Aromatic heterocyclic compounds, preparation method therefor and uses thereof

Abstract

Aromatic heterocyclic compounds as ENPP1 inhibitors, a preparation method therefor and the uses thereof. The compounds have structures as shown in formula (I).

Description

Technical Field This invention relates to the field of medical technology, specifically, it relates to aromatic heterocyclic compounds as ENPP1 inhibitors and preparation methods and uses of the compounds. Background of Art Cancer cells have chromosomal instability. As cancer cells cleavage, DNA fragments and even entire chromosomes may be duplicated, mutated, or completely lost. The more unstable the chromosomes are, the more likely DNA fragments will appear in inappropriate locations, e.g. floating in the cytoplasm outside the nucleus. Cells recognise these free DNA fragments as evidence of viral invasion, which in turn triggers an internal alarm within the cells, causing inflammation, and immune cells are recruited to the tumour site to launch an immune attack. STING (stimulator of interferon genes) is widely expressed on the endoplasmic reticulum of various immune cells. It mainly recognizes cyclic dinucleotides (CDNs) to detect DNA leakage in the cytoplasm and stimulate an immune response. DNA is usually present in the cell nucleus and mitochondria, and the presence of DNA in the cytoplasm is abnormal. cGAS can sense DNA in the cytoplasm and synthesize cyclic 2',3'-cGAMP from ATP or GTP. 2',3'-cGAMP binds to and activates STING, while ENPP1 is the only enzyme capable of hydrolyzing 2',3'-cGAMP. By hydrolyzing 2',3'-cGAMP, ENPP1 prevents signals from reaching immune cells. This process also releases the immunosuppressive molecule adenosine, which has a soothing effect on inflammation. Additionally, the expression of ENPP1 is associated with increased metastasis and resistance to immunotherapy. ENPP1 is a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase activities, belonging to the ectonucleotide pyrophosphatase / phosphodiesterase (ENPP) family, which consists of seven functionally distinct proteins (1-7). The structure of ENPP1 has two N-terminal SMB domains (SMB1 and SMB2), two linker regions (L1 and L2), a catalytic domain, and a nuclease-like domain. ENPP1 is differentially expressed in immune cells, with low levels in NK cells, DCs, and macrophages, and high levels in neutrophils. ENPP1 is also expressed in a small subset of B cells that may be involved in regulating T cell activity. Its expression is elevated in M2 subtype macrophages, which play a role in tumour promotion. The expression of ENPP1 increases in astrocytoma, breast cancer, and head and neck tumours, and varies greatly among different tumour tissues. The specific high expression of ENPP1 in some tumours may be a driving factor for tumour immune escape and metastasis. ENPP1 plays an important role in the immune response to multiple stimuli through the STING pathway, achieving high selectivity by selectively activating the STING signalling pathway in tumour cells and other cells in the tumour microenvironment. ENPP1 can also catalyze the hydrolysis of ATP to PPi and AMP, promoting the generation of adenosine, which has a strong immunosuppressive effect. Inhibiting ENPP1 can reduce adenosine production by inhibiting ATP hydrolysis, thereby lifting tumour immunosuppression. While STING agonists non-selectively activate STING in cancer cells and host cells, ENPP1 limits the scope of STING activation to tumour tissues and the tumour microenvironment, enhancing anti-tumour immunity. Moreover, 2022412821   03 Aug 2026 ENPP1 is selectively upregulated in metastatic and chromosomally unstable tumour cells. Systemic administration of ENPP1 inhibitors can interfere with the ability of diffused tumour cells to evade immune surveillance, bypassing the technical difficulties of intra-tumour administration of STING agonists. The combination of ENPP1 inhibitors and radiotherapy has achieved good results in animal models, and there is also a certain synergistic effect with immune checkpoint inhibitors such as PD-1 and PARP inhibitors. Currently, the development of ENPP1 inhibitors is still in the preclinical research stage, but several pharmaceutical companies have published patents on ENPP1 inhibitors, such as WO2021061803A1, WO2021158829A1, WO2020190912A1, WO2019177971A1, and WO2019046778A1. After heart injury, various cell populations are recruited to the heart. Using a mouse model of ischemic heart injury, it has been demonstrated that cardiomyocytes play a key role in heart repair by regulating nucleotide metabolism and the death of non-cardiomyocytes (Shen Li et al., 2022). Heart injury induces the expression of the ectonucleotide enzyme-ectonucleotide pyrophosphatase / phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes release adenine and specific ribonucleosides, disrupting pyrimidine biosynthesis at the orotidine monophosphate (OMP) synthesis step and inducing genotoxic stress and p53-mediated proliferation of non-cardiomyocyte death. Since non-muscle cells are crucial for heart repair, rescuing pyrimidine biosynthesis by administering uridine or genetically targeting the ENPP1 / AMP pathway can enhance repair after heart injury. Although some small molecule ENPP1 inhibitors have been disclosed in existing technologies, there are currently no clinically approved small molecule drugs on the market. Therefore, there is still an urgent need to develop new compounds with better efficacy and pharmacokinetic results that have the potential to be marketed. This invention designs a series of compounds with new structures represented by general formulae and finds that compounds with such structures exhibit excellent effects and functions, which is of positive significance for the development of ENPP1 inhibitors. The discussion of documents, acts, materials, devices, articles and the like is included in this specification solely for the purpose of providing a context for the present invention. It is not suggested or represented that any or all of these matters formed part of the prior art base or were common general knowledge in the field relevant to the present invention as it existed before the priority date of each claim of this application. Summary of the Invention This invention may provide a compound with an aromatic heterocyclic structure as an ENPP1 inhibitor, a process for preparing the compound, and its use in treating ENPP1-mediated diseases. In a first aspect, there is provided a compound represented by the following formula (I), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound: 2022412821   03 Aug 2026 wherein X1, X2, X3, and X4 are each independently CH or N; Y is N; RA is a substituent of the ring where X1 is located, RB is a substituent of the ring where Y is located; each RA is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclyl, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylthio, or C3-6cycloalkyl, wherein the alkyl is optionally substituted by one or more substituents selected from deuterium and halogen; and each RB is independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl; n1 is 1, 2, 3 or 4; n2 is 1; either each Rc is independently hydrogen, Cl, oxo, oxime, -CN, -OH, -SH, -NH2, -Boc, -COCH2OH, -NHC(O)CH3, carboxyl, -S(O)2CH3, -S(O)2NH2, -CH2S(O)2CH3, methoxy, methylthio, -CH2CH2CH2OH, -CH2CH2CH2OCH3, ethyl, -CH2CF3, cyclopropyl, phenyl, or ethenyl; n3 is 1, 2, or 3; and one or two RCs in (RC)n3 are oxo, the above-mentioned ring A substituted by one or two RCs is 2022412821   03 Aug 2026 or the ring A ** represents the site of fusing, \ represents the attachment position of the L group; .           . *^N^CF3 substituted by (Rc)n3 is I Jx. N''O o, or Z is a bond; ring B is phenyl, or 6-membered monocyclic-heteroaryl; RD is selected from -SO2NH2, -S(O)2OH, -S(O)2CH3, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHCH2C(O)OH, -S(O)2ND2, -S(O)2NHNH2, and -S(O)2NHOH; RE is each independently hydrogen, deuterium, F, Cl, carboxyl, -CN, -NH2, methyl, methylthio, -CF3, methoxy, - CH2NH2, -CH2OH, -CH2NHOH, -CH=NOH, -CH2CH2OH, -CHF2, -C(O)OCH3, -C(O)CH3,         , , cyclopropyl, ethenyl, ethynyl, propynyl, ethyl, or propenyl; 2022412821   03 Aug 2026 n4 is 1, 2, 3, 4, 5, or 6; L represents a bridging group between ring A and ring B and is selected from -O-, -CH2-, and        ; R1 at each occurrence is independently hydrogen, or C1-6alkyl; R2 and R3 at each occurrence are independently hydrogen, or C1-6alkyl; R4 at each occurrence is independently hydrogen, deuterium, C1-6alkyl, C1-6alkoxy, C3-6cycloalkyl, phenyl, or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-3alkyl, C1-4alkoxy, C1-3haloalkyl, and C1-3haloalkoxy; in the case that multiple RAs, RBs, RCs or REs appear at the same time, RAs, RBs, RCs or REs can be identical or different from each other; unless otherwise stated, the heteroatoms in the above-mentioned heterocyclyl and heteroaryl are independently selected from O, N and S, and the number of heteroatoms is 1, 2, 3, or 4. In an alternative first aspect, there is provided a compound represented by the following formula (I), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: wherein X1, X2, X3, X4 and Y are each independently CH or N; and when X1, X2, X3 and X4 are all CH, Y is not CH; RA is a substituent of the ring where X1 is located, RB is a substituent of the ring where Y is located, RA and RB are each independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)(CR5R6)nC(O)R4, -Z-C(O)(CR5R6)nC(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-20 membered heterocyclyl, 5-16 membered heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; n1 is 1, 2, 3 or 4; n2 is 1 or 2; ring A is 6-10 membered heterocyclyl or 6-12 membered heteroaryl; 2022412821   03 Aug 2026 RC is a substituent of ring A, and each RC is independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)(CR5R6)nC(O)R4, -Z-C(O)(CR5R6)nC(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-20 membered heterocyclyl, C6-12 aryl, 5-16 membered heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, aryl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; n3 is 1, 2, 3, 4, 5, or 6; Z is selected from a bond, C1-3 alkylene, C1-3 alkyleneoxy, and C1-3 alkylenethio, the alkylene, alkyleneoxy, or alkylenethio is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, and -NH2; ring B is C3-10 cycloalkyl, 3-20 membered heterocyclyl, C6-14 aryl or 5-16 membered heteroaryl; RD is selected from -W-OC(O)OR1, -W-C(O)NR2R3, -W-C(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-S(O)=NR2, -W-S(O)=NR2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O- P(S)(OR1)2, -W-B(OH)2, andR2N=S=O ; or Rd is selected from -W-OC(O)OR1, -W-CONR2R3, -W-C(O)NR2OR1, R4 -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-S(O)=NR2, -W-S(O)=NR2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O-P(S)(OR1)2, and -W-B(OH)2; each RE is independently hydrogen, deuterium, halogen, oxo, oxime, carboxyl, -CN, -OH, -SH, -NO2, -NH2, -W-OR1, -W-SR1, -W-C(O)R4, -W-C(O)OR1, -W-OC(O)R1, -W-OC(O)OR1, -W-C(O)NR2R3, -W-C(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O-P(S)(OR1)2, -W-B(OH)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-20 membered heterocyclyl, 5-16 membered heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; n is 1, 2, or 3; n4 is 1, 2, 3, 4, 5, or 6; W is selected from a bond, C1-3 alkylene, C1-3 alkyleneoxy, and C1-3 alkylenethio, the alkylene, alkyleneoxy, or alkylenethio is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, and -NH2; L is selected from a bond, -O-, -S-, C1-6 alkylene, C1-6 alkyleneoxy, C3-6 cycloalkylene, C1-6 alkylenethio, C2-6 alkenylene, and C2-6 alkynylene, the alkylene, alkyleneoxy, cycloalkylene, alkylenethio, alkenylene, or alkynylene is optionally substituted by one or more substituents selected from deuterium, halogen, C1-3 alkyl, C1-6 alkoxy, oxo, -CN, -OH, and -NH2; 2022412821   03 Aug 2026 R1 is independently at each occurrence hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, phenyl, or 3-20 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-3 alkyl, C1-4 alkoxy, phenyl, C1-3 haloalkyl, C1-4 haloalkoxy, and halophenyl; R2 and R3 are independently at each occurrence hydrogen, C1-6 alkyl, or C1-6 alkoxy, wherein the alkyl, or alkoxy is optionally substituted by one or more substituents selected from halogen, deuterium, cyano, hydroxy, amino, carboxyl, C1-3 alkyl, C1-4 alkoxy, C1-4 alkyl, C3-8 cycloalkyl, phenyl, C1-3 haloalkyl, C1-3 haloalkoxy, and halophenyl; R4 is independently at each occurrence hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, phenyl, or 3-20 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-3 alkyl, C1-4 alkoxy, phenyl, C1-3 haloalkyl, C1-3 haloalkoxy, and halophenyl; R5 and R6 are independently hydrogen, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-3 alkylthio, C3-6 cycloalkyl, C3-6 cycloalkenyl, 3-20 membered heterocyclyl, or 5-16 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NH2, C1-3 alkyl, and C1-3 haloalkyl. In the case that multiple RAs, RBs, RCs or REs appear at the same time, RAs, RBs, RCs or REs can be identical or different from each other. In a preferable embodiment according to the first aspect of this invention, X1 is N, and X2, X3, and X4 are all CH. In a preferable embodiment according to the first aspect of this invention, X3 is N, and X1, X2 and X4 are all CH. In a preferable embodiment according to the first aspect of this invention, X1 and X3 are both N, and X2 and X4 are both CH. In a preferable embodiment according to the first aspect of this invention, X1, X2, X3, and X4 are all CH. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, Y is CH; or Y is N. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, each RA is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclyl, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-8 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6h aloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RA is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclyl, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-4 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RA is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, - 2022412821   03 Aug 2026 Z-NR2C(O)OR1, 3-6 membered heterocyclyl, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or, each RA is independently hydrogen, deuterium, F, Cl, Br, oxime, -CN, -OH, -SH, -NO2, -NH2, -NR2C(O)R4, -NR2C(O)OR1, 3-6 membered heterocyclyl, -C(O)R4, -C(O)OR1, -C(O)NR2R3, -S(O)2R4, -S(O)2NR2R3, methyl, ethyl, propyl, isopropyl, tert-butyl, ethenyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl, ethenyl, ethynyl, propenyl, or propynyl; or, each RA is independently hydrogen, F, Cl, Br, oxime, -CN, -OH, -NH2, -NHC(O)C1-3alkyl, -NHC(O)OC1-3alkyl, 3-4 membered heterocyclyl, -C(O)C1-3 alkyl, -C(O)OC1-3 alkyl, -C(O)NHC1-3 alkyl, -S(O)2C1-3 alkyl, -S(O)2NH2, -S(O)2NHC1-3 alkyl, methyl, ethyl, methoxy, ethoxy, methylthio, ethenyl, propenyl, ethynyl, cyclopropyl, or tert-butyl; or, RA is selected from hydrogen, F, Cl, -CN, -NH2, oxime, methyl, methoxy, ethoxy, methylthio, -OCD3, -on NHCOCH3, -NHCOOCH3,       , -COCH3, -COOCH3, -COCH2OCH3, -CONHCH3, -SO2CH3, -SO2NH2, - CH=CH-CH3, ethynyl, cyclopropyl, and tert-butyl. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, n1 is 1, 2, or 3; or, n1 is 1 or 2. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, each RB is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RB is independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl; or, each RB is independently hydrogen, F, Cl, Br, -OH, -NH2, methyl, ethyl, methoxy, ethoxy, ethenyl, or ethynyl; or, RB is hydrogen, -NH2, methyl, methoxy, or ethynyl. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, n2 is 1. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, ring A is 6-9 membered heterocyclyl or 6-12 membered heteroaryl; or, ring A is 6-8 membered heterocyclyl or 6-8 membered heteroaryl; or, ring A is 6-membered heterocyclyl or 6-membered heteroaryl; or, ring A is piperidyl, hexahydropyrimidyl, piperazinyl, 1,3-oxazinanyl, morpholinyl, thiomorpholinyl, 1,3- 2022412821   03 Aug 2026 thiazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3,6-tetrahydropyrazinyl, 1,4,5,6-tetrahydropyrimidyl, homopiperidyl, homopiperazinyl, homomorpholinyl, pyridyl, pyridazinyl, pyrimidyl, 1,4-diazepane, 1,5-diazocane, 1,4-oxazepane, 1,3-oxazepane, 1,4-oxazacyclooctane, 2,3,6,7-tetrahydro-1,4-diazepine; or, ring A is N^NH , group; N ; \ represents the attachment position of the L * * * a .              yah *a .a           v ring Ais ^1,1^ ’ N^NH’znA ,.,^0,  ^,  ^,.^^8,.^ I      %          \                                                 % ** represents the site of fusing, \ represents the attachment position of the L group; or, when one or both of RCs is oxo, the above-mentioned ring A substituted by one or two RCs is ** represents the site of fusing, \ represents the attachment position of the L group; or, the ring A substituted by RC(s) is 2022412821   03 Aug 2026 0, or In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, each RC is independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, -ZC(O)OR1, -ZNR2C(O)R4, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloalkyl, 3-8 membered heterocyclyl, 5-8 membered heteroaryl, or C6-12 aryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RC is independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, -ZC(O)OR1, -ZNR2C(O)R4, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, or C6-12 aryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or, each RC is independently hydrogen, halogen, oxo, oxime, -CN, -OH, -SH, -NH2, -C(O)OC1-6 alkyl, carboxyl, -NHC(O)C1-6 alkyl, -S(O)2C1-6 alkyl, -S(O)2NH2, -CH2S(O)2C1-6 alkyl, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 alkylthio, C3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-8 membered heteroaryl, or C6-12 aryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclyl, heteroaryl or aryl is optionally substituted by one or more substituents selected from halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy; or, each RC is independently hydrogen, F, Cl, Br, oxo, oxime, -CN, -OH, -SH, -NH2, -C(O)OC1-4 alkyl, carboxyl, - 2022412821   03 Aug 2026 NHC(O)C1-4 alkyl, -S(O)2C1-4alkyl, -S(O)2NH2, -CH2S(O)2C1-4 alkyl, tetrahydrofuryl, pyrrolyl, phenyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl. or, each Rc is independently hydrogen, Cl, oxo, oxime, -CN, -OH, -SH, -NH2, -Boc, -COCH2OH, -NHC(O)CH3, carboxyl, -S(O)2CH3, -S(O)2NH2, -CH2S(O)2CH3, methoxy, methylthio, -CH2CH2CH2OH, -CH2CH2CH2OCH3, ethyl, T| n , I    Q, -CH2CF3, cyclopropyl, phenyl, or ethenyl. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, n3 is 1, 2, or 3. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, is selected from: , AAyA , AAaA , or A HNx^yNH HN^J HN\_ / °      HN In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, ring B is C5-10 cycloalkyl, 3-20 membered heterocyclyl, C6-14 aryl or 5-16 membered heteroaryl; or, ring B is C5-7 cycloalkyl, 5-7 membered monocyclic heterocyclyl, 5-14 membered spiro-heterocyclyl, 5-14 membered fused-heterocyclyl, C6-10 aryl, 5-6 membered monocyclic-heteroaryl or 5-14 membered fused-heteroaryl; or, ring B is C6 cycloalkyl, C7 cycloalkyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, 4-membered / 4-membered spiro-heterocyclyl, 4-membered / 5-membered spiro-heterocyclyl, 5-membered / 4-membered spiro-heterocyclyl, 5-membered / 5-membered spiro-heterocyclyl, 4-membered / 6-membered spiro-heterocyclyl, 6-membered / 4-membered spiro-heterocyclyl, 5-membered / 6-membered spiro-heterocyclyl, 6-membered / 5-membered spiro-heterocyclyl, 6-membered / 6-membered spiro-heterocyclyl, 4-membered / 4-membered fused-heterocyclyl, 4-membered / 5-membered fused-heterocyclyl, 5-membered / 4-membered fused-heterocyclyl, 5-membered / 5-membered fused-heterocyclyl, 5-membered / 6-membered fused-heterocyclyl, 6-membered / 5-membered fused-heterocyclyl, 4-membered / 6-membered fused-heterocyclyl, 6-membered / 4-membered fused- 2022412821   03 Aug 2026 heterocyclyl, 6-membered / 6-membered fused-heterocyclyl, phenyl, naphthyl, 5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl, 5-membered / 5-membered fused-heteroaryl, 5-membered / 6-membered fused-heteroaryl, 6-membered / 5-membered fused-heteroaryl, 6-membered / 6-membered fused-heteroaryl, the heteroatoms in the above-mentioned heterocyclyl, heteroaryl, fused-heterocyclyl, fused-heteroaryl, spiro-heterocyclyl are independently selected from O, N and S, the number of heteroatoms is 1, 2, or 3; or, ring B is or In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, RD is selected from -W-C(O)NR2R3, -W-C(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W- NR2SO2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O-P(S)(OR1)2, -W-B(OH)2, andR2N=s=0 R4 ; or RD is selected from -W-C(O)NR2R3, -W-C(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O-P(S)(OR1)2, and -W-B(OH)2; or, RD is selected from -C0-3 alkylene-C(O)NHOH, -C0-3 alkylene-OC(O)NH2, -C0-3 alkylene-SO2NH2, -C0-3 alkylene-NHS(O)2H, -C0-3 alkylene-OS(O)2H, -C0-3 alkylene-NHS(O)2NH2, -C0-3 alkylene-OS(O)2NH2, -C0-3 alkylene-P(O)(OH)2, -C0-3 alkylene-P(S)(OH)2, -C0-3 alkylene-O-P(S)(OH)2, -C0-3 alkylene-B(OH)2, -C0-3 alkylene-S(O)2OH, -C0-3 alkylene-C(O)NH2, -C0-3 alkylene-S(O)2C1-3 alkyl, -C0-3 alkylene-OS(O)2-C1-3 alkyl, -C0-3 alkylene-S(O)2-C1-3 alkylene-C(O)OH, -C0-3 alkylene-S(O)2C1-3 alkylene-NH2, -C0-3 alkylene-S(O)2NHCH2C(O)OH, -C0-3 alkylene-NHS(O)2CH3, -C0-3 alkylene-S(O)2ND2, -C0-3 alkylene-S(O)2NHNH2, -C0-3 alkylene-S(O)2NHSC1-3 alkyl, -C0-3 alkylene-NHS(O)2C1-3 alkyl, -C0-3 alkylene-NH-C(O)C1-3 alkyl, -C0-3 alkylene-NH-CONH2, -C0-3 alkylene-NH- ^CH2)o_3 COOC1-3 alkyl, -C0-3 alkylene-S(O)2NHOH, andHN=^=o ; or Rd is selected from -C0-3 alkylene-C(O)NHOH, -Co-I 3 alkylene-OC(O)NH2, -C0-3 alkylene-SO2NH2, -C0-3 alkylene-NHS(O)2H, -C0-3 alkylene-OS(O)2H, -C0-3 alkylene-NHS(O)2NH2, -C0-3 alkylene-OS(O)2NH2, -C0-3 alkylene-P(O)(OH)2, -C0-3 alkylene-P(S)(OH)2, -C0-3 alkylene-O-P(S)(OH)2, -C0-3 alkylene-B(OH)2, -C0-3 alkylene-S(O)2OH, -C0-3 alkylene-C(O)NH2, -C0-3 alkylene-S(O)2C1-3 alkyl, -C0-3 alkylene-OS(O)2-C1-3 alkyl, -C0-3 alkylene-S(O)2-C1-3 alkylene-C(O)OH, -C0-3 alkylene-S(O)2C1-3 alkylene-NH2, -C0-3 alkylene-S(O)2NHCH2C(O)OH, -C0-3 alkylene-NHS(O)2CH3, -C0-3 alkylene-S(O)2ND2, -C0-3 alkylene-S(O)2NHNH2, -C0-3 alkylene-S(O)2NHSC1-3 alkyl, -C0-3 alkylene-NHS(O)2C1-3 alkyl, -C0-3 alkylene-NH-C(O)C1-3 alkyl, -C0-3 alkylene-NH-CONH2, -C0-3 alkylene-NH-COOC1-3 alkyl, and -C0-3 alkylene-S(O)2NHOH; or, RD is selected from -methylene-C(O)NHOH, -methylene-OC(O)NH2, -methylene-SO2NH2, -methylene-NHS(O)2H, -methylene-OS(O)2H, -methylene-NHS(O)2NH2, -methylene-OS(O)2NH2, -methylene-P(O)(OH)2, - 2022412821   03 Aug 2026 methylene-P(S)(OH)2, -methylene-O-P(S)(OH)2, -methylene-B(OH)2, -C(O)NHOH, -OC(O)NH2, -SO2NH2, -NHS(O)2H, -OS(O)2H, -NHS(O)2NH2, -OS(O)2NH2, -P(O)(OH)2, -P(S)(OH)2, -O-P(S)(OH)2, -B(OH)2; -S(O)2OH, -C(O)NH2, -S(O)2C1-3 alkyl, -OS(O)2C1-3 alkyl, -S(O)2C1-3 alkylene-C(O)OH, -S(O)2C1-3 alkylene-NH2, -S(O)2NHCH2C(O)OH, -NHS(O)2CH3, -S(O)2ND2, -S(O)2NHNH2, -methylene-NHS(O)2C1-3 alkyl, -methylene-NH- C(O)Ci-3 alkyl, -methylene-NH-CONH2, -NH-COOC1-3 alkyl, -S(O)2NHOH, andHN=s=o; or, Rd is selected from - methylene-C(O)NHOH, -methylene-OC(O)NH2, -methylene-SO2NH2, -methylene-NHS(O)2H, -methylene-OS(O)2H, -methylene-NHS(O)2NH2, -methylene-OS(O)2NH2, -methylene-P(O)(OH)2, -methylene-P(S)(OH)2, -methylene-O-P(S)(OH)2, -methylene-B(OH)2, -C(O)NHOH, -OC(O)NH2, -SO2NH2, -NHS(O)2H, -OS(O)2H, -NHS(O)2NH2, -OS(O)2NH2, -P(O)(OH)2, -P(S)(OH)2, -O-P(S)(OH)2, -B(OH)2; -S(O)2OH, -C(O)NH2, -S(O)2C1-3 alkyl, -OS(O)2C1-3 alkyl, -S(O)2C1-3 alkylene-C(O)OH, -S(O)2C1-3 alkylene-NH2, -S(O)2NHCH2C(O)OH, -NHS(O)2CH3, -S(O)2ND2, -S(O)2NHNH2, -methylene-NHS(O)2C1-3 alkyl, -methylene-NH-C(O)C1-3 alkyl, -methylene-NH-CONH2, -NH-COOC1-3 alkyl, and -S(O)2NHOH; or, RD is selected from -C(O)NHOH, -SO2NH2, -methylene-NHS(O)2NH2, -NHS(O)2NH2, -B(OH)2, -P(O)(OH)2, -OP(S)(OH)2, -OS(O)2NH2, -S(O)2OH, -C(O)NH2, -S(O)2CH3, -OS(O)2CH3, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHCH2C(O)OH, -NHS(O)2CH3, -S(O)2ND2, -S(O)2NHNH2, -methylene-NHS(O)2CH3, - methylene-NH-C(O)CH3, -methylene-NH-CONH2, -NH-COOCH3, -S(O)2NHOH, andHN=s=o; or, Rd is selected from -C(O)NHOH, -SO2NH2, -methylene-NHS(O)2NH2, -NHS(O)2NH2, -B(OH)2, -P(O)(OH)2, -OP(S)(OH)2, -OS(O)2NH2, -S(O)2OH, -C(O)NH2, -S(O)2CH3, -OS(O)2CH3, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHCH2C(O)OH, -NHS(O)2CH3, -S(O)2ND2, -S(O)2NHNH2, -methylene-NHS(O)2CH3, -methylene-NH-C(O)CH3, -methylene-NH-CONH2, -NH-COOCH3, and -S(O)2NHOH. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, RE is each independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, or C3-8 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, RE is each independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-3alkyl, C1-3alkoxy, or C3-6cycloalkyl, the alkyl, alkoxy, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-3alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy; or, RE is each independently hydrogen, halogen, -OH, -SH, C1-3alkyl, C1-3alkoxy, or C3-6 cycloalkyl, the alkyl, alkoxy, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy; or, RE is each independently hydrogen, F, Cl, Br, -OH, -SH, -methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl; or, RE is each independently hydrogen, deuterium, F, Cl, carboxyl, -CN, -NH2, methyl, methylthio, -CF3, methoxy, - 2022412821   03 Aug 2026 CH2NH2, -CH2OH, -CH2NHOH, -CH=NOH, -CH2CH2OH, -CHF2, -C(O)OCH3, -C(O)CH3, , cyclopropyl, ethenyl, ethynyl, propynyl, ethyl, propenyl. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, n4 is 1, 2, 3 or 4; or, n4 is 1, 2, or 3. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, L is a bond, -O-, -S-, C1-3 alkylene, C1-3 alkyleneoxy, C3-6 cycloalkylene, C1-3 alkylenethio, C2-6 alkenylene, or C2-6 alkynylene, the alkylene, alkyleneoxy, cycloalkylene, alkylenethio, alkenylene, or alkynylene is optionally substituted by one or more substituents selected from deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, oxo, -CN, -OH, and -NH2; or, L is a bond, -O-, -S-, methylene, ethylene, propylene, cyclopropylene, cyclobutylene, C1-3alkyleneoxy, C1-3alkylenethio, ethenylene, or ethynylene, the methylene, ethylene, propylene, cyclopropylene, cyclobutylene, alkyleneoxy, alkylenethio, ethenylene, or ethynylene is optionally substituted by one or more substituents selected from deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -CN, -OH, and -NH2; or, L is a bond, -O-, -S-, cyclopropylene, methylenemethoxy, methylenemethyl, methylene-OH, methylene-NH2, ethylene, or propylene; or, L is a bond, -O-, -CH2-, . The second aspect of this invention provides a compound represented by the following formula (I), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: wherein X1, X2, X3, X4 and Y are each independently CH or N; and when X1, X2, X3 and X4 are all CH, Y is not CH; RA is a substituent of the ring where X1 is located, RB is a substituent of the ring where Y is located, RA and RB are each independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)(CR5R6)nC(O)R4, -Z-C(O)(CR5R6)nC(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-20 membered heterocyclyl, 5-16 membered heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, 2022412821   03 Aug 2026 C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; n1 is 1, 2, 3 or 4; n2 is 1 or 2; ring A is 6-10 membered heterocyclyl or 6-12 membered heteroaryl; RC is a substituent of ring A, and RC is each independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)(CR5R6)nC(O)R4, -Z-C(O)(CR5R6)nC(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-20 membered heterocyclyl, 516 membered heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; n3 is 1, 2, 3, 4, 5, or 6; Z is selected from a bond, C1-3 alkylene, C1-3 alkyleneoxy, and C1-3 alkylenethio, the alkylene, alkyleneoxy, or alkylenethio is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, and -NH2; ring B is C3-10 cycloalkyl, 3-20 membered heterocyclyl, C6-14 aryl or 5-16 membered heteroaryl; RD is selected from -W-OC(O)OR1, -W-C(O)NR2R3, -W-C(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O-P(S)(OR1)2, and -W-B(OH)2; each RE is independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, -W-OR1, -W-SR1, -W-C(O)R4, -W-C(O)OR1, -W-OC(O)R1, -W-OC(O)OR1, -W-C(O)NR2R3, -W-C(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O-P(S)(OR1)2, -W-B(OH)2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-20 membered heterocyclyl, 5-16 membered heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; n4 is 1, 2, 3, 4, 5, or 6; W is selected from a bond, C1-3 alkylene, C1-3 alkyleneoxy, and C1-3 alkylenethio, the alkylene, alkyleneoxy, or alkylenethio is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, and -NH2; L is selected from a bond, -O-, -S-, C1-6 alkylene, C1-6 alkyleneoxy, C3-6 cycloalkylene, C1-6 alkylenethio, C2-6 alkenylene, and C2-6 alkynylene, the alkylene, alkyleneoxy, cycloalkylene, alkylenethio, alkenylene, or alkynylene is optionally substituted by one or more substituents selected from deuterium, halogen, C1-3 alkyl, C1-6 alkoxy, oxo, -CN, -OH, and -NH2; R1 at each occurrence is independently hydrogen, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, phenyl, or 3-20 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-3 alkyl, C1-4 alkoxy, phenyl, C1-3 haloalkyl, C1-4 2022412821   03 Aug 2026 haloalkoxy, and halophenyl; R2 and R3 at each occurrence are independently hydrogen, C1-6 alkyl, or C1-6 alkoxy, wherein the alkyl, or alkoxy is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-3 alkyl, C1-4 alkoxy, phenyl, C1-3 haloalkyl, C1-3 haloalkoxy, and halophenyl; R4 at each occurrence is independently hydrogen, deuterium, C1-6 alkyl, C1-6 alkoxy, C3-8 cycloalkyl, phenyl, or 3-20 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-3 alkyl, C1-4 alkoxy, phenyl, C1-3 haloalkyl, C1-3 haloalkoxy, and halophenyl; R5 and R6 at each occurrence are independently hydrogen, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-3 alkylthio, C3-6 cycloalkyl, C3-6 cycloalkenyl, 3-20 membered heterocyclyl, or 5-16 membered heteroaryl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NH2, C1-3 alkyl, and C1-3 haloalkyl. In a preferable embodiment according to the second aspect of this invention, X1 is N, and X2, X3, and X4 are all CH. In a preferable embodiment according to the second aspect of this invention, X3 is N, and X1, X2, and X4 are all CH. In a preferable embodiment according to the second aspect of this invention, X1 and X3 are both N, and X2 and X4 are both CH. In a preferable embodiment according to the second aspect of this invention, X1, X2, X3, and X4 are all CH. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, Y is CH; or Y is N. In a preferable embodiment according to the first aspect of this invention, in any of the preceding embodiments of the first aspect, each RA is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-8 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RA is independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RA is independently hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-4 alkenyl, C2-4 alkynyl, C1-3 alkoxy, C1-3 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or, each RA is independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, ethenyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl; or, each RA is independently hydrogen, F, Cl, Br, -OH, methyl, ethyl, methoxy, ethoxy; 2022412821   03 Aug 2026 or, RA is hydrogen, F, Cl, or methoxy. In a preferable embodiment according to the second aspect of this invention, n1 is 1, 2, or 3; more preferably, n1 is 1 or 2. In a preferable embodiment according to the second aspect of this invention, each RB is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; further preferably, each RB is independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl; more preferably, each RB is independently hydrogen, F, Cl, Br, -OH, methyl, ethyl, methoxy, ethoxy; most preferably, RB is H. In a preferable embodiment according to the second aspect of this invention, n2 is 1. In a preferable embodiment according to the second aspect of this invention, ring A is 6-9 membered heterocyclyl or 6-12 membered heteroaryl; preferably, ring A is 6-membered heterocyclyl or 6-membered heteroaryl; preferably, ring A is piperidyl, hexahydropyrimidyl, piperazinyl, 1,3-oxazinanyl, morpholinyl, thiomorpholinyl, 1,3-thiazinyl, 1,2,3,6-tetrahydropyridyl, 1,2,3,6-tetrahydropyrazinyl, 1,4,5,6-tetrahydropyrimidyl, homopiperidyl, homopiperazinyl, homomorpholinyl, pyridyl, pyridazinyl, pyrimidyl; ...... i        O os" preferably, ring A is .M-N^ >,,N^NH. M.y .,.Nv0> -,Nj , .^N^J , -,N S, ,.N   , %                ।           