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WO2024260023A1 - Cyclic α-hydroxyimide compound and use thereof - Google Patents

Cyclic α-hydroxyimide compound and use thereof Download PDF

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Publication number
WO2024260023A1
WO2024260023A1 PCT/CN2024/080403 CN2024080403W WO2024260023A1 WO 2024260023 A1 WO2024260023 A1 WO 2024260023A1 CN 2024080403 W CN2024080403 W CN 2024080403W WO 2024260023 A1 WO2024260023 A1 WO 2024260023A1
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formula
cyclic
methyl
mmol
added
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French (fr)
Chinese (zh)
Inventor
刘炳禹
郝天龙
崔先露
龚超骏
张伟林
徐优俊
谢金
裴剑锋
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Infinite Intelligence Pharmaceutical Technology Co Ltd
Suzhou Fish Summoning Biotechnology Co Ltd
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Infinite Intelligence Pharmaceutical Technology Co Ltd
Suzhou Fish Summoning Biotechnology Co Ltd
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Publication of WO2024260023A1 publication Critical patent/WO2024260023A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/50—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/09—Geometrical isomers

Definitions

  • the present application relates to the technical field of biomedicine, and more specifically, to a cyclic ⁇ -hydroxyimide compound and application thereof.
  • Hepatitis B (abbreviated as "HB") is an infectious disease caused by hepatitis B virus (HBV) infection, mainly liver disease, and is a health issue of global concern. Hepatitis B patients have a high risk of dying from cirrhosis and liver cancer.
  • HBV infection of the liver is still not very clear, but most people believe that: after HBV enters the human body, it will replicate and multiply in large quantities in liver cells, and damage the liver by triggering abnormal immune responses, thereby causing liver lesions. Among them, the unique replication mechanism of HBV, the vulnerability of the host immune system and other factors are involved. At present, it is generally believed that HBV is endocytosed through the sodium ion-taurocholate cotransporting polypeptide (sodium taurocholate cotransporting polypeptide, NTCP). Inside the cell, rcDNA (double-linked relaxed circular DNA molecule) enters the cell nucleus and is repaired by host repair factors to form cccDNA (covalently closed circular DNA molecule).
  • sodium ion-taurocholate cotransporting polypeptide sodium taurocholate cotransporting polypeptide
  • cccDNA is used as a viral minichromosome for HBV RNA transcription.
  • pgRNA pregenomic RNA, pregenomic ribonucleic acid
  • HBV Pol polymerase protein
  • HBV HBV is difficult to eradicate and prone to relapse.
  • cccDNA exists stably in the nucleus of liver cells of HBV patients for a long time, and cccDNA is the starting template for HBV replication.
  • the host immune system cannot effectively respond to HBV, which is also a key factor in chronic HBV infection.
  • the complete elimination of cccDNA in HBV patients is a sign of complete cure of hepatitis B.
  • NAs nucleotide analogues
  • IFN interferon
  • the present application provides a cyclic ⁇ -hydroxyimide compound and application thereof.
  • FEN-1 Human flap endonuclease 1
  • MEF-1 Human flap endonuclease 1
  • the cyclic ⁇ -hydroxyimide compound provided in the present application has a strong FEN-1 inhibitory activity, which further inhibits the generation of hepatitis B surface antigen, hepatitis B E antigen, hepatitis B total DNA and even hepatitis B cccDNA, ultimately achieving the cure of hepatitis B.
  • the present application provides a cyclic ⁇ -hydroxyimide compound, which adopts the following technical solution:
  • a cyclic ⁇ -hydroxy imide compound the general structural formula of the cyclic ⁇ -hydroxy imide compound is as follows:
  • R1 is any one of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, aryl or heteroaryl-substituted C1-6 alkyl;
  • R2 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;
  • X is any of CH and N;
  • Y is any one of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and a group as shown in formula (2);
  • R 3 is any one of hydrogen, hydroxy, amino, C 1-6 alkoxy, and C 1-6 alkylamino.
  • the structural formula of the cyclic ⁇ -hydroxyimide compound is shown in formula (2) or formula (3):
