hydroxide (2.58 g, 64.62 mmol, 2.4 eq) was added. The mixture was stirred at 0 °C for 0.5 h, and then (R)-tert-butyl-10-bromo-7-... 14 g (26.92 mmol, 1 eq) of 11-dichloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester was added and allowed to rise naturally to room temperature. The mixture was stirred at room temperature until the reactants were completely reacted. Saturated brine was slowly added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 30:1) to give (R)-tert-butyl-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-yl)oxo)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.9 g, yield 15.05%).

[0913] MS m / z:716.2 / 718.2[M+H] + .

[0914] 1H NMR (400MHz, CDCl3) δ7.94 (s, 1H), 7.83 (d, J = 1.6Hz, 1H), 5.73-5.67 (m, 1 H),5.02-4.97(m,1H),4.18-4.11(m,1H),3.89-3.87(m,2H),3.60(s,1H), 3.29(d,J=13.2Hz,1H),3.19(br,1H),3.12-3.09(m,1H),2.84-2.73(m,2H ),2.63-2.58(m,1H),2.34(s,6H),0.82(s,9H),0.05(s,3H),0.01(s,3H).

[0915] Step 2: (R)-tert-butyl-10-bromo-11-chloro-7-(((R)-1-(dimethylamino)-3-hydroxypropane-2-yl)oxo)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[0916]

[0917] In a 250 mL single-necked flask, (R)-tert-butyl-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-yl)oxo)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.8 g, 3.92 mmol, 1 eq) was added and dissolved in anhydrous tetrahydrofuran (90 mL). Under nitrogen protection, a tetrabutylammonium fluoride tetrahydrofuran solution was added. 10 mL), stirred at room temperature until the reactants reacted completely, the solvent was evaporated, dissolved in ethyl acetate, and the organic phase was washed several times with brine. The sodium sulfate was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain (R)-tert-butyl-10-bromo-11-chloro-7-(((R)-1-(dimethylamino)-3-hydroxypropane-2-yl)oxo)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.4 g), which was directly used in the next step of the reaction.

[0918] MS m / z:602.1 / 604.1[M+H] + .

[0919] 1H NMR (400MHz, DMSO-d6) δ10.48(s,1H),7.94(s,1H),5.43(t,J=4.8Hz,1H),4.71(d,J=13.2H z,1H),3.91-3.67(m,4H),3.19-3.14(m,4H),2.74-2.60(m,2H),2.37(s,6H),1.44(s,9H).

[0920] Step 3: (4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0921]

[0922] In a 500 mL three-necked flask, add (R)-tert-butyl-10-bromo-11-chloro-7-(((R)-1-(dimethylamino)-3-hydroxypropane-2-yl)oxo)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.4 g, 3.99 mmol, 1 eq), triphenylphosphine (4.18 g, 15.97 mmol, 4 eq), tetrahydrofuran (100 mL), and diisopropyl azodicarbonate (3.23 g, 15.9 mmol, 1 eq). 7 mmol (4 eq) was added under argon protection and stirred at room temperature until the reactants were completely reacted. Saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give (4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (1.9 g, yield 81.5%).

[0923] MS m / z:584.3 / 586.3[M+H] + .

[0924] Step 4: (4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0925]

[0926] In a 100 mL reaction tube, add (4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (1.8 g, 3.09 mmol, 1 eq), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)boronic acid (2.04 g, 6.18 mmol, 2 eq), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'- Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (517 mg, 0.618 mmol, 0.2 eq), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (721 mg, 1.545 mmol, 0.5 eq), potassium phosphate (1.965 g, 9.27 mmol, 3 eq), toluene (96 mL), ethanol (48 mL), water (48 mL), under argon protection, the reaction was carried out at 80 °C for 4 hours. Heating was stopped, saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (dichloromethane:methanol = 15:1) to give (4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (438 mg, yield 17.9%).

[0927] MS m / z:790.3 / 792.3[M+H] + .

[0928] 1 H NMR (400MHz, DMSO-d6) δ12.19(s,1H),7.99(d,J=4.0Hz,1H),7.53-7.47(m,1H),4.93(d,J=16.8Hz,1H),4.76(d,J=13.6Hz,1H),4 .25-4.06(m,2H),3.94(br,1H),3.85-3.74(m,1H),3.28-3.19(m,3H),2.83-2.62(m,3H),2.30(s,6H),1.46(s,9H),1.45(s,9H).

[0929] Step 5: (4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[0930]

[0931] In a 100 mL single-necked flask, add (4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (400 mg, 0.507 mmol, 1 eq) and dichloromethane (18... Dissolve the sample in mL, add trifluoroacetic acid (9 mL) under nitrogen protection, stir at room temperature until the reactants are completely reacted, and evaporate the solvent to obtain crude (4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (455 mg), which can be used directly in the next step of the reaction.

[0932] MS m / z:590.1 / 592.1[M+H] + .

[0933] Step 6: Compounds 3-P1 and 3-P2

[0934] (4aR,7R,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[0935]

[0936] In a 100 mL single-necked flask, add (4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (455 mg, 0.507 mmol, 1 eq), and add acetonitrile (2... 5 mL of N,N-diisopropylethylamine (654 mg, 5.07 mmol, 10 eq) and acrylic acid (55 mg, 0.76 mmol, 1.5 eq) were added. 1-Propylphosphine anhydride (50% ethyl acetate solution) (322 mg, 1.01 mmol, 2 eq) was added. The mixture was stirred at 0°C until the reaction was complete. Saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (ethyl acetate:methanol = 25:1) to give compound 3-P1 (75 mg, yield 23%) and compound 3-P2 (64 mg, yield 19.6%).

[0937] Compound 3-P1:

[0938] MS m / z: 644.2 / 646.2 [M+H] + .

[0939] Compound 3-P2:

[0940] MS m / z: 644.2 / 646.2 [M+H] + .

[0941] Retention time (compound 3-P1): 2.758 min; retention time (compound 3-P2): 3.990 min.

[0942] Column: Chiralcel OD-3 100*4.6mm ID, 3um.

[0943] Mobile phase: A: CO2, B: ethanol (0.05% DEA), Isocratic elution: 40% B.

[0944] Flow rate: 2.8 mL / min.

[0945] Column temperature: 35℃.

[0946] ABPR: 1500psi.

[0947] Step 7: Compound 3-P1 methanesulfonate and compound 3-P2 methanesulfonate

[0948] (4aR,7R,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate

[0949]

[0950] Compound 3-P1 (75 mg, 0.11645 mmol, 1 eq) was dissolved in acetone (20 mL), and a solution of methanesulfonic acid (11 mg, 0.111 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 0.5 h, and then reacted at 40 °C for 0.5 h. The reaction solution was concentrated, and the residue was slurried with ethyl acetate to give compound 3-P1 methanesulfonate (66 mg, yield: 76.57%, white solid).

[0951] MS m / z: 644.2 / 646.2 [M+H] + .

[0952] 1 H NMR (400MHz, DMSO-d6) δ9.92(br s,1H),8.06(br s,3H),7.20(br t,J=9.23Hz,1H),7.10-6.68(m,1H),6.17(br d,J=16.14Hz,1H),5.78(br d,J=9.66Hz,1H),5.35-5.03(m,1H),4.81(br d,J=13.57Hz,1H),4.45(br d,J=10.64Hz,1H),4.25-3.91(m,3H),3.77-3.55(m,2H),3.30-3.15(m,2H),3.00-2.71(m,7H),2.31(br s,3H).

[0953] 13C NMR (101MHz, DMSO-d6) δ169.50,165.00,159.90,157.60,157.50,156.20,155.20,154.80,153.60,150.40,138.10,131.50,131.40,131. 00,128.80,127.70,123.30,119.00,118.90,117.60,112.90,112.70,106.40,106.20,97.10,96.80,96.50,70.20,57.30,55.80,48.10.

[0954] 19 F NMR(376MHz, DMSO-d6)δ-109.81(br s,1F),-115.65(br s,1F),-118.97(brs,1F).

[0955] The synthesis of compound 3-P2 methanesulfonate was the same as that of compound 3-P1 methanesulfonate, with a yield of 43% and a white solid.

[0956] MS m / z: 644.2 / 646.2 [M+H] + .

[0957] 1 H NMR(400MHz, DMSO-d6)δ9.82(br s,1H),8.11(s,2H),8.06(s,1H),7.25-7.16(m,1H),7.13-6.99(m,1H),6.19(d,J=2.01Hz,1H),5.78(br d,J=11.29Hz,1H),5.40-5.25(m,1H),4.80(br d,J=14.05Hz,1H),4.47(br d,J=12.30Hz,1H),4.22-4.09(m,2H),3.91(br d,J=11.29Hz,1H),3.69(br d,J=11.29Hz,1H),3.64-3.41(m,1H),3.31-3.17(m,1H),2.94-2.75(m,7H),2.31(s,3H).

[0958] 13C NMR(101MHz,DMSO-d6)δ169.50,164.90,164.60,159.80,157.40,157.30,156.20,155.20,155.00,155.00,153.60,150.40,138.10, 131.60,131.50,130.90,128.80,127.80,123.20,119.10,117.50,112.80,112.70,106.20,97.10,96.80,70.20,57.20,55.6,48.10.

[0959] 19 F NMR(376MHz, DMSO-d6)δ-109.79(s,1F),-115.70(s,1F),-118.99(s,1F).

[0960] Example 4: Compound 4-P1 and Compound 4-P2

[0961] (4aR,7R,11S)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthraphen-5(1H)-one and (4aR,7R,11R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthraphen-5(1H)-one

[0962]

[0963] Step 1: (4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0964]

[0965] The following substances were administered: (4aR,7R)-tert-butyl11-bromo-12-chloro-7-(((dimethylamino)methyl)-10-fluoro-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (80 mg, 0.14 mmol, 1 eq), (5-methyl-1H-indoleazol-4-yl)boronic acid (49 mg, 0.28 mmol, 2 eq), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (11 mg, 0.028 mmol, 0.2 eq), and tris(dibenzylene-BASEacetone)dipalladium (13 mg, 0.014 mmol, 0.1 eq). 1,4-dioxane (2 mL) and sodium bicarbonate (35 mg, 0.42 mmol, 3.0 eq) were dissolved in 1,4-dioxane (2 mL) and water (0.5 mL), and the mixture was microwaved at 120°C for 2 hours. The reaction solution was concentrated, and the residue was subjected to silica gel column chromatography (mobile phase methanol / dichloromethane = 10 / 1, v / v) to give a yellow solid (4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (80 mg, yield 79%).

[0966] MS m / z: 636.3 / 638.2 [M+H] + .

[0967] Step 2: (4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthyl[3,2,1-de]anthraphen-5(1H)-one

[0968]

[0969] (4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (80 mg, 0.11 mmol, 1.0 eq) was dissolved in dichloromethane (2 mL). Trifluoroacetic acid (2 mL) was added dropwise at 0°C, and the reaction was carried out at room temperature for 2 hours. The mixture was then concentrated to obtain crude (4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthyl[3,2,1-de]anthraphen-5(1H)-one (80 mg), which was used directly in the next step of the reaction.

[0970] MS m / z:536.2 / 538.1[M+H] + .

[0971] Step 3: Compounds 4-P1 and 4-P2

[0972] (4aR,7R,11S)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthraphen-5(1H)-one and (4aR,7R,11R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthraphen-5(1H)-one

[0973]

[0974] (4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxo-3,5a,9,13c-tetraazanaphthyl[3,2,1-de]anthraphen-5(1H)-one crude product (80 mg, 0.15 mmol, 1.0 eq), N,N-diisopropylethylamine (154 mg, 1.19 mmol, 8.0 eq) were dissolved in acetonitrile (4 mL), acrylic acid (13 mg, 0.18 mmol, 1.2 eq) was added, and 1-propylphosphonic anhydride (50% ethyl acetate solution) (143 mg, 0.22 mmol, 1.5 eq) was added at 0°C. The reaction was carried out at room temperature for 2 hours. The concentrated residue was purified by column chromatography (dichloromethane / methanol = 10 / 1, volume ratio) to give compound 4-P1 (5 mg, yield 11%, white solid) and compound 4-P2 (5 mg, yield 11%, white solid).

[0975] Compound 4-P1:

[0976] MS m / z: 590.2 / 592.2 [M+H] + .

[0977] 1 H NMR(400MHz,DMSO-d6)δ13.15(s,1H),8.07(s,1H),7.58(d,J=8.4Hz,1H),7.48(s,1H),7 .39(d,J=8.4Hz,1H),7.10-7.04(m,1H),6.17-6.13(m,1H),5.76(d,J=10.8Hz,1H),4.88- 4.79(m,2H),4.46(d,J=12.4Hz,1H),4.22-4.19(m,2H),3.75-3.64(m,2H),3.40-3.37(m ,1H),3.25-3.19(m,1H),2.83-2.78(m,1H),2.51-2.50(m,2H),2.22(s,6H),2.15(s,3H).

[0978] Compound 4-P2:

[0979] MS m / z: 590.2 / 592.2 [M+H] + .

[0980] 1H NMR(400MHz,DMSO-d6)δ13.16(s,1H),8.07(s,1H),7.57(d,J=8.4Hz,1H),7.52(s,1H), 7.39(d,J=8.8Hz,1H),7.10-7.04(m,1H),6.18-6.13(m,1H),5.77-5.74(m,1H),4.87-4. 78(m,2H),4.47(d,J=13.6Hz,1H),4.24-4.19(m,2H),3.75-3.70(m,2H),3.42-3.37(m, 1H),3.26-3.20(m,1H),2.84-2.79(m,1H),2.56-2.50(m,2H),2.21(s,6H),2.13(s,3H).

[0981] Example 5: Compound 5-P1 and Compound 5-P2

[0982] (4aR,7S,11R)-3-acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-(hydroxymethyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthra-5(1H)-one and (4aR,7S,11S)-3-acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-(hydroxymethyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthra-5(1H)-one

[0983]

[0984] Step 1: Compounds 5-1-1 and 5-1-2

[0985] (4aR,7S,11R)-tert-butyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-((((4-methoxybenzyl)oxy)methyl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester and (4aR,7S,11S)-tert-butyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-((((4-methoxybenzyl)oxy)methyl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[0986]

[0987] The following medications were administered: (4aR,7S)-tert-butyl-11-bromo-12-chloro-10-fluoro-7-((((4-methoxybenzyl)oxy)methyl)-5-oxo-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtheno[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (250 mg, 0.37 mmol, 1.0 eq), 2-dicyclohexylphosphine-2′,6′-dimethoxy-biphenyl (29 mg, 0.07 mmol, 0.2 eq), tris(dibenzylacetone)dipalladium (37 mg, 0.04 mmol, 0.1 eq), and sodium bicarbonate (124 mg, 1.48 mmol). 4.0 eq) of 1,4-dioxane (5 mL) and water (1.5 mL) were dissolved and heated to 120°C. The mixture was stirred at 120°C for 5 minutes under nitrogen protection. 2-Fluoro-6-hydroxyphenyl)boronic acid (173 mg, 1.11 mmol, 3 eq) was dissolved in dioxane (2 mL) and slowly added dropwise to the reaction mixture. The mixture was stirred at 120°C for 3 hours under nitrogen protection. The reaction mixture was concentrated, and the residue was subjected to silica gel column chromatography (mobile phase methanol / dichloromethane = 100 / 1-75 / 1, v / v) to give compound 5-1-1 (50 mg, 19% yield, yellow solid) and compound 5-1-2 (50 mg, 19% yield, yellow solid).

[0988] Compound 5-1-1:

[0989] MS m / z: 709.3 / 711.2 [M+H] + .

[0990] Compound 5-1-2:

[0991] MS m / z:709.3 / 711.3[M+H] + .

[0992] Step 2: Compounds 5-2-1 and 5-2-2

[0993] (4aR,7S,11R)-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-(hydroxymethyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthra-5(1H)-one and (4aR,7S,11S)-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-(hydroxymethyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthra-5(1H)-one

[0994]

[0995] Compound 5-1-1 (50 mg, 0.07 mmol, 1.0 eq) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added dropwise at 0°C. The reaction was carried out at 0°C for 1 hour, and the mixture was concentrated to obtain crude compound 5-2-1 (50 mg).

[0996] MS m / z:489.0 / 491.0[M+H] + .

[0997] The synthesis of compound 5-2-2 is the same as that of compound 5-2-1. Crude product (52 mg) is a yellow solid.

[0998] MS m / z:489.0 / 491.0[M+H] + .

[0999] Step 3: Compounds 5-P1 and 5-P2

[1000] (4aR,7S,11R)-3-acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-(hydroxymethyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthra-5(1H)-one and (4aR,7S,11S)-3-acryloyl-12-chloro-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-7-(hydroxymethyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphthalene[3,2,1-de]anthra-5(1H)-one

[1001]

[1002] Compound 5-2-1 (100 mg, 0.14 mmol, 1.0 eq) and N,N-diisopropylethylamine (126 mg, 0.98 mmol, 7.0 eq) were dissolved in acetonitrile (2 mL), and acrylic acid (10 mg, 0.14 mmol, 1.0 eq) was added. 1-propylphosphonic anhydride (50% ethyl acetate solution) (134 mg, 0.21 mmol, 1.5 eq) was added at 0°C, and the mixture was stirred at 0°C for 1 hour. Water was added, and the mixture was extracted with dichloromethane. The organic phase was concentrated, and the residue was subjected to silica gel column chromatography (mobile phase methanol / dichloromethane = 20 / 1, v / v) to give compound 5-P1 (25 mg, 32% yield, white solid).