c, JW N - r^N ; \ represents the attachment position of the L group. still- further preferably- ring A is * * y^NH _NVNH ’ * * * * * * *o *^n *^ i ‘A NS ’.N^’    \N^N\AJ\An.N a                                  % IN          IN ** represents the site of fusing’ \ represents the attachment position of the L group. preferably’ when one or two RCs therein are oxo’ the above-mentioned ring A substituted by one or two RCs is 2022412821   03 Aug 2026 ** represents the site of fusing, \ represents the attachment position of the L group. more preferably, the ring A substituted by RC(s) is In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, each RC is independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloalkyl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RC is independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C1-6 alkoxy, C1-6 alkylthio, C3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, and C1-6 haloalkoxy; or, each RC is independently hydrogen, halogen, oxo, C1-3 alkyl, C1-3 alkoxy, C1-3 alkylthio, C3-6 cycloalkyl; the alkyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy; or, each RC is independently hydrogen, F, Cl, Br, oxo, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl; or, each Rc is independently hydrogen, -CH2CF3, oxo, -CH2CH2CH2OH, -CH2CH2CH2OCH3. In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, n3 is 1, 2, or 3. In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, is selected from: NH , , 2022412821   03 Aug 2026 In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, ring B is C5-10cycloalkyl, 3-20 membered heterocyclyl, C6-14 aryl or 5-16 membered heteroaryl; or, ring B is C5-7 cycloalkyl, 5-7 membered monocyclic heterocyclyl, 5-14 membered spiro-heterocyclyl, 5-14 membered fused-heterocyclyl, C6-10 aryl, 5-6 membered monocyclic-heteroaryl or 5-14 membered fused-heteroaryl; or, ring B is C6 cycloalkyl, C7 cycloalkyl, 6-membered monocyclic heterocyclyl, 7-membered monocyclic heterocyclyl, 4-membered / 4-membered spiro-heterocyclyl, 4-membered / 5-membered spiro-heterocyclyl, 5-membered / 4-membered spiro-heterocyclyl, 5-membered / 5-membered spiro-heterocyclyl, 4-membered / 6-membered spiro-heterocyclyl, 6-membered / 4-membered spiro-heterocyclyl, 5-membered / 6-membered spiro-heterocyclyl, 6-membered / 5-membered spiro-heterocyclyl, 6-membered / 6-membered spiro-heterocyclyl, 4-membered / 4-membered fused-heterocyclyl, 4-membered / 5-membered fused-heterocyclyl, 5-membered / 4-membered fused-heterocyclyl, 5-membered / 5-membered fused-heterocyclyl, 5-membered / 6-membered fused-heterocyclyl, 6-membered / 5-membered fused-heterocyclyl, 4-membered / 6-membered fused-heterocyclyl, 6-membered / 4-membered fused-heterocyclyl, 6-membered / 6-membered fused-heterocyclyl, phenyl, naphthyl, 5-membered monocyclic-heteroaryl, 6-membered monocyclic-heteroaryl, 5-membered / 5-membered fused-heteroaryl, 5-membered / 6-membered fused-heteroaryl, 6-membered / 5-membered fused-heteroaryl, 6-membered / 6-membered fused-heteroaryl, the heteroatoms in the above-mentioned heterocyclyl, heteroaryl, fused-heterocyclyl, fused-heteroaryl, spiro-heterocyclyl are independently selected from O, N and S, the number of heteroatoms is 1, 2, or 3; or, ring B is In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, RD is selected from -W-C(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -W-S(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -W-P(O)(OR1)2, -W-P(S)(OR1)2, -W-O-P(S)(OR1)2, and -W-B(OH)2; or, RD is selected from -methylene-C(O)NHOH, -methylene-OC(O)NH2, -methylene-SO2NH2, -methylene-NHS(O)2H, -methylene-OS(O)2H, -methylene-NHS(O)2NH2, -methylene-OS(O)2NH2, -methylene-P(O)(OH)2, - 2022412821   03 Aug 2026 methylene-P(S)(OH)2, -methylene-O-P(S)(OH)2, -methylene-B(OH)2, -C(O)NHOH, -OC(O)NH2, -SO2NH2, -NHS(O)2H, -OS(O)2H, -NHS(O)2NH2, -OS(O)2NH2, -P(O)(OH)2, -P(S)(OH)2, -O-P(S)(OH)2, and -B(OH)2; or, RD is selected from -methylene-C(O)NHOH, -methylene-SO2NH2, -methylene-NHS(O)2H, -methylene-NHS(O)2NH2, -methylene-P(O)(OH)2, -methylene-P(S)(OH)2, -methylene-O-P(S)(OH)2, -methylene-B(OH)2, -C(O)NHOH, -SO2NH2, -NHS(O)2NH2, -OS(O)2NH2, -P(O)(OH)2, -P(S)(OH)2, -O-P(S)(OH)2, and -B(OH)2; or, RD is selected from -C(O)NHOH, -SO2NH2, -methylene-NHS(O)2NH2, -NHS(O)2NH2, -B(OH)2, -P(O)(OH)2, -OP(S)(OH)2, and -OS(O)2NH2. In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, RE is each independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, or C3-8 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, RE is each independently hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, or C3-6 cycloalkyl, the alkyl, alkoxy, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy; or, RE is each independently hydrogen, halogen, -OH, -SH, C1-3 alkyl, C1-3 alkoxy, or C3-6 cycloalkyl, the alkyl, alkoxy, or cycloalkyl is optionally substituted by one or more substituents selected from hydrogen, deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C1-3 alkyl, C1-3 alkoxy, C1-3 haloalkyl, and C1-3 haloalkoxy; or, RE is each independently hydrogen, F, Cl, Br, -OH, -SH, -methyl, ethyl, n-propyl, isopropyl, cyclopropyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl; or, RE is each independently hydrogen, F. In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, n4 is 1, 2, 3 or 4; or, n4 is 1, 2, or 3. In a preferable embodiment according to the second aspect of this invention, in any of the preceding embodiments of the second aspect, L is a bond, -O-, -S-, C1-3 alkylene, C1-3 alkyleneoxy, C3-6 cycloalkylene, C1-3 alkylenethio, C2-6 alkenylene, or C2-6 alkynylene, the alkylene, alkyleneoxy, cycloalkylene, alkylenethio, alkenylene, or alkynylene is optionally substituted by one or more substituents selected from deuterium, halogen, C1-3 alkyl, C1-3 alkoxy, oxo, -CN, -OH, and -NH2; or, L is a bond, -O-, -S-, methylene, ethylene, propylene, cyclopropylene, cyclobutylene, C1-3 alkyleneoxy, C1-3 alkylenethio, ethenylene, or ethynylene, the methylene, ethylene, propylene, cyclopropylene, cyclobutylene, alkyleneoxy, alkylenethio, ethenylene, or ethynylene is optionally substituted by one or more substituents selected from deuterium, halogen, methyl, ethyl, n-propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, oxo, -CN, -OH, and -NH2; or, L is a bond, -O-, -S-, cyclopropylene, methylenemethoxy, methylenemethyl, methylene-OH, methylene-NH2, ethylene, or propylene; 2022412821   03 Aug 2026 or, L is a bond, -O-, -CH2-, The third aspect of this invention further provides a compound represented by the following formula (I-a), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: (I-a) wherein Y1 and Y2 are independently selected from C, O or S, and Y1 and Y2 are different; n5 is 1 or 2; when Y2 is not C, n6 is 1, when Y2 is C, n6 is 1 or 2; X1-X4, Y, RA, RB, RC, RD, RE, L, ring B, and n1-n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention; In a preferable embodiment according to the third aspect of this invention, Y1 is O, Y2 is C; In a preferable embodiment according to the third aspect of this invention, Y1 is S, Y2 is C; In a preferable embodiment according to the third aspect of this invention, Y2 is O, Y1 is C; In a preferable embodiment according to the third aspect of this invention, Y2 is S, Y1 is C; In a preferable embodiment according to the third aspect of this invention, in any of the preceding embodiments of the third aspect, is selected from: jL^Y^'jOr^Jzi HNx^y° Hlk^o HN\__ / ° In a preferable embodiment according to the third aspect of this invention, in any of the preceding embodiments of the third aspect, at least one RC is oxo. The fourth aspect of this invention further provides a compound represented by the following formula (I-a1): 2022412821   03 Aug 2026 (I-a1) w wherein W is halogen or , halogen is preferably Cl or Br; other substituents are defined as in formula (I-a) according to any of the embodiments in the preceding third aspect. The fifth aspect of this invention further provides a compound represented by the following formula (I-b), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: N^vYi I n5O ,\   . ZT , x RC (I-b) n3 Rd wherein Y1 and Y2 are independently selected from C, O and S, and Y1 and Y2 are different; n5 is 1 or 2; when Y2 is not C, n6 is 1, when Y2 is C, n6 is 1 or 2; X1-X4, Y, RA, RB, RC, RD, RE, L, ring B, and n1-n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention; In a preferable embodiment according to the fifth aspect of this invention, Y1 is O, Y2 is C; In a preferable embodiment according to the fifth aspect of this invention, Y1 is S, Y2 is C; In a preferable embodiment according to the fifth aspect of this invention, Y2 is O, Y1 is C; In a preferable embodiment according to the fifth aspect of this invention, Y2 is S, Y1 is C; In a preferable embodiment according to the fifth aspect of this invention, in any of the preceding embodiments of the fifth aspect, In a preferable embodiment according to the fifth aspect of this invention, in any of the preceding embodiments of 2022412821   03 Aug 2026 the fifth aspect, at least one RC is oxo. The sixth aspect of this invention further provides a compound represented by the following formula (I-b1): n^y-, L \   (I-b1) n3 wherein W is halogen or , halogen is preferably Cl or Br; other substituents are defined as in formula (I-b) according to any of embodiments in the preceding fifth aspect. The seventh aspect of this invention further provides a compound represented by the following formula (I-c), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: (I-c) Rd wherein Y1 and Y2 are independently selected from C and N; n5 is 1 or 2; when Y2 is not C, n6 is 1, when Y2 is C, n6 is 1 or 2; represents single bond or double bond, and at most one double bond exists, X1-X4, Y, Ra, Rb, Rc, RD, RE, L, ring B, and n1-n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention; In a preferable embodiment according to the seventh aspect of this invention, Y1 is N, Y2 is C; In a preferable embodiment according to the seventh aspect of this invention, Y1 is C, Y2 is N; In a preferable embodiment according to the seventh aspect of this invention, Y1 is C, Y2 is C; In a preferable embodiment according to the seventh aspect of this invention, in any of the preceding embodiments In a preferable embodiment according to the seventh aspect of this invention, in any of the preceding embodiments of the seventh aspect, at least one RC is oxo. 2022412821   03 Aug 2026 The eighth aspect of this invention further provides a compound represented by the following formula (I-c1): w wherein W is halogen or , halogen is preferably Cl or Br; other substituents are defined as in formula (I-c) according to any of embodiments in the preceding seventh aspect. The ninth aspect of this invention further provides a compound represented by the following formula (I-d), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: Ra — I-n1 X3. n2 Rd (I-d) wherein Y1 and Y2 are independently selected from C and N; n5 is 1 or 2; when Y2 is not C, n6 is 1, when Y2 is C, n6 is 1 or 2; represents single bond or double bond, and at most one double bond exists, X1-X4, Y, Ra, Rb, Rc, RD, RE, L, ring B, and n1-n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention. In a preferable embodiment according to the ninth aspect of this invention, Y1 is N, Y2 is C; In a preferable embodiment according to the ninth aspect of this invention, Y1 is C, Y2 is N; In a preferable embodiment according to the ninth aspect of this invention, in any of the preceding embodiments of , In a preferable embodiment according to the ninth aspect of this invention, in any of the preceding embodiments of the ninth aspect, at least one RC is oxo. The tenth aspect of this invention further provides a compound represented by the following formula (I-d1): 2022412821   03 Aug 2026 zn4 w (I-d1) n3 wherein W is halogen or , halogen is preferably Cl or Br; other substituents are defined as in formula (I-d) according to any of embodiments in the preceding ninth aspect. The eleventh aspect of this invention further provides a compound represented by the following formula (I-e), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: (I-e) wherein Y1 and Y2 are independently selected from C and N, represents single bond or double bond, and at most one double bond exists, X1-X4, Y, RA, RB, RC, RD, RE, L, ring B, and n1-n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention. In a preferable embodiment according to the eleventh aspect of this invention, Y1 is N, Y2 is C; In a preferable embodiment according to the eleventh aspect of this invention, Y1 is C, Y2 is N; In a preferable embodiment according to the eleventh aspect of this invention, in any of the preceding embodiments of the eleventh aspect, In a preferable embodiment according to the eleventh aspect of this invention, in any of the preceding embodiments of the eleventh aspect, at least one RC is oxo. The twelfth aspect of this invention further provides a compound represented by the following formula (I-e1): 2022412821   03 Aug 2026 , halogen is preferably Cl or Br; other substituents are defined as in formula (I-e) according to any of embodiments in the preceding eleventh aspect. The thirteenth aspect of this invention further provides a compound represented by the following formula (I-f), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: (I-f) wherein Y1, Y2, and Y3 are independently selected from C and N, and Y1, Y2 and Y3 are not C or N at the same time, X1-X4, Y, RA, RB, RC, RD, RE, L, ring B, and n1-n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention. In a preferable embodiment according to the thirteenth aspect of this invention, one of Y1, Y2 and Y3 is N, and the others are C; In a preferable embodiment according to the thirteenth aspect of this invention, Y1 and Y3 are N, Y2 is C; In a preferable embodiment according to the thirteenth aspect of this invention, Y1 and Y2 are N, Y3 is C; In a preferable embodiment according to the thirteenth aspect of this invention, Y2 and Y3 are N, Y1 is C; In a preferable embodiment according to the thirteenth aspect of this invention, in any of the preceding embodiments of the thirteenth aspect, The fourteenth aspect of this invention further provides a compound represented by the following formula (I-f1): 2022412821   03 Aug 2026 , halogen is preferably Cl or Br; other substituents are defined as in formula (I-f) according to any of embodiments in the preceding thirteenth aspect. The fifteenth aspect of this invention further provides a compound represented by the following formula (II), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: wherein, X1, X2, X3, X4, RA, RD, RE, ring B, L, n1, and n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention; Y1 is N, Y2 is CRB' or N; RB' and RY are each independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)(CR5R6)nC(O)R4, -Z-C(O)(CR5R6)nC(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl, C3-8 cycloalkenyl, 3-20 membered heterocyclyl, 5-16 membered heteroaryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclyl, or heteroaryl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; n is 0, 1, 2, or 3. In a preferable embodiment according to the fifteenth aspect of this invention, X1 is N, and X2, X3, and X4 are all CH. In a preferable embodiment according to the fifteenth aspect of this invention, X3 is N, and X1, X2, and X4 are all CH. In a preferable embodiment according to the fifteenth aspect of this invention, X1 and X3 are both N, and X2 and X4 are both CH. In a preferable embodiment according to the fifteenth aspect of this invention, X1, X2, X3, and X4 are all CH. In a preferable embodiment according to the fifteenth aspect of this invention, in any of the preceding embodiments of the fifteenth aspect, Y2 is CH; or Y2 is N. 2022412821   03 Aug 2026 In a preferable embodiment according to the fifteenth aspect of this invention, in any of the preceding embodiments of the fifteenth aspect, RB' is hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, RB' is hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl, ethenyl, or ethynyl; or, RB' is hydrogen, F, Cl, Br, -OH, cyano, methyl, ethyl, methoxy, ethoxy, ethenyl, or ethynyl; or, RB' is hydrogen. In a preferable embodiment according to the fifteenth aspect of this invention, in any of the preceding embodiments of the fifteenth aspect, each RY is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, C1-3 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, or C3-6 cycloalkyl, the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl is optionally substituted by one or more substituents selected from deuterium, halogen, oxo, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, and halophenyl; or, each RY is independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, cyano, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl, ethenyl, ethynyl, propenyl, or propynyl; or, each RY is independently hydrogen, deuterium, F, Cl, Br, -OH, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, ethenyl, ethynyl, propenyl, or propynyl; or, RY is hydrogen, amino, methyl, ethenyl, or ethynyl. In a preferable embodiment according to the fifteenth aspect of this invention, in any of the preceding embodiments X'Y1^Y2 of the fifteenth aspect, ' |l / is ^x / 'Y, H The sixteenth aspect of this invention further provides a compound represented by the following formula (III), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: 2022412821   03 Aug 2026 wherein, RA, RB, RC, RD, RE, ring B, L, n2, n3, and n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention; X1, X2, X3 and Y are each independently CH or N; and when X1, X2, and X3 are all CH, Y is not CH; n1 is 1, 2, 3 or 4; ring A is 5-10 membered heterocyclyl or 5-12 membered heteroaryl. In a preferable embodiment according to the sixteenth aspect of this invention, X1 is N, and X2 and X3 are both CH. In a preferable embodiment according to the sixteenth aspect of this invention, X3 is N, and X1 and X2 are both CH. In a preferable embodiment according to the sixteenth aspect of this invention, X1 and X3 are both N, and X2 is CH. In a preferable embodiment according to the sixteenth aspect of this invention, X1, X2, and X3 are all CH. In a preferable embodiment according to the sixteenth aspect of this invention, in any of the preceding embodiments of the sixteenth aspect, Y is CH; or Y is N. In a preferable embodiment according to the sixteenth aspect of this invention, in any of the preceding embodiments of the sixteenth aspect, is HN^ or The seventeenth aspect of this invention further provides a compound represented by the following formula (IV-1), (IV-2), (IV-3), or (IV-4), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically 2022412821   03 Aug 2026 acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: wherein, X1, RA, RD, RE, RC, ring B, n1, and n4 are defined as in the compound of formula (I) according to any of the preceding embodiments of the first and second aspects of this invention; Y2 is C or N; In a preferable embodiment according to formula (IV-1), (IV-2), (IV-3), or (IV-4) of this invention, in any of the preceding formulae (IV-1), (IV-2), (IV-3), and (IV-4), each Rc is independently hydrogen, oxo, -OH, -SH, -NH2, -Boc, -C(O)CH2OH, -NHC(O)CH3, carboxyl, -S(O)2CH3, -S(O)2NH2, -methoxy, methylthio, -CH2CF3, cyclopropyl; In a preferable embodiment according to formula (IV-1), (IV-2), (IV-3), or (IV-4) of this invention, in any of the preceding formulae (IV-1), (IV-2), (IV-3), and (IV-4), each Rc is independently hydrogen, oxo, -Boc, -C(O)CH2OH, -CH2CF3, cyclopropyl; In a preferable embodiment according to formula (IV-1), (IV-2), (IV-3), or (IV-4) of this invention, in any of the preceding formulae (IV-1), (IV-2), (IV-3), and (IV-4), each Rc is independently hydrogen, oxo; In a preferable embodiment according to formula (IV-1), (IV-2), (IV-3), or (IV-4) of this invention, in any of the preceding formulae (IV-1), (IV-2), (IV-3), and (IV-4), ring B is or N^j]; In a preferable embodiment according to formula (IV-1), (IV-2), (IV-3), or (IV-4) of this invention, in any of the preceding formulae (IV-1), (IV-2), (IV-3), and (IV-4), ring B is ; In a preferable embodiment according to formula (IV-1), (IV-2), (IV-3), or (IV-4) of this invention, in any of the preceding formulae (IV-1), (IV-2), (IV-3), and (IV-4), ring B is N^j; In a preferable embodiment according to formula (IV-1), (IV-2), (IV-3), or (IV-4) of this invention, in any of the preceding formulae (IV-1), (IV-2), (IV-3), and (IV-4), RD is -SO2NH2. The eighteenth aspect of this invention further provides a compound represented by the following formula (V-1), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: 2022412821   03 Aug 2026 o=s=o nh2 (v-1) wherein, X1, RA, RE, RC, n1, and n4 are defined as in formula (I) according to any of the preceding embodiments of the first and second aspects of this invention or formula (IV-1), (IV-2), (IV-3), or (IV-4); Q is C or N; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), Q is C; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), , wherein RC is hydrogen, trifluoroethyl or cyclopropyl; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), RA is hydrogen, F, Cl, methoxy, or ethoxy; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), RA is hydrogen, F, or methoxy; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), RE is hydrogen, deuterium, F, or Cl; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), RE is hydrogen or F; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), n1 is 1 or 2; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), n4 is 1 or 2; In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), n4 is 2; 2022412821   03 Aug 2026 In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), <XV\SV                  SWM             . / VW            WW is            ,            or o=s=o o=s-nh2 o=s-nh2 o=s-nh2 nh2  doo In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), ; o=s=o nh2 o=s-nh2 d In a preferable embodiment according to formula (V-1) of this invention, in any of the preceding formulae (V-1), . o=s=o nh2 o=s-nh2 d The nineteenth aspect of this invention further provides a compound represented by the following formula (V-2), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: wherein, X1, RA, RE, RC, Q, n1, n4, and nh2 4 are defined as in formula (I) according to any of the preceding embodiments of the first and second aspects of this invention or formula (V-1); In a preferable embodiment according to formula (V-2) of this invention, in any of the preceding formulae (V-2), In a preferable embodiment according to formula (V-2) of this invention, in any of the preceding formulae (V-2), In a preferable embodiment according to formula (V-2) of this invention, in any of the preceding formulae (V-2), 2022412821   03 Aug 2026 is In a preferable embodiment according to formula (V-2) of this invention, in any of the preceding formulae (V-2), The twentieth aspect of this invention further provides a compound represented by the following formula (V-3), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: o=s=o nh2 (V-3) wherein, X1, RA, RE, RC, Q, n1, n4, and o=s=o nh2 are defined as in formula (I) according to any of the preceding embodiments of the first and second aspects of this invention or formula (V-1); In a preferable embodiment according to formula (V-3) of this invention, in any of the preceding formulae (V-3), RC is H; In a preferable embodiment according to formula (V-3) of this invention, in any of the preceding formulae (V-3), is or In a preferable embodiment according to formula (V-3) of this invention, in any of the preceding formulae (V-3), In a preferable embodiment according to formula (V-3) of this invention, in any of the preceding formulae (V-3), is The twenty-first aspect of this invention further provides a compound represented by the following formula (V-4), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, 2022412821   03 Aug 2026 polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound: o=s=o nh2 (V-4) wherein, X1, X4, RA, RE, RC, Q, n1, n4, and o=s=o are defined as in formula (I) according to any of the preceding embodiments of the first and second aspects of this invention or formula (V-1); In a preferable embodiment according to formula (V-4) of this invention, in any of the preceding formulae (V-4), , wherein RC is hydrogen, -C(O)CH2OH; In a preferable embodiment according to formula (V-4) of this invention, in any of the preceding formulae (V-4), Rc is , wherein RC is hydrogen; In a preferable embodiment according to formula (V-4) of this invention, in any of the preceding formulae (V-4), Rc O                    O ; In a preferable embodiment according to formula (V-4) of this invention, in any of the preceding formulae (V-4), ; In a preferable embodiment according to formula (V-4) of this invention, in any of the preceding formulae (V-4), Rc , wherein RC is hydrogen or Boc; In a preferable embodiment according to formula (V-4) of this invention, in any of the preceding formulae (V-4), , wherein RC is hydrogen; In a preferable embodiment according to formula (V-4) of this invention, in any of the preceding formulae (V-4), Rc wherein RC is Boc. 2022412821   03 Aug 2026 The twenty-second aspect of this invention relates to a preferable embodiment according to any of the first to twenty- first aspects of this invention, wherein X2 and / or X4 are substituted by RA, and further preferably X2 is substituted by RA. In a preferable embodiment of this invention, the compounds of this invention are selected from: No. Structure No. Structure No. Structure 1 rJ \ z -no 1c ft ■h q 2 XL ,hk / Y III 11 o=s=o nh2 3 XX M, III N~1 o=s' ' \\ h2n o 4 SbY o \ 5 zV O:"X 11 o=s=o nh2 6 ,0. _N. .N. oy fV '1 o=s=o nh2 7 pXXp^ n¥nh v O=S-NH2 0 8 XL^hk^hL 1111 IJ 11 o=s=o nh2 9 XL      N. Hl F             N F3 I 1 0.1H "S., h2n ° 10 III C? lift o=s=o nh2 11 AAzY III ^Y^N^CF, 110 o=s=o nh2 12 XL ,N. ,N. Ullo 1? o=s=o nh2 13 Hi i F'^^yl / NyN^CF3 v o=s=o nh2 14 ,0. ,N. ,N. Ill J ■'' '1 o=s=o nh2 15 Til II1 0=S=0 nh2 16 zCk ,N, ,N, III ^Y^N^CFs o=s=o nh2 17 zO. ,N. ,N. OY ny»b v o=s=o nh2 18 XL      ,N, uY Cr0 T? O=S=O nh2 19 vxi F 1^0 °JU^ H2N'%    f 20 TH Hll F H H?N1 f 21 \ z o ox c -36- 2022412821   03 Aug 2026 43 40 37 34 OJ 28 25 22 0 HO-d-OH A oV Yu, N N 0 CHN O=S=O „6 0"% X C xi. N N O A „0 oV Yxi. N N O ,N. Cxi, rNc° pc o=s=o nh2 CHN O=S=O A oV Y\<C^OX XXX y N      0 CD. / N. O N pl o=s=o nh2 \ o O   / -- /       /   z 11  X  X       X   / / T II   \    /    \    /    ' o      YY / ? T z X— / CHN O=S=O pY N^lC YY1„ N N O 44 H-‘ OJ OO OJ Oh 32 29 26 23 ho S=d-OH oV Yri, N N 0 HO OH ; . oV Yxx, N N O A P ZCU-X    X 11 x /                o O l_ /       __ / Z—G Z o^PP cP O^N^A 111 rNY° pc o=s=o nh2 o, A XX1 Xy0 p o=s=o nh2 eHN O=S=O pl ,N. ,0 pxY^ X XX - CHN O=S=O ^pS y^d N'^Y ^Y^cc XXX, N N 0 ,O N N up 0XNc O=S=O nh2 45 42 39 36 OJ OJ 30 27 24 ,0. ,N. ,N. XAY fNY° v 0 o=s=o nh2 Ho^y0 YY oV Yn, N N O CHN O=S=O ° p O^nP Yn, N N O % ,n2h o ZjN o oW CXI, N N O ^0 F\ Y. / N. XXp fNY° V o=s=o nh2 A / c / N. i A, fNc° pc o=s=o nh2 CHN O=S=O p. N'V Pll cep Y O=S=O nh2 46 ,0. ,N^.N^ CY rV 6° N 0=S=0 nh2 47 / 0 N N WN^Fj YY0 ,, h2n ° 48 YYY ny° o=s=o nh2 YY    N Y Y Y / 0^ N. N. Y Y Y YY X 49 NH o=s=o nh2 50 ^^^Y^NBoc F^f o=s=o nh2 51 o=s=o nh2 52 0.      N. YYY # 0=8=0 nh2 53 uY>° ■# o=s=o nh2 54 YY o=s=o nh2 55 YY 1 f ;::^ o=s=o nh2 56 uY Y^,YCF3 o=s=o nh2 57 uX° " N" v o=s=o OH 58 O^ N. N. YYY o=s=o nh2 59 TaX fl Y %.N^J h2n' 'b 60 / 0, ,N. ,N.. Lip,, Yr Yf NH o=s=o nh2 61 CQ^ jT \YF o=s=o nh2 62 n, / N, _N, Y T Y ''Y ''NH o=s-nh2 6 63 N N ■ ■ ' o=s=o nh2 64 ,O. ,N. ,N. u Y f'YNT° HN O=S=O nh2 65 / O N N oY„ o=s=o nh2 66 O. ,N. ,N. Y Y Y ^Y^Nn fr o=s=o nh2 67 ,0. ,N. ,N. u Y fNV° • o=s=o NH, 68 YX / O Y¥° v o=s=o nh2 69 YY Y F'^^'Y'NBoc Y Y° o=s=o nh2 -38- 2022412821   03 Aug 2026 oo oo oo Kb oo bJ UJ o Tv a o=s=o nh2 :HN O=S=O T- HN N Ho h AKAn- 0 aaa " aYz CHN O=S=O A-A. ° TX1nk H CHN O=S=O A 11 °vkA \AA%H CHN O=S=O A °yV HN. / X / N. aO. -N      0 \ -n o O  .-- /       /   z 11 / / 1        A / / z-co—x)—\  )—( FJ o         z—((   z oA Y" o— / CHN 0=S=0 A Al Yn, N N 0 KJ oo oo o OO L>J oo o -J H-‘ Tv A o=s=o nh2 Av Aa nynh o=s=o ^ih2 rV o=s=o nh2 CHN O=S=O A oV Ycix H CHN O=S=O A Al Yta N N S DX° N N 5 Ul -A A o=s=o nh2 1TV o=s=o nh2 \ o O  ,— /      /  Z 11 AA     A / / 2-«- / X—v   )—( X ll   \__ /    x     /    x o —  HA\ A °X Y o— / L>J o oo OO OO H— 3s 1! KJ Z-A11 € / o—7 An H2N I T 1 n¥nh A o=s=o nh2 0 AOA ntnh A o=s=o H2 OO N 1A1 x> o=s=o nh2 »fAA / 0^     .N. Til n¥nh fA o=s=o nh2 ox rNY° T° o=s=o nh2 OO 0 MyX-OoH o A o=s=o nh2 94 H A o=s=o nh2 95 NH2 '11 pX O=S=O nh2 96 '11 f'1f O=S=O nh2 97 ,1¾ o=s=o nh2 98 TV \1F o=s=o nh2 99 -0. -N. .N. o=s=o nh2 100 o ,N. _N. III FX” o=s=o nh2 101 .-0 N   N UA r'xN3Nl>N-0H 1 1° °' nh2 102 ,0. ,N. ,N. a;..-.. rV fX O=S=O nh2 103 \ o O  , /       /   z " rx    i / / z-to—I I—,   )—( T II   \ /    '      /    x O X=T  ZA\  2 t oA 13 o 104 11-1-nh2 v o=s=o nh2 105 ,0.       _N. TT1 X o=s=o nh2 106 / O^^N   N 11J x F l^O °JV1 h2n'%     f 107 Xk      _N. Hl    H Wy'r N^J o 1> O=S=O nh2 108 -0^-^.N   Q 11.1 A N 0H -N.J f'T O=S=O nh2 109 \ o h<15 z —cn=o 6' 110 H     ~ TX1 g Tf o=s=o nh2 111 H -¾ 1X1 0 -N^J 'X o=s=o nh2 112 ,0. ,N. ,N. IJX y / rV1 v o=s=o nh2 113 / 0 N N      0 IXXxi F11 o=s=o nh2 114 A / l-O T x O=S=O nh2 115 Til F'^^XX nynh X o<knh2 116 --0. ,N- ,N-III rV!» x O=S— 0 117 ,0. -N. -N. 1¾ |'”T° x 0 o=s=o 1 118 / 0^ .N. ,¾ UY nynh lp 0=3=0 O^OH 119 <L N N 1¾ N^ / NH '1' o=s=o ^nh2 120 JX ,,1¾ ,,1¾ III 7¾ "1 0=3=0 HN O^OH 121 ,0. ZN. K ,1¾ r'"Y"H v o' 122 : 1 o \ 123 ,N. ,N. Ill Y Y o=s=o u 124 , cl ,1¾ .1¾ UY nynh v o=s=o HO* 125 ,0. ,N, ,N, UY U° Y o=s=o u 126 / O N N Y N> NH,O 0¾ 127 1¼ \ o 128 / ¾¾ Y NH °Y nh2 129 / 0. >L / ¾ UY Y Y hn Y° °\ 130 ,0.¾. / N. ,1¾ I-VH Ytf o=s=o nh2 131 / ¾¾¾ Ill F^^YY nynh Y° 0=S=0 nh2 132 Ul / U / U Ill f^^^Yy nynh . ■ 0=S=0 nh2 133 / ¾ / ¾ III nynh ^¾. 0 V o=s=o nh2 134 AAA Ill ^Uy^nH [■"A F3C¾. 0 I 0=S=0 nh2 135 / CL / ¾ / ¾ ,-¾ »1 ° o=s=o nh2 136 U / N. / ¾ Ill F'^YY n¥nh o=s=onh2 nh2 137 Ill f^yy YYnh HoYyJ 0=S=0 nh2 138 / O^ / ¾ / ¾ Ill f^^yy ,¾° ¥-9 O=S=O nh2 139 .N, _N, Ill F^^Yl YY^ Y^n'°h 0=S=° nh2 140 / O N N ,1¾. HO ^^^Y O=S=O nh2 141 / 0^ / ¾ / ¾ Ill u^^Yo 0=S=0 F nh2 142 ,0. _N. _N. III - OO=S=O nh2 143 ,0. _N. ,N. Ill yy '°1 0 0=5=0 nh2 144 .0. ,N, ,N, Ill Wy^o a-K '1 oo=s=o nh2 145 ,0. .N. _N. Ill vyy Kip 0=S=0 nh2 146 ,0. _N. _N. Ill 1^° ciy) o=s=o nh2 147 ^hL ^hL Ill y0 aip) o=s=o nh2 148 .0. ,N. ,N. »ynh 1 o=s=o nh2 149 ,N. ,N. 01 N "" o=s=o nh2 150 _N. _N. Ill Vy^NH r"'A • • o=s=o nh2 151 ,N. ¢1 A” ci'^Y O=S=O nh2 152 \ m O o            \__ / O I---V H-cnylK—1_* i H \__ /   \    / o x—'   zi z oy y^ Vo 153 ,0. .N. .N. Ill F^v^yy rVH • 0=S=0 nh2 154 III F^^y^y v o=s=o nh2 155 .0. ,N. ,N. Ill F'V^y^ ^NH o=s=o nh2 156 N N jY rV>° 1-. 0 yy o=s=o nh2 157 ,N. ,N. Ill fzK^yp yy nh J. o yy o=s=o nh2 158 _N. _N. (¾ '1' o=s=o nh2 159 o=s=o nh2 160 / 0^y • o=s=o nh2 161 °^nVN"1 z IIaI iK 1 / o=s=o nh2 162 / Y1Y y '1 o=s=o nh2 163 oypy . :. o-Lo h2n 164 °^nVN"1 llfl o=s=o nh2 165 -°wn yc f ii° / Y / S-NH2 F     d 166 F ,S~NH2 F     d 167 ^0 N 00 L k^^NH, F     0 168 / 0Yn^n PH / X / B F      OH 169 XXZ F Xl? d^ / F'OH F    HO 170 JXk PH X=Z B F      OH 171 x^Xd '° rV v o=s=o nh2 172 b-^y^yN^, X' 0=8=0 nh2 173 NC-Yy-N r X o=s=o nh2 174 IW X' O=S=° nh2 175 \ N N-X v 0=S-0 nh2 176 by^'y^X X^NH y / 0=S=0 nh2 177 J. NH y? O=S=O nh2 178 °Vr\ nh xz 0=S=0 nh2 179 °XXX x^nh y? 0=S=0 nh2 180 \oyy y 'X^NH V F SA p F / nh2 181 s\ Mf XjLp F / nh2 182 °xX 1 n^y^nh Mf ^X'? F        Ss O / Z NH2 183 k^y y n*X^nh Mf AjLp F     c / 'nh2 184 i i Vf SAl? F d's'NH= 185 N I J z FiX o=s=o nh2 186 N'r'k, op ' ^V-N v o=s=o nh2 187 ■^x AJ v o=s=o nh2 188 °XX1N v o=s=o nh2 189 X 1 n'X-'n Xx xx o=s=o nh2 190 XXX X v o=s=o nh2 191 °-Q 1 ^yy v o=s=o nh2 192 \   N-^ / N 1 | zNj v o=s=o nh2 193 XQ, v o=s=o nh2 194 sy^ 1 1 ^y^o "if o=s=o nh2 195 z zTY% °              1 ,N^O v o=s=o nh2 196 j 1 N-^Q v o=s=o nh2 197 ,N^° v o=s=o nh2 198 X N-^yy °-^ 1    1 v o=s=o nh2 199 .N^NH v o=s=o nh2 200 \   N-^-N oy J 1 ,N^NH v o=s=o nh2 201 \ N-X-z MnXX .N^NH v o=s=o nh2 202 1                 1 N^,NH v o=s=o nh2 203 \   N-^-N^ C>y 1 ■ o=s=o nh2 204 \ / -A ° X J 1 '^'XXn y v o=s=o nh2 205 J 1 ^N-X v o=s=o nh2 206 0^nXxNh Fx?J o=s=o nh2 207 \ / ,NX °X J 1 'if o=s=o nh2 208 oy ■ ■■ o=s=o nh2 209 \   N-^-N 1 o=s=o nh2 210 \ N^N X X X^' o=s=o nh2 211 \ f-yy oy ■ ■■ o=s=o nh2 212 ] J z / U f^L,f 1 / o=s=o nh2 213 N~r-X “Wn • • o=s=o nh2 2022412821   03 Aug 2026 214 '"O O ,— /    z^z 11 / \           w / “ °  \ (p \=Z 215 N-^pp op^ 1 z A F. / L-F 0=S=0 nh2 216 _N. _N. cp 1 Nv° V HN=S=O 1 This invention may further include providing a process for preparing a compound represented by any of formulae (I) and (I-a) to (I-f), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound. The compound can be prepared by various processes, including but not limited to the following processes: Scheme I: Scheme II: 1) condensing 2) ring closing In a preferable embodiment of this invention, In a preferable embodiment of this invention, triphosgene etc. ring closing base 2022412821   03 Aug 2026 Scheme III: ring closing / coupling Hal In a preferable embodiment of this invention, n4 RD Hal Scheme IV: 2022412821   03 Aug 2026 In a preferable embodiment of this invention, In a preferable embodiment of this invention, RE 1) condensing 2) ring closing Hal coupling oxidation Hal oxidation RD In a preferable embodiment of this invention, 2022412821   03 Aug 2026 In a preferable embodiment of this invention, 1) substitution In a preferable embodiment of this invention, Hal coupling oxidation 2) ring closing chloroacetyl chloride etc. 1) substitution 2) ring closing coupling oxidation coupling oxidation In a preferable embodiment of this invention, Hal In a preferable embodiment of this invention, Hal                                                              R[ wherein in the above schemes, Hal represents halogen in the compound shown, and each substituent is defined as 2022412821   03 Aug 2026 described earlier. After reading the disclosure of this application, those skilled in the art can easily determine the reaction conditions such as temperature, time, solvent, etc. suitable for the above schemes. This invention further provides a pharmaceutical composition, containing the compound of this invention, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound. This invention further provides a pharmaceutical composition, containing the compound of this invention, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, and pharmaceutically acceptable adjuvant In some embodiments, a metaboliteof the compound is excluded. This invention may further comprise providing use of the compound of this invention, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound in the manufacture of a medicament for preventing and / or treating ENPP1-mediated diseases. In some embodiments, the ENPP1-mediated disease is cancer or tumour-related disease, e.g. pancreatic cancer. In some embodiments, the ENPP1-mediated disease is cardiovascular disease, e.g. heart failure or myocardial infarction. The present invention may further include providing a method for preventing and / or treating ENPP1-mediated diseases, which comprises administering a therapeutically effective dose of the compound of this invention, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound, or the pharmaceutical composition of this invention to patient. The compound of this invention, or prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof can be administered in combination with another anticancer agent or immune checkpoint inhibitor for treating or preventing ENPP1-mediated diseases, such as cancer or tumour. When the compound of this invention, or prodrug, tautomer, stereoisomer, solvate, isotope derivative or pharmaceutically acceptable salt thereof is administered in combination with another anticancer agent or immune checkpoint inhibitor for treating cancer or tumour, the compound of this invention or its pharmaceutically acceptable salt may provide an enhanced anticancer effect. Definition Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, including a linear or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (namely C1-10alkyl), further preferably containing 1-8 carbon atoms (C1-8alkyl), more preferably containing 1-6 carbon atoms (namely C1-6alkyl). For example "C1-6 alkyl" means that the group is an alkyl group, and the number of carbon atoms in the carbon chain is between 1 and 6 (specifically 1, 2, 3, 4, 5 or 6). Its example includes but is not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, tert-butyl, sec-butyl, n-pentyl, neo-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl and the like. 2022412821   03 Aug 2026 Unless otherwise specified, the term "alkenyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one double bond. The alkenyl can contain 2-20 carbon atoms, preferably contain 2-10 carbon atoms (namely C2-10alkenyl), further preferably contain 2-8 carbon atoms (C2-8alkenyl), more preferably contain 2-6 carbon atom (namely C2-6alkenyl), 2-5 carbon atom (namely C2-5alkenyl), 2-4 carbon atoms (namely C2-4alkenyl), 2-3 carbon atoms (namely C2-3alkenyl), 2 carbon atoms (namely C2alkenyl). For example "C2-6alkenyl" means that the group is alkenyl, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). The non-limiting examples of alkenyl include but are not limited to ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl and 1,3-butadienyl and the like. Unless otherwise specified, the term "alkynyl" refers to a linear or branched unsaturated aliphatic hydrocarbon group consisting of carbon atoms and hydrogen atoms and having at least one triple bond. The alkynyl can contain 2-20 carbon atoms, preferably contain 2-10 carbon atoms (namely C2-10alkynyl), further preferably contain 2-8 carbon atoms (namely C2-8alkynyl), more preferably contain 2-6 carbon atoms (namely C2-6alkynyl), 2-5 carbon atoms (namely C2-5alkynyl), 2-4 carbon atoms (namely C2-4alkynyl), 2-3 carbon atoms (namely C2-3alkynyl), 2 carbon atoms (namely C2alkynyl). For example "C2-6alkynyl" means that the group is alkynyl, and the number of carbon atoms in the carbon chain is between 2 and 6 (specifically 2, 3, 4, 5 or 6). The non-limiting examples of alkynyl include but are not limited to ethynyl, 1-propynyl, 2-propynyl, 1-butynyl and the like. Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbyl having a specified number of carbon atoms, preferably containing 3-12 carbon atoms (namely C3-12cycloalkyl), more preferably 3-10 carbon atoms (C3-10cycloalkyl), further preferably 3-6 carbon atoms (C3-6cycloalkyl), 4-6 carbon atoms (C4-6cycloalkyl), or 5-6 carbon atoms (C5-6cycloalkyl). Examples include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl and the like. Unless otherwise specified, the term "alkoxy" refers to -O-alkyl, where the alkyl is defined as above, i.e., containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8 carbon atoms, and even more preferably 1-6 carbon atoms (specifically 1, 2, 3, 4, 5 or 6). Representative examples include but are not limited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, 1-methylpropoxy, 2-methylpropoxy, tert-butoxy, pentoxy, 1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 2,2-dimethylpropoxy, 1-ethylpropoxy, etc. Unless otherwise specified, the term "alkylthio" refers to the substitution of oxygen in the aforementioned "alkoxy" with sulfur. Unless otherwise specified, the term "halogen" or "halo" refers to F, Cl, Br, or I. The term "haloalkyl" refers to an alkyl group as defined above, in which one, two or more hydrogen atoms or all hydrogen atoms are substituted by halogen. Representative examples of haloalkyl include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, CF2CF3, etc. Unless otherwise specified, the term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic, bicyclic or polycyclic hydrocarbon substituent, which is in a non-aromatic structure and contains 3-20 ring atoms, of which 1, 2, 3 or more ring atoms are selected from N, O and S, and the remaining ring atoms are C. Preferably, it contains 3-12 ring atoms, more preferably 3-10 ring atoms, or 3-8 ring atoms, or 3-6 ring atoms, or 4-6 ring atoms, or 5-6 ring atoms. The number of heteroatoms is preferably 1-4, more preferably 1-3 (namely 1, 2, or 3). Examples of monocyclic 2022412821   03 Aug 2026 heterocyclyl include pyrrolidinyl, imidazolinyl, tetrahydrofuryl, dihydropyrrolyl, piperidyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclyl include spiro, fused and bridged heterocyclyl. Unless otherwise specified, the term "fused heterocyclyl" refers to a 5-20 membered polycyclic heterocyclic group, in which each ring in the system shares an adjacent pair of atoms with other rings in the system. One or more rings may contain one or more double bonds, but none of the rings have a fully conjugated n-electron system, where one or more ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, it has 6-14, preferably 7-10 ring members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic heterocyclyl, more preferably 4-membered / 4-membered fused-heterocyclyl, 4-membered / 5-membered fused-heterocyclyl, 5-membered / 4-membered fused-heterocyclyl, 5-membered / 5-membered fused-heterocyclyl, 5-membered / 6- membered fused-heterocyclyl, 6-membered / 5-membered fused-heterocyclyl, 4-membered / 6-membered fused- heterocyclyl, 6-membered / 4-membered fused-heterocyclyl, 6-membered / 6-membered fused-heterocyclyl. The non limiting examples of fused-heterocyclyl include Unless otherwise specified, the term "spiro-heterocyclyl" refers to a 5-20 membered polycyclic heterocyclic group, in which each ring in the system shares one atom (called spiro-atom) with another ring in the system. One or more rings may contain one or more double bonds, but none of the rings have a fully conjugated n-electron system. Preferably, it has 6-14, preferably 7-10 ring members. According to the number of the spiro-atoms shared between rings, the spiro-heterocyclyl can be divided into mono-spiro-heterocyclyl, bis-spiro-heterocyclyl or poly-spiro-heterocyclyl, preferably mono-spiro-heterocyclyl and bis-spiro-heterocyclyl, more preferably 4-membered / 4-membered spiro-heterocyclyl, 4-membered / 5-membered spiro-heterocyclyl, 5-membered / 4-membered spiro-heterocyclyl, 5-membered / 5-membered spiro-heterocyclyl, 4-membered / 6-membered spiro-heterocyclyl, 6-membered / 4-membered spiro-heterocyclyl, 5-membered / 6-membered spiro-heterocyclyl, 6-membered / 5-membered spiro-heterocyclyl, 6-membered / 6-membered spiro-heterocyclyl. The non-limiting examples of spiro-heterocyclyl include: Unless otherwise specified, the term "aryl" refers to monocyclic, bicyclic and tricyclic aromatic carbocyclic ring systems containing 6-16, 6-14, 6-12 or 6-10 carbon atoms, preferably 6-10 carbon atoms. The term "aryl" may be used interchangeably with the term "aromatic ring". Examples of aryl may include but are not limited to phenyl, naphthyl, anthryl, phenanthryl or pyrenyl, etc. Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic or polycyclic ring system having a 5-16, 5-14, 5-12, 5-10, 5-8, or 5-6 membered structure, in which 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms are independently selected from O, N and S, and the number of heteroatoms is preferably 1, 2 or 3. Examples of heteroaryl may include but are not limited to furyl, thienyl, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, thiadiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, 2022412821   03 Aug 2026 pteridinyl, purinyl, indolyl, isoindolyl, indazolyl, benzofuryl, benzothienyl, benzopyridyl, benzopyrimidyl, benzopyrazinyl, benzimidazolyl, benzophthalazinyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidyl, [1,2,4]triazolo[1,5-a]pyridyl, etc. Unless otherwise specified, the term "fused-heteroaryl" refers to an unsaturated aromatic fused ring structure containing 5-14 ring atoms (including at least one heteroatom) and formed by connecting two or more ring structures that share two adjacent atoms with each other, wherein 1, 2, 3 or more ring atoms are heteroatoms and the remaining atoms are carbon. The heteroatoms are independently selected from O, N, and S, and the number of heteroatoms is preferably 1, 2, or 3. Preferably, it is 5-12-membered fused-heteroaryl, 7-12-membered fused-heteroaryl, 9-12membered fused-heteroaryl, etc., preferably 5-membered / 5-membered fused-heteroaryl, 5-membered / 6-membered fused-heteroaryl, 6-membered / 5-membered fused-heteroaryl, 6-membered / 6-membered bicyclic fused-heteroaryl. Examples of fused-heteroaryl may include but are not limited to benzofuryl, benzoisofuryl, benzothienyl, indolyl, isoindole, benzoxazolyl, benzimidazolyl, indazolyl, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridinyl, phenanthridinyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridinyl, purinyl, naphthyridinyl, phenazine, phenothiazine, etc. Unless otherwise specified, the term "pharmaceutically acceptable salt" or similar expressions refers to a salt that is suitable for use in contact with the tissues of mammals, especially humans, without undue toxicity, irritation, allergic response or the like and commensurates with a reasonable benefit / risk ratio within the range of reasonable medical judgment. For example, the pharmaceutically acceptable salts of amines, carboxylic acids and other types of compounds are well-known in the art. The salts can be prepared in situ during the final isolation and purification of the compounds of this invention, or separately by reacting the free base or acid with a suitable reagent. Unless otherwise specified, the term "isotope derivative" means that the compounds of this invention can exist in isotope-tagged or enriched form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes can be radioactive or non-radioactive isotopes. Isotopes commonly used as isotopic labels are: hydrogen isotopes: 2H and 3H; carbon isotopes: 13C and 14C; chlorine isotopes: 35Cl and 37Cl; fluorine isotope: 18F; iodine isotopes: 123I and 125I; nitrogen isotopes: 13N and 15N; oxygen isotopes: 15O, 17O and 18O; and sulfur isotope: 35S. These isotope-labelled compounds can be used to study the distribution of pharmaceutical molecules in tissues. In particular, 2H and 13C are more widely used due to their ease of labelling and ease of detection. The substitution with certain heavy isotopes, such as heavy hydrogen (2H), can enhance the stability of metabolism, and prolong the half-life, to achieve the purpose of reducing dosage and providing therapeutic advantages. Isotope-labelled compounds are generally synthesized starting from labelled starting materials in the same way as non-isotope-labelled compounds using known synthetic techniques. Unless otherwise specified, the term "solvate" or similar expressions refer to the physical association of the present compound with one or more solvent molecules, regardless of whether organic or inorganic. This physical association includes hydrogen bonds. In some cases, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvates can be isolated. Solvent molecules in the solvates may exist in regular and / or disordered arrangements. The solvates may contain stoichiometric or non-stoichiometric amounts of solvent molecules. The "solvate" encompasses both solution-phase and isolatable solvate. Exemplary solvates include but 2022412821   03 Aug 2026 are not limited to hydrates, ethanolates, methanolates and isopropanolates. Solvation methods are well-known in the art. Unless otherwise specified, the term "stereoisomers" refers to compounds which have identical chemical constitutions, but differ about the arrangement of the atoms or groups in space. Stereoisomers include enantiomer, diastereomers, conformer (rotamer), geometric (cis / trans) isomers, atropisomers, etc. A mixture of any resulting stereoisomers can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers, according to physicochemical differences of constituents, for example, by chromatography and / or fractional crystallization. Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can be converted to each other through low energy barriers. If tautomerism is possible (for example, in solution), a chemical equilibrium of tautomers can be reached. For example, protontautomer (also known as prototropic tautomer) includes interconversion through proton migration, e.g. ketone-enol isomerization and imine-enamine isomerization. Valence tautomer includes interconversion through the recombination of some bonding electrons. Unless otherwise indicated, structure formulae depicted in this invention include all isomeric forms (e.g. enantiomers, diastereomers, and geometric isomers (or conformational isomers)): e.g., R and S configurations with the asymmetric centre, (Z) and (E) isomers of double bond, and (Z) and (E) conformational isomers. Therefore, individual stereochemical isomers or mixtures of enantiomers, diastereomers, or geometric isomers (or conformational isomers) of the present compounds are within the scope of this invention. Unless otherwise specified, the term "co-crystal" is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physicochemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co-crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012). Unless otherwise specified, the term "polymorph" refers to the different arrangement of chemical drug molecules, which is generally presented as the existing form of the drug's raw materials in the solid state. A drug may exist in a variety of crystal forms, and different crystal forms of the same drug may have different dissolution and absorption properties in vivo, thereby affecting the dissolution and release of the formulation. Unless otherwise specified, the term "metabolite" refers to a product afforded through metabolism in the body of a specific compound or a salt thereof. Metabolite of a compound may be identified using routine techniques known in the art and its activity may be characterized using tests as those described herein. Such product may be obtained through routes such as oxidation, reduction, hydrolysis, amidation, deamidation, esterification, de-esterification, and enzymatic cleavage of the administered compound. Accordingly, this invention includes the metabolite of a compound, including a metabolite afforded by sufficiently contacting a compound of this invention with a mammal for some time. Unless otherwise specified, the term "prodrug" refers to a drug that is converted into the parent drug in vivo. The prodrug is usually useful, which may improve certain undesirable physical or biological properties. The physical properties usually refer to related solubility (excessive or insufficient solubility in lipid or water) or stability, while problematic biological properties include overquick metabolism or poor bioavailability, which may itself be related 2022412821   03 Aug 2026 to physical and chemical properties. For example, they are bioavailable via oral administration, whereas the parent drug cannot. Compared with the parent drug, the solubility of the prodrug in a pharmaceutical composition is also improved. An example of prodrug may be but is not limited to, any compound of this invention, which is administered as an ester ("prodrug") to facilitate transport through cell membranes, wherein the water solubility is detrimental to mobility but beneficial once it gets into the cell, and which is subsequently metabolically hydrolyzed to a carboxylic acid (i.e. active entity). Another example of the prodrug may be a short peptide (polyamino acid) bound to an acid group, wherein the peptide is metabolized to reveal the active moiety. Unless otherwise specified, the term "optionally substituted" means that the hydrogen at the substitutable site of the group is unsubstituted, or substituted by one or more substituents, which are preferably selected from the group consisting of halogen, hydroxy, mercapto, cyano, nitro, amino, azido, oxo, carboxyl, C2-6alkenyl, C2-6alkynyl, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, C3-10cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C6-14aryl, and 5-10 membered heteroaryl, wherein the C2-6alkenyl, C2-6alkynyl, C1-6alkyl, C1-6alkoxy, C3-10cycloalkyl, C3-10cycloalkylsulfonyl, 3-10 membered heterocycloalkyl, C6-14aryl or 5-10 membered heteroaryl may be optionally substituted by one or more substituents selected from halogen, hydroxy, amino, cyano, C1-6alkyl, and C1-6alkoxy, the oxo refers to the formation of a double bond by replacing two hydrogen atoms at the same substitution site with the same oxygen atom. In the claims below and the description herein, any one of the terms “comprising”, “comprised of” or “comprises” is an open term that means including at least the elements / features that follow, but not excluding others. These terms should not be interpreted as being limitative to the means or elements or steps listed thereafter. For example, the scope of the expression a method comprising step A and step B should not be limited to methods consisting only of methods A and B. Any one of the terms “including” or “includes” as used herein is also an open term that also means including at least the elements / features that follow the term, but not excluding others. Thus, “including” is synonymous with and means “comprising”. The invention may be described herein with reference to certain advantages. It is not suggested or represented that each embodiment of the invention has all of the advantages described. Any particular embodiment may have only a single advantage. In some embodiments, the invention may provide no advantage and merely provide a useful alternative to the prior art. Certain effects of this invention may lie in that: This invention designs a class of compounds with novel structures and provides a new direction for the development of ENPP1 inhibitor drugs. Biochemical enzyme activity in vitro and MDA-MB-231 cell enzyme activity inhibition studies showed that these compounds had a strong inhibitory effect on both recombinant ENPP1 enzymes and endogenously expressed ENPP1 enzymes in cells, while exhibiting minimal inhibitory activity on ENPP2 enzymes, demonstrating good selectivity. In vitro, ADME test results indicated relatively high stability in liver microsomes, no risk of hERG inhibition, and good cell permeability. In vivo pharmacokinetic assays in mice also showed good bioavailability and exposure with excellent metabolic characteristics, making these compounds promising for the treatment of ENPP1-mediated diseases. Detailed description 2022412821   03 Aug 2026 This invention is further described below in connection with specific examples. It should be understood that these examples are intended to illustrate this invention only and are not intended to limit the scope of this invention. Experimental methods for which no specific conditions are indicated in the following examples are generally by conventional conditions or in accordance with the conditions recommended by the manufacturers. Unless otherwise defined, all professional and scientific terms used herein have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar or equivalent to those described herein may be used in the methods of this invention. The preferred embodiments and materials shown in this disclosure are illustrative only. The structures of the compounds according to this invention are determined by nuclear magnetic resonance (NMR) or / and liquid chromatography-mass spectrometry (LC-MS) or / and liquid chromatography (HPLC). The NMR measurement instrument used is Bruker 400MHz or / and Varian 400MHz; the LC-MS instrument used is Agilent 1260 Infinity II-6120 / 6125MSD; the HPLC instrument used is Waters Acquity UPLC 2 or / and Shimadzu LC2030 or / and Agilent 1260 Infinity II. The starting materials in the examples of this invention are known and commercially available, or can be synthesized using those methods known in the art or according to those methods known in the art. This invention provides processes for preparing the compounds. The compounds can be prepared through the following steps. In the following examples, abbreviations have the following meanings: Ac acetyl ACN acetonitrile AcOH acetic acid Bn benzyl Boc tert-butoxycarbonyl Boc2O di-tert-butyl dicarbonate BTC bis(trichloromethyl)carbonate (triphosgene) DCM dichloromethane DIBAL-H diisobutylaluminium hydride DIEA N,N-diisopropylethylamine dioxane dioxane / 1,4-dioxacyclohexane DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide Et ethyl HATU O-(7-azabenzotriazol-1 -yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate Me methyl Pd2(dba)2 tris(dibenzylideneacetone)dipalladium PMB para-methoxybenzyl pTsNHNH2 para-toluenesulfonyl TFA trifluoroacetic acid 2022412821   03 Aug 2026 THF tetrahydrofuran Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium TEA triethylamine TMSCHN2 trimethylsilyldiazomethane PerkinElmer's Chemdraw® (Version 20.0.0.41) was used to name the example compounds. Preparation Example 1 Preparation of (4-bromo-2,6-difluorophenyl)methanamine: Step 1: Preparation of (E)-4-bromo-2,6-difluorobenzaldehyde oxime 4-bromo-2,6-difluorobenzaldehyde (50g, 0.23 mol, 1.0eq.), hydroxylamine hydrochloride (78.61g, 1.13 mol, 5.0eq.) and sodium acetate (79.1g, 1.13 mol, 5.0eq.) were added to ethanol (2 L). The resulting mixture was stirred, and heated to 90°C under refluxing for 4hrs. The completion of the reaction was monitored with LCMS. The reaction was cooled and distilled in vacuum to remove the solvent ethanol. Water (1L) was added. The mixture was extracted with EA (ethyl acetate, 1Lx2). The organic phases were washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to afford the target compound (50g, yield 93.64%). LCMS_(ESI):_[M+H]+=236.0. Step 2: Preparation of (4-bromo-2,6-difluorophenyl)methanamine (E)-4-bromo-2,6-difluorobenzaldehyde oxime (12.0g, 93.22mmol, 1.0eq.), and zinc powder (60.9g, 932.2mmol, 10.0eq.) were dissolved in an aqueous acetic acid solution (300mL). The mixed solution was stirred at rt (rt=room temperature, 20°C) for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The resulting filtrate was concentrated. The residue was dissolved in water (200mL). The solution was adjusted to alkalinity with saturated sodium hydroxide solution, and extracted with EA (3 x200mL). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography (Silica gel, DCM / MeOH=20:1) to afford the target compound (11.8g, yield 57%). LCMS (ESI): [M+H]+=222.0; 1HNMR(400MHz, DMSO-d6) 5 7.57-7.30 (m, 2H), 3.66 (s, 2H). Preparation Example 2 Preparation of 7-methoxy-1,8-naphthyridin-4-ol: °Y°^ Step 1: Preparation of 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione 2,2-dimethyl-1,3-dioxane-4,6-dione (23.82g, 165.3mmol, 0.9eq.) was dissolved in triethyl orthoformate (91mL, 615.27mmol, 3.35eq.). The mixture was reacted at 90°C for 1.5hrs, and then cooled to 70°C. 2-amino-6-methoxypyridine (22.8g, 183.66mmol, 1.0eq.) was slowly added in batch. The reaction continued at 70°C for 30 2022412821   03 Aug 2026 minutes. TLC and The completion of the reaction was monitored with LCMS. The mixture was cooled to rt, and filtered. The filter cake was washed with petroleum ether, and dried to afford the target compound (38.3g, yield 74.94%). LCMS_(ESI)_[2M+Na]+=579.1;_1H_NMR_(400MHz,_DMSO- d6) 5 11.33 (d, J=13.6 Hz, 1H), 9.18 (d, J=14.0 Hz, 1H), 7.78 (q, J=8.0 Hz, 1H), 7.21 (d, J=7.6 Hz, 1H ),_6.70_(d,_J=8.4_Hz,_1H),_3.91_(s,_3H),_1.69_(s,_6H). Step 2: Preparation of 7-methoxy-1,8-naphthyridin-4-ol 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (20g, 71.88mmol, 1.0eq.) was dissolved in diphenyl ether (95.3mL). The mixture was reacted at 200°C for 6hrs. After the completion of the reaction, the mixture was cooled to rt. A large amount of petroleum ether was added to precipitate a solid. The mixture was filtered. The filter cake was washed with petroleum ether, and dried to afford the target compound (10.3g, yield 81.34%). LCMS_(ESI)_[M+H]+=177.1;_1H_NMR_(400MHz,_DMSO- d6)_5_11.98_(s,_1H),_8.29_(d,_J=8.8_Hz,_1H),_7.78-7.75_(m,_1H),_6.79_(d,_J=8.4_Hz,_1H),_6.05-6.03_(m,_1H),_3.96_(s,_3H). Example 1 Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrimido[4,5-c]quinolin-2(1H)-yl)methyl)benzenesulfonamide (compound 1): THF, AcOH,H2O 0 "C NH4OH Step 1: Preparation of diethyl 2-(((4-fluoro-3-methoxyphenyl)amino)methylene)malonate 4-fluoro-3-methoxyaniline (9.79g, 0.07 mol, 1.5eq.) and 1,3-diethyl 2-(ethoxymethylene)malonate (10g, 0.05 mol, 2022412821   03 Aug 2026 1eq.) were added to ethanol (200mL). The mixture was stirred at rt for 4hrs. After the completion of the reaction, the reaction mixture was purified by flash silica gel column chromatography (Silica gel, PE:EA=5:95) to afford the target compound (12.8g, yield 88.91%). LCMS_(ESI)_[M+H]+=312.1;_1H_NMR_(400MHz,_DMSO- d6) 5 10.70 (d, J=13.6 Hz, 1H), 8.36 (d, J=13.6 Hz, 1H), 7.24 (m, J=5.6 Hz, 2H), 6.92 (d J=8.6 Hz, 1H ),_4.21_(m,_J=7.2_Hz,_2H),_4.13_(m,_J=7.2_Hz,_2H),_3.88_(s,_3H),_1.26_(m,_J=8.6_Hz,_6H). Step 2: Preparation of ethyl 4-chloro-6-fluoro-7-methoxyquinoline-3-carboxylate Diethyl 2-(((4-fluoro-3-methoxyphenyl)amino)methylene)malonate (5g, 16.06mmol) and phosphorus oxychloride (8mL) were placed in a flask (100mL), and warmed to 100°C. The mixture was reacted under stirring for 5hrs. LCMS monitoring indicated the completion of the reaction, the mixture was cooled to rt and slowly added dropwise to a flask containing 200mL of water. After the completion of the addition, the mixture was cooled. An aqueous sodium bicarbonate solution was gradually added to adjust the mixture to neutrality. The mixture was extracted with EA (200mL^2). The organic phases were combined, washed with brine, and distilled under reduced pressure to remove the solvent to afford the target compound (4.2g, yield 92.19%). LCMS_(ESI)_[M+H]+=284.0. Step 3: Preparation of ethyl 4-cyano-6-fluoro-7-methoxyquinoline-3-carboxylate Ethyl 4-chloro-6-fluoro-7-methoxyquinoline-3-carboxylate (3.1g, 10.93mmol, 1.0eq.) and cyanocopper (3.9g, 43.72mmol, 4.0eq.) were added to NMP(20mL). The mixture was reacted at 150°C for 15hrs, and filtered while hot. Water (100mL) was added. The mixture was extracted with EA (200mL^2). The organic phases were washed with brine five times, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by flash silica gel column chromatography (Silica gel, PE:EA=8:92) to afford the target compound (950mg, yield 31.7%). LCMS_(ESI)_[M+H]+=275.0;_1H_NMR_(400MHz,_DMSO- d6)_5_9.38_(s,_1H),_7.89_(m,_J=9.6_Hz,_2H),_4.47_(q,_J=7.2_Hz,_2H),_4.11_(s,_3H),_1.42_(t,_J=7.2_Hz,_3H) . Step 4: Preparation of 4-cyano-6-fluoro-7-methoxyquinoline-3-carboxylic acid Ethyl 4-cyano-6-fluoro-7-methoxyquinoline-3-carboxylate (950mg, 3.46mmol, 1.0eq.) was added to methanol (50mL). Then NaOH (2M, 3mL) solution was added. The mixture was stirred at rt for 1hr. After the completion of the reaction, methanol was removed by rotary-evaporation in vacuum. Water (20mL) was added. The mixture was adjusted to acidity, and extracted with EA (200mL^2). The organic phases were washed with saturated brine twice, then dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure to remove the solvent to afford the target compound (606mg, yield 75.27%). LCMS_(ESI)_[M+H]+=247.1. Step 5: Preparation of tert-butyl (4-cyano-6-fluoro-7-methoxyquinolin-3-yl)carbamate 4-cyano-6-fluoro-7-methoxyquinoline-3-carboxylic acid (330mg, 1.34mmol, 1.0eq.), triethylamine (1353.4mg, 13.4mmol, 10eq.), diphenylphosphoryl azide (1105mg, 4.02mmol, 3.0eq.) and tert-butanol (5mL) were added to DMF (5mL). The mixture was stirred at 80°C for 2hrs. After the completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent. Water (20mL) was added. The mixture was extracted with EA 2022412821   03 Aug 2026 (1000mLx2). The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (Silica gel, PE:EA=85:15) to afford the target compound (180mg, yield 42.55%). LCMS_(ESI)_[M+H]+=318.1. Step 6: Preparation of tert-butyl (4-cyano-6-fluoro-7-methoxyquinolin-3-yl)(2,2,2-trifluoroethyl)carbamate Tert-butyl (4-cyano-6-fluoro-7-methoxyquinolin-3-yl)carbamate (20mg, 0.13mmol, 1.0eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (60.3mg, 0.26mmol, 2.0eq.) were added to DMF (2mL). K2CO3 (35.8mg, 0.26mmol, 2.0eq.) was added. The mixture was stirred at 60°C for 1hr. After the completion of the reaction, water (20mL) was added. The mixture was extracted with EA (50mLx2). The organic phases were washed with saturated brine five times, then dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure to remove the solvent to afford a crude product, which was purified by silica gel column chromatography (Silica gel, PE:EA=13:87) to afford the target compound (20mg, yield 39.73%). LCMS_(ESI)_[M+H]+=400.0;_1H_NMR_(400MHz,_DMSO- d6) 5 9.10 (s, 1H), 7.88 (d, J=10.8 Hz, 1H), 7.83 (d, J=8.2 Hz, 1H), 4.72 (s, 3H), 4.08 (s, 3H), 1.37 (d, _J=35.8_Hz,_6H),_1.28-1.05_(m,_2H). Step 7: Preparation of tert-butyl (4-(aminomethyl)-6-fluoro-7-methoxyquinolin-3-yl)(2,2,2-trifluoroethyl)carbamate Tert-butyl (4-cyano-6-fluoro-7-methoxyquinolin-3-yl)(2,2,2-trifluoroethyl)carbamate (190mg, 0.12mmol, 1.0eq.) was added to acetic acid (5mL). Pd / C (40mg) was added. The mixture was reacted at rt under the protection of hydrogen gas for 2hrs. After the completion of the reaction, Pd / C was filtered off. Water (20mL) was added. The mixture was extracted with EA (50mLx2). The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to afford the target compound (190mg, yield 99%). LCMS_(ESI)_[M+H]+=404.1. Step 8: Preparation of tert-butyl (4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxyquinolin-3-yl)(2,2,2-trifluoroethyl)carbamate Tert-butyl (4-(aminomethyl)-6-fluoro-7-methoxyquinolin-3-yl)(2,2,2-trifluoroethyl)carbamate (160mg, 0.4mmol, 1.0eq.) and 4-bromo-2,6-difluorobenzaldehyde (32.8mg, 0.48mmol, 1.2eq.) were added to dichloromethane (10mL). A drop of was acetic acid added dropwise. sodium triacetoxyborohydride (420mg, 1.6mmol, 4.0eq.) and a molecular sieve were added. The mixture was stirred at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was purified by flash silica gel column chromatography (Silica gel, PE:EA=75:25) to afford the target compound (170mg, yield 70.45%). LCMS_(ESI)_[M+H]+=609.1;_1H_NMR_(400MHz,_DMSO- d6)_5_8.58_(s,_1H),_8.11_(s,_1H),_7.60_(s,_1H),_7.50_(s,_2H),_4.46_(s,_2H),_4.10-3.99_(m,J=1.6_Hz_4H),_3.87_(s,_3H),_3.78_(s,_1H),_1.44_(s,_3H),_1.21_(d,_J=16.2_Hz,_6H). Step 9:    Preparation of 4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxy-N-(2,2,2- trifluoroethyl)-quinoline-3-amine Tert-butyl              (4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxyquinolin-3-yl)(2,2,2- trifluoroethyl)carbamate (200mg, 0.32mmol, 1.0eq.) was added to HCl / dioxane (1M, 5mL). The mixture was stirred 2022412821   03 Aug 2026 at room temperature for 2hrs, and distilled under reduced pressure to remove the solvent to afford a crude target compound (160mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=509.1. Step 10: Preparation of 2-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrimidine[4,5-c]quinolin-3(2H)-one 4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxy-N-(2,2,2-trifluoroethyl)-quinoline-3-amine (160mg, crude) was added to tetrahydrofuran (10mL). Triphosgene (60mg) was added. The mixture was stirred at room temperature for 2hrs. After the completion of the reaction, the reaction mixture was extracted with EA (100mL^2). The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by flash silica gel column chromatography (Silica gel, PE:EA=70:30) to afford the target compound (140mg, yield 87.35%). LCMS_(ESI)_[M+H]+=534.0. Step 11: Preparation of 2-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrimidine[4,5-c]quinolin-3(2H)-one 2-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrimidine[4,5-c]quinolin-3(2H)-one (140mg, 0.26mmol, 1eq.) and phenylmethanethiol (39mg, 0.31mmol, 1.2eq.) were added to dioxane (10mL). Tris(dibenzylideneacetone)dipalladium (24mg, 0.026mmol, 0.1eq.), and caesium carbonate (169mg, 0.52mmol, 2eq.) were added. Under the protection of nitrogen gas, the mixture was reacted at 100°C for 3hrs. After the completion of the reaction, the reaction mixture was extracted with EA (100mLx2). The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and purified by flash silica gel column chromatography (Silica gel, PE:EA=65:35) to afford the target compound (85mg, yield 56.61%). LCMS_(ESI)_[M+H]+=578.1. Step 12:     Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-3-oxo-4-(2,2,2-trifluoroethyl)-3,4- dihydropyrimido[4,5-c]quinolin-2(1H)-yl)methyl)benzenesulfonamide 2-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrimidine[4,5-c]quinolin-3(2H)-one (80mg, 0.14mmol, 1.0eq.) was added to tetrahydrofuran (2mL) and and acetonitrile (1mL). At 0°C, a drop of acetic acid, a drop of water and 1,3-dichloro-5,5-dimethylhydantoin (110mg, 0.56mmol, 4eq.) were added. The mixture was reacted at 0°C for 2hrs. After the completion of the reaction, ammonia solution (2mL) was added dropwise at 0°C. The mixture was extracted with EA (100mL^2). The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent to afford a crude product, which was purified to afford the title compound (12mg, yield 13.33%). LCMS_(ESI)_[M+H]+=535.1;_1HNMR_(400MHz,_DMSO- d6) 5 8.90 (s, 1H), 7.69 (d, J=12.6 Hz, 1H), 7.58 (d, J=8.4 Hz, 1H), 7.45 (d, J=6.8 Hz, 2H), 7.18 (s, 2H ),_5.04_(d,_J=9.2_Hz,_2H),_4.96_(s,_2H),_4.79_(s,_2H),_3.99_(s,_3H). Example 2 Preparation             of             3,5-difluoro-4-((8-methoxy-2-oxopyrazino[2,3-c][1,8]naphthyridin-1(2H)- yl)methyl)benzenesulfonamide (compound 2): 2022412821   03 Aug 2026 Tol, 130 °C Pd2(dba)3, xantphos, diox, 90 °C THF, ACN, 0°C NH3H2O, rt Step 1: Preparation of 7-methoxy-3-nitro-1,8-naphthyridin-4-ol 7-methoxy-1,8-naphthyridin-4-ol (14g, 79.47mmol, 1.0eq.) was dissolved in acetic anhydride (100mL). In an ice bath, nitric acid (8.41mL, 133.51mmol, 1.68eq.) was slowly added dropwise. Then the mixture was heated to 90°C and reacted at 90°C for 2hrs. After the completion of the reaction, the reaction mixture was cooled to rt, and filtered. The filter cake was washed with petroleum ether, and dried to afford the target compound (5.8g, yield 33%). LCMS_(ESI)_[M+H]+=222.1;_1H_NMR_(400MHz,_DMSO- d6) 5 13.27 (s, 1H), 8.95 (s, 1H), 8.45 (d, J=8.8 Hz, 1H), 6.98 (d, J=8.8 Hz, 1H), 4.01 (s, 3H). Step 2: Preparation of 5-chloro-2-methoxy-6-nitro-1,8-naphthyridine 7-methoxy-3-nitro-1,8-naphthyridin-4-ol (8.8g, 39.79mmol, 1.0eq.) was dissolved in dichloromethane (50mL). A catalytic amount of N,N-dimethylformamide (1mL) was added. Then under an ice bath, sulfurous dichloride (9mL, 75.69mmol, 1.9eq.) was slowly added dropwise. The mixture was warmed to 40°C and reacted at 40°C for 2hrs. After the completion of the reaction, the reaction was quenched with ice water, and extracted with dichloromethane (100mL^3). The organic phases were collected, dried, filtered, concentrated, and purified by column chromatography (Silica gel, PE:EA=2:1) to afford the target compound (7.2g, yield 75.52%). LCMS_(ESI)_[M+H]+=239.9;_1H_NMR_(400MHz,_DMSO-d6)_5_8.95- 8.94_(m,_1H),_8.44_(d,_J=8.8_Hz,_1H),_6.98_(d,_J=8.8_Hz,_1H),_4.01_(s,_3H). Step 3: Preparation of N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-naphthyridin-4-amine 5-chloro-2-methoxy-6-nitro-1,8-naphthyridine (600mg, 2.5mmol, 1eq.) and 1-(4-bromo-2,6- 2022412821   03 Aug 2026 difluorophenyl)methanamine (610.6mg, 2.75mmol, 1.1eq.) were dissolved in acetonitrile (100mL). K2CO3 (1.04g, 7.5mmol, 3eq.) was added. The mixture was reacted at 40°C for 2hrs. After the completion of the reaction. The reaction mixture was concentrated, washed with water and extracted with EA (20mLx3). The organic phases were collected, dried, filtered, concentrated, and purified by column chromatography (Silica gel, PE:EA=1:1) to afford the target compound (700mg, yield 65.9%). LCMS (ESI) [M+H]+=427.0; 1H NMR (400MHz, DMSO-d6) 5 9.14 (s, 1H), 8.84-8.67_(m,_2H),_7.51_(d,_J=6.8_Hz,_2H),_7.10_(d,_J=8.6_Hz,_1H),_4.69_(s,_2H),_4.02_(s,_3H). Step 4: Preparation of N4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthyridine-3,4-diamine N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-naphthyridin-4-amine (660mg, 1.55mmol, 1.0eq.) was dissolved in methanol (50mL). Stannous chloride (2943mg, 15.52mmol, 10eq.) was added. The mixture was reacted at 20°C for 2hrs. After the completion of the reaction. The reaction mixture was concentrated to remove a part of the solvent. The residue was washed with an aqueous saturated sodium bicarbonate solution to weak alkalinity, and then washed with water and extracted with EA (50mLx3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (Silica gel, DCM:MeOH=20:1) to afford the target compound (700mg, crude). LCMS_(ESI)_[M+H]+=397.0;_1H_NMR_(400MHz,_DMSO- d6)_5_8.70_(d,_J=9.6_Hz,_1H),_8.08_(s,_1H),_7.51_(d,_J=7.2_Hz,_2H),_7.06_(d,_J=9.2_Hz,_1H),_5.00_(s,_2H) ,_4.07-3.94_(m,_6H). Step 5: Preparation of ethyl 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]naphthyridine-3-carboxylate To a single necked flask were added N4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthyridine-3,4-diamine (300mg, crude), diethyl 2-oxomalonate (264mg, 1.51mmol), and toluene (10mL). The reaction apparatus was equipped with a water separator. The mixture was reacted at 130°C for 16hrs. After the reaction product was monitored, the reaction mixture was concentrated to afford a crude product, which was purified by flash silica gel column chromatography (petroleum ether:EA=100:0-100:70) to afford the target compound (220mg). LCMS_(ESI)_[M+H]+=505 / 507;_1HNMR_(400MHz,_CDCl3)_5_9.33_(s,_1H),_8.37_(d,_J=12.0_Hz,_1H),_7.19-6.95(m,_3H),_5.69_(s,_2H),_4.44-4.42_(m,_2H),_4.06_(s,_3_H),_1.17_(t,_J=6.4_Hz,_3_H). Step 6: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid To a single-necked round-bottom flask were added ethyl 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]naphthyridine-3-carboxylate (220mg, 0.43mmol, 1.0eq.), ethanol (5mL), triethylamine (176mg, 1.74mmol, 4.0eq.), and water (2mL). The reaction mixture was warmed to 50°C and stirred for 16hrs. The reaction mixture was concentrated at rt to remove a part of the solvent. The residue was diluted with EA, and the resulting solution was adjusted with dilute hydrochloric acid (1mol / L) to a pH of 4. The EA layer was separated, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford the target compound (180mg, yield 90%). LCMS_(ESI)_[M+H]+=477.0 / 479.0;_1HNMR_(400MHz,_CDCl3)_5_9.54_(s,_1H),_8.45_(d,_J=6.4_Hz,_1H),_7.2 8_(d,_J=6.4_Hz,_1H),_7.05-7.01_(m,_3_H),_5.75_(s,_2H),_4.06_(s,_3_H). 2022412821   03 Aug 2026 Step 7: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrazino[2,3-c][1,8]naphthyridin-2(1H)-one To a wicrowave tube were added 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]naphthyridine-3-carboxylic acid (150mg, 0.31mmol, 1.0eq.) and nitrobenzene (3mL). The reaction mixture was heated to 160°C and stirred for 2hrs. After the completion of the reaction, the reaction mixture was directly purified by column chromatography (petroleum ether:EA=100:0-0:100) to afford the target compound (80mg, yield 59%). LCMS (ESI): [M+H]+=432.9 / 433.9; 1HNMR (400MHz, CDCI3) 5 9.33 (s, 1H), 8.40 (d, J=8.0 Hz, 1H), 8. 