  • R4 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;
  • Z is any one of CH 2 , NH, O and S.
  • R 1 is a C 1-6 alkyl substituted with an aryl or heteroaryl group
  • R2 is optionally substituted aryl or optionally substituted heteroaryl
  • X is any of CH and N;
  • Y is a group represented by formula (1); in formula (1), R 3 is an amino group or a C 1-6 alkoxy group;
  • Z is CH2 .
  • the structural formula of the cyclic ⁇ -hydroxyimide compound is any one of formula (4) to formula (20).
  • the cyclic ⁇ -hydroxyimide compound can also be any one of 3-hydroxy-2-oxo-1H-quinoline-4-carboxylic acid, 6- ⁇ [4-(3-chloro-4-hydroxyphenyl)piperazine-1-yl]methyl ⁇ -3-hydroxy-2-oxo-1H-1,5-naphthyridine-4-carboxamide, and 3-hydroxy-6-[2-(5-hydroxybenzo[d]thiazol-2-yl)ethyl]-2-oxo-1H-1,5-naphthyridine-4-carboxamide.
  • the cyclic ⁇ -hydroxyimide compound provided in the present application has strong FEN-1 inhibitory activity and can inhibit the production of hepatitis B surface antigen, hepatitis B E antigen, hepatitis B total DNA and cccDNA at the cellular level, and is expected to be developed into a new anti-hepatitis B drug.
  • FIG1 is a synthetic route diagram of a specific compound represented by formula (3).
  • FIG2 is a synthetic route diagram of a specific compound represented by formula (2).
  • FIG3 shows the inhibition rate of HbeAg by the compound provided in Example 13 of the present application.
  • Figure 4 shows the inhibitory effect of the compound provided in Example 13 of the present application on cccDNA (Southern-blot results).
  • C 1-6 alkyl alone or in combination means a saturated straight or branched alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl and the like.
  • the "C 1-6 alkyl group” is any one of methyl, ethyl, n-propyl, isopropyl and tert-butyl.
  • C 3-7 cycloalkyl alone or in combination means a saturated cycloalkyl group containing 3 to 7, especially 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • the "C 3-7 cycloalkyl group” is any one of cyclopropyl, cyclopentyl and cyclohexyl.
  • C 3-7 heterocycloalkyl refers to a cycloalkyl group containing 3 to 7 carbon atoms and heteroatoms in a monocyclic heterocycloalkyl group, including aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl and the like.
  • C 1-6 alkoxy alone or in combination refers to the group C 1-6 alkyl-O-, wherein “C 1-6 alkyl” is as defined above.
  • C 1-6 alkoxy includes, but is not limited to, methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy (-OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 )CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentoxy (-OCH 2 CH 2 CH 2 CH 3 ), neopentoxy (-OCH 2 C(CH 3 ) 3 ), and the like.
  • C 1-6 alkylamino alone or in combination refers to the group C 1-6 alkyl-N-, wherein “C 1-6 alkyl” is as defined above.
  • C 1-6 alkylamino includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl 2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-
  • the "C 1-6 alkylamino group” is any one of methylamino, ethylamino, isopropylamino and tert-butylamino.
  • heteroaryl alone or in combination means a group having one or more rings of 5 to 20 atoms, wherein at least one atom in one ring is a heteroatom selected from nitrogen, oxygen, sulfur; and wherein at least one ring containing heteroatoms is aromatic.
  • the ring with non-heteroatoms may be a carbocyclic ring.
  • Heteroaryl groups may be substituted.
  • pharmaceutically acceptable salt means that the compounds of the present application exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. "Pharmaceutically acceptable salts” are described in pharmaceutically salts described by SM Berge in J. Pharmaceutical Sciences (Volume 66: 1-19, 1977).
  • phrases “pharmaceutically acceptable, non-toxic acid addition salts” means salts formed by the compounds in the present application with organic acids or inorganic acids, and organic acids or inorganic acids include but are not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, peramic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc.
  • “Pharmaceutically acceptable, non-toxic base addition salts” refer to salts formed by the compounds in the present application with organic bases or inorganic bases, including but not limited to alkali metal salts, such as carbimethylenetetramine, sodium or potassium salts: alkaline earth metal salts, such as calcium or magnesium salts: organic base salts, such as salts formed with organic bases containing N groups or N + (C 1-6 alkyl) 4 salts; preferably, including lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia water, triethylamine, tetrabutylammonium hydroxide, etc.
