Aromatic heterocyclic compound and preparation method and use thereof

Abstract

The present application relates to aromatic heterocyclic compounds as ENPP1 inhibitors and the preparation method and use of the compounds.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical technology, and more specifically, to aromatic heterocyclic compounds as ENPP1 inhibitors, as well as methods for preparing and using said compounds. Background Technology

[0002] Cancer cells exhibit chromosomal instability; as cancer cells divide, DNA fragments, and even entire chromosomes, can be duplicated, mutated, or completely lost. The more unstable the chromosome, the more likely DNA fragments are to appear in unexpected locations, such as floating in the cytoplasm outside the cell nucleus. Cells recognize these free-floating DNA fragments as evidence of viral invasion, triggering internal alarms, inflammation, and the recruitment of immune cells to the tumor site to launch an immune attack.

[0003] STING, or Stimulator of Interferon Genes, is widely expressed on the endoplasmic reticulum of various immune cells. It mainly recognizes cyclic dinucleotides (CDNs), thereby detecting DNA leakage in the cytoplasm and eliciting an immune response.

[0004] DNA is normally found in the cell nucleus and mitochondria; the presence of DNA in the cytoplasm is abnormal. cGAS can sense DNA in the cytoplasm, synthesizing cyclic 2',3'-cGAMP from ATP or GTP. 2',3'-cGAMP binding activates STING, and 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 an anti-inflammatory effect. Furthermore, increased expression and metastasis of ENPP1 are associated with resistance to immunotherapy.

[0005] ENPP1 is a type II transmembrane glycoprotein with nucleotide pyrophosphatase and phosphodiesterase activities, belonging to the extracellular nucleotide pyrophosphatase / phosphodiesterase (Enpp) family, which consists of seven functionally distinct proteins (1-7). The ENPP1 structure contains 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, dendritic cells (DCs), and macrophages, and high levels in neutrophils. ENPP1 is also expressed in a small subset of B cells, which may be involved in the regulation of T cell activity. ENPP1 expression is elevated in M2 subtype macrophages, which play a role in tumor promotion. ENPP1 expression is increased in astrocytic tumors, breast cancer, and head and neck tumors. ENPP1 expression varies considerably among different tumor tissues. ENPP1 is specifically highly expressed in certain tumors and may be a driver of tumor immune escape and metastasis.

[0006] ENPP1 plays a crucial role in immune responses to various stimuli via the STING pathway, selectively activating the STING signaling pathway in tumor cells and other cells within the tumor microenvironment, achieving high selectivity. ENPP1 also catalyzes the hydrolysis of ATP into PPi and AMP, promoting adenosine production, which has a strong immunosuppressive effect. Inhibiting ENPP1 can reduce adenosine production by inhibiting ATP hydrolysis, thereby relieving tumor immunosuppression.

[0007] STING agonists indiscriminately activate STING in both cancer cells and host cells, while ENPP1 restricts STING activation to tumor tissue and the tumor microenvironment, thereby enhancing anti-tumor immunity. Furthermore, ENPP1 is selectively upregulated in metastatic and chromosomally unstable tumor cells. Systemic administration of ENPP1 inhibitors can interfere with the ability of spreading tumor cells to evade immune surveillance, avoiding the technical difficulties of intratumoral administration of STING agonists.

[0008] ENPP1 inhibitors combined with radiotherapy have shown good efficacy in animal models, and also exhibit synergistic effects when used in combination with immune checkpoint inhibitors such as PD-1 and PARP inhibitors. Currently, the development of ENPP1 inhibitors is in the preclinical research stage, but several pharmaceutical companies have already published patents related to ENPP1 inhibitors, such as WO2021061803A1, WO2021158829A1, WO2020190912A1, WO2019177971A1, and WO2019046778A1.

[0009] Following cardiac 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 crucial role in cardiac repair by regulating nucleotide metabolism and non-cardiomyocyte death (Shen Li et al., 2022). Cardiac injury induces the expression of the exonuclease exonuclease / phosphodiesterase 1 (ENPP1), which hydrolyzes extracellular ATP to form AMP. In response to AMP, cardiomyocytes release adenine and specific ribonucleosides, disrupting pyrimidine biosynthesis in the orrotidine monophosphate (OMP) synthesis step and inducing genotoxic stress and p53-mediated proliferation of non-cardiomyocyte death. Since non-cardiomyocytes are essential for cardiac repair, rescuing pyrimidine biosynthesis by administering uridine or through genetic targeting of the ENPP1 / AMP pathway can enhance repair after cardiac injury.

[0010] Although some small molecule ENPP1 inhibitors have been disclosed in existing technologies, there are currently no small molecule drugs on the market for clinical use. Therefore, the development of new compounds with market potential and better efficacy and pharmacokinetic results remains an urgent need. This invention designs a series of compounds with novel structures shown in the general formula and finds that compounds with such structures exhibit excellent effects and functions, which is of positive significance for the development of ENPP1 inhibitors. Summary of the Invention

[0011] The purpose of this invention is to provide a compound with an aromatic heterocyclic structure as an ENPP1 inhibitor, a method for preparing the compound, and its use in treating ENPP1-mediated diseases.

[0012] In a first aspect, the present invention provides a compound of formula (I), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0013]

[0014] Among them, X1, X2, X3, X4 and Y are independently CH or N;

[0015] And when X1, X2, X3, and X4 are all CH, Y is not CH;

[0016] R A R is a substituent in the ring containing X1. B For substituents in the ring containing Y, each R A and R BIndependently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -ZC(O)R4, -ZC(O)OR1, or -ZC(O)(CR5R6). n C(O)R4、-ZC(O)(CR5R6) n C(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-20 membered heterocyclic, 5-16 membered heteroaryl; wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0017] n1 is 1, 2, 3 or 4;

[0018] n2 is 1 or 2;

[0019] Ring A is a 6-10 membered heterocyclic group or a 6-12 membered heteroaryl group;

[0020] Rc is a substituent for ring A, and each R C Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -ZC(O)R4, -ZC(O)OR1, -ZC(O)(CR5R6) n C(O)R4、-ZC(O)(CR5R6) n C(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 cycloalkyl, C3-8 Cycloalkenyl, 3-20 membered heterocyclic groups, C 6-12 aryl, 5-16-membered heteroaryl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, aryl, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxime, -CN, -OH, -NO2, -NH2, C1-6 alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0021] n3 is 1, 2, 3, 4, 5, or 6;

[0022] Z is selected from key, C 1-3 Alkylene, C 1-3 alkeneoxy, C 1-3 The alkylene group, alkoxide group, and alkylene thionyl group may optionally be substituted by one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, and -NH2.

[0023] Ring B is C 3-10 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-14 Aryl or 5-16 heteroaryl groups;

[0024] R D Selected from -W-OC(O)OR1, -WC(O)NR2R3, -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2NR2R3, -WS(O)=N R2, -WS(O)=NR2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, -WB(OH)2, Or R DSelected from -W-OC(O)OR1, -WC(O)NR2R3, -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2NR2R3, -WS(O)=N R2, -WS(O)=NR2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, and -WB(OH)2;

[0025] Each R E Independently, it can be hydrogen, deuterium, halogen, oxo group, carboxyl group, -CN, -OH, -SH, -NO2, -NH2, -W-OR1, -W-SR1, -WC(O)R4, -WC(O)OR1, -W-OC(O)R1, -W-OC(O)OR1, -WC(O)NR2R3, -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2R3, -W-NR2C(O)R4. -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W -NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, -WB(OH)2, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-20 heterocyclic, 5-16 heteroaryl; wherein the alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0026] n is 1, 2, or 3;

[0027] n4 is 1, 2, 3, 4, 5, or 6;

[0028] W is selected from key, C 1-3 Alkylene, C 1-3 alkeneoxy, C 1-3 The alkylene group, alkoxide group, and alkylene thionyl group may optionally be substituted by one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, and -NH2.

[0029] L is selected from the bond, -O-, -S-, C. 1-6 Alkylene, C 1-6 alkeneoxy, C 3-6 Cycloalkylene, C 1-6 alkylthionyl, C 2-6 imidene group, C 2-6 The alkylene, alkoxyene, cycloalkylene, alkylthionylene, alkenylene, or alkynylene group may optionally be selected from one or more elements selected from deuterium, halogen, or C. 1-3 Alkyl, C 1-6 Substituted by alkoxy, oxo, -CN, -OH, or -NH2 substituents;

[0030] R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, phenyl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclic group is optionally selected from one or more halogens, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-4 Alkoxy, phenyl, C 1-3 Haloalkyl, C 1-4 Substituents of haloalkoxy and halophenyl groups;

[0031] R2 and R3 are independently hydrogen and C each time they appear. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally selected from one or more groups selected from halogen, deuterium, cyano, hydroxyl, amino, carboxyl, C 1-3 Alkyl, C 1-4 Alkoxy, C 1-4 Alkyl, C 3-8 Cycloalkyl, phenyl, C1-3 haloalkyl, C 1-3 Substituents of haloalkoxy and halophenyl groups;

[0032] R4 appears independently of hydrogen, deuterium, and C each time. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, phenyl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclic group is optionally selected from one or more halogens, cyano, hydroxyl, amino, C 1-3Alkyl, C 1-4 Alkoxy, phenyl, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy and halophenyl groups;

[0033] R5 and R6 are independently hydrogen and C. 1-3 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-3 Alkylthio, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-20 membered heterocyclic, 5-16 membered heteroaryl, wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, C1-3 alkyl, C 1-3 The alkyl halogroup is substituted by a substituent.

[0034] When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E They can be the same or different.

[0035] In a preferred embodiment of the first aspect of the invention, X1 is N, and X2, X3 and X4 are all CH.

[0036] In a preferred embodiment of the first aspect of the invention, X3 is N, and X1, X2 and X4 are all CH.

[0037] In a preferred embodiment of the first aspect of the invention, X1 and X3 are both N, and X2 and X4 are both CH.

[0038] In a preferred embodiment of the first aspect of the invention, X1, X2, X3 and X4 are all CH.

[0039] In a preferred embodiment of the first aspect of the invention, in any of the foregoing embodiments of the first aspect, Y is CH; or Y is N.

[0040] In a preferred embodiment of the first aspect of the invention, in any of the foregoing embodiments of the first aspect, each R AIndependently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclic groups, -ZC(O)R4, -ZC(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0041] Or, each R A Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclic groups, -ZC(O)R4, -ZC(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C 1-4 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0042] Or, each R A Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclic groups, -ZC(O)R4, -ZC(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C 1-4 Alkyl, C2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0043] Or, each R A Independently, it is hydrogen, deuterium, F, Cl, Br, oxime, -CN, -OH, -SH, -NO2, -NH2, -NR2C(O)R4, -NR2C(O)OR1, 3-6 membered heterocyclic group, -C(O)R4, -C(O)OR1, -C(O)NR2R3, -S(O)2R4, -S(O)2NR2R3, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl, vinyl, ethynyl, propynyl, propynyl;

[0044] Or, each R A Independently, it can be hydrogen, F, Cl, Br, oxime, -CN, -OH, -NH2, or -NHC(O)C. 1-3 Alkyl, -NHC(O)OC 1-3 Alkyl, 3-4 membered heterocyclic groups, -C(O)C 1-3 Alkyl, -C(O)OC 1-3 Alkyl group, -C(O)NHC 1-3 Alkyl group, -S(O)2C 1-3 Alkyl group, -S(O)2NH2, -S(O)2NHC 1-3 Alkyl, methyl, ethyl, methoxy, ethoxy, methylthio, vinyl, propenyl, ethynyl, cyclopropyl, tert-butyl;

[0045] Or, R A Selected from hydrogen, F, Cl, -CN, -NH2, oxime, methyl, methoxy, ethoxy, methylthio, -OCD3, -NHCOCH3, -NHCOOCH3, -COCH3, -COOCH3, -COCH2OCH3, -CONHCH3, -SO2CH3, -SO2NH2, -CH=CH-CH3, ethynyl, cyclopropyl, tert-butyl.

[0046] In a preferred embodiment of the first aspect of the invention, in any of the aforementioned embodiments of the first aspect, n1 is 1, 2 or 3; or, n1 is 1 or 2.

[0047] In a preferred embodiment of the first aspect of the invention, in any of the foregoing embodiments of the first aspect, each R B Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, C1-6 alkoxy group, C 1-6 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0048] Or, each R B Independently, it is hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, vinyl, propenyl, ethynyl, propynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl;

[0049] Or, each R B Independently, it can be hydrogen, F, Cl, Br, -OH, -NH2, methyl, ethyl, methoxy, ethoxy, vinyl, or ethynyl.

[0050] Or, R B Selected from hydrogen, -NH2, methyl, methoxy, and ethynyl.

[0051] In a preferred embodiment of the first aspect of the invention, n2 is 1 in any of the aforementioned embodiments of the first aspect.

[0052] In a preferred embodiment of the first aspect of the present invention, in any of the aforementioned embodiments of the first aspect, ring A is a 6-9 membered heterocyclic group or a 6-12 membered heteroaryl group;

[0053] Alternatively, ring A may be a 6-8 membered heterocyclic group or a 6-8 membered heteroaryl group;

[0054] Alternatively, ring A can be a 6-membered heterocyclic group or a 6-membered heteroaryl group;

[0055] Alternatively, ring A can be: piperidinyl, hexahydropyrimidinyl, piperazinyl, 1,3-oxazinyl, morpholinyl, thiomorpholinyl, 1,3-thiazinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, pyridinyl, pyridinyl, 1,4-diazacycloheptane, 1,5-diazacyclooctane, 1,4-oxazocycloheptane, 1,3-oxazocycloheptane, 1,4-oxazocyclooctane, 2,3,6,7-tetrahydro-1,4-diazacycloheptan;

[0056] Alternatively, ring A can be: Represents the location of the L group;

[0057] Alternatively, ring A can be: **Represents a fusion site. Represents the location of the L group;

[0058] Alternatively, when one or both Rc groups are oxo groups, the ring A substituted by the aforementioned one or two Rc groups is: **Represents a fusion site.

[0059] Represents the location of the L group;

[0060] Alternatively, the ring A substituted by Rc is:

[0061] In a preferred embodiment of the first aspect of the invention, in any of the foregoing embodiments of the first aspect, each R C Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, -ZC(O)OR1, -ZNR2C(O)R4, -ZS(O)2R4, -ZS(O)2NR2R3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-8 membered heterocyclic, 5-8 membered heteroaryl, C 6-12 aryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, heteroaryl, or aryl group may optionally be selected from one or more groups selected from hydrogen, deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0062] Or, each R C Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, -ZC(O)OR1, -ZNR2C(O)R4, -ZS(O)2R4, -ZS(O)2NR2R3, C 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-8 membered heteroaryl, C 6-12 aryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, heteroaryl, or aryl group may optionally be selected from one or more groups selected from hydrogen, deuterium, halogen, oxo, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0063] Or, each R C Independently hydrogen, halogen, oxo group, -CN, -OH, -SH, -NH2, -C(O)OC 1-6 Alkyl, carboxyl, -NHC(O)C 1-6 Alkyl group, -S(O)2C 1-6 Alkyl groups, -S(O)2NH2, -CH2S(O)2C 1-6 Alkyl, C 1-3 Alkyl, C 2-4 alkenyl, C2-4 ynyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 Cycloalkyl, 3-6 membered heterocyclic, 5-8 membered heteroaryl, C 6-12aryl; the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, cycloalkyl, heterocyclic, heteroaryl, or aryl group may optionally be selected from one or more halogens, oximes, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups;

[0064] Or, each R C Independently, it can be hydrogen, F, Cl, Br, oxo group, -CN, -OH, -SH, -NH2, -C(O)OC 1-4 Alkyl, carboxyl, -NHC(O)C 1-4 Alkyl group, -S(O)2C 1-4 Alkyl groups, -S(O)2NH2, -CH2S(O)2C 1-4 Alkyl, tetrahydrofuranyl, pyrrolyl, phenyl, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, vinyl, propynyl, ethynyl, propynyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl.

[0065] Alternatively, each Rc can be independently hydrogen, Cl, oxo group, oxime, -CN, -OH, -SH, -NH2, -Boc, -COCH2OH, -NHC(O)CH3, carboxyl group, -S(O)2CH3, -S(O)2NH2, -CH2S(O)2CH3, methoxy group, methylthio group, -CH2CH2CH2OH, -CH2CH2CH2OCH3, ethyl group, -CH2CF3, cyclopropyl, phenyl, vinyl.

[0066] In a preferred embodiment of the first aspect of the invention, in any of the aforementioned embodiments of the first aspect, n3 is 1, 2 or 3.

[0067] In a preferred embodiment of the first aspect of the invention, in any of the aforementioned embodiments of the first aspect, Selected from the following structure:

[0068]

[0069] In a preferred embodiment of the first aspect of the invention, in any of the aforementioned embodiments of the first aspect, ring B is C. 5-10 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-14 Aryl or 5-16 heteroaryl groups;

[0070] Alternatively, ring B is C. 5-7 Cycloalkyl, 5-7 member monocyclic heterocyclic groups, 5-14 member spirocyclic groups, 5-14 member fused heterocyclic groups, C 6-10 Aryl, 5-6 member mono-heteroaryl or 5-14 member fused heteroaryl;

[0071] Alternatively, ring B can be a C6 cycloalkyl, C7 cycloalkyl, 6-membered monocyclic heterocyclic group, 7-membered monocyclic heterocyclic group, 4-membered / 4-membered spiroheterocyclic group, 4-membered / 5-membered spiroheterocyclic group, 5-membered / 4-membered spiroheterocyclic group, 5-membered / 5-membered spiroheterocyclic group, 4-membered / 4-membered fused heterocyclic group, 4-membered / 5-membered fused heterocyclic group, 5-membered / 4-membered fused heterocyclic group, 5-membered / 5-membered fused heterocyclic group, 5-membered / 5-membered fused heterocyclic group, etc. The heteroatoms in the following heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0072] Alternatively, ring B is:

[0073] In a preferred embodiment of the first aspect of the invention, in any of the aforementioned embodiments of the first aspect, R D Selected from -WC(O)NR2R3, -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, -WB(OH)2, Or R DSelected from -WC(O)NR2R3, -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, -WB(OH)2;

[0074] Or, R D Selected from -C 0-3 Alkylene -C(O)NHOH, -C 0-3 Alkylene -OC(O)NH2, -C 0-3 Alkylene -SO2NH2, -C 0-3 Alkylene -NHS(O)2H, -C 0-3 Alkylene -OS(O)2H, -C 0-3 Alkylene -NHS(O)2NH2, -C 0-3 Alkylene -OS(O)2NH2, -C 0-3 Alkylene -P(O)(OH)2, -C 0-3 Alkylene -P(S)(OH)2, -C 0-3 Alkylene -OP(S)(OH)2, -C 0-3 Alkylene -B(OH)2, -C 0-3 Alkylene -S(O)2OH, -C 0-3 Alkylene C(O)NH2, -C 0-3 Alkylene S(O)2C 1-3 Alkyl, -C 0-3 Alkylene-OS(O)2-C 1-3 Alkyl, -C 0-3 Alkylene-S(O)2-C 1-3 Alkylene -C(O)OH, -C 0-3 Alkylene-S(O)2C 1-3 Alkylene -NH2, -C 0-3 Alkylene -S(O)2NHCH2C(O)OH, -C 0-3 Alkylene NHS(O)2CH3, -C 0-3 Alkylene S(O)2ND2, -C 0-3 Alkylene S(O)2NHNH2, -C 0-3 Alkylene S(O)2NHSC 1-3 Alkyl, -C 0-3 Alkylene-NHS(O)2C1-3 Alkyl, -C 0-3 Alkylene-NH-C(O)C 1-3 Alkyl, -C 0-3 Alkylene -NH-CONH2, -C 0-3 Alkylene-NH-COO C 1-3 Alkyl, or -C 0-3 Alkylene-S(O)2NHOH, or Or R D Selected from -C 0-3 Alkylene -C(O)NHOH, -C 0-3 Alkylene -OC(O)NH2, -C 0-3 Alkylene -SO2NH2, -C 0-3 Alkylene -NHS(O)2H, -C 0-3 Alkylene -OS(O)2H, -C 0-3 Alkylene -NHS(O)2NH2, -C 0-3 Alkylene -OS(O)2NH2, -C 0-3 Alkylene -P(O)(OH)2, -C 0-3 Alkylene -P(S)(OH)2, -C 0-3 Alkylene -OP(S)(OH)2, -C 0-3 Alkylene -B(OH)2, -C 0-3 Alkylene -S(O)2OH, -C 0-3 Alkylene C(O)NH2, -C 0-3 Alkylene S(O)2C 1-3 Alkyl, -C 0-3 Alkylene-OS(O)2-C 1-3 Alkyl, -C 0-3 Alkylene-S(O)2-C 1-3 Alkylene -C(O)OH, -C 0-3 Alkylene-S(O)2C 1-3 Alkylene -NH2, -C 0-3 Alkylene -S(O)2NHCH2C(O)OH, -C 0-3 Alkylene NHS(O)2CH3, -C 0-3 Alkylene S(O)2ND2, -C 0-3 Alkylene S(O)2NHNH2, -C 0-3 Alkylene S(O)2NHSC 1-3 Alkyl, -C 0-3 Alkylene-NHS(O)2C 1-3 Alkyl, -C 0-3 Alkylene-NH-C(O)C 1-3 Alkyl, -C 0-3Alkylene -NH-CONH2, -C 0-3 Alkylene-NH-COO C 1-3 Alkyl, or -C 0-3 Alkylene-S(O)2NHOH;

[0075] Or, R D 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-OP(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, -OP(S)(OH)2, -B(OH)2; -S(O)2OH, -C(O)NH2, -S(O)2C 1-3 Alkyl, -OS(O)2C 1-3 Alkyl group, -S(O)2C 1-3 Alkylene C(O)OH, -S(O)2C 1-3 Alkylene -NH2, -S(O)2NHCH2C(O)OH, -NHS(O)2CH3, -S(O)2ND2, -S(O)2NHNH2, -methylene -NHS(O)2C 1-3 Alkyl, -methylene-NH-C(O)C 1-3 Alkyl, -methylene-NH-CONH2, -NH-COOC 1-3 Alkyl, or -S(O)2NHOH, or Or perhaps, R DSelected 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-OP(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, -OP(S)(OH)2, -B(OH)2; -S(O)2OH, -C(O)NH2, -S(O)2C 1-3 Alkyl, -OS(O)2C 1-3 Alkyl group, -S(O)2C 1-3 Alkylene C(O)OH, -S(O)2C 1-3 Alkylene -NH2, -S(O)2NHCH2C(O)OH, -NHS(O)2CH3, -S(O)2ND2, -S(O)2NHNH2, -methylene -NHS(O)2C 1-3 Alkyl, -methylene-NH-C(O)C 1-3 Alkyl, -methylene-NH-CONH2, -NH-COOC 1-3 Alkyl group, or -S(O)2NHOH;

[0076] Or, R D 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, or -S(O)2NHOH, or Or, R DSelected 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, or -S(O)2NHOH.

[0077] In a preferred embodiment of the first aspect of the invention, in any of the foregoing embodiments of the first aspect, each R E Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, or C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 ynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl group is optionally selected from one or more groups selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C1-6 haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0078] Or, each R E Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups, wherein the alkyl, alkoxy, or cycloalkyl group is optionally surrounded by one or more elements selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups;

[0079] Or, each R E Independently hydrogen, halogen, -OH, -SH, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally surrounded by one or more elements selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C1-3 alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups;

[0080] Or, each R E Independently, it is 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, methoxymethyl;

[0081] Or, each R E Independently, it can be 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, vinyl, ethynyl, propynyl, ethyl, propenyl.

[0082] In a preferred embodiment of the first aspect of the invention, in any of the aforementioned embodiments of the first aspect, n4 is 1, 2, 3 or 4; or, n4 is 1, 2 or 3.

[0083] In a preferred embodiment of the first aspect of the invention, in any of the aforementioned embodiments of the first aspect, L represents a bond, -O-, -S-, or C. 1-3 Alkylene, C 1-3 alkeneoxy, C 3-6 Cycloalkylene, C 1-3 alkylthionyl, C 2-6 imidene group, C 2-6 The alkylene, alkoxyene, cycloalkylene, alkylthionylene, alkenylene, or alkynylene group may optionally be selected from one or more elements selected from deuterium, halogen, or C. 1-3 Alkyl, C 1-3 Substituted by alkoxy, oxo, -CN, -OH, or -NH2 substituents;

[0084] Alternatively, L can be a bond, such as -O-, -S-, methylene, ethylene, propylene, cyclopropylene, or cyclobutylene. 1-3The alkoxide, C1-3 alkoxidethion, vinylene, and ethynylene groups are 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.

[0085] Alternatively, L represents a bond, such as -O-, -S-, cyclopropyl, methylene methoxy, methylene methyl, methylene-OH, methylene-NH2, ethylene, or propylene;

[0086] Alternatively, L can be a bond, such as -O-, -CH2-,

[0087] A second aspect of the present invention provides a compound of formula (I), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0088]

[0089] Among them, X1, X2, X3, X4 and Y are independently CH or N;

[0090] And when X1, X2, X3, and X4 are all CH, Y is not CH;

[0091] R A R is a substituent in the ring containing X1. B For substituents in the ring containing Y, each R A and R B Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -ZC(O)R4, -ZC(O)OR1, or -ZC(O)(CR5R6). n C(O)R4、-ZC(O)(CR5R6) n C(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C 1-6 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 cycloalkyl, C 3-8Cycloalkenyl, 3-20 membered heterocyclic, 5-16 membered heteroaryl; wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0092] n1 is 1, 2, 3 or 4;

[0093] n2 is 1 or 2;

[0094] Ring A is a 6-10 membered heterocyclic group or a 6-12 membered heteroaryl group;

[0095] Rc is a substituent for ring A, and each R C Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -ZC(O)R4, -ZC(O)OR1, -ZC(O)(CR5R6) n C(O)R4、-ZC(O)(CR5R6) n C(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-20 membered heterocyclic, 5-16 membered heteroaryl; wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C1-6 alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0096] n3 is 1, 2, 3, 4, 5, or 6;

[0097] Z is selected from key, C 1-3 Alkylene, C 1-3 alkeneoxy, C 1-3The alkylene group, alkoxide group, and alkylene thionyl group may optionally be substituted by one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, and -NH2.

[0098] Ring B is C 3-10 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-14 Aryl or 5-16 heteroaryl groups;

[0099] R D Selected from -W-OC(O)OR1, -WC(O)NR2R3, -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2 NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, -WB(OH)2;

[0100] Each R E Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, -W-OR1, -W-SR1, -WC(O)R4, -WC(O)OR1, -W-OC(O)R1, -W-OC(O)OR1, -WC(O)NR2R3, -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2R3, -W-NR2C(O)R4, -W -NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2NR2R3, -W-NR2S(O)2R4, -W-OS(O)2R4, -W- NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, -WB(OH)2, C 1-6 Alkyl, C2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-20 heterocyclic, 5-16 heteroaryl; wherein the alkyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0101] n4 is 1, 2, 3, 4, 5, or 6;

[0102] W is selected from key, C 1-3 Alkylene, C 1-3 alkeneoxy, C 1-3 The alkylene group, alkoxide group, and alkylene thionyl group may optionally be substituted by one or more substituents selected from deuterium, halogen, oxo group, -CN, -OH, and -NH2.

[0103] L is selected from the bond, -O-, -S-, C. 1-6 Alkylene, C 1-6 alkeneoxy, C 3-6 Cycloalkylene, C 1-6 alkylthionyl, C 2-6 imidene group, C 2-6 The alkylene, alkoxyene, cycloalkylene, alkylthionylene, alkenylene, or alkynylene group may optionally be selected from one or more elements selected from deuterium, halogen, or C. 1-3 Alkyl, C 1-6 Substituted by alkoxy, oxo, -CN, -OH, or -NH2 substituents;

[0104] R1 is independently hydrogen or C each time it appears. 1-6 Alkyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, phenyl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclic group is optionally selected from one or more halogens, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-4 Alkoxy, phenyl, C 1-3 Haloalkyl, C 1-4 Substituents of haloalkoxy and halophenyl groups;

[0105] R2 and R3 are independently hydrogen and C each time they appear. 1-6 Alkyl, C 1-6 Alkoxy groups, wherein the alkyl or alkoxy group is optionally surrounded by one or more groups selected from halogen, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-4 Alkoxy, phenyl, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy and halophenyl groups;

[0106] R4 appears independently of hydrogen, deuterium, and C each time. 1-6 Alkyl, C 1-6 Alkoxy, C3-8 Cycloalkyl, phenyl, 3-20 membered heterocyclic groups, wherein the alkyl, alkoxy, cycloalkyl, phenyl, or heterocyclic group is optionally selected from one or more halogens, cyano, hydroxyl, amino, C 1-3 Alkyl, C 1-4 Alkoxy, phenyl, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy and halophenyl groups;

[0107] R5 and R6 are independently hydrogen and C. 1-3 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-3 Alkylthio, C 3-6 cycloalkyl, C 3-6 Cycloalkenyl, 3-20 membered heterocyclic, 5-16 membered heteroaryl, wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, -CN, -OH, -NH2, C1-3 alkyl, C 1-3 The alkyl halogroup is substituted by a substituent.

[0108] In a preferred embodiment of the second aspect of the invention, X1 is N, and X2, X3 and X4 are all CH.

[0109] In a preferred embodiment of the second aspect of the invention, X3 is N, and X1, X2 and X4 are all CH.

[0110] In a preferred embodiment of the second aspect of the invention, X1 and X3 are both N, and X2 and X4 are both CH.

[0111] In a preferred embodiment of the second aspect of the invention, X1, X2, X3 and X4 are all CH.

[0112] In a preferred embodiment of the first aspect of the invention, in any of the foregoing embodiments of the first aspect, Y is CH; or Y is N.

[0113] In a preferred embodiment of the first aspect of the invention, in any of the foregoing embodiments of the first aspect, each R A Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, or C. 1-6 Alkyl, C 2-6 alkenyl, C 2-6 Alkyne group, C1-6 alkoxy group, C 1-6 Alkylthio, C 3-8Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0114] Or, each R A Independently, it can be hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0115] Or, each R A Independently, it can be hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 2-4 alkenyl, C 2-4 alkynyl group, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0116] Or, each R AIndependently, it is hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, cyclopropyl, cyclobutyl, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl;

[0117] Or, each R A Independently, it can be hydrogen, F, Cl, Br, -OH, methyl, ethyl, methoxy, or ethoxy.

[0118] Or, R A Selected from hydrogen, F, Cl, and methoxy groups.

[0119] In a preferred embodiment of the second aspect of the invention, n1 is 1, 2 or 3; more preferably, n1 is 1 or 2.

[0120] In a preferred embodiment of the second aspect of the invention, each R B Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0121] Further preferred, each R B Independently, it is 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, methoxymethyl;

[0122] More preferably, each R BIndependently, it is hydrogen, F, Cl, Br, -OH, methyl, ethyl, methoxy, ethoxy; most preferably, R B Selected from hydrogen.

[0123] In a preferred embodiment of the second aspect of the invention, n2 is 1.

[0124] In a preferred embodiment of the second aspect of the present invention, ring A is a 6-9 membered heterocyclic group or a 6-12 membered heteroaryl group;

[0125] Preferably, ring A is a 6-membered heterocyclic group or a 6-membered heteroaryl group;

[0126] Preferably, ring A is: piperidinyl, hexahydropyrimidinyl, piperazinyl, 1,3-oxazinyl, morpholinyl, thiomorpholinyl, 1,3-thiazinyl, 1,2,3,6-tetrahydropyridinyl, 1,2,3,6-tetrahydropyrimidinyl, 1,4,5,6-tetrahydropyrimidinyl, homopiperidinyl, homopiperazinyl, homomorpholinyl, pyridinyl, pyridinyl, pyrimidinyl;

[0127] Preferably, ring A is: This represents the location where the L group is attached.

[0128] Furthermore, ring A is preferably: **Represents a fusion site. This represents the location where the L group is attached.

[0129] Preferably, when one or both Rc groups are oxo groups, the ring A substituted by the one or two Rc groups is: **Represents a fusion site. This represents the location where the L group is attached.

[0130] More preferably, the Rc-substituted ring A is:

[0131] In a preferred embodiment of the second aspect of the invention, in any of the foregoing embodiments of the second aspect, each R C Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, or C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 ynyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6Cycloalkyl; wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0132] Or, each R C Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl; wherein the alkyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy groups;

[0133] Or, each R C Independently hydrogen, halogen, oxo group, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Alkylthio, C 3-6 Cycloalkyl; wherein the alkyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more halogens, oxo groups, oximes, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups;

[0134] Or, each R C Independently, it can be hydrogen, F, Cl, Br, oxo group, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, methylthio, trifluoromethyl, difluoromethyl, monofluoromethyl, trifluoroethyl, difluoroethyl, monofluoroethyl, hydroxypropyl, hydroxyethyl, hydroxymethyl, methoxypropyl, methoxyethyl, methoxymethyl;

[0135] Alternatively, each Rc can be independently hydrogen, -CH2CF3, oxo group, -CH2CH2CH2OH, or -CH2CH2CH2OCH3.

[0136] In a preferred embodiment of the second aspect of the invention, in any of the foregoing embodiments of the second aspect, n3 is 1, 2 or 3.

[0137] In a preferred embodiment of the second aspect of the invention, in any of the foregoing embodiments of the second aspect, Selected from the following structure:

[0138]

[0139] In a preferred embodiment of the second aspect of the invention, in any of the aforementioned embodiments of the second aspect, ring B is C. 5-10 Cycloalkyl, 3-20 membered heterocyclic groups, C 6-14 Aryl or 5-16 heteroaryl groups;

[0140] Alternatively, ring B is C. 5-7 Cycloalkyl, 5-7 member monocyclic heterocyclic groups, 5-14 member spirocyclic groups, 5-14 member fused heterocyclic groups, C 6-10 Aryl, 5-6 member mono-heteroaryl or 5-14 member fused heteroaryl;

[0141] Alternatively, ring B can be a C6 cycloalkyl, C7 cycloalkyl, 6-membered monocyclic heterocyclic group, 7-membered monocyclic heterocyclic group, 4-membered / 4-membered spiroheterocyclic group, 4-membered / 5-membered spiroheterocyclic group, 5-membered / 4-membered spiroheterocyclic group, 5-membered / 5-membered spiroheterocyclic group, 4-membered / 4-membered fused heterocyclic group, 4-membered / 5-membered fused heterocyclic group, 5-membered / 4-membered fused heterocyclic group, 5-membered / 5-membered fused heterocyclic group, 5-membered / 5-membered fused heterocyclic group, etc. The heteroatoms in the following heterocyclic groups are independently selected from O, N, or S, and the number of heteroatoms is 1, 2, or 3.

[0142] Alternatively, ring B is:

[0143] In a preferred embodiment of the second aspect of the invention, in any of the foregoing embodiments of the second aspect, R DSelected from -WC(O)NR2OR1, -W-OC(O)NR2R3, -W-NR2C(O)R4, -W-NR2C(O)OR1, -W-NR2C(O)NR2R3, -WS(O)2R4, -W-SO2NR2R3, -W-NR2 S(O)2R4, -W-OS(O)2R4, -W-NR2S(O)2NR2R3, -W-OS(O)2NR2R3, -WP(O)(OR1)2, -WP(S)(OR1)2, -WOP(S)(OR1)2, -WB(OH)2;

[0144] Or, R D 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-OP(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, -OP(S)(OH)2, -B(OH)2;

[0145] Or, R D 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-OP(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, -OP(S)(OH)2, -B(OH)2;

[0146] Or, R D 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.

[0147] In a preferred embodiment of the second aspect of the invention, in any of the foregoing embodiments of the second aspect, each R EIndependently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, or C. 1-6 Alkyl, C 2-6 alkenyl, C2-6 ynyl, C 1-6 Alkoxy, C 3-8 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, or cycloalkyl group is optionally selected from one or more groups selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C1-6 haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0148] Or, each R E Independently, it can be hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl groups, wherein the alkyl, alkoxy, or cycloalkyl group is optionally surrounded by one or more elements selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-3 Alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups;

[0149] Or, each R E Independently hydrogen, halogen, -OH, -SH, C 1-3 Alkyl, C 1-3 Alkoxy, C 3-6 Cycloalkyl, wherein the alkyl, alkoxy, or cycloalkyl group is optionally surrounded by one or more elements selected from hydrogen, deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C1-3 alkyl, C 1-3 Alkoxy, C 1-3 Haloalkyl, C 1-3 Substituents of haloalkoxy groups;

[0150] Or, each R E Independently, it is 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, methoxymethyl;

[0151] Or, each R E Independently, it is hydrogen and F.