32_(s,_1H),_7.19-6.98_(m,_3H),_5.69_(s,_2_H),_4.21_(s,_3H). Step 8:     Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3- c][1,8]naphthyridin-2(1H)-one To a wicrowave tube were added 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrazino[2,3-c][1,8]naphthyridin-2(1H)-one (52mg, 0.12mmol, 1.0eq.), para-methoxyphenylmethanethiol (55mg, 0.36mmol, 3.0eq.), caesium carbonate (84mg, 0.26mmol, 2.2eq.) and tris(dibenzylideneacetone)dipalladium (10mg, 0.01mmol, 0.1eq.), and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10mg, 0.02mmol, 0.2eq.). The reaction system was purged with nitrogen gas for 1 minute, heated to 90°C in a sealed manner, and reacted for 4hrs. After the completion of the reaction, the reaction mixture was washed with water and extracted with EA. The EA layer was dried and concentrated to afford a crude product, which was purified (petroleum ether:EA=1:1) to afford the target compound (20mg, yield 32%). LCMS_(ESI):_[M+H]+=507.1;_1HNMR_(400MHz,_CDCl3)_5_9.33_(s,_1H),_8.44_(d,_J=8.0_Hz,_1H),_8.32_(s, _1H),_7.19_(d,_J=8.0_Hz,_2H),_6.78_(d,_J=8.0_Hz,_1H),_6.69_(d,_J=8.0_Hz,_2H),_6.55_(d,_J=8.0_Hz,_2H),_5 .69_(s,_2H),_4.17(s,_3H),_4.01(s,_2_H),_3.74(s,_3H). Step 9:     Preparation of 3,5-difluoro-4-((8-methoxy-2-oxopyrazino[2,3-c][1,8]naphthyridin-1(2H)- yl)methyl)benzenesulfonamide To a round-bottom flask were added 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3-c][1,8]naphthyridin-2(1H)-one (15mg, 0.029mmol, 1.0eq.), tetrahydrofuran (2mL), acetonitrile (1mL), acetic acid (2mg, 0.033mmol, 1.1eq.), and water (2mg, 0.11mmol, 3.7eq.). To the ice-water cooled solution was added 1,3-dichloro-5,5-dimethylhydantoin (12mg, 0.058mmol, 2.0eq.). The reaction was performed under stirring for 60 minutes. Ammonia solution (1mL) was added. The stirring continued for 60 minutes. After the completion of the reaction, the reaction mixture was washed with water and extracted with EA. The EA layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford a crude product, which was purified by liquid chromatography to afford the target compound (4.5mg, yield 35%). LCMS_(ESI)_[M+H]+=434.0;_1HNMR_(400MHz,_DMSO-d6)_5_9.24_(s,_1H),_8.77_(d,_J=8.0_Hz,_1H),_8.35_(s,_1H),_7.63_(s,_2H),_7.47_(d,_J=8.0_Hz,_2H),_7.17_(d,_ J=8.0_Hz,_1H),_5.83_(s,_2H),_4.06_(s,_3H). Example 3 Preparation of 4-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)-1,4-diazepane-1-sulfonamide (compound 3): 2022412821   03 Aug 2026 Zn (Boc)2O, DMAP DCM, rt AcOH, rt Step 1: Preparation of 4-chloro-7-methoxy-1,8-naphthyridin-3-amine To a single-neck flask was added 5-chloro-2-methoxy-6-nitro-1,8-naphthyridine (5.0g, 20.87mmol, 1.0eq.) dissolved in acetic acid (20mL). Zinc powder (2.7g, 41.74mmol, 2.0eq.) was added to the reaction mixture. The mixture was reacted at rt under stirring for 16hrs. After the reaction product was monitored, the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:EA=1:1) to afford the target compound (400mg, yield 9%). LCMS_(ESI)_[M+H]+=210.1;_1H_NMR_(400MHz,_DMSO- d6) 5 8.57 (s, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.11 (d, J=8.8 Hz, 1H), 4.01 (s, 2H), 3.96 (s, 3H). Step 2: Preparation of tert-butyl (tert-butoxycarbonyl)(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)carbamate In a single-neck round-bottom flask, 4-chloro-7-methoxy-1,8-naphthyridin-3-amine (800mg, 3.82mmol, 1.0eq.) and 4-dimethylaminopyridine (233mg, 1.91mmol, 0.5eq.) were dissolved in dichloromethane (20mL). Then di-tert-butyl dicarbonate (1.7g, 7.63mmol, 2.0eq.) was added. The mixture was reacted at rt under stirring for 4hrs. After the reaction product was monitored, the reaction mixture was concentrated. The resulting residue was purified by silica gel column chromatography (petroleum ether:EA=3:1) to afford the target compound (380mg, yield 23%). LCMS_(ESI)_[M+H]+=410.2. Step 3: Preparation of methyl 3-((tert-butoxycarbonyl)amino)-7-methoxy-1,8-naphthyridin-4-carboxylate To a single-neck round-bottom flask were added tert-butyl (tert-butoxycarbonyl)(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)carbamate (800mg, 2.02mmol, 1.0eq.) and 4-dimethylaminopyridine (247mg, 2.02mmol, 1.0eq.), palladium acetate (23.0mg, 0.1mmol, 0.05eq.) and methanol (10mL). Then 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (1169mg, 2.02mmol, 1.0eq.), octacarbonyldicobalt (CAS:10210-68-1) (765mg, 2.22mmol, 1.1eq.) were added. The mixture was reacted at 90°C under refluxing for 5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated. The residue was purified by silica gel column chromatography (petroleum ether:EA=7:3) to afford the target compound (400mg, yield 46%). 2022412821   03 Aug 2026 LCMS (ESI): [M+H]+=334.1; 1H NMR (400MHz, CD3OD) 5 9.04 (s, 1H), 8.47 (d, J=9.2 Hz, 1H), 7.12 ( d,_J=9.2_Hz,_1H),_4.09_(s,_3H),_4.01_(s,_3H),_1.53_(s,_9H). Step 4: Preparation of methyl 3-amino-7-methoxy-1,8-naphthyridin-4-carboxylate Methyl 3-((tert-butoxycarbonyl)amino)-7-methoxy-1,8-naphthyridin-4-carboxylate (400mg, 1.2mmol, 1.0eq.) was dissolved in HCl / methanol (4M, 10mL). The reaction system was stirred at rt for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was distilled under reduced pressure to remove the solvent to afford a crude target compound (250mg). LCMS_(ESI):_[M+H]+=234.1;_1H_NMR_(400MHz,_DMSO-d6)_5_8.81-8.66_(m,_2H),_7.16_(d,_J=9.2_Hz,_1H),_6.28_(s,_3H),_4.00_(s,_3_H),_3.99_(s,_3_H). Step 5: Preparation of 8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-ol To a round-bottom flask were added methyl 3-amino-7-methoxy-1,8-naphthyridin-4-carboxylate (310mg, crude) and formamidine acetate (831mg, 7.98mmol) and formamide (5mL). The reaction system was stirred at 130°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt and then washed with water to precipitate a solid. to precipitate a solid. The mixture was filtered. The filter cake was dried to afford the target compound (200mg, yield 66%). LCMS_(ESI)_[M+H]+=229.2;_1H_NMR_(400MHz,_DMSO-d6)_5_12.71_(s,_1H),_9.84_(d,_J=9.2_Hz,_1H),_9.31_(s,_1H),_8.31_(s,_1H),_7.30_(d,_J=9.2_Hz,_1H),_4.08_(s, _3H). Step 6: Preparation of tert-butyl 4-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)-1,4-diazepane-1-carboxylate To a single-neck round-bottom flask were added 8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-ol (50mg, 0.22mmol, 1.0eq.), and acetonitrile (2mL). Under stirring, a drop of 1,8-diazabicyclo[5.4.0]undec-7-ene (100mg, 0.66mmol, 3.0eq) was added. The reaction system became clear. Then a drop of diphenyl ether was added, and Castro's reagent (290mg, 0.66mmol, 3eq) was added to the reaction system. The mixture was stirred for 10 minutes, and then tert-butyl 1,4-diazepane-1-carboxylate (130mg, 0.66mmol, 3eq) was added to the above stirred solution. The reaction continued under stirring for 16hrs. After the completion of the reaction. The reaction mixture was concentrated to afford a crude product, which was purified by preparative plate chromatography to afford the target compound (20mg, yield 22%). LCMS_(ESI)_[M+H]+=411.2;_1HNMR_(400MHz,_DMSO- d6)_5_9.35_(s,_1H),_8.71_(s,_1H),_8.57_(t,_J=8.0_Hz,_1H),_7.24_(d,_J=8.0_Hz,_1H),_4.25-4.22_(m,_1H),_4.06_(s,_3H),_3.75-3.30_(m,_5H),_2.10-2.02_(m,_1H),_1.75-1.52_(m,_1H),_1.37_(s,_4.5H),_1.17_(s,_4.5H),_0.88-0.85_(m,_2H). Step 7: Preparation of 1-(1,4-diazepane-1-yl)-8-methoxypyrimido[4,5-c][1,8]naphthyridine hydrochloride To a single-neck round-bottom flask were added tert-butyl 4-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)-1,4-diazepane-1-carboxylate (20mg, 0.05mmol, 1.0eq.) and methanol (2mL). To the resulting solution was added a solution of HCl / ethanol (2mol / L, 1.0mL, 40eq.). The reaction mixture was stirred at rt for 16hrs. After the completion of the reaction. The reaction mixture was concentrated to afford a crude target compound (20mg), which was directly used in the next step reaction. LCMS_(ESI)_[M+H]+=311.2. 2022412821   03 Aug 2026 Step 8: Preparation of tert-butyl ((4-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)-1,4-diazepane-1-yl)sulfonyl)carbamate To a single-neck round-bottom flask were added tert-butyl (chlorosulfonyl)carbamate (40mg, 0.29mmol, 5eq.) and dichloromethane (2mL). Under cooling in an ice bath, tert-butanol (20mg, 0.29mmol, 5eq.) was added. The solution obtained after stirring for 30 minutes was added to another round-bottom single-neck flask under stirring, which flask contained a solution of 1-(1,4-diazepane-1-yl)-8-methoxypyrimido[4,5-c][1,8]naphthyridine hydrochloride (20mg, 0.06mmol, 40% purity, 1.0eq.) and diisopropylethylamine (39mg, 0.3mmol, 5eq) in dichloromethane (2mL). The reaction mixture was stirred at room temperature for 2hrs. After the completion of the reaction. The reaction mixture was concentrated to afford a crude target compound (80mg), which was directly used in the next step reaction. LCMS_(ESI):_[M+H]+=490.0. Step 9: Preparation of 4-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)-1,4-diazepane-1-sulfonamide To a single-neck flask was added the crude product obtained in the above step tert-butyl ((4-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)-1,4-diazepane-1-yl)sulfonyl)carbamate (80mg, crude), dichloromethane (1mL) and trifluoroacetic acid (1mL). The reaction mixture was stirred for 1hr. After the completion of the reaction. The reaction mixture was concentrated to afford a crude product, which was directly purified by preparative HPLC to afford the target compound (1.6mg, total yield of three steps: 8%). LCMS (ESI): [M+H]+=390.1; 1HNMR (400MHz, MeOD) 5 9.36 (s, 1H), 8.75 (s, 1H), 8.67 (d, J=8.0 Hz, _1H),_7.27_(d,_J=8.0_Hz,_1H),_4.15-4.10_(m,_4H),_3.95-3.80_(m,_5H),_3.60-3.50_(m,_2H),_2.01-1.98_(m,_2H). Example 4 Preparation of N-((1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4-yl)methyl)aminosulfonamide (compound 4): 2022412821   03 Aug 2026 t-BuOK, t-BuOH DME, DMF, 0~20 °C NHBoc Step 1: Preparation of tert-butyl 4-cyanoazepan-1-carboxylate Tert-butyl 4-oxoazepan-1-carboxylate (6g, 28.13mmol, 1eq.) was dissolved in DMF(30mL). Then a solution of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (6.87g, 35.16mmol, 1.25eq.) and potassium tert-butoxide (6.31g, 56.26mmol, 2eq.) in tert-butanol (30mL) and 1,2-dimethoxyethane (24.05mL) was added at 0°C. The mixture was warmed to 20°C and reacted at 20°C for 3hrs. After TLC monitoring indicated the completion of the reaction, the mixture was washed with water and extracted with EA. The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography (petroleum ether:EA=10:1) to afford the target compound (4.2g, yield 66.57%). LCMS (ESI) [M+Na]+=247.1; 1H_NMR_(400MHz, DMSO-d6) 5 3.45-3.20 (m, 4H), 3.15-3.05_(m,_1H),_1.95-1.82_(m,_2H),_1.80-1.65_(m,_4H),_1.40_(s,_9H). Step 2: Preparation of azepan-4-carbonitrile To a single-neck round-bottom flask were added tert-butyl 4-cyanoazepan-1-carboxylate (3.00g, 13.37mmol, 1eq.), trifluoroacetic acid (30mL) and dichloromethane (5mL). The reaction mixture was stirred at room temperature for 16hrs. After the completion of the reaction, the reaction was concentrated to afford a crude target compound (1.5g), which was directly used in the next step reaction. LCMS_(ESI)_[M+H]+=125.2;_1H_NMR(400MHz,_CDCl3)5_3.75-3.70_(m,_4H),_3.15-3.05_(m,_1H),_2.36-2.34_(m,_2H),_2.33-2.00_(m,_4H). Step 3: Preparation of benzyl 4-cyanoazepan-1-carboxylate 2022412821   03 Aug 2026 To a single-neck round-bottom flask were added azepan-4-carbonitrile (1500mg, crude), diisopropylethylamine (4.7g, 36.24mmol) and tetrahydrofuran (30mL). Under stirring, benzyl carbonochloridate (2060mg, 12.08mmol) was slowly added dropwise. The mixture was reacted at rt under stirring for 2hrs. After the completion of the reaction, the reaction was concentrated to afford a crude product, which was purified by column chromatography (petroleum ether:EA=10:1) to afford the target compound (2.3g, yield 74%). LCMS (ESI): [M+Na]+=281.1; 1H NMR (400MHz, CDCI3) 5 7.39-7.23 (m, 5H), 5.13 (s, 2H), 3.75-3.25_(m,_4H),_2.87-2.82_(m,_1H),_1.99-1.65(m,_6H). Step 4: Preparation of benzyl 4-(aminomethyl)azepan-1-carboxylate To a round-bottom single-neck flask was added a solution of benzyl 4-cyanoazepan-1-carboxylate (2200mg, 8.52mmol, 1eq.) and borane in tetrahydrofuran (1M, 30mL). The reaction mixture was stirred at 70°C for 16hrs. After the completion of the reaction. The reaction mixture was concentrated to afford a crude target compound (2.0g), which was directly used in the next step reaction. LCMS_(ESI):_[M+H]+=263.1. Step 5: Preparation of benzyl 4-(((tert-butoxycarbonyl)amino)methyl)azepan-1-carboxylate In a single-neck round-bottom flask, benzyl 4-(aminomethyl)azepan-1-carboxylate (2000mg, crude) was dissolved in dichloromethane (10mL), and 4-dimethylaminopyridine (465.68mg, 3.81mmol) was added. Under stirring, di-tert-butyl dicarbonate (3327.62mg, 15.25mmol) was slowly added. The mixture was reacted at rt under stirring for 2hrs. After the completion of the reaction. The reaction mixture was concentrated to afford a crude product, which was purified by column chromatography (petroleum ether:EA=100:20) to afford the target compound (900mg, total yield of two steps: 30%). LCMS_(ESI)_[M+Na]+=385.2;_1H_NMR_(400MHz,_CDCl3)_5_7.28-7.23_(m,_5H),_5.15_(s,_2H),_4.59-4.55_(m,_1H),_3.55-3.05_(m,_4H),_3.05-2.95_(m,_2H),_1.95-1.44_(m,_7H),_1.42_(s,_9H). Step 6: Preparation of tert-butyl (azepan-4-ylmethyl)carbamate To a single-neck round-bottom flask, benzyl 4-(((tert-butoxycarbonyl)amino)methyl)azepan-1-carboxylate (900mg, 2.48mmol, 1eq.) was dissolved in methanol (10mL), and Pd / C(10% content, 50% humidity) and 2 drops of ammonia solution were added. The reaction system was replaced with a hydrogen gas balloon and reacted in an atmosphere of hydrogen gas at 20°C for 16hrs. After the completion of the reaction, the reaction mixture was filtered. The filtrate was concentrated to afford a crude target compound (400mg), which was directly used in the next step reaction. LCMS_(ESI)_[M+H]+=229.2;_1HNMR_(400MHz,_DMSO-d6)_5_6.88-6.83_(m,_1H),_2.70- 2.59_(m,_4H),_2.67_(s,_2_H),_2.58-2.52_(m,_1H),_1.66-1.51_(m,_5H),_1.40_(s,_9H),_1.20-1.15_(m,_2H). Step 7: Preparation of tert-butyl ((1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4-yl)methyl)carbamate To a single-neck round-bottom flask were added 8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-ol (60mg, 0.026mmol, 1.0eq.) and N,N-dimethylformamide (4mL). Under stirring, a drop of DBU (160mg, 1.05mmol, 4.0eq.) was added. The reaction system became clear. Then benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (220mg, 0.5mmol, 2eq.) was added to the reaction system. After stirring for 10 minutes, tertbutyl (azepan-4-ylmethyl)carbamate (120mg, crude product, obtained from the above-step reaction) was added to the above-stirred solution. The mixture was reacted at 90°C under stirring for 16hrs. After the completion of the reaction, 2022412821   03 Aug 2026 the reaction mixture was directly purified by reverse-phase preparative HPLC to afford the target compound (20mg, yield 22%). LCMS (ESI) [M+H]+=439.3; 1HNMR (400MHz, DMSO-d6) 5 9.33 (s, 1H), 8.69 (s, 1H), 8.55-8.53_(m,_1H),_7.23_(d,_J=12.0_Hz,_1H),_6.85_(s,_1H),_4.06_(s,_3H),_3.83-3.75_(m,_2H),_3.23-3.05_(m,_2H),_2.83-2.74_(m,_2H),_1.85-1.52_(m,_7H),_1.37_(s,_9H). Step 8: Preparation of (1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4-yl)methanamine To a single-neck round-bottom flask were added tert-butyl ((1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4-yl)methyl)carbamate (15mg, 0.05mmol, 1.0eq.) and dichloromethane (1mL). To the solution was added trifluoroacetic acid (2.0mL, 40eq.). The reaction mixture was stirred at rt for 2hrs. The reaction mixture was concentrated to afford a crude target compound (20mg), which was directly used in the next step reaction. LCMS_(ESI)_[M+H]+=339.1. Step 9: Preparation of tert-butyl (N-((1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4-yl)methyl)aminosulfonyl)carbamate To a single-neck round-bottom flask were added tert-butyl (chlorosulfonyl)carbamate (40mg, 0.29mmol, 5eq.) and dichloromethane (2mL). Under cooling in an ice bath, tert-butanol (20mg, 0.29mmol) was added. After stirring for 30 minutes, the reaction mixture was added to another flask containing a solution of (1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4-yl)methanamine (20mg, crude, obtained from the above step reaction) and diisopropylethylamine (39mg, 0.3mmol) in dichloromethane (2mL). The reaction mixture was stirred at room temperature for 3hrs. After the completion of the reaction. The reaction mixture was concentrated to afford a crude target compound (20mg), which was directly used in the next step reaction. LCMS_(ESI)_[M+H]+=518.3. Step 10:      Preparation of N-((1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4- yl)methyl)aminosulfonamide To a single-neck round-bottom flask were added tert-butyl (N-((1-(8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-yl)azepan-4-yl)methyl)aminosulfonyl)carbamate (20 mg, the crude product obtained in the above step) dissolved in dichloromethane (2mL), and then trifluoroacetic acid (2mL). The reaction mixture was stirred at room temperature for 3hrs. After the completion of the reaction, the reaction was concentrated to afford a crude product, which was purified by preparative HPLC to afford the target compound (4.3mg, total yield of three steps: 25%). LCMS_(ESI)_[M+H]+=418.3;_1HNMR_(400MHz,_MeOD)_5_9.32_(s,_1H),_8.72_(s,_1H),_8.44-8.41(m,_1H),_7.30_(d,_J=12_Hz,_1H),_4.30-3.95_(m,_5H),_3.78-3.70_(m,_2H),_2.90-2.81_(m,_2H),_2.01-1.88_(m,_4H),_1.55-1.23_(m,_2H),_0.99-0.95_(m,_1H). Example 5 Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide (compound 5): 2022412821   03 Aug 2026 7-methoxy-1,8-naphthyridin-4-ol (12g, 68.12mmol, 1eq.) was dissolved in N,N-dimethylformamide (50mL). Then N-bromosuccinimide (7.3g, 40.87mmol, 0.6eq.) was added at 0°C. The mixture was reacted at 0°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was washed with water, and extracted with EA (30mL*2). The organic phases were concentrated, and then purified by flash silica gel column chromatography (Silica gel, PE:EA=50:50) to afford the target compound (2.0g, yield 11.5%). LCMS_(ESI)_[M+H]+=254.9. Step 2: Preparation of 6-bromo-5-chloro-2-methoxy-1,8-naphthyridine 3-bromo-7-methoxy-1,8-naphthyridin-4-ol (500mg, 1.96mmol, 1eq.) was dissolved in dichloromethane (50mL). A drop of N,N-dimethylformamide was added. Sulfurous dichloride (2332mg, 19.6mmol, 10eq.) was added. Then the mixture was reacted at 40°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was slowly added dropwise to ice-water, and divided into layers. The aqueous phase was extracted with dichloromethane (20mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to afford the target compound (520mg, yield 97%). LCMS_(ESI)_[M+H]+=272.9. Step 3: Preparation of 2-((3-bromo-7-methoxy-1,8-naphthyridin-4-yl)amino)ethyl-1-ol 6-bromo-5-chloro-2-methoxy-1,8-naphthyridine (500mg, 1.83mmol, 1eq.) was dissolved in N-methylpyrrolidinone (15mL). Ethanol amine (2.2g, 36.6mmol, 20eq.) was added. The mixture was reacted at 100°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was poured into water, and extracted with EA (20mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford the target compound (260mg, yield 57%). LCMS_(ESI)_[M+H]+=298.0;_1H_NMR_(400MHz,_DMSO- d6) 5 8.61 (d, J=9.2 Hz, 1H), 8.56 (s, 1H), 6.97 (d, J=9.2 Hz, 1H), 6.22 (t, J=5.6 Hz, 1H), 4.97 (t, J=5. 2022412821   03 Aug 2026 2_Hz,_1H),_3.97_(s,_3H),_3.76-3.67_(m,_2H),_3.65-3.57_(m,_2H). Step 4: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]naphthyridine 2-((3-bromo-7-methoxy-1,8-naphthyridin-4-yl)amino)ethyl-1-ol (200mg, 0.67mmol, 1eq.) was dissolved in N,N-dimethylpyrrolidinone (5mL). Cuprous iodide (128mg, 0.67mmol, 1.0eq.), trans-1,2-cyclohexanediamine (77mg, 0.67mmol, 1.0eq.) and potassium tert-butoxide (226mg, 2.01mmol, 3eq.) were added. The mixture was reacted in the microwave at 140°C for 2hrs. The completion of the reaction was monitored with LCMS. 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (284mg, 1.01mmol, 1.5eq.) was added to the reaction mixture. The mixture was reacted at 70°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was poured into water, and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by silica gel column to afford the target compound (100mg, yield 36%). LCMS (ESI) [M+H]+=422.0; 1H NMR (400MHz, DMSO-d6) 5 8.91- 8.82_(m,_1H),_8.75_(s,_1H),_7.54_(d,_J=8.0_Hz,_2H),_7.22_(d,_J=9.2_Hz,_1H),_5.78_(s,_2H),_4.32_(t,_J=4.4_ Hz,_2H),_3.93_(s,_3H),_3.74_(t,_J=4.0_Hz,_2H). Step 5: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]naphthyridine 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]naphthyridine (100mg, 0.24mmol, 1eq.) was dissolved in dioxane (10mL). (4-methoxyphenyl)methanethiol (73mg, 0.47mmol, 2eq.), (5-(diphenylphosphino)-9,9-dimethyl-9H-xanthene-4-yl)diphenylphosphine (27mg, 0.05mmol, 0.2eq.), tris(1,5-diphenylpent-1,4-diene-3-one)dipalladium (43mg, 0.05mmol, 0.2eq.) and triethylamine (48mg, 47mmol, 2eq.) were added. The mixture was reacted at 100°C and under the protection of nitrogen gas for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by silica gel column chromatography (Silica gel, DCM:MeOH=95:5) to afford the target compound (70mg, yield 60%). LCMS_(ESI)_[M+H]+=496.1. Step 6: Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]naphthyridin-1-yl)methyl)benzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3- c][1,8]naphthyridine (60mg, 0.12mmol, 1.0eq.), acetic acid (51mg, 0.85mmol, 7.0eq.), water (31mg, 1.7mmol, 14.0eq.) were dissolved in tetrahydrofuran (15mL). 1,3-dichloro-5,5-dimethylhydantoin (72mg, 0.36mmol, 3eq.) was added at 0°C. The mixture was reacted at 0°C for 2hrs, followed by adding ammonia solution (0.5mL), and then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified by preparative HPLC to afford the target compound (13.7mg, yield 27%). LCMS_(ESI)_[M+H]+=423.1;_1HNMR_(400MHz,_MeOD- d4)_5_8.53_(s,_1H),_8.48_(d,_J=9.2_Hz,_1H),_7.53_(d,_J=7.2_Hz,_2H),_7.11_(d,_J=8.8_Hz,_1H),_5.92_(s,_2H) ,_4.36_(t,_J=4.4_Hz,_2H),_4.01_(s,_3H),_3.81_(t,_J=4.4_Hz,_2H). Example 6 Preparation         of         3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)methyl)benzenesulfonamide (compound 6): 2022412821   03 Aug 2026 Step 1: Preparation of ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate 1,3-diethyl 2-(((6-methoxypyridin-2-yl)amino)methylene)malonate (12g, 22.7mmol, 1eq.) was dissolved in phosphorus oxychloride (60mL). The mixture was reacted under the protection of nitrogen gas at 110°C under stirring for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was distilled under reduced pressure to remove the solvent. The resulting residue was dissolved in EA (60mL) to become clear and quickly washed with water (20mL). The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary-evaporated to dryness. The resulting crude product was purified by flash chromatography (Silica gel, DCM:EA=1:1) to afford the target compound (1.5g, yield 12%). LCMS_(ESI)_[M+H]+=266.0. Step 2: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (3.0g, 18.75mmol, 1eq.) was dissolved in acetonitrile (80mL). Then K2CO3 (5.2g, 37.5mmol, 2.0eq.), and (4-bromo-2,6-difluorophenyl)methanamine (4.37g, 19.69mmol, 1.05eq.) were added. The reaction was performed under the protection of nitrogen gas at 40°C for 20hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, diluted with EA, and washed with water. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary-evaporated to dryness. The resulting crude product was purified by flash chromatography (Silica gel, DCM:EA=4:1) to afford the target compound (3.5g, yield 69.2%). LCMS_(ESI)_[M+H]+=452.0. Step 3: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (120mg, 22.7mmol, 1eq.) was dissolved in ethanol (10mL). Sodium borohydride (134mg, 5eq.) was slowly added. The mixture was reacted under the protection of nitrogen gas at 50°C under stirring for 16hrs. The completion of the reaction was monitored with LCMS. The mixture was rotary-evaporated to dryness to remove the solvent. The resulting residue was quenched with saturated NaCl solution (5mL), and extracted with EA (10mL). The organic phase was dried over 2022412821   03 Aug 2026 anhydrous sodium sulfate, and filtered. The filtrate was rotary-evaporated to dryness. The resulting crude product was purified by flash chromatography (Silica gel, DCM:MeOH=2:1) to afford the target compound (120mg, yield 38%). LCMS (ESI) [M+H]+=410.0; 1H NMR (400MHz, CDCI3) 5 8.43 (s, 1H), 8.35 (d, J=9.2 Hz, 1H), 7.09 (d, _J=6.8_Hz,_2H),_6.90_(d,_J=9.2_Hz,_1H),_4.75_(s,_2H),_4.69_(s,_2H),_4.12_(s,_3H). Step 4: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol (300mg, 0.73mmol, 1eq.) was dissolved in dichloromethane (15mL). N,N-diisopropylethylamine (473mg, 3.66mmol, 5eq.) and triphosgene (651mg, 2.19mmol, 3eq.) were added. The mixture was reacted at 0°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was rotary-evaporated to dryness. The resulting crude product was purified by flash silica gel column chromatography (Silica gel, MeOH:DCM=5:95) to afford the target compound (250mg, yield 78.51%). LCMS_(ESI)_[M+H]+=436.0. Step 5: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (200mg, 0.46mmol, 1eq.) was dissolved in dioxane (10mL). (4-methoxyphenyl)methanethiol (141mg, 0.92mmol, 2eq.), [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthene-4-yl]diphenylphosphine(53mg, 0.09mmol,   0.2eq.),  tris(1,5- diphenylpent-1,4-diene-3-one)dipalladium(84mg, 0.09mmol, 0.2eq.) and N,N-diisopropylethylamine (178mg, 1.38mmol, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, rotary-evaporated to dryness, and purified by flash silica gel column chromatography (Silica gel, MeOH:DCM=5:95) to afford the target compound (110mg, yield 47.09%) as yellow solid. LCMS_(ESI)_[M+H]+=510.1. Step 6: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)benzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (100mg, 0.2mmol, 1.0eq.), acetic acid (83mg, 1.37mmol, 7.0eq.), water (50mg, 2.75mmol, 14.0eq.) were dissolved in tetrahydrofuran (15mL). 1,3-dichloro-5,5-dimethylhydantoin (116mg, 0.59mmol, 3eq.) was added at 0°C. The mixture was reacted at 25°C for 1hr, followed by adding ammonia solution (0.5mL), then reacted at 25°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified by preparative HPLC to afford the target compound (14.6mg, yield 17.05%). LCMS_(ESI)_[M+H]+=437.1;_1HNMR_(400MHz,_MeOD- d4)_5_8.71_(s,_1H),_8.59_(d,_J=9.2_Hz,_1H),_7.46_(d,_J=7.6_Hz,_2H),_7.13_(d,_J=9.6_Hz,_1H),_5.57_(s,_2H) ,_5.30_(s,_2H),_4.12_(s,_3H). Example 7 Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-3,4-dihydropyrimido[5,4-c]quinolin-1(2H)- 2022412821   03 Aug 2026 yl)methyl)benzenesulfonamide (compound 7): Br THF, rt GDI Pd2(dba)3, Xantphos, DIEA, dioxane, 100 °C Step 1: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylate Ethyl 4-chloro-6-fluoro-7-methoxyquinoline-3-carboxylate (1g, 3.6mmol, 1eq.),    (4-bromo-2,6- difluorophenyl)methanamine (1.2g, 5.4mmol, 1.5eq.) and K2CO3 (1.47g, 10.8mmol, 3eq.) were dissolved in acetonitrile (50mL). The mixture was heated to 90°C and reacted for 12hrs. After the completion of the reaction, the reaction mixture was purified by flash silica gel column chromatography (Silica gel, DCM:MEOH=95:5) to afford the target compound (900mg, yield 54.41%). LCMS_(ESI)_[M+H]+=469.0;_1H_NMR_(400MHz,_DMSO- d6) 5 8.82 (s, 1H), 8.24 (t, J=5.2 Hz, 1H), 8.19 (d, J=13.4 Hz, 1H), 7.49 (dd, J=8.0 Hz, 3H), 4.73 (d J =5.2_Hz,_2H),_4.28_(d,_J=7.2_Hz,_2H),_4.00_(s,_3H),_1.30_(t,_J=7.2_Hz,_3H). Step 2: Preparation of 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylic acid Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylate (500mg, 1.07mmol, 1eq.) was added to methanol (5mL) and tetrahydrofuran (5mL). An aqueous NaOH solution (2M, 3mL) was added. The mixture was stirred at room temperature for 2hrs. After the completion of the reaction, the reaction mixture was distilled under reduced pressure to remove the solvent. Water (20 mL) was added, and the mixture was adjusted to acidity. A solid precipitated and the mixture was filtered. The filter cake was washed with petroleum ether, and the resulting solid was dried in vacuum to afford the target compound (400mg, yield 75.27%). LCMS_(ESI)_[M+H]+=440.9. Step 3: Preparation of 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-formamide 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylic acid (380mg, 0.76mmol, 1eq.) and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.8g, 7.6mmol, 10eq.) and ammonia / tetrahydrofuran (19mL, 7.6mmol, 10eq.) were added to N,N-dimethylformamide (10mL). N,N-diisopropylethylamine (98.0mg, 0.76mmol, 1eq.) was added dropwise. The mixture was reacted at rt for 40hrs. Water 2022412821   03 Aug 2026 (50mL) was added. The reaction mixture was extracted with EA (100mL^2). The organic phases were washed with brine five times, dried over anhydrous sodium sulfate, and filtered. The filtrate was distilled under reduced pressure to remove the solvent. The residue was purified by flash silica gel column chromatography (Silica gel, DCM:MeOH=70:30) to afford the target compound (250mg, yield 65.94%). LCMS_(ESI)_[M+H]+=440.0. Step 4: Preparation of 3-(aminomethyl)-N-(4-bromo-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinolin-4-amine 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-formamide (380mg, 0.86mmol, 1eq.) was added to tetrahydrofuran (20mL). A solution of borane in tetrahydrofuran (1M, 8.6mL, 8.6mmol, 10eq.) was added. The mixture was reacted at 60°C for 15hrs. After the completion of the reaction, a methanol solution (10mL) was added. The mixture was rotary-evaporated to dryness to remove the solvent, and purified by flash silica gel column chromatography (Silica gel, DCM:MeOH=65:35) to afford the target compound (160mg, yield 43.5%). LCMS_(ESI)_[M+H]+=426.1. Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrimido[5,4-c]quinolin-2(1H)-one 3-(aminomethyl)-N-(4-bromo-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinolin-4-amine (160mg, 0.38mmol, 1eq.) was added to tetrahydrofuran (10mL). N,N'-carbonyldiimidazole (123.1mg, 0.76mmol, 2eq.) was added. The mixture was reacted at rt for 15hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified by flash silica gel column chromatography (Silica gel, DCM:MeOH=70:30) was purified by to afford the target compound (70mg, yield 41.24%). LCMS_(ESI)_[M+H]+=452.1. Step 6:     Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-3,4- dihydropyrimido[5,4-c]quinolin-2(1H)-one 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrimido[5,4-c]quinolin-2(1H)-one (45mg, 0.1mmol, 1eq.) and (4-methoxyphenyl)methanethiol (18.5mg, 0.12mmol, 1.2eq.) were added to dioxane (10mL). Tris(dibenzylideneacetone)dipalladium (5mg, 0.03mmol, 0.3eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (39mg, 0.07mmol, 0.2eq.), N,N-diisopropylethylamine (25.8mg, 0.2mmol, 2eq.) were added. Under the protection of nitrogen gas, the mixture was reacted at 100°C for 1hr. After the completion of the reaction, the reaction mixture was purified by flash silica gel column chromatography (Silica gel, DCM:MeOH=95:5) to afford the target compound (20mg, yield 38.06%). LCMS_(ESI)_[M+H]+=526.1. Step 7: Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-3,4-dihydropyrimido[5,4-c]quinolin-1(2H)-yl)methyl)benzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-3,4-dihydropyrimido[5,4-c]quinolin-2(1H)-one (18mg, 0.03mmol, 1eq.) was added to tetrahydrofuran (2mL). At 0°C, a drop of acetic acid, a drop of water and 1,3-dichloro-5,5-dimethylhydantoin (20.2mg, 0.12mmol, 3eq.) were added. The mixture was reacted at 0°C for 2hrs. After the completion of the reaction, ammonia solution (2mL) was added dropwise at 0°C. LCMS monitoring indicated the completion of the reaction, the mixture was distilled under reduced pressure to remove the solvent and purified to afford the target compound (1.6mg, yield 11.12%). 2022412821   03 Aug 2026 LCMS (ESI) [M+H]+=453.0; 1H NMR (400MHz, CD3OD) 5 8.73 (s, 1H), 8.14 (d, J=12.6 Hz, 1H), 7.71 (d,_J=8.4_Hz,_1H),_7.62_(d,_J=7.6_Hz,_2H),_5.72_(s,_2H),_4.60_(s,_2H),_4.26_(s,_3H). Example 8 Preparation             of 3,5-difluoro-4-((8-methoxy-2-oxopyrido[2,3-h][1,6]naphthyridine-1(2H)- yl)methyl)benzenesulfonamide (compound 8): Step 1: Preparation of 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carbaldehyde (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol (300mg, 0.73mmol, 1eq.) were dissolved in dichloromethane (10mL) and tetrahydrofuran (10mL). MnO2 (317mg, 3.65mmol, 5eq.) was added. The mixture was reacted at 25°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was washed with water, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash silica gel column chromatography (Silica gel, MeOH:DCM=5:95) to afford the target compound (160mg, yield 53.42%). LCMS (ESI) [M+H]+=408.0; 1H NMR (400MHz, CDCI3) 3 10.10 (s, 1H), 9.77 (s, 1H), 8.68 (s, 1H), 8.4 4_(d,_J=9.2_Hz,_1H),_7.20_(d,_J=7.2_Hz,_2H),_6.84_(d,_J=8.8_Hz,_1H),_4.92_(d,_J=4.8_Hz,_2H),_4.10_(s,_3 H). Step 2: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrido[2,3-h][1,6]naphthyridine-2(1H)-one 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carbaldehyde (150mg, 0.37mmol, 1eq.) was dissolved in methanol (15mL). Ethyl 2-(dimethoxyphosphoryl)acetate (247mg, 1.1mmol, 3eq.) and K2CO3 (254mg, 1.84mmol, 5eq.) were added. The mixture was reacted at 85°C for 8hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified by flash silica gel column chromatography (Silica gel, MeOH:DCM=2:98) to afford the target compound (110mg, yield 69.26%). LCMS_(ESI)_[M+H]+=432.0;_1H_NMR_(400MHz,_DMSO- d6) 3 9.15 (s, 1H), 8.70 (d, J=9.2 Hz, 1H), 8.19 (d, J=9.2 Hz, 1H), 7.42 (d, J=8.0 Hz, 2H), 7.11 (d, J= 9.2_Hz,_1H),_6.71_(d,_J=9.2_Hz,_1H),_5.69_(s,_2H),_4.04_(s,_3H). Step 3:     Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrido[2,3- h][1,6]naphthyridine-2(1H)-one 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrido[2,3-h][1,6]naphthyridine-2(1H)-one (145mg, 0.34mmol, 1eq.) was dissolved in dioxane (10mL). (4-methoxyphenyl)methanethiol (103mg, 0.67mmol, 2eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (40mg, 0.07mmol, 0.2eq.), tris(1,5-diphenylpent-1,4-diene-3- 2022412821   03 Aug 2026 one)dipalladium(61mg, 0.07mmol, 0.2eq.) and N,N-diisopropylethylamine (130mg, 1.01mmol, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified by flash silica gel column chromatography (Silica gel, MeOH:DCM=5:95) to afford the target compound (110mg, yield 64.86%). LCMS_(ESI)_[M+H]+=506.1. Step 4:     Preparation of 3,5-difluoro-4-((8-methoxy-2-oxopyrido[2,3-h][1,6]naphthyridine-1(2H)- yl)methyl)benzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrido[2,3-h][1,6]naphthyridine-2(1H)-one (110mg, 0.22mmol, 1.0eq.), acetic acid (91mg, 1.52mmol, 7.0eq.), water (55mg, 3.05mmol, 14.0eq.) were dissolved in tetrahydrofuran (15mL). 1,3-dichloro-5,5-dimethylhydantoin (129mg, 0.65mmol, 3eq.) was added at 0°C. The mixture was reacted at 0°C for 1hr, followed by adding ammonia solution (0.5mL), then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified by preparative HPLC to afford the target compound (40.9mg, yield 43.47%). LCMS_(ESI)_[M+H]+=433.0;_1H_NMR_(400MHz,_DMSO- d6) 3 9.16 (s, 1H), 8.72 (d, J=9.2 Hz, 1H), 8.21 (d, J=9.6 Hz, 1H), 7.62 (s, 2H), 7.43 (d, J=7.6 Hz, 2H) ,_7.12_(d,_J=9.2_Hz,_1H),_6.70_(d,_J=9.2_Hz,_1H),_5.78_(s,_2H),_4.05_(s,_3H). Example 9 Preparation of 3,5-difluoro-4-((8-methoxy-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide (compound 11) Step 1: Preparation of N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)-2-chloroacetamide N4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthyridine-3,4-diamine (120mg, 0.3mmol, 1.0eq.), 2-chloroacetyl chloride (38mg, 0.34mmol, 1.1eq.), and K2CO3 (47mg, 0.34mmol, 1.1eq.) were dissolved in tetrahydrofuran (10mL). The mixture was reacted at normal temperature under stirring for 20 minutes. After the reaction product was monitored, the reaction mixture was concentrated to afford a crude product, which was purified by flash silica gel column chromatography (Silica gel, DCM:MeOH=20:1) to afford the target compound (68mg, yield 48%). LCMS_(ESI)_[M+H]+=471.0. Step 2: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one 2022412821   03 Aug 2026 N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)-2-chloroacetamide          (48mg, 0.15mmol, 1.0eq.), sodium hydride (4mg, 0.17mmol, 1.1eq.) were dissolved in N,N-dimethylformamide (10 mL). The mixture was reacted at rt under stirring for 20 minutes. After the reaction product was monitored, the reaction mixture was concentrated to afford a crude product, which was purified by flash silica gel column chromatography (Silica gel, DCM:MeOH=20:1) to afford the target product (50mg, yield 77%). LCMS_(ESI)_[M+H]+=435.0. Step 3: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one (50mg, 0.12mmol, 1eq.) and K2CO3 (49mg, 0.35mmol, 3eq.) was dissolved in N,N-dimethylformamide (10mL). Then 2,2,2-trifluoroethyl trifluoromethanesulfonate (27mg, 0.12mmol, 1eq.) was added. The mixture was reacted at 80°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water, and extracted with EA (20mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography (Silica gel, PE:EA=2:1) to afford the target compound (32mg, yield 53.93%). LCMS_(ESI)_[M+H]+=517.0. Step 4: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one (32mg, 0.06mmol, 1eq.) was dissolved in dioxane (10mL). Then (4-methoxyphenyl)methanethiol (19mg, 0.12mmol, 2eq.), tris(dibenzylideneacetone)dipalladium (10mg, 0.01mmol, 0.17eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (10.4mg, 0.02mmol, 0.3eq.) and diisopropylethylamine (23mg, 0.18mmol, 3eq.) were successively added. Under the protection of nitrogen gas, the mixture was reacted at 100°C for 2hrs. The completion of the reaction was monitored with LCMS. Then the reaction mixture was washed with water and extracted with EA (15mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography (Silica gel, PE:EA=2:1) to afford the target compound (10mg, yield 28.25%). LCMS_(ESI)_[M+H]+=591.1. Step 5: Preparation of 3,5-difluoro-4-((8-methoxy-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one (10mg, 0.017mmol, 1eq.) was dissolved in tetrahydrofuran (2mL) and acetonitrile (1mL). Acetic acid (7mg, 0.05mmol, 7eq.), water (1.8mg, 0.1mmol, 14eq.) and 1,3-dichloro-5,5-dimethylhydantoin (5.91mg, 0.03mmol, 1.8eq.) were added at 0°C. The mixture was reacted at 0°C for 2hrs, followed by adding ammonia solution (178mg, 5.1mmol, 300eq.), then reacted at 0°C for 1hr. After the completion of the reaction. Then the reaction mixture was washed with water and extracted with EA (15mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified to afford the target compound. 