[1003] Compound 5-P1:

[1004] MS m / z: 543.2 / 545.2 [M+H] + .

[1005] 1 H NMR (400MHz, DMSO-d6) δ10.19(s,1H),7.98(s,1H),7.34(d,J=7.2Hz,1H),7.07(t,J=9.2Hz,1 H),6.86-6.80(m,2H),6.16(d,J=16.8Hz,1H),5.76(d,J=9.6Hz,1H),5.21(s,1H),4.79(d,J= 13.2Hz,1H),4.67(s,1H),4.44(d,J=11.2Hz,1H),4.21-4.06(m,2H),3.80-3.63(m,4H),3.36-3.18(m,2H),2.78-2.73(m,1H).

[1006] The synthesis of compound 5-P2 was the same as that of compound 5-P1, with a yield of 36%, and it was a white solid.

[1007] Compound 5-P2:

[1008] MS m / z: 543.2 / 545.2 [M+H] + .

[1009] 1 H NMR (400MHz, DMSO-d6) δ10.21(s,1H),7.98(s,1H),7.34(q,J=7.6Hz,1H),7. 08-7.03(m,1H),6.86-6.77(m,2H),6.15(d,J=16.0Hz,1H),5.76(d,J=9.6Hz, 1H),5.20(s,1H),4.79(d,J=13.2Hz,1H),4.68(s,1H),4.45(d,J=12.4Hz,1H) ,4.23-4.06(m,2H),3.79-3.62(m,4H),3.35-3.18(m,2H),2.78-2.73(m,1H).

[1010] Example 6: Compound 6

[1011] (4aR)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2,3,4,4a,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one-8,8-dioxide

[1012]

[1013] Step 1: (R)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-((2-hydroxyethyl)thio)-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[1014]

[1015] (R)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (0.9 g, 1.73 mmol, 1 eq) was dissolved in dioxane (18 mL), and 2-mercaptoethanol (0.210 g, 2.69 mmol, 1.55 eq) and cesium carbonate (1.41 g, 4.33 mmol, 2.5 eq) were added. The reaction was carried out at 60 °C for 4 hours. The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0%-55%) to give (R)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-((2-hydroxyethyl)thio)-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (0.55 g, yield: 56.6%), a white solid.

[1016] MS m / z:561.3 / 563.3[M+H] + .

[1017] 1 H NMR (400MHz, CDCl3) δ7.92(d,J=1.76Hz,1H),7.78(br s,1H),5.01(br d,J=13.30Hz,1H),4.30-4.01(m,4H),3.94(t,J=5.65Hz,2H),3.63(br s,1H),1.54(s,9H).

[1018] Step 2: (R)-tert-butyl-11-bromo-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1019]

[1020] (R)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-((2-hydroxyethyl)thio)-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (0.5 g, 0.890 mmol, 1 eq) was dissolved in toluene (15 mL), and N,N,N',N'-tetramethylazodicarbonamide (459.69 mg, 2.67 mmol, 3 eq) and tributylphosphine (540.14 mg, 2.67 mmol, 3 eq) were added. The reaction was allowed to proceed at room temperature for three hours, and the reaction was monitored by LCMS until completion. The reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-50%) to give crude (0.4 g) (R)-tert-butyl-11-bromo-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester.

[1021] MS m / z:543.1 / 545.1[M+H] + .

[1022] 1 H NMR (400MHz, CDCl3) δ7.91 (d, J=1.76Hz, 1H), 5.34-5.26 (m, 1H), 5.02 (br d, J=12.30Hz, 1H), 4.22 (br s, 1H), 3.59 (br s,1H),3.40-3.31(m,3H),3.28-3.15(m,3H),2.79(td,J=3.01,11.92Hz,1H),1.56(s,9H).

[1023] Step 3: (R)-tert-butyl-11-bromo-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester-8,8-dioxide

[1024]

[1025] (R)-tert-butyl-11-bromo-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (0.5 g, 0.919 mmol, 1 eq) was dissolved in dichloromethane (10 mL), and m-chloroperoxybenzoic acid (634.63 mg, 3.68 mmol, 4 eq) was added at 0 °C. The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by LC-MS until complete. The reaction solution was poured into a saturated sodium sulfite aqueous solution and stirred for 0.5 hours. The mixture was then separated, and the organic phase was dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and column purification of the residue (tetrahydrofuran / petroleum ether: 0-55%) yielded (R)-tert-butyl-11-bromo-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester-8,8-dioxide (0.22 g, yield: 41.6%), a white solid.

[1026] MS m / z: 574.9 / 576.9 [M+H] + .

[1027] Step 4: (4aR)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thiazo-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylate-8,8-dioxide

[1028]

[1029] The (R)-tert-butyl-11-bromo-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester-8,8-dioxide (0.3 g, 0.521 mmol, 1 eq) and (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)boronic acid (343.97 m Dissolve 1.04 mg (2 eq) of dioxane (6 mL) and water (1.2 mL), add potassium carbonate (57.60 mg, 0.417 mmol, 3 eq) and (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium (65.36 mg, 0.0782 mmol, 0.15 eq), and microwave heat to 100 °C for 1 hour under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction solution was filtered and concentrated. The residue was purified by column chromatography (tetrahydrofuran / petroleum ether: 0-50%) to give (4aR)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester-8,8-dioxide (0.04 g, yield: 9.8%), a white solid.

[1030] MS m / z:781.1 / 783.1[M+H] + .

[1031] Step 5: (4aR)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2,3,4,4a,6,7-hexahydro-8-thiazo-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one-8,8-dioxide

[1032]

[1033] (4aR)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester-8,8-dioxide (0.07 g, 0.0896 mmol, 1 eq) and trifluoroacetic acid (462.00 mg, 4.05 mmol, 45.22 eq) were dissolved in dichloromethane (1 mL) and reacted at room temperature for 2 hours. The reaction was monitored by LCMS until complete. The reaction solution was concentrated to obtain crude (4aR)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2,3,4,4a,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one-8,8-dioxide (50 mg), which was used directly in the next step.

[1034] MS m / z:581.0 / 583.0[M+H] + .

[1035] Step 6: Compound 6

[1036] (4aR)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2,3,4,4a,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one-8,8-dioxide

[1037]

[1038] (4aR)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl)-12-chloro-10-fluoro-2,3,4,4a,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one-8,8-dioxide (52 mg, 0.0895 mmol, 1 eq), N,N-diisopropylethylamine (34.70 mg, 0.268 mmol, 3 eq), and acrylic acid (9.67 mg, 0.134 mmol, 1.5 eq) were dissolved in acetonitrile (1 mL), and tri-n-propylcyclophosphine (113.91 mg, 0.179 mmol, 50% purity, 2 eq) was added. The reaction was carried out at room temperature for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated and purified by HPLC to obtain (4aR)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2,3,4,4a,6,7-hexahydro-8-thia-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one-8,8-dioxide (10 mg, yield: 17.5%), a white solid.

[1039] MS m / z: 634.9 / 636.9 [M+H] + .

[1040] 1 H NMR (400MHz, CD3OD) δ8.25(br s,1H),7.15(br dd,J=10.2,16.4Hz,1H),7.02-6.87(m,1H),6.27(br d,J=16.8Hz,1H),5.84(br d,J=10.3Hz,1H),5.20(br s,1H),4.62-4.57(m,1H),4.23-4.01(m,2H),3.96-3.76(m,3H),3.57-3.42(m,1H),3.27-3.09(m,2H),3.04-2.92(m,1H).

[1041] Example 7: Compound 7-P1 methanesulfonate and Compound 7-P2 methanesulfonate

[1042] (2R,4aR,7R,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (2R,4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate

[1043]

[1044] Step 1: (2R,4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1045]

[1046] The following were prepared: (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (1.8 g, 3.01 mmol, 1 eq), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl)boronic acid (1.98 g, 6.01 mmol, 2 eq), and methanesulfonic acid ( 2-Dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium(II) (502.75 mg, 0.60-1.11 mmol, 0.2 eq), potassium phosphate (1.91 g, 9.02 mmol, 3 eq), and 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (701.25 mg, 1.50 mmol, 0.5 eq) were dissolved in water (8 mL), ethanol (8 mL), and toluene (16 mL). The mixture was purged three times with nitrogen and reacted overnight at 80 °C. The reaction was monitored by LC-MS until complete. The reaction solution was diluted with water and extracted with ethyl acetate. The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. Filtration, concentration of the filtrate, and column purification of the residue (tetrahydrofuran / petroleum ether: 0-40%) yielded (2R,4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (800 mg, yield: 16.55%), a white solid.

[1047] MS m / z:804.3 / 806.3[M+H] + .

[1048] Step 2: (2R,4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1049]

[1050] (2R,4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (650 mg, 0.808 mmol, 1 eq) was dissolved in dichloromethane (8 mL), and trifluoroacetic acid (6 mL) was added at 0 °C. The reaction was carried out at room temperature for 5 hours. The reaction was monitored by LCMS until complete. The reaction solution was concentrated to obtain crude (480 mg) (2R,4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one, a brown oily substance. This crude product was directly used in the next step.

[1051] MS m / z:604.1 / 606.0[M+H] + .

[1052] Step 3: Compound 7, Compound 7-P1 and Compound 7-P2

[1053] (2R,4aR,7R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (Compound 7)

[1054]

[1055] (2R,4aR,7R,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (2R,4aR, 7R,11S)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (compounds 7-P1 and 7-P2)

[1056]

[1057] (2R,4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (480 mg, 0.795 mmol, 1 eq) and acrylic acid (85.90 mg, 1.19 mmol, 1.5 eq) were dissolved in acetonitrile (5 mL). N,N-diisopropylethylamine (1.03 g, 7.95 mmol, 1.38 mL, 10 eq) and an ethyl acetate solution of propyl phosphoric anhydride (1.01 g, 1.59 mmol, 50% content, 2 eq) were added, and the mixture was reacted overnight at room temperature. The reaction was monitored by LCMS until complete, the reaction solution was concentrated, and the residue was separated by HPLC to prepare (2R,4aR,7R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (compound 7).

[1058] Compound 7:

[1059] MS m / z: 658.2 / 660.2 [M+H] + .

[1060] Compound 7 was purified by SFC to give compound 7-P1 (75 mg, white solid, yield 14.34%) and compound 7-P2 (85 mg, white solid, yield 16.25%).

[1061] Compound 7-P1:

[1062] MS m / z: 658.2 / 660.2 [M+H] + .

[1063] Compound 7-P2:

[1064] MS m / z: 658.2 / 660.2 [M+H] + .

[1065] HPLC separation conditions:

[1066] Column: Phenomenex Gemini-NX 80*40mm*3um; Mobile phase A: Water (0.05% ammoniahydroxide v / v), Mobile phase B: ACN;

[1067] Mobile phase B%: 34%-74%, 9 min.

[1068] SFC separation conditions:

[1069] Column: DAICEL CHIRALPAK AS (250mm*30mm, 10um); Mobile phase A: 0.1% NH3H2O, Mobile phase B: Ethanol;

[1070] Mobile phase B%: 35%-35%, min.

[1071] Retention time (compound 7-P1): 0.916 min; retention time (compound 7-P2): 1.260 min.

[1072] Column: Chiralcel OD-3 50*4.6mm ID, 3um

[1073] Mobile phase: A: CO2, B: Methanol (0.05% DEA), Isocratic: 40% B

[1074] Flow rate: 4 mL / min

[1075] Column temperature: 35℃

[1076] ABPR: 1500psi

[1077] Step 4: Compound 7-P1 methanesulfonate and compound 7-P2 methanesulfonate

[1078] (2R,4aR,7R,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (2R,4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate

[1079]

[1080] Compound 7-P1 (65 mg, 0.099 mmol, 1 eq) was dissolved in acetone (2 mL). A solution of methanesulfonic acid (9 mg, 0.094 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 7-P1 methanesulfonate (65 mg, yield 86.62%, white solid).

[1081] MS m / z: 658.2 / 660.2 [M+H] + .

[1082] 19 F NMR(376MHz, DMSO-d6)δ-109.77(s,1F),-115.69(s,1F),-118.84(s,1F).

[1083] 1 H NMR(400MHz,DMSO-d6)δ9.99(br s,1H),8.07(br s,2H),7.94-7.81(m,1H),7.20(t,J=9.8Hz,1H),7.08-6.76(m,1H),6.15(dd,J=1.9,16.8Hz,1H),5.81-5.68(m,1H),5.25(br s,1H),5.17-4.35(m,2H),4.23-4.11(m,1H),4.08-3.92(m,2H),3.83(br dd,J=3.6,14.1Hz,1H),3.73-3.57(m,1H),3.53-3.42(m,1H),3.28-3.14(m,1H),3.09-2.96(m,1H),2.87(br s,6H),2.30(s,3H),1.61-1.42(m,3H).

[1084] 13 C NMR(101MHz,DMSO-d6)δ169.5,165.1,164.8,157.7,156.2,155.0,154.8,153.7,150.4,138.2,131.4,130.8,1 29.1,128.6,127.8,123.1,119.0,118.9,117.6,117.3,112.8,96.8,70.2,57.2,55.9,51.8,44.4,37.5,15.0.

[1085] Compound 7-P2 (85.48 mg, 0.130 mmol, 1 eq) was dissolved in acetone (2 mL). A solution of methanesulfonic acid (12 mg, 0.123 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 7-P2 methanesulfonate (70 mg, yield 70.68%, white solid).

[1086] MS m / z: 658.2 / 660.2 [M+H] + .

[1087] 19 F NMR(376MHz, DMSO-d6)δ-109.75(s,1F),-115.71(s,1F),-118.79(s,1F).

[1088] 1 H NMR(400MHz,DMSO-d6)δ9.80(br s,1H),8.09(br s,2H),7.95-7.82(m,1H),7.20(t,J=9.8Hz,1H),7.08-6.75(m,1H),6.16(dd,J=1.9,16.8Hz,1H),5.85-5.66(m,1H),5.31(br d,J=8.6Hz,1H),5.16-4.40(m,2H),4.23-4.10(m,2H),3.99-3.78(m,2H),3.72-3.55(m,1H),3.50-3.40(m,1H),3.18(br d,J=11.4Hz,1H),3.11-2.98(m,1H),2.95-2.74(m,6H),2.37-2.24(m,3H),1.65-1.43(m,3H).

[1089] 13C NMR(101MHz,DMSO-d6)δ169.5,165.6,165.1,164.4,159.7,157.7,157.5,157.4,15 7.3,156.2,155.2,155.0,154.9,153.7,150.3,138.3,131.7,131.5,130.8,129.1,1 28.5,127.9,123.0,119.1,118.9,118.1,117.5,117.1,112.9,112.7,106.3,106.1,97.1,96.8,96.5,70.1,57.1,55.7,51.9,48.0,44.8,44.3,42.5,37.4,16.6,15.0.

[1090] Example 8: Compound 8-P1 and Compound 8-P2

[1091] (2R,4aR,7R,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (2R,4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[1092]

[1093] Step 1: (R)-1-((tert-butyldimethylsilyl)oxo)propane-2-ol

[1094]

[1095] In a 250 mL three-necked flask, (R)-1,2-propanediol (5 g, 65.7 mmol, 1 eq) and imidazole (4.47 g, 65.7 mmol, 1 eq) were added and dissolved in anhydrous dichloromethane (40 mL). Under nitrogen protection, the mixture was cooled to 0 °C. Tert-butyldimethylsilyl chloride (9.9 g, 65.7 mmol, 1 eq) was dissolved in dichloromethane (5 mL) and slowly added dropwise to the system. The reaction was carried out at 0 °C until the reactants were completely reacted. The mixture was filtered and evaporated to dryness to obtain (R)-1-((tert-butyldimethylsilyl)oxo)propane-2-ol (11.2 g), which was used directly in the next step.

[1096] MS m / z: 191.2 [M+H] + .

[1097] 1 H NMR (400MHz, CDCl3) δ3.84-3.78(m,1H),3.61-3.57(m,1H),3.37-3.32(m,1H),2.25(br s,1H),1.11(d,J=6.0Hz,3H),0.90(s,9H),0.07(s,6H).

[1098] Step 2: (2R,4aR)-tert-butyl-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxo)propane-2-yl)oxo)-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[1099]

[1100] In a 250 mL three-necked flask, (R)-1-((tert-butyldimethylsilyl)oxo)propane-2-ol (2.35 g, 12.35 mmol, 2.2 eq) was added and dissolved in toluene (55 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and (539 mg, 13.48 mmol, 2.4 eq) was added. The mixture was stirred at 0 °C for 0.5 hours, and then (2R,4aR)-tert-butyl-10-bromo-7,11-dioxane was added. Chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (3 g, 5.616 mmol, 1 eq) was added and allowed to rise naturally to room temperature. The mixture was stirred at room temperature until the reactants were completely reacted. Saturated brine was slowly added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 40:1) to give (2R,4aR)-tert-butyl-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxo)propane-2-yl)oxo)-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.3 g, yield 59.5%).

[1101] MS m / z: 687.2 / 689.2 [M+H] + .

[1102] 1H NMR (400MHz, DMSO-d6) δ10.43(d,J=10.8Hz,1H),7.75(d,J=1.6Hz,1H),5.52(q,J=6.4 Hz,1H),6.65-4.59(m,1H),4.31-4.26(m,1H),3.92-3.85(m,1H),3.70-3.66(m,1H),3 .61-3.45(m,1H),3.40(d,J=12.8Hz,1H),3.28-3.23(m,1H),2.96-2.90(m,1H),2.79- 2.73(m,1H),1.44(d,J=10.0Hz,12H),1.37(d,J=6.4Hz,3H),0.73(s,9H),0.00(s,6H).