[0152] In a preferred embodiment of the second aspect of the invention, in any of the aforementioned embodiments of the second aspect, n4 is 1, 2, 3 or 4; or, n4 is 1, 2 or 3.

[0153] In a preferred embodiment of the second aspect of the invention, in any of the foregoing embodiments of the second aspect, L represents a bond, -O-, -S-, or C. 1-3 Alkylene, C 1-3 alkeneoxy, C 3-6 Cycloalkylene, C 1-3 alkylthionyl, C 2-6 imidene group, C 2-6 The alkylene, alkoxyene, cycloalkylene, alkylthionylene, alkenylene, or alkynylene group may optionally be selected from one or more elements selected from deuterium, halogen, or C. 1-3 Alkyl, C 1-3 Substituted by alkoxy, oxo, -CN, -OH, or -NH2 substituents;

[0154] Alternatively, L can be a bond, such as -O-, -S-, methylene, ethylene, propylene, cyclopropylene, or cyclobutylene. 1-3 The alkoxide, C1-3 alkoxidethion, vinylene, and ethynylene groups are 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.

[0155] Alternatively, L represents a bond, such as -O-, -S-, cyclopropyl, methylene methoxy, methylene methyl, methylene-OH, methylene-NH2, ethylene, or propylene;

[0156] Alternatively, L can be a bond, such as -O-, -CH2-,

[0157] In a third aspect of the invention, a compound of formula (Ia) is also provided, a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0158]

[0159] Y1 and Y2 are independently selected from C, O, or S, and Y1 and Y2 are not the same; n5 is selected from 1 or 2; when Y2 is not C, n6 is 1, and when Y2 is C, n6 is selected from 1 or 2; X1~X4, Y, R A R BR C R D R E L, ring B, n1 to n4 are as described in any of the foregoing embodiments of formula (I) in the first and second aspects of the present invention;

[0160] In a preferred embodiment of the third aspect of the present invention, Y1 is O and Y2 is C;

[0161] In a preferred embodiment of the third aspect of the present invention, Y1 is S and Y2 is C;

[0162] In a preferred embodiment of the third aspect of the present invention, Y2 is O and Y1 is C;

[0163] In a preferred embodiment of the third aspect of the present invention, Y2 is S and Y1 is C;

[0164] In a preferred embodiment of the third aspect of the invention, in any of the foregoing embodiments of the third aspect, Selected from the following structure:

[0165]

[0166] In a preferred embodiment of the third aspect of the invention, in any of the foregoing embodiments of the third aspect, at least one R C It is an oxo group.

[0167] In a fourth aspect, the present invention also provides a compound represented by the formula (I-a1):

[0168]

[0169] Where W is selected from halogen or The halogen is preferably Cl or Br; other substituents are as described in formula (Ia) of any of the third aspects above.

[0170] In a fifth aspect, the present invention also provides a compound of formula (Ib), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0171]

[0172] Y1 and Y2 are independently selected from C, O, or S, and Y1 and Y2 are not the same; n5 is selected from 1 or 2; when Y2 is not C, n6 is 1, and when Y2 is C, n6 is selected from 1 or 2; X1~X4, Y, R A RB R C R D R E L, ring B, n1 to n4 are as described in any of the foregoing embodiments of formula (I) in the first and second aspects of the present invention;

[0173] In a preferred embodiment of the fifth aspect of the present invention, Y1 is O and Y2 is C;

[0174] In a preferred embodiment of the fifth aspect of the present invention, Y1 is S and Y2 is C;

[0175] In a preferred embodiment of the fifth aspect of the present invention, Y2 is O and Y1 is C;

[0176] In a preferred embodiment of the fifth aspect of the present invention, Y2 is S and Y1 is C;

[0177] In a preferred embodiment of the fifth aspect of the invention, in any of the foregoing embodiments of the fifth aspect, Selected from the following structure:

[0178]

[0179] In a preferred embodiment of the fifth aspect of the invention, in any of the foregoing embodiments of the fifth aspect, at least one R C It is an oxo group.

[0180] In a sixth aspect, the present invention also provides a compound represented by the following formula (I-b1):

[0181]

[0182] Where W is selected from halogen or The halogen is preferably Cl or Br; other substituents are as described in formula (Ib) of any of the fifth aspects above.

[0183] In a seventh aspect, the present invention also provides a compound of formula (Ic), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0184]

[0185] Y1 and Y2 are independently selected from C or N; n5 is selected from 1 or 2; when Y2 is not C, n6 is 1, and when Y2 is C, n6 is selected from 1 or 2. Indicates a single or double bond, with at most one double bond, X1~X4, Y, R A R B R C R D R E L, ring B, n1 to n4 are as described in any of the foregoing embodiments of formula (I) in the first and second aspects of the present invention;

[0186] In a preferred embodiment of the seventh aspect of the present invention, Y1 is N and Y2 is C;

[0187] In a preferred embodiment of the seventh aspect of the present invention, Y1 is C and Y2 is N;

[0188] In a preferred embodiment of the seventh aspect of the present invention, Y1 is C and Y2 is C;

[0189] In a preferred embodiment of the seventh aspect of the invention, in any of the foregoing embodiments of the seventh aspect, Selected from the following structure:

[0190]

[0191] In a preferred embodiment of the seventh aspect of the invention, in any of the foregoing embodiments of the seventh aspect, at least one R C It is an oxo group.

[0192] In an eighth aspect, the present invention also provides a compound represented by the formula (I-c1):

[0193]

[0194] Where W is selected from halogen or The halogen is preferably Cl or Br; other substituents are as described in formula (Ic) of any of the seventh aspects above.

[0195] In a ninth aspect of the invention, the invention also provides a compound of formula (Id), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0196]

[0197] Y1 and Y2 are independently selected from C or N; n5 is selected from 1 or 2; when Y2 is not C, n6 is 1, and when Y2 is C, n6 is selected from 1 or 2. Indicates a single or double bond, with at most one double bond present, X1~X4, Y, RA R B R C R D R E L, ring B, n1 to n4 are as described in the compound of formula (I) in any of the foregoing embodiments of the first and second aspects of the present invention.

[0198] In a preferred embodiment of the ninth aspect of the present invention, Y1 is N and Y2 is C;

[0199] In a preferred embodiment of the ninth aspect of the present invention, Y1 is C and Y2 is N;

[0200] In a preferred embodiment of the ninth aspect of the invention, in any of the foregoing embodiments of the ninth aspect, Selected from the following structure:

[0201]

[0202] In a preferred embodiment of the ninth aspect of the invention, in any of the foregoing embodiments of the ninth aspect, at least one R C It is an oxo group.

[0203] In a tenth aspect, the present invention also provides a compound represented by the following formula (I-d1):

[0204]

[0205] Where W is selected from halogen or The halogen is preferably Cl or Br; other substituents are as described in formula (Id) in any of the preceding ninth aspects.

[0206] In an eleventh aspect of the invention, the invention also provides a compound of formula (Ie), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0207]

[0208] Where Y1 and Y2 are independently selected from C or N, Indicates a single or double bond, with at most one double bond present, X1~X4, Y, R A R B R C R D R E L, ring B, n1 to n4 are as described in the compound of formula (I) in any of the foregoing embodiments of the first and second aspects of the present invention.

[0209] In a preferred embodiment of the 11th aspect of the present invention, Y1 is N and Y2 is C;

[0210] In a preferred embodiment of the 11th aspect of the present invention, Y1 is C and Y2 is N;

[0211] In a preferred embodiment of the eleventh aspect of the invention, in any of the aforementioned embodiments of the eleventh aspect, Selected from the following structure:

[0212] In a preferred embodiment of the eleventh aspect of the invention, in any of the aforementioned embodiments of the eleventh aspect, at least one R C It is an oxo group.

[0213] In a 12th aspect of the invention, the invention also provides a compound represented by the formula (I-e1):

[0214]

[0215] Where W is selected from halogen or The halogen is preferably Cl or Br; other substituents are as described in formula (Ie) in any of the aforementioned 11th aspect.

[0216] In a 13th aspect of the invention, the invention also provides a compound of the following formula (If), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0217]

[0218] Where Y1, Y2, and Y3 are independently selected from C or N, and Y1, Y2, and Y3 are not simultaneously C or N, X1~X4, Y, R A R B R C R D R E L, ring B, n1 to n4 are as described in the compound of formula (I) in any of the foregoing embodiments of the first and second aspects of the present invention.

[0219] In a preferred embodiment of the 13th aspect of the invention, one of Y1, Y2 and Y3 is N, and the rest are C;

[0220] In a preferred embodiment of the 13th aspect of the invention, Y1 and Y3 are N, and Y2 is C;

[0221] In a preferred embodiment of the 13th aspect of the invention, Y1 and Y2 are N, and Y3 is C;

[0222] In a preferred embodiment of the 13th aspect of the invention, Y2 and Y3 are N, and Y1 is C;

[0223] In a preferred embodiment of the 13th aspect of the invention, in any of the aforementioned embodiments of the 13th aspect, Selected from the following structure:

[0224] In a 14th aspect of the invention, the invention also provides a compound represented by the formula (I-f1):

[0225]

[0226] Where W is selected from halogen or The halogen is preferably Cl or Br; other substituents are as described in formula (If) in any of the aforementioned aspects 13.

[0227] In a 15th aspect of the invention, the invention also provides a compound of formula (II), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0228]

[0229] Among them, X1, X2, X3, X4, R A R D R E Rings B, L, n1, and n4 are as described in formula (I) in any of the foregoing embodiments of the first and second aspects of the present invention;

[0230] Y1 is N, Y2 is CR B’ Or N;

[0231] Each R B’ and R Y Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, -Z-OR1, -Z-SR1, -Z-NR2R3, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, -ZC(O)R4, -ZC(O)OR1, or -ZC(O)(CR5R6). n C(O)R4、-ZC(O)(CR5R6) nC(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, -ZS(O)2NR2R3, C1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-8 cycloalkyl, C 3-8 Cycloalkenyl, 3-20 membered heterocyclic, 5-16 membered heteroaryl; wherein the alkyl, alkenyl, alkoxy, alkylthio, cycloalkyl, cycloalkenyl, heterocyclic, or heteroaryl group is optionally selected from one or more of deuterium, halogen, oxo group, oxime, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0232] n is 0, 1, 2, or 3;

[0233] In a preferred embodiment of the 15th aspect of the invention, X1 is N, and X2, X3 and X4 are all CH.

[0234] In a preferred embodiment of the 15th aspect of the invention, X3 is N, and X1, X2 and X4 are all CH.

[0235] In a preferred embodiment of the 15th aspect of the invention, X1 and X3 are both N, and X2 and X4 are both CH.

[0236] In a preferred embodiment of the 15th aspect of the invention, X1, X2, X3 and X4 are all CH.

[0237] In a preferred embodiment of the invention relating to the 15th aspect, in any of the aforementioned embodiments of the 15th aspect, Y2 is CH; or Y2 is N.

[0238] In a preferred embodiment of the invention relating to the 15th aspect, in any of the aforementioned embodiments of the 15th aspect, R B’ For hydrogen, deuterium, halogens, oximes, -CN, -OH, -SH, -NO2, -NH2, C 1-3 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0239] Or, R B’ The following are the groups: 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, vinyl, ethynyl;

[0240] Or, R B’ The radicals are hydrogen, F, Cl, Br, -OH, cyano, methyl, ethyl, methoxy, ethoxy, vinyl, and ethynyl.

[0241] Or, R B’ Selected from hydrogen.

[0242] In a preferred embodiment of the invention relating to the 15th aspect, in any of the foregoing embodiments of the 15th aspect, each R Y Independently, it can be hydrogen, deuterium, halogen, oxime, -CN, -OH, -SH, -NO2, -NH2, or C. 1-3 Alkyl, C 2-6 alkenyl, C 2-6 alkynyl group, C 1-6 Alkoxy, C 1-6 Alkylthio, C 3-6 Cycloalkyl, wherein the alkyl, alkenyl, alkynyl, alkoxy, alkylthio, or cycloalkyl group is optionally selected from one or more groups selected from deuterium, halogen, oxo group, -CN, -OH, -NO2, -NH2, C 1-6 Alkyl, phenyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Substituents of haloalkoxy and halophenyl groups;

[0243] Or, each R YIndependently, it can be 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, vinyl, ethynyl, propynyl, propynyl;

[0244] Or, each R Y Independently, it can be hydrogen, deuterium, F, Cl, Br, -OH, cyano, amino, methyl, ethyl, methoxy, ethoxy, methylthio, ethylthio, vinyl, ethynyl, propenyl, or propynyl.

[0245] Or, R Y Selected from hydrogen, amino, methyl, vinyl, and ethynyl groups.

[0246] In a preferred embodiment of the invention relating to the 15th aspect, in any of the aforementioned embodiments of the 15th aspect, Selected from the following structure:

[0247]

[0248] In a 16th aspect of the invention, the invention also provides a compound of formula (Ⅲ), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0249]

[0250] Among them, R A R B R C R D R E Rings B, L, n2, n3, and n4 are as described in formula (I) in any of the foregoing embodiments of the first and second aspects of the present invention;

[0251] X1, X2, X3, and Y are independently CH or N;

[0252] And when X1, X2, and X3 are all CH, Y is not CH;

[0253] n1 is 1, 2, 3 or 4;

[0254] Ring A is a 5-10 membered heterocyclic group or a 5-12 membered heteroaryl group;

[0255] In a preferred embodiment of the 16th aspect of the present invention, X1 is N, and X2 and X3 are both CH.

[0256] In a preferred embodiment of the 16th aspect of the present invention, X3 is N, and X1 and X2 are both CH.

[0257] In a preferred embodiment of the 16th aspect of the invention, X1 and X3 are both N, and X2 is CH.

[0258] In a preferred embodiment of the 16th aspect of the present invention, X1, X2, and X3 are all CH.

[0259] In a preferred embodiment of the 16th aspect of the invention, in any of the aforementioned embodiments of the 16th aspect, Y is CH; or Y is N.

[0260] In a preferred embodiment of the 16th aspect of the invention, in any of the aforementioned embodiments of the 16th aspect, Selected from the following structure:

[0261]

[0262] In a 17th aspect of the invention, the invention also provides a compound represented by formula (IV-1), (IV-2), (IV-3), or (IV-4), a stereoisomer, tautomer, or mixture thereof of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0263]

[0264] Among them, X1, R A R D R E R C Rings B, n1, and n4 are as described in formula (I) in any of the foregoing embodiments of the first and second aspects of the present invention;

[0265] Y2 is either C or N;

[0266] In a preferred embodiment of the present invention relating to formula (IV-1), (IV-2), (IV-3), or (IV-4), in any one of the aforementioned formulas (IV-1), (IV-2), (IV-3), and (IV-4), each Rc is independently hydrogen, oxo group, -OH, -SH, -NH2, -Boc, -C(O)CH2OH, -NHC(O)CH3, carboxyl group, -S(O)2CH3, -S(O)2NH2, -methoxy group, methylthio group, -CH2CF3, cyclopropyl group;

[0267] In a preferred embodiment of the present invention relating to formula (IV-1), (IV-2), (IV-3), or (IV-4), in any one of the aforementioned formulas (IV-1), (IV-2), (IV-3), and (IV-4), each Rc is independently hydrogen, oxo group, -Boc, -C(O)CH2OH, -CH2CF3, or cyclopropyl.

[0268] In a preferred embodiment of the present invention relating to formulas (IV-1), (IV-2), (IV-3), or (IV-4), in any one of the aforementioned formulas (IV-1), (IV-2), (IV-3), and (IV-4), each Rc is independently a hydrogen or oxy group;

[0269] In a preferred embodiment of formula (IV-1), (IV-2), (IV-3), or (IV-4) of the present invention, in any one of the aforementioned formulas (IV-1), (IV-2), (IV-3), and (IV-4), ring B is:

[0270] In a preferred embodiment of formula (IV-1), (IV-2), (IV-3), or (IV-4) of the present invention, in any one of the aforementioned formulas (IV-1), (IV-2), (IV-3), and (IV-4), ring B is:

[0271] In a preferred embodiment of formula (IV-1), (IV-2), (IV-3), or (IV-4) of the present invention, in any one of the aforementioned formulas (IV-1), (IV-2), (IV-3), and (IV-4), ring B is:

[0272] In a preferred embodiment of the invention relating to formulas (IV-1), (IV-2), (IV-3), or (IV-4), in any one of the aforementioned formulas (IV-1), (IV-2), (IV-3), and (IV-4), R D It is -SO2NH2.

[0273] In an 18th aspect of the invention, the invention also provides a compound of formula (V-1), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0274]

[0275] Among them, X1, R A R E R C n1 and n4 are as described in any of formula (I) or formula (IV-1), (IV-2), (IV-3), or (IV-4) in any of the foregoing embodiments of the first and second aspects of the present invention;

[0276] Q is either C or N;

[0277] In a preferred embodiment of formula (V-1) of the present invention, Q is C in any of the aforementioned formulas (V-1);

[0278] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formulas (V-1), for

[0279] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formulas (V-1), for Where R C Selected from hydrogen, trifluoroethyl, or cyclopropyl;

[0280] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formulas (V-1), for

[0281] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formula (V-1), R A Selected from hydrogen, F, Cl, methoxy, and ethoxy;

[0282] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formula (V-1), R A Selected from hydrogen, F, and methoxy groups;

[0283] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formula (V-1), R E Selected from hydrogen, deuterium, F, and Cl;

[0284] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formula (V-1), R E Selected from hydrogen and F;

[0285] In a preferred embodiment of formula (V-1) of the present invention, n1 is 1 or 2 in any of the aforementioned formulas (V-1);

[0286] In a preferred embodiment of formula (V-1) of the present invention, n4 is 1 or 2 in any of the aforementioned formulas (V-1);

[0287] In a preferred embodiment of formula (V-1) of the present invention, n4 is 2 in any of the aforementioned formula (V-1);

[0288] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formulas (V-1), for

[0289] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formulas (V-1), for

[0290] In a preferred embodiment of formula (V-1) of the present invention, in any of the aforementioned formulas (V-1), for

[0291] In a 19th aspect of the invention, the invention also provides a compound of the following formula (V-2), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0292]

[0293] Among them, X1, R A R E R C Q, n1, n4 As described in either equation (I) or equation (V-1);

[0294] In a preferred embodiment of formula (V-2) of the present invention, in any of the aforementioned formulas (V-2), for

[0295] In a preferred embodiment of formula (V-2) of the present invention, in any of the aforementioned formulas (V-2), for

[0296] In a preferred embodiment of formula (V-2) of the present invention, in any of the aforementioned formulas (V-2), for

[0297] In a preferred embodiment of formula (V-2) of the present invention, in any of the aforementioned formulas (V-2), for

[0298] In a 20th aspect of the invention, the invention also provides a compound of formula (V-3), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound:

[0299]

[0300] Among them, X1, R A R E R C Q, n1, n4 As described in any of the formulas (I) or (V-1) in any of the foregoing embodiments of the first and second aspects of the present invention;

[0301] In a preferred embodiment of formula (V-3) of the present invention, in any of the aforementioned formula (V-3), R C It is hydrogen;

[0302] In a preferred embodiment of formula (V-3) of the present invention, in any of the aforementioned formulas (V-3), for

[0303] In a preferred embodiment of formula (V-3) of the present invention, in any of the aforementioned formulas (V-3), for

[0304] In a preferred embodiment of formula (V-3) of the present invention, in any of the aforementioned formulas (V-3), for

[0305] In a 21st aspect of the invention, the invention also provides a compound of the following formula (V-4), a stereoisomer, tautomer, or mixture thereof, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotopic derivative, metabolite, or prodrug of the compound:

[0306]

[0307] Among them, X1, X4, R A RE R C Q, n1, n4 As described in any of the formulas (I) or (V-1) in any of the foregoing embodiments of the first and second aspects of the present invention;

[0308] In a preferred embodiment of the present invention relating to formula (V-4), in any of the aforementioned formulas (V-4), for Where Rc represents hydrogen and -C(O)CH2OH;

[0309] In a preferred embodiment of the present invention relating to formula (V-4), in any of the aforementioned formulas (V-4), for Where Rc is hydrogen;

[0310] In a preferred embodiment of the present invention relating to formula (V-4), in any of the aforementioned formulas (V-4), for

[0311] In a preferred embodiment of the present invention relating to formula (V-4), in any of the aforementioned formulas (V-4), for

[0312] In a preferred embodiment of the present invention relating to formula (V-4), in any of the aforementioned formulas (V-4), for Where R C It is hydrogen or Boc;

[0313] In a preferred embodiment of the present invention relating to formula (V-4), in any of the aforementioned formulas (V-4), for Where R C It is hydrogen;

[0314] In a preferred embodiment of the present invention relating to formula (V-4), in any of the aforementioned formulas (V-4), for Where R C For Boc.

[0315] The 22nd aspect of the invention relates to a preferred embodiment of the invention relating to any one of aspects 1-21, wherein X2, X4 are R A Instead, the further preferred X2 is R A replace.

[0316] In a preferred embodiment of the present invention, the compounds of the present invention are selected from:

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325]

[0326]

[0327]

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342] The object of the present invention also includes providing methods for preparing compounds of formulas (I), (Ia) to (If), stereoisomers, tautomers or mixtures thereof of the compounds, pharmaceutically acceptable salts, eutectics, polymorphs or solvates of the compounds, or stable isotopic derivatives, metabolites or prodrugs of the compounds.

[0343] The compound can be prepared by a variety of methods, including but not limited to the following:

[0344] Option 1:

[0345]

[0346] Option 2:

[0347]

[0348] In a preferred embodiment of the present invention

[0349]

[0350] In a preferred embodiment of the present invention

[0351] Option 3:

[0352]

[0353] In a preferred embodiment of the present invention

[0354]

[0355] Option 4:

[0356]

[0357] In a preferred embodiment of the present invention

[0358]

[0359] Option 5:

[0360]

[0361] In a preferred embodiment of the present invention

[0362]

[0363] In a preferred embodiment of the present invention

[0364]

[0365] In a preferred embodiment of the present invention

[0366]

[0367] In a preferred embodiment of the present invention

[0368]

[0369] In a preferred embodiment of the present invention

[0370]

[0371] In a preferred embodiment of the present invention

[0372]

[0373] In the above scheme, Hal represents a halogen in the compound shown, and the definitions of each substituent are as described above. Those skilled in the art, after reading the disclosure of this application, can easily determine the appropriate reaction conditions such as temperature, time, and solvent used in the above scheme.

[0374] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, a stereoisomer, tautomer or mixture thereof of the compound, a pharmaceutically acceptable salt, eutectic, polymorph or solvate of the compound, or a stable isotope derivative, metabolite or prodrug of the compound.

[0375] The present invention also provides a pharmaceutical composition comprising the compound shown in the present invention, stereoisomers, tautomers or mixtures thereof of the compound, pharmaceutically acceptable salts, eutectics, polymorphs or solvates of the compound, or stable isotope derivatives, metabolites or prodrugs of the compound, and pharmaceutically acceptable excipients.

[0376] The object of the present invention also includes the use of the compounds shown in the present invention, stereoisomers, tautomers or mixtures thereof, pharmaceutically acceptable salts, eutectics, polymorphs or solvates of the compounds, or stable isotope derivatives, metabolites or prodrugs of the compounds in the preparation of medicaments for the treatment or prevention of ENPP1-mediated diseases.

[0377] In some embodiments, the ENPP1-mediated disease is cancer or tumor-related disease, such as pancreatic cancer.

[0378] In some embodiments, the ENPP1-mediated disease is a cardiovascular disease, such as heart failure or myocardial infarction.

[0379] The object of the present invention also includes providing a method for preventing and / or treating diseases mediated by ENPP1, comprising administering to a patient a therapeutically effective dose of the compound shown in the present invention, a stereoisomer, tautomer, or mixture thereof of the compound, a pharmaceutically acceptable salt, cocrystal, polymorph, or solvate of the compound, or a stable isotope derivative, metabolite, or prodrug of the compound, or a pharmaceutical composition of the present invention.

[0380] The compounds shown in this invention, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof, may be administered in combination with other anticancer agents or immune checkpoint inhibitors used to treat or prevent ENPP1-mediated diseases, such as cancer or tumors.

[0381] When the compounds of the present invention, or their prodrugs, tautomers, stereoisomers, solvates, isotope derivatives, or pharmaceutically acceptable salts thereof, are administered in combination with other anticancer agents or immune checkpoint inhibitors for the treatment of cancer or tumors, the compounds of the present invention or their pharmaceutically acceptable salts may provide enhanced anticancer effects.

[0382] definition

[0383] Unless otherwise specified, the term "alkyl" refers to a monovalent saturated aliphatic hydrocarbon group, a straight-chain or branched group containing 1-20 carbon atoms, preferably containing 1-10 carbon atoms (i.e., C10). 1-10 Alkyl groups, more preferably containing 1-8 carbon atoms (C64- ... 1-8 Alkyl groups, more preferably containing 1-6 carbon atoms (i.e., C64-C ... 1-6 Alkyl), for example, "C 1-6 "Alkyl" refers to a group that is alkyl and has 1 to 6 carbon atoms in its carbon chain (specifically, 1, 2, 3, 4, 5, or 6). Examples include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, neopentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, n-heptyl, n-octyl, etc.

[0384] Unless otherwise specified, the term "alkenyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one double bond. Alkenyl groups may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkenyl), further preferably containing 2-8 carbon atoms (C 2-8 Alkenyl), more preferably containing 2-6 carbon atoms (i.e., C14-C2 ... 2-6 alkenyl), 2-5 carbon atoms (i.e., C) 2-5 alkenyl), 2-4 carbon atoms (i.e., C)2-4 alkenyl), 2-3 carbon atoms (i.e., C) 2-3 Alkenyl), 2 carbon atoms (i.e., C2 alkenyl), for example "C 2-6 "Alkenyl" refers to a group that is alkenyl and has 2 to 6 carbon atoms in its carbon chain (specifically, 2, 3, 4, 5, or 6). Non-limiting examples of alkenyl groups include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, isobutenyl, and 1,3-butadienyl.

[0385] Unless otherwise specified, the term "alkynyl" refers to an unsaturated aliphatic hydrocarbon group consisting of a straight or branched chain of carbon and hydrogen atoms, having at least one triple bond. The alkynyl group may contain 2-20 carbon atoms, preferably 2-10 carbon atoms (i.e., C2H2O). 2-10 Alkyne group), further preferably containing 2-8 carbon atoms (C 2-8 Alkyne group), more preferably containing 2-6 carbon atoms (i.e., C64-C ... 2-6 acetylsyl group), 2-5 carbon atoms (i.e., C64) 2-5 acetylsyl group), 2-4 carbon atoms (i.e., C64) 2-4 acetylsyl group), 2-3 carbon atoms (i.e., C64) 2-3 Alkynyl group), 2 carbon atoms (i.e., C2 alkynyl group), for example "C 2-6 "Alynyl" refers to a group that is alkynyl and has 2 to 6 carbon atoms in its carbon chain (specifically 2, 3, 4, 5, or 6). Non-limiting examples of alkynyl include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl.

[0386] Unless otherwise specified, the term "cycloalkyl" refers to a monocyclic saturated aliphatic hydrocarbon group having a specific number of carbon atoms, preferably containing 3-12 carbon atoms (i.e., C12-C12). 3-12 cycloalkyl), more preferably containing 3-10 carbon atoms (C 3-10 cycloalkyl groups, more preferably 3-6 carbon atoms (C 3-6 cycloalkyl groups), 4-6 carbon atoms (C 4-6 cycloalkyl groups), 5-6 carbon atoms (C 5-6 (Cycloalkyl). Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methylcyclopropyl, 2-ethyl-cyclopentyl, dimethylcyclobutyl, etc.

[0387] Unless otherwise specified, the term "alkoxy" refers to an -O-alkyl group, which 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). 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.

[0388] Unless otherwise specified, the term "alkoxy" refers to the form in which the oxygen in "alkoxy" is replaced by sulfur.

[0389] Unless otherwise specified, the terms "halogen" or "halogenated" refer to F, Cl, Br, and I. The term "halogenated alkyl" refers to an alkyl group as defined above in which one, two, or more hydrogen atoms, or all hydrogen atoms, are replaced by a halogen. Representative examples of halogenated alkyl groups include CCl3, CF3, CHCl2, CH2Cl, CH2Br, CH2I, CH2CF3, and CF2CF3.

[0390] Unless otherwise specified, the term "heterocyclic group" refers to a saturated or partially unsaturated monocyclic, bicyclic, or polycyclic cyclic hydrocarbon substituent, which is a non-aromatic structure containing 3-20 ring atoms, wherein one, two, three, or more ring atoms are selected from N, O, or 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 (i.e., 1, 2, or 3). Examples of monocyclic heterocyclic groups include pyrrolidinyl, imidazoalkyl, tetrahydrofuranyl, dihydropyrrolidinyl, piperidinyl, piperazinyl, pyranyl, etc. Bicyclic or polycyclic heterocyclic groups include spirocyclic, fused-ring, and bridged-ring heterocyclic groups.

[0391] Unless otherwise specified, the term "fused heterocyclic group" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with the other rings in the system. One or more rings may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. One or more ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. Preferably, it is 6- to 14-membered, more preferably 7- to 10-membered. Depending on the number of constituent rings, it can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic fused heterocyclic groups, preferably bicyclic or tricyclic, more preferably 4-membered / 4-membered fused heterocyclic groups, 4-membered / 5-membered fused heterocyclic groups, 5-membered / 4-membered fused heterocyclic groups, 5-membered / 5-membered fused heterocyclic groups, 5-membered / 6-membered fused heterocyclic groups, 6-membered / 5-membered fused heterocyclic groups, 4-membered / 6-membered fused heterocyclic groups, 6-membered / 4-membered fused heterocyclic groups, and 6-membered / 6-membered fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

[0392] Unless otherwise specified, the term "spiroheterocyclic group" refers to a polycyclic heterocyclic group consisting of 5 to 20 cyclic rings sharing a single atom (called a spiro atom), wherein one or more ring atoms are heteroatoms selected from N, O, or S, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings has a fully conjugated π-electron system. Preferably, it is 6 to 14 cyclic, more preferably 7 to 10 cyclic. Spiroheterocyclic groups are classified into monospirocyclic, bispirocyclic, or polyspirocyclic groups according to the number of shared spiro atoms between rings, with monospirocyclic and bispirocyclic groups being preferred. More preferably, it is a 4-membered / 4-membered spiroheterocyclic group, a 4-membered / 5-membered spiroheterocyclic group, a 5-membered / 4-membered spiroheterocyclic group, a 5-membered / 5-membered spiroheterocyclic group, a 4-membered / 6-membered spiroheterocyclic group, a 6-membered / 4-membered spiroheterocyclic group, a 5-membered / 6-membered spiroheterocyclic group, a 6-membered / 5-membered spiroheterocyclic group, and a 6-membered / 6-membered spiroheterocyclic group. Non-limiting examples of spiroheterocyclic groups include:

[0393] Unless otherwise specified, the term "aryl" refers to an aromatic carbocyclic system containing 6-16 carbon atoms, or 6-14 carbon atoms, or 6-12 carbon atoms, 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 groups may include, but are not limited to, phenyl, naphthyl, anthraceneyl, phenanthryl, or pyreneyl.

[0394] Unless otherwise specified, the term "heteroaryl" refers to an aromatic monocyclic, bicyclic, or polycyclic cyclic system containing a 5-16 member structure, or a 5-14 member structure, a 5-12 member structure, a 5-10 member structure, a 5-8 member structure, or a 5-6 member structure, wherein one, two, three, or more ring atoms are heteroatoms and the remaining atoms are carbon atoms, the heteroatoms being independently selected from O, N, or S, and the number of heteroatoms is preferably one, two, or three. Examples of heteroaryl groups may include, but are not limited to, furanyl, thiophene, oxazolyl, thiazolyl, isoxazolyl, oxadiazolyl, thiazolyl, pyrrole, pyrazolyl, imidazole, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, thiodiazolyl, triazinyl, phthalazinyl, quinolinyl, isoquinolinyl, pteridinyl, purine, indoleyl, isoindoleyl, indazoleyl, benzofuranyl, benzothiophene, benzopyridyl, benzopyrimidinyl, and benzene. Pyrazinyl, benzimidazolyl, benziphthalazolyl, pyrrolo[2,3-b]pyridyl, imidazo[1,2-a]pyridyl, pyrazolo[1,5-a]pyridyl, pyrazolo[1,5-a]pyrimidinyl, imidazo[1,2-b]pyridazinyl, [1,2,4]triazolo[4,3-b]pyridazinyl, [1,2,4]triazolo[1,5-a]pyrimidinyl, [1,2,4]triazolo[1,5-a]pyridyl, etc.

[0395] Unless otherwise specified, the term "fused aryl" refers to an unsaturated aromatic fused ring structure containing 5-14 ring atoms (at least one of which is a heteroatom) formed by two or more ring structures sharing two adjacent atoms, wherein one, two, three or more ring atoms are heteroatoms and the remaining atoms are carbon, the heteroatoms being independently selected from O, N or S, and the number of heteroatoms is preferably one, two or three. Preferably, it is a 5-12 fused aryl, 7-12 fused aryl, 9-12 fused aryl, etc., more preferably a 5 / 5 fused aryl, 5 / 6 fused aryl, 6 / 5 fused aryl, or 6 / 6 bicyclic fused aryl. Examples of fused aryl groups may include, but are not limited to, benzofuranyl, benzoisofuranyl, benzothiopheneyl, indolyl, isoindolyl, benzoxazolyl, benzoimidazolyl, indazole, benzotriazolyl, quinolinyl, 2-quinolinone, 4-quinolinone, 1-isoquinolinone, isoquinolinyl, acridineyl, phenanthidineyl, benzopyridazinyl, phthalazinyl, quinazolinyl, quinoxalinyl, phenazinyl, pteridineyl, purineyl, naphthidineyl, phenazine, phenothiazine, etc.

[0396] Unless otherwise specified, the terms "pharmaceutically acceptable salt" or "medicinal salt" refer to a salt that, within reasonable medical judgment, is suitable for contact with mammalian, particularly human, tissues without excessive toxicity, irritation, allergic reactions, etc., and is proportionate to a reasonable benefit / risk ratio. Medically 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 solely by reacting a free base or free acid with a suitable reagent.

[0397] Unless otherwise specified, the term "isotope derivative" refers to compounds of the present invention that can exist in an isotopically traced or enriched form, containing one or more atoms whose atomic weights or mass numbers differ from the atomic weights or mass numbers of the most abundant atoms found in nature. Isotopes can be radioactive or non-radioactive. Commonly used isotopes for isotopic labeling are: hydrogen isotopes, 2 H and 3 H; Carbon isotopes: 13 C and 14 C; Chlorine isotopes: 35 Cl and 37 Cl; Fluorine isotopes: 18 F; Iodine isotopes: 123 I and 125 I; Nitrogen isotopes: 13 N and 15 N; oxygen isotopes: 15 O, 17 O and 18 O and sulfur isotopes 35 S. These isotope-labeled compounds can be used to study the distribution of pharmaceutical molecules in tissues. Especially 3 H and 13 C, because they are easy to label and convenient to detect, are more widely used. Some heavy isotopes, such as deuterium (… 2 Substitution with H can enhance metabolic stability and prolong the half-life, thereby achieving the goal of reducing dosage and providing therapeutic advantages. Isotope-labeled compounds are generally synthesized from labeled starting materials using known synthetic techniques, just like non-isotope-labeled compounds.

[0398] Unless otherwise specified, the terms "solvent" or "solvent compound" refer to the physical association of the compound of the present invention with one or more solvent molecules (organic or inorganic). This physical association includes hydrogen bonding. In some cases, such as when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid, the solvate can be separated. The solvent molecules in the solvate may be present in a regular and / or disordered arrangement. The solvate may contain stoichiometric or non-stoichiometric solvent molecules. "Solvent compound" encompasses both solution phases and separable solvates. Exemplary solvates include, but are not limited to, hydrates, ethanolates, methanolates, and isopropanolates. Solvation methods are well known in the art.

[0399] Unless otherwise specified, the term "stereoisomer" refers to compounds having the same chemical structure but with different spatial arrangements of atoms or groups. Stereoisomers include enantiomers, diastereomers, conformational isomers (rotational isomers), geometric isomers (cis / trans) isomers, and inhibited isomers. Any mixture of stereoisomers obtained can be separated into pure or substantially pure geometric isomers, enantiomers, and diastereomers based on differences in the physicochemical properties of the components, for example, by chromatography and / or fractional crystallization.