  • “Pharmaceutically acceptable salts” can be synthesized by general chemical methods.
  • hydrate refers to an association formed between water and a compound in the present application.
  • solvate refers to an association formed by one or more solvent molecules and the compound in the present application.
  • Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and the like.
  • isomeric forms including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Therefore, the single stereochemical isomers of the compounds involved in the present application or mixtures of their enantiomers, diastereomers, tautomers or geometric isomers (cis-trans isomers) all fall within the scope of protection claimed in the present application.
  • prodrug refers to a chemical derivative of the compound of the present application, which is converted into the compound represented by formula (1) through a chemical reaction in vivo.
  • isotopic derivative refers to an isotopic derivative obtained by replacing hydrogen atoms in the compound represented by formula (1) with 1 to 6 deuterium atoms, or an isotopic derivative obtained by replacing carbon atoms in the compound represented by formula (1) with 1 to 3 carbon 14 atoms.
  • the present application provides a cyclic ⁇ -hydroxyimide compound, and the general structural formula of the cyclic ⁇ -hydroxyimide compound is as follows:
  • R1 is any one of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, aryl or heteroaryl-substituted C1-6 alkyl;
  • R2 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;
  • X is any of CH and N;
  • Y is any one of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and a group as shown in formula (2);
  • R 3 is any one of hydrogen, hydroxy, amino, C 1-6 alkoxy, and C 1-6 alkylamino.
  • the structural formula of the cyclic ⁇ -hydroxyimide compound is shown in formula (2) or formula (3):
  • R4 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;
  • Z is any one of CH 2 , NH, O and S.
  • the present application also provides a method for preparing the above-mentioned cyclic ⁇ -hydroxyimide compound.
  • the following describes the synthesis route of the cyclic ⁇ -hydroxyimide compound provided by the present application to further describe the technical solution of the present application.
  • the product 8 in the synthetic route shown in FIG1 is a specific compound of the above formula (3).
  • formula (3) is product 8 in the synthesis route shown in FIG1 .
  • the synthetic route of product 8 specifically includes the following steps:
  • the product 18 in the synthetic route shown in FIG2 is a specific compound of the above formula (2).
  • formula (2) is the product 12 in the synthesis route shown in FIG. 2 .
  • the synthetic route of product 12 specifically includes the following steps:
  • liquid chromatography-mass spectrometry uses Waters ACQUITY Arc equipped with QDa Detector.
  • MS mass spectrometer
  • the injection volume is determined by the sample concentration: the flow rate is mL/min.
  • the peak of the high performance liquid chromatography (HPLC) is recorded and read by UV Vis wavelengths at 220nm and 254nm.
  • the mobile phases are A and B, and the gradient elution conditions are shown in Table 2 below. The elution conditions mentioned in Table 2 can all achieve the elution of the ⁇ -hydroxy ketone nitrogen-containing fused ring compounds in the following examples.
  • nuclear magnetic resonance (NMR) spectra are obtained using a 400 MHz NMR spectrometer, often using CDCl 3 and DMSO-d6 as solvents, and reporting chemical shifts ( ⁇ ) in ppm (parts per million).
  • the descriptions of the various peaks are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz (Hertz).
  • This embodiment provides 3-hydroxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester, the structural formula of which is shown in formula (4), and the specific preparation method is as follows.
  • reaction solution was filtered, the filter cake was collected, and washed with 40 mL water and 40 mL EtOH, respectively. It was purified by reverse phase high performance liquid chromatography (Pre-HPLC) and dried in a vacuum oven to obtain a white solid - 3-hydroxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (yield 42 g, 46%).