[1103] Step 3: (2R,4aR)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-(((R)-1-hydroxypropane-2-yl)oxo)-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[1104]

[1105] In a 250 mL single-necked flask, (2R,4aR)-tert-butyl-10-bromo-7-(((R)-1-((tert-butyldimethylsilyl)oxo)propane-2-yl)oxo)-11-chloro-9-fluoro-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2.3 g, 3.34 mmol, 1 eq) was dissolved in anhydrous tetrahydrofuran (75 mL) under nitrogen protection, and then tetrabutylammonium fluoride tetrahydrofuran was added. The solution (8.5 mL) was stirred at room temperature until the reactants reacted completely. The solvent was evaporated to dryness, and the solution was dissolved in ethyl acetate. The organic phase was then washed several times with brine, and the sodium sulfate was dried over anhydrous sodium sulfate. The mixture was filtered and evaporated to dryness to obtain crude (2.06 g) (2R,4aR)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-(((R)-1-hydroxypropane-2-yl)oxo)-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester. This crude product was used directly in the next reaction.

[1106] MS m / z:573.1 / 575.1[M+H] + .

[1107] Step 4: (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-10-fluoro-2,7-dimethyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1108]

[1109] In a 500 mL three-necked flask, add (2R,4aR)-tert-butyl-10-bromo-11-chloro-9-fluoro-7-(((R)-1-hydroxypropane-2-yl)oxo)-2-methyl-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2 g, 3.48 mmol, 1 eq), triphenylphosphine (1.37 g, 5.22 mmol, 1.5 eq), anhydrous tetrahydrofuran (70 mL), and diisopropyl azodicarbonate (1.06 g, 5.2 mmol, 1 eq). 2 mmol (1.5 eq) was added under argon protection and stirred at room temperature until the reactants were completely reacted. Saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-10-fluoro-2,7-dimethyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (1.8 g, yield 93.2%).

[1110] MS m / z:555.1 / 557.1[M+H] + .

[1111] 1 H NMR(400MHz,DMSO-d6)δ7.83(d,J=1.6Hz,1H),4.90-4.86(m,1H),4.69-4.63(m,1H),4.28-4.1 6(m,1H),4.02-3.96(m,2H),3.82-3.78(m,1H),3.49-3.45(m,1H),3.05-2.91(m,1H),1.44(br s,12H),1.36(d,J=6.4Hz,3H).

[1112] Step 5: (2R,4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1113]

[1114] In a 250 mL three-necked flask, add (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-10-fluoro-2,7-dimethyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (900 mg, 1.62 mmol, 1 eq), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)boronic acid (802 mg, 2.43 mmol, 1.5 eq), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-di-di-2-di-2-ethylhexylphosphino-2',6' ... Isopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (271 mg, 0.324 mmol, 0.2 eq), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (377 mg, 0.81 mmol, 0.5 eq), potassium phosphate (1.03 g, 4.86 mmol, 3 eq), toluene (45 mL), ethanol (22.5 mL), water (22.5 mL), under argon protection, the reaction was carried out at 80 °C for 4 hours. Heating was stopped, saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (dichloromethane:methanol = 20:1) to give (2R,4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (230 mg, yield 18.7%).

[1115] MS m / z:761.2 / 763.2[M+H] + .

[1116] 1H NMR (400MHz, DMSO-d6) δ12.18(s,1H),7.85(d,J=2.8Hz,1H),7.52-7.47(m,1H),4.91-4.84(m,1H),4.72-4.65(m,1H),4.39-4.30(m, 1H),4.10-4.00(m,2H),3.89-3.80(m,1H),3.49(d,J=12.4Hz,1H),3.06-2.96(m,2H),1.47(d,J=2.0Hz,21H),1.38(t,J=6.4Hz,3H).

[1117] Step 6: (2R,4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1118]

[1119] In a 100 mL single-necked flask, add (2R,4aR,7R)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl)-12-chloro-10-fluoro-2,7-dimethyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (215 mg, 0.28 mmol, 1 eq) and dichloromethane (6 mL). L) Dissolve, under nitrogen protection, add trifluoroacetic acid (3 mL), stir at room temperature until the reactants react completely, evaporate the solvent to obtain crude (2R,4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl)-12-chloro-10-fluoro-2,7-dimethyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (230 mg), which can be used directly in the next step of the reaction.

[1120] MS m / z:561.1 / 563.1[M+H] + .

[1121] Step 7: Compounds 8-P1 and 8-P2

[1122] (2R,4aR,7R,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (2R,4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[1123]

[1124] In a 100 mL single-necked flask, add (2R,4aR,7R)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2,7-dimethyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (230 mg, 0.28 mmol, 1 eq), and add acetonitrile (4.5 g / mL). The mixture was cooled to 0°C, and N,N-diisopropylethylamine (361 mg, 2.8 mmol, 10 eq) and acrylic acid (30 mg, 0.42 mmol, 1.5 eq) were added. 1-Propylphosphine anhydride (50% ethyl acetate solution) (356 mg, 0.56 mmol, 2 eq) was added. The mixture was stirred at 0°C until the reaction was complete. Saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (ethyl acetate:methanol = 30:1) to give compound 8-P1 (20 mg, yield 11.6%, white solid) and compound 8-P2 (44 mg, yield 25.6%, white solid).

[1125] Compound 8-P1:

[1126] MS m / z: 615.1 / 617.1 [M+H] + .

[1127] 11H NMR (400 MHz, DMSO-d6) δ 8.16 (s, 2H), 7.84 (s, 1H), 7.15 (t, J = 10.0 Hz, 1H), 7.03 - 6.96 (m, 1H), 6.13 (dd, J = 2.4, 14.4 Hz, 1H), 5.77 - 5.73 (m, 1H), 4.85 - 4.82 (m, 1H), 4.74 - 4.71 (m, 1H), 4.66 (d, J = 14.4 Hz, 1H), 4.24 - 4.20 (m, 1H), 3.96 - 3.91 (m, 1H), 3.86 - 3.76 (m, 2H), 3.21 - 3.17 (m, 1H), 2.99 - 2.95 (m, 1H), 1.54 - 1.48 (m, 3H), 1.37 (d, J = 6.4 Hz, 3H).

[1128] 13 13C NMR (101 MHz, DMSO-d6) δ 169.05, 164.70, 164.62, 157.05, 155.73, 154.59, 153.19, 151.23, 137.42, 131.21, 129.87, 128.78, 127.32, 122.48, 118.30, 117.20, 116.72, 112.44, 105.97, 96.27, 71.08, 55.33, 51.27, 43.85, 42.57, 37.14, 17.54, 14.61.

[1129] 19 19F NMR (376 MHz, DMSO-d6) δ -110.048 (s, 1F), -115.617 (s, 1F), -118.948 (s, 1F).

[1130] Compound 8-P2:

[1131] MS m / z: 615.1 / 617.1 [M+H] + .

[1132] 1H NMR(400MHz,DMSO-d6)δ8.15(s,2H),7.84(s,1H),7.15(t,J=10.0Hz,1H),7.03- 6.96(m,1H),6.14(dd,J=2.4,14.4Hz,1H),5.77-5.74(m,1H),4.90-4.85(m,1H), 4.79-4.76(m,1H),4.67(d,J=14.4Hz,1H),4.20-4.15(m,1H),4.00-3.96(m,1H) ,3.84-3.76(m,2H),3.17-2.96(m,1H),1.56-1.50(m,3H),1.36(d,J=6.4Hz,3H).

[1133] 13 C NMR(101MHz,DMSO-d6)δ169.07,164.69,164.44,157.12,155.73,154.67,153.19,151.21,137.41,131.29,129.93,128.75 ,127.33,122.44,118.32,117.23,116.57,112.37,105.93,96.27,71.08,55.24,51.38,43.72,42.38,37.10,17.53,14.63.

[1134] 19 F NMR(376MHz, DMSO-d6)δ-110.014(s,1F),-115.660(s,1F),-119.296(s,1F).

[1135] Example 9: Compound 9, Compound 9-P1 and Compound 9-P2

[1136] (4aR,7S)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (Compound 9)

[1137]

[1138] (4aR,7S,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (4aR,7S, 11S)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (compounds 9-P1 and 9-P2)

[1139]

[1140] Step 1: (S)-3-(dimethylamino)propane-1,2-diol

[1141]

[1142] Sodium hydroxide (52.47 g, 1.31 mol, 14.5 eq) was dissolved in water (100 mL) and cooled to 0 °C. (R)-3-chloropropane-1,2-diol (10 g, 90.47 mmol, 1 eq) and N,N-dimethylamine hydrochloride (84.84 g, 1.04 mol, 11.5 eq) were added. The reaction was allowed to proceed overnight at room temperature. The reaction was monitored by TLC until complete. The mixture was filtered, and the filtrate was extracted with chloroform. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give crude (S)-3-(dimethylamino)propane-1,2-diol (3.8 g, yield: 35.25%), a colorless liquid.

[1143] 1 H NMR (400MHz, CDCl3) δ3.83-3.76(m,1H),3.72(d,J=3.8Hz,1H),3.70(d,J=3.5Hz,1H),3.50(dd ,J=4.9,11.4Hz,1H),2.54(dd,J=9.8,12.3Hz,1H),2.30(s,6H),2.22(dd,J=3.8,12.3Hz,1H).

[1144] Step 2: (S)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-ol

[1145]

[1146] (S)-3-(dimethylamino)propane-1,2-diol (4.32 g, 36.25 mmol, 1 eq) was added to dichloromethane (85 mL), followed by imidazole (3.70 g, 54.38 mmol, 1.5 eq). Dimethyl-tert-butylchlorosilane (5.19 g, 34.44 mmol, 0.95 eq) was added at 0 °C, and the reaction was carried out at room temperature for 2 hours. TLC (petroleum ether: ethyl acetate = 3:1) confirmed complete consumption of the starting material. The reaction mixture was extracted with water and dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography [tetrahydrofuran (0.1% ammonia) / petroleum ether: 0%-30%] to give (S)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-ol (6.2 g, yield: 73.27%), a colorless oily liquid.

[1147] 1 H NMR (400MHz, CDCl3) δ3.81-3.69(m,1H),3.62(d,J=5.0Hz,2H),3.44-2.66(m ,1H),2.47-2.36(m,1H),2.35-2.24(m,7H),0.92(s,9H),0.10-0.04(m,6H).

[1148] Step 3: (R)-tert-butyl-10-bromo-7-(((S)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-yl)oxo)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[1149]

[1150] (S)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-ol (4.08 g, 17.47 mmol, 2.02 eq) was dissolved in toluene (200 mL), and sodium hydrogen (830.40 mg, 20.76 mmol, 60% content, 2.4 eq) was added at 0 °C. After reacting at this temperature for half an hour, (R)-tert-butyl-10-bromo-7,11-dichloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (4.5 g, 8.65 mmol, 1 eq) was added, and the reaction was carried out at 50 °C for 4 hours. The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction was quenched with saturated ammonium chloride aqueous solution, extracted, and the organic phase was concentrated. The residue was purified by column chromatography (tetrahydrofuran / petroleum ether: 0%-55%) to give (R)-tert-butyl-10-bromo-7-(((S)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-yl)oxo)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester crude product (6.2 g), white solid.

[1151] MS m / z:716.4 / 718.4[M+H] + .

[1152] 1 H NMR(400MHz,DMSO-d6)δ10.53(br s,1H),7.98-7.89(m,1H),5.63-5.56(m,1H),4.72(br d,J=13.0Hz,1H),3.93-3.73(m,4H),3.25-3.13(m,3H),2.77-2.53(m,3H),2.23(s,6H),1.44(br s,9H),0.77(s,9H),0.01(d,J=1.2Hz,6H).

[1153] Step 4: (R)-tert-butyl-10-bromo-11-chloro-7-(((S)-1-(dimethylamino)-3-hydroxypropane-2-yl)oxo)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[1154]

[1155] (R)-tert-butyl-10-bromo-7-(((S)-1-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-2-yl)oxo)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (7.2 g, 10.04 mmol, 1 eq) was dissolved in tetrahydrofuran (120 mL), and tetrabutylammonium fluoride (1 M, 30.12 mL, 3 eq) was added. The reaction was carried out at room temperature for 4 hours. The reaction was monitored by LCMS until complete. The reaction solution was washed with saturated brine, the organic phase was concentrated, and the residue was purified by column chromatography (tetrahydrofuran / petroleum ether: 0-30%) to give crude (R)-tert-butyl-10-bromo-11-chloro-7-(((S)-1-(dimethylamino)-3-hydroxypropane-2-yl)oxo)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (2 g), a white solid.

[1156] MS m / z:602.8 / 604.8[M+H] + .

[1157] 1 H NMR (400MHz, CDCl3) δ7.97(s,1H),5.52(br s,1H),5.12(br d,J=13.4Hz,1H),4.38-4.21(m,1H),4.12(br d,J=3.6Hz,2H),3.72(br s,1H),3.54-3.12(m,4H),3.11-2.92(m,3H),2.84(dd,J=5.6,12.9Hz,1H),2.56-2.48(m,6H),1.65(br s,9H).

[1158] Step 5: (4aR,7S)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1159]

[1160] (R)-tert-butyl-10-bromo-11-chloro-7-(((S)-1-(dimethylamino)-3-hydroxypropane-2-yl)oxo)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (1.6 g, 2.65 mmol, 1 eq) and triphenylphosphine (2.09 g, 7.96 mmol, 3 eq) were dissolved in tetrahydrofuran (24 mL), and diisopropyl azodicarbonate (1.61 g, 7.96 mmol, 3 eq) was added. The reaction was carried out at room temperature for three hours, and the reaction was monitored by LCMS until it was complete. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography (methanol / dichloromethane: 0-3%) to give (4aR,7S)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (0.7 g, yield: 45%), as a yellow solid.

[1161] MS m / z:584.2 / 586.2[M+H] + .

[1162] 1 H NMR(400MHz, CDCl3)δ7.82-7.76(m,1H)4.99(br d,J=13.6Hz,1H)4.93-4.79(m,1H)4.45-4.32(m,1H)4.15(br s,1H)3.73-3.58(m,1H)3.35(br d,J=11.5Hz,1H)3.26-3.06(m,3H)2.88-2.68(m,3H)2.40-2.29(m,6H)1.50(br s,9H).

[1163] Step 6: (4aR,7S)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1164]

[1165] (4aR,7S)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (0.5 g, 0.855 mmol, 1 eq) and (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)boronic acid (564.43 mg, 1.71 mmol, 2 eq) were dissolved in toluene (5 mL). In a mixture of ethanol (2.5 mL) and water (2.5 mL), potassium carbonate (354.46 mg, 2.56 mmol, 3 eq), (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl,)[2-(2-amino-1,1-biphenyl)]palladium (143.00 mg, 0.171 mmol, 0.2 eq), and 2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl (199.46 mg, 0.427 mmol, 0.5 eq) were added. The mixture was then reacted at 80 °C for 8 hours under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction solution was filtered and concentrated. The residue was purified by column purification (tetrahydrofuran / dichloromethane: 0-45%) to obtain crude (4aR,7S)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (0.36 g), a white solid.

[1166] MS m / z:790.2 / 792.2[M+H] + .

[1167] Step 7: (4aR,7S)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1168]

[1169] (4aR,7S)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (500 mg, 0.633 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1.5 mL) was added. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated to obtain crude (4aR,7S)-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (373 mg), which was used directly in the next step.

[1170] MS m / z:590.3 / 592.3[M+H] + .

[1171] Step 8: Compound 9, Compound 9-P1 and Compound 9-P2

[1172] (4aR,7S)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (Compound 9)

[1173]

[1174] (4aR,7S,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (4aR,7S, 11S)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (compounds 9-P1 and 9-P2)

[1175]

[1176] (4aR,7S)-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (373 mg, 0.632 mmol, 1 eq), N,N-diisopropylethylamine (653.64 mg, 5.06 mmol, 8 eq) and acrylic acid (68.34 mg, 0.948 mmol, 1.5 eq) were dissolved in acetonitrile (5 mL), and tri-n-propylcyclophosphine (804.59 mg, 1.26 mmol, 50% ethyl acetate solution, 2 eq) was added. The reaction was carried out at room temperature for 3 hours. The reaction was monitored by LCMS until completion. The reaction solution was concentrated and purified by HPLC to obtain (4aR,7S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (compound 9) (150 mg, yield 36.9%), a white solid.

[1177] Compound 9:

[1178] MS m / z: 644.3 / 646.3 [M+H] + .

[1179] Compound 9 was isolated by chiral SFC to give compound 9-P1 (50 mg, yield: 12.3%) and compound 9-P2 (42 mg, yield: 10.3%).

[1180] HPLC separation conditions:

[1181] Column: Phenomenex Gemini-NX 80*40mm*3um; Mobile phase A: Water (0.05% ammoniahydroxide v / v), Mobile phase B: ACN;

[1182] Mobile phase B%: 28%-68%, 9 min

[1183] Compound 9-P1:

[1184] MS m / z: 644.3 / 646.3 [M+H] + .

[1185] 19F NMR(376MHz, DMSO-d6)δ-109.92(br s,1F),-115.46(br s,1F),-119.18(brs,1F).

[1186] 1 H NMR (400MHz, DMSO-d6) δ8.11 (s, 2H), 7.99 (s, 1H), 7.20 (t, J = 9.9Hz, 1H), 7.07 (br dd,J=11.3,16.3Hz,1H),6.16(dd,J=2.3,16.8Hz,1H),5.82-5.71(m,1H),4.79(brd,J=14.3Hz,1H),4.64-4.48(m,2H),4.42(br d,J=14.8Hz,1H),4.09-3.96(m,1H),3.72-3.57(m,1H),3.42-3.38(m,1H),3.30-3.20(m,2H),2.73-2.68(m,3H),2.28(s,6H).