[0400] Unless otherwise specified, the term "tautomer" refers to structural isomers with different energies that can interconvert through a low energy barrier. If tautomerism is possible (e.g., in solution), chemical equilibrium can be achieved in the tautomer. For example, proton tautomers (also called proton transfer tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions via the rearrangement of some bonding electrons.

[0401] Unless otherwise indicated, the structural formulas described in this invention include all isomers (e.g., enantiomers, diastereomers, and geometric isomers (or conformational isomers)): for example, R and S configurations containing an asymmetric center, (Z) and (E) isomers of double bonds, and (Z) and (E) conformational isomers. Therefore, any single stereochemical isomer of the compounds of this invention, or its enantiomers, diastereomers, or mixtures of geometric isomers (or conformational isomers), is within the scope of this invention.

[0402] Unless otherwise specified, the term "cocrystal" is used to describe a situation in which neutral molecular components are present in a crystalline compound in a defined stoichiometric ratio. The preparation of pharmaceutical cocrystals allows for alteration of the crystal form of the active pharmaceutical ingredient, which in turn alters its physicochemical properties without impairing its desired biological activity (see Pharmaceutical Salts and Cocrystals, eds. J. Wouters and L. Quere, RSC Publishing, 2012).

[0403] Unless otherwise specified, the term "polymorphism" refers to different arrangements of chemical drug molecules, generally manifested as the form in which the drug raw material exists in a solid state. A drug can exist in multiple crystalline forms, and different crystalline forms of the same drug may have different solubility and absorption in the body, thus affecting the dissolution and release of the formulation.

[0404] Unless otherwise specified, the term "metabolite" refers to the product obtained in vivo by the metabolism of a specific compound or its salt. A metabolite of a compound can be identified using techniques known in the art, and its activity can be characterized by experimental methods as described in this invention. Such products can be obtained by subjecting the compound to oxidation, reduction, hydrolysis, acylation, deacylation, esterification, defatting, enzymatic cleavage, etc. Accordingly, this invention includes metabolites of compounds, including metabolites produced by sufficient contact of the compounds of this invention with mammals for a period of time.

[0405] Unless otherwise specified, the term "prodrug" refers to a drug that is converted into a parent drug in vivo. Prodrugs are generally useful because they can improve certain, undesirable physical or biological properties. Physical properties are generally related to solubility (excessive or insufficient lipid or water solubility) or stability, while problematic biological properties include metabolism that is too rapid or poor bioavailability, which may itself be related to physicochemical properties. For example, they can be bioavailable orally, whereas the parent drug cannot. Prodrugs also have improved solubility in pharmaceutical compositions compared to the parent drug. An example of a prodrug, but not limited thereto, can be any compound of the present invention administered as an ester ("prodrug") to facilitate transmembrane transport, where water solubility is detrimental to migration but beneficial once inside the cell, and which is subsequently metabolized and hydrolyzed into a carboxylic acid, the active entity. Another example of a prodrug can be a short peptide (polyamino acid) bound to an acid group, where the peptide is metabolized to exhibit the active moiety.

[0406] Unless otherwise specified, the term "optional substitution" means that the hydrogen at the substituted site of the group is not substituted, or is substituted by one or more substituents, preferably selected from the group consisting of: halogen, hydroxyl, mercapto, cyano, nitro, amino, azide, oxo, carboxyl, C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 Aryl or 5-10 membered heteroaryl rings, wherein the C 2-6 Alkenyl, C 2-6 alkynyl group, C 1-6 Alkyl, C 1-6 Alkoxy, C 3-10 cycloalkyl, C 3-10 Cycloalkylsulfonyl, 3-10 membered heterocyclic alkyl, C 6-14 The aryl or 5-10 membered heteroaryl group may optionally be selected from halogen, hydroxyl, amino, cyano, C 1-6 Alkyl or C 1-6 One or more substituents in the alkoxy group are substituted, wherein the oxo group refers to two H atoms at the same substitution position being replaced by the same O atom to form a double bond.

[0407] The beneficial effects of this invention are as follows:

[0408] This invention designs a class of novel compounds, providing a new direction for the development of ENPP1 inhibitors. In vitro biochemical enzyme activity and MDA-MB-231 cell enzyme activity inhibitory activities showed that these compounds exhibited strong inhibitory effects on both recombinant ENPP1 enzyme and endogenously expressed ENPP1 enzyme, with extremely low inhibitory activity against ENPP2 enzyme, demonstrating good selectivity. In vitro ADME assays showed high stability in liver microsomes, no risk of hERG inhibition, and good cell permeability. In vivo pharmacokinetic studies in mice also showed good bioavailability and exposure, exhibiting excellent metabolic characteristics; therefore, they can be considered promising compounds for the treatment of ENPP1-mediated diseases. Detailed Implementation

[0409] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments, unless otherwise specified, are generally performed under conventional conditions or as recommended by the manufacturer. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as are familiar to those skilled in the art. Furthermore, any methods and materials similar to or equivalent to those described herein may be applied to the methods of the present invention. The preferred embodiments and materials shown herein are for illustrative purposes only.

[0410] The structures of the compounds of this invention were determined by nuclear magnetic resonance (NMR) and / or liquid chromatography-mass spectrometry (LC-MS) and / or high-performance liquid chromatography (HPLC). The instruments used for NMR measurements were a Bruker 400MHz and / or a Varian 400MHz; the instrument used for LC-MS was an Agilent 1260Infinity II-6120 / 6125MSD; and the instrument used for HPLC was a WatersAcquity UPLC_2 and / or a Shimadzu LC2030 and / or an Agilent 1260Infinity II.

[0411] The starting materials used in the embodiments of the present invention are known and commercially available, or can be synthesized using or in accordance with methods known in the art.

[0412] This invention provides a method for preparing the compound. The compound can be prepared by the following steps.

[0413] In the following embodiments, the abbreviations have the following meanings:

[0414] Acetyl group

[0415] ACN Acetonitrile

[0416] AcOH (acetic acid)

[0417] Bn benzyl

[0418] Boc tert-butoxycarbonyl

[0419] Boc2O ditert-butyl dicarbonate

[0420] BTC Three Lights

[0421] DCM dichloromethane

[0422] DIBAL-H Diisobutylaluminum Hydrogenation

[0423] DIEA N,N-Diisopropylethylamine

[0424] dioxane dioxane

[0425] DMAP 4-Dimethylaminopyridine

[0426] DMF N,N-dimethylformamide

[0427] Et Ethyl

[0428] HATU O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate

[0429] Me methyl

[0430] Pd2(dba)2 Tris(dibenzylacetone dipalladium)

[0431] PMB p-methoxybenzyl

[0432] pTsNHNH2 p-Toluenesulfonyl

[0433] TFA (trifluoroacetic acid)

[0434] THF Tetrahydrofuran

[0435] Xantphos 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene

[0436] Pd(dppf)Cl2 (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride

[0437] TEA Triethylamine

[0438] TMSCHN2 Trimethylsilanediazomethane

[0439] Using PerkinElmer (Version 20.0.0.41), named the compounds in the examples.

[0440] Preparation Example 1

[0441] Preparation of (4-bromo-2,6-difluorophenyl)methylamine:

[0442]

[0443] Step 1: Preparation of (E)-4-bromo-2,6-difluorobenzaldehyde oxime

[0444] 4-Bromo-2,6-difluorobenzaldehyde (50 g, 0.23 mol, 1.0 eq.), hydroxylamine hydrochloride (78.61 g, 1.13 mol, 5.0 eq.), and sodium acetate (79.1 g, 1.13 mol, 5.0 eq.) were added to ethanol (2 L), stirred, heated to 90 °C, and refluxed for 4 h. The reaction was monitored by LCMS to indicate completion. After cooling, the solvent ethanol was removed by vacuum distillation. 1 L of water was added, and the mixture was extracted with ethyl acetate (1 L × 2). The organic phase was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was removed by vacuum distillation to obtain the target compound (50 g, yield 93.64%).

[0445] LCMS(ESI):[M+H] + =236.0.

[0446] Step 2: Preparation of (4-bromo-2,6-difluorophenyl)methylamine

[0447] (E)-4-bromo-2,6-difluorobenzaldehyde oxime (12.0 g, 93.22 mmol, 1.0 eq.) and zinc powder (60.9 g, 932.2 mmol, 10.0 eq.) were dissolved in acetic acid solution (300 mL), and the mixture was stirred at room temperature (20 °C) for 4 hours.

[0448] The reaction was monitored by LCMS. The reaction solution was filtered, the filtrate was concentrated, the residue was dissolved in water (200 mL), the solution was adjusted to alkalinity with saturated sodium hydroxide solution, extracted with ethyl acetate (3 × 200 mL), the organic phases were combined and dried over anhydrous sodium sulfate, the residue was concentrated and purified by rapid chromatography (Silica gel, DCM / MeOH = 20:1) to give the target compound (11.8 g, yield 57%).

[0449] LCMS(ESI):[M+H] + =222.0; 1 HNMR(400MHz,DMSO-d6)δ7.57-7.30(m,2H),3.66(s,2H).

[0450] Preparation Example 2

[0451] Preparation of 7-methoxy-1,8-diazanaphthalene-4-ol:

[0452]

[0453] Step 1: Preparation of 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione

[0454] 2,2-Dimethyl-1,3-dioxane-4,6-dione (23.82 g, 165.3 mmol, 0.9 eq.) was dissolved in triethyl orthoformate (91 mL, 615.27 mmol, 3.35 eq.), and reacted at 90 °C for 1.5 h. The mixture was then cooled to 70 °C, and 2-amino-6-methoxypyridine (22.8 g, 183.66 mmol, 1.0 eq.) was slowly added in portions. The reaction was continued at 70 °C for 30 min. The reaction was monitored for completion by TLC and LCMS. After cooling to room temperature, the mixture was filtered, the filter cake was washed with petroleum ether, and dried to obtain the target compound (38.3 g, yield 74.94%).

[0455] LCMS(ESI)[2M+Na] + =579.1; 1 H NMR (400MHz, DMSO-d6) δ11.33 (d, J=13.6Hz, 1H), 9.18

[0456] (d, J=14.0Hz, 1H), 7.78 (q, J=8.0Hz, 1H), 7.21 (d, J=7.6Hz, 1H), 6.70 (d, J=8.4Hz, 1H), 3.91 (s, 3H), 1.69 (s, 6H).

[0457] Step 2: Preparation of 7-methoxy-1,8-diazanaphthalene-4-ol

[0458] 5-(((6-methoxypyridin-2-yl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (20 g, 71.88 mmol, 1.0 eq.) was dissolved in diphenyl ether (95.3 mL) and reacted at 200 °C for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, and a large amount of petroleum ether was added. A solid precipitated, which was filtered, washed with petroleum ether, and dried to obtain the target compound (10.3 g, yield 81.34%).

[0459] LCMS(ESI)[M+H] + =177.1; 1 H NMR (400MHz, DMSO-d6) δ11.98 (s, 1H), 8.29 (d, J = 8.8Hz,

[0460] 1H),7.78-7.75(m,1H),6.79(d,J=8.4Hz,1H),6.05-6.03(m,1H),3.96(s,3H).

[0461] Example 1

[0462] Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrimidino[4,5-c]quinoline-2(1H)-yl)methyl)benzenesulfonamide (compound 1):

[0463]

[0464] Step 1: Preparation of diethyl 2-(((4-fluoro-3-methoxyphenyl)amino)methylene)malonate

[0465] 4-Fluoro-3-methoxyaniline (9.79 g, 0.07 mol, 1.5 eq.) and 1,3-diethyl 2-(ethoxymethylene)malonate (10 g, 0.05 mol, 1 eq.) were added to ethanol (200 mL) and stirred at room temperature for 4 hours. After the reaction was completed, the mixture was purified by rapid silica gel column chromatography (PE:EA = 5:95) to obtain the target compound (12.8 g, yield 88.91%).

[0466] LCMS(ESI)[M+H] + =312.1; 1 H NMR (400MHz, DMSO-d6) δ10.70 (d, J=13.6Hz, 1H), 8.36 (d,

[0467] J=13.6Hz,1H),7.24(m,J=5.6Hz,2H),6.92(d,J=8.6Hz,1H),4.21(m,J=7.2Hz,2H),4.13(m,J=7.2Hz,2H),3.88(s,3H),1.26(m,J=8.6Hz,6H).

[0468] Step 2: Preparation of ethyl 4-chloro-6-fluoro-7-methoxyquinoline-3-carboxylate

[0469] Diethyl 2-(((4-fluoro-3-methoxyphenyl)amino)methylene)malonate (5 g, 16.06 mmol) and phosphorus oxychloride (8 mL) were placed in a 100 mL flask, heated to 100 °C, and stirred for 5 h.

[0470] The reaction was monitored by LCMS until it ended. After cooling to room temperature, the solution was slowly added dropwise to a bottle containing 200 mL of water. After the addition was complete, the solution was cooled and gradually added to adjust to neutral. The solution was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with brine, and the solvent was removed by vacuum distillation to obtain the target compound (4.2 g, yield 92.19%).

[0471] LCMS(ESI)[M+H]+ =284.0.

[0472] Step 3: Preparation of ethyl 4-cyano-6-fluoro-7-methoxyquinoline-3-carboxylate

[0473] Ethyl 4-chloro-6-fluoro-7-methoxyquinoline-3-carboxylic acid (3.1 g, 10.93 mmol, 1.0 eq.) and cuprous cyanide (3.9 g, 43.72 mmol, 4.0 eq.) were added to 20 mL of NMP and reacted at 150 °C for 15 hours. The mixture was filtered while hot, and water (100 mL) was added. The mixture was extracted with ethyl acetate (200 mL × 2). The organic phase was washed five times with brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was stirred with silica gel and purified by rapid silica gel column chromatography (Silica gel, PE:EA = 8:92) to obtain the target compound (950 mg, yield 31.7%).

[0474] LCMS(ESI)[M+H] + =275.0; 1 H NMR (400MHz, DMSO-d6) δ9.38 (s, 1H), 7.89 (m, J = 9.6Hz,

[0475] 2H), 4.47 (q, J = 7.2Hz, 2H), 4.11 (s, 3H), 1.42 (t, J = 7.2Hz, 3H).

[0476] Step 4: Preparation of 4-cyano-6-fluoro-7-methoxyquinoline-3-carboxylic acid

[0477] Ethyl 4-cyano-6-fluoro-7-methoxyquinoline-3-carboxylate (950 mg, 3.46 mmol, 1.0 eq.) was added to methanol (50 mL) along with sodium hydroxide solution (2 M, 3 mL). The mixture was stirred at room temperature for 1 hour. After the reaction was complete, the methanol was removed under vacuum, and 20 mL of water was added to adjust the pH to acidic. The mixture was extracted with ethyl acetate (200 mL × 2). The organic phase was washed twice with saturated brine and dried over anhydrous sodium sulfate. The mixture was filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain the target compound (606 mg, yield 75.27%).

[0478] LCMS(ESI)[M+H] + =247.1.

[0479] Step 5: Preparation of (4-cyano-6-fluoro-7-methoxyquinoline-3-yl)tert-butyl carbamate

[0480] 4-Cyano-6-fluoro-7-methoxyquinoline-3-carboxylic acid (330 mg, 1.34 mmol, 1.0 eq.), triethylamine (1353.4 mg, 13.4 mmol, 10 eq.), diphenyl azidophosphate (1105 mg, 4.02 mmol, 3.0 eq.), and tert-butanol (5 mL) were added to DMF (5 mL). The mixture was stirred at 80 °C for 2 hours. After the reaction was completed, the solvent was removed by vacuum distillation. 20 mL of water was added, and the mixture was extracted with ethyl acetate (1000 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation. The mixture was stirred with silica gel and purified by chromatography using a column (Silica gel, PE:EA = 85:15) to obtain the target compound (180 mg, yield 42.55%).

[0481] LCMS(ESI)[M+H] + =318.1.

[0482] Step 6: Preparation of (4-cyano-6-fluoro-7-methoxyquinoline-3-yl)(2,2,2-trifluoroethyl)carbamate tert-butyl ester

[0483] (4-cyano-6-fluoro-7-methoxyquinoline-3-yl)carbamate tert-butyl ester (20 mg, 0.13 mmol, 1.0 eq.) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (60.3 mg, 0.26 mmol, 2.0 eq.) were added to DMF (2 mL), followed by potassium carbonate (35.8 mg, 0.26 mmol, 2.0 eq.). The mixture was stirred at 60 °C for 1 hour. After the reaction was complete, 20 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed five times with saturated brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate to obtain the crude product. The crude product was mixed with silica gel and purified by silica gel column chromatography (PE:EA = 13:87) to obtain the target compound (20 mg, yield 39.73%).

[0484] LCMS(ESI)[M+H] + =400.0; 1 H NMR (400MHz, DMSO-d6) δ9.10 (s, 1H), 7.88 (d, J = 10.8Hz,

[0485] 1H),7.83(d,J=8.2Hz,1H),4.72(s,3H),4.08(s,3H),1.37(d,J=35.8Hz,6H),1.28-1.05(m,2H).

[0486] Step 7: Preparation of tert-butyl (4-(aminomethyl)-6-fluoro-7-methoxyquinoline-3-yl)(2,2,2-trifluoroethyl)carbamate

[0487] (4-cyano-6-fluoro-7-methoxyquinoline-3-yl)(2,2,2-trifluoroethyl) tert-butyl carbamate (190 mg, 0.12 mmol, 1.0 eq.) was added to acetic acid (5 mL) along with palladium on carbon (40 mg). The reaction was carried out at room temperature under hydrogen protection for 2 hours. After the reaction was completed, the palladium on carbon was filtered off, 20 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain the target compound (190 mg, yield 99%).

[0488] LCMS(ESI)[M+H] + =404.1.

[0489] Step 8: Preparation of tert-butyl (4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxyquinoline-3-yl)(2,2,2-trifluoroethyl)carbamate

[0490] (4-(aminomethyl)-6-fluoro-7-methoxyquinoline-3-yl)(2,2,2-trifluoroethyl) tert-butyl carbamate (160 mg, 0.4 mmol, 1.0 eq.) and 4-bromo-2,6-difluorobenzaldehyde (32.8 mg, 0.48 mmol, 1.2 eq.) were added to dichloromethane (10 mL), followed by 1 drop of acetic acid, sodium borohydride acetate (420 mg, 1.6 mmol, 4.0 eq.), and molecular sieves. The mixture was stirred at room temperature for 2 hours. After the reaction was complete as monitored by LCMS, silica gel was added, and the mixture was purified by rapid silica gel column chromatography (PE:EA = 75:25) to obtain the target compound (170 mg, yield 70.45%).

[0491] LCMS(ESI)[M+H] + =609.1; 1 H NMR(400MHz,DMSO-d6)δ8.58(s,1H),8.11(s,1H),7.60(s,

[0492] 1H),7.50(s,2H),4.46(s,2H),4.10-3.99(m,J=1.6Hz 4H),3.87(s,3H),3.78(s,1H),1.44(s,3H),1.21(d,J=16.2Hz,6H).

[0493] Step 9: Preparation of 4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxy-N-(2,2,2-trifluoroethyl)-quinoline-3-amine

[0494] (4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxyquinoline-3-yl)(2,2,2-trifluoroethyl)carbamate tert-butyl ester (200 mg, 0.32 mmol, 1.0 eq.) was added to a dioxane solvent (1 M, 5 mL) in hydrochloric acid and stirred at room temperature for 2 hours. The solvent was removed by vacuum distillation to obtain the crude target compound (160 mg). This crude compound was used directly in the next reaction without further purification.

[0495] LCMS(ESI)[M+H] + =509.1.

[0496] 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]quinoline-3(2H)-one

[0497] 4-(((4-bromo-2,6-difluorobenzyl)amino)methyl)-6-fluoro-7-methoxy-N-(2,2,2-trifluoroethyl)-quinoline-3-amine (160 mg, crude) was added to 10 mL of tetrahydrofuran solution, followed by the addition of triphosgene (60 mg). The mixture was stirred at room temperature for 2 hours. After the reaction was complete, the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, mixed with silica gel, and purified by rapid silica gel column chromatography (PE:EA = 70:30) to obtain the target compound (140 mg, yield 87.35%).

[0498] LCMS(ESI)[M+H] + =534.0.

[0499] 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]quinoline-3(2H)-one

[0500] 2-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrimidine[4,5-c]quinoline-3(2H)-one (140 mg, 0.26 mmol, 1 eq.) and benzyl mercaptan (39 mg, 0.31 mmol, 1.2 eq.) were added to 10 mL of dioxane, followed by tris(dibenzylideneacetone)palladium (24 mg, 0.026 mmol, 0.1 eq.) and cesium carbonate (169 mg, 0.52 mmol, 2 eq.). The mixture was reacted at 100 °C for 3 hours under nitrogen protection. After the reaction was completed, the sample was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine, dried with anhydrous sodium sulfate, mixed with silica gel, and purified by rapid silica gel column chromatography (Silica gel, PE:EA = 65:35) to obtain the target compound (85 mg, yield 56.61%).

[0501] LCMS(ESI)[M+H] + =578.1.

[0502] Step 12: Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrimidino[4,5-c]quinoline-2(1H)-yl)methyl)benzenesulfonamide

[0503] 2-(4-(phenylmethylthio)-2,6-difluorophenylmethyl)-9-fluoro-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrimidine[4,5-c]quinoline-3(2H)-one (80 mg, 0.14 mmol, 1.0 eq.) was added to 2 mL of tetrahydrofuran and 1 mL of acetonitrile solution. At 0 °C, 1 drop of acetic acid, 1 drop of water, and dichlorohydantoin (110 mg, 0.56 mmol, 4 eq.) were added, and the reaction was carried out at 0 °C for 2 hours. After the reaction was completed, 2 mL of ammonia water was added dropwise at 0 °C, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by vacuum distillation to obtain the crude product. Purification yielded the title compound (12 mg, yield 13.33%).

[0504] LCMS(ESI)[M+H] + =535.1; 1 HNMR(400MHz,DMSO-d6)δ8.90(s,1H),7.69(d,J=12.6Hz,

[0505] 1H),7.58(d,J=8.4Hz,1H),7.45(d,J=6.8Hz,2H),7.18(s,2H),5.04(d,J=9.2Hz,2H),4.96(s,2H),4.79(s,2H),3.99(s,3H).

[0506] Example 2

[0507] Preparation of 3,5-difluoro-4-((8-methoxy-2-oxopyrazino[2,3-c][1,8]diazanaphthyl-1(2H)-yl)methyl)benzenesulfonamide (compound 2):

[0508]

[0509] Step 1: Preparation of 7-methoxy-3-nitro-1,8-diazanaphthalene-4-ol

[0510] 7-Methoxy-1,8-diazanaphthalene-4-ol (14 g, 79.47 mmol, 1.0 eq.) was dissolved in acetic anhydride (100 mL), and nitric acid (8.41 mL, 133.51 mmol, 1.68 eq.) was slowly added dropwise under ice bath conditions. The temperature was then raised to 90 °C, and the reaction was carried out at 90 °C for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, the filter cake was washed with petroleum ether, and dried to obtain the target compound (5.8 g, yield 33%).

[0511] LCMS(ESI)[M+H] + =222.1; 1 H NMR(400MHz,DMSO-d6)δ13.27(s,1H),8.95(s,1H),8.45

[0512] (d,J=8.8Hz,1H),6.98(d,J=8.8Hz,1H),4.01(s,3H).

[0513] Step 2: Preparation of 5-chloro-2-methoxy-6-nitro-1,8-diazanaphthalene

[0514] 7-Methoxy-3-nitro-1,8-diazanaphth-4-ol (8.8 g, 39.79 mmol, 1.0 eq.) was dissolved in dichloromethane (50 mL), and a catalytic amount of N,N-dimethylformamide (1 mL) was added. Then, thionyl chloride (9 mL, 75.69 mmol, 1.9 eq.) was slowly added dropwise under ice bath conditions. The temperature was then raised to 40 °C, and the reaction was carried out at 40 °C for 2 hours. After the reaction was complete, the mixture was quenched with ice water, extracted with dichloromethane (100 mL × 3), and the organic phase was collected, dried, filtered, concentrated, and purified by column chromatography (Silicagel, PE:EA = 2:1) to obtain the target compound (7.2 g, yield 75.52%).

[0515] LCMS(ESI)[M+H] + =239.9; 1 H NMR (400MHz, DMSO-d6) δ8.95-8.94 (m, 1H), 8.44 (d, J = 8.8

[0516] Hz, 1H), 6.98 (d, J = 8.8Hz, 1H), 4.01 (s, 3H).

[0517] Step 3: Preparation of N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-diazanaphthalene-4-amine

[0518] 5-Chloro-2-methoxy-6-nitro-1,8-diazanaphthalene (600 mg, 2.5 mmol, 1 eq.) and 1-(4-bromo-2,6-difluorophenyl)methylamine (610.6 mg, 2.75 mmol, 1.1 eq.) were dissolved in acetonitrile (100 mL), and potassium carbonate (1.04 g, 7.5 mmol, 3 eq.) was added. The mixture was then reacted at 40 °C for 2 hours. After the reaction was complete, the mixture was concentrated, washed with water and ethyl acetate (20 mL × 3), and the organic phase was collected, dried, filtered, concentrated, and purified by column chromatography (Silica gel, PE:EA = 1:1) to obtain the target compound (700 mg, yield 65.9%).

[0519] LCMS(ESI)[M+H] + =427.0; 1 H NMR(400MHz,DMSO-d6)δ9.14(s,1H),8.84-8.67(m,2H),

[0520] 7.51(d,J=6.8Hz,2H),7.10(d,J=8.6Hz,1H),4.69(s,2H),4.02(s,3H).

[0521] Step 4: N4 Preparation of 3,4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-diazanaphthalene-3,4-diamine

[0522] N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-diazanaphth-4-amine (660 mg, 1.55 mmol, 1.0 eq.) was dissolved in methanol (50 mL), and stannous chloride (2943 mg, 15.52 mmol, 10 eq.) was added. The mixture was then reacted at 20 °C for 2 hours. After the reaction was complete, part of the solvent was concentrated, washed with saturated sodium bicarbonate solution until weakly alkaline, and then extracted with water and ethyl acetate (50 mL × 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography (Silica gel, DCM:MeOH = 20:1) to obtain the target compound (700 mg, crude product).

[0523] LCMS(ESI)[M+H] + =397.0; 1 H NMR (400MHz, DMSO-d6) δ8.70 (d, J=9.6Hz, 1H), 8.08 (s,

[0524] 1H),7.51(d,J=7.2Hz,2H),7.06(d,J=9.2Hz,1H),5.00(s,2H),4.07-3.94(m,6H).

[0525] Step 5: Preparation of ethyl 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]diazanaphthalene-3-carboxylic acid

[0526] Add N to a single-necked flask 4 -(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-diazanaphthalene-3,4-diamine (300 mg, crude), diethyl 2-oxomethacrylate (264 mg, 1.51 mmol), 10 mL toluene, the reaction apparatus was equipped with a water separator, the reaction was carried out at 130 °C for 16 hours, the product was monitored, the crude product obtained by concentration of the reaction solution was purified by rapid silica gel column chromatography (petroleum ether: ethyl acetate = 100:0~100:70) to obtain the target compound (220 mg).

[0527] LCMS(ESI)[M+H] + =505 / 507; 1 HNMR (400MHz, CDCl3) δ9.33 (s, 1H), 8.37 (d, J = 12.0Hz,

[0528] 1H),7.19-6.95(m,3H),5.69(s,2H),4.44-4.42(m,2H),4.06(s,3H),1.17(t,J=6.4Hz,3H).

[0529] Step 6: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]diazanaphthalene-3-carboxylic acid

[0530] In a single-necked round-bottom flask, ethyl 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]diazanaphthalene-3-carboxylic acid (220 mg, 0.43 mmol, 1.0 eq.), 5 mL of ethanol, and triethylamine (176 mg, 1.74 mmol, 4.0 eq.), along with 2 mL of water, were added. The reaction mixture was heated to 50 °C and stirred for 16 hours. The reaction solution was concentrated at room temperature to remove some of the solvent. The remaining solution was diluted with ethyl acetate, and the pH was adjusted to 4 with 1 mol / L dilute hydrochloric acid. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (180 mg, 90% yield).

[0531] LCMS(ESI)[M+H] + =477.0 / 479.0; 1 HNMR (400MHz, CDCl3) δ9.54 (s, 1H), 8.45 (d, J = 6.4Hz,

[0532] 1H),7.28(d,J=6.4Hz,1H),7.05-7.01(m,3H),5.75(s,2H),4.06(s,3H).

[0533] Step 7: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrazino[2,3-c][1,8]diazanaphth-2(1H)-one

[0534] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2-oxo-1,2-dihydropyrazino[2,3-c][1,8]diazanaphthalene-3-carboxylic acid (150 mg, 0.31 mmol, 1.0 eq.) and 3 mL nitrobenzene were added to a microwave-safe tube, and the reaction was heated to 160 °C and stirred for 2 hours. After the reaction was complete, direct column chromatography (petroleum ether:ethyl acetate = 100:0 to 0:100) was performed to give the target compound (80 mg, yield 59%).

[0535] LCMS(ESI):[M+H] + =432.9 / 433.9; 1HNMR (400MHz, CDCl3) δ9.33 (s, 1H), 8.40 (d, J = 8.0Hz,

[0536] 1H),8.32(s,1H),7.19-6.98(m,3H),5.69(s,2H),4.21(s,3H).

[0537] Step 8: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3-c][1,8]diazanaphthalene-2(1H)-one

[0538] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrazino[2,3-c][1,8]diazanaphthyl-2(1H)-one (52 mg, 0.12 mmol, 1.0 eq.), p-methoxybenzylthiol (55 mg, 0.36 mmol, 3.0 eq.), cesium carbonate (84 mg, 0.26 mmol, 2.2 eq.), tris(dibenzylideneacetone)palladium (10 mg, 0.01 mmol, 0.1 eq.), and 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (10 mg, 0.02 mmol, 0.2 eq.) were added to a microwave-safe tube. The reaction system was purged with nitrogen for 1 minute, sealed, and heated to 90 °C for 4 hours. After the reaction was completed, the reaction solution was separated into layers with water and ethyl acetate. The ethyl acetate layer was dried and concentrated to obtain the crude product. The crude product was purified (petroleum ether: ethyl acetate = 1:1) to obtain the target compound (20 mg, yield 32%).

[0539] LCMS(ESI):[M+H] + =507.1; 1 HNMR (400MHz, CDCl3) δ9.33 (s, 1H), 8.44 (d, J = 8.0Hz, 1H),

[0540] 8.32(s,1H),7.19(d,J=8.0Hz,2H),6.78(d,J=8.0Hz,1H),6.69(d,J=8.0Hz,2 H),6.55(d,J=8.0Hz,2H),5.69(s,2H),4.17(s,3H),4.01(s,2H),3.74(s,3H).

[0541] Step 9: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxopyrazino[2,3-c][1,8]diazanaphth-1(2H)-yl)methyl)benzenesulfonamide

[0542] In a round-bottom flask, 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3-c][1,8]diazanaphth-2(1H)-one (15 mg, 0.029 mmol, 1.0 eq.), 2 mL tetrahydrofuran, 1 mL acetonitrile, acetic acid (2 mg, 0.033 mmol, 1.1 eq.), and water (2 mg, 0.11 mmol, 3.7 eq.) were added. The solution was cooled with ice water, and dichlorohydantoin (12 mg, 0.058 mmol, 2.0 eq.) was added. The reaction mixture was stirred for 60 minutes, followed by the addition of 1 mL ammonia water and stirring for another 60 minutes. After the reaction was complete, the layers were separated by water and ethyl acetate. The ethyl acetate layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was then purified by liquid chromatography to obtain the target compound (4.5 mg, 35% yield).

[0543] LCMS(ESI)[M+H] + =434.0; 1 HNMR (400MHz, DMSO-d6) δ9.24 (s, 1H), 8.77 (d, J = 8.0Hz,

[0544] 1H),8.35(s,1H),7.63(s,2H),7.47(d,J=8.0Hz,2H),7.17(d,J=8.0Hz,1H),5.83(s,2H),4.06(s,3H).

[0545] Example 3

[0546] Preparation of 4-(8-methoxypyrimido[4,5-c][1,8]diazanaphth-1-yl)-1,4-diazacycloheptane-1-sulfonamide (compound 3):

[0547]

[0548] Step 1: Preparation of 4-chloro-7-methoxy-1,8-diazanaphthalene-3-amine

[0549] 5-Chloro-2-methoxy-6-nitro-1,8-diazanaphthalene (5.0 g, 20.87 mmol, 1.0 eq.) was dissolved in acetic acid (20 mL) in a single-necked flask. Zinc powder (2.7 g, 41.74 mmol, 2.0 eq.) was added to the reaction solution, and the reaction was stirred at room temperature for 16 hours. Once the product was detected, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to give the target compound (400 mg, yield 9%).

[0550] LCMS(ESI)[M+H] + =210.1;1 H NMR (400MHz, DMSO-d6) δ8.57 (s, 1H), 8.24 (d, J = 8.8Hz,

[0551] 1H),7.11(d,J=8.8Hz,1H),4.01(s,2H),3.96(s,3H).

[0552] Step 2: Preparation of (tert-butoxycarbonyl)(4-chloro-7-methoxy-1,8-diazanaphth-3-yl)carbamate tert-butyl ester

[0553] In a single-necked round-bottom flask, 4-chloro-7-methoxy-1,8-diazanaphthyl-3-amine (800 mg, 3.82 mmol, 1.0 eq.) and 4-dimethylaminopyridine (233 mg, 1.91 mmol, 0.5 eq.) were dissolved in dichloromethane (20 mL), followed by the addition of di-tert-butyl dicarbonate (1.7 g, 7.63 mmol, 2.0 eq.). The reaction was stirred at room temperature for 4 hours. Once the product was detected, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 3:1) to give the target compound (380 mg, yield 23%).

[0554] LCMS(ESI)[M+H] + =410.2.

[0555] Step 3: Preparation of methyl 3-((tert-butoxycarbonyl)amino)-7-methoxy-1,8-diazanaphthalene-4-carboxylic acid

[0556] In a single-necked round-bottom flask, tert-butyl carbamate (4-chloro-7-methoxy-1,8-diazanaphth-3-yl)carbamate (800 mg, 2.02 mmol, 1.0 eq.) and 4-dimethylaminopyridine (247 mg, 2.02 mmol, 1.0 eq.), palladium acetate (23.0 mg, 0.1 mmol, 0.05 eq.) and methanol (10 mL) were added, followed by 4,5-bis(diphenylphosphine)-9,9-dimethylxanthine (1169 mg, 2.02 mmol, 1.0 eq.) and octacarbonyldicobalt (CAS: 10210-68-1) (765 mg, 2.22 mmol, 1.1 eq.). The reaction was refluxed at 90 °C for 5 hours.

[0557] The reaction was monitored by LCMS until it ended. The reaction solution was concentrated, and the remaining residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 7:3) to obtain the target compound (400 mg, yield 46%).

[0558] LCMS(ESI):[M+H] + =334.1;1 H NMR (400MHz, CD3OD) δ9.04 (s, 1H), 8.47 (d, J = 9.2Hz,

[0559] 1H),7.12(d,J=9.2Hz,1H),4.09(s,3H),4.01(s,3H),1.53(s,9H).

[0560] Step 4: Preparation of methyl 3-amino-7-methoxy-1,8-diazanaphthalene-4-carboxylic acid

[0561] Methyl 3-((tert-butoxycarbonyl)amino)-7-methoxy-1,8-diazanaphthalene-4-carboxylic acid (400 mg, 1.2 mmol, 1.0 eq.) was dissolved in methanol hydrochloric acid (4 M, 10 mL), and the reaction system was stirred at room temperature for 16 hours.

[0562] The reaction was detected by LCMS and the reaction solution was removed by vacuum distillation to obtain the crude target compound (250 mg).

[0563] LCMS(ESI):[M+H] + =234.1; 1 H NMR(400MHz,DMSO-d6)δ8.81-8.66(m,2H),7.16(d,J=

[0564] 9.2Hz,1H),6.28(s,3H),4.00(s,3H),3.99(s,3H).