2022412821   03 Aug 2026 LCMS (ESI) [M+H]+=518.0; 1H NMR (400MHz, CD3OD) 3 8.80 (s, 1H), 8.57 (d, J=9.0 Hz, 1H), 8.52 ( s,_2H),_7.39_(d,_J=7.0_Hz,_2H),_7.13_(d,_J=9.0_Hz,_1H),_4.78-4.66_(m,_4H),_4.11_(s,_3H),_4.04_(s,_2H). Example 10 Preparation         of         3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- Step 1: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-yl)methanol Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylate (500mg, 1.07mmol, 1eq.) was dissolved in ethanol (15mL). Sodium borohydride (202mg, 5.35mmol, 5eq.) was added. The mixture was reacted at 25°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was poured into water, extracted with EA, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by silica gel column chromatography (Silica gel, DCM:MeOH=97:3) to afford the target compound (300mg, yield 65.63%). LCMS_(ESI)_[M+H]+=427.0. Step 2: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-yl)methanol (150mg, 0.35mmol, 1eq.) was dissolved in dichloromethane (10mL). Triphosgene (313mg, 1.05mmol, 3eq.) and N,N-diisopropylethylamine (227mg, 1.76mmol, 5eq.) were added. The mixture was reacted at 25°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by silica gel column chromatography (Silica gel, DCM:MeOH=97:3) to afford the target compound (100mg, yield 62.66%). LCMS_(ESI)_[M+H]+=453.0. Step 3: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (90mg, 0.2mmol, 1eq.) was dissolved in dioxane (10mL). (4-methoxyphenyl)methanethiol (61mg, 0.4mmol, 2eq.), tris(dibenzylideneacetone)dipalladium (18mg,    0.02mmol,    0.1eq.), 4,5-bis(diphenylphosphino)-9,9- dimethylxanthene (23mg, 0.04mmol, 0.2eq.), and N,N-diisopropylethylamine (77mg, 0.13mmol, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction 2022412821   03 Aug 2026 mixture was concentrated, and purified by silica gel column chromatography (Silica gel, DCM:MeOH=97:3) to afford the target compound (60mg, yield 57.38%). LCMS_(ESI)_[M+H]+=527.0. Step 4: Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- yl)methyl)benzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4- c]quinolin-2-one (5mg, 0.01mmol, 1.0eq.), acetic acid (4.0mg, 0.07mmol, 7.0eq.), water (2.4mg, 0.13mmol, 14.0eq.) were dissolved in tetrahydrofuran (15mL). 1,3-dichloro-5,5-dimethylhydantoin (5.6mg, 0.03mmol, 3eq.) was added at 0°C. The mixture was reacted at 0°C for 2hrs, followed by adding ammonia solution (0.5mL), then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified to afford the target compound (12.1mg, yield 25.55%). LCMS (ESI) [M+H]+=454.0; 1H NMR (400MHz, MeOD) 3 8.65 (s, 1H), 8.01 (d, J=12.8 Hz, 1H), 7.57 ( d,_J=8.4_Hz,_1H),_7.48_(d,_J=7.2_Hz,_2H),_5.61_(s,_2H),_5.31_(s,_2H),_4.08_(s,_3H). Example 11 Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dioxo-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide (compound 62): Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dioxo-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide To a 50mL round-bottom flask were added 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3-c][1,8]naphthyridine-2(1H)-one (100mg, 1.0eq.), tetrahydrofuran (10mL), acetic acid (10mg, 0.84eq.), water (10mg, 2.81eq.). While the mixture was cooled in ice water, 1,3-dichloro-5,5-dimethylhydantoin (118mg, 3.0eq.) was added. The resulting mixture was reacted under stirring for 1hr, followed by adding ammonia solution (3mL), then reacted under stirring for 1hr. LCMS monitoring indicated the completion of the reaction, the reaction mixture was extracted with EA. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford a crude product, which was purified to afford the target compound (19.3mg, yield: 21%). LCMS_(ESI)_[M+H]+=450.1;_1HNMR_(400MHz,_DMSO- d6) 3 12.44 (s, 1H), 8.76 (s, 1H), 8.67 (d, J=9.6 Hz, 1H), 7.60 (s, 2H), 7.43 (d, J= 7.2 Hz, 2H), 7.11 (d, _J=9.2_Hz,_1H),_5.69_(s,_2H),_4.01_(s,_3H). Example 12 Preparation of 7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin- 2022412821   03 Aug 2026 2(1H)-sulfonamide (compound 39): triphosgene, DIEA THF Step 1: Preparation of ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (600mg,    1eq.), tert-butyl 7-amino-3,4- dihydroisoquinolin-2(1H)-carboxylate (838.4mg, 1.5eq.) and N,N-diisopropylethylamine (1.45g, 5eq.) were dissolved in ethanol (150mL). The mixture was heated to 90°C and reacted for 24hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was purified by flash silica gel column chromatography to afford the target compound (800mg, yield: 74.3%). LCMS_(ESI)_[M+H]+=479.0;_1H_NMR_(400MHz,_DMSO- d6) 3 9.85 (s, 1H), 9.02 (s, 1H), 8.10 (d, J=9.6 Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 6.93 (d, J=9.6 Hz, 1H) ,_6.90_(d,_J=9.6_Hz,_2H),_4.41_(s,_2H),_4.16_(q,_J=7.2_Hz,_2H),_4.00_(s,_3H),_3.54_(t,_J=5.6_Hz,_2H),_2.7 3_(t,_J=5.6_Hz,_2H),_1.42_(s,_9H),_1.24_(t,_J=7.2_Hz,_3H). Step 2: Preparation of tert-butyl 7-((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-carboxylate Ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (400mg, 1eq.) and sodium borohydride (307.8mg, 10eq.) were dissolved in ethanol (40mL). The mixture was warmed to 60°C and reacted under stirring for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated in vacuum to remove the solvent, diluted with water (100mL), extracted with EA (200mL^2). The organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by flash chromatography to afford the target compound (230mg, yield 62%). LCMS_(ESI)_[M+H]+=437.3;_1H_NMR_(400MHz,_DMSO- d6)_3_8.86_(s,_1H),_8.35_(s,_1H),_8.18_(d,_J=9.0_Hz,_1H),_6.97_(d,_J=9.0_Hz,_2H),_6.55_(d,_J=8.8_Hz,_2H) ,_5.33_(t,_J=5.4_Hz,_1H),_4.46_(d,_J=5.4_Hz,_2H),_4.36_(s,_2H),_4.00_(s,_3H),_3.51_(t,_J=5.8_Hz,_2H),_2.6 7_(t,_J=5.6_Hz,_2H),_1.41_(s,_9H). Step 3: Preparation of tert-butyl 7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-carboxylate Tert-butyl        7-((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)- 2022412821   03 Aug 2026 carboxylate (230mg, 1eq.) was added to tetrahydrofuran (20mL). N,N-diisopropylethylamine (683.7mg, 10eq.) was added. Then triphosgene (312.7mg, 2eq.) was added. The resulting mixture was reacted at rt for 1hr. LCMS monitoring indicated the completion of the reaction, the reaction mixture was purified by flash chromatography to afford the target compound (200mg, yield: 81.61%). LCMS (ESI) [M+H]+=463.0; 1H NMR (400MHz, DMSO-d6) 3 8.84 (s, 1H), 8.57- 8.43_(m,_1H),_7.33_(s,_2H),_7.18_(d,_J=9.6_Hz,_1H),_6.78_(d,_J=9.2_Hz,_1H),_5.60_(s,_2H),_4.45_(s,_2H),_ 3.58_(s,_3H),_3.14_(s,_2H),_2.85_(s,_2H),_1.41_(s,_9H). Step 4: Preparation of 8-methoxy-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one Tert-butyl 7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-carboxylate (200mg, 1eq.) was added to dichloromethane (10mL). Then trifluoroacetic acid (3mL) was added. The mixture was reacted at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated in vacuum to remove the solvent to afford a crude target compound (140mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=363.1. Step 5: Preparation of tert-butyl ((7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate 8-methoxy-1-(1,2,3,4-tetrahydroisoquinolin-7-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (130mg, crude) and triethylamine (54.6mg) were added to dichloromethane (20mL). Tert-butyl N-(chlorosulfonyl)carbamate (154.7mg) was added dropwise at 0°C. The mixture was reacted at rt for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (50mL), and extracted with dichloromethane (100mL^2). The organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum to afford a crude target compound (150mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=542.1. Step 6: Preparation of 7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-sulfonamide Tert-butyl ((7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate (150mg, crude) was added to dichloromethane (10mL). Then trifluoroacetic acid (2mL) was added. The mixture was reacted at rt for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated in vacuum to remove the solvent, dissolved in N,N-dimethylformamide (3mL), and purified by preparative HPLC to afford the target compound (27mg, yield: 22%). LCMS_(ESI)_[M+H]+=442.1;_1H_NMR_(400MHz,_DMSO- d6) 3 8.83 (s, 1H), 7.38 (s, 1H), 7.30 (s, 2H), 7.18 (d, J=9.2, 1H), 6.95 (s, 2H), 6.79 (d, J=9.2, 1H), 5.6 0_(s,_2H),_4.17(s,_2H),_3.95_(s,_3H),_3.28_(t,_J=5.6,_2H),_2.98_(t,_J=5.6,_2H). Example 13 Preparation of 3,5-difluoro-4-((2-hydroxy-8-methoxy-3-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide (compound 65) 2022412821   03 Aug 2026 Step 1: Preparation of 5-chloro-2-methoxy-6-nitro-1,8-naphthyridine 7-methoxy-3-nitro-1,8-naphthyridine-4-ol (3g, 1eq.) was dissolved in dichloromethane (30mL). Then N,N-dimethylformamide (1mL) was added. In an ice bath, sulfurous dichloride (3mL, 1.9eq.) was slowly added dropwise. Then the mixture was warmed to 40°C and reacted for 2hrs. The completion of the reaction was monitored with LCMS. The reaction was quenched with ice water, and extracted with dichloromethane (100mL^3). The organic phases were collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography to afford the target compound (2.8g, yield: 88%). LCMS_(ESI)_[M+H]+=240.0. Step 2: Preparation of N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-naphthyridine-4-amine 5-chloro-2-methoxy-6-nitro-1,8-naphthyridine (2g, 1eq.) and 1-(4-bromo-2,6-difluorophenyl)methanamine (5.07g, 1.1eq.) were dissolved in acetonitrile (100mL). Then K2CO3 (8.63g, 3eq.) was added. Then the mixture was reacted at 40°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, diluted with water, and extracted with EA (20mL^3). The organic phases were collected, dried over anhydrous ammonium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography to afford the target compound (3g, yield: 85%). LCMS_(ESI)_[M+H]+=427.0. Step 3: Preparation of N4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthyridine-3,4-diamine N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-naphthyridine-4-amine (3g, 1eq.) was dissolved in ethanol (50mL). Then Fe powder (4g, 10eq.) and a saturated NH4Cl solution (2mL) were added. The resulting mixture was reacted at 80°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to remove a part of the solvent, then diluted with water, and extracted with EA (50mL^3). The organic phases were collected, dried over anhydrous ammonium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography to afford N4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthyridine-3,4- 2022412821   03 Aug 2026 diamine (1.5g, yield: 54%). LCMS_(ESI)_[M+H]+=397.0. Step 4: Preparation of N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)-2-chloroacetamide N4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthyridine-3,4-diamine (500mg,   1.0eq.), 2-chloroacetyl chloride (154mg, 1.1eq.), and K2CO3 (197mg, 1.1eq.) were dissolved in tetrahydrofuran (30mL). The mixture was reacted at rt for 20 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to afford a crude product, which was purified by flash silica gel column chromatography to afford the target compound (330mg, yield: 56%). LCMS_(ESI)_[M+H]+=471.0;_1H_NMR_(400MHz,_dmso- d6) 3 10.49 (s, 1H), 8.88 (d, J=9.2 Hz, 1H), 8.42 (s, 1H), 7.51 (d, J=7.4 Hz, 2H), 7.19 (d, J=9.2 Hz, 1 H),_4.94_(d,_J=4.4_Hz,_2H),_4.38_(s,_2H),_4.05_(s,_3H),_3.17_(s,_1H). Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)-2-chloroacetamide (320mg, 1.0eq.), and sodium hydride (18mg, 1.1eq.) were dissolved in N,N-dimethylformamide (20mL). The mixture was reacted at rt for 20 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to afford a crude product, which was purified by flash silica gel column chromatography to afford the target compound (120mg, yield: 42%). LCMS_(ESI)_[M+H]+=435.0;_1H_NMR_(400MHz,_dmso- d6)_3_10.56_(s,_1H),_8.48_(d,_J=9.0_Hz,_1H),_8.37_(s,_1H),_7.41_(d,_J=7.2_Hz,_2H),_7.12_(d,_J=9.0_Hz,_1 H),_4.49_(s,_2H),_3.99_(s,_3H),_3.77_(s,_2H). Step 6: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one (120mg, 1eq.) was dissolved in dioxane (10mL). Then (4-methoxyphenyl)methanethiol (73mg,    2eq.), tris(dibenzylideneacetone)dipalladium (32mg), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (72mg) and diisopropylethylamine (58mg, 3eq.) were successively added. Under the protection of nitrogen gas, the mixture was reacted at 100°C for 2hrs. The completion of the reaction was monitored with LCMS. Then the reaction mixture was washed with water and extracted with EA (15mL^3). The organic phases were collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography to afford the target product (76mg, yield: 64%). LCMS_(ESI)_[M+H]+=509.1. Step 7: Preparation of 3,5-difluoro-4-((2-hydroxy-8-methoxy-3-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide) 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthyridine-3(2H)-one (40mg, 1eq.) was dissolved in tetrahydrofuran (2mL) and acetonitrile (1mL). Acetic acid (41mg, 7eq.), water (11.5mg, 14eq.) and N-chlorosuccinimide (25mg, 1.8eq.) were added at 0°C. The mixture was reacted at 0°C 2022412821   03 Aug 2026 for 2hrs, followed by adding ammonia solution (1g, 300eq.), then reacted at 0°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water, and extracted with EA (15mL^3). The organic phases were collected, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by preparative chromatography to afford the target compound (5.1mg, yield: 17%). LCMS (ESI) [M+H]+=452.0; 1H NMR (400MHz, MeOD) d 8.63 (d, J=9.2 Hz, 1H), 8.44 (s, 1H), 7.41 (d ,_J=7.0_Hz,_2H),_7.14_(d,_J=9.0_Hz,_1H),_5.21_(s,_1H),_5.03_(s,_2H),_4.12_(s,_3H). Example 14 Preparation of 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)piperidine-1-sulfonamide (compound 46) Step 1: Preparation of ethyl 4-(((1-(tert-butoxycarbonyl)piperidine-4-yl)methyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (300mg, 1eq.), tert-butyl 4-(aminomethyl)piperidine-1-carboxylate (241mg, 1eq.) and N,N-diisopropylethylamine (726mg, 5eq.) were dissolved in ethanol (100mL). The mixture was heated to 90°C and reacted for 24hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was purified by flash silica gel column chromatography to afford the target compound (300mg, yield: 24%). LCMS_(ESI)_[M+H]+=445.2. Step 2: Preparation of tert-butyl 4-(((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)piperidine-1-carboxylate Ethyl 4-(((1-(tert-butoxycarbonyl)piperidine-4-yl)methyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (300mg, 1eq.) and sodium borohydride (248mg, 10eq.) were dissolved in ethanol (40mL). The mixture was warmed to 60°C and reacted for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated in vacuum to remove the solvent, diluted with water (50mL), and extracted with EA (100mLx2). The organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by flash chromatography to afford the target compound (50mg, yield: 18%). LCMS_(ESI)_[M+H]+=403.3. Step 3: Preparation of tert-butyl 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)piperidine-1-carboxylate 2022412821   03 Aug 2026 Tert-butyl 4-(((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4-yl)amino)methyl)piperidine-1-carboxylate (50mg, 1eq.) was added to tetrahydrofuran (5mL). Then N,N-diisopropylethylamine (160mg, 10eq.) was added. Triphosgene (73mg, 2eq.) was added. The mixture was reacted at rt for 1hr. LCMS monitoring indicated the completion of the reaction, the reaction mixture was diluted with water (10mL), and extracted with EA (20mL^3). The organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford a crude target compound (50mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=429.2. Step 4: Preparation of 8-methoxy-1-(piperidine-4-ylmethyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one Tert-butyl           4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)piperidine-1- carboxylate (50mg, crude) was added to dichloromethane(5mL). Then trifluoroacetic acid (1mL) was added. The mixture was reacted at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated in vacuum to remove the solvent to afford a crude target compound (30mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=329.2. Step 5: Preparation of tert-butyl ((4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)piperidine-1-yl)sulfonyl)carbamate 8-methoxy-1-(piperidine-4-ylmethyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (30mg, crude) and triethylamine (46mg) were added to dichloromethane (5mL). At 0°C, Tert-butyl N-(chlorosulfonyl)carbamate (39mg) was added dropwise. The mixture was reacted at rt for 5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (10mL), and extracted with dichloromethane (20mL^2). The organic phases were dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford a crude target compound (30mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=508.2. Step 6: Preparation of 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)piperidine-1-sulfonamide Tert-butyl         ((4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)piperidine-1- yl)sulfonyl)carbamate (28mg, crude) was added to dichloromethane (5mL). Then trifluoroacetic acid (1mL) was added. The mixture was reacted at rt for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated in vacuum to remove the solvent to afford a crude product, which was purified by liquid-phase preparative HPLC to afford the target compound (5.2mg, yield: 18%). LCMS_(ESI)_[M+H]+=408.1;_1H_NMR_(400MHz,_DMSO- d6) 3 8.77 (s, 1H), 8.53 (d, J= 9.2, 1H), 7.11 (d, J= 9.2, 1H), 6.62 (s, 2H), 5.41 (s, 2H), 4.12 (d, J= 6.8, 2H),_4.02_(s,_3H),_2.39-2.33_(m,_2_H),_1.73-1.61_(m,_3H),_1.13-1.06_(m,_2H). Example 15 Preparation of tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthyridine-4(1H)-carboxylate (compound 50): 2022412821   03 Aug 2026 NaBH(OAc)3, DCM MeOH / THF / H2O Zn / NH4CI Boc2O, DMAP 2) NH4OH Pd2(dba)3, xantphos, TEA dioxane Step 1: Preparation of 2-((4-bromo-2,6-difluorobenzyl)amino)ethan-1-ol 4-bromo-2,6-difluorobenzaldehyde (10g, 1eq.) and 2-aminoethan-1-ol (8.29g, 3eq.) were dissolved in dichloromethane (200mL). Acetic acid (5.43g, 2eq.) was added. The mixture was reacted at rt for 30 minutes. Sodium triacetoxyborohydride (19.18g, 2eq.) was added. The mixture was reacted at rt overnight. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford a crude product, which was purified by column chromatography (DCM / MeOH=10:1) to afford the target compound (8.5g, yield 70%). LCMS (ESI) [M+H]+=266.0; 1H NMR (400MHz, CDCI3) 5 7.13-7.06 (m, 2H), 3.87 (s, 2H), 3.68-3.62_(m,_2H),_2.77-2.69_(m,_2H). Step 2: Preparation of 2-((4-bromo-2,6-difluorobenzyl)(7-methoxy-3-nitro-1,8-naphthyridin-4-yl)amino)ethan-1-ol 5-chloro-2-methoxy-6-nitro-1,8-naphthyridine (5.00g, 1eq.) and 2-((4-bromo-2,6-difluorobenzyl)amino)ethan-1-ol (8.32g, 1.5eq.) were dissolved in dimethylformamide (100mL). Ethyldi(propane-2-yl)amine (10.78g, 4eq.) was added. The mixture was reacted at rt overnight. The completion of the reaction was monitored with LCMS. Water was added to the reaction mixture. A large amount of solid precipitated. The mixture was filtered. The filter cake was dried to afford the target compound (4.5g, yield 45%). LCMS_(ESI)_[M+H]+=468.9;_1H_NMR_(400MHz,_CDCl3)_5_9.23_(s,_1H),_8.10_(d,_J=9.0_Hz,_1H),_7.09_(d, _J=6.8_Hz,_2H),_6.99_(d,_J=9.1_Hz,_1H),_4.45_(s,_2H),_4.17_(s,_3H),_3.96-3.81_(m,_2H),_3.59-3.46_(m,_2H),_2.66_(s,_1H). Step 3: Preparation of 2-((3-amino-7-methoxy-1,8-naphthyridin-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethan-1-ol 2-((4-bromo-2,6-difluorobenzyl)(7-methoxy-3-nitro-1,8-naphthyridin-4-yl)amino)ethan-1-ol (4.5g,   1eq.) was dissolved in methanol (20mL), tetrahydrofuran (20mL) and water (10mL). Zn (3.13g, 5eq.) and NH4Cl (5.13g, 10eq.) were added. The mixture was reacted at rt overnight. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford a crude product, which was dissolved in dichloromethane (100mL), washed with water (100mL) and saturated brine (80mL), dried over 2022412821   03 Aug 2026 anhydrous sodium sulfate, filtered, and concentrated to afford the target compound (3.0g, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=440.9. Step 4: Preparation of 2-((3-amino-7-methoxy-1,8-naphthyridin-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethyl methanesulfonate 2-((3-amino-7-methoxy-1,8-naphthyridin-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethan-1-ol (1.2g, crude) was dissolved in dichloromethane (30mL). Triethylamine (829.3mg) was added. In an ice bath, methanesulfonyl chloride (469.4mg) was added. The mixture was reacted in an ice bath for 30 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (30mL), extracted with dichloromethane (30mLx2). The organic phases were combined, washed with saturated brine (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the target compound (1.2g, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=519.0. Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthyridine 2-((3-amino-7-methoxy-1,8-naphthyridin-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethyl methanesulfonate (1.5g, crude) was dissolved in acetonitrile (50mL). Caesium carbonate (2.83g) was added. The mixture was reacted at 50°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford a crude product, which was purified by column chromatography (DCM / EA=1:1) to afford the target compound (500mg, yield 41%). LCMS (ESI) [M+H]+=423.1; 1H NMR (400MHz, CDCI3) 5 8.50 (d, J=8.9 Hz, 1H), 8.39 (s, 1H), 7.17 (d, _J=7.0_Hz,_2H),_6.94_(d,_J=9.0_Hz,_1H),_4.32_(s,_2H),_4.11_(s,_3H),_3.37-3.30_(m,_2H),_3.09-3.02_(m,_2H). Step 6: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthyridine 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthyridine (300mg, 1eq.) and phenylmethanethiol (2.13g, 1.5eq.) were dissolved in dioxane (15mL). Tris((1E,4E)-1,5-diphenylpenta-1,4-diene-3-one) dipalladium (31.8mg, 0.1eq.), (5-(diphenylphosphino)-9,9-dimethyl-9H-xanthene-4-yl)diphenylphosphine (82.4mg, 0.2eq.) and triethylamine (216.2mg, 3eq.) were successively added. The atmosphere was replaced with argon three times. The mixture was reacted at 90°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to afford a crude product, which was purified by column chromatography to afford the target compound (300mg, yield 91%). LCMS_(ESI)_[M+H]+=465.2;_1H_NMR_(400MHz,_CDCl3)_5_8.48_(d,_J=8.9_Hz,_1H),_8.43_(s,_1H),_7.38-7.30_(m,_5H),_6.92_(d,_J=9.0_Hz,_1H),_6.85_(d,_J=8.2_Hz,_2H),_4.36_(s,_2H),_4.17_(s,_2H),_4.11_(s,_3H),_ 3.32-3.27_(m,_2H),_3.11-3.06_(m,_2H). Step 7: Preparation of tert-butyl 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthyridine-4(1H)-carboxylate 2022412821   03 Aug 2026 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthyridine (100mg, 1eq.) was dissolved in di-tert-butyl dicarbonate (5mL, 106.38eq.). 4-dimethylaminopyridine (100mg, 3.8eq.) was added. The mixture was reacted at 40°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to afford a crude product, which was purified by column chromatography to afford the target compound (100mg, yield 82%). LCMS_(ESI)_[M+H]+=565.3. Step 8: Preparation of tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthyridine-4(1H)-carboxylate Tert-butyl 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthyridine-4(1H)-carboxylate (230mg, 1eq.) was dissolved in tetrahydrofuran (5mL). Water (102.8mg, 14eq.) and acetic acid (171.2mg, 7eq.) were added. In an ice bath, 1,3-dichloro-5,5-dimethylhydantoin (240.8mg, 3eq.) was added. The mixture was reacted in an ice bath for 10 minutes. In an ice bath, the reaction mixture was slowly added dropwise to the ammonia solution (5mL). The mixture was reacted in an ice bath for 30 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was extracted with EA (20mL). The organic phase was concentrated under reduced pressure to afford a crude product, which was purified by preparative HPLC to afford the target compound (13.0mg, yield 6%). LCMS_(ESI)_[M+H]+=522.5;_1H_NMR_(400MHz,_MeOD- d4) 5 8.85 (s, 1H), 8.54 (d, J=9.1 Hz, 1H), 7.48 (d, J=7.0 Hz, 2H), 7.00 (d, J=9.1 Hz, 1H), 4.98 (s, 2H) ,_4.09_(s,_3H),_3.71-3.64_(m,_2H),_3.46-3.38_(m,_2H),_1.48_(s,_9H). Example 16 Preparation         of         3,5-difluoro-4-((8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)- yl)methyl)benzenesulfonamide (compound 66) Tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthyridine-4(1H)-carboxylate (10mg, 1eq.) was dissolved in dichloromethane (1mL). Trifluoroacetic acid (0.2mL) was added. The mixture was reacted at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to afford a crude product, which was purified by preparative chromatography to afford the target compound 3,5-difluoro-4-((8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide (4.4mg, yield 52%). LCMS_(ESI)_[M+H]+=422.1;_1H_NMR_(400MHz,_MeOD- d4)_5_8.54_(d,_J=9.1_Hz,_1H),_8.11_(s,_1H),_7.54_(t,_J=5.3_Hz,_2H),_6.99_(d,_J=9.1_Hz,_1H),_4.83_(s,_2H), _4.07_(s,_3H),_3.30-3.27_(m,_2H),_3.24-3.20_(m,_2H). Example 17 2022412821   03 Aug 2026 Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrido[2,3-h][1,6]naphthyridine-1(2H)- yl)methyl)benzenesulfonamide (compound 54): NaH, THF Step 1: Preparation of (4-chloro-7-methoxy-1,8-naphthyridin-3-yl)methanol Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (10g, 1eq.) was dissolved in dichloromethane (200mL). The atmosphere was replaced with nitrogen gas. The temperature was lowered to -68°C. A solution of diisobutylaluminium hydride in cyclohexane (86mL, 1M) was slowly added dropwise to the reaction mixture. The mixture was stirred at -68°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with saturated NH4C1 solution. The aqueous phase was extracted with EA (100mL^5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by column chromatography to afford the target product (5.5g, yield 83%). LCMS_(ESI)_[M+H]+=225.0. Step 2: Preparation of 4-chloro-7-methoxy-1,8-naphthyridine-3-carbaldehyde (4-chloro-7-methoxy-1,8-naphthyridin-3-yl)methanol (5.5g, 1eq.) was dissolved in dichloromethane (20mL). An active MnO2 was added (10.64g, 5eq.). The reaction mixture was stirred at 40°C overnight. The completion of the reaction was monitored with LCMS. The mixture was filtered through celite. The filtrate was washed with dichloromethane, and concentrated to afford a crude product, which was purified by column chromatography to afford the target compound (4.5g, yield 99%). LCMS_(ESI)_[M+H]+=223.0;_1H_NMR_(400MHz,_DMSO- d6) 5 10.47 (s, 1H), 9.20 (s, 1H), 8.67 (d, J=9.0 Hz, 1H), 7.37 (d, J=9.0 Hz, 1H), 4.10 (s, 3H). Step 3: Preparation of ethyl (E)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)acrylate Sodium hydride (808.5mg, 3eq.) was dissolved in tetrahydrofuran (20mL). In an ice bath, a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.81g, 1.2eq.) in tetrahydrofuran (3mL) was slowly added. The mixture was stirred for 30 minutes. Then 4-chloro-7-methoxy-1,8-naphthyridine-3-carbaldehyde (1.5g, 1eq.) dissolved in tetrahydrofuran (30mL) was added. The mixture was reacted at rt for 30 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with water (20mL), extracted with EA (30mL^2). The organic phases were combined, washed with saturated brine (30mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the target compound (1.5g, yield 76%). 2022412821   03 Aug 2026 LCMS (ESI) [M+H]+=293.0; 1H NMR (400MHz, CDCI3) 5 9.14 (s, 1H), 8.47 (d, J=9.0 Hz, 1H), 8.15 (d, _J=16.2_Hz,_1H),_7.11_(d,_J=9.0_Hz,_1H),_6.68_(d,_J=16.2_Hz,_1H),_4.32_(q,_J=7.1_Hz,_2H),_4.19_(s,_3H) ,_1.37_(t,_J=7.1_Hz,_3H). Step 4: Preparation of (E)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)acrylic acid Ethyl (E)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)acrylate (1.5g, 1eq.) was dissolved in tetrahydrofuran (30mL) and water (10mL). LiOH (613.6mg, 5eq.) was added. The mixture was reacted at rt overnight. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to remove tetrahydrofuran. The aqueous phase was adjusted with 1N HCl to a pH of 4. A large amount of solid precipitated. The mixture was filtered. The filter cake was dried to afford the target compound (1.3g, yield 96%). LCMS_(ESI)_[M+H]+=265.3;_1H_NMR_(400MHz,_DMSO- d6)_5_12.78_(s,_1H),_9.39_(s,_1H),_8.56_(d,_J=9.0_Hz,_1H),_7.94_(d,_J=16.1_Hz,_1H),_7.30_(d,_J=9.0_Hz,_1 H),_6.94_(d,_J=16.1_Hz,_1H),_4.07_(s,_3H). Step 5: Preparation of (E)-N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)acrylamide (E)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)acrylic acid (1.3g, 1eq.) was dissolved in dimethylformamide (30mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (2.24g, 1.2eq.) and ethyldi(propane-2-yl)amine (2.54g, 4eq.) were added. The mixture was reacted at rt for 30 minutes. (4-(benzylthio)-2,6-difluorophenyl)methanamine (1.3g, 1eq.) was added to the reaction mixture and reacted at rt for 1hr. The completion of the reaction was monitored with LCMS. Water (50mL) was added to the reaction mixture. A large amount of solid precipitated. The mixture was filtered. The filter cake was dried to afford the target compound (1.5g, yield 59%). LCMS_(ESI)_[M+H]+=512.2. Step 6: Preparation of N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)propanamide (E)-N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)acrylamide (1.5g, 1eq.) was dissolved in tetrahydrofuran (60mL) and water (20mL). 4-toluenesulfonyl hydrazide (5.45g, 10eq.) and sodium acetate trihydrate (3.99g, 10eq.) were added. The reaction mixture reacted at 80°C for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt. An aqueous sodium bicarbonate solution (60mL) was added. The resulting mixture was extracted with EA (80mL^2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude product, which was purified by column chromatography to afford the target compound (800mg, yield 53%). LCMS_(ESI)_[M+H]+=514.2. Step 7:     Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrido[2,3- h][1,6]naphthyridine-2(1H)-one N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthyridin-3-yl)propanamide (750mg, 1eq.) was dissolved in dimethylformamide (10mL). Caesium carbonate (1.43g, 3eq.) was added. The mixture was reacted at 100°C for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (20mL), and extracted with EA (30mL^2). The organic phases were combined, washed with saturated brine 2022412821   03 Aug 2026 (50mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford the target compound (300mg, yield 43%). LCMS (ESI) [M+H]+=478.2; 1H NMR (400MHz, CDCI3) 5 8.70 (s, 1H), 8.19 (d, J=9.1 Hz, 1H), 7.33-7.27_(m,_4H),_7.02-6.91_(m,_2H),_6.61_(t,_J=6.0_Hz,_2H),_5.36_(s,_2H),_4.15_(s,_3H),_4.05_(s,_2H),_2.94-2.91_(m,_2H),_2.71-2.68_(m,_2H). Step 8: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrido[2,3-h][1,6]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrido[2,3-h][1,6]naphthyridine-2(1H)-one (250mg, 1eq.) was dissolved in tetrahydrofuran (5mL). Water (132.1mg, 14eq.) and acetic acid (220.1mg, 7eq.) were added. In an ice bath, 1,3-dichloro-5,5-dimethylhydantoin (309.4mg, 3eq.) was added. The mixture was reacted in an ice bath for 10 minutes. In an ice bath, the reaction mixture was slowly added dropwise to the ammonia solution (5mL). The mixture was reacted in an ice bath for 30 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was extracted with EA (20mL). The organic phase was concentrated under reduced pressure to afford a crude product, which was purified by preparative chromatography to afford the target compound (93mg, yield 41%). LCMS_(ESI)_[M+H]+=435.1;_1H_NMR_(400MHz,_MeOD-d4)_5_8.68_(s,_1H),_8.48_(d,_J=9.2_Hz,_1H),_7.40-7.33_(m,_2H),_7.09_(d,_J=9.2_Hz,_1H),_5.50_(s,_2H),_4.10_(s,_3H),_2.99-2.92_(m,_2H),_2.72-2.64_(m,_2H). Example 18 Preparation of tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate (compound 52): 2022412821   03 Aug 2026 Step 1: Preparation of 7-methoxy-3-nitroquinolin-4-ol 7-methoxyquinolin-4-ol (1g, 1eq.) was dissolved in propionic acid (10mL). Nitric acid (70%, 1mL) was added. The reaction mixture was stirred at 140°C for 12hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was slowly poured into ice water to precipitate a solid. The mixture was filtered, and the resulting solid was washed with methanol three times, and rotary-evaporated to dryness to afford the target product (800mg, yield 63%). LCMS (ESI) [M+H]+=221.3; 1H NMR (400MHz, DMSO-d6) 5 12.77 (s, 1H), 9.14 (s, 1H), 8.29-8.02_(m,_1H),_7.26-7.01_(m,_2H),_3.89_(s,_3H). Step 2: Preparation of 4-chloro-7-methoxy-3-nitroquinoline 7-methoxy-3-nitroquinolin-4-ol (800mg, 1eq.) was dissolved in N,N-dimethylformamide (10mL). Sulfurous dichloride (0.66mL, 2.51eq.) was added to the reaction mixture. The resulting mixture was stirred at 25°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was poured into ice water. The mixture was adjusted with Na2CO3 solution to alkalinity, extracted with EA (20mL), and washed with saturated brine (20mL^3). The organic phases were dried and concentrated to afford the target product (600mg, yield 69%). LCMS_(ESI)_[M+H]+=239.2;_1H_NMR_(400MHz,_DMSO- d6)_5_9.34_(s,_1H),_8.34_(d,_J=9.1_Hz,_1H),_7.60_(dd,_J=7.2,_5.7_Hz,_2H),_4.02_(s,_3H). Step 3: Preparation of N-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-3-nitroquinolin-4-amine 4-chloro-7-methoxy-3-nitroquinoline (2.6g, 1eq.) was dissolved in N,N-dimethylformamide (30mL). (4-(benzylthio)-2,6-difluorophenyl)methanamine (4.34g, 1.5eq.) and N,N-diisopropylethylamine (4.22g, 3eq.) were successively added. The mixture was reacted at 25°C under stirring for 12hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filter cake was washed with acetonitrile. The resulting solid was dried to afford the target product (2g, yield 39%). LCMS_(ESI)_[M+H]+=468.2. Step 4: Preparation of N4-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxyquinoline-3,4-diamine N-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-3-nitroquinolin-4-amine (2g,   1eq.) was dissolved in tetrahydrofuran (10mL), methanol (10mL), and water (5mL). NH4Cl (2.29g, 10eq.) and zinc powder (1.4g, 5eq.) was added. The mixture was stirred at 25°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filtrate was rotary-evaporated to dryness, washed with water, extracted with EA. The organic phase was dried and concentrated to afford the target product (1.5g, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=438.2. Step 5: Preparation of (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-7-methoxyquinolin-3-yl)glycine N4-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxyquinoline-3,4-diamine (1g, crude, obtained from the above step reaction) and ethyl 2-oxoacetate (466.7mg) were dissolved in methanol (10mL). The mixture was stirred for 1hr. Sodium cyanoborohydride (424.0mg) was added. The mixture was reacted at 25°C under stirring for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with water, extracted with dichloromethane (20mL^3). The organic phases were dried and concentrated to afford the target product (1g, crude), which was not further purified but directly used in the next step reaction. 