[1187] Compound 9-P2:

[1188] MS m / z: 644.3 / 646.3 [M+H] + .

[1189] 19 F NMR(376MHz, DMSO-d6)δ-109.91(br s,1F),-115.53(br s,1F),-119.51(brs,1F).

[1190] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,2H),8.00(s,1H),7.19(t,J=9.9Hz,1H),7.15-6.73(m,1H),6.20-6.11(m,1H),5.80-5.70(m,1H),4.79(br d,J=14.3Hz,1H),4.62-4.42(m,3H),3.99(br s,1H),3.67(br d,J=13.8Hz,1H),3.30-3.20(m,3H),2.74-2.66(m,3H),2.28(s,6H).

[1191] Retention time (compound 9-P1): 4.997 min; retention time (compound 9-P2): 2.350 min.

[1192] SFC chiral separation conditions:

[1193] Column: DAIICEL CHIRALPAK IG (250mm*30mm, 10um); Mobile phase A: 0.1% NH3H2O, Mobile phase B: Ethanol;

[1194] Mobile phase B%: 60%-60%.

[1195] Example 10: Compound 10-P1 and Compound 10-P2

[1196] (2R,4aR,7R,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-7-((methylamino)methyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (2R,4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-7-((methylamino)methyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1197]

[1198] Step 1: Compound 10-1-1 and Compound 10-1-2

[1199] 1-Chloroethyl-(((2R,4aR,7S,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-5-oxoylide-1,2,3,4,4a,5,6,7-octahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-7-yl)methyl)(methyl)aminomethyl ester and 1-chloroethyl-(((2R,4aR,7S,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-5-oxoylide-1,2,3,4,4a,5,6,7-octahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-7-yl)methyl)(methyl)aminomethyl ester

[1200]

[1201] Compound 3-P1 (0.02 g, 0.0304 mmol, 1 eq) was dissolved in 1,2-dichloroethane (2 mL), and N,N-diisopropylethylamine (7.86 mg, 0.0608 mmol, 2 eq) was added. Then, 1-chloroethyl chloroformate (8.69 mg, 0.0608 mmol, 2 eq) was added at 0 °C, and the reaction was carried out at 60 °C for 8 hours. The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction solution was concentrated to obtain the crude product (compound 10-1-1), which was directly used in the next reaction.

[1202] MS m / z:750.3 / 752.3[M+H] + .

[1203] Compound 3-P2 (0.04 g, 0.0608 mmol, 1 eq) was dissolved in 1,2-dichloroethane (2 mL), and N,N-diisopropylethylamine (15.71 mg, 0.122 mmol, 2 eq) was added. Then, 1-chloroethyl chloroformate (17.38 mg, 0.122 mmol, 2 eq) was added at 0 °C, and the reaction was carried out at 60 °C for 8 hours. The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction solution was concentrated to obtain the crude product (10⁻¹⁻²), which was directly used in the next reaction step.

[1204] MS m / z:750.3 / 752.3[M+H] + .

[1205] Step 2: Compound 10-P1 and Compound 10-P2

[1206] (2R,4aR,7R,11R)-3-Acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-7-((methylamino)methyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one and (2R,4aR,7R,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-10-fluoro-2-methyl-7-((methylamino)methyl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1207]

[1208] The residue obtained in the previous step (compound 10-1-1) was added to methanol (1 mL) and reacted at 50 °C for 8 hours. The reaction was monitored by LCMS until complete. The reaction solution was purified by HPLC to obtain compound 10-P1 (5 mg, yield 25.5%) as a white solid.

[1209] MS m / z: 644.2 / 646.2 [M+H] + .

[1210] HPLC separation conditions:

[1211] Column: Phenomenex Gemini-NX 80*40mm*3um; Mobile phase A: Water (0.225% FA), Mobile phase B: ACN;

[1212] Mobile phase B%: 13%-53%, 9 min

[1213] The residue obtained in the previous step (compound 10-1-2) was added to methanol (1 mL) and reacted at 50 °C for 8 hours. The reaction was monitored by LCMS until complete. The reaction solution was purified by HPLC to obtain compound 10-P2 (5 mg, yield 12.7%) as a white solid.

[1214] MS m / z: 644.2 / 646.2 [M+H] + .

[1215] HPLC separation conditions:

[1216] Column: Phenomenex Gemini-NX 80*40mm*3um; Mobile phase A: Water (0.225% FA), Mobile phase B: ACN;

[1217] Mobile phase B%: 13%-53%, 9 min

[1218] Example 11: Compound 11-P1 and Compound 11-P2

[1219] (4aR,6S,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (4aR,6S,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[1220]

[1221] Step 1: (R)-tert-butyl-10-bromo-7-((R)-2-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propoxy)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[1222]

[1223] In a 100 mL three-necked flask, (R)-2-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propane-1-ol (1.95 g, 8.37 mmol, 2.4 eq) was added and dissolved in toluene (36 mL). Under nitrogen protection, the mixture was cooled to 0 °C, and sodium hydride (335 mg, 8.37 mmol, 2.4 eq) was added. The mixture was stirred at 0 °C for 0.5 hours, and then (R)-tert-butyl-10-bromo-7-... 11-Dichloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (1.81 g, 3.49 mmol, 1 eq) was added and allowed to rise naturally to room temperature. The mixture was stirred at room temperature until the reaction was complete. Saturated brine was slowly added, and the mixture was extracted three times with ethyl acetate. The mixture was dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography (dichloromethane:methanol = 20:1) to give (R)-tert-butyl-10-bromo-7-((R)-2-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propoxy)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (505 mg, yield 20.2%).

[1224] MS m / z:716.1 / 718.1[M+H] + .

[1225] Step 2: (R)-tert-butyl-10-bromo-11-chloro-7-((R)-3-(dimethylamino)-2-hydroxypropoxy)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester

[1226]

[1227] In a 100 mL single-necked flask, (R)-tert-butyl-10-bromo-7-((R)-2-((tert-butyldimethylsilyl)oxo)-3-(dimethylamino)propoxy)-11-chloro-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (448 mg, 0.627 mmol, 1 eq) was added and dissolved in anhydrous tetrahydrofuran (15 mL). Under nitrogen protection, a tetrabutylammonium fluoride tetrahydrofuran solution (1... 0.6 mL), stirred at room temperature until the reactants reacted completely, the solvent was evaporated, dissolved in ethyl acetate, and the organic phase was washed several times with brine. The sodium sulfate was dried with anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude (R)-tert-butyl-10-bromo-11-chloro-7-((R)-3-(dimethylamino)-2-hydroxypropoxy)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (480 mg), which was directly used in the next step of the reaction.

[1228] MS m / z:602.2 / 604.2[M+H] + .

[1229] Step 3: (4aR,6S)-tert-butyl-11-bromo-12-chloro-6-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1230]

[1231] In a 100 mL three-necked flask, add tributylphosphine (404 mg, 2 mmol, 4 eq), toluene (14 mL), and diisopropyl azodicarbonate (404 mg, 2 mmol, 4 eq). Under argon protection, add (R)-tert-butyl-10-bromo-11-chloro-7-((R)-3-(dimethylamino)-2-hydroxypropoxy)-9-fluoro-5-carbonyl-4,4a,5,6-tetrahydro-1H-pyrano[1',2':4,5]pyrano[2,3-c]quinoline-3(2H)-carboxylic acid ester (300 mg, 0.5 mmol). , 1 eq), stirred at room temperature until the reactants reacted completely, added saturated sodium bicarbonate solution, extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain crude product, purified by column chromatography (dichloromethane:methanol = 20:1) to give (4aR,6S)-tert-butyl-11-bromo-12-chloro-6-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (144 mg, yield 49.3%).

[1232] MS m / z:584.3 / 586.3[M+H] + .

[1233] 1 H NMR(400MHz, CDCl3) δ7.86(d,J=2.0Hz,1H),5.03-4.99(m,1H),4.69-4.66(m,1H),4.26-4.11(m,2H),3.88(dd,J=3.2,10.4Hz,1H ),3.65(br,1H),3.35(dd,J=4.0,9.6Hz,1H),3.23-3.16(m,2H),2.90-2.83(m,1H),2.69-2.55(m,2H),2.31(s,6H),1.53(s,9H).

[1234] Step 4: (4aR,6S)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1235]

[1236] In a 100 mL reaction tube, add (4aR,6S)-tert-butyl-11-bromo-12-chloro-6-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (105 mg, 0.18 mmol, 1 eq), (2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)boronic acid (89 mg, 0.27 mmol, 1.5 eq), and methanesulfonic acid (2-dicyclohexylphosphino-2',6'-... 2-Diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (30 mg, 0.036 mmol, 0.2 eq), 2-bicyclohexylphosphine-2',6'-diisopropoxybiphenyl (42 mg, 0.09 mmol, 0.5 eq), potassium phosphate (115 mg, 0.54 mmol, 3 eq), toluene (5.6 mL), ethanol (2.8 mL), water (2.8 mL), under argon protection, the reaction was carried out at 80 °C for 4 hours. Heating was stopped, saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to obtain the crude product. The crude product was purified by preparative plate (ethyl acetate: methanol = 9:1) to give (4aR,6S)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (78 mg, yield 54.9%).

[1237] MS m / z:790.1 / 792.1[M+H] + .

[1238] Step 5: (4aR,6S)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1239]

[1240] In a 100 mL single-necked flask, add (4aR,6S)-tert-butyl-11-(2-((tert-butoxycarbonyl)amino)-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (78 mg, 0.1 mmol, 1 eq) and dichloromethane (7 mL). Dissolve the sample, add trifluoroacetic acid (3.5 mL) under nitrogen protection, stir at room temperature until the reactants are completely reacted, and evaporate the solvent to obtain crude (4aR,6S)-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (85 mg), which was directly used in the next step of the reaction.

[1241] MS m / z:590.1 / 592.1[M+H] + .

[1242] Step 6: Compound 11-P1 and Compound 11-P2

[1243] (4aR,6S,11R)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (4aR,6S,11S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[1244]

[1245] In a 100 mL single-necked flask, add (4aR,6S)-11-(2-amino-5,7-difluorobenzo[d]thiazo-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (85 mg, 0.1 mmol, 1 eq), add acetonitrile (5.5 mL), cool to 0 °C, add N,N-diisopropylethylamine (129 mg, 1 mmol, 10 eq), and acrylic acid (11 mg, 0.15 mmol, 1 eq). 0.5 eq) of 1-propylphosphoric anhydride (50% ethyl acetate solution) (125 mg, 0.2 mmol, 2 eq) was added, and the mixture was stirred at 0 °C until the reactants were completely reacted. Saturated brine was added, and the mixture was extracted with dichloromethane, dried over anhydrous sodium sulfate, filtered, and evaporated to dryness to give crude (4aR,6S)-3-acryloyl-11-(2-amino-5,7-difluorobenzo[d]thiazolyl-4-yl)-12-chloro-6-((dimethylamino)methyl)-10-fluoro-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracite-5(1H)-one. The crude product was purified by preparative plate (ethyl acetate:methanol = 12:1) to give compound 11-P1 (13 mg, yield 20.2%) and compound 11-P2 (20 mg, yield 31%).

[1246] Compound 11-P1:

[1247] MS m / z: 644.2 / 646.2 [M+H] + .

[1248] 1 H NMR (400MHz, DMSO-d6) δ8.09(s,3H),8.00(s,1H),7.20(t,J=9.8Hz,1H),6.16(dd,J=2.3,16.8Hz,1H),5.77(br d,J=10.8Hz,1H),4.91-4.76(m,2H),4.26-4.07(m,2H),3.80-3.74(m,2H),3.66(br d,J=11.5Hz,1H),3.25-3.16(m,1H),2.81-2.73(m,1H),2.22(s,9H).

[1249] 19 F NMR(376MHz, DMSO-d6)δ-109.917(br s,1F),-115.528(br s,1F),-118.984(br s,1F).

[1250] Compound 11-P2:

[1251] MS m / z: 644.2 / 646.2 [M+H] + .

[1252] 1 H NMR (400MHz, DMSO-d6) δ8.11(s,2H),8.05(s,1H),7.19(t,J=9.8Hz,1H),7.12-6.96(m,1H),6.17(dd,J=2.1,16.9Hz,1H),5.78(br d,J=10.3Hz,1H),5.28(br s,1H),4.79(br d,J=14.6Hz,1H), 4.47(br d,J=10.8Hz,1H),4.26-4.03(m,3H),3.88(br d,J=13.1Hz,1H),3.69(br d,J=12.5Hz,1H),3.29-3.24(m,2H),2.80(br s, 6H), 2.60-2.56 (m, 1H).

[1253] 19 F NMR(376MHz, DMSO-d6)δ-109.950(br s,1F),-115.686(br s,1F),-119.150(br s,1F).

[1254] Retention time (compound 11-P1): 7.281 min; retention time (compound 11-P2): 6.252 min.

[1255] Column: Chiralpak AD-3 150*4.6mm ID, 3um

[1256] Mobile phase: A: CO2 B: Isopropanol (0.05% DEA)

[1257] Elution procedure: from 5% to 40% mobile phase B (within 5 minutes), then hold at 40% mobile phase B for 2.5 minutes, followed by hold at 5% mobile phase B for 2.5 minutes.

[1258] Flow rate: 2.5 mL / min

[1259] Column temperature: 35℃

[1260] ABPR: 1500psi

[1261] Example 12: Compound 12-P1 methanesulfonate and Compound 12-P2 methanesulfonate

[1262] (2R,4aR,7R,11S)-3-Acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (2R,4aR,7R,11R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate

[1263]

[1264] Step 1: (2R,4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1265]

[1266] (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (150 mg, 0.250 mmol, 1 eq), 5-methyl-1H-indazole-4-boronic acid (88.15 mg) (41.90 mg, 0.0501 mmol, 2 eq), (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl,)[2-(2-amino-1,1-biphenyl)]palladium(II) (41.90 mg, 0.0501 mmol, 0.2 eq), and potassium phosphate (159.49 mg, 0.751 mmol, 3 eq) were dissolved in a mixed solvent of toluene (3 mL), ethanol (1.5 mL), and water (1.5 mL). The reaction was carried out at 80 °C for 1 hour under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction solution was concentrated, and the residue was purified by silica gel plate [tetrahydrofuran (0.1% ammonia): petroleum ether = 2:1] to give crude (2R,4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester, a yellow solid, which was used directly for the next step.

[1267] MS m / z: 650.2 / 652.2 [M+H] + .

[1268] Step 2: (2R,4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1269]

[1270] The crude product of (2R,4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (160 mg, 0.246 mmol, 1 eq) was dissolved in a mixed solution of dichloromethane (6 mL) and trifluoroacetic acid (2 mL) and reacted at room temperature for 2 hours. The reaction was monitored by LCMS until complete, and the reaction solution was concentrated to obtain crude (2R,4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one, an orange oil, which was used directly in the next step.

[1271] MS m / z: 550.2 / 552.2 [M+H] + .

[1272] Step 3: Compound 12-P1 and Compound 12-P2

[1273] (2R,4aR,7R,11S)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (2R,4aR,7R,11R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[1274]

[1275] The crude product of (2R,4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (135.36 mg, 0.246 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and N,N-diisopropylethylamine (254.45 mg, 1.97 mmol, 8 eq), acrylic acid (26.60 mg, 0.369 mmol, 1.5 eq), and tri-n-propyl cyclic phosphoric anhydride (50% ethyl acetate solution) (156.61 mg, 0.492 mmol, 2 eq) were added sequentially. The reaction was carried out at room temperature for 2 hours. The reaction was monitored by LCMS until it was complete. The reaction solution was washed with saturated brine. The organic phase was prepared and separated by HPLC to obtain compound 12-P1 (2.4 mg, yield: 1.61%) and compound 12-P2 (1.2 mg, yield: 0.8%).

[1276] Compound 12-P1:

[1277] MS m / z: 604.2 / 606.2 [M+H] + .

[1278] 19 F NMR(376MHz,CDCl3)δ-118.88(br s,1F).

[1279] 1 H NMR (400MHz, CDCl3) δ7.96(s,1H),7.55(br d,J=8.5Hz,2H),7.43(d,J=8.8Hz,1H),7.02(dd,J=10.5,16.8Hz,1H),6.38(br d,J=17.1Hz,1H),5.83(br d,J=10.5Hz,1H),5.05(br s,1H),4.85(br d,J=14.1Hz,2H),4.34(br dd,J=5.4,13.7Hz,1H),3.95-3.78(m,3H),3.29-3.07(m,2H),2.89-2.67(m,2H),2.44(br s,6H),2.30-2.25(m,3H),1.69(br d,J=6.5Hz,3H).

[1280] Compound 12-P2:

[1281] MS m / z: 604.2 / 606.2 [M+H] + .

[1282] 19 F NMR(376MHz,CDCl3)δ-118.87(br s,1F).

[1283] 1 H NMR (400MHz, CDCl3) δ7.93(s,1H),7.54-7.48(m,1H),7.42-7.35(m,1H),7.05-6.91(m,1H),6.37(br d,J=17.1Hz,1H),5.81(br d,J=12.0Hz,1H),5.14-4.72(m,3H),4.38-3.71(m,4H),3.44-2.98(m,3H),2.94-2.73(m,2H),2.62-2.41(m,6H),2.26-2.18(m,3H),1.66(br d,J=6.8Hz,3H).