[0565] Step 5: Preparation of 8-methoxypyrimido[4,5-c][1,8]diazanaphthalene-1-ol

[0566] 8-methoxypyrimido[4,5-c][1,8]naphthyridin-1-ol

[0567] In a round-bottom flask, methyl 3-amino-7-methoxy-1,8-diazanaphthalene-4-carboxylic acid (310 mg, crude product), formamidine acetate (831 mg, 7.98 mmol), and formamide (5 mL) were added. The reaction system was stirred at 130 °C for 16 hours.

[0568] The reaction was monitored by LCMS until it ended. The mixture was cooled to room temperature, and then the reaction solution was washed with water. The precipitated solid was filtered, and the filter cake was dried to obtain the target compound (200 mg, yield 66%).

[0569] LCMS(ESI)[M+H] + =229.2; 1H NMR (400MHz, DMSO-d6) δ12.71 (s, 1H), 9.84 (d, J = 9.2Hz,

[0570] 1H), 9.31 (s, 1H), 8.31 (s, 1H), 7.30 (d, J = 9.2Hz, 1H), 4.08 (s, 3H).

[0571] Step 6: Preparation of tert-butyl 4-(8-methoxypyrimido[4,5-c][1,8]diazanaphth-1-yl)-1,4-diazacycloheptan-1-carboxylic acid. In a single-necked round-bottom flask, add 50 mg of 8-methoxypyrimido[4,5-c][1,8]diazanaphth-1-ol (0.22 mmol, 1.0 eq.), 2 mL of acetonitrile, and while stirring, add 1 drop of 1,8-diazabispyrospiro[5.4.0]undecyl-7-ene (100 mg, 0.66 mmol). The reaction system (3.0 mmol, 1 ol) became clear. Then, 1 drop of diphenyl ether was added, and Carter's condensing agent (290 mg, 0.66 mmol, 3 eq) was added to the reaction system. After stirring for 10 minutes, 1,4-diazacycloheptan-1-carboxylic acid tert-butyl ester (130 mg, 0.66 mmol, 3 eq) was added to the above stirred solution. The reaction was continued to be stirred for 16 hours. After the reaction was completed, the crude product obtained by concentration of the reaction solution was separated and purified by preparative plate to obtain the target compound (20 mg, yield 22%).

[0572] LCMS(ESI)[M+H] + =411.2; 1 HNMR(400MHz,DMSO-d6)δ9.35(s,1H),8.71(s,1H),8.57(t,

[0573] J=8.0Hz,1H),7.24(d,J=8.0Hz,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).

[0574] Step 7: Preparation of 1-(1,4-diazacycloheptan-1-yl)-8-methoxypyrimido[4,5-c][1,8]diazanaphthalene hydrochloride

[0575] In a single-necked round-bottom flask, 20 mg (0.05 mmol, 1.0 eq.) of 4-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)-1,4-diazacycloheptane-1-carboxylic acid tert-butyl ester and 2 mL of methanol were added. A hydrogen chloride / ethanol solution (2 mol / L, 1.0 mL, 40 eq.) was then added. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was complete, the crude target compound (20 mg) was concentrated and used directly in the next reaction step.

[0576] LCMS(ESI)[M+H] + =311.2.

[0577] Step 8: Preparation of ((4-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)-1,4-diazacycloheptane-1-yl)sulfonyl)tert-butyl carbamate

[0578] In a single-necked round-bottom flask, tert-butyl (chlorosulfonyl)carbamate (40 mg, 0.29 mmol, 5 eq.) and 2 mL of dichloromethane were added. Under ice bath cooling, tert-butanol (20 mg, 0.29 mmol, 5 eq.) was added, and the mixture was stirred for 30 minutes. The resulting solution was then transferred to another stirred single-necked round-bottom flask containing a 2 mL dichloromethane solution of 1-(1,4-diazacycloheptane-1-yl)-8-methoxypyrimidino[4,5-c][1,8]diazanaphthalene hydrochloride (20 mg, 0.06 mmol, 40% purity, 1.0 eq.) and diisopropylethylamine (39 mg, 0.3 mmol, 5 eq.). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was complete, the reaction solution was concentrated to obtain a crude product of the target compound (80 mg), which was directly used in the next reaction step.

[0579] LCMS(ESI):[M+H] + =490.0.

[0580] Step 9: Preparation of 4-(8-methoxypyrimido[4,5-c][1,8]diazanaphth-1-yl)-1,4-diazacycloheptane-1-sulfonamide

[0581] Add the crude product ((4-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)-1,4-diazacycloheptane-1-yl)sulfonyl)tert-butyl carbamate (80 mg, crude product) obtained in the previous step, 1 mL of dichloromethane and 1 mL of trifluoroacetic acid to a single-necked flask. Stir the reaction solution for 1 hour. After the reaction is complete, concentrate the reaction solution to obtain the crude product. The target compound (1.6 mg, total yield of three steps 8%) was obtained directly by preparative HPLC purification.

[0582] LCMS(ESI):[M+H] + =390.1; 1 HNMR(400MHz,MeOD)δ9.36(s,1H),8.75(s,1H),8.67(d,J

[0583] =8.0Hz,1H),7.27(d,J=8.0Hz,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).

[0584] Example 4

[0585] Preparation of N-((1-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)azacycloheptane-4-yl)methyl)aminosulfonamide (compound 4):

[0586]

[0587] Step 1: Preparation of tert-butyl 4-cyanoazacycloheptan-1-carboxylic acid

[0588] 4-oxazacycloheptan-1-carboxylic acid tert-butyl ester (6 g, 28.13 mmol, 1 eq.) was dissolved in DMF (30 mL). Then, at 0 °C, a solution of 1-((isocyanomethyl)sulfonyl)-4-methylbenzene (6.87 g, 35.16 mmol, 1.25 eq.), potassium tert-butoxide (6.31 g, 56.26 mmol, 2 eq.) in tert-butanol (30 mL), and 1,2-dimethoxyethane (24.05 mL) were added. The temperature was then raised to 20 °C, and the reaction was carried out at 20 °C for 3 hours. The reaction was monitored by TLC until complete. The mixture was washed with ethyl acetate and water, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the target compound (4.2 g, yield 66.57%).

[0589] LCMS(ESI)[M+Na] + =247.1; 1 H NMR(400MHz,DMSO-d6)δ3.45-3.20(m,4H),3.15-3.05(m,

[0590] 1H),1.95-1.82(m,2H),1.80-1.65(m,4H),1.40(s,9H).

[0591] Step 2: Preparation of azircycloheptan-4-carboxynitrile

[0592] 3.00 g (13.37 mmol, 1 eq.) of 4-cyanozycycloheptan-1-carboxylic acid tert-butyl ester, 30 mL of trifluoroacetic acid, and 5 mL of dichloromethane were added to a single-necked round-bottom flask. The reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, the solution was concentrated to obtain 1.5 g of the crude target compound, which was directly used in the next step of the reaction.

[0593] LCMS(ESI)[M+H] + =125.2; 1 H NMR(400MHz, CDCl3)δ3.75-3.70(m,4H),3.15-3.05(m,1H),

[0594] 2.36-2.34(m,2H),2.33-2.00(m,4H).

[0595] Step 3: Preparation of 4-cyanoazacycloheptan-1-carboxylic acid benzyl ester

[0596] In a single-necked round-bottom flask, aziridine-4-carboxynitrile (1500 mg, crude product), diisopropylethylamine (4.7 g, 36.24 mmol), and tetrahydrofuran (30 mL) were added. While stirring, benzyl chloroformate (2060 mg, 12.08 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 2 hours. After the reaction was complete, the crude product was concentrated and subjected to column chromatography (petroleum ether:ethyl acetate = 10:1) to give the target compound (2.3 g, yield 74%).

[0597] LCMS(ESI):[M+Na] + =281.1; 1 H NMR(400MHz, CDCl3)δ7.39-7.23(m,5H),5.13(s,2H),

[0598] 3.75-3.25(m,4H),2.87-2.82(m,1H),1.99-1.65(m,6H).

[0599] Step 4: Preparation of 4-(aminomethyl)azacycloheptan-1-carboxylic acid benzyl ester

[0600] 4-cyanoazacycloheptan-1-carboxylic acid methyl ester (2200 mg, 8.52 mmol, 1 eq.) and a tetrahydrofuran solution of borane (1 M, 30 mL) were added to a round-bottom single-necked flask. The reaction solution was stirred at 70 °C for 16 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product of the target compound (2.0 g), which was directly used for the next reaction.

[0601] LCMS(ESI):[M+H] + =263.1.

[0602] Step 5: Preparation of 4-(((tert-Butoxycarbonyl)amino)methyl)azacycloheptan-1-carboxylic acid benzyl ester

[0603] In a single-necked round-bottom flask, 2000 mg of crude 4-(aminomethyl)azacycloheptan-1-carboxylic acid methyl ester was dissolved in 10 mL of dichloromethane, and 4-dimethylaminopyridine (465.68 mg, 3.81 mmol) was added. Di-tert-butyl dicarbonate (3327.62 mg, 15.25 mmol) was slowly added with stirring. The reaction was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated to obtain the crude product, which was then subjected to column chromatography (petroleum ether: ethyl acetate = 100:20) to obtain the target compound (900 mg, total yield of 30% in both steps).

[0604] LCMS(ESI)[M+Na] + =385.2; 1 H NMR(400MHz, CDCl3)δ7.28-7.23(m,5H),5.15(s,2H),

[0605] 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).

[0606] Step 6: Preparation of (azacycloheptan-4-ylmethyl)tert-butyl carbamate

[0607] In a single-necked round-bottom flask, 4-(((tert-butoxycarbonyl)amino)methyl)azacycloheptan-1-carboxylic acid methyl ester (900 mg, 2.48 mmol, 1 eq.) was dissolved in 10 mL of methanol, and palladium / carbon (10% purity, 50% humidity) and 2 drops of ammonia were added. The reaction system was purged with a hydrogen balloon and reacted at 20 °C for 16 hours in a hydrogen atmosphere. After the reaction was complete, the reaction solution was filtered, and the filtrate was concentrated to obtain the crude target compound (400 mg), which was directly used in the next reaction step.

[0608] LCMS(ESI)[M+H] + =229.2; 1 HNMR(400MHz,DMSO-d6)δ6.88-6.83(m,1H),2.70-2.59(m,

[0609] 4H),2.67(s,2H),2.58-2.52(m,1H),1.66-1.51(m,5H),1.40(s,9H),1.20-1.15(m,2H).

[0610] Step 7: Preparation of tert-butyl ((1-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)azacycloheptane-4-yl)methyl)carbamate

[0611] In a single-necked round-bottom flask, 60 mg of 8-methoxypyrimido[4,5-c][1,8]diazanaphthalene-1-ol (0.026 mmol, 1.0 eq.) and 4 mL of N,N-dimethylformamide were added. While stirring, 1 drop of DBU (160 mg, 1.05 mmol, 4.0 eq.) was added, and the reaction mixture became clear. Then, benzotriazole-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (220 mg, 0.5 mmol, 2 eq.) was added to the reaction mixture, and the mixture was stirred for 10 minutes. Finally, tert-butyl (azacycloheptane-4-ylmethyl)carbamate (120 mg, crude product, obtained from the previous step) was added to the stirred solution. The reaction was carried out at 90 °C for 16 h. After the reaction was complete, the reaction solution was directly purified by reverse-phase preparative HPLC to obtain the target compound (20 mg, yield 22%).

[0612] LCMS(ESI)[M+H] + =439.3; 1 HNMR(400MHz,DMSO-d6)δ9.33(s,1H),8.69(s,1H),8.55-

[0613] 8.53(m,1H),7.23(d,J=12.0Hz,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).

[0614] Step 8: Preparation of (1-(8-methoxypyrimido[4,5-c][1,8]diazanaphth-1-yl)azacycloheptane-4-yl)methylamine

[0615] In a single-necked round-bottom flask, 15 mg (1-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)azacycloheptane-4-yl)methyl)tert-butyl carbamate (1.0 eq.) and 1 mL dichloromethane were added. Trifluoroacetic acid (2.0 mL, 40 eq.) was then added to the solution, and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated to obtain a crude sample of the target compound (20 mg), which was used directly in the next reaction step.

[0616] LCMS(ESI)[M+H] + =339.1.

[0617] Step 9: Preparation of (N-((1-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)azacycloheptane-4-yl)methyl)aminosulfonyl)tert-butyl carbamate

[0618] In a single-necked round-bottom flask, tert-butyl (chlorosulfonyl)carbamate (40 mg, 0.29 mmol, 5 eq.) and 2 mL of dichloromethane were added. Under ice bath cooling, tert-butanol (20 mg, 0.29 mmol) was added and stirred for 30 minutes. The reaction mixture was then added to another 2 mL solution of dichloromethane containing (1-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)azacycloheptane-4-yl)methylamine (20 mg, crude product, obtained from the previous step) and diisopropylethylamine (39 mg, 0.3 mmol). The reaction mixture was stirred at room temperature for 3 hours. After the reaction was complete, the mixture was concentrated to obtain the crude target compound (20 mg), which was directly used in the next step.

[0619] LCMS(ESI)[M+H] + =518.3.

[0620] Step 10: Preparation of N-((1-(8-methoxypyrimidino[4,5-c][1,8]diazanaphth-1-yl)azacycloheptane-4-yl)methyl)aminosulfonamide

[0621] The crude product (N-((1-(8-methoxypyrimidino[4,5-c][1,8]diazanaphthyl-1-yl)azacycloheptane-4-yl)methyl)aminosulfonyl)carbamate tert-butyl ester (20 mg) obtained in the previous step was added to 2 mL of dichloromethane, and 2 mL of trifluoroacetic acid was added. The reaction solution was stirred at room temperature for 3 hours. After the reaction was completed, the reaction was concentrated to obtain the crude product, which was purified by HPLC to obtain the target compound (4.3 mg, total yield of three steps 25%).

[0622] LCMS(ESI)[M+H] + =418.3; 1 HNMR(400MHz,MeOD)δ9.32(s,1H),8.72(s,1H),8.44-

[0623] 8.41(m,1H),7.30(d,J=12Hz,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).

[0624] Example 5

[0625] Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]diazanaphth-1-yl)methyl)benzenesulfonamide (compound 5):

[0626]

[0627] Step 1: Preparation of 3-bromo-7-methoxy-1,8-diazanaphthalene-4-ol

[0628] 7-Methoxy-1,8-diazanaphth-4-ol (12 g, 68.12 mmol, 1 eq.) was dissolved in N,N-dimethylformamide (50 mL), and then N-bromosuccinimide (7.3 g, 40.87 mmol, 0.6 eq.) was added at 0 °C, and the reaction was carried out at 0 °C for 2 hours.

[0629] The reaction was monitored by LCMS until complete. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). After concentration of the organic phase, the mixture was purified by rapid silica gel column chromatography (PE:EA = 50:50) to obtain the target compound (2.0 g, yield 11.5%).

[0630] LCMS(ESI)[M+H] + =254.9.

[0631] Step 2: Preparation of 6-bromo-5-chloro-2-methoxy-1,8-diazanaphthalene

[0632] 3-Bromo-7-methoxy-1,8-diazanaphth-4-ol (500 mg, 1.96 mmol, 1 eq.) was dissolved in dichloromethane (50 mL), one drop of N,N-dimethylformamide was added, and thionyl chloride (2332 mg, 19.6 mmol, 10 eq.) was added. The mixture was then reacted at 40 °C for 16 hours.

[0633] The reaction was monitored by LCMS until complete. The reaction solution was slowly added dropwise to ice water, and the layers separated. The aqueous phase was extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the target compound (520 mg, yield 97%).

[0634] LCMS(ESI)[M+H] + =272.9.

[0635] Step 3: Preparation of 2-((3-bromo-7-methoxy-1,8-diazanaphth-4-yl)amino)ethyl-1-ol

[0636] 6-Bromo-5-chloro-2-methoxy-1,8-diazanaphthalene (500 mg, 1.83 mmol, 1 eq.) was dissolved in N-methylpyrrolidone (15 mL), and ethanolamine (2.2 g, 36.6 mmol, 20 eq.) was added. The reaction was carried out at 100 °C for 2 hours, and the reaction was monitored by LC-MS until complete. The reaction solution was poured into water and extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to give the target compound (260 mg, yield 57%).

[0637] LCMS(ESI)[M+H] + =298.0; 1 H NMR (400MHz, DMSO-d6) δ8.61 (d, J=9.2Hz, 1H), 8.56 (s,

[0638] 1H), 6.97 (d, J = 9.2Hz, 1H), 6.22 (t, J = 5.6Hz, 1H), 4.97 (t, J = 5.2Hz, 1H), 3.97 (s, 3H), 3.76-3.67 (m, 2H), 3.65-3.57 (m, 2H).

[0639] Step 4: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]diazanaphthalene

[0640] 2-((3-bromo-7-methoxy-1,8-diazanaphth-4-yl)amino)ethyl-1-ol (200 mg, 0.67 mmol, 1 eq.) was dissolved in N,N-dimethylpyrrolidone (5 mL), and cuprous iodide (128 mg, 0.67 mmol, 1.0 eq.), trans-1,2-cyclohexanediamine (77 mg, 0.67 mmol, 1.0 eq.), and potassium tert-butoxide (226 mg, 2.01 mmol, 3 eq.) were added. The reaction was carried out in a microwave oven at 140 °C for 2 hours, and the reaction was monitored by LCMS until complete. 5-bromo-2-(bromomethyl)-1,3-difluorobenzene (284 mg, 1.01 mmol, 1.5 eq.) was added to the reaction solution, and the reaction was carried out in a microwave oven at 70 °C for 1 hour.

[0641] The reaction was monitored by LCMS until complete. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain the target compound (100 mg, yield 36%).

[0642] LCMS(ESI)[M+H] + =422.0; 1H NMR(400MHz,DMSO-d6)δ8.91-8.82(m,1H),8.75(s,1H),

[0643] 7.54(d,J=8.0Hz,2H),7.22(d,J=9.2Hz,1H),5.78(s,2H),4.32(t,J=4.4Hz,2H),3.93(s,3H),3.74(t,J=4.0Hz,2H).

[0644] 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]diazanaphthalene

[0645] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]diazanaphthalene (100 mg, 0.24 mmol, 1 eq.) was dissolved in dioxane (10 mL), followed by (4-methoxyphenyl)methanethiol (73 mg, 0.47 mmol, 2 eq.), (5-(diphenylphosphino)-9,9-dimethyl-9H-xanthan-4-yl)diphenylphosphine (27 mg, 0.05 mmol, 0.2 eq.), tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (43 mg, 0.05 mmol, 0.2 eq.), and triethylamine (48 mg, 47 mmol, 2 eq.). The reaction was carried out at 100 °C under nitrogen protection for 2 hours.

[0646] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness, mixed with silica gel, and purified by chromatography using a column (Silica gel, DCM:MeOH = 95:5) to obtain the target compound (70 mg, yield 60%).

[0647] LCMS(ESI)[M+H] + =496.1.

[0648] Step 6: Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dihydro-1H-[1,4]oxazino[2,3-c][1,8]diazanaphth-1-yl)methyl)benzenesulfonamide

[0649] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-2,3-dihydro-1H-[1,4]oxazinofo[2,3-c][1,8]diazanaphthalene (60 mg, 0.12 mmol, 1.0 eq.), acetic acid (51 mg, 0.85 mmol, 7.0 eq.), and water (31 mg, 1.7 mmol, 14.0 eq.) were dissolved in tetrahydrofuran (15 mL). Dichlorohydantoin (72 mg, 0.36 mmol, 3 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 2 hours. Ammonia water (0.5 mL) was added, and the mixture was reacted at 0 °C for 10 minutes.

[0650] The reaction was monitored by LCMS until the reactants were fully reacted. The reaction solution was concentrated and purified by preparative HPLC to obtain the target compound (13.7 mg, yield 27%).

[0651] LCMS(ESI)[M+H] + =423.1; 1 HNMR(400MHz,MeOD-d4)δ8.53(s,1H),8.48(d,J=9.2Hz,

[0652] 1H),7.53(d,J=7.2Hz,2H),7.11(d,J=8.8Hz,1H),5.92(s,2H),4.36(t,J=4.4Hz,2H),4.01(s,3H),3.81(t,J=4.4Hz,2H).

[0653] Example 6

[0654] Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)benzenesulfonamide (compound 6):

[0655]

[0656] Step 1: Preparation of ethyl 4-chloro-7-methoxy-1,8-diazanaphthalene-3-carboxylate

[0657] 1,3-diethyl 2-(((6-methoxypyridin-2-yl)amino)methylene)malonic acid (12 g, 22.7 mmol, 1 eq.) was dissolved in phosphorus oxychloride (60 mL), and the reaction was carried out under nitrogen protection at 110 °C with stirring for 4 hours.

[0658] The reaction was monitored by LCMS until it ended. The solvent was removed by vacuum distillation, and the residue was dissolved in ethyl acetate (60 mL), washed quickly with water (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by rapid chromatography (Silica gel, DCM:EA = 1:1) to obtain the target compound (1.5 g, yield 12%).

[0659] LCMS(ESI)[M+H] + =266.0.

[0660] Step 2: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-diazanaphthalene-3-carboxylic acid

[0661] Ethyl 4-chloro-7-methoxy-1,8-diazanaphthalene-3-carboxylic acid (3.0 g, 18.75 mmol, 1 eq.) was dissolved in acetonitrile (80 mL), followed by the addition of potassium carbonate (5.2 g, 37.5 mmol, 2.0 eq.) and (4-bromo-2,6-difluorophenyl)methylamine (4.37 g, 19.69 mmol, 1.05 eq.). The reaction was carried out at 40 °C for 20 hours under nitrogen protection.

[0662] The reaction was monitored by LCMS until completion. The reaction solution was concentrated, diluted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by rapid chromatography (Silica gel, DCM:EA = 4:1) to obtain the target compound (3.5 g, yield 69.2%).

[0663] LCMS(ESI)[M+H] + =452.0.

[0664] Step 3: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-diazanaphth-3-yl)methanol

[0665] Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-diazanaphthalene-3-carboxylic acid (120 mg, 22.7 mmol, 1 eq.) was dissolved in ethanol (10 mL), and sodium borohydride (134 mg, 5 eq.) was slowly added. The reaction was carried out under nitrogen protection at 50 °C with stirring for 16 hours.

[0666] The reaction was monitored by LCMS until it ended. The solvent was evaporated to dryness, and the residue was quenched with saturated sodium chloride solution (5 mL). Ethyl acetate (10 mL) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by rapid chromatography (Silica gel, DCM:MeOH = 2:1) to obtain the target compound (120 mg, yield 38%).

[0667] LCMS(ESI)[M+H] + =410.0; 1 H NMR (400MHz, CDCl3) δ8.43 (s, 1H), 8.35 (d, J = 9.2Hz, 1H),

[0668] 7.09(d,J=6.8Hz,2H),6.90(d,J=9.2Hz,1H),4.75(s,2H),4.69(s,2H),4.12(s,3H).

[0669] Step 4: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]diazanaphth-2-one

[0670] (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-diazanaphth-3-yl)methanol (300 mg, 0.73 mmol, 1 eq.) was dissolved in dichloromethane (15 mL), and N,N-diisopropylethylamine (473 mg, 3.66 mmol, 5 eq.) and triphosgene (651 mg, 2.19 mmol, 3 eq.) were added. The mixture was reacted at 0 °C for 2 hours.

[0671] The reaction was monitored by LCMS until complete. The reaction solution was washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated to dryness. The crude product was purified by rapid silica gel column chromatography (MeOH:DCM = 5:95) to obtain the target compound (250 mg, yield 78.51%).

[0672] LCMS(ESI)[M+H] + =436.0.

[0673] Step 5: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazinco[5,4-c][1,8]diazanaphth-2-one

[0674] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-2-one (200 mg, 0.46 mmol, 1 eq.) was dissolved in dioxane (10 mL), and (4-methoxyphenyl)methanethiol (141 mg, 0.92 mmol, 2 eq.), [5-(diphenylphosphino)-9,9-dimethyl-9H-xanthan-4-yl]diphenylphosphine (53 mg, 0.09 mmol, 0.2 eq.), tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (84 mg, 0.09 mmol, 0.2 eq.), and N,N-diisopropylethylamine (178 mg, 1.38 mmol, 3 eq.) were added. The reaction was carried out at 90°C for 2 hours, and the reaction was monitored by LCMS to ensure complete reaction. The reaction solution was concentrated and evaporated to dryness, and then purified by rapid silica gel column chromatography (Silica gel, MeOH:DCM = 5:95) to obtain the target compound (110 mg, yield 47.09%) as a yellow solid.

[0675] LCMS(ESI)[M+H] + =510.1.

[0676] Step 6: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)benzenesulfonamide

[0677] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazinofo[5,4-c][1,8]diazanaphth-2-one (100 mg, 0.2 mmol, 1.0 eq.), acetic acid (83 mg, 1.37 mmol, 7.0 eq.), and water (50 mg, 2.75 mmol, 14.0 eq.) were dissolved in tetrahydrofuran (15 mL). Dichlorohydantoin (116 mg, 0.59 mmol, 3 eq.) was added at 0 °C, and the mixture was reacted at 25 °C for 1 hour. Ammonia (0.5 mL) was then added, and the reaction was continued at 25 °C for 10 minutes.

[0678] The reaction was monitored by LCMS until complete. The reaction solution was concentrated and purified by preparative HPLC to obtain the target compound (14.6 mg, yield 17.05%).

[0679] LCMS(ESI)[M+H] + =437.1; 1 HNMR(400MHz,MeOD-d4)δ8.71(s,1H),8.59(d,J=9.2Hz,

[0680] 1H),7.46(d,J=7.6Hz,2H),7.13(d,J=9.6Hz,1H),5.57(s,2H),5.30(s,2H),4.12(s,3H).

[0681] Example 7

[0682] Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-3,4-dihydropyrimidino[5,4-c]quinoline-1(2H)-yl)methyl)benzenesulfonamide (compound 7):

[0683]

[0684] Step 1: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylic acid

[0685] Ethyl 4-chloro-6-fluoro-7-methoxyquinoline-3-carboxylate (1 g, 3.6 mmol, 1 eq.), (4-bromo-2,6-difluorophenyl)methylamine (1.2 g, 5.4 mmol, 1.5 eq.), and potassium carbonate (1.47 g, 10.8 mmol, 3 eq.) were dissolved in acetonitrile (50 mL), heated to 90 °C, and reacted for 12 hours. After the reaction was completed, the mixture was purified by rapid silica gel column chromatography (DCM:MEOH = 95:5) to obtain the target compound (900 mg, yield 54.41%).

[0686] LCMS(ESI)[M+H] + =469.0; 1 H NMR (400MHz, DMSO-d6) δ8.82 (s, 1H), 8.24 (t, J = 5.2Hz,

[0687] 1H), 8.19 (d, J = 13.4Hz, 1H), 7.49 (dd, J = 8.0Hz, 3H), 4.73 (d, J = 5.2Hz, 2H), 4.28 (d, J = 7.2Hz, 2H), 4.00 (s, 3H), 1.30 (t, J = 7.2Hz, 3H).

[0688] Step 2: Preparation of 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylic acid

[0689] Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylic acid (500 mg, 1.07 mmol, 1 eq.) was added to methanol (5 mL) and tetrahydrofuran (5 mL), followed by 3 mL of sodium hydroxide (2 M) aqueous solution. The mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solvent was removed by vacuum distillation, and 20 mL of water was added to adjust the pH to acidic. A solid precipitated out, which was filtered. The filter cake was washed with petroleum ether, and the solid was dried under vacuum to obtain the target compound (400 mg, yield 75.27%).

[0690] LCMS(ESI)[M+H] + =440.9.

[0691] Step 3: Preparation of 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxamide

[0692] 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylic acid (380 mg, 0.76 mmol, 1 eq.), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.8 g, 7.6 mmol, 10 eq.), and ammoniacal tetrahydrofuran (19 mL, 7.6 mmol, 10 eq.) were added to N,N-dimethylformamide (10 mL), followed by dropwise addition of N,N-diisopropylethylamine (98.0 mg, 0.76 mmol, 1 eq.). The reaction was carried out at room temperature for 40 hours. Water (50 mL) was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed five times with brine, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation of the filtrate. The sample was mixed with silica gel and subjected to rapid silica gel column chromatography (Silica). The target compound (250 mg, yield 65.94%) was obtained by gel (DCM:MeOH = 70:30).

[0693] LCMS(ESI)[M+H] + =440.0.

[0694] Step 4: Preparation of 3-(aminomethyl)-N-(4-bromo-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinoline-4-amine

[0695] 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxamide (380 mg, 0.86 mmol, 1 eq.) was added to tetrahydrofuran (20 mL), followed by 1 M borane solution in tetrahydrofuran (8.6 mL, 8.6 mmol, 10 eq.). The reaction was carried out at 60 °C for 15 hours. After the reaction was completed, 10 mL of methanol solution was added, the solvent was evaporated to dryness, the sample was mixed, and the target compound (160 mg, yield 43.5%) was obtained by rapid silica gel column chromatography (DCM:MeOH = 65:35).

[0696] LCMS(ESI)[M+H] + =426.1.

[0697] Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrimidino[5,4-c]quinoline-2(1H)-one

[0698] 3-(aminomethyl)-N-(4-bromo-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinoline-4-amine (160 mg, 0.38 mmol, 1 eq.) was added to tetrahydrofuran (10 mL), followed by N,N'-carbonyldiimidazole (123.1 mg, 0.76 mmol, 2 eq.). The reaction mixture was reacted at room temperature for 15 hours, and the product was observed by LCMS. The reaction solution was concentrated and purified by rapid silica gel column chromatography (Silicagel, DCM:MeOH = 70:30) to obtain the target compound (70 mg, yield 41.24%).

[0699] LCMS(ESI)[M+H] + =452.1.

[0700] Step 6: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-3,4-dihydropyrimidino[5,4-c]quinoline-2(1H)-one

[0701] 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrimidino[5,4-c]quinoline-2(1H)-one (45 mg, 0.1 mmol, 1 eq.) and (4-methoxyphenyl)methanethiol (18.5 mg, 0.12 mmol, 1.2 eq.) were added to dioxane (10 mL), along with tris(diphenylmethylacetone)dipalladium (5 mg, 0.03 mmol, 0.3 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (39 mg, 0.07 mmol, 0.2 eq.), and N,N-diisopropylethylamine (25.8 mg, 0.2 mmol, 2 eq.). The mixture was reacted at 100 °C for 1 hour under nitrogen protection. After the reaction was completed, the reaction solution was mixed with silica gel and purified by rapid silica gel column chromatography (Silica gel, DCM:MeOH = 95:5) to obtain the target compound (20 mg, yield 38.06%).

[0702] LCMS(ESI)[M+H] + =526.1.

[0703] Step 7: Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-3,4-dihydropyrimidino[5,4-c]quinoline-1(2H)-yl)methyl)benzenesulfonamide

[0704] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-3,4-dihydropyrimidino[5,4-c]quinoline-2(1H)-one (18 mg, 0.03 mmol, 1 eq.) was added to 2 mL of tetrahydrofuran, and 1 drop of acetic acid, 1 drop of water, and dichlorohydantoin (20.2 mg, 0.12 mmol, 3 eq.) were added at 0 °C. The reaction was carried out at 0 °C for 2 hours. After the reaction was completed, 2 mL of ammonia water was added dropwise at 0 °C. The presence of product was detected by LCMS. The solvent was removed by vacuum distillation, and the target compound (1.6 mg, yield 11.12%) was obtained after purification.

[0705] LCMS(ESI)[M+H] + =453.0; 1 H NMR (400MHz, CD3OD) δ8.73 (s, 1H), 8.14 (d, J = 12.6Hz,

[0706] 1H),7.71(d,J=8.4Hz,1H),7.62(d,J=7.6Hz,2H),5.72(s,2H),4.60(s,2H),4.26(s,3H).

[0707] Example 8

[0708] Preparation of 3,5-difluoro-4-((8-methoxy-2-oxopyrido[2,3-h][1,6]naphthidium-1(2H)-yl)methyl)benzenesulfonamide (compound 8):

[0709]

[0710] Step 1: Preparation of 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxaldehyde

[0711] (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)methanol (300 mg, 0.73 mmol, 1 eq.) was dissolved in dichloromethane (10 mL) and tetrahydrofuran (10 mL), and manganese dioxide (317 mg, 3.65 mmol, 5 eq.) was added. The reaction was carried out at 25 °C for 2 hours.

[0712] The reaction was monitored by LCMS until complete. The reaction solution was washed with water, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by rapid silica gel column chromatography (MeOH:DCM = 5:95) to obtain the target compound (160 mg, yield 53.42%).

[0713] LCMS(ESI)[M+H] + =408.0; 1 H NMR(400MHz, CDCl3)δ10.10(s,1H),9.77(s,1H),8.68(s,

[0714] 1H), 8.44 (d, J = 9.2Hz, 1H), 7.20 (d, J = 7.2Hz, 2H), 6.84 (d, J = 8.8Hz, 1H), 4.92 (d, J = 4.8Hz, 2H), 4.10 (s, 3H).

[0715] Step 2: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrido[2,3-h][1,6]naphthidium-2(1H)-one

[0716] 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxaldehyde (150 mg, 0.37 mmol, 1 eq.) was dissolved in methanol (15 mL), and ethyl 2-(dimethoxyphosphoryl)acetate (247 mg, 1.1 mmol, 3 eq.) and potassium carbonate (254 mg, 1.84 mmol, 5 eq.) were added. The reaction was carried out at 85 °C for 8 hours, and the reaction was monitored to be complete by LC-MS. The reaction solution was concentrated and purified by rapid silica gel column chromatography (MeOH:DCM = 2:98) to give the target compound (110 mg, yield 69.26%).

[0717] LCMS(ESI)[M+H] + =432.0; 1 H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.70 (d, J = 9.2Hz,

[0718] 1H), 8.19 (d, J = 9.2Hz, 1H), 7.42 (d, J = 8.0Hz, 2H), 7.11 (d, J = 9.2Hz, 1H), 6.71 (d, J = 9.2Hz, 1H), 5.69 (s, 2H), 4.04 (s, 3H).

[0719] Step 3: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrido[2,3-h][1,6]naphthidin-2(1H)-one

[0720] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxypyrido[2,3-h][1,6]naphthidin-2(1H)-one (145 mg, 0.34 mmol, 1 eq.) was dissolved in dioxane (10 mL), and (4-methoxyphenyl)methanethiol (103 mg, 0.67 mmol, 2 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (40 mg, 0.07 mmol, 0.2 eq.), tris(1,5-diphenylpenta-1,4-dien-3-one)dipalladium (61 mg, 0.07 mmol, 0.2 eq.) and N,N-diisopropylethylamine (130 mg, 1.01 mmol, 3 eq.) were added. The mixture was reacted at 90 °C for 2 hours.

[0721] The reaction was monitored by LCMS until complete. The reaction solution was concentrated and purified by rapid silica gel column chromatography (MeOH:DCM = 5:95) to obtain the target compound (110 mg, yield 64.86%).

[0722] LCMS(ESI)[M+H]+ =506.1.

[0723] Step 4: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxopyridano[2,3-h][1,6]naphthidin-1(2H)-yl)methyl)benzenesulfonamide. 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyridano[2,3-h][1,6]naphthidin-2(1H)-one (110 mg, 0.22 mmol, 1.0 eq.), acetic acid (91 mg, 1.52 mmol, 7.0 eq.), and water (55 mg, 3.05 mmol, 14.0 eq.) were dissolved in tetrahydrofuran (15 mL). Dichlorohydantoin (129 mg, 0.65 mmol, 3 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 1 hour. Ammonia (0.5 mL) was added, and the reaction was continued at 0 °C for 10 minutes.

[0724] The reaction of the starting materials was monitored by LCMS until complete. After concentration, the reaction solution was purified by preparative HPLC to obtain the target compound (40.9 mg, yield 43.47%).

[0725] LCMS(ESI)[M+H] + =433.0; 1 H NMR (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.72 (d, J = 9.2Hz,

[0726] 1H), 8.21 (d, J = 9.6Hz, 1H), 7.62 (s, 2H), 7.43 (d, J = 7.6Hz, 2H), 7.12 (d, J = 9.2Hz, 1H), 6.70 (d, J = 9.2Hz, 1H), 5.78 (s, 2H), 4.05 (s, 3H).