2022412821   03 Aug 2026 LCMS_(ESI)_[M+H]+=496.3. Step 6: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c]quinolin-2(1H)-one (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-7-methoxyquinolin-3-yl)glycine (1g, crude, obtained from the above step reaction) was dissolved in tetrahydrofuran (10mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (1.45g) was added. The mixture was stirred at room temperature for 1hr. N,N-diisopropylethylamine (740.6mg) was added. The resulting mixture was reacted at 25°C under stirring for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was washed with water (10mL), and extracted with EA (20mL). The organic phase was dried and concentrated to afford a crude product, which was purified by column chromatography to afford the target compound (600mg). LCMS_(ESI)_[M+H]+=478.2. Step 7: Preparation of tert-butyl 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c]quinolin-2(1H)-one (300mg, 1eq.), ditert-butyl dicarbonate(5mL) and 4-dimethylaminopyridine (230.25mg, 3eq.) were stirred at 40°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to afford a crude product, which was purified by flash chromatography to afford the target product (270mg, yield 74%). LCMS_(ESI)_[M+H]+=578.1. Step 8: Preparation of tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate Tert-butyl 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate (270mg, 1eq.) was dissolved in tetrahydrofuran (5mL). Glacial acetic acid (196.5mg, 7eq.) and water (117.9mg, 14eq.) were added. In an ice bath, 1,3-dichloro-5,5-dimethylhydantoin (276.3mg, 3eq.) was added. The mixture was stirred at 0°C for 6 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was added to the ammonia solution (6mL). The resulting mixture was stirred for 6 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was adjusted with 1M HCl to neutral pH, and extracted with EA (5mL^2). The aqueous phase was concentrated to precipitate a solid. The solid was separated by filtering. The filtrate was purified by preparative HPLC to afford the target compound (22.4mg, yield 9%). LCMS_(ESI)_[M+H]+=534.9;_1H_NMR_(400MHz,_MeOD- d4) 5 8.92 (s, 1H), 8.13 (d, J=9.3 Hz, 1H), 7.37 (d, J=2.3 Hz, 1H), 7.34 (d, J=9.3 Hz, 1H), 7.27 (d, J= 7.2_Hz,_2H),_5.59_(s,_2H),_4.36_(s,_2H),_3.96_(s,_3H),_1.54_(s,_9H). Example 19 Preparation           of           3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)- yl)methyl)benzenesulfonamide (compound 51): 2022412821   03 Aug 2026 Tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)- carboxylate (8mg, 1eq.) was dissolved in dichloromethane (1mL). Trifluoroacetic acid (1mL) was added. The reaction mixture was stirred at rt for 1hr. The completion of the reaction was monitored with LCMS. reaction mixture was concentrated to afford a crude product, which was purified by preparative HPLC to afford the target compound (1.4mg, yield 21%). LCMS (ESI) [M+H]+=434.9; 1H_NMR_(400MHz, MeOD-d4) 5 8.54 (s, 1H), 8.12 (d, J=9.5 Hz, 1H), 7.397.32 (m, 4H), 5.55 (s, 2H), 3.98 (s, 3H), 3.85 (s, 2H). Example 20 Preparation             of             4-((8-ethoxy-2-oxopyrido[2,3-h][1,6]naphthyridine-1(2H)-yl)methyl)-3,5- difluorobenzenesulfonamide (compound 63): Step 1: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-ethoxypyrido[2,3-h][1,6]naphthyridine-2(1H)-one 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carbaldehyde (120mg, 1eq.) was dissolved in ethanol (15mL). 2-(dimethoxyphosphoryl)ethyl acetate (198mg, 3.4eq.) and K2CO3 (203mg, 5eq.) were added. The mixture was reacted at 85°C for 36hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by flash silica gel column chromatography to afford the target product (100mg, yield: 76%). LCMS_(ESI)_[M+H]+=446.0. Step 2: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-ethoxypyrido[2,3-h][1,6]naphthyridine-2(1H)-one 2022412821   03 Aug 2026 1-(4-bromo-2,6-difluorobenzyl)-8-ethoxypyrido[2,3-h][1,6]naphthyridine-2(1H)-one (90mg, 1eq.) was dissolved in dioxane (5mL). (4-methoxyphenyl)methanethiol (62mg, 2eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23mg, 0.2eq.), tris(dibenzylideneacetone)dipalladium (37mg, 0.2eq.) and N,N-diisopropylethylamine (78mg, 3eq.) were added. The mixture was reacted under the protection of nitrogen gas at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by flash silica gel column chromatography to afford the target product (70mg, yield: 66%). LCMS_(ESI)_[M+H]+=520.1. Step 3:     Preparation of 4-((8-ethoxy-2-oxopyrido[2,3-h][1,6]naphthyridine-1(2H)-yl)methyl)-3,5- difluorobenzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-ethoxypyrido[2,3-h][1,6]naphthyridine-2(1H)-one (65mg, 1eq.), acetic acid (53mg, 7eq.), water (32mg, 14eq.) were dissolved in tetrahydrofuran (5mL). 1,3-dichloro-5,5-dimethylhydantoin (74mg, 3eq.) was added at 0°C. The mixture was reacted at 0°C for 1hr, followed by adding ammonia solution (0.5mL), then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by preparative HPLC to afford the target compound (2.6mg, yield: 4.7%). LCMS_(ESI)_[M+H]+=447.1;_1H_NMR_(400MHz,_DMSO- d6) 3 9.15 (s, 1H), 8.71 (d,L=9.6 Hz, 1H), 8.20 (d,_7=9.2 Hz, 1H), 7.62 (s, 2H), 7.43 (d,L=7.2 Hz, 2H) ,_7.09_(d,_J=9.6_Hz,_1H),_6.69_(d,_J=9.6_Hz,_1H),_5.77_(s,_2H),_4.53_(q,_J=7.1_Hz,_2H),_1.41_(t,_J=7.2_H z,_3H). Example 21 Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide (compound 49): Step 1: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-2(1H)-one 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3-c][1,8]naphthyridine-2(1H)-one (50mg, 1eq.) was dissolved in ethanol (5mL). Then sodium borohydride (11mg, 3eq.) was added. The mixture was reacted at 25°C under stirring for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (10mL), and extracted with EA (50mL^3). The organic phases were washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford a crude product (50mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=509.1. 2022412821   03 Aug 2026 Step 2: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-1(2H)-yl)methyl)benzenesulfonamide To a 25mL round-bottom flask were added 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthyridine-2(1H)-one (20mg, crude, obtained from the above step reaction), tetrahydrofuran (10mL), acetic acid (10mg), water (10mL). While the solution was cooled in ice water, 1,3-dichloro-5,5-dimethylhydantoin (23mg) was added. The resulting mixture was reacted under stirring for 60 minutes, followed by adding ammonia solution (1mL). The stirring continued for 60 minutes. Sodium borohydride (15mg, 10eq.) was added. After the completion of the reaction, the reaction mixture was washed with water and extracted with EA. The EA layer was dried, and concentrated to afford a crude product, which was purified by liquid chromatography to afford the target compound (2.1mg). LCMS_(ESI)_[M+H]+=436.1;_1HNMR_(400MHz,_DMSO- d6) 3 8.55 (s, 1H), 8.44 (d, J=9.2 Hz, 1H), 7.32 (d, J=6.8 Hz, 2H), 7.02 (d, J=9.2 Hz, 1H), 6.44 (s, 1H) ,_5.32_(s,_2H),_3.96_(s,_3H),_3.70_(s,_2H). Example 22 Preparation          of          4-((8,9-dimethoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)-yl)methyl)-3,5- difluorobenzenesulfonamide (compound 31): Step 1: Preparation of 2-(((3,4-dimethoxyphenyl)amino)methylene)malonate diethyl 3,4-dimethoxyaniline (7g, 1eq.) and 1,3-diethyl 2-(ethoxymethylene)malonate (10g, 1.01eq.) were added to ethanol (200mL). The mixture was stirred at rt for 4hrs. After the completion of the reaction, the reaction mixture was directly distilled under reduced pressure to remove the solvent to afford a crude target compound (18g), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=324.1. Step 2: Preparation of ethyl 4-chloro-6,7-dimethoxyquinoline-3-carboxylate 2-(((3,4-dimethoxyphenyl)amino)methylene)malonate diethyl (18g, crude, obtained from the above step reaction) 2022412821   03 Aug 2026 and phosphorus oxychloride (8mL) were placed in a flask (100mL) and warmed to 100°C. The mixture was reacted under stirring for 5hrs. LCMS monitoring indicated the completion of the reaction, the mixture was cooled to rt and slowly added dropwise to a flask containing 200mL of water. After the completion of the addition, the mixture was cooled, gradually adjusted with an aqueous sodium bicarbonate solution to neutrality, and extracted with EA (200mLx2). The organic phases were combined, washed with brine, was concentrated in vacuum to afford a crude target compound (16g), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=296.1. Step 3: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinoline-3-carboxylate Ethyl 4-chloro-6,7-dimethoxyquinoline-3-carboxylate (1g, crude, obtained from the above step reaction) was dissolved in acetonitrile (20mL). Then K2CO3 (1g) and (4-bromo-2,6-difluorophenyl)methanamine (0.79g) were added. The mixture was reacted under the protection of nitrogen gas at 100°C under refluxing for 20hrs. LCMS monitoring indicated the completion of the reaction, the reaction mixture was rotary-evaporated to dryness, and diluted with EA. The organic phase was washed with water, dried over anhydrous sodium sulfate, and rotary-evaporated to dryness to afford a crude product, which was purified by flash chromatography to afford the target compound (0.68g). LCMS_(ESI)_[M+H]+=481.0. Step 4: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinolin-3-yl)methanol Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinoline-3-carboxylate (150mg, 1eq.) was dissolved in ethanol (15mL). Sodium borohydride (60mg, 5eq.) was added. The mixture was reacted at 25°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was poured into water, extracted with EA. The organic phase was dried over anhydrous sodium sulfate, concentrated to dryness, and purified by silica gel column chromatography to afford the target compound (100mg, yield: 72%). LCMS_(ESI)_[M+H]+=439.0. Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinolin-3-yl)methanol (100mg, 1eq.) was dissolved in dichloromethane (10mL). Triphosgene (219mg, 3.2eq.) and N,N-diisopropylethylamine (159mg, 5.4eq.) were added. The mixture was reacted at 25°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by silica gel column chromatography to afford the target compound (85mg, yield: 80%). LCMS_(ESI)_[M+H]+=465.0. Step 6: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one 1-(4-bromo-2,6-difluorobenzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (85mg, 1eq.) was dissolved in dioxane (10mL). (4-methoxyphenyl)methanethiol (55mg,     2eq.), tris(dibenzylideneacetone)dipalladium (18mg, 0.1eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (23mg, 0.2eq.) and N,N-diisopropylethylamine (71mg, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and 2022412821   03 Aug 2026 purified by silica gel column chromatography to afford the target compound (50mg, yield: 51%). LCMS_(ESI)_[M+H]+=539.2. Step 7: Preparation of 4-((8,9-dimethoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)-yl)methyl)-3,5-difluorobenzenesulfonamide 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (50mg, 1.0eq.), acetic acid (28.0mg, 5eq.), water (24mL) were dissolved in tetrahydrofuran (15mL). 1,3-dichloro-5,5-dimethylhydantoin (19mg, 1eq.) was added at 0°C. The mixture was reacted at 0°C for 2hrs, followed by adding ammonia solution (0.5mL), then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by preparative HPLC to afford the target compound (2.7mg, yield: 6%). LCMS (ESI) [M+H] +=466.0; 1H NMR (400MHz, CD3OD) d 8.69 (s, 1H), 7.52 (s, 1H), 7.50- 7.43_(m,_2H),_7.25_(d,_J=8.8_Hz,_1H),_6.87_(d,_J=8.8_Hz,_1H),_5.71_(s,_2H),_5.34_(s,_2H),_4.07_(s,_3H),_ 4.02_(s,_3H). Example 23 Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- yl)methyl)benzenesulfonamide (compound 30): O EtOH POCl3 Step 1: Preparation of diethyl 2-((3-methoxyphenyl)amino)methylene)malonate 3-methoxyaniline (10.0g, 1eq.) was dissolved in ethanol (100mL). Diethyl 2-(ethoxymethylene)malonate (21g, 2022412821   03 Aug 2026 1.2eq.) was added. The mixture was reacted at 90°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to dryness to afford a crude target compound (20g), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=294.1. Step 2: Preparation of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate : diethyl 2-((3-methoxyphenyl)amino)methylene)malonate (5g, crude, obtained from the above step reaction) was dissolved in phosphorus oxychloride (15mL). The mixture was reacted at 110°C for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to dryness to afford a mixture of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate and ethyl 4-chloro-5-methoxyquinoline-3-carboxylate (3.8g), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=266.0. Step 3: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-carboxylate The mixture of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate and ethyl 4-chloro-5-methoxyquinoline-3-carboxylate (2g, the mixture obtained from the above step reaction) was dissolved in N,N-dimethylformamide (10mL). 1-(4-bromo-2,6-difluorophenyl)methanamine (1.84g) and N,N-diisopropylethylamine (2.92g, 3eq.) were added. The mixture was reacted at 50°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, poured into water, and extracted with EA. The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by silica gel column chromatography to afford a mixture of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-carboxylate and ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-5-methoxyquinoline-3-carboxylate (1.6g). LCMS_(ESI)_[M+H]+=451.0. Step 4: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinolin-3-yl)methanol The mixture of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-carboxylate and ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-5-methoxyquinoline-3-carboxylate (1.6g, the mixture obtained from the above step reaction) was dissolved in ethanol (50mL). Sodium borohydride (671mg, 5.0eq.) was added. The mixture was reacted at 50°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, quenched with water, extracted with EA. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by silica gel column chromatography to afford a mixture of (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinolin-3-yl)methanol        and        (4-((4-bromo-2,6- difluorobenzyl)amino)-5-methoxyquinolin-3-yl)methanol (400mg). LCMS_(ESI)_[M+H]+=409.1. Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one The mixture of ((4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinolin-3-yl)methanol and (4-((4-bromo-2,6-difluorobenzyl)amino)-5-methoxyquinolin-3-yl)methanol (400mg, the mixture obtained from the above step reaction) was dissolved in dichloromethane (10mL). Triphosgene (870mg, 3eq.) and N,N-diisopropylethylamine (632mg, 5eq.) were added. The mixture was reacted at 25°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with water, extracted with EA. The organic phase was dried over 2022412821   03 Aug 2026 anhydrous sodium sulfate and filtered. The filtrate was concentrated, purified by silica gel column chromatography to afford 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (70mg) and 1-(4-bromo-2,6-difluorobenzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (60mg). LCMS_(ESI)_[M+H]+=435.1. Step 6: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (65mg, 1eq.) was dissolved in dioxane (5mL). (4-methoxyphenyl)methanethiol (46mg, 2eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17mg,   0.2eq.), tris(dibenzylideneacetone)dipalladium (27mg,   0.2eq.) and N,N- diisopropylethylamine (58mg, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, and purified by silica gel column chromatography to afford the target compound (60mg, yield 79%). LCMS_(ESI)_[M+H]+=509.1. Step 7:     Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- yl)methyl)benzenesulfonamide A mixture of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (30mg, 1.0eq.), acetic acid (25mg, 7.0eq.), and water (15mL) was dissolved in tetrahydrofuran (5mL). 1,3-dichloro-5,5-dimethylhydantoin (35mg, 3eq.) was added at 0°C. The mixture was reacted at 0°C for 1hr, followed by adding ammonia solution (0.5mL), then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, and purified by preparative HPLC to afford the target compound (5.8mg, yield 22%). LCMS (ESI) [M+H]+=436.0; 1H NMR (400MHz, DMSO) 5 8.72 (s, 1H), 8.22 (d, J=9.6 Hz, 1H), 7.62 (s, _2H),_7.49-7.43_(m,_3H),_7.29_(dd,_J=9.2,_2.4_Hz,_1H),_5.50_(s,_2H),_5.27_(s,_2H),_3.94_(s,_3H). Example 24 Preparation            of            3,5-difluoro-4-((10-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- yl)methyl)benzenesulfonamide (compound 68): Step 1: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one 1-(4-bromo-2,6-difluorobenzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (60mg, 1eq.) was dissolved in dioxane (5mL). (4-methoxyphenyl)methanethiol (43mg, 2eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (16mg,   0.2eq.), tris(dibenzylideneacetone)dipalladium (25mg,   0.2eq.) and N,N- diisopropylethylamine (53mg, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the 2022412821   03 Aug 2026 reaction was monitored with LCMS. The reaction mixture was cooled to rt, concentrated under reduced pressure, and purified by silica gel column chromatography to afford the target compound (50mg), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=509.1. Step 2:     Preparation of 3,5-difluoro-4-((10-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- yl)methyl)benzenesulfonamide A mixture of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (30mg, 1.0eq.), acetic acid (25mg, 7.1eq.), and water (15mg, 14.1eq.) was dissolved in tetrahydrofuran (5mL). 1,3-dichloro-5,5-dimethylhydantoin (35mg, 3eq.) was added at 0°C. The mixture was reacted at 0°C for 1hr, followed by adding ammonia solution (0.2mL), then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, and purified by preparative HPLC to afford the target compound (2.0mg, yield: 8%). LCMS (ESI) [M+H]+=436.0; 1H NMR (400MHz, DMSO) 5 8.74 (s, 1H), 7.73 (t, J=8.0 Hz, 1H), 7.64 (d, _J=8.0_Hz,_1H),_7.60_(s,_2H),_7.41_(d,_J=6.4_Hz,_2H),_7.20_(d,_J=8.0_Hz,_1H),_5.21_(s,_2H),_5.08_(s,_2H) ,_4.05_(s,_3H). Example 25 Preparation of 6-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)pyridine-3-sulfonamide (compound 70): Step 1: Preparation of ethyl 4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (200mg, 1eq.) and (5-bromopyridin-2-yl)methanamine (210.4mg, 1.5e.q) and N,N-diisopropylethylamine (289.0mg, 3eq.) were dissolved in ethanol (50mL). The mixture was heated to 90°C and reacted for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, and purified by flash silica gel column chromatography to afford the target compound (150mg, yield: 48%). LCMS_(ESI)_[M+H]+=417.1. 2022412821   03 Aug 2026 Step 2: Preparation of (4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol Ethyl 4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (150mg, 1eq.) was added to dichloromethane (20mL). A solution of diisobutylaluminium hydride in tetrahydrofuran (1mol / L, 7.2mL, 20eq.) was added at -78°C. The mixture was reacted at -78°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with water, extracted with dichloromethane (100mL^2). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by flash chromatography to afford the target compound (100mg, yield: 74%). LCMS_(ESI)_[M+H]+=377.1. Step 3: Preparation of 1-((5-bromopyridin-2-yl)methyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol (100mg, 1eq.) was added to tetrahydrofuran (20mL). N,N-diisopropylethylamine (335.4mg, 9.74eq.) was added. Triphosgene (154.3mg, 1.95eq.) was added. The mixture was reacted at rt for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with water (20mL), extracted with EA (50mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography to afford the target compound (60mg, yield: 56%). LCMS_(ESI)_[M+H]+=401.2. Step 4: Preparation of 8-methoxy-1-((5-((4-methoxybenzyl)thio)pyridin-2-yl)methyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one 1-((5-bromopyridin-2-yl)methyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (60mg, 1eq.), (4-methoxyphenyl)methanethiol (46.2mg, 2eq.), tris(dibenzylideneacetone)dipalladium (6mg, 0.04eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (17.4mg, 0.2eq.) and N,N-diisopropylethylamine (97.5mg, 5eq.) were added to 1,4-dioxane (10mL). The atmosphere was replaced with nitrogen gas three times. The mixture was reacted at 90°C for 3hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, then diluted with water (20mL), and extracted with EA. The organic phase was combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography to afford the target compound (50mg, yield: 70%). LCMS_(ESI)_[M+H]+=475.1. Step 5: Preparation of 6-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)pyridine-3-sulfonamide To a 25mL round-bottom flask were added 8-methoxy-1-((5-((4-methoxybenzyl)thio)pyridin-2-yl)methyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (50mg, 1.0eq.), tetrahydrofuran (10mL), acetic acid (8.0mg, 1.3eq.), and water (4.0mg, 2.1eq.). 1,3-dichloro-5,5-dimethylhydantoin (43.1mg, 2.1eq.) was added at 0°C. The mixture was reacted for 1hr. The completion of the reaction was monitored with LCMS. Ammonia solution (1mL) was added. The mixture was reacted at rt for 1hr. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, and purified by analytic preparative HPLC to afford the target compound (3.8mg, yield: 9%). LCMS_(ESI)_[M+H]+=402.1;_1H_NMR_(400MHz,_DMSO- 2022412821   03 Aug 2026 d6) 5 8.88 (d, J=2.2 Hz, 1H), 8.79 (s, 1H), 8.42 (d, J=9.2 Hz, 1H), 8.15 (m, J=8.2,1H), 7.66 (d, J=8.4 Hz,_1H),_7.59_(s,_2H),_7.07_(d,_J=9.2_Hz,_1H),_5.55_(s,_2H),_5.51_(s,_2H),_4.00_(s,_3H). Example 26 Preparation           of           3-fluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)methyl)benzenesulfonamide (compound 71): Step 1: Preparation of ethyl 4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (500mg,      1eq.),      1-(4-bromo-2- fluorophenyl)methanamine (381mg, 1eq.) and N,N-diisopropylethylamine (2.45g, 10.1eq.) were dissolved in acetonitrile (20mL). The mixture was warmed to 70°C and reacted for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, diluted with water (20mL), extracted with EA (50mL^3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to afford the target compound (500mg, yield: 61%). LCMS_(ESI)_[M+H]+=434.0. Step 2: Preparation of (4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol Ethyl 4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (250mg, 1.0eq.) was dissolved in ethanol (20mL). Then sodium borohydride (211mg, 9.7eq.) was added. The mixture was reacted at 60°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, quenched with water, and distilled under reduced pressure to remove ethanol. Water (50mL) was added to the residue. The mixture was extracted with EA (100mL^2). The organic phases were combined, and washed with brine five times, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated in vacuum, and purified by flash silica gel purified by column chromatography to afford the target compound (100mg, yield: 44%). LCMS_(ESI)_[M+H]+=392.0. Step 3:     Preparation of 1-(4-bromo-2-fluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4- c][1,8]naphthyridin-2-one (4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol (100mg, 1eq.) was added to tetrahydrofuran (10mL). N,N-diisopropylethylamine (329mg, 10eq.) was added. Triphosgene (378mg, 5eq.) was added. The mixture was reacted at rt for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with water (10mL), and extracted with EA (20mL^3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to afford the target compound (35mg, 2022412821   03 Aug 2026 yield: 32%). LCMS_(ESI)_[M+H]+=418.0. Step 4: Preparation of 1-(2-fluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one 1-(4-bromo-2-fluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (33mg, 1eq.) was dissolved in dioxane (10mL). (4-methoxyphenyl)methanethiol (24mg,     2eq.), tris(dibenzylideneacetone)dipalladium (10mg, 0.1eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (9mg, 0.2eq.) and N,N-diisopropylethylamine (30mg, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to dryness, and purified by thin-layer chromatography to afford the target compound (22mg, yield: 56%). LCMS_(ESI)_[M+H]+=492.1. Step 5: Preparation of 3-fluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)benzenesulfonamide 1-(2-fluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (20mg, 1.0eq.), acetic acid (16mg, 6.6eq.), water (10mg, 13.6eq.) were dissolved in tetrahydrofuran (5mL). 1,3-dichloro-5,5-dimethylhydantoin (16mg, 2eq.) was added at 0°C. The mixture was reacted at 0°C for 2hrs, followed by adding ammonia solution (0.5mL), then reacted at 0°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to dryness, and purified by preparative HPLC to afford the target compound (2.5mg, yield: 15%). LCMS (ESI) [M+H]+=419.0; 1H NMR (400MHz, DMSO) 5 8.79 (s, 1H), 8.41 (d, J=9.2 Hz, 1H), 7.65-7.56_(m,_3H),_7.48_(s,_2H),_7.08_(d,_J=9.2_Hz,_1H),_5.43_(s,_4H),_4.01_(s,_3H). Example 27 Preparation              of              4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)methyl)benzenesulfonamide (compound 67): Step 1: Preparation of ethyl 4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (500mg, 1.0eq.) was dissolved in acetonitrile (30mL). Then K2CO3 (1.3g, 5.0eq.), and (4-bromophenyl)methanamine (523.2mg, 1.5eq.) were added. The reaction was performed under the protection of nitrogen gas at 70°C for 5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, diluted with water and extracted with EA. The organic phase was dried over anhydrous sodium sulfate, and concentrated to afford a crude product, which was purified by flash chromatography to afford the target compound (0.5g, yield: 64%). 2022412821   03 Aug 2026 LCMS_(ESI)_[M+H]+=416.1. Step 2: Preparation of (4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol Ethyl 4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (300mg, 1.0eq.) was dissolved in ethanol (10mL). Sodium borohydride (245.4mg, 9.0eq.) was added. The atmosphere was replaced with nitrogen gas, and the reaction system was stirred at 70°C for 10hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, quenched with saturated aqueous NH4Cl solution, and extracted with EA. The organic phase was combined, washed with saturated NaHCO3, and concentrated to afford a crude product, which was purified by flash chromatography to afford the target compound (200mg, yield: 74%). LCMS_(ESI)_[M+H]+=376.0. Step 3: Preparation of 1-(4-bromobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol (300mg, 1.0eq.) was dissolved in dichloromethane (10mL). Then N,N-diisopropylethylamine (243mg, 2.35eq.), triphosgene (237mg, 1.0eq.) were successively added at 0°C. The mixture was reacted at 0°C under stirring for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with saturated brine (20mL), extracted with dichloromethane (10mL^2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and distilled under reduced pressure to remove the solvent to afford a crude product, which was purified by flash chromatography to afford the target compound (200mg, yield 62%). LCMS_(ESI)_[M+H]+=402.0. Step 4: Preparation of 8-methoxy-1-(4-((4-methoxybenzyl)thio)benzyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one 1-(4-bromobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (200mg, 1.0eq.) was dissolved in dioxane (10mL). (4-methoxyphenyl)methanethiol (154mg, 2.0eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57mg,   0.2eq.), tris(dibenzylideneacetone)dipalladium (44mg,   0.1eq.) and N,N- diisopropylethylamine (193mg, 3eq.) were added. The mixture was reacted at 90°C for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, concentrated, and purified by flash silica gel column chromatography to afford the target compound (100mg, yield: 42%). LCMS_(ESI)_[M+H]+=474.1. Step 5:     Preparation of 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)methyl)benzenesulfonamide 8-methoxy-1-(4-((4-methoxybenzyl)thio)benzyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (90mg, 1.0eq.), acetic acid (80mg, 7.0eq.), water (50mg, 14.6eq.) were dissolved in tetrahydrofuran (15mL). 1,3-dichloro-5,5-dimethylhydantoin (112mg, 3.0eq.) was added at 0°C. The mixture was reacted at 25°C for 1hr, followed by adding ammonia solution (0.5mL), then reacted at 25°C for 10 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated, and purified by preparative HPLC to afford the target compound (13.9mg, yield: 18%). LCMS_(ESI)_[M+H]+=401.1;_1HNMR_(400MHz,_MMSO- d6) 5 8.79 (s, 1H), 8.37 (d, J=8.0 Hz, 1H), 7.74 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.0 Hz, 2H), 7.33 (s, 2H) ,_7.02_(d,_J=8.0_Hz,_1H),_5.51_(s,_2H),_5.43_(s,_2H),_3.99_(s,_3H). 2022412821   03 Aug 2026 Example 28 Preparation of (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)methyl)phenyl)boronic acid (compound 41): Pd(dppf)CI2, NaOAc dioxane, H2O HO' 'OH 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (100mg, 1.0eq., prepared in step 4, Example 6) was dissolved in 1,4-dioxane (10mL). Bis(pinacolato)diboron (76mg, 1.3eq.), (1,1'-bis(diphenylphosphino)ferrocene)dichloropalladium(34mg, 0.2eq.), sodium acetate (38mg, 2.0eq.) were added. The mixture was reacted at 90°C under the protection of nitrogen gas for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to dryness, and purified by preparative HPLC to afford the target compound (15.8mg, yield 17%). LCMS (ESI) [M+H]+=402.1; 1H NMR (400MHz, MeOD) 5 8.71 (s, 1H), 8.62 (d, J=9.2 Hz, 1H), 7.15-7.04_(m,_3H),_5.57_(s,_2H),_5.31_(s,_2H),_4.13_(s,_3H). Example 29 Preparation of (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)phenyl)phosphonic acid (compound 43): Step 1: Preparation of diethyl (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)phenyl)phosphonate 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (25mg, 1.0eq., prepared in step 4, Example 6) was added to ethanol (5mL). Diethyl phosphonate (12mg, 1.5eq.), N-methyldicyclohexylamine (18mg, 1.5eq.), triphenylphosphine (24mg, 1.6eq.) and palladium acetate (6mg, 0.5eq.) were added. Under nitrogen, the mixture was reacted at 80°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, diluted with water (5mL), extracted with EA (20mLx2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by preparative chromatography to afford the target compound (15mg, yield: 53%). LCMS_(ESI)_[M+H]+=494.1. Step 2: Preparation of (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)methyl)phenyl)phosphonic acid Diethyl                       (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)methyl)phenyl)phosphonate (15mg,   1.0eq.) was added to anhydrous dichloromethane (5mL). Trimethylbromosilane (0.46mg, 0.1eq.) was added. Under the protection of nitrogen gas, the mixture was reacted at 2022412821   03 Aug 2026 rt for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with methanol (3mL), and stirred at rt for 1hr. LCMS monitoring indicated the completion of the reaction, the reaction mixture was purified by preparative HPLC to afford the target compound (1.5mg, yield 11%). LCMS (ESI) [M+H]+=438.1; 1H NMR (400MHz, MeOD) 5 8.72 (s, 1H), 8.63 (d, J=9.2 Hz, 1H), 7.28-7.25_(m,_2H),_7.15_(d,_J=9.2Hz,_1H),_5.57_(s,_2H),_5.30_(s,_2H),_4.12_(s,_3H). Example 30 Preparation of tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate (compound 69) SBn SBn Step 1: Preparation of 5-(((4-fluoro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione 2,2-dimethyl-1,3-dioxane-4,6-dione (5.11g, 1eq.) was dissolved in triethoxymethane (15.75g, 3eq.). The mixture was stirred at 90°C for 1hr and cooled down to70°C. 4-fluoro-3-methoxyaniline (5g, 1eq.) was added. The mixture was reacted at 70°C for 0.5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, and filtered. The filter cake was washed with petroleum ether, and dried to afford the target compound (10g, yield: 95%). 1H_NMR_(400MHz,_DMSO- d6)_5_11.24_(d,_J=14.5_Hz,_1H),_8.59_(d,_J=14.5_Hz,_1H),_7.50_(dd,_J=7.6,_2.6_Hz,_1H),_7.27_(dd,_J=11.1 ,_8.8_Hz,_1H),_7.19-7.03_(m,_1H),_3.90_(s,_3H),_1.68_(s,_6H). Step 2: Preparation of 6-fluoro-7-methoxyquinolin-4-ol 5-(((4-fluoro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10g, 1eq.) was dissolved in diphenylether (40mL). The mixture was stirred at 200°C for 6hrs. The completion of the reaction was monitored with LCMS. The reaction system was recovered to rt, and filtered. The filter cake was washed with petroleum ether to afford the target product (6.3g, yield: 96%). LCMS_(ESI)_[M+H]+=194.1;_1H_NMR_(400MHz,_DMSO-d6)_5_11.65_(s,_1H),_7.92- 7.81_(m,_1H),_7.71_(d,_J=11.8_Hz,_1H),_7.13_(d,_J=7.4_Hz,_1H),_5.97_(d,_J=7.4_Hz,_1H),_3.94_(s,_3H). Step 3: Preparation of 6-fluoro-7-methoxy-3-nitroquinolin-4-ol 6-fluoro-7-methoxyquinolin-4-ol (3g, 1eq.) was dissolved in propionic acid (50mL). Nitric acid (70%, 5mL) was 2022412821   03 Aug 2026 added. The mixture was reacted at 140°C for 12hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, diluted with water, filtered. The filter cake was washed with water and EA to afford the target compound (2.4g, yield: 65%). LCMS_(ESI)_[M+H]+=239.3;_1H_NMR_(400MHz,_DMSO- d6) 5 12.89 (s, 1H), 9.17 (s, 1H), 7.90 (d, J=11.5 Hz, 1H), 7.32 (d, J= 7.3 Hz, 1H), 3.98 (s, 3H). Step 4: Preparation of 4-chloro-6-fluoro-7-methoxy-3-nitroquinoline 6-fluoro-7-methoxy-3-nitroquinolin-4-ol (2.4g, 1eq.) was dissolved in dichloromethane (70mL) and N,N-dimethylformamide (20mL). Sulfonyl dichloride (3g, 2.2eq.) was added. The mixture was stirred at 40°C for 3hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to afford a crude product, which was washed with water to precipitate a solid. The mixture was filtered. The filter cake was washed with water and EA to afford the target compound (2.5g, yield: 96%). LCMS_(ESI)_[M+H]+=257.3. Step 5: Preparation of N-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxy-3-nitroquinolin-4-amine 4-chloro-6-fluoro-7-methoxy-3-nitroquinoline (2.8g, 1eq.) and (4-(benzylthio)-2,6-difluorophenyl)methanamine (2.89g, 1eq.) were dissolved in tetrahydrofuran (40mL). N,N-diisopropylethylamine (4.23g, 3eq.) was added. The mixture was stirred at rt for 1.5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, filtered. The filter cake was washed with methanol to afford the target compound (3.2g, yield: 60%). LCMS_(ESI)_[M+H]+=486.1. Step 6: Preparation of N4-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinoline-3,4-diamine N-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxy-3-nitroquinolin-4-amine (3.1g, 1eq.) was dissolved in a mixture of methanol (50mL) and tetrahydrofuran (50mL). Zinc powder (2.09g, 5eq.) and aqueous NH4Cl solution (3.4mg, 10eq., 25mL) were added. The mixture was reacted at rt for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered to remove zinc powder, diluted with water (20mL), extracted with EA (30mL^3). The organic phases were combined, distilled under reduced pressure rotary-evaporated to dryness to afford a crude target compound (2.2g), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=456.0. Step 7: Preparation of ethyl (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-yl)glycinate N4-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinoline-3,4-diamine (1.9g, crude) and ethyl glyoxylate / toluene solution (50wt%, 20mL) were dissolved in methanol (10mL). The mixture was stirred at rt for 1.5hrs, followed by adding sodium cyanoborohydride (1.29g), then stirred at rt for 0.5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated to dryness, diluted with water (30mL), extracted with EA (20mL^3). The organic phases were combined, rotary-evaporated to dryness to afford the target compound (4g, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=542.2. Step 8: Preparation of (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-yl)glycine 2022412821   03 Aug 2026 Ethyl (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-yl)glycinate (2g, crude) was dissolved in a mixture of tetrahydrofuran (50mL) and methanol (15mL). Aqueous LiOH solution (353.8mg, 10mL) was added. The mixture was stirred at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was adjusted to pH=2, rotary-evaporated to dryness, diluted with water (30mL), extracted with EA (30mLx3). The organic phases were combined and rotary-evaporated to dryness to afford the target product (1.1g, yield: 58%). LCMS_(ESI)_[M+H]+=514.1. Step 9: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrazino[2,3-c]quinolin-2(1H)-one (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinolin-3-yl)glycine (1.1g, 1eq.) was dissolved in N,N-dimethylformamide (10mL). HATU (2443.4mg, 3eq.) and N,N-diisopropylethylamine (830.5mg, 3eq.) was added. The mixture was stirred at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (20mL), extracted with EA (20mLx3). The organic phases were combined, washed with saturated brine, and filtered. The filtrate was rotary-evaporated to dryness to afford a crude product, which was purified by column chromatography to afford the target product (800mg, yield: 75%). LCMS_(ESI)_[M+H]+=496.1. Step 10: Preparation of tert-butyl 1-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate 1-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrazino[2,3-c]quinolin-2(1H)-one (300mg, 1eq.) was dissolved in di-tert-butyl dicarbonate (3mL). 