[1284] Retention time (compound 12-P1): 2.761 min; retention time (compound 12-P2): 2.201 min.

[1285] HPLC separation conditions:

[1286] Column: Diamonsil C18 150*30mm*5um; Mobile phase A: Water (0.05% ammonia hydroxide v / v), Mobile phase B: ACN;

[1287] Mobile phase B%: 26%-66%, 9 min

[1288] Step 4: Compound 12-P1 methanesulfonate and compound 12-P2 methanesulfonate

[1289] (2R,4aR,7R,11S)-3-Acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (2R,4aR,7R,11R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-11-(5-methyl-1H-indazol-4-yl)-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate

[1290]

[1291] Compound 12-P1 (83.78 mg, 0.138 mmol, 1 eq) was dissolved in acetone (2 mL). A solution of methanesulfonic acid (13 mg, 0.13176 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 12-P1 methanesulfonate (80 mg, yield: 82.38%) as a white solid.

[1292] MS m / z: 604.2 / 606.2 [M+H] + .

[1293] 19 F NMR(376MHz,DMSO-d6)δ-120.81(s,1F).

[1294] 1 H NMR(400MHz,DMSO-d6)δ13.22(br s,1H),9.83(br s,1H),8.02-7.90(m,1H),7.61(d,J=8.5Hz,1H),7.51-7.36(m,2H),7.10-6.78(m,1H),6.17(dd,J=2.1,16.9Hz,1H),5.85-5.68(m,1H),5.31(br d,J=9.0Hz,1H),5.18-4.37(m,2H),4.24-4.05(m,2H),4.00-3.78(m,2H),3.73-3.59(m,1H),3.45(br s,1H),3.33-3.17(m,1H),3.13-2.98(m,1H),2.96-2.76(m,6H),2.38-2.27(m,3H),2.17(s,3H),1.64-1.46(m,3H).

[1295] Compound 12-P2 (66.16 mg, 0.109 mmol, 1 eq) was dissolved in acetone (2 mL). A solution of methanesulfonic acid (10 mg, 0.10405 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 12-P2 methanesulfonate (70 mg, yield: 91.87%) as a white solid.

[1296] MS m / z: 604.2 / 606.2 [M+H] + .

[1297] 19 F NMR(376MHz,DMSO-d6)δ-120.81(s,1F).

[1298] 1 H NMR(400MHz,DMSO-d6)δ13.22(br s,1H),9.79(br s,1H),8.02-7.92(m,1H),7.60(d,J=8.5Hz,1H),7.53(s,1H),7.41(d,J=8.5Hz, 1H),7.07-6.80(m,1H),6.17(dd,J=2.0,16.8Hz,1H),5.85-5.69(m,1H),5.32(br d,J=9.3Hz,1H),5.17-4.43(m,2H),4.24-4.08(m,2H),4.00-3.78(m,2H),3.73-3.59(m,1H),3.49-3.45(m, 1H),3.34-3.18(m,1H),3.14-3.00(m,1H),2.97-2.76(m,6H),2.31(s,3H),2.13(s,3H),1.63-1.48(m,3H).

[1299] Example 13: Compound 13-P1 methanesulfonate and Compound 13-P2 methanesulfonate

[1300] (2R,4aR,7R,11R)-3-Acryloyl-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (2R,4aR,7R,11S)-3-acryloyl-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate

[1301]

[1302] Step 1: 4-Bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[1303]

[1304] 4-Bromo-5-chloro-1H-indazole (4.18 g, 18.06 mmol, 1 eq) was dissolved in tetrahydrofuran (100 mL), and p-toluenesulfonic acid monohydrate (343.49 mg, 1.81 mmol, 0.1 eq) and 2,3-dihydropyran (3.04 g, 36.12 mmol, 2.0 eq) were added. The reaction was allowed to proceed overnight at room temperature. TLC (petroleum ether: ethyl acetate = 5:1) showed that the reaction was complete, with a new spot of lower polarity than the starting material. The reaction solution was concentrated, and the residue was purified by column chromatography (ethyl acetate / petroleum ether: 0-10%) to give 4-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.8 g, yield: 84.23%), a white solid.

[1305] 1 H NMR (400MHz, DMSO-d6) δ8.12(s,1H),7.84(dd,J=0.79,8.86Hz,1H),7.61(d,J=8.93Hz,1H),5.90(dd,J=2.32,9.54Hz, 1H),3.91-3.84(m,1H),3.81-3.70(m,1H),2.42-2.31(m,1H),2.07-1.96(m,2H),1.79-1.70(m,1H),1.61-1.56(m,2H).

[1306] Step 2: 4-Bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole

[1307]

[1308] 4-Bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (4.5 g, 14.26 mmol, 1 eq) was dissolved in tetrahydrofuran (70 mL), and n-butyllithium (2.5 M, 8.56 mL, 1.5 eq) was added dropwise at -70 °C with stirring for 1 hour. Then, trimethyl borate (4.45 g, 42.78 mmol, 3 eq) was added, and the mixture was stirred at -70 °C for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was prepared by HPLC to give 4-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2.1 g, yield: 52.50%), a white solid.

[1309] HPLC separation conditions:

[1310] Column: YMC Triart C18 250*50mm*7um; Mobile phase A: Water (0.225% FA); Mobile phase B: ACN.

[1311] Mobile phase B%: 11%-51%, 9 min)

[1312] MS m / z:281.0 / 283.0[M+H] + .

[1313] 1 H NMR (400MHz, DMSO-d6) δ8.60(s,2H),7.94(s,1H),7.70(dd,J=0.73,8.93Hz,1H),7.36(d,J=8.93Hz,1H),5.84(dd,J=2.51,9.60Hz,1H),3.87(br d,J=12.10Hz,1H),3.79-3.70(m,1H),2.46-2.32(m,1H),2.08-1.99(m,1H),1.99-1.91(m,1H),1.81-1.68(m,1H),1.64-1.54(m,2H).

[1314] Step 3: (2R,4aR,7R)-tert-butyl-12-chloro-11-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1315]

[1316] (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (800 mg, 1.34 mmol, 1 eq), 4-bromo-5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indyl Azole (563.83 mg, 2.01 mmol, 1.5 eq), (2-dicyclohexylphosphino-2,6-diisopropoxy-1,1-biphenyl)[2-(2-amino-1,1-biphenyl)]palladium(II) (112.07 mg, 0.134 mmol, 0.1 eq), and potassium phosphate (568.88 mg, 2.68 mmol, 2 eq) were dissolved in a mixed solvent of toluene (10 mL), ethanol (5 mL), and water (5 mL). The reaction was carried out at 80 °C for 1 hour under nitrogen protection. The reaction was monitored by LCMS until complete. The reaction solution was concentrated, and the residue was purified by column chromatography [tetrahydrofuran (containing 1% ammonia) / petroleum ether: 10%-50%] to give crude (2R,4aR,7R)-tert-butyl-12-chloro-11-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester, a yellow solid, which was used directly for the next step.

[1317] MS m / z:754.3 / 756.3[M+H] + .

[1318] Step 4: (2R,4aR,7R)-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1319]

[1320] (2R,4aR,7R)-tert-butyl-12-chloro-11-(5-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (1.46 g, 1.93 mmol, 1 eq) was dissolved in dichloromethane (15 mL), and trifluoroacetic acid (5 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was concentrated to obtain a crude product (1.1 g) of (2R,4aR,7R)-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one, which was a brown oil. This crude product was directly added to the next step of the reaction.

[1321] MS m / z:570.1 / 572.1[M+H] + .

[1322] Step 5: Compound 13-P1 and Compound 13-P2

[1323] (2R,4aR,7R,11R)-3-acryloyl-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (2R,4aR,7R,11S)-3-acryloyl-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[1324]

[1325] (2R,4aR,7R)-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one (1.10 g, 1.93 mmol, 1 eq) and acrylic acid (138.96 mg, 1.93 mmol, 1 eq) were dissolved in acetonitrile (10 mL), and N,N-diisopropylethylamine (1.99 g, 15.43 mmol, 8 eq) and tri-n-propylcyclophosphine (1.84 g, 2.89 mmol, 50% ethyl acetate solution, 1.5 eq) were added. The mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until complete. The reaction solution was diluted with water, extracted with ethyl acetate, dried with anhydrous sodium sulfate, filtered and concentrated, and the residue was prepared by HPLC to obtain compound 13-P1 (80 mg, yield: 6.7%) and compound 13-P2 (55 mg, yield: 4.6%).

[1326] HPLC separation conditions:

[1327] Column: Phenomenex Gemini 150*25mm*10um; Mobile phase A: Water (0.05% ammoniahydroxide v / v), Mobile phase B: ACN;

[1328] Mobile phase B%: 40%-80%, 9 min

[1329] Compound 13-P1:

[1330] MS m / z:624.3 / 626.3[M+H] + .

[1331] 19 F NMR(376MHz,DMSO-d6)δ-120.63(s,1F).

[1332] 1H NMR (400MHz, DMSO-d6) δ13.52(br s,1H),7.95-7.89(m,1H),7.75(d,J=8.9Hz,1H),7.67(br s,1H),7.59(d,J=8.8Hz,1H),7.06-6.72(m,1H),6.16(br d,J=16.8Hz,1H),5.82-5.69(m,1H),5.16-4.38(m,3H),4.27-4.14(m,2H),3.86-3 .71(m,2H),3.29-2.86(m,2H),2.59-2.53(m,2H),2.22(s,6H),1.59-1.50(m,3H).

[1333] Compound 13-P2:

[1334] MS m / z:624.3 / 626.3[M+H] + .

[1335] 19 F NMR(376MHz,DMSO-d6)δ-120.73(s,1F).

[1336] 1 H NMR(400MHz,DMSO-d6)δ13.52(br s,1H),7.98-7.87(m,1H),7.80-7.65(m,2H),7.59(d,J=8.8Hz,1H),7.09-6.76(m,1H),6.22-6.12(m,1H),5.83-5.69(m,1H),5.1 7-4.41(m,3H),4.28-4.16(m,2H),4.07-3.67(m,2H),3.23-2.97(m,2H),2.55-2.53(m,2H),2.27-2.16(m,6H),1.59-1.49(m,3H).

[1337] Retention time (compound 13-P1): 6.323 min; retention time (compound 13-P2): 3.391 min.

[1338] Column: Chiralpak AD-3 150*4.6mm ID, 3um

[1339] Mobile phase: 40% of ethanol (0.05% DEA) in CO2

[1340] Flow rate: 2.5 mL / min

[1341] Column temperature: 35℃

[1342] ABPR: 1500psi

[1343] Step 6: Compound 13-P1 methanesulfonate and compound 13-P2 methanesulfonate

[1344] (2R,4aR,7R,11R)-3-Acryloyl-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one methanesulfonate and (2R,4aR,7R,11S)-3-acryloyl-12-chloro-11-(5-chloro-1H-indazol-4-yl)-7-((dimethylamino)methyl)-10-fluoro-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate

[1345]

[1346] Compound 13-P1 (80 mg, 0.128 mmol, 1 eq) was dissolved in acetone (1 mL). A solution of methanesulfonic acid (11.70 mg, 0.122 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 13-P1 methanesulfonate (81.6 mg, yield: 93.2%) as a white solid.

[1347] MS m / z:624.3 / 626.3[M+H] + .

[1348] 19 F NMR(376MHz,DMSO-d6)δ-120.32(br s,1F).

[1349] 1H NMR(400MHz,DMSO-d6)δ13.55(s,1H),9.83(br s,1H),8.00-7.93(m,1H),7.76(d,J=8.9Hz,1H),7.66-7.57(m,2H),7.07-6.79(m,1H),6.17(dd,J=2.2,16.8Hz,1H),5.82-5.69(m,1H),5.26(br s,1H),5.18-4.64(m,2H),4.53-3.79(m,5H),3.60(br s,1H),3.28-3.17(m,1H),3.11-2.99(m,1H),2.85(br s,6H),2.31(s,3H),1.60-1.52(m,3H).

[1350] 13 C NMR (101MHz, DMSO-d6) δ165.6,165.1,164.5,155.8,153.2,150.7,139.0,138. 2,138.1,132.7,131.7,131.6,129.8,129.7,129.6,129.1,128.6,128.3,127.8 ,127.5,125.5,124.1,123.5,123.4,123.2,121.9,121.7,118.5,118.0,117.7,117.6,113.3,70.4,57.3,55.8,51.8,48.1,44.3,43.8,37.5,33.4,16.5,15.0.

[1351] Compound 13-P2 (55 mg, 0.0881 mmol, 1 eq) was dissolved in acetone (1 mL). A solution of methanesulfonic acid (8.04 mg, 0.0837 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 13-P2 methanesulfonate (62.1 mg, yield: 97.87%) as a white solid.

[1352] MS m / z:624.3 / 626.3[M+H] + .

[1353] 19 F NMR(376MHz,DMSO-d6)δ-120.35(br s,1F).

[1354] 1H NMR (400MHz, DMSO-d6) δ13.54(s,1H),9.77(br s,1H),8.00-7.94(m,1H),7.80-7.67(m,2H),7.59(d,J=8.9Hz,1H),7.08-6.80(m,1H),6.17(br d,J=16.6Hz,1H),5.84-5.68(m,1H),5.31(br d,J=8.1Hz,1H),5.17-4.41(m,2H),4.27-4.10(m,2H),4.03-3.79(m,2H),3.73 -3.51(m,1H),3.46-3.38(m,1H),3.29-3.18(m,1H),3.13-3.00(m,1H),2.86(br s,6H),2.30(s,3H),1.64-1.48(m,3H).

[1355] 13 C NMR(101MHz,DMSO-d6)δ165.1,164.5,155.8,153.2,150.5,139.0,138.4,138.2,132.8,131.8,131.7,129.7,129.1,128.6,1 28.3,127.9,127.5,125.4,124.2,123.4,123.2,121.9,121.7,117.8,113.3,70.3,57.2,55.7,51.8,44.3,37.5,16.5,15.0.

[1356] Example 14: Compound 14-P1 methanesulfonate and Compound 14-P2 methanesulfonate

[1357] (2R,4aR,7R)-3-Acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-((R)-2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate and (2R,4aR,7R)-3-Acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate

[1358]

[1359] Step 1: Potassium trifluoroborate (2-fluoro-6-hydroxyphenyl)

[1360]

[1361] (2-fluoro-6-hydroxyphenyl)boronic acid (6 g, 38.48 mmol, 1 eq) was dissolved in acetonitrile (150 mL), and an aqueous solution of potassium fluoride (8.94 g, 153.93 mmol, 4 eq) (15 mL) was added. After stirring at room temperature for 2 minutes, a tetrahydrofuran solution of (2R,3R)-2,3-dihydroxysuccinic acid (14.44 g, 96.20 mmol, 2.5 eq) (75 mL) was slowly added over ten minutes. After reacting at room temperature for 1 hour, the reaction solution was filtered. The filter cake was washed with a small amount of tetrahydrofuran. The filtrate was concentrated to a small volume, slurried with isopropanol, filtered, and the filter cake was collected to give potassium trifluoroborate (2-fluoro-6-hydroxyphenyl) (7.74 g, yield: 92.22%), a white solid.

[1362] 1 H NMR (400MHz, DMSO-d6) δ8.07 (q, J = 14.55Hz, 1H), 6.99-6.87 (m, 1H), 6.40-6.26 (m, 2H).

[1363] Step 2: (2R,4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester

[1364]

[1365] The following were prepared: (2R,4aR,7R)-tert-butyl-11-bromo-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (0.48 g, 0.801 mmol, 1 eq), and potassium trifluoroborate (2-fluoro-6-hydroxyphenyl) (349.44 mg, 1 eq). 0.60 mmol (2 eq) and potassium carbonate (332.32 mg, 2.40 mmol, 3 eq) were dissolved in a mixed solution of dioxane (6 mL) and water (2 mL). Then, methanesulfonic acid (2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)(2-amino-1,1'-biphenyl-2-yl)palladium(II) (67.03 mg, 0.0802 mmol, 0.1 eq) was added. After nitrogen purging, the reaction was carried out at 85 °C for 4 hours. The reaction solution was filtered and concentrated. The crude product was purified by HPLC to obtain (2R,4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (640 mg, yield: 63.4%), a white solid.

[1366] MS m / z: 630.2 / 632.2 [M+H] + .

[1367] HPLC separation conditions:

[1368] Column: Phenomenex Gemini-NX 150*30mm*5um; Mobile phase: Mobile phase A: Water (0.05% NH3H2O ​​+ 10mM NH4HCO3), Mobile phase B: ACN;

[1369] Mobile phase B%: 21%-61%, 9 min

[1370] Step 3: (2R,4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one

[1371]

[1372] (2R,4aR,7R)-tert-butyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-5-carbonyl-1,2,4a,5,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-3(4H)-carboxylic acid ester (640 mg, 1.015 mmol, 1 eq) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (3 mL) was added. The reaction was carried out at room temperature for 1 hour. The reaction was confirmed to be complete by LCMS. The reaction solution was concentrated to obtain crude (654 mg) (2R,4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one, a yellow solid, which was used directly in the next step.

[1373] MS m / z:530.3 / 532.3[M+H] + .