[0727] Example 9

[0728] Preparation of 3,5-difluoro-4-((8-methoxy-3-oxo-4-(2,2,2-trifluoroethyl)-3,4-dihydropyrazino[2,3-c][1,8]naphthidium-1(2H)-yl)methyl)benzenesulfonamide (compound 11)

[0729]

[0730] Step 1: Preparation of N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)-2-chloroacetamide

[0731] N 4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthidine-3,4-diamine (120 mg, 0.3 mmol, 1.0 eq.), 2-chloroacetyl chloride (38 mg, 0.34 mmol, 1.1 eq.), and potassium carbonate (47 mg, 0.34 mmol, 1.1 eq.) were dissolved in 10 mL of tetrahydrofuran. The reaction was stirred at room temperature for 20 minutes. The product was monitored, and the crude product obtained by concentration of the reaction solution was purified by rapid silica gel column chromatography (DCM:MeOH = 20:1) to obtain the target compound (68 mg, yield 48%).

[0732] LCMS(ESI)[M+H] + =471.0.

[0733] Step 2: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthidium-3(2H)-one

[0734] N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)-2-chloroacetamide (48 mg, 0.15 mmol, 1.0 eq.) and sodium hydride (4 mg, 0.17 mmol, 1.1 eq.) were dissolved in 10 mL of N,N-dimethylformamide. The reaction was stirred at room temperature for 20 minutes. The product was monitored during the reaction. The crude product obtained by concentration of the reaction solution was purified by rapid silica gel column chromatography (DCM:MeOH = 20:1) to obtain the target product (50 mg, yield 77%).

[0735] LCMS(ESI)[M+H] + =435.0.

[0736] 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]naphthidium-3(2H)-one

[0737] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthidium-3(2H)-one (50 mg, 0.12 mmol, 1 eq.) and potassium carbonate (49 mg, 0.35 mmol, 3 eq.) were dissolved in N,N-dimethylformamide (10 mL), and then 2,2,2-trifluoroethyl trifluoromethanesulfonate (27 mg, 0.12 mmol, 1 eq.) was added. The mixture was reacted at 80 °C for 2 hours.

[0738] The reaction was monitored by LCMS until complete. The mixture was then diluted with water, extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography (Silica gel, PE:EA = 2:1) to obtain the target compound (32 mg, yield 53.93%).

[0739] LCMS(ESI)[M+H] + =517.0.

[0740] 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]naphthidin-3(2H)-one

[0741] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrazino[2,3-c][1,8]naphthidium-3(2H)-one (32 mg, 0.06 mmol, 1 eq.) was dissolved in dioxane (10 mL), followed by the addition of (4-methoxyphenyl)methanethiol (19 mg, 0.12 mmol, 2 eq.), tris(dibenzylideneacetone)dipalladium (10 mg, 0.01 mmol, 0.17 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxa) (10.4 mg, 0.02 mmol, 0.3 eq.), and diisopropylethylamine (23 mg, 0.18 mmol, 3 eq.). The reaction was carried out under nitrogen protection at 100 °C for 2 hours.

[0742] The reaction was monitored by LCMS until complete. The mixture was then extracted with water and ethyl acetate (15 mL × 3) in layers. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography (Silica gel, PE:EA = 2:1) to obtain the target compound (10 mg, yield 28.25%).

[0743] LCMS(ESI)[M+H] + =591.1.

[0744] 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]naphthidin-1(2H)-yl)methyl)benzenesulfonamide

[0745] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-4-(2,2,2-trifluoroethyl)-1,4-dihydropyrazino[2,3-c][1,8]naphthidin-3(2H)-one (10 mg, 0.017 mmol, 1 eq.) was dissolved in tetrahydrofuran (2 mL) and acetonitrile (1 mL). Acetic acid (7 mg, 0.05 mmol, 7 eq.), water (1.8 mg, 0.1 mmol, 14 eq.), and dichlorohydantoin (5.91 mg, 0.03 mmol, 1.8 eq.) were added at 0 °C, and the reaction was carried out at 0 °C for 2 hours. Then, ammonia water (178 mg, 5.1 mmol, 300 eq.) was added, and the reaction was continued at 0 °C for 1 hour. After the reaction was complete, the mixture was extracted with water and ethyl acetate (15 mL × 3) in layers. The organic phases were combined, dried with anhydrous sodium sulfate, filtered, concentrated and purified to obtain the target compound.

[0746] LCMS(ESI)[M+H] + =518.0; 1 H NMR (400MHz, CD3OD) δ8.80 (s, 1H), 8.57 (d, J = 9.0Hz,

[0747] 1H),8.52(s,2H),7.39(d,J=7.0Hz,2H),7.13(d,J=9.0Hz,1H),4.78-4.66(m,4H),4.11(s,3H),4.04(s,2H).

[0748] Example 10

[0749] Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonyl (compound 48)

[0750]

[0751] Step 1: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-yl)methanol

[0752] Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-carboxylic acid (500 mg, 1.07 mmol, 1 eq.) was dissolved in ethanol (15 mL), and sodium borohydride (202 mg, 5.35 mmol, 5 eq.) was added. The mixture was reacted at 25 °C for 16 hours.

[0753] The reaction was monitored by LCMS until complete. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel chromatography (DCM:MeOH = 97:3) to obtain the target product (300 mg, yield 65.63%).

[0754] LCMS(ESI)[M+H] + =427.0.

[0755] Step 2: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one. (4-((4-bromo-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-yl)methanol (150 mg, 0.35 mmol, 1 eq.) was dissolved in dichloromethane (10 mL), and triphosgene (313 mg, 1.05 mmol, 3 eq.) and N,N-diisopropylethylamine (227 mg, 1.76 mmol, 5 eq.) were added. The reaction was carried out at 25 °C for 1 hour.

[0756] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness and purified by silica gel chromatography (DCM:MeOH = 97:3) to obtain the target compound (100 mg, yield 62.66%).

[0757] LCMS(ESI)[M+H] + =453.0.

[0758] Step 3: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazinco[5,4-c]quinoline-2-one

[0759] 1-(4-bromo-2,6-difluorobenzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (90 mg, 0.2 mmol, 1 eq.) was dissolved in dioxane (10 mL), followed by (4-methoxyphenyl)methanethiol (61 mg, 0.4 mmol, 2 eq.), tris(dibenzylideneacetone)dipalladium (18 mg, 0.02 mmol, 0.1 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (23 mg, 0.04 mmol, 0.2 eq.), and N,N-diisopropylethylamine (77 mg, 0.13 mmol, 3 eq.). The reaction was carried out at 90 °C for 2 hours.

[0760] The reaction was monitored by LCMS until complete. The reaction solution was concentrated and purified by silica gel column chromatography (Silica gel, DCM:MeOH = 97:3) to obtain the target compound (60 mg, yield 57.38%).

[0761] LCMS(ESI)[M+H]+=527.0.

[0762] Step 4: Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonamide

[0763] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-9-fluoro-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (5 mg, 0.01 mmol, 1.0 eq.), acetic acid (4.0 mg, 0.07 mmol, 7.0 eq.), and water (2.4 mg, 0.13 mmol, 14.0 eq.) were dissolved in tetrahydrofuran (15 mL). Dichlorohydantoin (5.6 mg, 0.03 mmol, 3 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 2 hours. Ammonia water (0.5 mL) was added, and the mixture was reacted at 0 °C for 10 minutes.

[0764] The reaction mixture was monitored by LCMS to ensure complete reaction. The reaction solution was concentrated and purified to obtain the target compound (12.1 mg, yield 25.55%).

[0765] LCMS(ESI)[M+H] + =454.0; 1 H NMR (400MHz, MeOD) δ8.65 (s, 1H), 8.01 (d, J = 12.8Hz,

[0766] 1H),7.57(d,J=8.4Hz,1H),7.48(d,J=7.2Hz,2H),5.61(s,2H),5.31(s,2H),4.08(s,3H).

[0767] Example 11

[0768] Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dioxo-3,4-dihydropyrazino[2,3-c][1,8]naphthidin-1(2H)-yl)methyl)benzenesulfonamide (compound 62):

[0769]

[0770] Preparation of 3,5-difluoro-4-((8-methoxy-2,3-dioxo-3,4-dihydropyrazino[2,3-c][1,8]naphthidin-1(2H)-yl)methyl)benzenesulfonamide

[0771] In a 50 mL round-bottom flask, add 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3-c][1,8]naphthidin-2(1H)-one (100 mg, 1.0 eq.), 10 mL tetrahydrofuran, acetic acid (10 mg, 0.84 eq.), and water (10 mg, 2.81 eq.). After cooling the mixture with ice water, add dichlorohydantoin (118 mg, 3.0 eq.). After stirring the reaction for 1 hour, add 3 mL ammonia water and continue stirring the reaction for another hour.

[0772] After the reaction was monitored by LCMS, the mixture was extracted with ethyl acetate, separated into layers, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The target compound (19.3 mg, yield: 21%) was obtained after separation and purification.

[0773] LCMS(ESI)[M+H] + =450.1; 1 HNMR(400MHz,DMSO-d6)δ12.44(s,1H),8.76(s,1H),8.67(d,

[0774] J=9.6Hz,1H),7.60(s,2H),7.43(d,J=7.2Hz,2H),7.11(d,J=9.2Hz,1H),5.69(s,2H),4.01(s,3H).

[0775] Example 12

[0776] Preparation of 7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (compound 39):

[0777]

[0778] Step 1: Preparation of ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid

[0779] Ethyl 4-chloro-7-methoxy-1,8-naphthyl-3-carboxylate (600 mg, 1 eq.), tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (838.4 mg, 1.5 eq.), and N,N-diisopropylethylamine (1.45 g, 5 eq.) were dissolved in ethanol (150 mL), heated to 90 °C, and reacted for 24 hours.

[0780] After the reaction was completed as monitored by LCMS, the target compound (800 mg, yield: 74.3%) was separated and purified by rapid silica gel column chromatography.

[0781] LCMS(ESI)[M+H] + =479.0; 1 H NMR(400MHz,DMSO-d6)δ9.85(s,1H),9.02(s,1H),8.10(d,

[0782] J=9.6Hz,1H),7.10(d,J=8.2Hz,1H),6.93(d,J=9.6Hz,1H),6.90(d,J=9.6Hz,2H),4.41(s,2H),4.16(q,J= 7.2Hz,2H),4.00(s,3H),3.54(t,J=5.6Hz,2H),2.73(t,J=5.6Hz,2H),1.42(s,9H),1.24(t,J=7.2Hz,3H).

[0783] Step 2: Preparation of tert-butyl 7-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[0784] Ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-7-yl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid (400 mg, 1 eq.) and sodium borohydride (307.8 mg, 10 eq.) were dissolved in ethanol (40 mL), the mixture was heated to 60 °C, and the reaction was stirred for 4 hours.

[0785] After the reaction was monitored by LCMS, the solvent was removed by vacuum rotary evaporation, dissolved in 100 mL of water, extracted with ethyl acetate (200 mL × 2), dried over anhydrous sodium sulfate, filtered, concentrated the filtrate, and purified by rapid chromatography to obtain the target compound (230 mg, yield 62%).

[0786] LCMS(ESI)[M+H] + =437.3; 1H NMR(400MHz,DMSO-d6)δ8.86(s,1H),8.35(s,1H),8.18(d,

[0787] J=9.0Hz,1H),6.97(d,J=9.0Hz,2H),6.55(d,J=8.8Hz,2H),5.33(t,J=5.4Hz,1H),4.46(d,J=5 .4Hz,2H),4.36(s,2H),4.00(s,3H),3.51(t,J=5.8Hz,2H),2.67(t,J=5.6Hz,2H),1.41(s,9H).

[0788] Step 3: Preparation of tert-butyl 7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[0789] 7-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester (230 mg, 1 eq.) was added to tetrahydrofuran (20 mL), followed by N,N-diisopropylethylamine (683.7 mg, 10 eq.) and triphosgene (312.7 mg, 2 eq.). The mixture was reacted at room temperature for 1 hour.

[0790] The reaction was monitored by LCMS until it ended. The sample was mixed with silica gel and purified by rapid chromatography to obtain the target compound (200 mg, yield: 81.61%).

[0791] LCMS(ESI)[M+H] + =463.0; 1 H NMR(400MHz,DMSO-d6)δ8.84(s,1H),8.57-8.43(m,1H),

[0792] 7.33(s,2H),7.18(d,J=9.6Hz,1H),6.78(d,J=9.2Hz,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).

[0793] 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]naphthidin-2-one

[0794] 200 mg, 1 eq. of 7-(8-methoxy-2-oxo-2H-[1,3]oxazin[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester was added to dichloromethane (10 mL), followed by trifluoroacetic acid (3 mL). The reaction was carried out at room temperature for 2 hours. The reaction was complete as monitored by LCMS. The solvent was removed by rotary evaporation under vacuum to obtain 140 mg of the crude target compound. This crude compound was used directly in the next reaction without further purification.

[0795] LCMS(ESI)[M+H] + =363.1.

[0796] Step 5: Preparation of tert-butyl carbamate ((7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthidium-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)carbamate

[0797] 8-Methoxy-1-(1,2,3,4-tetrahydroisoquinoline-7-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one (130 mg, crude) and triethylamine (54.6 mg) were added to dichloromethane (20 mL), and N-(chlorosulfonyl)carbamate tert-butyl ester (154.7 mg) was added dropwise at 0 °C. The reaction was carried out at room temperature for 4 hours.

[0798] After the reaction was completed as monitored by LCMS, 50 mL of water was added, and the mixture was extracted with (100 mL × 2) dichloromethane. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum to obtain the crude target compound (150 mg). This crude compound was used directly in the next reaction without further purification.

[0799] LCMS(ESI)[M+H] + =542.1.

[0800] Step 6: Preparation of 7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[0801] ((7-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)tert-butyl carbamate (150 mg, crude) was added to dichloromethane (10 mL), followed by trifluoroacetic acid (2 mL). The reaction was carried out at room temperature for 4 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by rotary evaporation under vacuum, and the product was dissolved in 3 mL of N,N-dimethylformamide. The target compound (27 mg, yield: 22%) was obtained by preparative HPLC purification.

[0802] LCMS(ESI)[M+H] + =442.1; 1 H NMR(400MHz,DMSO-d6)δ8.83(s,1H),7.38(s,1H),7.30(s,

[0803] 2H),7.18(d,J=9.2,1H),6.95(s,2H),6.79(d,J=9.2,1H),5.60(s,2H),4.17(s,2H),3.95(s,3H),3.28(t,J=5.6,2H),2.98(t,J=5.6,2H).

[0804] Example 13

[0805] Preparation of 3,5-difluoro-4-((2-hydroxy-8-methoxy-3-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthidium-1(2H)-yl)methyl)benzenesulfonamide (compound 65)

[0806]

[0807] Step 1: Preparation of 5-chloro-2-methoxy-6-nitro-1,8-naphthidine

[0808] Dissolve 3 g of 7-methoxy-3-nitro-1,8-naphthidine-4-ol (1 eq.) in dichloromethane (30 mL), then add N,N-dimethylformamide (1 mL), and then slowly add thionyl chloride (3 mL, 1.9 eq.) dropwise under ice bath conditions. Then heat to 40 °C and react for 2 hours.

[0809] After the reaction was monitored by LCMS to be complete, it was quenched with ice water, extracted with dichloromethane (100 mL × 3), the organic phase was collected, dried with anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain the target compound (2.8 g, yield: 88%).

[0810] LCMS(ESI)[M+H] + =240.0.

[0811] Step 2: Preparation of N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-naphthidine-4-amine

[0812] 5-Chloro-2-methoxy-6-nitro-1,8-naphthidine (2 g, 1 eq.) and 1-(4-bromo-2,6-difluorophenyl)methylamine (5.07 g, 1.1 eq.) were dissolved in acetonitrile (100 mL), and potassium carbonate (8.63 g, 3 eq.) was added. The mixture was then reacted at 40 °C for 2 hours.

[0813] After the reaction was monitored by LCMS until it was complete, the solution was concentrated, diluted with water, extracted with ethyl acetate (20 mL × 3), the organic phase was collected, dried over anhydrous ammonium sulfate, filtered, the filtrate was concentrated, and purified by column chromatography to obtain the target compound (3 g, yield: 85%).

[0814] LCMS(ESI)[M+H] + =427.0.

[0815] Step 3: N 4 Preparation of 3,4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthidine-3,4-diamine

[0816] N-(4-bromo-2,6-difluorobenzyl)-7-methoxy-3-nitro-1,8-naphthidine-4-amine (3 g, 1 eq.) was dissolved in ethanol (50 mL), and then iron powder (4 g, 10 eq.) and saturated ammonium chloride solution (2 mL) were added. The mixture was then reacted at 80 °C for 2 hours.

[0817] After the reaction was monitored by LCMS until complete, the solvent was concentrated to remove some of the solvent, then diluted with water, extracted with ethyl acetate (50 mL × 3), and the organic phase was collected. The organic phase was dried over anhydrous ammonium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain N. 4 -(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthidine-3,4-diamine (1.5 g, yield: 54%).

[0818] LCMS(ESI)[M+H] + =397.0.

[0819] Step 4: Preparation of N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)-2-chloroacetamide

[0820] N 4-(4-bromo-2,6-difluorobenzyl)-7-methoxy-1,8-naphthidine-3,4-diamine (500 mg, 1.0 eq.), 2-chloroacetyl chloride (154 mg, 1.1 eq.), and potassium carbonate (197 mg, 1.1 eq.) were dissolved in 30 mL of tetrahydrofuran and reacted at room temperature for 20 minutes. The reaction was monitored by LCMS until complete. The crude product obtained by concentration of the reaction solution was purified by rapid silica gel column chromatography to obtain the target compound (330 mg, yield: 56%).

[0821] LCMS(ESI)[M+H] + =471.0; 1 H NMR (400MHz, dmso-d6) δ10.49 (s, 1H), 8.88 (d, J = 9.2Hz,

[0822] 1H),8.42(s,1H),7.51(d,J=7.4Hz,2H),7.19(d,J=9.2Hz,1H),4.94(d,J=4.4Hz,2H),4.38(s,2H),4.05(s,3H),3.17(s,1H).

[0823] Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthidium-3(2H)-one

[0824] N-(4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)-2-chloroacetamide (320 mg, 1.0 eq.) and sodium hydride (18 mg, 1.1 eq.) were dissolved in N,N-dimethylformamide (20 mL) and reacted at room temperature for 20 minutes.

[0825] The reaction was monitored by LCMS until it was complete. The crude product obtained by concentration of the reaction solution was purified by rapid silica gel column chromatography to obtain the target compound (120 mg, yield: 42%).

[0826] LCMS(ESI)[M+H] + =435.0; 1 H NMR (400MHz, dmso-d6) δ10.56 (s, 1H), 8.48 (d, J = 9.0Hz,

[0827] 1H), 8.37 (s, 1H), 7.41 (d, J = 7.2Hz, 2H), 7.12 (d, J = 9.0Hz, 1H), 4.49 (s, 2H), 3.99 (s, 3H), 3.77 (s, 2H).

[0828] Step 6: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthidin-3(2H)-one

[0829] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthidium-3(2H)-one (120 mg, 1 eq.) was dissolved in dioxane (10 mL), followed by the addition of (4-methoxyphenyl)methanethiol (73 mg, 2 eq.), tris(dibenzylideneacetone)dipalladium (32 mg), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (72 mg), and diisopropylethylamine (58 mg, 3 eq.). The reaction was carried out at 100 °C for 2 hours under nitrogen protection.

[0830] The reaction was monitored by LCMS until complete. The product was then washed with water and ethyl acetate (15 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by column chromatography to obtain the target product (76 mg, yield: 64%).

[0831] LCMS(ESI)[M+H] + =509.1.

[0832] Step 7: Preparation of 3,5-difluoro-4-((2-hydroxy-8-methoxy-3-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthidium-1(2H)-yl)methyl)benzenesulfonamide)

[0833] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydropyrazino[2,3-c][1,8]naphthidin-3(2H)-one (40 mg, 1 eq.) was dissolved in tetrahydrofuran (2 mL) and acetonitrile (1 mL). Acetic acid (41 mg, 7 eq.), water (11.5 mg, 14 eq.) and N-chlorosuccinimide (25 mg, 1.8 eq.) were added at 0 °C, and the reaction was carried out at 0 °C for 2 hours. Then, ammonia water (1 g, 300 eq.) was added, and the reaction was continued at 0 °C for 1 hour.

[0834] After the reaction was monitored by LCMS to be complete, the mixture was diluted with water, extracted with ethyl acetate (15 mL × 3), the organic phase was collected, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and purified by preparative separation to obtain the target compound (5.1 mg, yield: 17%).

[0835] LCMS(ESI)[M+H] + =452.0; 1H NMR (400MHz, MeOD) δ8.63 (d, J = 9.2Hz, 1H), 8.44 (s, 1H),

[0836] 7.41(d,J=7.0Hz,2H),7.14(d,J=9.0Hz,1H),5.21(s,1H),5.03(s,2H),4.12(s,3H).

[0837] Example 14

[0838] Preparation of 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphth-1(4H)-yl)methyl)piperidine-1-sulfonamide (compound 46)

[0839]

[0840] Step 1: Preparation of ethyl 4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-7-methoxy-1,8-diazanaphthalene-3-carboxylate: Ethyl 4-chloro-7-methoxy-1,8-naphthyl-3-carboxylate (300 mg, 1 eq.), tert-butyl 4-(aminomethyl)piperidin-1-carboxylate (241 mg, 1 eq.), and N,N-diisopropylethylamine (726 mg, 5 eq.) were dissolved in ethanol (100 mL), heated to 90 °C, and reacted for 24 hours.

[0841] After the reaction was monitored by LCMS, the target compound (300 mg, yield: 24%) was obtained by rapid silica gel column chromatography.

[0842] LCMS(ESI)[M+H] + =445.2.

[0843] Step 2: Preparation of tert-butyl 4-(((3-(hydroxymethyl)-7-methoxy-1,8-diazanaphthyl-4-yl)amino)methyl)piperidine-1-carboxylic acid

[0844] Ethyl 4-(((1-(tert-butoxycarbonyl)piperidin-4-yl)methyl)amino)-7-methoxy-1,8-diazanaphthalene-3-carboxylic acid (300 mg, 1 eq.) and sodium borohydride (248 mg, 10 eq.) were dissolved in ethanol (40 mL), and the mixture was heated to 60 °C and reacted for 16 hours. After the reaction was completed as monitored by LCMS, the solvent was removed by vacuum rotary evaporation, 50 mL of water was added, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography to obtain the target compound (50 mg, yield: 18%).

[0845] LCMS(ESI)[M+H]+ =403.3.

[0846] Step 3: Preparation of tert-butyl 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)piperidine-1-carboxylic acid

[0847] 4-(((3-(hydroxymethyl)-7-methoxy-1,8-diazanaphthyl-4-yl)amino)methyl)piperidine-1-carboxylic acid tert-butyl ester (50 mg, 1 eq.) was added to tetrahydrofuran (5 mL), followed by N,N-diisopropylethylamine (160 mg, 10 eq.) and triphosgene (73 mg, 2 eq.). The mixture was reacted at room temperature for 1 hour.

[0848] After the reaction was monitored by LCMS, 10 mL of water was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude target compound (50 mg).

[0849] LCMS(ESI)[M+H] + =429.2. Used directly in the next reaction without further purification.

[0850] Step 4: Preparation of 8-methoxy-1-(piperidin-4-ylmethyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]diazanaphth-2-one

[0851] 50 mg of crude 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)piperidine-1-carboxylic acid tert-butyl ester was added to dichloromethane (5 mL), followed by trifluoroacetic acid (1 mL). The reaction was carried out at room temperature for 2 hours. The reaction was complete as monitored by LCMS. The solvent was removed by rotary evaporation under vacuum to obtain 30 mg of the crude target compound. This crude compound was used directly in the next reaction without further purification.

[0852] LCMS(ESI)[M+H] + =329.2.

[0853] Step 5: Preparation of tert-butyl carbamate ((4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)piperidin-1-yl)sulfonyl)carbamate)

[0854] 8-Methoxy-1-(piperidin-4-ylmethyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]diazanaphth-2-one (30 mg, crude) and triethylamine (46 mg) were added to dichloromethane (5 mL), and N-(chlorosulfonyl)carbamate tert-butyl ester (39 mg) was added dropwise at 0 °C. The reaction was carried out at room temperature for 5 hours.

[0855] After the reaction was completed as monitored by LCMS, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude target compound (30 mg). This crude compound was used directly in the next reaction without further purification.

[0856] LCMS(ESI)[M+H] + =508.2.

[0857] Step 6: Preparation of 4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphth-1(4H)-yl)methyl)piperidine-1-sulfonamide

[0858] ((4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)piperidin-1-yl)sulfonyl)tert-butyl carbamate (28 mg, crude) was added to dichloromethane (5 mL), followed by trifluoroacetic acid (1 mL). The reaction was carried out at room temperature for 4 hours. The reaction was confirmed to be complete by LCMS. The solvent was removed by vacuum rotary evaporation to obtain the crude product, which was then purified by preparative HPLC to obtain the target compound (5.2 mg, yield: 18%).

[0859] LCMS(ESI)[M+H] + =408.1; 1 H NMR (400MHz, DMSO-d6) δ8.77 (s, 1H), 8.53 (d, J = 9.2, 1H),

[0860] 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,2H),1.73-1.61(m,3H),1.13-1.06(m,2H).

[0861] Example 15

[0862] Preparation of 1-(2,6-difluoro-4-aminosulfonylbenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthidine-4(1H)-carboxylic acid tert-butyl ester (compound 50):

[0863]

[0864] Step 1: Preparation of 2-((4-bromo-2,6-difluorobenzyl)amino)ethane-1-ol

[0865] 4-Bromo-2,6-difluorobenzaldehyde (10 g, 1 eq.) and 2-aminoethane-1-ol (8.29 g, 3 eq.) were dissolved in dichloromethane (200 mL), and acetic acid (5.43 g, 2 eq.) was added. The mixture was reacted at room temperature for 30 minutes, and then sodium bis(acetoxy)borate (19.18 g, 2 eq.) was added. The mixture was reacted overnight at room temperature, and the reaction was monitored by LCMS until completion. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / MeOH = 10:1) to obtain the target compound (8.5 g, yield 70%).

[0866] LCMS(ESI)[M+H] + =266.0; 1 H NMR(400MHz, CDCl3)δ7.13-7.06(m,2H),3.87(s,2H),3.68

[0867] -3.62(m,2H), 2.77-2.69(m,2H).

[0868] Step 2: Preparation of 2-((4-bromo-2,6-difluorobenzyl)(7-methoxy-3-nitro-1,8-naphthid-4-yl)amino)ethane-1-ol

[0869] 5-Chloro-2-methoxy-6-nitro-1,8-naphthidine (5.00 g, 1 eq.) and 2-((4-bromo-2,6-difluorobenzyl)amino)ethane-1-ol (8.32 g, 1.5 eq.) were dissolved in dimethylformamide (100 mL), and ethyldi(propane-2-yl)amine (10.78 g, 4 eq.) was added. The reaction was carried out overnight at room temperature, and the reaction was monitored by LCMS until completion. Water was added to the reaction solution, and a large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to give the target compound (4.5 g, yield 45%).

[0870] LCMS(ESI)[M+H] + =468.9; 1 H NMR (400MHz, CDCl3) δ9.23 (s, 1H), 8.10 (d, J = 9.0Hz, 1H),

[0871] 7.09(d,J=6.8Hz,2H),6.99(d,J=9.1Hz,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).

[0872] Step 3: Preparation of 2-((3-amino-7-methoxy-1,8-naphthid-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethane-1-ol

[0873] 2-((4-bromo-2,6-difluorobenzyl)(7-methoxy-3-nitro-1,8-naphthid-4-yl)amino)ethane-1-ol (4.5 g, 1 eq.) was dissolved in methanol (20 mL), tetrahydrofuran (20 mL), and water (10 mL). Zinc (3.13 g, 5 eq.) and ammonium chloride (5.13 g, 10 eq.) were added, and the mixture was reacted overnight at room temperature.

[0874] LCMS showed the reaction was complete. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, the crude product was dissolved in dichloromethane (100 mL), washed with water (100 mL) and saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound (3.0 g, crude product). It was used directly in the next reaction without further purification.

[0875] LCMS(ESI)[M+H] + =440.9.

[0876] Step 4: Preparation of 2-((3-amino-7-methoxy-1,8-naphthid-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethyl methylsulfonic acid: 2-((3-amino-7-methoxy-1,8-naphthid-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethane-1-ol (1.2 g, crude product) was dissolved in dichloromethane (30 mL), triethylamine (829.3 mg) was added, and methanesulfonyl chloride (469.4 mg) was added under ice bath conditions. The reaction was carried out under ice bath conditions for 30 minutes.

[0877] LCMS showed that the reaction was complete. Water (30 mL) was added, and the mixture was extracted with dichloromethane (30 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound (1.2 g, crude product).

[0878] LCMS(ESI)[M+H] + =519.0. Used directly in the next reaction without further purification.

[0879] Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthidine

[0880] 1.5 g of crude 2-((3-amino-7-methoxy-1,8-naphthid-4-yl)(4-bromo-2,6-difluorobenzyl)amino)ethyl methylsulfonic acid was dissolved in acetonitrile (50 mL), and cesium carbonate (2.83 g) was added. The mixture was reacted at 50 °C for 16 hours.

[0881] LCMS showed that the reaction was complete. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (DCM / EA = 1:1) to obtain the target compound (500 mg, yield 41%).

[0882] LCMS(ESI)[M+H] + =423.1; 1 H NMR (400MHz, CDCl3) δ8.50 (d, J = 8.9Hz, 1H), 8.39 (s, 1H),

[0883] 7.17(d,J=7.0Hz,2H),6.94(d,J=9.0Hz,1H),4.32(s,2H),4.11(s,3H),3.37-3.30(m,2H),3.09-3.02(m,2H).

[0884] Step 6: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthidine

[0885] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthidine (300 mg, 1 eq.) and benzyl mercaptan (2.13 g, 1.5 eq.) were dissolved in dioxane (15 mL), followed by the addition of (1E,4E)-1,5-diphenylpenta-1,4-dien-3-one dipalladium (31.8 mg, 0.1 eq.), (5-(diphenylphosphino)-9,9-dimethyl-9H-xanthan-4-yl)diphenylphosphine (82.4 mg, 0.2 eq.), and triethylamine (216.2 mg, 3 eq.). The mixture was purged three times with argon gas, and the reaction solution was reacted at 90 °C for 16 hours.

[0886] LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain the target compound (300 mg, yield 91%).

[0887] LCMS(ESI)[M+H] + =465.2;1 H NMR (400MHz, CDCl3) δ8.48 (d, J = 8.9Hz, 1H), 8.43 (s, 1H),

[0888] 7.38-7.30(m,5H),6.92(d,J=9.0Hz,1H),6.85(d,J=8.2Hz,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).

[0889] Step 7: Preparation of tert-butyl 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthidine-4(1H)-carboxylic acid

[0890] The compound 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-1,2,3,4-tetrahydropyrazino[2,3-c][1,8]naphthidine (100 mg, 1 eq.) was dissolved in di-tert-butyl dicarbonate (5 mL, 106.38 eq.) and 4-dimethylaminopyridine (100 mg, 3.8 eq.) was added. The reaction was carried out at 40 °C for 2 hours.

[0891] LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography to obtain the target compound (100 mg, yield 82%).

[0892] LCMS(ESI)[M+H] + =565.3.

[0893] Step 8: Preparation of tert-butyl 1-(2,6-difluoro-4-aminosulfonylbenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthidine-4(1H)-carboxylic acid

[0894] Compound 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthyl-4(1H)-carboxylic acid tert-butyl ester (230 mg, 1 eq.) was dissolved in tetrahydrofuran (5 mL), and water (102.8 mg, 14 eq.) and acetic acid (171.2 mg, 7 eq.) were added. Dichlorohydantoin (240.8 mg, 3 eq.) was added under ice bath conditions, and the reaction was carried out for 10 minutes. The reaction solution was then slowly added dropwise to ammonia water (5 mL) under ice bath conditions, and the reaction was carried out for 30 minutes. LC-MS showed that the starting material reacted completely. The reaction solution was extracted with ethyl acetate (20 mL), the organic phase was concentrated under reduced pressure, and the crude product was purified by preparative HPLC to obtain the target compound (13.0 mg, yield 6%).

[0895] LCMS(ESI)[M+H] + =522.5; 1 H NMR (400MHz, MeOD-d4) δ8.85 (s, 1H), 8.54 (d, J = 9.1Hz,

[0896] 1H),7.48(d,J=7.0Hz,2H),7.00(d,J=9.1Hz,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).

[0897] Example 16

[0898] Preparation of 3,5-difluoro-4-((8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthidium-1(2H)-yl)methyl)benzenesulfonamide (compound 66)

[0899]

[0900] 10 mg, 1 eq. of compound 1-(2,6-difluoro-4-aminosulfonylbenzyl)-8-methoxy-2,3-dihydropyrazino[2,3-c][1,8]naphthidine-4(1H)-carboxylic acid tert-butyl ester was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (0.2 mL) was added. The mixture was reacted at room temperature for 2 hours.

[0901] LCMS showed that the reaction was complete. The reaction solution was concentrated under reduced pressure, and the crude product was purified to obtain the target compound 3,5-difluoro-4-((8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthid-1(2H)-yl)methyl)benzenesulfonamide (4.4 mg, yield 52%).

[0902] LCMS(ESI)[M+H] + =422.1; 1 H NMR (400MHz, MeOD-d4) δ8.54 (d, J = 9.1Hz, 1H), 8.11 (s,

[0903] 1H),7.54(t,J=5.3Hz,2H),6.99(d,J=9.1Hz,1H),4.83(s,2H),4.07(s,3H),3.30-3.27(m,2H),3.24-3.20(m,2H).

[0904] Example 17

[0905] Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyridino[2,3-h][1,6]naphthidin-1(2H)-yl)methyl)benzenesulfonamide (compound 54):

[0906]

[0907] Step 1: Preparation of (4-chloro-7-methoxy-1,8-naphthid-3-yl)methanol

[0908] Ethyl 4-chloro-7-methoxy-1,8-naphthidine-3-carboxylic acid (10 g, 1 eq.) was dissolved in dichloromethane (200 mL), purged with nitrogen, and the temperature was lowered to -68 °C. A cyclohexane solution of diisobutylaluminum hydride (86 mL, 1 M) was slowly added dropwise to the reaction solution, and the mixture was stirred at -68 °C for 2 hours.

[0909] The reaction was confirmed to be complete by LCMS. The reaction solution was quenched with saturated ammonium chloride solution, and the aqueous phase was extracted with ethyl acetate (100 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target product (5.5 g, yield 83%).

[0910] LCMS(ESI)[M+H] + =225.0.

[0911] Step 2: Preparation of 4-chloro-7-methoxy-1,8-naphthidine-3-carboxaldehyde

[0912] (4-chloro-7-methoxy-1,8-naphthid-3-yl)methanol (5.5 g, 1 eq.) was dissolved in dichloromethane (20 mL), and active manganese dioxide (10.64 g, 5 eq.) was added. The reaction solution was stirred overnight at 40 °C.

[0913] The reaction was confirmed by LCMS. The mixture was filtered through diatomaceous earth and washed with dichloromethane. The filtrate was concentrated to obtain a crude product, which was then purified by column chromatography to obtain the target compound (4.5 g, 99% yield).

[0914] LCMS(ESI)[M+H] + =223.0; 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),9.20(s,1H),8.67

[0915] (d,J=9.0Hz,1H),7.37(d,J=9.0Hz,1H),4.10(s,3H).

[0916] Step 3: Preparation of (E)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)ethyl acrylate

[0917] Sodium hydride (808.5 mg, 3 eq.) was dissolved in tetrahydrofuran (20 mL). Under ice bath conditions, ethyl 2-(diethoxyphosphoryl)acetate (1.81 g, 1.2 eq.) in tetrahydrofuran (3 mL) was slowly added. After stirring for 30 minutes, 4-chloro-7-methoxy-1,8-naphthidine-3-carboxaldehyde (1.5 g, 1 eq.) dissolved in tetrahydrofuran (30 mL) was added. The mixture was reacted at room temperature for 30 minutes.

[0918] LCMS showed that the reaction was complete. The reaction solution was quenched with water (20 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound (1.5 g, yield 76%).