  • This embodiment provides 1-( ⁇ 3-[3-(acetylamino)phenyl]phenyl ⁇ methyl)-3-hydroxy-2-oxoquinoline-4-carboxylic acid, whose structural formula is shown in formula (5).
  • the specific preparation method is as follows, see Table 3 and Table 4 for details.
  • 3-Hydroxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (the product prepared in Example 1) was dissolved in THF/MeOH; TMSCHN 2 ((trimethylsilyl)diazomethane) was then added to the solution and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a white solid, 3-methoxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (2A).
  • Ethyl 1-( ⁇ 3-[3-(acetylamino)phenyl]phenyl ⁇ methyl)-3-hydroxy-2-oxoquinoline-4-carboxylate (2D) was dissolved in THF, and an aqueous solution of LiOH was added to the solution at room temperature, and then reacted at room temperature for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by Pre-HPLC to obtain a white solid, 1-( ⁇ 3-[3-(acetylamino)phenyl]phenyl ⁇ methyl)-3-hydroxy-2-oxoquinoline-4-carboxylic acid.
  • This embodiment provides 3-hydroxy-2-oxo-1H-1,5-naphthyridine-4-carboxamide, the structural formula of which is shown in formula (6), and the specific preparation method is as follows, as shown in Table 3 and Table 4.
  • tert-butyl (2-bromopyridin-3-yl)carbamate (3A) Dissolve tert-butyl (2-bromopyridin-3-yl)carbamate (3A) in THF, cool to -68°C under nitrogen protection, add n-butyl lithium dropwise, stir at this temperature for 10 min, then add DMF, and keep the temperature for 2 h. After the reaction, add 200 mL of saturated saline and 600 mL of EA, separate the liquids, dry and concentrate the organic phase, and purify the crude product by column chromatography to obtain a light yellow oily substance - tert-butyl (2-formylpyridin-3-yl)carbamate (3B).
  • tert-butyl (2-formylpyridin-3-yl)carbamate (3B) in DCM, add TFA, react at 30°C for 4 hours, and concentrate after the reaction is complete.
  • Dilute with DCM add saturated sodium bicarbonate solution to adjust pH to 7-8, separate and collect the organic phase, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain a yellow solid - 3-aminopyridinecarboxaldehyde (3C).
  • 3-Aminopyridinecarboxaldehyde (3C) was dissolved in THF, ethyl 2-[(4-methoxybenzyl)oxy]acetate was added, and LiHMDS (lithium hexamethyldisilazide) was added dropwise at -10°C. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, a yellow solid was obtained by filtration, namely 3-[(4-methoxybenzyl)oxy]-1H-1,5-naphthyridine-2-one (3D).
  • 3-Hydroxy-1H-1,5-naphthyridin-2-one (3E) was dissolved in acetic acid, and NBS was added to react at room temperature for 2 hours. After the reaction was completed, a yellow solid, 4-bromo-3-hydroxy-1H-1,5-naphthyridin-2-one (3F), was obtained by filtration.
  • This embodiment provides 3-hydroxy-6- ⁇ [4-(4-hydroxyphenyl)pyridin-2-yl]methyl ⁇ -2-oxo-1H-1,5-naphthyridine-4-carboxamide, whose structural formula is shown in formula (7).
  • the specific preparation method is as follows, see Table 3 and Table 4 for details.
  • 2,6-Dichloro-3-nitropyridine was dissolved in THF, and then anhydrous potassium carbonate and tert-butyl cyanoacetate were added in sequence, stirred evenly, and heated to 70°C for 12 hours. After the reaction was completed, the filtrate was filtered and concentrated to obtain a brown oily substance, tert-butyl 2-(6-chloro-3-nitropyridine-2-yl)-2-cyanoacetate (4A).
  • This embodiment provides 3-hydroxy-6- ⁇ [3-(4-hydroxyphenyl)phenyl]methyl ⁇ -2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (8).
  • the specific preparation method is as follows, as shown in Table 3.
  • tert-butyl 2-(3-bromophenyl)acetate (3.30 g, 12.17 mmol)
  • 4-methoxyphenylboronic acid (2.22 g, 14.60 mmol)
  • potassium carbonate 5.05 g, 36.51 mmol
  • 1,4-dioxane 55 mL
  • water 11 mL
  • This embodiment provides 3-hydroxy-6- ⁇ [5-(3-hydroxyphenyl)thiophen-2-yl]methyl ⁇ -2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (9).
  • the specific preparation method is as follows, as shown in Table 3.
  • tert-butyl 2-(5-bromothiophene-2-yl)acetate (1.60 g, 5.77 mmol)
  • 3-methoxyphenylboronic acid (1.32 g, 8.66 mmol)
  • potassium carbonate (2.39 g, 17.32 mmol)