[1374] Step 4: 2-((2R,4aR,7R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,3,4,4a,5,6,7-octahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-11-yl)-3-fluorophenylacryloyl ester

[1375]

[1376] (2R,4aR,7R)-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-(2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthraphen-5(1H)-one crude product (654 mg, 1.015 mmol, 1 eq) and triethylamine (821.65 mg, 8.12 mmol, 8 eq) were dissolved in dichloromethane (9 mL). Acryloyl chloride (192.79 mg, 2.13 mmol, 2.1 eq) was slowly added at 0 °C, and the reaction was carried out at 0 °C for 30 min. The reaction was confirmed to be complete by LCMS. The reaction solution was quenched with water (5 mL), extracted with dichloromethane, washed with saturated brine, and dried over anhydrous sodium sulfate. Filtration and concentration of the filtrate yielded crude 2-((2R,4aR,7R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,3,4,4a,5,6,7-octahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-11-yl)-3-fluorophenylacryloyl ester (646.75 mg), a yellow solid, which was used directly for the next step.

[1377] MS m / z: 638.2 / 640.2 [M+H] + .

[1378] Step 5: Compound 14-P1 and Compound 14-P2

[1379] (2R,4aR,7R)-3-Acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-((R)-2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (2R,4aR,7R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one

[1380]

[1381] 2-((2R,4aR,7R)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-2-methyl-5-carbonyl-1,2,3,4,4a,5,6,7-octahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-11-yl)-3-fluorophenylacryloyl ester (646.75 mg, 1.015 mmol, 1 eq) was dissolved in dichloromethane (8 mL), and 7M amine methanol solution (5 mL, 34.48 eq) was added at room temperature. The reaction was allowed to proceed for 1 hour at room temperature. The reaction was monitored by LCMS until complete, and the reaction solution was concentrated to obtain the crude product. The crude product was purified by preparative TLC (ethyl acetate:methanol = 8:1) to obtain the crude product. The product was isolated by SFC to obtain compound 14-P1 (166.96 mg, yield: 28.21%), a white solid; and compound 14-P2 (197.30 mg, yield: 33.34%), a white solid.

[1382] Compound 14-P1:

[1383] MS m / z:584.1 / 586.1[M+H] + .

[1384] 19 F NMR(376MHz,DMSO-d6)δ-113.76(s,1F),-119.71(s,1F).

[1385] 1 H NMR (400MHz, DMSO-d6) δ10.22(s,1H),7.85-7.81(m,1H),7.38-7.30(m,1H),7.05-6.75(m,3H),6.14(dd,J=2.2,16.8Hz,1H),5 .81-5.68(m,1H),5.12-4.39(m,3H),4.26-4.07(m,2H),3.84-3.65(m,2H),3.32-2.92(m,4H),2.20(s,6H),1.57-1.45(m,3H).

[1386] Compound 14-P2:

[1387] MS m / z:584.1 / 586.1[M+H] + .

[1388] 19 F NMR(376MHz,DMSO-d6)δ-113.70(s,1F),-119.52(s,1F).

[1389] 1H NMR(400MHz,DMSO-d6)δ10.22(br s,1H),7.89-7.76(m,1H),7.40-7.29(m,1H),7.05-6.74(m,3H),6.14(dd,J=2.3,16.8Hz,1H),5.80-5.66(m,1H),5. 12-4.38(m,3H),4.23-4.09(m,2H),3.76(dt,J=3.5,13.7Hz,2H),3.33-2.87(m,4H),2.21(s,6H),1.58-1.44(m,3H).

[1390] Retention time (compound 14-P1): 2.152 min; retention time (compound 14-P2): 3.090 min.

[1391] SFC chiral separation conditions:

[1392] Column: DAIICEL CHIRALPAK AD (250mm*30mm, 10um); Mobile phase A: 0.1% NH3H2O, Mobile phase B: IPA;

[1393] Mobile phase B%: 50%-50%

[1394] Step 6: Compound 14-P1 methanesulfonate and Compound 14-P2 methanesulfonate

[1395] (2R,4aR,7R)-3-Acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-((R)-2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate and (2R,4aR,7R)-3-Acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthracene-5(1H)-one methanesulfonate

[1396]

[1397] Compound 14-P1 (166.96 mg, 0.286 mmol, 1 eq) was dissolved in acetone (2 mL). A solution of methanesulfonic acid (26 mg, 0.272 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 14-P1 methanesulfonate (150 mg, yield 77.15%) as a white solid.

[1398] MS m / z:584.3 / 586.3[M+H] + .

[1399] 19 F NMR(376MHz,DMSO-d6)δ-113.88(s,1F),-119.29(s,1F).

[1400] 1 H NMR(400MHz,DMSO-d6)δ10.24(s,1H),9.77(br s,1H),7.96-7.83(m,1H),7.36(q,J=8.0Hz,1H),7.00(dd,J=10.5,17.1Hz,1H ),6.89-6.74(m,2H),6.16(dd,J=2.1,16.7Hz,1H),5.83-5.69(m,1H),5.27(br s,1H),5.16-4.37(m,2H),4.23-4.05(m,2H),3.94(br d,J=13.6Hz,1H),3.88-3.77(m,1H),3.67-3.52(m,1H),3.28-3.22(m,1H),3.21-2.99(m,2H),2.86(br s,6H),2.30(s,3H),1.62-1.45(m,3H).

[1401] 13C NMR (101MHz, DMSO-d6) δ165.6,165.1,164.5,161.8,159.4,157.3,157.2,156. 1,153.6,150.2,138.3,138.2,131.7,131.6,131.5,131.0,129.1,128.5,128.3 ,127.8,123.0,122.8,118.4,118.2,118.0,117.4,117.1,112.1,108.2,108.0,106.1,105.9,70.2,57.1,55.7,51.8,48.1,44.4,43.7,37.5,33.4,16.5,15.0.

[1402] Compound 14-P2 (197.30 mg, 0.338 mmol, 1 eq) was dissolved in acetone (2 mL). A solution of methanesulfonic acid (31 mg, 0.321 mmol, 0.95 eq) in acetone (0.2 mL) was slowly added at 0 °C. The mixture was stirred at room temperature for 1 hour and then reacted at 40 °C for 0.5 hours. The reaction solution was concentrated, and the residue was slurried with ethyl acetate. The filtrate was removed, and the residue was dissolved in water and lyophilized to give compound 14-P2 methanesulfonate (160 mg, yield: 69.64%) as a white solid.

[1403] MS m / z:584.3 / 586.3[M+H] + .

[1404] 19 F NMR(376MHz,DMSO-d6)δ-113.78(s,1F),-119.13(s,1F).

[1405] 1H NMR (400MHz, DMSO-d6) δ10.24(s,1H),9.85(br s,1H),7.96-7.80(m,1H),7.35(q,J=8.0Hz,1H),7.00(br dd,J=10.4,16.7Hz,1H),6.90-6.75(m,2H),6.24-6.09(m,1H),5.83-5.67(m,1H),5.28(br d,J=8.0Hz,1H),5.17-4.38(m,2H),4.20-4.03(m,2H),4.01-3.89(m,1H),3.88-3.77(m, 1H),3.71-3.56(m,1H),3.50-3.40(m,1H),3.29-3.16(m,1H),3.09-2.98(m,1H),2.89(br s,6H),2.32(s,3H),1.64-1.43(m,3H).

[1406] 13 C NMR(101MHz,DMSO-d6)δ165.6,165.1,164.5,161.8,159.4,157.2,157.2,156.1,1 53.6,150.2,138.3,138.1,131.7,131.6,131.5,131.1,131.0,130.9,129.1,128.5 ,128.3,127.9,123.1,122.9,118.4,118.2,118.0,117.4,117.1,112.1,108.2,108.0,106.1,105.9,70.2,57.1,55.8,51.8,48.1,44.4,44.0,37.5,33.4,16.5,15.0.

[1407] Example 15: Compound 15-P1 and Compound 15-P2

[1408] (2R,4aR,7S)-3-acryloyl-12-chloro-7-((dimethylamino)methyl)-10-fluoro-11-((S)-2-fluoro-6-hydroxyphenyl)-2-methyl-2,3,4,4a,6,7-hexahydro-8-oxa-3,5a,9,13c-tetraazanaphtho[3,2,1-de]anthra-5(1H)-one and (2R,4aR,7S)...

Claims

1. A compound as shown in Formula I or a pharmaceutically acceptable salt thereof; ， X is O, SO, or SO2; Y is CH or does not exist; Z is O; X1 is either CR7 or N; Y1 is either CR7 or N; A is ; Each R1 is independently C 1-6 alkyl; R2 and R3 are each independently C 1-6 Alkyl, H, deuterium, C substituted with one or more deuterium atoms 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl or 3-12 membered heterocyclic alkyl; wherein the 3-12 membered heterocyclic alkyl is optionally composed of 1-3 members each independently selected from C 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different; Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted with substituents, and when there are 2-5 substituents, the substituents may be the same or different; wherein the C... 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; Each R5 is independently H, deuterium, or halogen; Each R6 is independently H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; Each R7 is independently halogenated; R 7A For H; n is 0 or 1; The heteroatoms in the heterocyclic alkyl and heteroaryl groups are selected from one or more of N, O and S, and the number of heteroatoms is 1, 2, 3 or 4; When with " When the carbon atom in "" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

2. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 Substituent substitution of the alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; And / or, when R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from 1-5 groups selected from -NR. 11 R 12 When the substituent is replaced, the R 11 For H; And / or, when R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from 1-5 groups selected from -NR. 11 R 12 When the substituent is replaced, the R 12 For H.

3. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R2 or R3 are each independently H and C. 1-6 Alkyl, deuterium, C substituted with one or more deuterium atoms 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 3-12 membered heterocyclic alkyl groups, with 2 or 3 carbon atoms 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl.

4. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: X1 is CR7; And / or, Y1 is CR7; And / or, Y is CH; And / or, each R5 is independently H or halogen; And / or, each R6 is independently H or C substituted with one or more halogens. 1-6 alkyl; And / or, R1 is methyl; And / or, R2 or R3 are each independently H, C 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 , by 1-3 C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each can be independently H, methyl, CD3, or R. 11 R 12 Formed together with the adjacent atoms ; And / or, R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C10, C20, C30, C4 ... 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Substitution with alkyl, amino, -OH and halogen groups; wherein the C 1-6 Alkyl groups are optionally -CN or C 2-6 Alkyne substitution.

5. The compound of formula I as claimed in claim 4, or a pharmaceutically acceptable salt thereof, characterized in that: R2 or R3 are each independently H and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 , by 2 or 3 C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl.

6. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: X is O; And / or, R5 is H or fluorine; And / or, R6 is H or a monofluoromethyl group; And / or, R2 or R3 are each independently H, C 1-6 Alkyl group, with 1-3 carbon atoms 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or -C 1-6 Alkylene-NR 11 R 12 ; And / or, R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally composed of 1-5 groups selected from amino, hydroxyl, fluorine, chlorine, methyl, difluoromethyl, etc. , ethyl, trifluoromethyl, , Substitution with methoxy groups.

7. The compound of formula I as claimed in claim 6, or a pharmaceutically acceptable salt thereof, characterized in that: R2 or R3 are each independently H and C. 1-6 Alkyl groups, with 2 or 3 carbon atoms 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or -C 1-6 Alkylene-NR 11 R 12 .

8. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: When X1 is CR7, R7 is chlorine or fluorine; And / or, when Y1 is CR7, the R7 is chlorine or fluorine; And / or, R2 or R3 are each independently H, methyl, , , , , , , or ; And / or, R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally substituted by 1-5 substituents selected from amino, hydroxyl, fluorine, chlorine, methyl, ethyl, difluoromethyl, trifluoromethyl and methoxy.

9. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: When X1 is CR7, R7 is chlorine; And / or, when Y1 is CR7, the R7 is fluorine; And / or, R4 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

10. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R2 represents H and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl or 3-12-membered heterocyclic alkyl; wherein the 3-12-membered heterocyclic alkyl is optionally surrounded by 1, 2 or 3 carbon atoms. 1-6 Alkyl substitution, where there are 2 or 3 substituents, and the substituents may be the same or different; And / or, R3 is H, deuterium, C 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 Or be 1-3 Cs 1-6 Alkyl-substituted 3-12 membered heterocyclic alkyl groups; And / or, R4 is a 10-membered aryl or a 9-10-membered heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1, C2, C3, C4, or C5. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted with substituents, and when there are 2-5 substituents, the substituents may be the same or different; wherein the C... 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution.

11. The compound of formula I as claimed in claim 10, or a pharmaceutically acceptable salt thereof, characterized in that: R3 is H, deuterium, and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 Or by 2 or 3 Cs 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups.

12. The compound of formula I as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that: When R1 is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R2 or R3 is independently C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, the C mentioned 1-6 The alkylene group is methylene, ethylene, propylene, isopropylene, butylene, isobutylene, or tert-butylene; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each independently is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl groups are used, the plurality of them is two or three; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 11 Or R 12 Each independently is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl groups are used, the plurality of them is two or three; And / or, when R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atom, the 3-7 membered heterocyclic alkyl group is a tetrahydropyrrole group; And / or, when R2 or R3 is each independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl groups are used, the plurality of them is two or three; And / or, when R2 or R3 is each independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the 3-12 membered heterocyclic alkyl group is a 3-6 membered heterocyclic alkyl group; And / or, when R4 is a 6-10 aryl group, the 6-10 aryl group is phenyl or naphthyl; And / or, when R4 is a 5-10 member heteroaryl, the 5-10 member heteroaryl is pyridinyl, pyrazolyl, benzothiazolyl, indazole, benzoxazolyl, indolyl, benzimidazolyl, benzofuranyl or quinolinyl. And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 When the alkyl group is substituted, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 When the alkoxy group is substituted, the C 1-6 The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, or tert-butoxy; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the halogen is fluorine, chlorine, bromine, or iodine; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with multiple halogens. 1-6 When alkyl groups are substituents, the plurality of substituents may be two or three; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from -NR 11 R 12 When the substituent is replaced, the R 11 and R 12 For H; And / or, when R4 is a 6-10 aryl or a 5-10 heteroaryl, and the aryl or heteroaryl is substituted by a substituent selected from halogens, the halogen is fluorine, chlorine, bromine or iodine. And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 2-6 When the alkenyl group is substituted, the C 2-6 The alkenyl group is vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 1-isobutenyl, or 2-isobutenyl; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 2-6 When the alkynyl group is substituted, the C 2-6 The alkynyl group is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl, or 2-isobutynyl; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl substituent substitution, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl groups are -CN or C 2-6 When alkynyl is substituted, the C 2-6 The alkynyl group is ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-isobutynyl, or 2-isobutynyl; And / or, when R5 is a halogen, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R6 is a C substituted with multiple halogens 1-6 When alkyl groups are used, the plurality of them is two or three; And / or, when R6 is a C substituted with one or more halogens 1-6 When alkyl, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R6 is a C substituted with one or more halogens 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or tert-butyl; And / or, when R7 is a halogen, the halogen is fluorine, chlorine, bromine or iodine.

13. The compound of formula I as claimed in claim 12, or a pharmaceutically acceptable salt thereof, characterized in that: When R4 is a 5-10 member heteroaryl, the 5-10 member heteroaryl is pyridyl, pyrazolyl, benzothiazolyl, indazole, benzoxazolyl, indolyl, benzimidazolyl, or quinolinyl.

14. The compound of formula I as claimed in claim 12, or a pharmaceutically acceptable salt thereof, characterized in that: When R1 is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, the C mentioned 1-6 The alkylene group is methylene; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each independently is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R2 or R3 is each independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R 11 Or R 12 Each independently is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the 3-7 membered heterocyclic alkyl group is... ; And / or, when R2 or R3 is each independently a C substituted with a hydroxyl group 1-6 When alkyl, the C substituted with one hydroxyl group 1-6 Alkyl is ; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is a tetrahydropyrrole group; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the C 1-6 The alkyl group is methyl; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the 3-12 membered heterocyclic alkyl group is a tetrahydropyrrole group; And / or, when R4 is a 6-10 aryl group, the 6-10 aryl group is a phenyl group or... ; And / or, when R4 is a 5-10 member heteroaryl, the 5-10 member heteroaryl is , , , , , , , , , , , or ; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 When the alkyl group is substituted, the C 1-6 The alkyl group is methyl or ethyl; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 When the alkoxy group is substituted, the C 1-6 The alkoxy group is a methoxy group; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the halogen is fluorine; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with one or more halogens. 1-6 When alkyl groups are substituents, the C 1-6 The alkyl group is methyl; And / or, when R4 is a 6-10 aryl or a 5-10 heteroaryl, and the aryl or heteroaryl is substituted by a substituent selected from halogens, the halogen is fluorine or chlorine; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 2-6 When the alkenyl group is substituted, the C 2-6 The alkenyl group is vinyl; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl substituent substitution, C 1-6 Alkyl, C 1-6 Alkoxy or C 2-6 Alkenyl groups are -CN or C 2-6 When alkynyl is substituted, the C 2-6 The alkynyl group is an ethynyl group; And / or, when R5 is a halogen, the halogen is fluorine; And / or, when R6 is a C substituted with one or more halogens 1-6 When alkyl, the halogen is fluorine; And / or, when R6 is a C substituted with one or more halogens 1-6 When alkyl, the C 1-6 The alkyl group is methyl; And / or, when R7 is a halogen, the halogen is fluorine or chlorine.