[0919] LCMS(ESI)[M+H] + =293.0; 1 H NMR (400MHz, CDCl3) δ9.14 (s, 1H), 8.47 (d, J = 9.0Hz, 1H),

[0920] 8.15(d,J=16.2Hz,1H),7.11(d,J=9.0Hz,1H),6.68(d,J=16.2Hz,1H),4.32(q,J=7.1Hz,2H),4.19(s,3H),1.37(t,J=7.1Hz,3H).

[0921] Step 4: Preparation of (E)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)acrylic acid

[0922] Ethyl (E)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)acrylate (1.5 g, 1 eq.) was dissolved in tetrahydrofuran (30 mL) and water (10 mL), and then lithium hydroxide (613.6 mg, 5 eq.) was added. The mixture was reacted overnight at room temperature.

[0923] LCMS showed the reaction was complete. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the pH of the aqueous phase was adjusted to 4 with 1N hydrochloric acid, resulting in the precipitation of a large amount of solid. The mixture was filtered, and the filter cake was dried to give the target compound (1.3 g, yield 96%).

[0924] LCMS(ESI)[M+H] + =265.3; 1 H NMR(400MHz,DMSO-d6)δ12.78(s,1H),9.39(s,1H),8.56

[0925] (d,J=9.0Hz,1H),7.94(d,J=16.1Hz,1H),7.30(d,J=9.0Hz,1H),6.94(d,J=16.1Hz,1H),4.07(s,3H).

[0926] Step 5: Preparation of (E)-N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)acrylamide

[0927] Compound (E)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)acrylic acid (1.3 g, 1 eq.) was dissolved in dimethylformamide (30 mL), and O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (2.24 g, 1.2 eq.) and ethyl di(propane-2-yl)amine (2.54 g, 4 eq.) were added. The reaction was carried out at room temperature for 30 minutes. (4-(benzylthio)-2,6-difluorophenyl)methylamine (1.3 g, 1 eq.) was added to the reaction solution and the reaction was carried out at room temperature for 1 hour.

[0928] LCMS showed that the reaction was complete. Water (50 mL) was added to the reaction solution, and a large amount of solid precipitated out. The solid was filtered, and the filter cake was dried to give the target compound (1.5 g, yield 59%).

[0929] LCMS(ESI)[M+H] + =512.2.

[0930] Step 6: Preparation of N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)propionamide

[0931] Compound (E)-N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)acrylamide (1.5 g, 1 eq.) was dissolved in tetrahydrofuran (60 mL) and water (20 mL), and 4-toluene-1-sulfonylhydrazine (5.45 g, 10 eq.) and sodium acetate trihydrate (3.99 g, 10 eq.) were added. The reaction solution was reacted at 80 °C for 4 hours.

[0932] LCMS showed the reaction was complete. The reaction solution was cooled to room temperature, and 60 mL of sodium bicarbonate aqueous solution was added. Extraction was performed with ethyl acetate (80 mL × 2). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography to obtain the target compound (800 mg, yield 53%).

[0933] LCMS(ESI)[M+H] + =514.2.

[0934] Step 7: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrido[2,3-h][1,6]naphthidium-2(1H)-one

[0935] The compound N-(4-(benzylthio)-2,6-difluorobenzyl)-3-(4-chloro-7-methoxy-1,8-naphthid-3-yl)propionamide (750 mg, 1 eq.) was dissolved in dimethylformamide (10 mL), and cesium carbonate (1.43 g, 3 eq.) was added. The mixture was reacted at 100 °C for 4 hours.

[0936] LCMS showed that the reaction was complete. The reaction solution was added to water (20 mL), extracted with ethyl acetate (30 mL × 2), the combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the target compound (300 mg, yield 43%).

[0937] LCMS(ESI)[M+H] + =478.2; 1 H NMR (400MHz, CDCl3) δ8.70 (s, 1H), 8.19 (d, J = 9.1Hz, 1H),

[0938] 7.33-7.27(m,4H),7.02-6.91(m,2H),6.61(t,J=6.0Hz,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).

[0939] Step 8: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyridino[2,3-h][1,6]naphthidium-1(2H)-yl)methyl)benzenesulfonamide

[0940] Compound 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrido[2,3-h][1,6]naphthidin-2(1H)-one (250 mg, 1 eq.) was dissolved in tetrahydrofuran (5 mL), and water (132.1 mg, 14 eq.) and acetic acid (220.1 mg, 7 eq.) were added. Dichlorohydantoin (309.4 mg, 3 eq.) was added under ice bath conditions, and the reaction was carried out for 10 minutes. The reaction solution was then slowly added dropwise to ammonia water (5 mL) under ice bath conditions, and the reaction was carried out for 30 minutes. LC-MS showed that the starting material reacted completely. The reaction solution was extracted with ethyl acetate (20 mL), and the organic phase was concentrated under reduced pressure. The crude product was purified by preparative separation to obtain the target compound (93 mg, yield 41%).

[0941] LCMS(ESI)[M+H] + =435.1; 1 H NMR (400MHz, MeOD-d4) δ8.68 (s, 1H), 8.48 (d, J = 9.2Hz,

[0942] 1H),7.40-7.33(m,2H),7.09(d,J=9.2Hz,1H),5.50(s,2H),4.10(s,3H),2.99-2.92(m,2H),2.72-2.64(m,2H).

[0943] Example 18

[0944] Preparation of 1-(2,6-difluoro-4-aminosulfonylbenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid tert-butyl ester (compound 52):

[0945]

[0946] Step 1: Preparation of 7-methoxy-3-nitroquinoline-4-ol

[0947] 7-Methoxyquinoline-4-ol (1 g, 1 eq.) was dissolved in propionic acid (10 mL), and 70% nitric acid (1 mL) was added. The reaction mixture was stirred at 140 °C for 12 h.

[0948] LCMS analysis confirmed complete reaction of the reactants and the appearance of the product. The reaction mixture was slowly poured into ice water, causing the solid to precipitate. The solid was filtered, washed three times with methanol, and evaporated to dryness to obtain the target product (800 mg, yield 63%).

[0949] LCMS(ESI)[M+H] + =221.3; 1H NMR(400MHz,DMSO-d6)δ12.77(s,1H),9.14(s,1H),8.29-

[0950] 8.02(m,1H),7.26-7.01(m,2H),3.89(s,3H).

[0951] Step 2: Preparation of 4-chloro-7-methoxy-3-nitroquinoline

[0952] 7-Methoxy-3-nitroquinoline-4-ol (800 mg, 1 eq.) was dissolved in N,N-dimethylformamide (10 mL), and thionyl chloride (0.66 mL, 2.5 eq.) was added to the reaction solution. The mixture was stirred at 25 °C for 1 h.

[0953] The reaction was confirmed by LCMS. The reaction solution was poured into ice water, adjusted to alkaline with sodium carbonate solution, extracted with ethyl acetate (20 mL), washed with saturated brine (20 mL × 3), and the organic phase was dried and concentrated to obtain the target product (600 mg, yield 69%).

[0954] LCMS(ESI)[M+H] + =239.2; 1 H NMR (400MHz, DMSO-d6) δ9.34 (s, 1H), 8.34 (d, J = 9.1Hz,

[0955] 1H), 7.60 (dd, J=7.2, 5.7Hz, 2H), 4.02 (s, 3H).

[0956] Step 3: Preparation of N-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-3-nitroquinoline-4-amine

[0957] 4-Chloro-7-methoxy-3-nitroquinoline (2.6 g, 1 eq.) was dissolved in N,N-dimethylformamide (30 mL), and (4-(benzylthio)-2,6-difluorophenyl)methylamine (4.34 g, 1.5 eq.) and N,N-diisopropylethylamine (4.22 g, 3 eq.) were added sequentially. The reaction was stirred at 25 °C for 12 h.

[0958] LCMS analysis confirmed the reaction was successful. The reaction solution was filtered, the filter cake was washed with acetonitrile, and the solid was dried to obtain the target product (2 g, yield 39%).

[0959] LCMS(ESI)[M+H] + =468.2.

[0960] Step 4: N 4Preparation of 3,4-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxyquinoline-3,4-diamine

[0961] N-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-3-nitroquinoline-4-amine (2 g, 1 eq.) was dissolved in tetrahydrofuran (10 mL), methanol (10 mL), and water (5 mL). Ammonium chloride (2.29 g, 10 eq.) and zinc powder (1.4 g, 5 eq.) were added, and the mixture was stirred at 25 °C for 1 hour.

[0962] The reaction was confirmed to be successful by LCMS. The mixture was filtered, the filtrate was evaporated to dryness, washed with water, extracted with ethyl acetate, and the organic phase was dried and concentrated to obtain the target product (1.5 g, crude product). It was used directly in the next reaction without further purification.

[0963] LCMS(ESI)[M+H] + =438.2.

[0964] Step 5: Preparation of (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-yl)glycine

[0965] N 4 -(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxyquinoline-3,4-diamine (1 g, crude product, obtained from the previous step) and ethyl glyoxylate (466.7 mg) were dissolved in methanol (10 mL), stirred for 1 hour, and then sodium cyanoborohydride (424.0 mg) was added. The reaction was stirred at 25 °C for 1 hour.

[0966] The reaction was confirmed to be successful by LCMS. The reaction solution was quenched with water, extracted with dichloromethane (20 mL × 3), and the organic phase was dried and concentrated to obtain the target product (1 g, crude product). It was used directly in the next reaction without further purification.

[0967] LCMS(ESI)[M+H] + =496.3.

[0968] Step 6: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c]quinoline-2(1H)-one. (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-yl)glycine (1 g, crude product, obtained from the previous step) was dissolved in tetrahydrofuran (10 mL). O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea hexafluorophosphate (1.45 g) was added. After stirring at room temperature for 1 hour, N,N-diisopropylethylamine (740.6 mg) was added, and the reaction was stirred at 25 °C for 1 hour.

[0969] The reaction was confirmed to be successful by LCMS. The reaction solution was washed with water (10 mL), extracted with ethyl acetate (20 mL), dried and concentrated by organic phase, and the crude product was purified by column chromatography to obtain the target compound (600 mg).

[0970] LCMS(ESI)[M+H] + =478.2.

[0971] 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)-carboxylic acid

[0972] 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c]quinoline-2(1H)-one (300 mg, 1 eq.), ditert-butyl dicarbonate (5 mL), and 4-dimethylaminopyridine (230.25 mg, 3 eq.) were stirred at 40 °C for 1 hour.

[0973] LCMS analysis confirmed the reaction was successful. The reaction solution was concentrated, and the crude product was purified by rapid chromatography to obtain the target product (270 mg, yield 74%).

[0974] LCMS(ESI)[M+H] + =578.1.

[0975] Step 8: Preparation of tert-butyl 1-(2,6-difluoro-4-aminosulfonylbenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid

[0976] Dissolve 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid tert-butyl ester (270 mg, 1 eq.) in tetrahydrofuran (5 mL), add glacial acetic acid (196.5 mg, 7 eq.) and water (117.9 mg, 14 eq.), add dichlorohydantoin (276.3 mg, 3 eq.) under ice bath, and stir at 0 °C for 6 minutes.

[0977] The reaction was confirmed to be successful by LCMS. The reaction solution was added to ammonia water (6 mL) and stirred for 6 minutes. The product was detected by LCMS. The pH of the reaction solution was adjusted to neutral with 1 M hydrochloric acid, extracted with ethyl acetate (5 mL × 2), concentrated in aqueous phase, and a solid precipitated. The solid was filtered, and the filtrate was purified by preparative HPLC to obtain the target compound (22.4 mg, yield 9%).

[0978] LCMS(ESI)[M+H] +=534.9; 1 H NMR (400MHz, MeOD-d4) δ8.92 (s, 1H), 8.13 (d, J = 9.3Hz,

[0979] 1H),7.37(d,J=2.3Hz,1H),7.34(d,J=9.3Hz,1H),7.27(d,J=7.2Hz,2H),5.59(s,2H),4.36(s,2H),3.96(s,3H),1.54(s,9H).

[0980] Example 19

[0981] Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinoline-1(2H)-yl)methyl)benzenesulfonamide (compound 51):

[0982]

[0983] The raw material 1-(2,6-difluoro-4-aminosulfonylbenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid tert-butyl ester (8 mg, 1 eq.) was dissolved in dichloromethane (1 mL), and trifluoroacetic acid (1 mL) was added. The reaction solution was stirred at room temperature for 1 hour.

[0984] The product was detected by LCMS, the reaction solution was concentrated, and the crude product was purified by HPLC to obtain the target compound (1.4 mg, yield 21%).

[0985] LCMS(ESI)[M+H] + =434.9; 1 H NMR (400MHz, MeOD-d4) δ8.54 (s, 1H), 8.12 (d, J = 9.5Hz,

[0986] 1H),7.39-7.32(m,4H),5.55(s,2H),3.98(s,3H),3.85(s,2H).

[0987] Example 20

[0988] Preparation of 4-((8-ethoxy-2-oxopyrido[2,3-h][1,6]naphthidium-1(2H)-yl)methyl)-3,5-difluorobenzenesulfonamide (compound 63):

[0989]

[0990] Step 1: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-ethoxypyrido[2,3-h][1,6]naphthidium-2(1H)-one

[0991] 120 mg (1 eq.) of 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxaldehyde was dissolved in 15 mL of ethanol, and 198 mg (3.4 eq.) of 2-(dimethoxyphosphoryl)ethyl acetate and 203 mg (5 eq.) of potassium carbonate were added. The reaction was carried out at 85 °C for 36 hours, and the reaction was monitored to be complete by LC-MS. The reaction solution was concentrated to dryness and purified by rapid silica gel column chromatography to obtain the target product (100 mg, yield: 76%).

[0992] LCMS(ESI)[M+H] + =446.0.

[0993] Step 2: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-ethoxypyrido[2,3-h][1,6]naphthidin-2(1H)-one

[0994] 1-(4-bromo-2,6-difluorobenzyl)-8-ethoxypyrido[2,3-h][1,6]naphthidium-2(1H)-one (90 mg, 1 eq.) was dissolved in dioxane (5 mL), and (4-methoxyphenyl)methanethiol (62 mg, 2 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (23 mg, 0.2 eq.), tris(dibenzylideneacetone)dipalladium (37 mg, 0.2 eq.) and N,N-diisopropylethylamine (78 mg, 3 eq.) were added. The mixture was reacted at 90 °C for 2 hours under nitrogen protection.

[0995] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness and purified by rapid silica gel column chromatography to obtain the target product (70 mg, yield: 66%).

[0996] LCMS(ESI)[M+H] + =520.1.

[0997] Step 3: Preparation of 4-((8-ethoxy-2-oxopyridano[2,3-h][1,6]naphthidin-1(2H)-yl)methyl)-3,5-difluorobenzenesulfonamide: 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-ethoxypyridano[2,3-h][1,6]naphthidin-2(1H)-one (65 mg, 1 eq.), acetic acid (53 mg, 7 eq.), and water (32 mg, 14 eq.) were dissolved in tetrahydrofuran (5 mL). Dichlorohydantoin (74 mg, 3 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 1 hour. After adding ammonia (0.5 mL), the mixture was reacted at 0 °C for 10 minutes.

[0998] The reaction mixture was monitored by LCMS until complete. The reaction solution was concentrated to dryness and purified by HPLC to obtain the target compound (2.6 mg, yield: 4.7%).

[0999] LCMS(ESI)[M+H] + =447.1; 1 H NMR (400MHz, DMSO-d6) δ9.15 (s, 1H), 8.71 (d, J = 9.6Hz,

[1000] 1H),8.20(d,J=9.2Hz,1H),7.62(s,2H),7.43(d,J=7.2Hz,2H),7.09(d,J=9.6Hz,1H ), 6.69 (d, J = 9.6Hz, 1H), 5.77 (s, 2H), 4.53 (q, J = 7.1Hz, 2H), 1.41 (t, J = 7.2Hz, 3H).

[1001] Example 21

[1002] Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthidin-1(2H)-yl)methyl)benzenesulfonamide (compound 49):

[1003]

[1004] Step 1: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthidin-2(1H)-one

[1005] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxypyrazino[2,3-c][1,8]naphthidin-2(1H)-one (50 mg, 1 eq.) was dissolved in ethanol (5 mL), and then sodium borohydride (11 mg, 3 eq.) was added. The reaction was carried out with stirring at 25 °C for 2 hours.

[1006] The reaction was confirmed to be complete by LCMS. The reaction solution was diluted with water (10 mL), extracted three times with ethyl acetate (50 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the crude product (50 mg). This crude product was used directly in the next reaction without further purification.

[1007] LCMS(ESI)[M+H] + =509.1.

[1008] Step 2: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c][1,8]naphthidium-1(2H)-yl)methyl)benzenesulfonamide

[1009] In a 25 mL round-bottom flask, 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c][1,8]naphthidin-2(1H)-one (20 mg, crude product, obtained from the previous step), tetrahydrofuran (10 mL), acetic acid (10 mg), and water (10 mL) were added. The solution was cooled with ice water, and dichlorohydantoin (23 mg) was added. The reaction was stirred for 60 minutes, followed by the addition of 1 mL of ammonia water and stirring for another 60 minutes. Sodium borohydride (15 mg, 10 eq.) was then added. After the reaction was complete, the layers were separated by water and ethyl acetate. The ethyl acetate layer was dried and concentrated to obtain the crude product, which was then purified by liquid chromatography to obtain the target compound (2.1 mg).

[1010] LCMS(ESI)[M+H] + =436.1; 1 HNMR (400MHz, DMSO-d6) δ8.55 (s, 1H), 8.44 (d, J = 9.2Hz,

[1011] 1H),7.32(d,J=6.8Hz,2H),7.02(d,J=9.2Hz,1H),6.44(s,1H),5.32(s,2H),3.96(s,3H),3.70(s,2H).

[1012] Example 22

[1013] Preparation of 4-((8,9-dimethoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)-3,5-difluorobenzenesulfonamide (compound 31):

[1014]

[1015] first step: 2 Preparation of 3,4-dimethoxyphenyl)amino)methylene)diethyl malonate

[1016] 3,4-Dimethoxyaniline (7 g, 1 eq.) and 1,3-diethyl 2-(ethoxymethylene)malonate (10 g, 1.01 eq.) were added to ethanol (200 mL) and stirred at room temperature for 4 hours. After the reaction was completed, the solvent was removed by direct vacuum distillation to obtain the crude target compound (18 g). It was used directly in the next reaction without further purification.

[1017] LCMS(ESI)[M+H] + =324.1.

[1018] Step 2: Preparation of ethyl 4-chloro-6,7-dimethoxyquinoline-3-carboxylate

[1019] Diethyl 2-(((3,4-dimethoxyphenyl)amino)methylene)malonate (18 g, crude product, obtained from the previous step) and phosphorus oxychloride (8 mL) were placed in a 100 mL flask, heated to 100 °C, and stirred for 5 hours.

[1020] The reaction was monitored by LCMS until it ended. After cooling to room temperature, the solution was slowly added dropwise to a flask containing 200 mL of water. After the addition was complete, the mixture was cooled, and sodium bicarbonate aqueous solution was gradually added to adjust the pH to neutral. The mixture was extracted with ethyl acetate (200 mL × 2). The organic phases were combined, washed with brine, and concentrated under vacuum to obtain the crude target compound (16 g). This crude compound was used directly in the next reaction without further purification.

[1021] LCMS(ESI)[M+H] + =296.1.

[1022] Step 3: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinoline-3-carboxylic acid

[1023] Ethyl 4-chloro-6,7-dimethoxyquinoline-3-carboxylate (1 g, crude product, obtained from the previous step) was dissolved in acetonitrile (20 mL), and then potassium carbonate (1 g) and (4-bromo-2,6-difluorophenyl)methylamine (0.79 g) were added. The reaction was carried out under nitrogen protection and reflux at 100 °C for 20 hours.

[1024] The reaction was monitored by LCMS until completion. The reaction solution was evaporated to dryness, diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. The crude product was purified by rapid chromatography to obtain the target compound (0.68 g).

[1025] LCMS(ESI)[M+H] + =481.0.

[1026] Step 4: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinoline-3-yl)methanol

[1027] Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinoline-3-carboxylic acid (150 mg, 1 eq.) was dissolved in ethanol (15 mL), and sodium borohydride (60 mg, 5 eq.) was added. The mixture was reacted at 25 °C for 16 hours.

[1028] The reaction was monitored by LCMS until complete. The reaction solution was poured into water, extracted with ethyl acetate, dried over anhydrous sodium sulfate on the organic phase, concentrated to dryness, and purified by silica gel column chromatography to obtain the target compound (100 mg, yield: 72%).

[1029] LCMS(ESI)[M+H] + =439.0.

[1030] Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one. (4-((4-bromo-2,6-difluorobenzyl)amino)-6,7-dimethoxyquinoline-3-yl)methanol (100 mg, 1 eq.) was dissolved in dichloromethane (10 mL), and triphosgene (219 mg, 3.2 eq.) and N,N-diisopropylethylamine (159 mg, 5.4 eq.) were added. The reaction was carried out at 25 °C for 1 hour.

[1031] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness and purified by silica gel column chromatography to obtain the target compound (85 mg, yield: 80%).

[1032] LCMS(ESI)[M+H] + =465.0.

[1033] Step 6: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazinco[5,4-c]quinoline-2-one

[1034] 1-(4-bromo-2,6-difluorobenzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (85 mg, 1 eq.) was dissolved in dioxane (10 mL), and (4-methoxyphenyl)methanethiol (55 mg, 2 eq.), tris(dibenzylideneacetone)dipalladium (18 mg, 0.1 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (23 mg, 0.2 eq.), and N,N-diisopropylethylamine (71 mg, 3 eq.) were added. The reaction was carried out at 90 °C for 2 hours.

[1035] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness and purified by silica gel column chromatography to obtain the target compound (50 mg, yield: 51%).

[1036] LCMS(ESI)[M+H] + =539.2.

[1037] Step 7: Preparation of 4-((8,9-dimethoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)-3,5-difluorobenzenesulfonamide

[1038] 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8,9-dimethoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (50 mg, 1.0 eq.), acetic acid (28.0 mg, 5 eq.), and water (24 mL) were dissolved in tetrahydrofuran (15 mL). Dichlorohydantoin (19 mg, 1 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 2 hours. Ammonia water (0.5 mL) was added, and the mixture was reacted at 0 °C for 10 minutes.

[1039] The reaction mixture was monitored by LCMS until complete. The reaction solution was concentrated to dryness and purified by preparative HPLC to obtain the target compound (2.7 mg, yield: 6%).

[1040] LCMS(ESI)[M+H] + =466.0; 1 H NMR(400MHz,CD3OD)δ8.69(s,1H),7.52(s,1H),7.50-

[1041] 7.43(m,2H),7.25(d,J=8.8Hz,1H),6.87(d,J=8.8Hz,1H),5.71(s,2H),5.34(s,2H),4.07(s,3H),4.02(s,3H).

[1042] Example 23

[1043] Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonamide (compound 30):

[1044]

[1045] Step 1: Preparation of diethyl 2-((3-methoxyphenyl)amino)methylene)malonate

[1046] 3-Methoxyaniline (10.0 g, 1 eq.) was dissolved in ethanol (100 mL), and diethyl 2-(ethoxymethylene)malonate (21 g, 1.2 eq.) was added. The mixture was reacted at 90 °C for 16 hours.

[1047] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness under reduced pressure to obtain a crude product of the target compound (20 g). This product was used directly in the next reaction without further purification.

[1048] LCMS(ESI)[M+H] + =294.1.

[1049] Step 2: Preparation of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate:

[1050] Diethyl 2-((3-methoxyphenyl)amino)methylene)malonate (5 g, crude product, obtained from the previous step) was dissolved in phosphorus oxychloride (15 mL). The reaction was carried out at 110 °C for 4 hours.

[1051] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness under reduced pressure to obtain a mixture (3.8 g) of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate and ethyl 4-chloro-5-methoxyquinoline-3-carboxylate. This mixture was used directly in the next reaction without further purification.

[1052] LCMS(ESI)[M+H] + =266.0.

[1053] Step 3: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-carboxylic acid

[1054] A mixture of ethyl 4-chloro-7-methoxyquinoline-3-carboxylate and ethyl 4-chloro-5-methoxyquinoline-3-carboxylate (2 g, mixture obtained from the previous step) was dissolved in N,N-dimethylformamide (10 mL), and 1-(4-bromo-2,6-difluorophenyl)methylamine (1.84 g) and N,N-diisopropylethylamine (2.92 g, 3 eq.) were added. The reaction was carried out at 50 °C for 16 hours.

[1055] The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction solution was poured into water and extracted with ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to give a mixture (1.6 g) 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.

[1056] LCMS(ESI)[M+H] + =451.0.

[1057] Step 4: Preparation of (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-yl)methanol

[1058] A mixture of 1.6 g 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, obtained from the previous step, was dissolved in ethanol (50 mL), and sodium borohydride (671 mg, 5.0 eq.) was added. The mixture was reacted at 50 °C for 16 hours.

[1059] The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction was quenched with water, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, and purified by silica gel column chromatography to obtain a mixture (400 mg) of (4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-yl)methanol and (4-((4-bromo-2,6-difluorobenzyl)amino)-5-methoxyquinoline-3-yl)methanol.

[1060] LCMS(ESI)[M+H] + =409.1.

[1061] Step 5: Preparation of 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one

[1062] ((4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxyquinoline-3-yl)methanol and (4-((4-bromo-2,6-difluorobenzyl)amino)-5-methoxyquinoline-3-yl)methanol (400 mg, mixture, obtained from the previous step) were dissolved in dichloromethane (10 mL), and triphosgene (870 mg, 3 eq.) and N,N-diisopropylethylamine (632 mg, 5 eq.) were added. The reaction was carried out at 25 °C for 2 hours.

[1063] The reaction was monitored by LCMS until complete. The reaction solution was quenched with water and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by silica gel column chromatography to obtain 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazin[5,4-c]quinoline-2-one (70 mg) and 1-(4-bromo-2,6-difluorobenzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazin[5,4-c]quinoline-2-one (60 mg).

[1064] LCMS(ESI)[M+H] + =435.1.

[1065] Step 6: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazinco[5,4-c]quinoline-2-one

[1066] 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (65 mg, 1 eq.) was dissolved in dioxane (5 mL), followed by (4-methoxyphenyl)methanethiol (46 mg, 2 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (17 mg, 0.2 eq.), tris(dibenzylideneacetone)dipalladium (27 mg, 0.2 eq.), and N,N-diisopropylethylamine (58 mg, 3 eq.). The reaction was carried out at 90 °C for 2 hours.

[1067] The reaction was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target compound (60 mg, yield 79%).

[1068] LCMS(ESI)[M+H] + =509.1.

[1069] Step 7: Preparation of 3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonamide

[1070] A mixture of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (30 mg, 1.0 eq.), acetic acid (25 mg, 7.0 eq.), and water (15 mL) was dissolved in tetrahydrofuran (5 mL). Dichlorohydantoin (35 mg, 3 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 1 hour. Ammonia water (0.5 mL) was added, and the mixture was reacted at 0 °C for 10 minutes.

[1071] The reaction of the starting materials was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to obtain the target compound (5.8 mg, yield 22%).

[1072] LCMS(ESI)[M+H] + =436.0; 1 H NMR (400MHz, DMSO) δ8.72 (s, 1H), 8.22 (d, J = 9.6Hz, 1H),

[1073] 7.62(s,2H),7.49-7.43(m,3H),7.29(dd,J=9.2,2.4Hz,1H),5.50(s,2H),5.27(s,2H),3.94(s,3H).

[1074] Example 24

[1075] Preparation of 3,5-difluoro-4-((10-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonamide (compound 68):

[1076]

[1077] Step 1: Preparation of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazinco[5,4-c]quinoline-2-one

[1078] 1-(4-bromo-2,6-difluorobenzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (60 mg, 1 eq.) was dissolved in dioxane (5 mL), followed by (4-methoxyphenyl)methanethiol (43 mg, 2 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (16 mg, 0.2 eq.), tris(dibenzylideneacetone)dipalladium (25 mg, 0.2 eq.), and N,N-diisopropylethylamine (53 mg, 3 eq.). The reaction was carried out at 90 °C for 2 hours.

[1079] The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction solution was concentrated under reduced pressure and purified by silica gel column chromatography to obtain the target compound (50 mg). This compound was used directly in the next reaction without further purification.

[1080] LCMS(ESI)[M+H] + =509.1.

[1081] Step 2: Preparation of 3,5-difluoro-4-((10-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonamide

[1082] A mixture of 1-(2,6-difluoro-4-((4-methoxybenzyl)thio)benzyl)-10-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c]quinoline-2-one (30 mg, 1.0 eq.), acetic acid (25 mg, 7.1 eq.), and water (15 mg, 14.1 eq.) was dissolved in tetrahydrofuran (5 mL). Dichlorohydantoin (35 mg, 3 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 1 hour. Ammonia (0.2 mL) was then added, and the mixture was reacted at 0 °C for 10 minutes.

[1083] The reaction of the starting materials was monitored by LCMS until complete. The reaction solution was concentrated under reduced pressure and purified by preparative HPLC to obtain the target compound (2.0 mg, yield: 8%).

[1084] LCMS(ESI)[M+H] + =436.0; 1 H NMR (400MHz, DMSO) δ8.74 (s, 1H), 7.73 (t, J = 8.0Hz, 1H),

[1085] 7.64(d,J=8.0Hz,1H),7.60(s,2H),7.41(d,J=6.4Hz,2H),7.20(d,J=8.0Hz,1H),5.21(s,2H),5.08(s,2H),4.05(s,3H).

[1086] Example 25

[1087] Preparation of 6-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)methyl)pyridine-3-sulfonamide (compound 70):

[1088]

[1089] Step 1: Preparation of ethyl 4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid

[1090] Ethyl 4-chloro-7-methoxy-1,8-naphthyl-3-carboxylate (200 mg, 1 eq.), (5-bromopyridin-2-yl)methylamine (210.4 mg, 1.5 eq.), and N,N-diisopropylethylamine (289.0 mg, 3 eq.) were dissolved in ethanol (50 mL), heated to 90 °C, and reacted for 16 hours. The reaction was monitored by LCMS until complete. After concentration under reduced pressure, the target compound (150 mg, yield: 48%) was obtained by rapid silica gel column chromatography.

[1091] LCMS(ESI)[M+H] + =417.1.

[1092] Step 2: Preparation of (4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthidin-3-yl)methanol

[1093] Ethyl 4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthyl-3-carboxylic acid (150 mg, 1 eq.) was added to dichloromethane (20 mL), and a 1 mol / L solution of diisobutylaluminum hydride in tetrahydrofuran (7.2 mL, 20 eq.) was added at -78 °C. The reaction was carried out at -78 °C for 2 hours, and the reaction was monitored by LCMS to ensure complete reaction. The reaction was quenched with water and extracted with dichloromethane (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The target compound (100 mg, yield: 74%) was obtained by rapid chromatography.

[1094] LCMS(ESI)[M+H] + =377.1.

[1095] Step 3: Preparation of 1-((5-bromopyridin-2-yl)methyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one

[1096] (100 mg, 1 eq.) of (4-(((5-bromopyridin-2-yl)methyl)amino)-7-methoxy-1,8-naphthidin-3-yl)methanol was added to tetrahydrofuran (20 mL), followed by N,N-diisopropylethylamine (335.4 mg, 9.74 eq.) and triphosgene (154.3 mg, 1.95 eq.). The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by LCMS until complete. The mixture was quenched with 20 mL of water, and extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the target compound (60 mg, yield: 56%).

[1097] LCMS(ESI)[M+H] +=401.2.

[1098] 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]naphthidin-2-one

[1099] 1-((5-bromopyridin-2-yl)methyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthid-2-one (60 mg, 1 eq.), (4-methoxyphenyl)methanethiol (46.2 mg, 2 eq.), tris(dibenzylideneacetone)dipalladium (6 mg, 0.04 eq.), 4,5-bisdiphenylphosphine-9,9-dimethyloxanthracene (17.4 mg, 0.2 eq.), and N,N-diisopropylethylamine (97.5 mg, 5 eq.) were added to 1,4-dioxane (10 mL), the mixture was purged with nitrogen three times, and the reaction was carried out at 90 °C for 3 hours. The reaction was monitored by LCMS until complete. The reaction solution was cooled to room temperature, and then water (20 mL) was added. The mixture was extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the target compound (50 mg, yield: 70%).

[1100] LCMS(ESI)[M+H] + =475.1.

[1101] Step 5: Preparation of 6-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthidium-1(4H)-yl)methyl)pyridine-3-sulfonamide

[1102] In a 25 mL round-bottom flask, 8-methoxy-1-((5-(((4-methoxybenzyl)thio)pyridin-2-yl)methyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyl-2-one (50 mg, 1.0 eq.), tetrahydrofuran (10 mL), acetic acid (8.0 mg, 1.3 eq.), and water (4.0 mg, 2.1 eq.) were added. Dichlorohydantoin (43.1 mg, 2.1 eq.) was added at 0 °C, and the reaction was allowed to proceed for 1 hour. The reaction was monitored by LCMS until complete. 1 mL of ammonia was added, and the reaction was allowed to proceed for another hour at room temperature. After the reaction was complete, the reaction solution was concentrated under reduced pressure, and the target compound (3.8 mg, yield: 9%) was obtained by HPLC purification.

[1103] LCMS(ESI)[M+H] + =402.1; 1H NMR (400MHz, DMSO-d6) δ8.88 (d, J = 2.2Hz, 1H), 8.79 (s,

[1104] 1H),8.42(d,J=9.2Hz,1H),8.15(m,J=8.2,1H),7.66(d,J=8.4Hz,1H),7. 59(s,2H),7.07(d,J=9.2Hz,1H),5.55(s,2H),5.51(s,2H),4.00(s,3H).

[1105] Example 26

[1106] Preparation of 3-fluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthid-1(4H)-yl)methyl)benzenesulfonamide (compound 71):

[1107]

[1108] Step 1: Preparation of ethyl 4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid

[1109] Ethyl 4-chloro-7-methoxy-1,8-naphthyl-3-carboxylic acid (500 mg, 1 eq.), 1-(4-bromo-2-fluorophenyl)methylamine (381 mg, 1 eq.), and N,N-diisopropylethylamine (2.45 g, 10.1 eq.) were dissolved in acetonitrile (20 mL), and the mixture was heated to 70 °C and reacted for 16 hours. The reaction was monitored by LCMS until complete. The reaction solution was cooled to room temperature, and water (20 mL) was added. The mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (500 mg, yield: 61%).

[1110] LCMS(ESI)[M+H] + =434.0.

[1111] Step 2: Preparation of (4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)methanol

[1112] Ethyl 4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid (250 mg, 1.0 eq.) was dissolved in ethanol (20 mL), and then sodium borohydride (211 mg, 9.7 eq.) was added. The reaction was carried out at 60 °C for 16 hours, and the reaction was monitored by LCMS until complete. The reaction solution was cooled to room temperature, quenched with water, and the ethanol was removed by vacuum distillation. Water (50 mL) was added to the residue, and the solution was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, washed five times with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under vacuum. After stirring with silica gel, the solution was separated and purified by rapid silica gel column chromatography to obtain the target compound (100 mg, yield: 44%).

[1113] LCMS(ESI)[M+H] + =392.0.

[1114] Step 3: Preparation of 1-(4-bromo-2-fluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one

[1115] (4-((4-bromo-2-fluorobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)methanol (100 mg, 1 eq.) was added to tetrahydrofuran (10 mL), followed by N,N-diisopropylethylamine (329 mg, 10 eq.) and triphosgene (378 mg, 5 eq.). The reaction was carried out at room temperature for 1 hour, and the reaction was monitored by LCMS until complete. The reaction solution was quenched with 10 mL of water, and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, concentrated under reduced pressure, and purified by column chromatography to obtain the target compound (35 mg, yield: 32%).

[1116] LCMS(ESI)[M+H] + =418.0.

[1117] 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]naphthidin-2-one

[1118] 1-(4-bromo-2-fluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one (33 mg, 1 eq.) was dissolved in dioxane (10 mL), and (4-methoxyphenyl)methanethiol (24 mg, 2 eq.), tris(dibenzylideneacetone)dipalladium (10 mg, 0.1 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (9 mg, 0.2 eq.), and N,N-diisopropylethylamine (30 mg, 3 eq.) were added. The reaction was carried out at 90 °C for 2 hours.

[1119] The reaction was monitored by LCMS until complete. The reaction solution was concentrated and reduced to dryness, and purified by thin-layer chromatography to obtain the target compound (22 mg, yield: 56%).

[1120] LCMS(ESI)[M+H] + =492.1.