  • This embodiment provides 3-hydroxy-6- ⁇ [4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazol-1-yl]methyl ⁇ -2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (10).
  • the specific preparation method is as follows, as shown in Table 3.
  • 3-Bromo-7-azaindole (10 g, 50.75 mmol) and DBU (23.18 g, 152.25 mmol) were added to a 500 mL round-bottom flask, and DMF (200 mL) was added and stirred to dissolve.
  • SEM-Cl (10.15 g, 60.90 mmol) was then slowly added dropwise to the solution under an ice-water bath, and the ice-water bath was removed after the addition, and the reaction was continued for 16 h.
  • This embodiment provides 3-hydroxy-6- ⁇ 2-[(4-hydroxyphenyl)amino]-2-oxoethyl ⁇ -2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (11).
  • the specific preparation method is as follows, as shown in Table 3.
  • tert-butyl cyanoacetate 255 mg, 1.81 mmol
  • 6-chloro-3-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile 4E
  • lithium tert-butoxide 361 mg, 4.51 mmol
  • bis(tricyclohexylphosphine)palladium dichloride 67 mg, 0.09 mmol
  • imid-phos ligand 71 mg, 0.18 mmol
  • This embodiment provides 3-hydroxy-2-oxo-6- ⁇ [4-(2-oxo-1H-pyridin-4-yl)pyridin-2-yl]methyl ⁇ -1H-1,5-naphthyridine-4-carboxamide, whose structural formula is shown in formula (12).
  • the specific preparation method is as follows, see Table 3 for details.
  • This embodiment provides 3-hydroxy-2-oxo-6- ⁇ [5-(4-formamidophenyl)thiophen-2-yl]methyl ⁇ -1H-1,5-naphthyridine-4-carboxamide, whose structural formula is shown in formula (13).
  • the specific preparation method is as follows, see Table 3 for details.
  • This embodiment provides 3-hydroxy-2-oxo-6- ⁇ [3-(4-formamidophenyl)phenyl]methyl ⁇ -1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (14). The specific preparation method is as follows, as shown in Table 3.
  • tert-butyl 2-(3-bromophenyl)acetate (11A) (3.0 g, 11.1 mmol), 4-cyanophenylboronic acid (2.11 g, 14.4 mmol), potassium carbonate (4.59 g, 33.2 mmol), Pd(dppf)Cl2 (catalyst) (809 mg, 1.11 mmol) were added, and 40 mL of 1,4-dioxane was added and stirred to dissolve. The temperature was raised to 90 ° C under nitrogen protection and reacted for 12 h.
  • This embodiment provides 3-hydroxy-2-oxo-6- ⁇ [4-(5-carboxamido-1H-pyrrol-3-yl)pyrazol-1-yl]methyl ⁇ -1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (15). The specific preparation method is as follows, as shown in Table 3.
  • This embodiment provides 3-hydroxy-2-oxo-6- ⁇ [6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]methyl-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (16). The specific preparation method is as follows, as shown in Table 3.
  • 3-Bromo-1H-pyrrolo[2,3-b]pyridine (30 g, 156 mmol) and DBU (70 g, 457 mmol) were added to a 100 mL round-bottom flask, and 300 mL THF was added and stirred to dissolve.
  • SEM-Cl 38 g, 228 mmol was added dropwise under an ice-water bath, and the mixture was reacted at room temperature for 16 h.
  • This embodiment provides 3-hydroxy-2-oxo-6- ⁇ [5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl]methyl ⁇ -1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (17).
  • the specific preparation method is as follows, as shown in Table 3.
  • This embodiment provides 3-hydroxy-2-oxo-6-( ⁇ 5-[3-(4-methylpiperazin-1-yl)phenyl]thiophen-2-yl ⁇ methyl)-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (18). The specific preparation method is as follows, see Table 3 for details.
  • 1-(3-bromophenyl)-4-methylpiperazine (15A) (8.50 g, 33.31 mmol), biboronic acid pinacol ester (16.92 g, 66.62 mmol), potassium acetate (9.81 g, 99.94 mmol), Pd(dppf)Cl 2 (catalyst) (1.22 g, 1.67 mmol) were added to a 100 mL round-bottom flask, and 250 mL of 1,4-dioxane was added and stirred to dissolve, and the temperature was raised to 90°C under nitrogen protection, and the reaction was carried out for 12 hours.
  • This embodiment provides 4- ⁇ 3-[(8-formamido-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)methyl]phenyl ⁇ benzoic acid. Its structural formula is shown in formula (19). The specific preparation method is as follows, as shown in Table 3.
  • 3'-Methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16A) (4.8 g, 21.2 mmol), NBS reagent (4.15 g, 23.3 mmol) were added to a 100 mL round-bottom flask, and 60 mL of carbon tetrachloride was added, and then dibenzoyl peroxide (0.51 mg, 2.12 mmol) was added to the solution, and the temperature was raised to 80°C and reacted for 12 hours.