4-dimethylaminopyridine (221.9mg, 3eq.) was added and the mixture was stirred at 40°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (10mL), extracted with EA (20mLx3). The organic phases were combined, and rotary-evaporated to dryness to afford a crude product, which was purified by column chromatography to afford the target compound (100mg, yield: 28%). LCMS_(ESI)_[M+H]+=596.4. Step 11: Preparation of tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate Tert-butyl 1-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate (80mg, 1eq.) was dissolved in tetrahydrofuran (2mL). In an ice bath, water (33.9mg, 14eq.), acetic acid (56.5mg, 7eq.), 1,3-dichloro-5,5-dimethylhydantoin (52.9mg, 2eq.) were added. The mixture was stirred in an ice bath for 5 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was added to the ammonia solution (3mL) under stirring. The completion of the reaction was monitored with LCMS. The mixture was extracted with EA (5mLx3). The organic phases were combined, and distilled under reduced pressure to afford a crude product, which was purified by preparative HPLC to afford the target compound (6mg, yield: 8%). LCMS_(ESI)_[M+H]+=553.1;_1H_NMR_(400MHz,_MeOD- d4) 5 8.91 (s, 1H), 7.94 (d, J= 12.4 Hz, 1H), 7.50 (d, J= 8.2 Hz, 1H), 7.27 (d, J=7.2 Hz, 2H), 5.59 (s, 2 H),_4.36_(s,_2H),_4.03_(s,_3H),_1.54_(s,_9H). Example 31 2022412821   03 Aug 2026 Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)- yl)methyl)benzenesulfonamide (compound 55) Tert-butyl 1-(2,6-difluoro-4-sulfamoylbenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylate (50mg, 1eq.) prepared in Example 30 was dissolved in dichloromethane (2mL). Trifluoroacetic acid (0.5mL) was added. The mixture was stirred at rt stirred for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, and purified by preparative HPLC to afford the target compound (1.23mg, yield: 3%). LCMS (ESI) [M+H]+=453.1. Example 32 Preparation of 3,5-difluoro-4-((4-(2-hydroxyacetyl)-8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)- yl)methyl)benzenesulfonamide (compound 72) Step 1: Preparation of 2-(1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinolin-4(1H)-yl)-2-oxoethyl acetate 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c]quinolin-2(1H)-one (400mg,   1eq., prepared in step 6, Example 18) was dissolved in dichloromethane (4mL). 2-chloro-2-oxoethyl acetate (171.6mg, 1.5eq.) and triethylamine (254.3mg, 3eq.) were added. The mixture was reacted at rt for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water, and extracted. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford a crude product, which was purified by column chromatography to afford the target compound (120mg, yield: 25%). LCMS_(ESI)_[M+H]+=578.2. Step 2: Preparation of 3,5-difluoro-4-((4-(2-hydroxyacetyl)-8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinolin-1(2H)-yl)methyl)benzenesulfonamide 2-(1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinolin-4(1H)-yl)-2-oxoethyl acetate (50mg, 1eq.) was dissolved in superdry tetrahydrofuran (2mL). In an ice bath, glacial acetic acid (39.3mg, 7.6eq.), water (23.6mg, 15.1eq.) and 1,3-dichloro-5,5-dimethylhydantoin (55.3mg, 3.2eq.) were added. The mixture was stirred at 0°C for 5 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was added to the ammonia solution (5mL), stirred for 30 minutes, followed by adding NaHCO3 (39.3mg, 5.4eq.), then stirred for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filtrate was adjusted with 1M HCl to neutral pH, and concentrated. The residue was purified by preparative HPLC to afford the target compound (3.2mg, yield: 7.5%). 2022412821   03 Aug 2026 LCMS_(ESI)_[M+H]+=493.0;_1H_NMR_(400MHz,_MeOD- d4) 5 9.10 (s, 1H), 8.25 (d, J=10.3 Hz, 1H), 7.43 (s, 2H), 7.33 (d, J=6.4 Hz, 2H), 5.63 (s, 2H), 4.46 (d, _J=20.1_Hz,_4H),_4.00_(s,_3H). Example 33 Preparation             of             3,5-difluoro-4-((7-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- yl)methyl)benzenesulfonamide (compound 61) O 0 Step 1: Preparation of diethyl 2-(((2-methoxyphenyl)amino)methylene)malonate 2-methoxyaniline (20g, 1eq.) was dissolved in diethyl 2-(ethoxymethylene)malonate (35.12g, 1eq.). The mixture was stirred at 140°C for 45 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, and diluted with petroleum ether to precipitate a white solid. The mixture was filtered. The filter cake was washed with petroleum ether to afford the target compound (39.6g, yield: 83%). LCMS_(ESI)_[M+H]+=294.1;_1H_NMR_(400MHz,_CDCl3)_5_11.12_(d,_J=13.4_Hz,_1H),_8.57_(d,_J=14.1_Hz ,_1H),_7.24_(s,_1H),_6.99_(dd,_J=42.4,_26.6_Hz,_3H),_4.33_(q,_J=7.1_Hz,_2H),_4.25_(q,_J=7.1_Hz,_2H),_3.9 4_(s,_3H),_1.39_(t,_J=7.1_Hz,_3H),_1.33_(t,_J=7.1_Hz,_3H). Step 2: Preparation of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate To diphenyl ether (75mL) was added diethyl 2-(((2-methoxyphenyl)amino)methylene)malonate (15g, 1eq.). The mixture was reacted at 260°C for 45 minutes. The completion of the reaction was monitored with LCMS. The reaction mixture was cooled to rt, and diluted with petroleum ether to precipitate a solid. The mixture was filtered. The filter cake was washed with petroleum ether, and dried to afford the target compound (8.5g, yield: 67%). LCMS_(ESI)_[M+H]+=248.0. Step 3: Preparation of ethyl 4-chloro-8-methoxyquinoline-3-carboxylate Ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate (4g, 1eq.) was dissolved in dichloromethane (40mL). N,N-dimethylformamide (4mL) was added. Oxalyl chloride (3.08g, 1.5eq.) was slowly added dropwise. The mixture was stirred at rt stirred for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated to dryness. Ethyl acetate was added. The mixture was filtered. The filter cake was washed with 2022412821   03 Aug 2026 EA, and dried to afford the target product (4g, yield: 93%). LCMS (ESI) [M+H]+=266.1; 1H NMR (400MHz, CDCI3) 5 9.67 (s, 1H), 8.15 (d, J=8.6 Hz, 1H), 7.94 (t, _J=8.3_Hz,_1H),_7.49_(d,_J=7.9_Hz,_1H),_4.55_(d,_J=7.1_Hz,_2H),_4.26_(s,_3H),_1.48_(t,_J=7.1_Hz,_3H). Step 4: Preparation of ethyl 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinoline-3-carboxylate Ethyl 4-chloro-8-methoxyquinoline-3-carboxylate (2g, 1eq.) and (4-(benzylthio)-2,6-difluorophenyl)methanamine (2g, 1eq.) were dissolved in DMF (40mL). N,N-diisopropylethylamine (3.89g, 4eq.) was added. The mixture was reacted at 50°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (40mL), extracted with EA (30mLx3). The organic phases were combined, concentrated, and purified by column chromatography to afford the target compound (2.3g, yield: 62%). LCMS_(ESI)_[M+H]+=495.0. Step 5: Preparation of 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinolin-3-yl)methanol Ethyl 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinoline-3-carboxylate (2.1g, 1eq.) was dissolved in a mixed solution of tetrahydrofuran (30mL) and methanol (8mL). Lithium borohydride (462.4mg, 5eq.) was added. The mixture was reacted at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with aqueous saturated NH4Cl solution, concentrated under reduced pressure to precipitate a solid. The mixture was filtered. The filter cake was washed with EA, and dried to afford the target compound (1.2g, yield: 62%). LCMS_(ESI)_[M+H]+=452.9. Step 6: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinolin-3-yl)methanol (400mg, 1eq.) was dissolved in superdry tetrahydrofuran (40mL). N,N-diisopropylethylamine (342.7mg, 3eq.) was added. In an ice bath, triphosgene (262.3mg, 2eq.) was added. The mixture was stirred at room temperature for 3hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, and purified by reverse column to afford the target compound (100mg, yield: 24%). LCMS_(ESI)_[M+H]+=479.1. Step 7:     Preparation of 3,5-difluoro-4-((7-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinolin-1(4H)- yl)methyl)benzenesulfonamide 1-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinolin-2-one (50mg, 1eq.) was dissolved in tetrahydrofuran (2mL). In an ice bath, water (26.4mg, 14eq.) and acetic acid (43.9mg, 7eq.), 1,3-dichloro-5,5-dimethylhydantoin (41.2mg, 2eq.) were added. The mixture was stirred for 5 minutes in an ice bath. Ammonia solution (1mL) was added. The stirring continued. The completion of the reaction was monitored with LCMS. The reaction mixture was distilled under reduced pressure to remove tetrahydrofuran, extracted with EA (10mL). The organic phase was concentrated, and purified by preparative HPLC to afford the target compound (2.0mg, yield: 4.4%). LCMS_(ESI)_[M+H]+=436.0;_1H_NMR_(400MHz,_MeOD- d4)_5_8.67_(s,_1H),_8.50_(s,_2H),_7.79_(d,_J=8.5_Hz,_1H),_7.63_(t,_J=8.3_Hz,_1H),_7.44_(d,_J=7.4_Hz,_2H) ,_7.27_(d,_J=8.2_Hz,_1H),_5.59_(s,_2H),_5.32_(s,_2H),_4.07_(s,_3H). 2022412821   03 Aug 2026 Example 34 Preparation of 6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin- 2(1H)-sulfonamide (compound 59) Step 1: Preparation of ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (2g, 1eq.) was dissolved in N,N-dimethylformamide (20mL). N,N-diisopropylethylamine (2.91g, 3eq.) and tert-butyl 6-amino-3,4-dihydroisoquinolin-2(1H)-carboxylate (2.79g, 1.5eq.) were added. The mixture was stirred at 50°C for 10hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (100mL), extracted with EA (30mL^3). The organic phases were combined, washed with saturated brine (50mL^2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by column chromatography to afford the target compound (2.3g, yield: 64%). LCMS (ESI) [M+H]+=479.1; 1H NMR (400MHz, CDCI3) 5 10.37 (s, 1H), 9.30 (s, 1H), 7.81 (d, J=9.1 H z,_1H),_7.04_(d,_J=8.0_Hz,_1H),_6.93- 6.81_(m,_2H),_6.58_(d,_J=9.1_Hz,_1H),_4.56_(s,_2H),_4.43_(q,_J=7.1_Hz,_2H),_4.13_(s,_3H),_3.63_(t,_J=5.0 _Hz,_2H),_2.74_(s,_2H),_1.50_(s,_9H),_1.45_(t,_J=7.1_Hz,_3H). Step 2: Preparation of tert-butyl 6-((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2(1H)-carboxylate Ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (2g, 1eq.) was dissolved in tetrahydrofuran (20mL). In an ice bath, lithium borohydride (0.27g, 3eq.) and methanol (2mL) were added. The reaction mixture was stirred at 25°C for 2hrs. The completion of the reaction was monitored with LCMS. In an ice bath, a saturated NH4Cl solution (10mL) was slowly added dropwise. The mixture was extracted with EA (30mL^3). The organic phases were combined, washed with saturated brine (50mL^2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford the target compound (1.5g, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=437.3. Step 3: Preparation of tert-butyl 6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-carboxylate 2022412821   03 Aug 2026 T ert-butyl         6-((3-(hydroxymethyl)-7-methoxy- 1,8-naphthyridin-4-yl)amino)-3,4-dihydroisoquinolin-2( 1H)- carboxylate (1.9g, crude) was dissolved in tetrahydrofuran (20mL). N,N-diisopropylethylamine (1.69g) and triphosgene (1.29g) were added. The reaction mixture was stirred at 25°C for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (10mL), extracted with EA (10mLx3), washed with saturated brine (20mLx2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to afford a crude product, which was purified by column chromatography to afford the target compound (300mg). LCMS (ESI) [M+H]+=463.1; 1H NMR (400MHz, CDCb) 3 8.75 (s, 1H), 7.24 (dd, J=18.5, 9.1 Hz, 3H), 7.16 (d, J=9.3 Hz, 1H), 6.63 (d, J=9.3 Hz, 1H), 5.47 (s, 2H), 4.64 (s, 2H), 4.11 (s, 3H), 3.67 (s, 2H), 2 .83 (t, J=5.7 Hz, 2H), 1.51 (s, 9H). Step 4: Preparation of 8-methoxy-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one Tert-butyl 6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-carboxylate (200mg) was dissolved in trifluoroacetic acid (2mL). The reaction mixture was stirred at 40°C for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to remove trifluoroacetic acid to afford the target compound (170mg, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=363.3. Step 5: Preparation of tert-butyl ((6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate Tert-butyl chlorosulfonylcarbamate (128.9mg) was dissolved in dichloromethane (2mL). In an ice bath, tert-butanol (67.5mg) was added. The reaction mixture was stirred in an ice bath for 0.5hrs. 8-methoxy-1-(1,2,3,4-tetrahydroisoquinolin-6-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (300mg, crude) was dissolved in dichloromethane (8mL). In an ice bath, triethylamine (100.5mg) was added. The former was slowly added dropwise to this reaction mixture. In an ice bath, the resulting mixture was stirred for 1.5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to remove the solvent, diluted with water (10mL), extracted with EA (5mLx3). The organic phases were combined, washed with saturated brine (20mLx2), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness to afford the target compound (203mg, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=542.2. Step 6: Preparation of 6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-sulfonamide Tert-butyl ((6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)-3,4-dihydroisoquinolin-2(1H)-yl)sulfonyl)carbamate (203mg, crude) was dissolved in trifluoroacetic acid (3mL). The reaction mixture was stirred at 40°C for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to remove trifluoroacetic acid to afford a crude product, which was purified by preparative HPLC to afford the target compound (1.06mg). LCMS_(ESI)_[M+H]+=442.1;1H_NMR_(400MHz,_MeOD- 2022412821   03 Aug 2026 d4) 5 8.88 (s, 1H), 7.43 (d, J= 6.4 Hz, 2H), 7.38 (d, J=8.9 Hz, 1H), 7.19 (d, J=9.5 Hz, 1H), 6.88 (d, J= 9.5_Hz,_1H),_5.66_(s,_2H),_4.44_(s,_2H),_4.12_(s,_3H),_3.47_(t,_J=5.8_Hz,_2H),_3.02_(t,_J=5.8_Hz,_2H). Example 35 Preparation             of (N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)cycloheptyl)sulfamoyl)amine (compound 64): Step 1: Preparation of tert-butyl (4-oxocycloheptyl)carbamate n-butyl lithium (2.5M, in hexane)(4.2mL) was dissolved in tetrahydrofuran (100mL). The reaction system was replaced with nitrogen gas. Then trimethylsilyldiazomethane TMSCHN2 (2M, in hexane)(6.96mL) was added at -78°C. The mixture was stirred for 30 minutes. Then tert-butyl (4-oxocyclohexyl)carbamate (10.0g, 1eq.) was added at -78°C. The reaction system was replaced with nitrogen gas and stirred at -78°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction system was quenched with aqueous saturated NH4Cl solution, and extracted with EA. The organic phase was concentrated, and purified by flash chromatography to afford the target compound (9.0g, yield: 84.4%). LCMS_(ESI)_[M+Na]+=250.1. Step 2: Preparation of tert-butyl (4-aminocycloheptyl)carbamate Tert-butyl (4-oxocycloheptyl)carbamate (2.0g, 1eq.) and ammonium formate (3.33g, 6eq.) were dissolved in methanol (30mL). Pd / C (936mg, 1eq.) was added. The reaction system was replaced with hydrogen gas and stirred under the atmosphere of hydrogen gas at 20°C for 5hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filtrate was rotary-evaporated to dryness and dissolved in HCl (5M, 5mL). Ethyl acetate was added, and the mixture was divided into layers. The phases were separated. The aqueous phase was alkalized, and extracted with EA. The organic phase was washed with brine, dried over sodium sulfate, and filtered. The filtrate was rotary-evaporated under reduced pressure to dryness to afford the target compound (1.0g, yield: 50%). LCMS_(ESI)_[M+H]+=229.2. Step 3: Preparation of ethyl 4-((4-((tert-butoxycarbonyl)amino)cycloheptyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (50mg, 1eq.) was dissolved in acetonitrile (10mL). Then 2022412821   03 Aug 2026 K2CO3 (77mg, 3.0eq.), tert-butyl (4-aminocycloheptyl)carbamate (128mg, 3eq.) were added. The reaction was performed under the protection of nitrogen gas at 40°C for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated under reduced pressure to dryness, dissolved in ethyl acetate, and washed with water. The organic phase was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by flash chromatography to afford the target compound (50mg, yield: 58%). LCMS_(ESI)_[M+H]+=459.3. Step 4:      Preparation of tert-butyl (4-((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4- yl)amino)cycloheptyl)carbamate Ethyl 4-((4-((tert-butoxycarbonyl)amino)cycloheptyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (30.0mg, 1eq.) was suspended in ethanol (2mL) and methanol (0.5mL). Then sodium borohydride (15.1mg, 6.1eq.) was added. The reaction was performed under the protection of nitrogen gas at 80°C for 10hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with saturated aqueous NH4Cl solution (5mL), and extracted with EA (5mL^3). The organic phases were combined, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by flash chromatography to afford the target compound (10mg, yield: 37%). LCMS_(ESI)_[M+H]+=417.3. Step 5: Preparation of tert-butyl (4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)cycloheptyl)carbamate Tert-butyl (4-((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4-yl)amino)cycloheptyl)carbamate (10mg, 1eq.) was dissolved in dichloromethane (1mL). Then triethylamine (7.3mg, 3eq.), triphosgene (7.1mg, 1eq.) were successively added at 0°C. The mixture was reacted at 0°C under stirring for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with saturated brine (10mL), extracted with EA (5mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated, and purified by flash chromatography to afford the target compound (10mg, yield: 94%). LCMS_(ESI)_[M+H]+=443.2. Step 6: Preparation of 1-(4-aminocycloheptyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one Tert-butyl (4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)cycloheptyl)carbamate (10mg) was dissolved in dichloromethane (1mL). Then a solution of trifluoroacetic acid (0.5mL) in dichloromethane (0.5mL) was added at 0°C. The mixture was reacted at 20°C stirred for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated under reduced pressure to remove the solvent to afford the target compound (10mg, crude), which was not further purified but directly used in the next step reaction. LCMS_(ESI)_[M+H]+=343.2. Step 7: Preparation of tert-butyl (N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)cycloheptyl)sulfamoyl)carbamate To a 50 mL single-neck round-bottom flask were added tert-butyl chlorosulfonylcarbamate (2mL), and dichloromethane (2mL). Then tert-butanol (2mL) was slowly added at 0°C. The reaction mixture was stirred at 0°C for 1hr and added to a solution of 1-(4-aminocycloheptyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4- 2022412821   03 Aug 2026 c][1,8]naphthyridin-2-one (10mg, crude, obtained from the above step reaction) in dichloromethane (2mL) at 0°C. The mixture was stirred at 0°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was under reduced pressure rotary-evaporated to dryness to afford the target compound (10mg, crude), which was not further purified but directly used in the next step reaction. Step 8:     Preparation of (N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)cycloheptyl)sulfamoyl)amine Tert-butyl                             (N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)cycloheptyl)sulfamoyl)carbamate (9mg, crude) was dissolved in dichloromethane (1mL). Then a solution of trifluoroacetic acid (0.5mL) in dichloromethane (0.5mL) was added at 20°C. The mixture was reacted at 20°C under stirring for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure, and purified by preparative chromatography to afford the target compound (1.2mg). LCMS_(ESI)_[M+H]+=422.2;_1HNMR_(400MHz,_MeOD- d4) 38.18 (d, J=8.0 Hz, 1H), 7.07 (d, J=4.0 Hz, 1H), 5.21 (s, 2H), 5.10 (s, 2H), 4.03 (s, 3H), 3.35 (s, 1 H),_3.03_(s,_1H),_2.93_(m,_1H),_2.56_(s,_1H),_2.5_(s,_1H),_2.4_(m,_1H),_2.10_(m,_2H),_1.94_(m,_2H),_1.51 _(m,_1H),_1.30_(m,_1H),_1.25_(m,_3H). Example 36 Preparation              of              5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)hexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide (compound 36) Step 1: Preparation of tert-butyl 5-(benzylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Tert-butyl 5-oxohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.0g) was dissolved in dichloromethane (100mL). Phenylmethanamine (475mg) and acetic acid (266mg) were added at 0°C. The mixture was reacted at 0°C under stirring for 30 minutes. Then sodium triacetoxyborohydride (1.88g) was added in batches. The mixture was warmed to rt and the reaction continued for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (20mL), extracted with dichloromethane (50mL^3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to afford the target compound (1.2g, crude). LCMS_(ESI)_[M+H]+=317.3. Step 2: Preparation of tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate 2022412821   03 Aug 2026 Tert-butyl 5-(benzylamino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (1.2g, crude) was dissolved in methanol (30mL). Dihydroxypalladium (10%, 400mg) was added. The atmosphere was replaced with hydrogen gas three times, and the mixture was reacted under the atmosphere of hydrogen gas at 40°C under stirring for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was filtered. The filtrate was concentrated under reduced pressure to afford the target compound (700mg, crude). LCMS_(ESI)_[M+H]+=227.2. Step 3: Preparation of ethyl 4-((2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (707mg), tert-butyl 5-aminohexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (600mg, crude) and N,N-diisopropylethylamine (3.43g) were dissolved in ethanol (20mL). The mixture was heated to 90°C and reacted for 16hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated under reduced pressure to remove ethanol, diluted with water (50mL), extracted with EA (50mL^3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH=20:1) to afford the target compound (1.0g, yield: 82%). LCMS_(ESI)_[M+H]+=457.2. Step 4:      Preparation of tert-butyl 5-((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4- yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Ethyl 4-((2-(tert-butoxycarbonyl)octahydrocyclopenta[c]pyrrol-5-yl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (100mg, 1.0eq.) was dissolved in dichloromethane (20mL). The mixture was cooled to -78°C. Then diisobutylaluminium hydride (2M, 0.55mL) was slowly added. The mixture was reacted at -78°C for 2hrs. The reaction mixture was quenched with water, extracted with dichloromethane (20mL^3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH=10:1) to afford the target compound (40mg, yield: 44%). LCMS_(ESI)_[M+H]+=415.2. Step 5: Preparation of tert-butyl 5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate Tert-butyl 5-((3-(hydroxymethyl)-7-methoxy-1,8-naphthyridin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (40mg, 1.0eq.) was added to tetrahydrofuran (5mL). N,N-diisopropylethylamine (124mg, 10.0eq.) was added. Triphosgene (86mg, 3.0eq.) was added. The mixture was reacted at rt for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (10mL), extracted with EA (20mL^3). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH=10:1) to afford the target compound (30mg, yield: 70%). LCMS_(ESI)_[M+H]+=441.2. Step 6: Preparation of 8-methoxy-1-(octahydrocyclopenta[c]pyrrol-5-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one Tert-butyl 5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxylate (30mg) was added to dichloromethane (10mL). Trifluoroacetic acid (1mL) was added. The 2022412821   03 Aug 2026 mixture was reacted at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated to dryness in vacuum to afford the target compound (20mg, crude). LCMS_(ESI)_[M+H]+=341.2. Step 7: Preparation of tert-butyl ((5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)sulfonyl)carbamate 8-methoxy-1-(octahydrocyclopenta[c]pyrrol-5-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (20mg, crude) and triethylamine (30mg) were added to dichloromethane (10mL). Tert-butyl N-(chlorosulfonyl)carbamate (25mg) was added dropwise at 0°C. The mixture was reacted at rt for 2hrs. The reaction mixture was diluted with water (10mL), extracted with EA (20mL^3). The organic phases were combined, dried, filtered, and concentrated to afford the target compound (20mg, crude). LCMS_(ESI)_[M+H]+=520.1. Step 8:      Preparation of 5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)hexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide Tert-butyl                                 ((5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-1(4H)- yl)hexahydrocyclopenta[c]pyrrole-2(1H)-yl)sulfonyl)carbamate (20mg, crude) was added to dichloromethane (5mL). Trifluoroacetic acid (0.5mL) was added. The mixture was reacted at rt for 4hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was rotary-evaporated to dryness in vacuum to afford a crude product, which was purified by liquid-phase preparative HPLC to afford the target compound (2.8mg). LCMS_(ESI)_[M+H]+=420.1;_1H_NMR_(400MHz,_DMSO- d6) 5 8.79 (s, 1H), 8.33 (d, J=9.2 Hz, 1H), 7.17 (d, J=9.2 Hz, 1H), 6.78 (s, 2H), 5.33 (s, 2H), 4.34-4.25_(m,_1H),_4.03_(s,_3H),_3.10-3.06_(m,_2H),_2.99-2.97_(m,_2H),_2.62-2.54_(m,_2H),_2.40-2.36_(m,_2H),_2.27-2.19_(m,_2H). Example 37 Preparation of 1-(2,6-difluoro-4-(S-methylsulfonimidoyl)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (compound 216) Step 1: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-chloro-7-methoxy-1,8-naphthyridine-3-carboxylate (20g,       1.0eq.),       (4-bromo-2,6- difluorophenyl)methanamine (16.65g, 1.0eq.) and N,N-diisopropylethylamine (29.08g, 3.0eq.) were added to dimethylformamide (200mL). The mixture was stirred at room temperature for 12hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was added to petroleum ether (250mL), stirred, and cooled to rt. 2022412821   03 Aug 2026 The stirring continued for 3hrs to fully precipitate a solid. The mixture was filtered, The filter cake was dried to afford the target compound (19g, yield: 56%). LCMS_(ESI)_[M+H]+=453.9. Step 2: Preparation of ethyl 4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (450mg, 1.0eq.), sodium methyl mercaptide (69.74mg, 1.0eq.), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (57.57mg, 0.1eq.), N,N-diisopropylethylamine (385.79mg, 3.0eq.) and bis(dibenzylideneacetone)palladium (91.12mg, 0.1eq.) were dissolved in dioxane (7mL) and water (1mL). The mixture was stirred at 90°C for 8hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water (10mL), extracted with EA (10mLx3). The organic phases were combined, dried, filtered, concentrated, and purified by a positive phase column (eluting with PE:EA=5:1) to afford the target compound (250mg, yield: 60%). LCMS_(ESI)_[M+H]+=419.9. Step 3: Preparation of (4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol Ethyl 4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthyridine-3-carboxylate (190mg, 1.0eq.) was dissolved in tetrahydrofuran (5mL). In an ice bath, lithium aluminium hydride (126.75mg, 7.4eq.) was added. The mixture was stirred for 2hrs in an ice bath. The completion of the reaction was monitored with LCMS. The reaction mixture was quenched with water (10mL), extracted with EA (10mLx3). The organic phases were combined, dried, filtered, concentrated, and purified by eluting with a reverse phase system to afford the target compound (120mg, yield: 70%). LCMS_(ESI)_[M+H]+=378.0. Step 4: Preparation of 1-(2,6-difluoro-4-(methylthio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthyridin-3-yl)methanol (100mg, 1.0eq.) was dissolved in tetrahydrofuran (2mL). Triphosgene (235.8mg, 3.0eq.) and N,N-diisopropylethylamine (136.98mg, 4.0eq.) were added. The mixture was reacted at 25°C for 1hr. The completion of the reaction was monitored with LCMS. The reaction mixture was diluted with water, extracted with EA. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to afford the target compound (105mg, yield: 98.24%). LCMS_(ESI)_(M+H)+=404.1. Step 5: Preparation of 1-(2,6-difluoro-4-(S-methylsulfonimidoyl)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one 1-(2,6-difluoro-4-(methylthio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyridin-2-one (100mg, 1.0eq.) was dissolved in ethanol (4mL). Iodobenzene diacetate (239.54mg, 3.0eq.) and ammonium acetate (96.43mg, 5.0eq.) were added. The mixture was reacted at rt for 2hrs. The completion of the reaction was monitored with LCMS. The reaction mixture was concentrated to afford a crude product, which was purified by preparative HPLC to afford the target compound (24.05mg, yield: 22%). LCMS_(ESI)_(M+H)+=435.1;_1H_NMR_(400MHz,_DMSO- 2022412821   03 Aug 2026 d6) 5 8.80 (s, 1H), 8.66 (d, J=9.2 Hz, 1H), 7.59 (d, J=7.2 Hz, 2H), 7.14 (d, J=9.2 Hz, 1H), 5.49 (s, 2H) ,_5.29_(s,_2H),_4.54_(s,_1H),_4.04_(s,_3H),_3.14_(s,_3H). The following compounds were prepared with reference to the preparation methods of Example 1-37: No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 9 \ -n O ip    d "to                        / \ - y 520.17 10 jy^hL^hL Ill yl o=s=o nh2 437.09 12 .N, .N, XIXo o=s=o nh2 435.11 13 Ill 1 F'^^yy / NyN-^CF3 Fy o=s=o nh2 535.07 14 \ o O  ,-- /       /   z 11  1  1       1   / / z-co—I   —.   )—( i ii   \__ /    x     /    x o         z \\   / z T z ) o 518.10 15 Til F^^Y^O y Y o=s=o nh2 440.09 16 ,0. _N. .N. Ill ^^y^N^CF, 1g Vf o=s=o nh2 504.13 17 Xyn n xiy nynh Fy o=s=o nh2 450.06 18 .N, .N, ......Gy y° o=s=o nh2 451.05 19 \ z     -no 11 cK o 511.12 20 XI      .N. nci F Ho h2n'%    f 525.14 21 \ z            o 11 0 518.10 22 O N N 1X1.0 N^N T' o=s=o nh2 434.08 23 zV N UA dl X1F o=s=o nh2 420.07 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 24 y, IyF o=s=o nh2 418.10 25 \ o ° viL y z-cc—X X—,   )—X i ii \__ /   \   /   7 o y yy y T Z 1-Y 417.08 26 ,0. .N. .N. UI H F\J\ ylF o=s=o nh2 418.09 27 \ o ° zH^ uf z-co—I X—.   )—\ Xll \__ /   \   /   x o ^y z—I z -n z 1— 418.10 28 O N yp o=s=o nh2 419.06 29 T¥ 1 O N ¥’ o=s=o nh2 436.07 32 y ,-. _N. 1111 y v o=s=o nh2 471.03 33 F. X _N_ XJy rY° d o=s=o nh2 454.06 34 ,0.      ,N. £11, f¥ F¥ o=s=o nh2 437.07 35 ,0. _N. _N. Ill, rV y 0=S=0 nh2 438.06 37 ,0. ,N. ,N. ££1, 1° 1° %" h2n' 0 422.15 38 ul vVy0 0 N-^ / "0 h2n 448.16 40 ,N. ,N. QX £V 1° o=s=o nh2 428.10 42 / O^N^N^ ux, r V y ol-OH H 417.12 44 ,0. ,N, ,N, 1¾ rV v 0 HO-P=S OH 470.05 45 ,0. ,N, ,N, uy y° d 0 o=s=o nh2 453.06 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 47 ,NX ,NS h2n 0 489.15 53 ,OX ,N. ,NS u / x v o=s=o nh2 532.07 56 ,N UY v o=s=o nh2 518.09 57 ,N. ^N. ujY0 N N" v o=s=o OH 451.05 58 ,.0, ,N, ,N, UI ^^r'N'^'CF, fr1 Fx>° o=s=o nh2 518.09 60 ,0.,.. ,N.., Oy xy NH o=s=o nh2 452.08 73 .0. ,N, ,N, u f^^Yi u° v o=s=o nh2 437.07 74 XUN Y UA U-U,, ■ : O=S=O nh2 476.12 75 1¾ u o=s=o nh2 437.08 76 ,0, ni N Y^ NH O=S=O nh2 450.07 77 D.7.O  N,^N., I U _ ^Y^N^CFs Y"' F-^° o=s=o nh2 521.13 78 Uj 1. NC'^^Y] nyNH v O=S=O nh2 460.10 79 uu fV Fx>° 0=S=0 nh2 449.07 80 ^S, ,N, ,N, UY rV O=S=O nh2 453.05 81 nh2 «x r"'A o=s=o nh2 434.07 82 H VvU 1J O N ■ ■ o=s=o nh2 445.07 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 99 \ o m     ,—( ° aX \\ A Z-A7 X--,   )--( I II \    / O -n oA 0 470.04 100 ,0. ,N, ,N. UI tA o=s=o nh2 468.05 101 N N AA ^^nAm^^oh Ny °' nh2 461.17 102 \ 0 m     ,—( A Z-W—\    / — I II \ / x     / x 0 '-y  ZA\  z -n o4 co / 482.07 103 \ o O  .-- /       /   z 11 AA     A / / z-ccA7 v—, )—( i H \_ /  y /  y o A^  ZA\ ,z t o4 A7 O 460.08 104 T? o=s=o nh2 449.11 105 ..-Ox / x A Al N^^ FA' O=S=O NH2 449.14 106 / O. x5; N       N AXA A> F ° / Ul h2n'%    f 518.11 107 At t h aaa N^A 0 A- o=s=o nh2 477.14 108 w. ^-A Af o=s=o nh2 465.11 109 1A 1 ° ^A^N'®''O ^A Af o=s=o nh2 499.09 110 Ay, Af o=s=o nh2 500.08 111 „Ox .A Try N'O\ A1 O=S=O NH2 451.12 112 z°YN<A uX-a ? / A o=s=o nh2 476.12 113 n N LX1nX> Ar1 A o=s=o nh2 506.13 114 xy.N..o rV A o=s=o nh2 511.12 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 115 XL      N, IY1 n¥nh Y o^nh2 417.11 116 _O. _N, ,N, Ill lY YP o=s— d 449.07 117 ,0, ,N. ,N. 1¾ rV v 0 o=s=o 1 452.06 118 UY rNYNH Y 0=3=0 O^O H 493.09 119 ,0. / N. 1¾ N^NH v o=s=o ^nh2 436.12 120 Ill '^Y^0 rNI v O=S=O HN 0^0 H 495.07 121 zYYl. ex / )—(   \___ / \  ' "O p I O □-\ 468.09 122 \ O °-HlX. O ■■w.           X / X = Alx o— / 452.08 123 JX / N. ,N. Ill rNl Y o=s=o Xo 439.08 124 JX.N^X 1¾ nynh Y o=s=o HeX 452.08 125 JX,N. 1¾ N^o v o=s=o h1h2 438.11 126 \ _              o 417.17 127 \               o 381.20 128 Yl NH °Y nh2 382.19 129 \ o / O 431.11 130 ^°ynynx XA rVH Y o=s=o nh2 420.11 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 131 III nynh 0=S=0 nh2 464.08 132 ,0. ,N, ,N. Ill F'xV^Y| nynh Y° O=S=O nh2 448.10 133 ,0. _N. .N. Ill F'^^Yl nynh H2N      0 1 0=S=0 nh2 433.10 134 .0. ,N. ,N. Ill ^^y^nh Y 1 O=S=O nh2 482.07 135 .0, ,N. ,N. 99 nynh »1° o=s=o nh2 443.09 136 XL / Y / Y III f^^yy nynh O=S=ONH2 nh2 447.12 137 III F^^^Yl Y^^ ho^JY 0=S=0 nh2 448.10 138 III f-^^y^y Y „.^9 O=S=O nh2 464.10 139 ,0. _N. _N. Ill f^^^yy nynh CY^oh 0=S=0 nh2 461.10 140 III A'1 1 ° HO^-^Y o=s=o nh2 463.10 141 ,0, III ^Y^o / / lrF 0=S=0 F nh2 451.08 142 ^-o N N f1Ynh . " 0 0=5=0 nh2 476.06 143 JX    ,N, III Yl^ Ari 00=5=0 nh2 476.10 144 ^■o N N 199 Y oo=s=o nh2 443.10 145 XL ^N. III <N-A ijY 0=S=0 nh2 457.11 146 999 a-A 0.....1 O=S=O nh2 490.15 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 147 ,CL .N, _N, YU ^Y^NH 0=S=0 nh2 479.15 148 AzXX ¢¢¢, ny,h 1 O=S=O nh2 418.09 149 ,0. LlX i^."" 0=S=0 nh2 418.09 150 \ o ° >\ o H-CoA7 I—,   )— I II \    /    1     /    1 o — ZY\ / z °Y Y3" 432.07 151 ,0. ,N, IX, ny«b .4° 0=S=0 nh2 435.06 152 ,O.      ,N. Ill ,ll .1 o=s=o nh2 420.08 153 ,0. ,N, ,N, III nynh ■ 0=S=0 nh2 432.11 154 N N xa rNrl,o 1. 0 xV V O=S=O nh2 471.11 155 ,0. _N, .N, III 0=S=0 nh2 444.11 156 ^.0 N N ';ul x O=S=O nh2 455.08 157 O ,N, ,N, III N^NH X. o 1) 0=S=0 nh2 456.11 158 ¢¢, N-x / 0 v 0=S=0 nh2 423.09 159 XY o=s=o nh2 451.08 160 / °yYx o=s=o nh2 450.09 161 o^X x XXX Y Y o=s=o nh2 450.10 162 -OX fl v o=s=o nh2 451.08 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 163 ^22^ o~s=o h2n 465.10 164 ' IJA o=s=o nh2 448.08 165 / °yvn U3 f o 2^ / ®^nh2 F      0 354.07 166 -°Vn^n IJO F o r2^^^NH2 F      O 355.06 167 N. UJ . o \ '2" ^2^ / ,^nh2 F      0 354.07 168 / °vnvn IJO F N \ 2 z0H 2^ / B( F       OH 320.10 169 ^°V IT> f ^T\ 0 \ \V " 2^ / 2~0H F    HO 356.06 170 IT> F 7    OH 2^^^ F       OH 338.09 171 <'^2^2 -° mo o=s=o nh2 425.07 172 b-^^r'T 22 O=S=O nh2 393.08 173 ncT^ n-2 v O=S=O nh2 389.06 174 N-^ F2f O=s=o nh2 395.07 175 nTT Ln 22 0=S=0 nh2 394.07 176 bn nh T O=S=O nh2 409.07 177 ^22 J. NH 2 / 0=S=0 nh2 411.06 178 T^NH T 0=S-0 nh2 410.07 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 179 "X O-S=O nh2 409.07 180 ° - / i  । XF JAL p F     / 'nh2 409.11 181 A N^<N^1 Ln Xa nh2 406.11 182 A A g'Q M 411.10 183 ° \ J 1 XF F      q'S'NH2 410.11 184 \ .A o - / 1  1 Vf XX / F     / 'NH2 410.12 185 N oX ] J / XAN nA v o=s=o nh2 407.09 186 NvX oX z X o=s=o nh2 408.09 187 7=\ / r\ z ax —x o x-- / / -W-'Z \\           \___ / II XX )— ° 405.08 188 aX\ a x Z XX --X O CN \ / \ / XA 11 1 / —{   —\   / —(f)-^ / \\         \ / H zX    / —° 406.08 189 7=\ z AX -X O ™ \ /  \    / / X  11 1 )— /   x— / / -<f)--z / W          \__ /   ii zyz    / — ° 407.07 190 An ,n v o=s=o nh2 405.08 191 °-€I 1 Xj v o=s=o nh2 410.09 192 \ °XX 1 X o=s=o nh2 411.09 193 \ JA / A / J v o=s=o nh2 412.08 194 \ / zNa"X sXX 1 ^^X0 / Nj v o=s=o nh2 426.07 No. Structure LCMS (ESI) [M+H]+ No. Structure LCMS (ESI) [M+H] 195 1  ...