[1121] Step 5: Preparation of 3-fluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthid-1(4H)-yl)methyl)benzenesulfonamide

[1122] 1-(2-fluoro-4-((4-methoxybenzyl)thio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazinofo[5,4-c][1,8]naphthidin-2-one (20 mg, 1.0 eq.), acetic acid (16 mg, 6.6 eq.), and water (10 mg, 13.6 eq.) were dissolved in tetrahydrofuran (5 mL). Dichlorohydantoin (16 mg, 2 eq.) was added at 0 °C, and the mixture was reacted at 0 °C for 2 hours. Ammonia water (0.5 mL) was added, and the mixture was reacted at 0 °C for 10 minutes.

[1123] The reaction mixture was monitored by LCMS until complete. The reaction solution was concentrated to dryness under reduced pressure and purified by preparative HPLC to obtain the target compound (2.5 mg, yield: 15%).

[1124] LCMS(ESI)[M+H] + =419.0; 1 H NMR (400MHz, DMSO) δ8.79 (s, 1H), 8.41 (d, J = 9.2Hz,

[1125] 1H),7.65-7.56(m,3H),7.48(s,2H),7.08(d,J=9.2Hz,1H),5.43(s,4H),4.01(s,3H).

[1126] Example 27

[1127] Preparation of 4-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthid-1(4H)-yl)methyl)benzenesulfonamide (compound 67):

[1128]

[1129] Step 1: Preparation of ethyl 4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid

[1130] Ethyl 4-chloro-7-methoxy-1,8-naphthidine-3-carboxylic acid (500 mg, 1.0 eq.) was dissolved in acetonitrile (30 mL), and then potassium carbonate (1.3 g, 5.0 eq.) and (4-bromophenyl)methylamine (523.2 mg, 1.5 eq.) were added. The reaction was carried out at 70 °C for 5 hours under nitrogen protection.

[1131] The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction solution was diluted with ethyl acetate, washed with water, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by rapid chromatography to obtain the target compound (0.5 g, yield: 64%).

[1132] LCMS(ESI)[M+H] + =416.1.

[1133] Step 2: Preparation of (4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)methanol

[1134] Ethyl 4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid (300 mg, 1.0 eq.) was dissolved in ethanol (10 mL), sodium borohydride (245.4 mg, 9.0 eq.) was added, the reaction system was purged with nitrogen, and stirred at 70 °C for 10 hours.

[1135] The reaction was monitored by LCMS analysis to ensure complete reaction. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride aqueous solution, extracted with ethyl acetate, and the organic phases were combined, washed with saturated sodium bicarbonate, and concentrated to obtain the crude product. The crude product was purified by rapid chromatography to obtain the target compound (200 mg, yield: 74%).

[1136] LCMS(ESI)[M+H] + =376.0.

[1137] Step 3: Preparation of 1-(4-bromobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one

[1138] (4-((4-bromobenzyl)amino)-7-methoxy-1,8-naphthid-3-yl)methanol (300 mg, 1.0 eq.) was dissolved in dichloromethane (10 mL), and then N,N-diisopropylethylamine (243 mg, 2.35 eq.) and triphosgene (237 mg, 1.0 eq.) were added successively at 0 °C. The reaction was stirred at 0 °C for 2 hours.

[1139] The reaction was monitored by LCMS until complete. The reaction solution was quenched with saturated brine (20 mL), extracted with dichloromethane (10 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation to obtain the crude product. The crude product was purified by rapid chromatography to obtain the target compound (200 mg, yield 62%).

[1140] LCMS(ESI)[M+H] + =402.0.

[1141] Step 4: Preparation of 8-methoxy-1-(4-((4-methoxybenzyl)thio)benzyl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one

[1142] 1-(4-bromobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one (200 mg, 1.0 eq.) was dissolved in dioxane (10 mL), followed by the addition of (4-methoxyphenyl)methanethiol (154 mg, 2.0 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (57 mg, 0.2 eq.), tris(dibenzylideneacetone)dipalladium (44 mg, 0.1 eq.), and N,N-diisopropylethylamine (193 mg, 3 eq.). The reaction was carried out at 90 °C for 2 hours.

[1143] The reaction was monitored by LCMS until complete. After cooling to room temperature, the reaction solution was concentrated and separated by rapid silica gel column chromatography to obtain the target compound (100 mg, yield: 42%).

[1144] LCMS(ESI)[M+H] + =474.1.

[1145] Step 5: Preparation of 4-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthid-1(4H)-yl)methyl)benzenesulfonamide

[1146] 8-Methoxy-1-(4-((4-methoxybenzyl)thio)benzyl)-1,4-dihydro-2H-[1,3]oxazinofo[5,4-c][1,8]naphthidin-2-one (90 mg, 1.0 eq.), acetic acid (80 mg, 7.0 eq.), and water (50 mg, 14.6 eq.) were dissolved in tetrahydrofuran (15 mL). Dichlorohydantoin (112 mg, 3.0 eq.) was added at 0 °C, and the mixture was reacted at 25 °C for 1 hour. Ammonia water (0.5 mL) was added, and the mixture was reacted at 25 °C for 10 minutes.

[1147] The reaction was monitored by LCMS until complete. The reaction solution was concentrated and purified by preparative HPLC to obtain the target compound (13.9 mg, yield: 18%).

[1148] LCMS(ESI)[M+H] + =401.1; 1 HNMR(400MHz,MMSO-d6)δ8.79(s,1H),8.37(d,J=8.0Hz,

[1149] 1H),7.74(d,J=8.0Hz,2H),7.51(d,J=8.0Hz,2H),7.33(s,2H),7.02(d,J=8.0Hz,1H),5.51(s,2H),5.43(s,2H),3.99(s,3H).

[1150] Example 28

[1151] Preparation of (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphth-1(4H)-yl)methyl)phenyl)boronic acid (compound 41):

[1152]

[1153] The 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-2-one (100 mg, 1.0 eq.) prepared in step 4 of Example 6 was dissolved in 1,4-dioxane (10 mL), and pinacol diboronate (76 mg, 1.3 eq.), (1,1'-bis(diphenylphosphino)ferrocene)palladium dichloride (34 mg, 0.2 eq.), and sodium acetate (38 mg, 2.0 eq.) were added. The reaction was carried out at 90 °C under nitrogen protection for 2 hours.

[1154] The reaction was monitored by LCMS until complete. The reaction solution was concentrated to dryness and purified by preparative HPLC to obtain the target compound (15.8 mg, yield 17%).

[1155] LCMS(ESI)[M+H]+=402.1; 1 H NMR (400MHz, MeOD) δ8.71 (s, 1H), 8.62 (d, J = 9.2Hz, 1H),

[1156] 7.15-7.04(m,3H),5.57(s,2H),5.31(s,2H),4.13(s,3H).

[1157] Example 29

[1158] Preparation of (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)phenyl)phosphonic acid (compound 43):

[1159]

[1160] Step 1: Preparation of diethyl (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)phenyl)phosphonate

[1161] The 1-(4-bromo-2,6-difluorobenzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]diazanaphthyl-2-one (25 mg, 1.0 eq.) prepared in step 4 of Example 6 was added to ethanol (5 mL), followed by diethyl phosphonate (12 mg, 1.5 eq.), N-methyldicyclohexylamine (18 mg, 1.5 eq.), triphenylphosphine (24 mg, 1.6 eq.), and palladium acetate (6 mg, 0.5 eq.). The reaction was carried out under nitrogen at 80 °C for 16 hours, and the reaction was monitored by LCMS until complete. After cooling to room temperature, water (5 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by preparative chromatography to obtain the target compound (15 mg, yield: 53%).

[1162] LCMS(ESI)[M+H] + =494.1.

[1163] Step 2: Preparation of (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)phenyl)phosphonic acid

[1164] Diethyl (3,5-difluoro-4-((8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]diazanaphthyl-1(4H)-yl)methyl)phenyl)phosphonate (15 mg, 1.0 eq.) was added to anhydrous dichloromethane (5 mL), followed by trimethylbromosilane (0.46 mg, 0.1 eq.). The reaction was carried out under nitrogen protection at room temperature for 16 hours. The reaction was monitored by LCMS until it ended. Then, 3 mL of methanol was added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. The reaction was monitored by LCMS until it ended. The target compound (1.5 mg, yield 11%) was obtained by preparative HPLC purification.

[1165] LCMS(ESI)[M+H] + =438.1; 1 H NMR (400MHz, MeOD) δ8.72 (s, 1H), 8.63 (d, J = 9.2Hz, 1H),

[1166] 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).

[1167] Example 30

[1168] Preparation of 1-(2,6-difluoro-4-aminosulfonylbenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid tert-butyl ester (compound 69)

[1169]

[1170] 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 (5.11 g, 1 eq.) was dissolved in triethoxymethane (15.75 g, 3 eq.), stirred at 90 °C for 1 hour, cooled to 70 °C, and 4-fluoro-3-methoxyaniline (5 g, 1 eq.) was added. The reaction was carried out at 70 °C for 0.5 hours.

[1171] The reaction was confirmed by LCMS. The mixture was cooled to room temperature and filtered. The filter cake was washed with petroleum ether and dried to obtain the target compound (10 g, yield: 95%).

[1172] 1H NMR (400MHz, DMSO-d6) δ11.24(d,J=14.5Hz,1H),8.59(d,J=14.5Hz,1H),7.50(dd,J=7.6 ,2.6Hz,1H),7.27(dd,J=11.1,8.8Hz,1H),7.19-7.03(m,1H),3.90(s,3H),1.68(s,6H).

[1173] Step 2: Preparation of 6-fluoro-7-methoxyquinoline-4-ol

[1174] 5-(((4-fluoro-3-methoxyphenyl)amino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (10 g, 1 eq.) was dissolved in diphenyl ether (40 mL) and stirred at 200 °C for 6 hours.

[1175] The reaction was confirmed by LCMS. The reaction system was allowed to return to room temperature, filtered, and the filter cake was washed with petroleum ether to obtain the target product (6.3 g, yield: 96%).

[1176] LCMS(ESI)[M+H] + =194.1; 1 H NMR(400MHz,DMSO-d6)δ11.65(s,1H),7.92-7.81(m,1H),

[1177] 7.71(d,J=11.8Hz,1H), 7.13(d,J=7.4Hz,1H), 5.97(d,J=7.4Hz,1H), 3.94(s,3H).

[1178] Step 3: Preparation of 6-fluoro-7-methoxy-3-nitroquinoline-4-ol

[1179] 6-Fluoro-7-methoxyquinoline-4-ol (3 g, 1 eq.) was dissolved in propionic acid (50 mL). 70% nitric acid (5 mL) was added, and the mixture was reacted at 140 °C for 12 hours.

[1180] The reaction was confirmed by LCMS. The mixture was cooled to room temperature, water was added, and the mixture was filtered. The filter cake was washed with water and ethyl acetate to obtain the target compound (2.4 g, yield: 65%).

[1181] LCMS(ESI)[M+H] + =239.3; 1 H NMR(400MHz,DMSO-d6)δ12.89(s,1H),9.17(s,1H),7.90(d,

[1182] J=11.5Hz,1H),7.32(d,J=7.3Hz,1H),3.98(s,3H).

[1183] Step 4: Preparation of 4-chloro-6-fluoro-7-methoxy-3-nitroquinoline

[1184] 6-Fluoro-7-methoxy-3-nitroquinoline-4-ol (2.4 g, 1 eq.) was dissolved in dichloromethane (70 mL) and N,N-dimethylformamide (20 mL), and sulfonyl dichloro (3 g, 2.2 eq.) was added. The mixture was stirred at 40 °C for 3 hours.

[1185] The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, and water was added to the crude product, resulting in the precipitation of solids. The product was filtered, and the filter cake was washed with water and ethyl acetate to obtain the target compound (2.5 g, yield: 96%).

[1186] LCMS(ESI)[M+H] + =257.3.

[1187] Step 5: Preparation of N-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxy-3-nitroquinoline-4-amine

[1188] 4-Chloro-6-fluoro-7-methoxy-3-nitroquinoline (2.8 g, 1 eq.) and (4-(benzylthio)-2,6-difluorophenyl)methylamine (2.89 g, 1 eq.) were dissolved in tetrahydrofuran (40 mL), and N,N-diisopropylethylamine (4.23 g, 3 eq.) was added. The mixture was stirred at room temperature for 1.5 hours.

[1189] The reaction was confirmed by LCMS. The reaction solution was concentrated under reduced pressure, filtered, and the filter cake was washed with methanol to obtain the target compound (3.2 g, yield: 60%).

[1190] LCMS(ESI)[M+H] + =486.1.

[1191] Step 6: N 4 Preparation of 3,4-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinoline-3,4-diamine

[1192] N-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxy-3-nitroquinoline-4-amine (3.1 g, 1 eq.) was dissolved in a mixed solution of methanol (50 mL) and tetrahydrofuran (50 mL), and a solution of zinc powder (2.09 g, 5 eq.) and ammonium chloride (3.4 mg, 10 eq.) in water (25 mL) was added. The reaction was carried out at room temperature for 1 hour.

[1193] After LCMS analysis confirmed the reaction was complete, zinc powder was removed by filtration, water (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, and the organic phase was evaporated to dryness under reduced pressure to obtain the crude target compound (2.2 g). This crude compound was used directly in the next reaction without further purification.

[1194] LCMS(ESI)[M+H] + =456.0.

[1195] Step 7: Preparation of ethyl (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-yl)aminoacetate. 4 A toluene solution (50wt%, 20mL) of 1-(4-(benzylthio)-2,6-difluorobenzyl)-6-fluoro-7-methoxyquinoline-3,4-diamine (1.9g, crude) and ethyl glyoxylate was dissolved in methanol (10mL). The mixture was stirred at room temperature for 1.5 hours, and sodium cyanoborohydride (1.29g) was added. The mixture was then stirred at room temperature for another 0.5 hours.

[1196] The reaction was confirmed by LCMS. The reaction mixture was evaporated to dryness, water (30 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined and evaporated to dryness to obtain the target compound (4 g, crude product). This crude product was used directly in the next reaction without further purification.

[1197] LCMS(ESI)[M+H] + =542.2.

[1198] Step 8: Preparation of (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-yl)aminoacetic acid

[1199] Ethyl (4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-yl)aminoethyl acetate (2 g, crude) was dissolved in a mixed solution of tetrahydrofuran (50 mL) and methanol (15 mL), and a solution of lithium hydroxide (353.8 mg) in water (10 mL) was added. The mixture was stirred at room temperature for 2 hours.

[1200] The reaction was confirmed by LCMS. The pH of the solution was adjusted to 2, the reaction mixture was evaporated to dryness, water (30 mL) was added, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined and evaporated to dryness to obtain the target product (1.1 g, yield: 58%).

[1201] LCMS(ESI)[M+H] + =514.1.

[1202] Step 9: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrazino[2,3-c]quinoline-2(1H)-one

[1203] Dissolve 1.1 g ((4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-6-fluoro-7-methoxyquinoline-3-yl)aminoacetic acid in 10 mL of N,N-dimethylformamide, add HATU (2443.4 mg, 3 eq.) and N,N-diisopropylethylamine (830.5 mg, 3 eq.), and stir at room temperature for 2 hours.

[1204] After the reaction was detected by LCMS, water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine, filtered, and the filtrate was evaporated to dryness to obtain the crude product. The crude product was purified by column chromatography to obtain the target product (800 mg, yield: 75%).

[1205] LCMS(ESI)[M+H] + =496.1.

[1206] 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)-carboxylic acid

[1207] 1-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-3,4-dihydropyrazino[2,3-c]quinoline-2(1H)-one (300 mg, 1 eq.) was dissolved in di-tert-butyl dicarbonate (3 mL), and 4-dimethylaminopyridine (221.9 mg, 3 eq.) was added. The mixture was stirred at 40 °C for 1 hour.

[1208] After the reaction was detected by LCMS, water (10 mL) was added, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, evaporated to dryness, and the crude product was obtained. The target compound (100 mg, yield: 28%) was obtained by separation and purification by column chromatography.

[1209] LCMS(ESI)[M+H] + =596.4.

[1210] Step 11: Preparation of tert-butyl 1-(2,6-difluoro-4-aminosulfonylbenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid

[1211] Dissolve 1-(4-(benzylthio)-2,6-difluorobenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid tert-butyl ester (80 mg, 1 eq.) in tetrahydrofuran (2 mL), add water (33.9 mg, 14 eq.) and acetic acid (56.5 mg, 7 eq.) and dichlorohydantoin (52.9 mg, 2 eq.) in an ice bath, and stir for 5 minutes in an ice bath.

[1212] The reaction was confirmed by LCMS. The reaction solution was added to stirred ammonia water (3 mL), and the reaction was confirmed by LCMS. Extraction was performed with ethyl acetate (5 mL × 3). The organic phases were combined and distilled under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC to obtain the target compound (6 mg, yield: 8%).

[1213] LCMS(ESI)[M+H] + =553.1; 1 H NMR (400MHz, MeOD-d4) δ8.91 (s, 1H), 7.94 (d, J = 12.4Hz,

[1214] 1H),7.50(d,J=8.2Hz,1H),7.27(d,J=7.2Hz,2H),5.59(s,2H),4.36(s,2H),4.03(s,3H),1.54(s,9H).

[1215] Example 31

[1216] Preparation of 3,5-difluoro-4-((9-fluoro-8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinoline-1(2H)-yl)methyl)benzenesulfonamide (compound 55)

[1217]

[1218] The tert-butyl 1-(2,6-difluoro-4-aminosulfonylbenzyl)-9-fluoro-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-carboxylic acid ester (50 mg, 1 eq.) prepared in Example 30 was dissolved in dichloromethane (2 mL), and trifluoroacetic acid (0.5 mL) was added. The mixture was stirred at room temperature for 1 hour.

[1219] The reaction was confirmed by LCMS. After concentration under reduced pressure, the reaction solution was purified by preparative HPLC to obtain the target compound (1.23 mg, yield: 3%).

[1220] LCMS(ESI)[M+H] + =453.1.

[1221] Example 32

[1222] Preparation of 3,5-difluoro-4-((4-(2-hydroxyacetyl)-8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinoline-1(2H)-yl)methyl)benzenesulfonamide (compound 72)

[1223]

[1224] Step 1: Preparation of 2-(1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-yl)-2-oxoethyl ester of acetate

[1225] The 1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-3,4-dihydropyrazino[2,3-c]quinoline-2(1H)-one (400 mg, 1 eq.) prepared in step 6 of Example 18 was dissolved in dichloromethane (4 mL), and 2-chloro-2-oxoethyl acetate (171.6 mg, 1.5 eq.) and triethylamine (254.3 mg, 3 eq.) were added. The mixture was reacted at room temperature for 1 h.

[1226] The reaction was confirmed to be successful by LCMS. The mixture was diluted with water, extracted with the organic phase, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to obtain the target compound (120 mg, yield: 25%).

[1227] LCMS(ESI)[M+H] + =578.2.

[1228] Step 2: Preparation of 3,5-difluoro-4-((4-(2-hydroxyacetyl)-8-methoxy-2-oxo-3,4-dihydropyrazino[2,3-c]quinoline-1(2H)-yl)methyl)benzenesulfonamide

[1229] 2-(1-(4-(benzylthio)-2,6-difluorobenzyl)-8-methoxy-2-oxo-2,3-dihydropyrazino[2,3-c]quinoline-4(1H)-yl)-2-oxoethyl ester (50 mg, 1 eq.) was dissolved in ultra-dry tetrahydrofuran (2 mL), and glacial acetic acid (39.3 mg, 7.6 eq.), water (23.6 mg, 15.1 eq.), and dichlorohydantoin (55.3 mg, 3.2 eq.) were added under ice bath conditions, and the mixture was stirred at 0 °C for 5 minutes.

[1230] After the LCMS detected the disappearance of the raw material, ammonia water (5 mL) was added to the reaction solution, and after stirring for 30 minutes, sodium bicarbonate (39.3 mg, 5.4 eq.) was added, and stirring was continued for 1 hour.

[1231] The product was detected by LCMS. The reaction solution was filtered, and the pH of the filtrate was adjusted to neutral with 1M hydrochloric acid. After concentration, the residue was purified by preparative HPLC to obtain the target compound (3.2 mg, yield: 7.5%).

[1232] LCMS(ESI)[M+H] + =493.0; 1 H NMR (400MHz, MeOD-d4) δ9.10 (s, 1H), 8.25 (d, J = 10.3Hz,

[1233] 1H), 7.43 (s, 2H), 7.33 (d, J = 6.4Hz, 2H), 5.63 (s, 2H), 4.46 (d, J = 20.1Hz, 4H), 4.00 (s, 3H).

[1234] Example 33

[1235] Preparation of 3,5-difluoro-4-((7-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonamide (compound 61)

[1236]

[1237] Step 1: Preparation of diethyl 2-(((2-methoxyphenyl)amino)methylene)malonate

[1238] 2-Methoxyaniline (20 g, 1 eq.) was dissolved in diethyl 2-(ethoxymethylene)malonate (35.12 g, 1 eq.) and stirred at 140 °C for 45 minutes.

[1239] The reaction was confirmed by LCMS. After cooling to room temperature, petroleum ether was added and stirred. A white solid precipitated out. The mixture was filtered, and the filter cake was washed with petroleum ether to obtain the target compound (39.6 g, yield: 83%).

[1240] LCMS(ESI)[M+H] + =294.1; 1 H NMR (400MHz, CDCl3) δ11.12 (d, J=13.4Hz, 1H), 8.57 (d, J=

[1241] 14.1Hz,1H),7.24(s,1H),6.99(dd,J=42.4,26.6Hz,3H),4.33(q,J=7.1Hz,2H), 4.25(q,J=7.1Hz,2H), 3.94(s,3H), 1.39(t,J=7.1Hz,3H), 1.33(t,J=7.1Hz,3H).

[1242] Step 2: Preparation of ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylic acid

[1243] Diethyl 2-(((2-methoxyphenyl)amino)methylene)malonate (15 g, 1 eq.) was added to diphenyl ether (75 mL), and the reaction was carried out at 260 °C for 45 min. The reaction was completed by LCMS. After cooling to room temperature, petroleum ether was added, and a solid precipitated out. The mixture was filtered, the filter cake was washed with petroleum ether, and dried to give the target compound (8.5 g, yield: 67%).

[1244] LCMS(ESI)[M+H] + =248.0.

[1245] Step 3: Preparation of ethyl 4-chloro-8-methoxyquinoline-3-carboxylic acid

[1246] Ethyl 4-hydroxy-8-methoxyquinoline-3-carboxylate (4 g, 1 eq.) was dissolved in dichloromethane (40 mL), N,N-dimethylformamide (4 mL) was added, and oxalyl chloride (3.08 g, 1.5 eq.) was slowly added dropwise. The mixture was stirred at room temperature for 1 hour.

[1247] The reaction was confirmed by LCMS. The reaction mixture was evaporated to dryness, ethyl acetate was added, and the mixture was filtered. The filter cake was washed with ethyl acetate and dried to obtain the target product (4 g, yield: 93%).

[1248] LCMS(ESI)[M+H] + =266.1; 1 H NMR (400MHz, CDCl3) δ9.67 (s, 1H), 8.15 (d, J = 8.6Hz, 1H),

[1249] 7.94(t,J=8.3Hz,1H),7.49(d,J=7.9Hz,1H),4.55(d,J=7.1Hz,2H),4.26(s,3H),1.48(t,J=7.1Hz,3H).

[1250] Step 4: Preparation of ethyl 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinoline-3-carboxylate

[1251] Ethyl 4-chloro-8-methoxyquinoline-3-carboxylate (2 g, 1 eq.) and (4-(benzylthio)-2,6-difluorophenyl)methylamine (2 g, 1 eq.) were dissolved in DMF (40 mL), and N,N-diisopropylethylamine (3.89 g, 4 eq.) was added. The mixture was reacted at 50 °C for 16 hours.

[1252] The reaction was detected by LCMS. The solution was diluted with water (40 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, concentrated, and purified by column chromatography to obtain the target compound (2.3 g, yield: 62%).

[1253] LCMS(ESI)[M+H] + =495.0.

[1254] Step 5: Preparation of 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinoline-3-yl)methanol

[1255] Ethyl 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinoline-3-carboxylic acid (2.1 g, 1 eq.) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and methanol (8 mL), and lithium borohydride (462.4 mg, 5 eq.) was added. The mixture was reacted at room temperature for 2 hours.

[1256] The reaction was detected by LCMS. The reaction was quenched by adding saturated ammonium chloride aqueous solution, and the reaction solution was concentrated under reduced pressure. A solid precipitated out. The solid was filtered, the filter cake was washed with ethyl acetate, and dried to give the target compound (1.2 g, yield: 62%).

[1257] LCMS(ESI)[M+H] + =452.9.

[1258] Step 6: Preparation of 1-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-1,4-dihydro-2H-[1,3]oxazinco[5,4-c]quinoline-2-one

[1259] 4-((4-(benzylthio)-2,6-difluorobenzyl)amino)-8-methoxyquinoline-3-yl)methanol (400 mg, 1 eq.) was dissolved in ultra-dry tetrahydrofuran (40 mL), N,N-diisopropylethylamine (342.7 mg, 3 eq.) was added, and triphosgene (262.3 mg, 2 eq.) was added under ice bath conditions. The mixture was stirred at room temperature for 3 hours.

[1260] The reaction was confirmed by LCMS. After concentration under reduced pressure, the reaction solution was purified by reverse column chromatography to obtain the target compound (100 mg, yield: 24%).

[1261] LCMS(ESI)[M+H] + =479.1.

[1262] Step 7: Preparation of 3,5-difluoro-4-((7-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c]quinoline-1(4H)-yl)methyl)benzenesulfonamide

[1263] Dissolve 1-(4-(benzylthio)-2,6-difluorobenzyl)-7-methoxy-1,4-dihydro-2H-[1,3]oxazin[5,4-c]quinoline-2-one (50 mg, 1 eq.) in tetrahydrofuran (2 mL), add water (26.4 mg, 14 eq.) and acetic acid (43.9 mg, 7 eq.) and dichlorohydantoin (41.2 mg, 2 eq.) in an ice bath, and stir for 5 minutes in an ice bath.

[1264] Ammonia (1 mL) was added, and stirring continued. The reaction was monitored by LCMS until complete. Tetrahydrofuran was removed by vacuum distillation, followed by extraction with ethyl acetate (10 mL). After concentration of the organic phase, the target compound (2.0 mg, yield: 4.4%) was obtained by preparative HPLC purification.

[1265] LCMS(ESI)[M+H] + =436.0; 1 H NMR(400MHz,MeOD-d4)δ8.67(s,1H),8.50(s,2H),7.79(d,J

[1266] =8.5Hz,1H),7.63(t,J=8.3Hz,1H),7.44(d,J=7.4Hz,2H),7.27(d,J=8.2Hz,1H),5.59(s,2H),5.32(s,2H),4.07(s,3H).

[1267] Example 34

[1268] Preparation of 6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide (compound 59)

[1269]

[1270] Step 1: Preparation of ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-7-methoxy-1,8-naphthidine-3-carboxylate

[1271] Ethyl 4-chloro-7-methoxy-1,8-naphthidine-3-carboxylate (2 g, 1 eq.) was dissolved in N,N-dimethylformamide (20 mL), and N,N-diisopropylethylamine (2.91 g, 3 eq.) and tert-butyl 6-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (2.79 g, 1.5 eq.) were added. The mixture was stirred at 50 °C for 10 hours.

[1272] The reaction was confirmed by LCMS. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by column chromatography to obtain the target compound (2.3 g, yield: 64%).

[1273] LCMS(ESI)[M+H] + =479.1; 1 H NMR (400MHz, CDCl3) δ10.37(s,1H),9.30(s,1H),7.81(d,J=9.1Hz,1H),7.04(d,J=8.0Hz,1H),6.93-6.81(m,2H),6.58(d,J=9.1 Hz,1H),4.56(s,2H),4.43(q,J=7.1Hz,2H),4.13(s,3H),3.63(t,J=5.0Hz,2H),2.74(s,2H),1.50(s,9H),1.45(t,J=7.1Hz,3H).

[1274] Step 2: Preparation of tert-butyl 6-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[1275] Ethyl 4-((2-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroisoquinoline-6-yl)amino)-7-methoxy-1,8-naphthidine-3-carboxylate (2 g, 1 eq.) was dissolved in tetrahydrofuran (20 mL), and lithium borohydride (0.27 g, 3 eq.) and methanol (2 mL) were added under ice bath conditions. The reaction mixture was stirred at 25 °C for 2 hours.

[1276] The reaction was confirmed by LCMS. A saturated ammonium chloride solution (10 mL) was slowly added dropwise under ice bath, followed by extraction with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the target compound (1.5 g, crude). This crude compound was used directly in the next reaction without further purification.

[1277] LCMS(ESI)[M+H] + =437.3.

[1278] Step 3: Preparation of tert-butyl 6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid

[1279] 1.9 g of crude 6-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester was dissolved in tetrahydrofuran (20 mL), and N,N-diisopropylethylamine (1.69 g) and triphosgene (1.29 g) were added. The reaction mixture was stirred at 25 °C for 4 hours.

[1280] The reaction was confirmed by LCMS. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (20 mL × 2), dried with anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain the target compound (300 mg).

[1281] LCMS(ESI)[M+H] + =463.1; 1 H NMR (400MHz, CDCl3) δ8.75(s,1H),7.24(dd,J=18.5,9.1Hz,3H),7.16(d,J=9.3Hz,1H),6.63(d,J=9 .3Hz,1H),5.47(s,2H),4.64(s,2H),4.11(s,3H),3.67(s,2H),2.83(t,J=5.7Hz,2H),1.51(s,9H).

[1282] 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]naphthidin-2-one

[1283] 200 mg of 6-(8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-carboxylic acid tert-butyl ester was dissolved in 2 mL of trifluoroacetic acid, and the reaction solution was stirred at 40 °C for 4 hours.

[1284] The reaction was confirmed by LCMS. The target compound (170 mg, crude product) was obtained by concentration to remove trifluoroacetic acid. It was used directly in the next reaction without further purification.

[1285] LCMS(ESI)[M+H] + =363.3.

[1286] Step 5: Preparation of tert-butyl carbamate ((6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthidium-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)carbamate

[1287] 128.9 mg of chlorosulfonyl carbamate tert-butyl ester was dissolved in 2 mL of dichloromethane, and 67.5 mg of tert-butanol was added under ice bath conditions. The reaction mixture was stirred under ice bath conditions for 0.5 hours. 300 mg of crude 8-methoxy-1-(1,2,3,4-tetrahydroisoquinoline-6-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyl-2-one was dissolved in 8 mL of dichloromethane, and 100.5 mg of triethylamine was added under ice bath conditions. The former was then slowly added dropwise to this reaction mixture, and the mixture was stirred under ice bath conditions for 1.5 hours.

[1288] The reaction was confirmed by LCMS. The solvent was concentrated, and the reaction mixture was added to water (10 mL). The mixture was extracted with ethyl acetate (5 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the target compound (203 mg, crude product). This crude compound was used directly in the next reaction without further purification.

[1289] LCMS(ESI)[M+H] + =542.2.

[1290] Step 6: Preparation of 6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-sulfonamide

[1291] 203 mg of crude ((6-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)-3,4-dihydroisoquinoline-2(1H)-yl)sulfonyl)carbamate tert-butyl ester was dissolved in trifluoroacetic acid (3 mL), and the reaction solution was stirred at 40 °C for 4 hours.

[1292] The reaction was detected by LCMS. The crude product was obtained by concentration to remove trifluoroacetic acid, and then purified by preparative HPLC to yield the target compound (1.06 mg).

[1293] LCMS(ESI)[M+H] + =442.1; 1 H NMR (400MHz, MeOD-d4) δ8.88 (s, 1H), 7.43 (d, J = 6.4Hz,

[1294] 2H),7.38(d,J=8.9Hz,1H),7.19(d,J=9.5Hz,1H),6.88(d,J=9.5Hz,1H),5.66( s, 2H), 4.44 (s, 2H), 4.12 (s, 3H), 3.47 (t, J = 5.8Hz, 2H), 3.02 (t, J = 5.8Hz, 2H).

[1295] Example 35

[1296] Preparation of (N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthid-1(4H)-yl)cycloheptyl)aminosulfonyl)amine (compound 64):

[1297]

[1298] Step 1: Preparation of (4-oxocycloheptyl) tert-butyl carbamate

[1299] 4.2 mL of 2.5 M butyllithium in hexane was dissolved in 100 mL of tetrahydrofuran. The reaction system was purged with nitrogen. Then, 6.96 mL of 2 M trimethylsilane-diazomethane (TMSCHN2) in hexane was added at -78 °C and stirred for 30 minutes. Then, 10.0 g of tert-butyl 4-oxocyclohexylcarbamate (1 eq.) was added at -78 °C. The reaction system was purged with nitrogen and stirred at -78 °C for 1 hour.

[1300] The reaction was monitored by LCMS until it was complete. The reaction system was saturated and quenched with ammonium chloride aqueous solution. After extraction with ethyl acetate and concentration of the organic phase, the target compound was separated and purified by rapid chromatography (9.0 g, yield: 84.4%).

[1301] LCMS(ESI)[M+Na] + =250.1.

[1302] Step 2: Preparation of (4-aminocycloheptyl)carbamate tert-butyl ester

[1303] 2.0 g (1 eq.) of tert-butyl (4-oxocycloheptyl)carbamate and 3.33 g (6 eq.) of ammonium formate were dissolved in methanol (30 mL), and Pd / C (936 mg, 1 eq.) was added. The reaction system was purged with hydrogen and stirred at 20 °C for 5 hours in a hydrogen atmosphere.

[1304] The reaction was monitored by LCMS until complete. The reaction solution was filtered, and the filtrate was evaporated to dryness. The solution was then dissolved in hydrochloric acid (5M, 5mL), and ethyl acetate was added to separate the layers. The aqueous phase was alkalized and extracted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate, filtered, and the filtrate was evaporated to dryness under reduced pressure to give the target compound (1.0 g, yield: 50%).

[1305] LCMS(ESI)[M+H] + =229.2.

[1306] Step 3: Preparation of ethyl 4-((4-((tert-butoxycarbonyl)amino)cycloheptyl)amino)-7-methoxy-1,8-naphthyl-3-carboxylic acid

[1307] Ethyl 4-chloro-7-methoxy-1,8-naphthyl-3-carboxylate (50 mg, 1 eq.) was dissolved in acetonitrile (10 mL), followed by the addition of potassium carbonate (77 mg, 3.0 eq.) and tert-butyl (4-aminocycloheptyl)carbamate (128 mg, 3 eq.). The reaction was carried out at 40 °C for 16 hours under nitrogen protection.

[1308] The reaction was monitored by LCMS until it was dry under reduced pressure. The solution was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The target compound (50 mg, yield: 58%) was obtained by rapid chromatography.

[1309] LCMS(ESI)[M+H] + =459.3.

[1310] Step 4: Preparation of tert-butyl (4-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)cycloheptyl)carbamate

[1311] Ethyl 4-((4-((tert-butoxycarbonyl)amino)cycloheptyl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid (30.0 mg, 1 eq.) was suspended in ethanol (2 mL) and methanol (0.5 mL), followed by the addition of sodium borohydride (15.1 mg, 6.1 eq.). The reaction was carried out at 80 °C for 10 hours under nitrogen protection, and the reaction was monitored for completeness by LC-MS. The reaction solution was quenched with saturated ammonium chloride aqueous solution (5 mL), extracted three times with ethyl acetate (5 mL), and the organic phases were combined. The organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography to obtain the target compound (10 mg, yield: 37%).

[1312] LCMS(ESI)[M+H] + =417.3.

[1313] Step 5: Preparation of tert-butyl (4-(8-methoxy-2-oxo-2H-[1,3]oxazinyl[5,4-c][1,8]naphthidium-1(4H)-yl)cycloheptyl)carbamate

[1314] (4-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)cycloheptyl)tert-butyl carbamate (10 mg, 1 eq.) was dissolved in dichloromethane (1 mL), and then triethylamine (7.3 mg, 3 eq.) and triphosgene (7.1 mg, 1 eq.) were added successively at 0 °C. The reaction was stirred at 0 °C for 2 hours.

[1315] The reaction was monitored by LCMS until complete. The reaction solution was quenched with saturated saline (10 mL), extracted three times with ethyl acetate (5 mL), and the organic phases were combined. The organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and purified by rapid chromatography to obtain the target compound (10 mg, yield: 94%).