  • This embodiment provides 3-hydroxy-2-oxo-6-( ⁇ 3-[(4-hydroxyphenyl)methyl]phenyl ⁇ methyl)-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (20), and its preparation method is as follows, as shown in Table 3.
  • Triphenylphosphine (2.59 g, 9.86 mmol) was added to a 100 mL round-bottom flask, and 50 mL of THF was added and stirred to dissolve.
  • Carbon tetrabromide (3.27 g, 9.86 mmol) and [3-(4-methoxybenzyl)phenyl]methanol (17A) (1.50 g, 6.57 mmol) were slowly added to the above solution under an ice-water bath, and the mixture was slowly added dropwise to the above solution under an ice-water bath. After the addition, the mixture was reacted at room temperature for 2 h.
  • test subjects are the cyclic ⁇ -hydroxyimide compounds provided in Examples 1-17 of the present application, and the test type is to detect the inhibitory ability of the above compounds on FEN-1.
  • the wild-type human FEN-1 protein expression system was constructed using the E. coli BL21 (DE3) expression system (Vazyme BL21 (DE3) competent cells), and the purified FEN-1 protein was obtained through the E. coli BL21 (DE3) expression system.
  • the FEN-1 plasmid was synthesized by Genscript (UniProt Entry: P39748).
  • DNA substrate with HBV r sequence 5'-flap structure connected with fluorescence generating group and fluorescence quenching group structure, prepared by annealing "flap", “quencher” and “template” oligonucleotide sequences (F is 5-TAMRA fluorescence group, Q represents BHQ fluorescence quenching group).
  • F is 5-TAMRA fluorescence group
  • Q represents BHQ fluorescence quenching group
  • the annealing program was as follows: 95°C, 5 min; then cooled to 25°C.
  • the annealed DNA substrate was co-incubated with the purified FEN-1 protein (100 nM).
  • the F fragment cleaved by FEN-1 emits fluorescence because it is separated from the Q fragment. Therefore, the increased fluorescence intensity can be used to indicate the cleavage activity of FEN-1 on the "flap".
  • Different concentration gradients of the compounds to be tested (compounds provided in Examples 1-17) were added to this system, and the fluorescence change data were collected by a fluorescence detection device.
  • the calculation formulas for the inhibition rate and IC 50 half-maximal inhibitory concentration) are as follows:
  • IC 50 of the compound is calculated by XL fit software-Fit models(205).
  • IC 50 half-maximal inhibitory concentration indicates the concentration of the test compound at half the amount of FEN-1 protein inhibition; the stronger the inhibitory ability, the lower the concentration;
  • test subject is the cyclic ⁇ -hydroxyimide compound provided in Example 13 of the present application
  • test type is a functional test to detect the compound on PHH cells (primary human hepatocytes) to evaluate the in vitro anti-HBV efficacy of the compound provided in the present application.
  • the test method is as follows:
  • HBV subtype D was added to infect PHH cells.
  • the test compound had a starting concentration of 50 ⁇ M, 4-fold dilution, 5 concentrations, and duplicate wells.
  • the reference compound GLS4 (a new drug for hepatitis B) had a starting concentration of 5 ⁇ M, 4-fold dilution, 5 concentrations, and duplicate wells.
  • the fresh medium containing the compound was replaced every 2 days.
  • the final concentration of DMSO (dimethyl sulfoxide) in the medium was 2%.
  • the supernatant of PHH cells was collected in a 24-well plate, and HBeAg (hepatitis B e antigen) in the supernatant of PHH cells was detected by ELISA, and the fluorescence change data was collected by a fluorescence detection device.
  • HBeAg hepatitis B e antigen
  • PHH cells The viability of PHH cells was determined using the CCK-8 method. PHH cells were collected, Hirt DNA in PHH cells was extracted, and cccDNA was detected using Southern blot (two replicate wells were combined as one well for the test).
  • EC 50 half lethal effect concentration
  • CC 50 half inhibitory concentration
  • the inhibition rate of HbeAg by the tested compounds on day 8 is shown in FIG3 .
  • the results of Southern blot detection of cccDNA are shown in FIG4 .
  • Example 13 of the present application can not only significantly reduce the production of HBeAg in PHH cells, but also inhibit the formation of cccDNA, showing the potential to cure hepatitis B.