15. The compound of formula I as claimed in claim 14, or a pharmaceutically acceptable salt thereof, characterized in that: When R4 is a 6-10 aryl group, the 6-10 aryl group is a phenyl group; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 Or R 12 Each independently represents a C that has been replaced by multiple deuterium atoms. 1-6 In the case of alkyl groups, the C groups substituted with multiple deuterium groups... 1-6 The alkyl group is CD3; And / or, when R 11 Or R 12 Each independently represents a C that has been replaced by multiple deuterium atoms. 1-6 In the case of alkyl groups, the C groups substituted with multiple deuterium groups... 1-6 Alkyl group is CD ３ ; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, the -C 1-6 Alkylene-NR 11 R 12 for , , or ; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is ; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the 3-12 membered heterocyclic alkyl group is ; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C groups substituted with multiple halogens. 1-6 When alkyl groups are substituented, the C atoms are replaced by multiple halogens. 1-6 The alkyl group is difluoromethyl or trifluoromethyl; And / or, when R6 is a C substituted with a halogen 1-6 When alkyl, the C substituted with a halogen 1-6 The alkyl group is a monofluoromethyl group.

16. The compound of formula I as claimed in claim 15, or a pharmaceutically acceptable salt thereof, characterized in that: When R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the C 1-6 Alkyl-substituted 3-12 membered heterocyclic alkyl groups are , or .

17. The compound of formula I as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that: When R1 is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R2 or R3 is independently C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, the C mentioned 1-6 The alkylene group is methylene, ethylene, propylene, isopropylene, n-butylene, isobutylene, sec-butylene, or tert-butylene; And / or, when R 11 Or R 12 Each independently is C 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R 11 Or R 12 Each is independently a C substituted by one or more deuteriums. 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atom, the 3-7 membered heterocyclic alkyl group is a monocyclic, bicyclic, or tricyclic alkyl group; And / or, when R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atom, the 3-7 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group; And / or, when R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atom, the heteroatom in the 3-7 membered heterocyclic alkyl group is N; And / or, when R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atoms, the number of heteroatoms in the 3-7 membered heterocyclic alkyl group is 1 or 2; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atom, the 3-7 membered heterocyclic alkyl group is a monocyclic, bicyclic, or tricyclic alkyl group; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atom, the 3-7 membered heterocyclic alkyl group is a 4-6 membered heterocyclic alkyl group; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atom, the heteroatom in the 3-7 membered heterocyclic alkyl group is N; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When forming a 3-7 membered heterocyclic alkyl group together with the attached atoms, the number of heteroatoms in the 3-7 membered heterocyclic alkyl group is 1 or 2; And / or, when R2 or R3 is each independently a C substituted with one or more hydroxyl groups. 1-6 When alkyl, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is monocyclic, bicyclic or tricyclic; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the heteroatom in the 3-12 membered heterocyclic alkyl group is N; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the number of heteroatoms in the 3-12 membered heterocyclic alkyl group is 1 or 2; And / or, when R2 or R3 is each independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is C 1-6 When alkyl is substituted, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R4 is a 6-10 aryl group, the 6-10 aryl group is a phenyl group. or ; And / or, when R4 is a 6-10 aryl group, the 6-10 aryl group does not fuse with cycloalkyl or heterocyclic groups; And / or, when R4 is a 5-10 member heteroaryl, the 5-10 member heteroaryl is a monocyclic or bicyclic ring; And / or, when R4 is a 5-10 membered heteroaryl group, the 5-10 membered heteroaryl group does not fuse with cycloalkyl or heterocyclic groups; And / or, when R4 is a 5-10 member heteroaryl, the number of heteroatoms in the 5-10 member heteroaryl is 1 or 2; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 When the alkyl group is substituted, the C 1-6 The alkyl group is methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, or tert-butyl; And / or, when R4 is a 6-10 aryl or 5-10 heteroaryl, the aryl or heteroaryl group is selected from C 1-6 When the alkoxy group is substituted, the C 1-6 The alkoxy group is methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, or tert-butoxy; And / or, when R7 in X1 is a halogen, the halogen is fluorine, chlorine, bromine or iodine; And / or, when R7 in Y1 is a halogen, the halogen is fluorine, chlorine, bromine or iodine.

18. The compound of formula I as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that: When R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the 3-7 membered heterocyclic alkyl group is a spirocyclic or bridged ring; And / or, when R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 R 11 R 12 When a 3-7 membered heterocyclic alkyl group is formed together with the attached atoms, the 3-7 membered heterocyclic alkyl group is a spirocyclic or bridged ring; And / or, when R2 or R3 is independently a 3-12 membered heterocyclic alkyl group, the 3-12 membered heterocyclic alkyl group is a spirocyclic or bridged ring.

19. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: R4 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or .

20. The compound of formula I as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that: In R2 and R3, the 3-12 membered heterocyclic alkyl group is monocyclic, bicyclic, or tricyclic; And / or, in R4, the 6-10 aryl group is a monocyclic or bicyclic ring; And / or, in R4, the 6-10 aryl group is not fused with cycloalkyl or heterocyclic groups; And / or, in R4, the 5-10 member heteroaryl group is monocyclic or bicyclic; And / or, in R4, the 5-10 membered heteroaryl group is not fused with cycloalkyl or heterocyclic groups; And / or, except for isotopic atoms specifically indicated, all atoms are atoms of the element at their natural abundance, that is, a mixture of isotopes at their natural abundance.

21. The compound of formula I as claimed in any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, characterized in that: In R2 and R3, the 3-12 membered heterocyclic alkyl group is a spirocyclic or bridged ring.

22. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by Formula I is any of the following schemes: Option 1: X is O, SO, or SO2; Z is O; A is ; R1 is C 1-6 alkyl; R2 or R3 are each independently H and C. 1-6 Alkyl, deuterium, C substituted with one or more deuterium atoms 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 3-12 membered heterocyclic alkyl groups, surrounded by 1-3 carbon atoms 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl; When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 Substituent substitution of the alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; R5 is H, deuterium, or halogen; R6 is composed of H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; X1 is CR7, and R7 is halogen; Y1 is CR7, and R7 is halogen; R 7A For H; n is 0 or 1; Option 2: X is O, SO, or SO2; Z is O; A is ; R1 is C 1-6 alkyl; R2 or R3 are each independently H and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 , by 1-3 C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl; When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 Substituent substitution of the alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; R5 is H or halogen; R6 is H or C substituted with one or more halogens. 1-6 alkyl; X1 is CR7, and R7 is halogen; Y1 is CR7, and R7 is halogen; n is 0 or 1; Option 3: X is O; Y represents CH; Z is O; A is ; R1 is C 1-6 alkyl; R2 or R3 are each independently H and C. 1-6 Alkyl group, with 1-3 carbon atoms 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or -C 1-6 Alkylene-NR 11 R 12 ; When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Substitution with alkyl, amino, -OH and halogen groups; wherein the C 1-6 Alkyl groups are optionally -CN or C 2-6 Alkyne substitution; R5 is H or halogen; R6 is H or C substituted with one or more halogens. 1-6 alkyl; X1 is CR7, and R7 is halogen; Y1 is CR7, and R7 is halogen; n is 0 or 1; Option 4: X is O, SO, or SO2; Z is O; A is ; R1 is a methyl group; R2 or R3 are each independently H, methyl, , , , , , , or ; R4 is a 6-10 aryl group or a 5-10 heteroaryl group, wherein the aryl or heteroaryl group is optionally surrounded by 1-5 groups selected from amino, hydroxyl, fluorine, chloro, methyl, difluoromethyl, etc. , ethyl, trifluoromethyl, , Substitution with methoxy groups; R5 is H or fluorine; R6 is H or a monofluoromethyl group; X1 is CR7, and R7 is chlorine; Y1 is CR7, and R7 is fluorine; n is 0 or 1; Option 5: X is O, SO, or SO2; Z is O; A is ; R1 is a methyl group; R2 or R3 are each independently H, methyl, , , , , , , or ; R4 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R5 is H or fluorine; R6 is H or a monofluoromethyl group; X1 is CR7, and R7 is chlorine; Y1 is CR7, and R7 is fluorine; n is 0 or 1; Option Six: X is O; Y represents CH; Z is O; A is ; R1 is a methyl group; R2 or R3 are each independently H, methyl, , , , , , or ; R4 is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or ; R5 is H or fluorine; R6 is H or a monofluoromethyl group; X1 is CR7, and R7 is chlorine; Y1 is CR7, and R7 is fluorine; n is 0 or 1; Option Seven: X is O, SO, or SO2; Y is CH or does not exist; Z is O; X1 is either CR7 or N; Y1 is either CR7 or N; A is ; Each R1 is independently C 1-6 alkyl; R2 and R3 are independently H and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl or 3-12 membered heterocyclic alkyl; wherein the 3-12 membered heterocyclic alkyl is optionally composed of 1, 2 or 3 independently selected from C 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different; Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally composed of 1, 2, 3, 4 or 5 selected from C. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted with substituents, and when there are 2-5 substituents, the substituents may be the same or different; wherein the C... 1-6 Alkoxy or C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; Each R5 is independently H or halogen; Each R6 is independently H, or C substituted with one or more halogens. 1-6 alkyl; Each R7 is independently halogenated; R 7A For H; n is 0 or 1; Option 8: X is O, SO, or SO2; Y represents CH; Z is O; X1 is either CR7 or N; Y1 is either CR7 or N; A is ; Each R1 is independently C 1-6 alkyl; R2 is H, deuterium, or a 3-12 membered heterocyclic alkyl group; wherein the 3-12 membered heterocyclic alkyl group is optionally selected by one, two, or three independently from C. 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different; R3 is H, deuterium, or a 3-12 membered heterocyclic alkyl group; wherein the 3-12 membered heterocyclic alkyl group is optionally selected by one, two, or three independently from C. 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different; Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 10-membered aryl or a 9-10-membered heteroaryl; the aryl or heteroaryl group is optionally composed of 1, 2, 3, 4, or 5 selected from C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted with substituents, and when there are 2-5 substituents, the substituents may be the same or different; wherein the C... 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; Each R5 is independently H, deuterium, or halogen; Each R6 is independently H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; Each R7 is independently halogenated; R 7A For H; n is 0 or 1; Option Nine: X is O, SO, or SO2; Y is CH or does not exist; Z is O; X1 is either CR7 or N; Y1 is either CR7 or N; A is ; Each R1 is independently C 1-6 alkyl; R2 represents H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 C substituted with one or more hydroxyl groups 1-6 Alkyl or 3-12 membered heterocyclic alkyl; wherein the 3-12 membered heterocyclic alkyl is optionally composed of 1, 2 or 3 independently selected from C 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different; R3 is H, deuterium, or -C. 1-6 Alkylene-NR 11 R 12 ; Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally composed of 1, 2, 3, 4 or 5 selected from C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted with substituents, and when there are 2-5 substituents, the substituents may be the same or different; wherein the C... 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; Each R5 is independently H, deuterium, or halogen; Each R6 is independently H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; Each R7 is independently halogenated; R 7A For H; n is 0 or 1; Option 10: X is O, SO, or SO2; Y represents CH; Z is O; X1 is either CR7 or N; Y1 is either CR7 or N; A is ; Each R1 is independently C 1-6 alkyl; R2 is a 3-12 membered heterocyclic alkyl group; wherein the 3-12 membered heterocyclic alkyl group is optionally selected by 1, 2 or 3 independently from C10. 1-6 Alkyl substituents are used for substitution, and when there are 2 or 3 substituents, the substituents may be the same or different; R3 is H, deuterium, or -C. 1-6 Alkylene-NR 11 R 12 ; Each R 11 and R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 10-membered aryl or a 9-10-membered heteroaryl; the aryl or heteroaryl group is optionally composed of 1, 2, 3, 4, or 5 selected from C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 The alkynyl group is substituted with substituents, and when there are 2-5 substituents, the substituents may be the same or different; wherein the C... 1-6 Alkyl, C 1-6 Alkoxy and C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; Each R5 is independently H, deuterium, or halogen; Each R6 is independently H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; Each R7 is independently halogenated; R 7A For H; n is 0 or 1; Option 11: X is O, SO, or SO2; Y is CH or does not exist; Z is O; X1 can be CCl, CF, or N; Y1 is either CF or N; A is ; R1 is a methyl group; R2 or R3 are each independently H, methyl, , , , , , , or ; R4 is , , , , , , , , , , , , , , , , , , , or ; R5 is H or fluorine; R6 is H or a monofluoromethyl group; R 7A For H; n is 0 or 1.

23. The compound of formula I as claimed in claim 22, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by Formula I is any of the following schemes: Option 1: X is O, SO, or SO2; Z is O; A is ; R1 is C 1-6 alkyl; R2 or R3 are each independently H and C. 1-6 Alkyl, deuterium, C substituted with one or more deuterium atoms 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 3-12 membered heterocyclic alkyl groups, with 2 or 3 carbon atoms 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl; When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 Substituent substitution of the alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; R5 is H, deuterium, or halogen; R6 is composed of H, deuterium, and C. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Alkyl groups or C groups substituted with one or more deuterium atoms 1-6 alkyl; X1 is CR7, and R7 is halogen; Y1 is CR7, and R7 is halogen; R 7A For H; n is 0 or 1; Option 2: X is O, SO, or SO2; Z is O; A is ; R1 is C 1-6 alkyl; R2 or R3 are each independently H and C. 1-6 Alkyl, -C 1-6 Alkylene-NR 11 R 12 , by 2 or 3 C 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or C groups substituted with one or more hydroxyl groups 1-6 alkyl; When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl, C 1-6 Alkoxy groups, C atoms substituted with one or more halogens 1-6 Alkyl, -NR 11 R 12 -OH, halogen, C 2-6 alkenyl and C 2-6 Substituent substitution of the alkynyl group, wherein the C 1-6 Alkyl, C 1-6 Alkoxy, C 2-6 Alkenyl groups are optionally -CN or C 2-6 Alkyne substitution; R5 is H or halogen; R6 is H or C substituted with one or more halogens. 1-6 alkyl; X1 is CR7, and R7 is halogen; Y1 is CR7, and R7 is halogen; n is 0 or 1; Option 3: X is O; Y represents CH; Z is O; A is ; R1 is C 1-6 alkyl; R2 or R3 are each independently H and C. 1-6 Alkyl groups, with 2 or 3 carbon atoms 1-6 Alkyl-substituted 3-12-membered heterocyclic alkyl groups or -C 1-6 Alkylene-NR 11 R 12 ; When R2 or R3 is independently -C 1-6 Alkylene-NR 11 R 12 At that time, each R 11 Or R 12 Each independently represents H and C. 1-6 Alkyl groups, C substituted with one or more deuterium groups 1-6 Alkyl or R 11 R 12 Together with the attached atoms, they form 3-7 membered heterocyclic alkyl groups; R4 is a 6-10 aryl or a 5-10 heteroaryl; wherein the aryl or heteroaryl group is optionally selected from C1 to C5. 1-6 Alkyl groups, C substituted with one or more halogens 1-6 Substitution with alkyl, amino, -OH and halogen groups; wherein the C 1-6 Alkyl groups are optionally -CN or C 2-6 Alkyne substitution; R5 is H or halogen; R6 is H or C substituted with one or more halogens. 1-6 alkyl; X1 is CR7, and R7 is halogen; Y1 is CR7, and R7 is halogen; n is 0 or 1.

24. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by Formula I has any of the following structures: , , , , , , , , , , , or ; Among them, X, Y, Z, X1, Y1, R1, R2, R3, R4, R5, R6, A, n and R 7A The definition is as described in claim 1. When with " When the carbon atom in "" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

25. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: The compound represented by Formula I is any one of the following compounds: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 ， Under the following conditions, the retention time is 2.758 min or 3.990 min. : Pillar: Chiralcel OD-3 100 4.6mm ID, 3μm; Mobile phase: A: CO2; B: ethanol containing 0.05% DEA; isocratic elution: 40% B; flow rate: 2.8 mL / min; column temperature: 35 °C o C; ABPR: 1500 psi; The retention time is 0.916 min or 1.260 min under the following conditions. : Pillar: Chiralcel OD-3 50 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: methanol containing 0.05% DEA, isocratic elution: 40% B; Flow rate: 4 mL / min; Column temperature: 35 °C; ABPR: 1500 psi; The retention time is 4.997 min or 2.350 min under the following conditions. Column: DAICEL CHIRALPAK IG 250mm 30mm, 10μm; Mobile phase A: 0.1% NH3H2O, Mobile phase B: Ethanol; Mobile phase B%: 60%-60%; The retention time is 7.281 min or 6.252 min under the following conditions. : Pillar: Chiralpak AD-3 150 4.6mm ID, 3μm; Mobile phase: A: CO2; B: Isopropanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 5 minutes, then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35 °C o C; ABPR: 1500psi; The retention time is 2.761 min or 2.201 min under the following conditions. : Pillar: Diamonsil C18 150 30mm 5 μm; Mobile phase A: Water containing 0.05% ammonia (% is v / vammoniahydroxide); Mobile phase B: ACN; Mobile phase B %: 26%-66%, 9 min; The retention time is 6.323 min or 3.391 min under the following conditions. : Pillar: Chiralpak AD-3 150 4.6 mm ID, 3 μm; Mobile phase: 40% ethanol in CO2, wherein the ethanol contains 0.05% DEA; Flow rate: 2.5 mL / min; Column temperature: 35 °C; ABPR: 1500 psi; Under the following conditions, the retention time is 2.152 min or 3.090 min. : Column: DAICEL CHIRALPAK AD 250mm 30mm, 10μm; Mobile phase A: 0.1% NH3H2O, Mobile phase B: IPA; Mobile phase B%: 50%-50%; The retention time is 1.848 min or 3.799 min under the following conditions. : Column: ChiralPak AD-3 150×4.6mm ID, 3μm; Mobile phase: 40% ethanol in CO2, containing 0.05% DEA; Flow rate: 2.5mL / min; Column temperature: 35℃ o C; ABPR: 1500psi; The retention time is 0.660 min or 1.016 min under the following conditions. : Pillar: Chiralpak AD-3 50 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: ethanol containing 0.05% DEA, isocratic elution: 40% B; Column temperature: 35℃; ABPR: 1500 psi; The retention time is 1.979 min or 2.457 min under the following conditions. : Pillar: Phenomenex Gemini-NX 80 40mm 3μm; Mobile phase A: Water containing 0.05% ammonia (v / v); Mobile phase B: ACN; Mobile phase B %: 36%-76%, 9min; The retention time is 1.489 min or 0.706 min under the following conditions. : Pillar: Chiralpak AD-3 150 4.6mm ID, 3μm; Mobile phase: A: CO2; B: ethanol containing 0.05% DEA; isocratic elution: 40% B; flow rate: 4 mL / min; column temperature: 35°C o C; ABPR: 1500 psi; The proton spectrum data are shown below. : 1 H NMR (400 MHz, CDCl3) δ 7.86(s, 1H), 7.37-7.28 (m, 1H), 6.99 (br dd, J = 10.8, 16.7 Hz, 1H), 6.87 (br d,J = 8.1 Hz, 1H), 6.78 (br t, J = 8.4 Hz, 1H), 6.36 (br d, J = 17.0 Hz, 1H), 5.81 (br d, J = 11.1 Hz, 1H), 4.95 (br s, 1H), 4.85-4.68 (m, 2H), 4.24 (br s,1H), 3.89-3.77 (m, 1H), 3.74 (br s, 1H), 3.37-2.85 (m, 5H), 2.67-2.32 (m,4H), 2.16-1.75 (m, 4H), 1.68-1.61 (m, 3H); The proton spectrum data are shown below. : 1 H NMR (400 MHz, CDCl3) δ 7.79(s, 1H), 7.33-7.27 (m, 1H), 7.06-6.83 (m, 2H), 6.75 (br t, J = 8.6 Hz, 1H), 6.34 (br d, J = 16.6 Hz, 1H), 5.78 (br d, J = 10.9 Hz, 1H), 5.48-4.87 (m,1H), 4.77 (br t, J = 12.4 Hz, 2H), 4.28 (br s, 1H), 3.86-3.61 (m, 2H), 3.41-2.85 (m, 5H), 2.70-2.40 (m, 4H), 2.16-1.78 (m, 4H), 1.63 (br d, J = 6.5 Hz, 3H); The retention time is 1.238 min or 0.927 min under the following conditions. : Pillar: Chiralpak IG-3 50 4.6mm ID, 3μm; Mobile phase: A: CO2; B: ethanol containing 0.05% DEA; isocratic elution: 40% B; flow rate: 4 mL / min; column temperature: 35°C; ABPR: 1500 psi; The retention time is 6.729 min or 6.169 min under the following conditions. : Column: ChiralPak AD-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 5.5 min, then hold at 40% mobile phase B for 3 min, then hold at 5% mobile phase B for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40℃; ABPR: 100 bar; The retention time is 5.082 min or 3.099 min under the following conditions. : Column: ChiralPak AD-3 150×4.6mm ID, 3μm; Mobile phase: A: CO2, B: ethanol containing 0.05% DEA, isocratic elution: 40% B; Flow rate: 2.5mL / min; Column temperature: 40℃ o C; ABPR: 100 bar; The retention time is 5.279 min or 6.689 min under the following conditions. : Pillar: Phenomenex Gemini-NX 80 40 mm 3 μm; Mobile phase A: Water containing 0.05% ammonia (v / v); Mobile phase B: ACN; Mobile phase B %: 50%-90%, 9 min; The retention time is 2.463 min or 2.780 min under the following conditions. : Pillar: Diamonsil C18 150 30mm 5μm; Mobile phase A: Water containing 0.05% ammonia (v / v); Mobile phase B: ACN; Mobile phase B %: 40%-80%, 9min; The retention time is 1.214 min or 0.744 min under the following conditions. : Pillar: Phenomenex Gemini 150 25mm 10μm; Mobile phase A: Water containing 0.05% ammonia (v / v); Mobile phase B: ACN; Mobile phase B %: 45%-85%, 9min; The retention time is 6.803 min or 5.848 min under the following conditions. : Pillar: Chiralpak AD-3 150 4.6mm ID, 3μm; Mobile phase: A: CO2; B: Ethanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 5 minutes, then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 2.5 minutes; Flow rate: 2.5 mL / min; Column temperature: 35°C o C; ABPR: 1500 psi; The retention time is 3.701 min or 3.222 min under the following conditions. : Column: Chiralcel OJ-3 100×4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: ethanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 4 minutes, then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35 ℃; ABPR: 1500 psi; The retention time is 1.437 min or 0.736 min under the following conditions. : Pillar: Chiralpak AD-3 50 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: ethanol containing 0.05% DEA; Gradient: 40% B; Flow rate: 4 mL / min; Column temperature: 35°C; ABPR: 1500 psi; The retention time is 4.975 min or 5.600 min under the following conditions. : Column: Chiralcel OJ-3 100 4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: Isopropanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 4 minutes, then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35 °C o C; ABPR: 1500psi; Under the following conditions, the retention time is 3.456 min or 3.337 min. : Column: Chiralcel OJ-3 100 4.6mm ID, 3μm; Mobile phase: A: CO2; B: Ethanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 4 minutes, then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35 °C; ABPR: 1500 psi; The retention time is 3.645 min or 5.527 min under the following conditions. : Pillar: Chiralpak AS-3 100 4.6mm ID, 3μm; Mobile phase: A: CO2; B: Ethanol containing 0.05% DEA; Flow rate: 2.8 mL / min; Column temperature: 35 ℃; ABPR: 1500 psi; The retention time is 3.826 min or 1.706 min under the following conditions. : Pillar: Chiralpak AS-3 100 4.6mm ID, 3μm; Mobile phase: A: CO2; B: Ethanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 4 minutes, then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35 ℃; ABPR: 1500 Psi; The retention time is 4.032 min or 2.090 min under the following conditions. : Pillar: Chiralcel OD-3 100 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: Ethanol containing 0.05% DEA; Flow rate: 2.8 mL / min; Column temperature: 35 ℃; ABPR: 1500 Psi; The retention time is 2.052 min or 2.580 min under the following conditions. : Pillar: Chiralpak AD-3 50 4.6 mm ID, 3 μm; Mobile phase: A: CO2; B: Ethanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 2 minutes, then hold at 40% mobile phase B for 1.2 minutes, then hold at 5% mobile phase B for 0.8 minutes; Flow rate: 4 mL / min; Column temperature: 35 °C; ABPR: 1500 psi; The retention time is 3.536 min or 3.573 min under the following conditions. : Pillar: Chiralpak AS-3 100 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: ethanol containing 0.05% DEA; Elution program: from 5% to 40% mobile phase B over 4 minutes, then hold at 40% mobile phase B for 2.5 minutes, then hold at 5% mobile phase B for 1.5 minutes; Flow rate: 2.8 mL / min; Column temperature: 35 °C; ABPR: 1500 psi; The retention time is 0.477 min or 1.927 min under the following conditions. : Pillar: Chiralpak AD-3 50 4.6mm ID, 3μm; Mobile phase: A: CO2; B: ethanol containing 0.05% DEA; isocratic elution: 40% B; flow rate: 4 mL / min; column temperature: 35°C; ABPR: 1500 psi.

26. The compound of formula I as claimed in claim 1, or a pharmaceutically acceptable salt thereof, characterized in that: A pharmaceutically acceptable salt of a compound represented by Formula I has any of the following structures: , , , , , , , , , , , , and .

27. A method for preparing a compound of formula I as described in any one of claims 1 to 26, characterized in that, It includes the following steps: The compound shown in Formula II is subjected to an acylation reaction with A-OH or A-Cl as shown below to give the compound shown in Formula I. ， Among them, R1, R2, R3, R4, A, Z, X1, Y1, X, Y, R 7A The definition of n is as described in any one of claims 1 to 26, when n is accompanied by " When the carbon atom in "" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

28. A method for preparing a compound as shown in Formula IV, characterized in that, It includes the following steps: The compound shown in Formula V was subjected to the following cyclization reaction to obtain the compound shown in Formula IV. ， Among them, R1, R2, R3, X1, Y1, X, Y, R 7A The definition of n is as described in any one of claims 1 to 26, when n is accompanied by " When the carbon atom in "" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

29. A method for preparing a compound as shown in Formula VII, characterized in that, It includes the following steps: In the presence of a reducing agent, the compound shown in Formula IX undergoes a reductive cyclization reaction as shown below to yield the compound shown in Formula VII. ， Among them, R1, X1, Y1, R 7A The definition of n is as described in any one of claims 1 to 26, when n is accompanied by " When the carbon atom in "" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

30. A method for preparing a compound of formula I as described in any one of claims 1 to 26, characterized in that, It is route 1 or 2; route 1 includes the following steps: ， Where Z is O; The reaction parameters for step 1 are as follows: Curtius rearrangement reaction; The reaction parameters for step 2 are as follows: deprotection reaction, acidic conditions; The reaction parameters for step 3 are as follows: iodination reaction, acidic conditions, iodination reaction with N-iodosuccinimide; The reaction parameters for step 4 are as follows: carbonyl insertion reaction, palladium catalysis, alkaline conditions, carbonyl insertion reaction with CO / ethanol; The reaction parameters for step 5 are as follows: acylation reaction, acylation reaction with monoethyl malonate chloride; The reaction parameters for step 6 are as follows: cyclization reaction, under alkaline conditions; The reaction parameters for step 7 are as follows: decarboxylation reaction, acidic conditions; The reaction parameters for step 8 are as follows: nitration reaction, acidic conditions; The reaction parameters for step 9 are as follows: chlorination reaction, involving chlorination with POCl3, phosphorus pentachloride, or thionyl chloride; The reaction parameters for step 10 are as follows: substitution reaction, basic conditions; The reaction parameters for step 11 are as follows: reduction cyclization, with the reducing agent being iron powder, zinc powder, sodium hydrosulfite, or H2; The reaction parameters for step 12 are as follows: esterification reaction, alkaline conditions, esterification reaction with trifluoromethanesulfonic anhydride; The reaction parameters for step 13 are as follows: substitution reaction, under acidic conditions, substitution reaction with bromide; The reaction parameters for step 14 are as follows: substitution reaction, basic conditions; The reaction parameters for step 15 are as follows: deprotection, acidic conditions, and reaction in the presence of HF, tetrabutylammonium fluoride, or KF; The reaction parameters for step 16 are as follows: cyclization reaction, carried out in the presence of diethyl azodicarboxylate or diisopropyl azodicarboxylate and PPh3 or PBu3; The reaction parameters for step 17 are as follows: coupling reaction, Suzuki coupling reaction; The reaction parameters for step 18 are as follows: deprotection, acidic conditions; The reaction parameters for step 19 are as follows: acylation reaction, acylation reaction with A-OH or A-Cl; Route 2 includes the following steps: ， Where Z is O; The reaction parameters for step 1 are as follows: coupling reaction, palladium catalysis, alkaline conditions, coupling reaction with methanol; The reaction parameters for step 2 are as follows: chlorination reaction, involving chlorination with POCl3, phosphorus pentachloride, or thionyl chloride; The reaction parameters for step 3 are as follows: substitution and fluorination reactions are carried out under alkaline conditions; The reaction parameters for step 4 are as follows: reduction cyclization, with the reducing agent being iron powder, zinc powder, sodium hydrosulfite, or H2; The reaction parameters for step 5 are as follows: substitution reaction, basic conditions; The reaction parameters for step 6 are as follows: deprotection, acidic conditions, and reaction in the presence of HF, tetrabutylammonium fluoride, or KF; The reaction parameters for step 7 are as follows: cyclization reaction, carried out in the presence of diethyl azodicarboxylate or diisopropyl azodicarboxylate and PPh3 or PBu3; The reaction parameters for step 8 are as follows: demethylation reaction, with HI undergoing a demethylation reaction; The reaction parameters for step 9 are as follows: esterification reaction, alkaline conditions, esterification reaction with trifluoromethanesulfonic anhydride; The reaction parameters for step 10 are as follows: substitution reaction, under acidic conditions, substitution reaction with bromide; The reaction parameters for step 11 are as follows: coupling reaction, Suzuki coupling reaction; The reaction parameters for step 12 are as follows: deprotection, acidic conditions; The reaction parameters for step 13 are as follows: acylation reaction, with A-OH or A-Cl.

31. The method for preparing the compound as shown in Formula I according to claim 30, characterized in that, In the aforementioned route 1, The reaction parameters for step 2 are as follows: Deprotection reaction, acidic conditions are dilute hydrochloric acid or TFA; And / or, the reaction parameters for step 3 are as follows: iodination reaction, acidic conditions are glacial acetic acid, with N-iodosuccinimide undergoing iodination reaction; And / or, the reaction parameters for step 4 are as follows: carbonyl insertion reaction, palladium catalysis, in the presence of organic or inorganic bases, with CO / ethanol undergoing carbonyl insertion reaction; And / or, the reaction parameters for step 6 are as follows: cyclization reaction, in the presence of an organic or inorganic base; And / or, the reaction parameters for step 10 are as follows: substitution reaction, in the presence of an organic or inorganic base; And / or, the reaction parameters for step 11 are as follows: reduction cyclization, with H2 as the reducing agent, in the presence of palladium / carbon and Pd(OH)2 / carbon catalysts; And / or, the reaction parameters for step 12 are as follows: esterification reaction, in the presence of an organic or inorganic base, with trifluoromethanesulfonic anhydride; And / or, the reaction parameters for step 13 are as follows: substitution reaction, under acidic conditions, with sodium bromide or potassium bromide; And / or, the reaction parameters for step 14 are as follows: substitution reaction, in the presence of an organic or inorganic base; And / or, the reaction parameters for step 15 are as follows: deprotection, reaction in the presence of dilute hydrochloric acid and HF, tetrabutylammonium fluoride or KF; And / or, the reaction parameters for step 18 are as follows: deprotection, acidic conditions are dilute hydrochloric acid or TFA.

32. The method for preparing the compound as shown in Formula I according to claim 30, characterized in that, In the aforementioned route 2, The reaction parameters for step 4 are as follows: reduction cyclization, with H2 as the reducing agent, in the presence of palladium / carbon and Pd(OH)2 / carbon catalysts; And / or, the reaction parameters for step 5 are as follows: substitution reaction, in the presence of an organic or inorganic base; And / or, the reaction parameters for step 6 are as follows: deprotection, reaction in the presence of dilute hydrochloric acid and HF, tetrabutylammonium fluoride or KF; And / or, the reaction parameters for step 9 are as follows: esterification reaction, in the presence of an organic or inorganic base, with trifluoromethanesulfonic anhydride; And / or, the reaction parameters for step 10 are as follows: substitution reaction, under acidic conditions, with sodium bromide or potassium bromide; And / or, the reaction parameters for step 12 are as follows: deprotection, acidic conditions are dilute hydrochloric acid or TFA.

33. The following compounds are listed: ； in, R1, R2, R3, R4, Z, X1, Y1, X, Y, R 7A The definition of n is as described in any one of claims 1 to 26, when n is accompanied by " When the carbon atom in "" is a chiral carbon atom, it is in the R configuration, S configuration, or a mixture thereof.

34. The following compounds are listed: 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 , , , , , or .

35. A pharmaceutical composition comprising a compound of Formula I as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

36. Use of a compound of Formula I as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 35, in the preparation of a cell proliferation inhibitor or a KRAS G12C mutant protein inhibitor.

37. The application as described in claim 36, wherein the cells are Ba / F3 KRAS-G12C cells expressing KRAS G12C mutant protein, NCI-H358 cells expressing KRAS G12C mutant protein, or MIAPaCa-2 cells expressing KRAS G12C mutant protein.

38. The use of a compound of Formula I as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 35, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is a cancer associated with the KRAS G12C mutant protein.

39. The application as described in claim 38, wherein the cancer associated with the KRAS G12C mutant protein is non-small cell lung cancer, pancreatic cancer, leukemia, breast cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, sarcoma, osteoma, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine fibroids, thyroid tumors, colon cancer, brain cancer, cervical cancer, testicular cancer, head or neck cancer, rectal cancer, small cell lung cancer, esophageal cancer, lymphoma, gastrointestinal stromal tumor, bile duct cancer, endometrial cancer, or multiple myeloma.

40. The application as described in claim 38, wherein the cancer associated with the KRAS G12C mutant protein is bone cancer, glioma, thyroid cancer, lung adenocarcinoma, or lung squamous cell carcinoma.

41. The application as described in claim 38, wherein the cancer associated with the KRAS G12C mutant protein is glioblastoma.

42. The use of a compound of Formula I as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 35, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is non-small cell lung cancer, pancreatic cancer, leukemia, breast cancer, melanoma, neuroblastoma, gastric cancer, liver cancer, prostate cancer, skin cancer, sarcoma, osteoma, ovarian cancer, bladder cancer, kidney cancer, seminoma, uterine fibroids, thyroid tumors, colon cancer, brain cancer, cervical cancer, testicular cancer, head or neck cancer, rectal cancer, small cell lung cancer, esophageal cancer, lymphoma, gastrointestinal stromal tumor, bile duct cancer, endometrial cancer, or multiple myeloma.

43. The use of a compound of Formula I as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 35, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is bone cancer, glioma, thyroid cancer, lung adenocarcinoma, or lung squamous cell carcinoma.

44. The use of a compound of Formula I as described in any one of claims 1 to 26, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as described in claim 35, in the preparation of a medicament for treating and / or preventing cancer, wherein the cancer is glioblastoma.

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