[1316] LCMS(ESI)[M+H] + =443.2.

[1317] Step 6: Preparation of 1-(4-aminocycloheptyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one

[1318] 10 mg of tert-butyl (4-(8-methoxy-2-oxo-2H-[1,3]oxazinyl[5,4-c][1,8]naphthid-1(4H)-yl)cycloheptyl)carbamate was dissolved in 1 mL of dichloromethane. Then, a solution of 0.5 mL of trifluoroacetic acid in dichloromethane was added sequentially at 0 °C. The reaction was stirred at 20 °C for 1 hour.

[1319] The reaction was monitored by LCMS until complete. The solvent was removed from the reaction solution by rotary evaporation under reduced pressure to obtain the target compound (10 mg, crude product). It was used directly in the next reaction without further purification.

[1320] LCMS(ESI)[M+H] + =343.2.

[1321] Step 7: Preparation of N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)cycloheptyl)aminosulfonyl)tert-butyl carbamate

[1322] Add 2 mL of tert-butyl chlorosulfonyl carbamate and 2 mL of dichloromethane to a 50 mL single-necked round-bottom flask, then slowly add 2 mL of tert-butanol at 0 °C, and stir the reaction at 0 °C for 1 hour. At 0 °C, add the reaction solution to a solution of 1-(4-aminocycloheptyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidium-2-one (10 mg, crude product, obtained from the previous step) in 2 mL of dichloromethane, and stir at 0 °C for 1 hour.

[1323] The reaction was monitored by LCMS until complete. The reaction solution was evaporated to dryness under reduced pressure to obtain the target compound (10 mg, crude product). It was used directly in the next reaction without further purification.

[1324] Step 8: Preparation of (N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazinofo[5,4-c][1,8]naphthidium-1(4H)-yl)cycloheptyl)aminosulfonyl)amine

[1325] N-(4-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)cycloheptyl)aminosulfonyl)tert-butyl carbamate (9 mg, crude) was dissolved in dichloromethane (1 mL), and then a solution of trifluoroacetic acid (0.5 mL) in dichloromethane (0.5 mL) was added at 20 °C. The reaction was stirred at 20 °C for 1 hour.

[1326] The reaction was monitored by LCMS until it was complete. After concentration under reduced pressure, the reaction solution was purified by preparative separation to obtain the target compound (1.2 mg).

[1327] LCMS(ESI)[M+H] + =422.2; 1 HNMR(400MHz,MeOD-d4)δ8.18(d,J=8.0Hz,1H),7.07(d,J=

[1328] 4.0Hz,1H),5.21(s,2H),5.10(s,2H),4.03(s,3H),3.35(s,1H),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).

[1329] Example 36

[1330] Preparation of 5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)hexahydrocyclopenta[c]pyrrole-2(1H)-sulfonamide (compound 36)

[1331]

[1332] Step 1: Preparation of tert-butyl 5-(benzylamino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid

[1333] 1.0 g of 5-oxohexahydrocyclopentadien[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester was dissolved in 100 mL of dichloromethane. Benzylamine (475 mg) and acetic acid (266 mg) were added at 0 °C, and the mixture was stirred at 0 °C for 30 minutes. Then, sodium borohydride acetate (1.88 g) was added in portions, and the mixture was allowed to rise to room temperature and reacted for another 16 hours. The reaction was confirmed to be complete by LCMS. 20 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain the target compound (1.2 g, crude product). LCMS (ESI) [M+H] + =317.3.

[1334] Step 2: Preparation of tert-butyl 5-aminohexahydrocyclopentadiene[c]pyrrole-2(1H)-carboxylic acid

[1335] 1.2 g (crude) of 5-(benzylamino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester was dissolved in methanol (30 mL), and palladium hydroxide (10%, 400 mg) was added. The mixture was purged with hydrogen three times, and the reaction was carried out under hydrogen atmosphere at 40 °C with stirring for 16 hours. The reaction was confirmed to be complete by LCMS. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain the target compound (700 mg, crude). LCMS (ESI) [M+H] + =227.2.

[1336] Step 3: Preparation of ethyl 4-((2-(tert-butoxycarbonyl)octahydrocyclopentadien[c]pyrrolo-5-yl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid

[1337] Ethyl 4-chloro-7-methoxy-1,8-naphthyl-3-carboxylate (707 mg), tert-butyl 5-aminohexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylate (600 mg, crude), and N,N-diisopropylethylamine (3.43 g) were dissolved in ethanol (20 mL). The mixture was heated to 90 °C and reacted for 16 hours. LC-MS analysis showed the reaction was complete. The ethanol was removed by vacuum concentration, 50 mL of water was added, and the mixture was extracted three times with ethyl acetate (50 mL). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 20:1) to give the target compound (1.0 g, yield: 82%). LC-MS (ESI) [M+H] + =457.2.

[1338] Step 4: Preparation of tert-butyl 5-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)hexahydrocyclopentadien[c]pyrrole-2(1H)-carboxylic acid

[1339] Ethyl 4-((2-(tert-butoxycarbonyl)octahydrocyclopentadieno[c]pyrrolo-5-yl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid (100 mg, 1.0 eq.) was dissolved in dichloromethane (20 mL), cooled to -78 °C, and then diisobutylaluminum hydride (2 M, 0.55 mL) was slowly added. The reaction was carried out at -78 °C for two hours. The reaction solution was quenched with water, extracted three times with dichloromethane (20 mL), the organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 10:1) to give the target compound (40 mg, yield: 44%). LCMS (ESI) [M+H] + =415.2.

[1340] Step 5: Preparation of tert-butyl 5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid

[1341] 5-((3-(hydroxymethyl)-7-methoxy-1,8-naphthid-4-yl)amino)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester (40 mg, 1.0 eq.) was added to tetrahydrofuran (5 mL), followed by N,N-diisopropylethylamine (124 mg, 10.0 eq.) and triphosgene (86 mg, 3.0 eq.). The reaction was carried out at room temperature for 1 hour, and the reaction was confirmed to be complete by LCMS. The reaction solution was added to water (10 mL), and extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried, filtered, concentrated, and purified by column chromatography (DCM:MeOH = 10:1) to give the target compound (30 mg, yield: 70%). LCMS (ESI) [M+H]+ =441.2.

[1342] Step 6: Preparation of 8-methoxy-1-(octahydrocyclopentadieno[c]pyrrolo-5-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one

[1343] 30 mg of 5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-carboxylic acid tert-butyl ester was added to 10 mL of dichloromethane, followed by 1 mL of trifluoroacetic acid. The reaction was carried out at room temperature for two hours. The reaction was monitored by LCMS until complete, and the solution was evaporated to dryness under vacuum to obtain the target compound (20 mg, crude product). LCMS (ESI) [M+H] + =341.2.

[1344] Step 7: Preparation of tert-butyl carbamate ((5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthidine-1(4H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-yl)sulfonyl)carbamate

[1345] 8-Methoxy-1-(octahydrocyclopentadieno[c]pyrrolo-5-yl)-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one (20 mg, crude) and triethylamine (30 mg) were added to dichloromethane (10 mL), and N-(chlorosulfonyl)carbamate tert-butyl ester (25 mg) was added dropwise at 0 °C. The reaction was carried out at room temperature for 2 hours. The reaction solution was added to water (10 mL), and the mixture was extracted three times with ethyl acetate (20 mL). The organic phases were combined, dried, filtered, and concentrated to obtain the target compound (20 mg, crude). LCMS(ESI)[M+H] + =520.1.

[1346] Step 8: Preparation of 5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthid-1(4H)-yl)hexahydrocyclopentadieno[c]pyrrole-2(1H)-sulfonamide

[1347] ((5-(8-methoxy-2-oxo-2H-[1,3]oxazino[5,4-c][1,8]naphthyl-1(4H)-yl)hexahydrocyclopentadieno[c]pyrrolo-2(1H)-yl)sulfonyl)tert-butyl carbamate (20 mg, crude) was added to dichloromethane (5 mL), followed by trifluoroacetic acid (0.5 mL). The reaction was carried out at room temperature for 4 hours. The reaction was monitored by LCMS and found to be complete. The crude product was obtained by vacuum drying and purified by preparative HPLC to yield the target compound (2.8 mg). LCMS (ESI) [M+H] + =420.1; 1 H NMR (400MHz, DMSO-d6) δ8.79(s,1H),8.33(d,J=9.2Hz,1H),7.17(d,J=9.2Hz,1H),6.78(s,2H),5.33(s,2H),4.34-4.2 5(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).

[1348] Example 37

[1349] Preparation of 1-(2,6-difluoro-4-(S-methylsulfonyl)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one (compound 216)

[1350]

[1351] Step 1: Preparation of ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthidine-3-carboxylic acid

[1352] Ethyl 4-chloro-7-methoxy-1,8-naphthyl-3-carboxylate (20 g, 1.0 eq.), (4-bromo-2,6-difluorophenyl)methylamine (16.65 g, 1.0 eq.), and N,N-diisopropylethylamine (29.08 g, 3.0 eq.) were added to dimethylformamide (200 mL) and stirred at room temperature for 12 hours. LC-MS showed the reaction was complete. The reaction mixture was added to 250 mL of petroleum ether, stirred, cooled to room temperature, and stirred for another 3 hours to allow the solid to precipitate. The solid was filtered, and the filter cake was dried to give the target compound (19 g, yield: 56%).

[1353] LCMS(ESI)[M+H] + =453.9.

[1354] Step 2: Preparation of ethyl 4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthyl-3-carboxylic acid

[1355] Ethyl 4-((4-bromo-2,6-difluorobenzyl)amino)-7-methoxy-1,8-naphthyl-3-carboxylate (450 mg, 1.0 eq.), sodium methanethiol (69.74 mg, 1.0 eq.), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (57.57 mg, 0.1 eq.), N,N-diisopropylethylamine (385.79 mg, 3.0 eq.), and bis(dibenzylideneacetone)palladium (91.12 mg, 0.1 eq.) were dissolved in dioxane (7 mL) and water (1 mL) and stirred at 90 °C for 8 hours. LCMS showed that the reaction was complete. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, dried, filtered, concentrated, and eluted with a normal phase column (PE:EA = 5:1) to obtain the target compound (250 mg, yield: 60%).

[1356] LCMS(ESI)[M+H] + =419.9.

[1357] Step 3: Preparation of (4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthid-3-yl)methanol

[1358] Ethyl 4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthyl-3-carboxylic acid (190 mg, 1.0 eq.) was dissolved in tetrahydrofuran (5 mL), and lithium aluminum hydride (126.75 mg, 7.4 eq.) was added under ice bath conditions. The mixture was stirred under ice bath conditions for 2 hours. LC-MS showed product formation. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (10 mL * 3), the organic phases were combined, dried, filtered, concentrated, and eluted with a reversed-phase system to give the target compound (120 mg, yield: 70%). LC-MS (ESI) [M+H] + =378.0.

[1359] 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]naphthidin-2-one

[1360] The compound (4-((2,6-difluoro-4-(methylthio)benzyl)amino)-7-methoxy-1,8-naphthid-3-yl)methanol (100 mg, 1.0 eq.) was dissolved in tetrahydrofuran (2 mL), and triphosgene (235.8 mg, 3.0 eq.) and N,N-diisopropylethylamine (136.98 mg, 4.0 eq.) were added. The reaction was carried out at 25 °C for 1 h. LC-MS showed that the reaction was complete. The reaction solution was added to water, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give the target compound (105 mg, yield: 98.24%).

[1361] LCMS(ESI)(M+H) + =404.1.

[1362] Step 5: Preparation of 1-(2,6-difluoro-4-(S-methylsulfonyl)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthidin-2-one

[1363] Compound 1-(2,6-difluoro-4-(methylthio)benzyl)-8-methoxy-1,4-dihydro-2H-[1,3]oxazino[5,4-c][1,8]naphthyl-2-one (100 mg, 1.0 eq.) was dissolved in ethanol (4 mL), and iodophenyl diacetic acid (239.54 mg, 3.0 eq.) and ammonium acetate (96.43 mg, 5.0 eq.) were added. The reaction was carried out at room temperature for 2 hours. LCMS showed successful reaction. The reaction solution was concentrated, and the crude product was purified by preparative HPLC to obtain the target compound (24.05 mg, yield: 22%). LCMS (ESI) (M+H) + =435.1; 1 H NMR (400MHz, DMSO-d6) δ8.80(s,1H),8.66(d,J=9.2Hz,1H),7.59(d,J=7.2Hz,2H),7. 14(d,J=9.2Hz,1H),5.49(s,2H),5.29(s,2H),4.54(s,1H),4.04(s,3H),3.14(s,3H).

[1364] The following compounds were prepared according to the preparation methods described in Examples 1-37:

[1365]

[1366]

[1367]

[1368]

[1369]

[1370]

[1371]

[1372]

[1373]

[1374]

[1375]

[1376]

[1377]

[1378]

[1379]

[1380]

[1381]

[1382]

[1383]

[1384]

[1385]

[1386]

[1387]

[1388] Biological testing evaluation

[1389] Test Example 1: In vitro ENPP1 enzyme inhibition test

[1390] ENPP1 is a transmembrane glycoprotein capable of hydrolyzing nucleotides and derivatives with a nucleotide-5'-monophosphate structure. ENPP1 hydrolyzes synthetically produced p-nitrophenyl 5'-monophosphate (TMP-pNP) into nucleotide '-monophosphate and p-nitrophenol, with p-nitrophenol being the chromogenic product. The amount of p-nitrophenol product generated can be directly measured by its absorbance at 405 nm, which is directly proportional to enzyme activity.

[1391] Experimental steps

[1392] Prepare 100x serially diluted compounds using DMSO, starting at 1 mM and followed by 4-fold serial dilutions for 10 concentration points. Transfer 300 nL of the compound at each concentration to a 384-well plate using an Echo transducer (final concentration starting at 10 μM, followed by 4-fold serial dilutions for 10 concentration points). Add 15 μL of 0.2 ng / μL hENPP1 enzyme (2x final concentration) prepared with experimental buffer (250 mM NaCl, 50 mM Tris, pH 9.5) to each well. Then add 15 μL of 400 μM TMP-pNP (2x final concentration) prepared with experimental buffer. Incubate at 37°C for 0.5 hours, then measure the OD value using a microplate reader. 405nm Reading value. Formula for calculating percentage inhibition rate: % Inhibition rate = (OD 高信号对照 -OD 样品孔 ) / (OD 高信号对照 -OD 低信号对照 )*100, perform four-parameter fitting calculation IC 50 Values, high signal control: DMSO group without inhibitor, low signal control: blank control group.

[1393] Data for the selected compounds, including compound 131 (ZX-131) disclosed in WO2021061803A1, are shown in Table 1:

[1394] Table 1. Inhibitory activity of ENPP1 enzyme

[1395]

[1396]

[1397] A represents IC 50 ≤0.1nM, where B represents 0.1nM <IC 50 ≤0.2nM, where C represents 0.2nM <IC 50 ≤2nM

[1398] Test Example 2: In vitro ENPP1 cellular level enzymatic inhibition test

[1399] ENPP1 is primarily expressed on the cell membrane surface and can hydrolyze 2'3'-cGAMP into 5'-GMP and 5'-AMP. Similarly, ENPP1 can also hydrolyze the synthetic phosphate ester TMP-pNP to generate the nucleotide-5'-monophosphate and the chromogenic product p-nitrophenol. Therefore, in cultured MDA-MB-231 cells, TMP-pNP was used as a substrate to reflect the enzymatic activity of ENPP1. The amount of p-nitrophenol formed in the culture medium was measured by absorbance at 405 nm, and this absorbance was directly proportional to the activity of ENPP1.

[1400] Experimental Procedure: 6000 MDA-MB-231 cells were seeded per well in 384-well cell culture plates and incubated overnight (approximately 18 hours) at 37°C. A 50× serially diluted compound was prepared using experimental buffer (250mM NaCl, 50mM Tris, pH 9.5), starting at 500 μM and followed by 4-fold serial dilutions for 10 concentration points. The cell culture medium was removed, and 10 μL of the compound at each well was added to the 384-well plate (final concentration 10 μM starting, 4-fold serial dilutions for 10 concentration points). Then, 10 μL of 1mM TMP-pNP (2× final concentration) prepared with experimental buffer was added to each well. After incubation at 37°C for 3 hours, the OD value was measured using a microplate reader. 405nm Reading value. Formula for calculating percentage inhibition rate: % Inhibition rate = (OD 高信号对照 -OD 样品孔 ) / (OD 高信号对照 -OD 低信号对照 )*100, perform four-parameter fitting calculation IC 50 Values, high signal control: DMSO group without inhibitor, low signal control: blank control group.

[1401] Table 2. Enzymatic inhibitory activity of ENPP1 at the cellular level

[1402] ZX-131 B 006 A 007 A 008 A 048 A 062 A

[1403] A represents IC 50 ≤0.5nM, where B represents 0.5nM <IC 50 ≤2nM

[1404] Test Example 3: Pharmacokinetic Study of Compound Concentration in Mice Using LC-MS / MS

[1405] Test principle: The concentration of the target drug in plasma at different time points is determined using LC-MS / MS, and the pharmacokinetic curve of the target compound in vivo is plotted.

[1406] Experimental Methods: The test compound was dissolved in DMSO to prepare a stock solution with a final concentration of 20 mg / mL. The compound was then dissolved to a concentration of 1 mg / mL using a solvent containing 5% DMSO (Sigma-Aldrich, SHBJ2847), 45% PEG400 (Sigma-Aldrich, BCCC0015), and 50% dd H2O. The mouse source was CD-1 male (JH Laboratory Animal Co., Ltd.). Nine mice were used for each compound group. The mice were administered 10 mg / kg PO. Blood samples were collected at 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 8 hr, and 24 hr (three samples per time point). 110 μL of whole blood (K2EDTA anticoagulated) was collected and immediately centrifuged at 2000g 4°C for 5 minutes. Serum was collected and stored at -70°C. Blood drug concentrations were determined using a Triple-quadrupole MS system (SCIEX), including standard curve and quality control preparation and sample preparation. Standard and control preparation: The working solution was prepared by diluting MeOH:H2O (1:1). 3 μL of the standard and control working solution was added to 57 μL of blank plasma. Sample preparation: 200 μL of internal standard solution (Propranolol, 40 ng / mL) was added to 30 μL of plasma sample. The mixture was stirred for 1 minute, centrifuged at 5800 rpm for 10 minutes, and 100 μL of supernatant was transferred to a new plate for analysis. Chromatographic conditions were optimized according to the sample, including mobile phase composition, elution gradient, flow rate, and retention time. A Waters BEH C18 column (2.1 × 50 mm, 1.7 μm) was used, with an injection volume of 1 μL. Mass spectrometry was performed using an electrospray ionization source (TuREo spray) in positive ion detection mode, with multichannel reaction monitoring (MRM) mode selected for secondary mass spectrometry analysis. Based on drug concentration-time data, pharmacokinetic parameters, including peak concentration Cmax, time to peak concentration Tmax, area under the drug-time curve (AUC), and elimination half-life t1 / 2, were calculated using WinNonlin 8.2 software according to a non-compartmental model. The AUC was calculated using the linear trapezoidal rule (linear up log down...

Claims

1. A compound represented by formula (I), or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently selected from hydrogen, F, Cl, methyl, methoxy, and ethoxy; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; Ring A is: ; **Represents a fusion site. Represents the location of the L group; Rc is a substituent for ring A, and each R C Independently, it is hydrogen, deuterium, halogen, oxo group, -CN, -ZC(O)R4, -ZC(O)OR1, C1-6 alkyl, C1-6 alkoxy, cyclopropyl; said alkyl group is optionally substituted by one or more substituents selected from halogens; n3 is 1, 2, or 3; Z is selected from the key; Ring B is: ; R D 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, -C(O)NH2, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHNH2, -methylene-NH-CONH2, or -S(O)2NHOH; Each R E Independently, it can be hydrogen, deuterium, F, Cl, oxo group, -CN, -SH, methyl, ethyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, methoxy, cyclopropyl; n4 is 1, 2, 3, 4, 5; L is selected from -CH2-; R1 is independently hydrogen or C1-6 alkyl each time it appears; R4 is independently a C1-6 alkyl group each time it appears, wherein the alkyl group is optionally substituted by one or more substituents selected from hydroxyl, amino, and C1-4 alkoxy groups; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different.

2. The compound of claim 1, or a pharmaceutically acceptable salt of the compound, wherein: Rc is a substituent of ring A, and each Rc is independently hydrogen, Cl, oxo, -CN, -Boc, -COCH2OH, methoxy, ethyl, -CH2CF3, or cyclopropyl.

3. A compound represented by formula (I) or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently selected from hydrogen, F, Cl, methyl, methoxy, and ethoxy; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; n3 is 1, 2, or 3; Rc is a substituent for ring A, and each R C Independently, it is hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NH2, -Z-NR2C(O)R4, -ZC(O)R4, -ZC(O)OR1, -ZS(O)2R4, -ZS(O)2NR2R3, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, cyclopropyl; wherein the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, C1-6 alkoxy; One or both Rc groups are oxo groups. The ring A substituted by one or two of the above Rc is: ** represents the fusion site. Represents the location of the L group; Z is selected from the key; Ring B is: ; R D 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, -C(O)NH2, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHNH2, -methylene-NH-CONH2, or -S(O)2NHOH; Each R E Independently, it can be hydrogen, deuterium, F, Cl, oxo group, -CN, -SH, methyl, ethyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, methoxy, cyclopropyl; n4 is 1, 2, 3, 4, 5; L is selected from -CH2-; R1 is independently hydrogen or C1-6 alkyl each time it appears; R2 and R3 are each hydrogen atoms when they appear independently; R4 is independently a C1-6 alkyl group each time it appears, wherein the alkyl group is optionally substituted by one or more substituents selected from hydroxyl, amino, and C1-4 alkoxy groups; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different.

4. A compound represented by formula (I) or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclic group, -ZC(O)R4, -ZC(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; (Rc) n3 The replaced ring A is: ** represents the fusion site. Represents the location of the L group; Z is selected from the key; Ring B is: ; R D Selected from -C 0-3 Alkylene -C(O)NHOH, -C 0-3 Alkylene -OC(O)NH2, -C 0-3 Alkylene -SO2NH2, -C 0-3 Alkylene -NHS(O)2NH2, -C 0-3 Alkylene -OS(O)2NH2, -C 0-3 Alkylene -P(O)(OH)2, -C 0-3 Alkylene -P(S)(OH)2, -C 0-3 Alkylene -OP(S)(OH)2, -C 0-3 Alkylene -B(OH)2, -C 0-3 Alkylene C(O)NH2, -C 0-3 Alkylene-S(O)2C 1-3 Alkylene -NH2, or -C 0-3 Alkylene-NH-CONH2; Each R E Independently hydrogen, deuterium, halogen, oxo group, -CN, -SH, C1-3 alkyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, C1-3 alkoxy, C3-6 cycloalkyl; n4 is 1, 2, 3, 4, 5; L is selected from the bond, -O-, -CH2-, ; R1 is independently hydrogen or C1-6 alkyl each time it appears; R2 and R3 are independently hydrogen and C1-6 alkyl groups each time they appear; R4 is independently a C1-6 alkyl group each time it appears, wherein the alkyl group is optionally substituted by one or more substituents selected from hydroxyl, amino, and C1-4 alkoxy groups; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different; The heteroatoms in the above heterocyclic groups are independently selected from O, and the number of heteroatoms is 1.

5. A compound represented by formula (I) or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, propenyl, propynyl, -NHCOCH3, -NHCOOCH3. , -COCH3, -COOCH3, -CONHCH3, -SO2CH3; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; (Rc) n3 The replaced ring A is: ** represents the fusion site. Represents the location of the L group; Ring B is: ; R D 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, -C(O)NH2, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHNH2, -methylene-NH-CONH2, or -S(O)2NHOH; Each R E Independently, it can be hydrogen, deuterium, F, Cl, oxo group, -CN, -SH, methyl, ethyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, methoxy, cyclopropyl; n4 is 1, 2, 3, 4, 5; L is selected from the bond, -O-, -CH2-, ; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different.

6. A compound represented by formula (I) or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently selected from hydrogen, F, Cl, methyl, methoxy, and ethoxy; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; (Rc) n3 The replaced ring A is: ** represents the fusion site. Represents the location of the L group; Ring B is: ; R D 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, -C(O)NH2, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHNH2, -methylene-NH-CONH2, or -S(O)2NHOH; Each R E Independently, it can be hydrogen, deuterium, F, Cl, oxo group, -CN, -SH, methyl, ethyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, methoxy, cyclopropyl; n4 is 1, 2, 3, 4, 5; L is selected from -CH2-; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different.

7. A compound represented by formula (I) or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently selected from hydrogen, F, Cl, methyl, methoxy, and ethoxy; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; n3 is 1, 2, or 3; Rc is a substituent for ring A, and each R C Independently, it is hydrogen, deuterium, halogen, oxo group, -CN, -OH, -SH, -NH2, -Z-NR2C(O)R4, -ZC(O)R4, -ZC(O)OR1, -ZS(O)2R4, -ZS(O)2NR2R3, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, cyclopropyl; the alkyl group is optionally substituted by one or more substituents selected from halogen, -OH, C1-6 alkoxy; one or two Rc groups are oxo groups, and the ring A substituted by the above one or two Rc groups is: ** represents the fusion site. Represents the location of the L group; Z is selected from the key; Ring B is: ; R D 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, -C(O)NH2, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHNH2, -methylene-NH-CONH2, or -S(O)2NHOH; Each R E Independently, it can be hydrogen, deuterium, F, Cl, oxo group, -CN, -SH, methyl, ethyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, methoxy, cyclopropyl; n4 is 1, 2, 3, 4, 5; L is selected from -CH2-; R1 is independently hydrogen or C1-6 alkyl each time it appears; R2 and R3 are each hydrogen atoms when they appear independently; R4 is independently a C1-6 alkyl group each time it appears, wherein the alkyl group is optionally substituted by one or more substituents selected from hydroxyl, amino, and C1-4 alkoxy groups; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different.

8. A compound represented by formula (I) or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, deuterium, halogen, -CN, -OH, -SH, -NO2, -NH2, -Z-NR2C(O)R4, -Z-NR2C(O)OR1, 3-6 membered heterocyclic group, -ZC(O)R4, -ZC(O)OR1, -ZC(O)NR2R3, -ZS(O)2R4, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 alkoxy, C1-6 alkylthio, C3-8 cycloalkyl; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; (Rc) n3 The replaced ring A is: ** represents the fusion site. Represents the location of the L group; Z is selected from the key; Ring B is: ; R D Selected from -C 0-3 Alkylene -C(O)NHOH, -C 0-3 Alkylene -OC(O)NH2, -C 0-3 Alkylene -SO2NH2, -C 0-3 Alkylene -NHS(O)2NH2, -C 0-3 Alkylene -OS(O)2NH2, -C 0-3 Alkylene -P(O)(OH)2, -C 0-3 Alkylene -P(S)(OH)2, -C 0-3 Alkylene -OP(S)(OH)2, -C 0-3 Alkylene -B(OH)2, -C 0-3 Alkylene C(O)NH2, -C 0-3 Alkylene-S(O)2C 1-3 Alkylene -NH2, or -C 0-3 Alkylene-NH-CONH2; Each R E Independently hydrogen, deuterium, halogen, oxo group, -CN, -SH, C1-3 alkyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, C1-3 alkoxy, C3-6 cycloalkyl; n4 is 1, 2, 3, 4, 5; L is selected from the bond, -O-, -CH2-, ; R1 is independently hydrogen or C1-6 alkyl each time it appears; R2 and R3 are independently hydrogen and C1-6 alkyl groups each time they appear; R4 is independently a C1-6 alkyl group each time it appears, wherein the alkyl group is optionally substituted by one or more substituents selected from hydroxyl, amino, and C1-4 alkoxy groups; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different; The heteroatoms in the above heterocyclic groups are independently selected from O, and the number of heteroatoms is 1.

9. A compound represented by formula (I), or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, deuterium, F, Cl, Br, -CN, -OH, -SH, -NO2, -NH2, methyl, ethyl, propyl, isopropyl, tert-butyl, vinyl, ethynyl, methoxy, ethoxy, propoxy, isopropoxy, methylthio, ethylthio, propylthio, isopropylthio, propenyl, propynyl, -NHCOCH3, -NHCOOCH3. , -COCH3, -COOCH3, -CONHCH3, -SO2CH3; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; (Rc) n3 The replaced ring A is: ** represents the fusion site. Represents the location of the L group; Ring B is: ; R D 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, -C(O)NH2, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHNH2, -methylene-NH-CONH2, or -S(O)2NHOH; Each R E Independently, it can be hydrogen, deuterium, F, Cl, oxo group, -CN, -SH, methyl, ethyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, methoxy, cyclopropyl; n4 is 1, 2, 3, 4, 5; L is selected from the bond, -O-, -CH2-, ; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different.

10. A compound represented by formula (I) or a pharmaceutically acceptable salt of said compound, wherein: X1 is N, and X2, X3 and X4 are all CH; or X4 is N, and X1, X2 and X3 are all CH; or X1, X2, X3 and X4 are all CH. Y is N; R A For substituents in the ring containing X1, each R A Independently selected from hydrogen, F, Cl, methyl, methoxy, and ethoxy; R B For substituents in the ring containing Y, each R B Independently hydrogen; n1 is 1 or 2; n2 is 1; (Rc) n3 The replaced ring A is: ** represents the fusion site. Represents the location of the L group; Ring B is: ; R D 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, -C(O)NH2, -S(O)2CH2CH2C(O)OH, -S(O)2CH2NH2, -S(O)2NHNH2, -methylene-NH-CONH2, or -S(O)2NHOH; Each R E Independently, it can be hydrogen, deuterium, F, Cl, oxo group, -CN, -SH, methyl, ethyl, -CF3, -CHF2, -C(O)OCH3, -C(O)CH3, vinyl, propenyl, ethynyl, propynyl, methoxy, cyclopropyl; n4 is 1, 2, 3, 4, 5; L is selected from -CH2-; When multiple R A R B R C or R E When they occur simultaneously, each R A R B R C or R E Same or different.

11. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

12. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

13. The compound of any one of claims 4 and 8, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently hydrogen, halogen, or C1-6 alkoxy; R D Selected from -SO2NH2; Each R E Independently hydrogen or halogen; n4 is 1 or 2; L is selected from -CH2-.

14. The compound of claim 13, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

15. The compound of claim 13, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

16. The compound of claim 13, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, F, methoxy, or ethoxy. Each R E It can be hydrogen or F independently.

17. The compound of claim 16, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

18. The compound of claim 16, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

19. The compound of any one of claims 4 and 8, or a pharmaceutically acceptable salt of the compound, wherein the compound has a structure as shown in formula (IV-1), (IV-2), (IV-3), or (IV-4): in, X1, R A R D R E R C Rings B, n1, and n4 are as defined in any one of claims 4 and 8; Y2 is C or N.

20. The compound of claim 19, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently hydrogen, halogen, or C1-6 alkoxy; X1 is either N or CH; Each Rc is independently hydrogen, oxo group, -Boc, -COCH2OH, -CH2CF3, or cyclopropyl; R D Selected from -SO2NH2; Each R E Independently hydrogen or halogen; n4 is 1 or 2.

21. The compound of claim 20, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, F, methoxy, or ethoxy. Each R E It can be hydrogen or F independently.

22. The compound of claim 21, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

23. The compound of claim 22, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

24. The compound of any one of claims 4 and 8, or a pharmaceutically acceptable salt of the compound, wherein the compound has a structure as shown in formula (V-1), (V-2), (V-3), or (V-4): in, X1, X4, R A R E R C n1 and n4 are as defined in any one of claims 4 and 8; Y2 is C or N; Q is C or N.

25. The compound of claim 24, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently hydrogen, halogen, or C1-6 alkoxy; For equations (V-1), (V-2), and (V-3), X1 is N or CH; For equation (V-4), X4 is N and X1 is CH; Each Rc is independently hydrogen, oxo group, -Boc, -COCH2OH, -CH2CF3, or cyclopropyl; Each R E Independently hydrogen or halogen; n4 is 1 or 2.

26. The compound of claim 25, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, F, methoxy, or ethoxy. Each R E It can be hydrogen or F independently.

27. The compound of claim 26, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

28. The compound of claim 26, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

29. The compound of any one of claims 1-2, or a pharmaceutically acceptable salt of the compound, wherein: Rc is a substituent of ring A, and each Rc is independently a hydrogen, oxo group, -Boc, -COCH2OH, -CH2CF3, or cyclopropyl group; n3 is 1 or 2; R D Selected from -SO2NH2; Each R E Independently hydrogen or halogen; n4 is 1 or 2.

30. The compound of claim 29, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

31. The compound of claim 29, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

32. The compound of claim 29, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, F, methoxy, or ethoxy. Each R E It can be hydrogen or F independently.

33. The compound of claim 32, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

34. The compound of claim 32, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

35. The compound of any one of claims 1-3, 5-7, and 9-10, or a pharmaceutically acceptable salt of the compound, wherein the compound has a structure as shown in formula (IV-1), (IV-2), (IV-3), or (IV-4): in, X1, R A R D R E R C Rings B, n1, and n4 are as defined in any one of claims 1-3, 5-7, and 9-10; Y2 is C or N.

36. The compound of claim 35, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, F, methoxy, or ethoxy. n1 is 1 or 2; X1 is either N or CH; Each Rc is independently hydrogen, oxo group, -Boc, -COCH2OH, -CH2CF3, or cyclopropyl; R D Selected from -SO2NH2; Each R E Independently hydrogen or halogen; n4 is 1 or 2.

37. The compound of claim 36, or a pharmaceutically acceptable salt of the compound, wherein: Each R E It can be hydrogen or F independently.

38. The compound of claim 37, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

39. The compound of claim 37, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

40. The compound of any one of claims 1-3, 5-7, and 9-10, or a pharmaceutically acceptable salt of the compound, wherein the compound has a structure as shown in formula (V-1), (V-2), (V-3), or (V-4): in, X1, X4, R A R E R C n1 and n4 are as defined in any one of claims 1-3, 5-7 and 9-10; Y2 is C or N; Q is C or N.

41. The compound of claim 40, or a pharmaceutically acceptable salt of the compound, wherein: R A For substituents in the ring containing X1, each R A Independently, it can be hydrogen, F, methoxy, or ethoxy. n1 is 1 or 2; For equations (V-1), (V-2), and (V-3), X1 is N or CH; For equation (V-4), X4 is N and X1 is CH; Each Rc is independently hydrogen, oxo group, -Boc, -COCH2OH, -CH2CF3, or cyclopropyl; Each R E Independently hydrogen or halogen; n4 is 1 or 2.

42. The compound of claim 41, or a pharmaceutically acceptable salt of the compound, wherein: Each R E It can be hydrogen or F independently.

43. The compound of claim 42, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 2; each R A They are different; R A For substituents in the ring containing X1, each R A Independently, it is F or methoxy. Each R E Independently defined as F; n4 is 2.

44. The compound of claim 42, or a pharmaceutically acceptable salt of the compound, wherein... n1 is 1; R A R is a substituent in the ring containing X1. A It is a methoxy group; Each R E Independently defined as F; n4 is 2.

45. The compound of any one of claims 1-10, or a pharmaceutically acceptable salt of the compound, wherein... R D 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, -C(O)NH2, -S(O)2CH2NH2, or -methylene-NH-CONH2.

46. ​​The compound of claim 45, or a pharmaceutically acceptable salt of the compound, wherein... R D Selected from -SO2NH2, -methylene-NHS(O)2NH2, -NHS(O)2NH2, -OS(O)2NH2, -C(O)NH2, -S(O)2CH2NH2, or -methylene-NH-CONH2.

47. Selected from the following compounds, or pharmaceutically acceptable salts thereof:

48. A pharmaceutical composition comprising any one of claims 1 to 47, or a pharmaceutically acceptable salt of said compound.

49. Use of any compound of claims 1 to 47, or a pharmaceutically acceptable salt of said compound, or the pharmaceutical composition of claim 48, in the preparation of a medicament for treating or preventing diseases mediated by ENPP1.

50. The use as claimed in claim 49, wherein the disease mediated by ENPP1 is cancer.

51. The use of claim 49, wherein the ENPP1-mediated disease is a tumor.

52. The use of claim 49, wherein the disease mediated by ENPP1 is a cardiovascular disease.

53. The use as claimed in claim 49, wherein the disease mediated by ENPP1 is pancreatic cancer, heart failure, or myocardial infarction.

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