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Abstract

The present application relates to the technical field of biomedicines. Specifically disclosed are a cyclic α-hydroxyimide compound and the use thereof. In the general structural formula of the compound, R1 is any one of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, and aryl- or heteroaryl-substituted C1-6 alkyl; R2 is any one of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl, or optionally substituted heteroaryl; X is any one of CH and N; Y is any one of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and a group as represented by formula (1); R3 is any one of hydrogen, hydroxyl, amino, C1-6 alkoxy, and C1-6 alkylamino; and Z is any one of CH2, NH, O, and S. The compound provided in the present application has relatively strong FEN-1 inhibitory activity.

Description

一种环状α-羟基酰亚胺化合物及其应用A cyclic α-hydroxyimide compound and its application 技术领域Technical Field

本申请涉及生物医药的技术领域，更具体地说，涉及一种环状α-羟基酰亚胺化合物及其应用。The present application relates to the technical field of biomedicine, and more specifically, to a cyclic α-hydroxyimide compound and application thereof.

背景技术Background Art

肝脏是人体最大的消化腺，也是人体新陈代谢过程中最活跃的器官，具有参与消化、新陈代谢、免疫和体内营养储存等重要功能。当肝脏发生病变时，人体很多功能都会失常。乙型肝炎(简称“乙肝”)是一种由乙型肝炎病毒(Hepatitis B virus，HBV)感染引起的、以肝脏病变为主的传染病，是全球关注的卫生问题。乙肝患者死于肝硬化和肝癌的风险很高。The liver is the largest digestive gland in the human body and the most active organ in the human body's metabolism. It plays an important role in digestion, metabolism, immunity, and nutrient storage. When the liver is diseased, many functions of the human body will malfunction. Hepatitis B (abbreviated as "HB") is an infectious disease caused by hepatitis B virus (HBV) infection, mainly liver disease, and is a health issue of global concern. Hepatitis B patients have a high risk of dying from cirrhosis and liver cancer.

HBV感染肝脏的致病原理还不是很确切，但是大部分观点认为：HBV进入人体后，会在肝脏细胞内大量复制繁殖，通过引发自身异常免疫反应，从而损伤肝脏，进而引起肝脏病变。其中，涉及HBV独特的复制机制、宿主免疫系统漏洞以及其他多方面的因素。目前，普遍认为HBV通过钠离子-牛磺胆酸共转运蛋白(sodium taurocholate cotransporting polypeptide，NTCP)进行内吞作用。在细胞内部，rcDNA(双联松弛环状DNA分子)进入细胞核，并通过宿主修复因子修复形成cccDNA(共价闭合环状DNA分子)。cccDNA的形成用于作为HBV RNA转录的病毒微染色体。pgRNA(pregenomic RNA，前基因组核糖核酸)与胞质溶胶中HBV Pol(聚合酶蛋白)结合以诱导包装过程，随后合成HBV DNA。新的HBV病毒颗粒在内质网中组装并易位，以病毒粒子的形成分泌到肝细胞外，从而实现HBV的复制。The pathogenic mechanism of HBV infection of the liver is still not very clear, but most people believe that: after HBV enters the human body, it will replicate and multiply in large quantities in liver cells, and damage the liver by triggering abnormal immune responses, thereby causing liver lesions. Among them, the unique replication mechanism of HBV, the vulnerability of the host immune system and other factors are involved. At present, it is generally believed that HBV is endocytosed through the sodium ion-taurocholate cotransporting polypeptide (sodium taurocholate cotransporting polypeptide, NTCP). Inside the cell, rcDNA (double-linked relaxed circular DNA molecule) enters the cell nucleus and is repaired by host repair factors to form cccDNA (covalently closed circular DNA molecule). The formation of cccDNA is used as a viral minichromosome for HBV RNA transcription. pgRNA (pregenomic RNA, pregenomic ribonucleic acid) binds to HBV Pol (polymerase protein) in the cytosol to induce the packaging process, and then synthesizes HBV DNA. New HBV virus particles are assembled and translocated in the endoplasmic reticulum, and secreted outside the liver cells in the form of virus particles, thereby achieving HBV replication.

HBV之所以难以根除和容易复发，究其原因是：cccDNA长期稳定存在于HBV患者的肝细胞核中，而cccDNA是HBV复制的起始模板，同时，宿主免疫系统无法对HBV产生有效应答，这也是慢性HBV感染的关键因素。HBV患者体内cccDNA的完全清除是乙肝完全治愈的标志。The reason why HBV is difficult to eradicate and prone to relapse is that cccDNA exists stably in the nucleus of liver cells of HBV patients for a long time, and cccDNA is the starting template for HBV replication. At the same time, the host immune system cannot effectively respond to HBV, which is also a key factor in chronic HBV infection. The complete elimination of cccDNA in HBV patients is a sign of complete cure of hepatitis B.