Claims

1. A compound represented by the following formula (I), a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound:wherein X1, X2, X3, and X4 are each independently CH or N;Y is N;RA is a substituent of the ring where X1 is located, RB is a substituent of the ring where Y is located;each RA is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclyl, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C1-6alkylthio, or C3-6cycloalkyl, wherein the alkyl is optionally substituted by one or more substituents selected from deuterium and halogen; andeach RB is independently hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, ethenyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, or methoxymethyl;n1 is 1, 2, 3 or 4;n2 is 1;eithereach Rc is independently hydrogen, Cl, oxo, oxime, -CN, -OH, -SH, -NH2, -Boc, -COCH2OH, -NHC(O)CH3, carboxyl, -S(O)2CH3, -S(O)2NH2, -CH2S(O)2CH3, methoxy, methylthio, -CH2CH2CH2OH, -CH2CH2CH2OCH3,¥> L / °ethyl,          ,          , -CH2CF3, cyclopropyl, phenyl, or ethenyl;n3 is 1, 2, or 3; and* ^-<0. . . . .one or two Res in (Rc)n3 are oxo, the above-mentioned ring A substituted by one or two Res is a          ,2022412821   15 Sep 2026*0      , ** represents the site of fusing, a represents the attachment position of the L group;orthe ring Asubstituted by (RC)n3 is,,cf3,OH,OH,NH2,,,represents the site of fusing,NNY O ,NNBocGF 3,N_NHCF3NHNHrepresents the attachment position of the L group; Z is a bond;2022412821   15 Sep 2026ring B is phenyl, or 6-membered monocyclic-heteroaryl;RD  is selected from  -SO2NH2,  -S(O)2OH,  -S(O)2CH3,  -S(O)2CH2CH2C(O)OH,  -S(O)2CH2NH2,  -S(O)2NHCH2C(O)OH, -S(O)2ND2, -S(O)2NHNH2, and -S(O)2NHOH;RE is each independently hydrogen, deuterium, F, Cl, carboxyl, -CN, -NH2, methyl, methylthio, -CF3, methoxy, -CH2NH2, -CH2OH, -CH2NHOH, -CH=NOH, -CH2CH2OH, -CHF2, -C(O)OCH3, -C(O)CH3,, cyclopropyl, ethenyl, ethynyl, propynyl, ethyl, or propenyl;n4 is 1, 2, 3, 4, 5, or 6;zy\L represents a bridging group between ring A and ring B and is selected from -O-, -CH2-, and >~wR1 at each occurrence is independently hydrogen, or C1-6alkyl;R2 and R3 at each occurrence are independently hydrogen, or C1-6alkyl;R4 at each occurrence is independently hydrogen, deuterium, C1-6alkyl, C1-6alkoxy, C3-6cycloalkyl, phenyl, or 3-6 membered heterocyclyl, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclyl is optionally substituted by one or more substituents selected from halogen, cyano, hydroxy, amino, C1-3alkyl, C1-4alkoxy, C1-3haloalkyl, and C1-3haloalkoxy;in the case that multiple RAs, RBs, RCs or REs appear at the same time, RAs, RBs, RCs or REs can be identical or different from each other;unless otherwise stated, the heteroatoms in the above-mentioned heterocyclyl and heteroaryl are independently selected from O, N and S, and the number of heteroatoms is 1, 2, 3, or 4.

2. The compound according to claim 1, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereinX1 is N, and X2, X3, and X4 are all CH; orX3 is N, and X1, X2 and X4 are all CH; orX1 and X3 are both N and X2 and X4 are both CH; orX1, X2, X3, and X4 are all CH.

3. The compound according to any of claims 1-2, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereineach RA is independently hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclyl, -Z-C(O)R4, -Z-C(O)OR1, -Z-C(O)NR2R3, -Z-S(O)2R4, -Z-S(O)2NR2R3, C1-4alkyl, C2-4alkenyl, C2-4alkynyl, C1-3alkoxy, C1-3alkylthio, or C3-6cycloalkyl, wherein the alkyl is optionally substituted by one or more substituents selected from deuterium.2022412821   15 Sep 20264. The compound according to any of claims 1-2, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereineach RA is independently hydrogen, deuterium, F, Cl, Br, oxime, -CN, -OH, -SH, -NO2, -NH2, -NR2C(O)R4, -NR2C(O)OR1, 3-6 membered heterocyclyl, -C(O)R4, -C(O)OR1, -C(O)NR2R3, -S(O)2R4, -S(O)2NR2R3, methyl, ethyl, propyl, isopropyl, tert-butyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, ethenyl, ethynyl, propenyl, or propynyl.

5. The compound according to any of claims 1-2, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereinRA is selected from hydrogen, F, Cl, -CN, -NH2, oxime, methyl, methoxy, ethoxy, methylthio, -OCD3, -NHCOCH3,-NHCOOCH3,    A , -COCH3, -COOCH3, -COCH2OCH3, -CONHCH3, -SO2CH3, -SO2NH2, -CH=CH-CH3,ethynyl, cyclopropyl, and tert-butyl.

6. The compound according to any of claims 1-5, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, wherein n1 is 1, 2, or 3.

7. The compound according to any of claims 1-5, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, wherein n1 is 1 or 2.

8. The compound according to any of claims 1-7, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereineach RB is independently hydrogen, F, Cl, Br, -OH, -NH2, methyl, ethyl, methoxy, ethoxy, ethenyl, or ethynyl.

9. The compound according to any of claims 1-7, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereineach RB is hydrogen, -NH2, methyl, methoxy, or ethynyl.

10. The compound according to any of claims 1-9, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative,2022412821   15 Sep 2026pN^CF3i*^0or prodrug of the compound, the ring A substituted by (RC)n3 is*O     , ** represents the site of fusing, represents the attachment position of the L group.

11. The compound according to any of claims 1-10, a stereoisomer or tautomer of the compound or a mixture thereof,a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative,or prodrug of the compound, wherein         J is selected from:2022412821   15 Sep 2026n^ / N;=a n^nHN 0       HNx__ / or12. The compound according to any of claims 1-11, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereinring B is     or13. The compound according to any of claims 1-12, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, wherein RD is selected from -SO2NH2, and -S(O)2ND2.

14. The compound according to any of claims 1-13, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, wherein n4 is 1, 2, 3 or 4.

15. The compound according to any of claims 1-13, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, wherein n4 is 1, 2, or 3.

16. The compound according to any of claims 1-15, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, whereinL is -CH2-.

17. A compound, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound, wherein said compound is selected from:2022412821   15 Sep 2026No. Structure No. Structure No. Structure 1 yti F         N ^CF3 F 1Y „S        F H2N 2 XX ,N, „N. III YYY r¥ v o=s=o nh2 5 XX ,N. ,N. Ill ^Y^0 o=s=o nh2 6 n. ,N. ,N. u fY V o=s=o nh2 7 ,0.      ,, U fYYY nynh v 0=S-NH2 n 0 8 yYY Y' o=s=o nh2 10 / 0.     ,N. UI / V v o=s=o nh2 11 / 0. Ill ^Y^N^CF3 o=s=o nh2 12 UQyO Y o=s=o nh2 13 ,0.      ,N, fXX^ UNU v o=s=o nh2 14 ,0. „IU ,N, Ill Y / ^Y N F3 rV v o=s=o nh2 15 ,0.      ,, u mi F'^'-'^Y^0 Y o=s=o nh2 16 XX      ,N. Uzi ^^Y^n^cf3 M. o=s=o nh2 17 ,O. ,N. ,N. uY fV" v o=s=o nh2 18 / 0. ^-N. ,N. uu fV Y o=s=o nh2 19 .1 \ YY o I 20 YY1 F N F N^O °n .S F h2n 21 ,N. Y Y 1 Y^ N ^CF3 F N Yq °n HU%   F 22 ,O. ,N. 1¾. zNUN Y o=s=o nh2 23 UNU UA cAj 1> o=s=o nh2 24 ,0. Y J1 YuY^n u u o=s=o nh21442022412821   15 Sep 2026p O UJ H— tp OO IP Pl \ o oJpl s Ypp^z \ o Ppyp 0 T 11 \_ /  \— / \ ” Q   Z—G Z 7P o— / \ \ \ o z-cnp / x)—\   )—( I ii \__ /  \   /  \ w O ^7 2rP ,z -n Z H-‘ bJ tp IP O \ o z      7     / =( ? pY 4 z o-T-o—( / v—v V—\ YYpp Xo °>p0 M - p^^p \ \ \ o <Cp2 z-cn— / x)—. )—( Z II \__ /  \ / P “ ° V ^p Z=Z Pl tP L»J (p o tp \ o ° P0 xf z-w-op7 \—< V—( - M P o—7 °    p Z-CZl-Z   >=x     / =< Z ° Mp O zA z MP ■n ?     <y° o ^pz 2 P\ / Z -MP o—' \ - J - -- \ o O ,--- /        /   'Z 11 \ / / Z-(T>—( /   x)---\     )---( I II \__ /  \   /  P “ ° V <p Z= / 1452022412821   15 Sep 2026o O O Ui Q0 Ui Ui Ui bo / 0. / N. / N. rV A o=s=o nh2 AN 0=S = 0 A oV Yta N N '0 O   / --(       \\ 11 Al     y ' Z-U) —(Z   7--\    / —\ " °      r O—7 SHN 0=8=0 A A7 EdO^,N^ / L / x, III / N N 0 An 0=8=0 A 11 IAA N      0 An o=s=o A 11 IIJA / 0. / N. / N. Ill ^AlxfAxNH fN0 A-o=s=o nh2 Os QO o Ah O bO Ui *0 Ui o Ui UJ Ah o AN 0 = 8 = 0 A oV YAa N N 0 A / ° a o=s=o nh2 AN 0=8=0 Al N N 0 ,O. / N. / N. ux o=s-nh2 o Q NZH ,sC A? 0 0 Arr oA-V An., N N 0 \ f w1 An o=s=o A N'X'^ oAdxi / N N 0 \ o ° aX z - co —0 3 s ) ( z it \ / ' / ' M ° —7   z\ / Z CD O o bO o 'sO o Os o UJ O o Xj Ah / 0. / x N. H 3 I? IAA A .OH N rN? x>° 0 = 3 = 0 nh2 / O.      N Al F            n Boc rV v o=s=o nh2 \ o °   O z-<z>A7  0—>.   )—( i ii  \_ /  A / I M ° —\  z—X X 1: v o=s=o nh2 \ jt’Al HO 0=8=0 oljX HhH °Vta N N 0 \ o Z - U> —0 3 >    ) ( I II \ / \, /  X M °  —7     X / Z -n oA / -^ rV '1-o=s=o nh2CD2022412821   15 Sep 2026no H— OO OO OO N / i OO bJ \0 UJ A / P,zu u o=s=o nh2 \ / u 0 N / ■ o=s=o nh2 / zz Wo z-cn—1 / C--\ C / Z 11   \__ /    \    )   \ w ° —\   zW z A' z— I Wo z-oi —C--, C / z ii \__ /    \     /   \ M ° —zU z z iWx f^f o=s=o nh2 HO. x?\ / ¾. ,N. "Xp 1 w° o=s=o nh2 ,0. YXl N       NH f-A v o=s=o nh2 2hn o=s=o A eV Wi\ N N 0 no no bo OO NO OO cn OO L>J OO o Yj u) u> o=s=o nh2 \U\ / u W-0 N o=s=o nh2 \ w=O I / o Wo z-tn—$ \--. C / z ii \__ /   \   2 w ° -\ zW z w^ qW \ o °PZT 2hn o=s=o A oW Yrw N N S D DY / O^N N. I UI -       N CF3 rV u o=s=o nh2 / 0. ,N. ,N. up o=s=o nh2 no cn no L>J no o OO OO OO H— OO u! / 0. / --      / ■ 0 N ■ ■ o=s=o nh2 'Up O—7 O z. / / in., z \ o zj^f^L Cj -WW z ° V \— z o' 1 ZHN 0=5=0 w HN^N^ kJ\W\ / 0N IXX / N      0 SHN 0 = S=0 X oV X A / N       097 A / xA ,0, n¥nh v o=s=o nh2 98 Yu o=s=o nh2 99 \ o Z-CZ)—(z x)--->     )---( I II \___ /    x     / x O — /  Z—\ / Z -n 0=(^ O 100 .

0. ,N. 1X1 o=s=o nh2 102 / 0. ,N. .N. 1X1 rY fY o=s=o nh2 103 XX ,N. <N'Y^CM v o=s=o nh2 104 ILY-NMi "4° o=s=o nh2 105 / 0. x<^ X^x TX1 o=s=o nh2 106 / Vv% r-N XXIX? F N^O i-Y h2n "o 107 XX x^xN^ WlY N^> O VF o=s=o nh2 108 x-O^x^xN^ T X      0 V / Z- o=s=o nh2 109 TY ° o=s=o nh2 110 XX YY ° ONHz Y' o=s=o nh2 111 / O. / ^xNx Y^ N o=s=o nh2 112 Xk ,N, ,N. 1X1 Y^ N f? v o=s=o nh2 113 / Vv% r-0 U / xO rY v o=s=o nh2 114 YXW Y v-o=s=o nh2 115 XI x^ pXXp^ n¥nh '7' cr nh2 116 ,(X ,N. ,N. UI v o-s— 0 117 XX xN. ,N. 1¾ r"Y° Y° 0 o=s=o 1 118 .

0. ,N, , N... 1¾ n¥nh v o=s=o O^OH 119 ,0.      / IX 1¾ N^NH v o=s=o ^nh2 120 .

0. yN, ,N. Ill Y~? v o=s=o HN O^OH2022412821   15 Sep 2026121 : O □- \ 122 Xk ,N. ,¾ 1¾ rV X HlL,° s, 6' NH2 123 ,0. UJ v o=s=o >.D 124 ,0.,,¾ ,¾ 1¾ n¥nh v o=s=o ,NH HO 125 ^0. ,¾ ,N. 1¾ N^O v o=s=o HN. nh2 129 .0^     yn.._ 1¾ rV v HN^O °\ 130 ,0. ,¾ ,¾ »Y»" °xy o=s=o nh2 131 ,0. ,¾ ,N. ,1¾ XY" o=s=o nh2 132 _N. ,30¾ j-Y” o=s=o nh2 133 ,Ck ,¾ ,¾ ,1¾ n¥nh H!NvA, 0 V o=s=o nh2 134 XX ,N. ,N. X T 1 N^Xo f3C^X 0 V o=s=o nh2 135 / 0. ,N. ,N. ,xiA [-V X o=s=o nh2 136 ,0.,¾ ,¾ n¥nh o=s=o nh2 nh2 137 / 0.,¾¾. ,1¾ XX HoXy^ o=s=o nh2 138 ,1¾ X ,0-¾ o=s=o nh2 139 X^^ o=s=o nh2 140 I JI J r j o=s=o nh2 141 ,0. .,¾ ,,¾ y yyf 0=S=0 F nh2 142 ,0. ,N. ,¾ IJ J xy "X 0 o=s = o nh2 143 ,0. _N. _N. ,xxA xV aY oo=s=o nh2 144 Xk ,N Y T Y, X- 0 o = s=o nh218. A pharmaceutical composition, containing the compound according to any of claims 1-17, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope derivative, or prodrug of the compound.

19. Use of the compound according to any of claims 1-17, a stereoisomer or tautomer of the compound or a mixture thereof, a pharmaceutically acceptable salt, co-crystal, polymorph or solvate of the compound, or a stable isotope2022412821   15 Sep 2026derivative, or prodrug of the compound or the pharmaceutical composition according to claim 18 in the manufacture of a medicament for preventing and / or treating ENPP1-mediated diseases;preferably, the ENPP1-mediated disease is cancer or tumour-related disease, or cardiovascular disease,more preferably, the ENPP1-mediated disease is pancreatic cancer, heart failure or myocardial infarction.