目前，针对乙肝的抗病毒药物为核苷酸类似物(Nucleotide analogue，NAs)和干扰素(Interferon，IFN)，但两者均无法直接影响cccDNA的生成过程。NAs对HBV抗原作用较差，长期使用NAs还会导致患者产生耐药性。而IFN也有治愈率或应答率低、给药方式不便捷、不良反应和禁忌症较多的不足之处。清除肝细胞内的cccDNA，才能彻底抑制HBV感染，从而实现乙肝“根治”的目标。At present, the antiviral drugs for hepatitis B are nucleotide analogues (NAs) and interferon (IFN), but neither of them can directly affect the generation process of cccDNA. NAs have a poor effect on HBV antigens, and long-term use of NAs can also cause patients to develop drug resistance. IFN also has the disadvantages of low cure rate or response rate, inconvenient administration method, and many adverse reactions and contraindications. Only by clearing cccDNA in liver cells can HBV infection be completely suppressed, thus achieving the goal of "curing" hepatitis B.

综上所述，由于当前的抗病毒药物还不能彻底清除HBV，乙肝的治疗依然存在着庞大的市场需求。开发新的乙肝药物，尤其是通过新的机制来抑制cccDNA的生成，将为治疗乙肝提供新的方向。In summary, since current antiviral drugs cannot completely eliminate HBV, there is still a huge market demand for the treatment of hepatitis B. The development of new hepatitis B drugs, especially inhibiting the generation of cccDNA through new mechanisms, will provide a new direction for the treatment of hepatitis B.

发明内容Summary of the invention

本申请提供一种环状α-羟基酰亚胺化合物及其应用。The present application provides a cyclic α-hydroxyimide compound and application thereof.

人瓣状内切核酸酶1(FEN-1)是一种镁离子参与催化的金属核酸酶，主要参与DNA复制过程中冈崎片段成熟和5’瓣状(5’-flap)切除的过程。这一过程具有底物结构特异性，只识别底物DNA的特定5’-flap结构，而与底物DNA的序列无关。现已有多项研究证明FEN-1在HBV的cccDNA修复过程中具有至关重要的作用。本申请提供的环状α-羟基酰亚胺化合物，具有较强的FEN-1抑制活性，进一步地抑制乙肝表面抗原、乙肝E抗原、乙肝总DNA乃至乙肝cccDNA的生成，最终实现乙型肝炎的治愈。Human flap endonuclease 1 (FEN-1) is a metallo-nuclease catalyzed by magnesium ions, and is mainly involved in the maturation of Okazaki fragments and the excision of 5'-flap during DNA replication. This process is substrate structure specific and only recognizes the specific 5'-flap structure of the substrate DNA, regardless of the sequence of the substrate DNA. A number of studies have shown that FEN-1 plays a vital role in the cccDNA repair process of HBV. The cyclic α-hydroxyimide compound provided in the present application has a strong FEN-1 inhibitory activity, which further inhibits the generation of hepatitis B surface antigen, hepatitis B E antigen, hepatitis B total DNA and even hepatitis B cccDNA, ultimately achieving the cure of hepatitis B.

第一方面，本申请提供了一种环状α-羟基酰亚胺化合物，采用如下的技术方案：In the first aspect, the present application provides a cyclic α-hydroxyimide compound, which adopts the following technical solution:

一种环状α-羟基酰亚胺化合物，所述环状α-羟基酰亚胺化合物的结构通式以下：
A cyclic α-hydroxy imide compound, the general structural formula of the cyclic α-hydroxy imide compound is as follows:

所述结构通式中，R1是氢、C1-6烷基、C3-7环烷基、C3-7杂环烷基、芳基或杂芳基取代的C1-6烷基中的任一种；In the general structural formula, R1 is any one of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, aryl or heteroaryl-substituted C1-6 alkyl;

R2是氢、氘、C1-6烷基、C3-7环烷基、C3-7杂环烷基、C1-6烷氧基、C1-6烷基氨基、任选取代的芳基或任选取代的杂芳基中的任一种； R2 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;

X是CH、N中的任一种；X is any of CH and N;

Y是氢、氘、卤素、羟基、氨基、氰基、如式(2)所示的基团中的任一种；
Y is any one of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and a group as shown in formula (2);

所述式(2)中，R3是氢、羟基、氨基、C1-6烷氧基、C1-6烷基氨基中的任一种。In the formula (2), R 3 is any one of hydrogen, hydroxy, amino, C 1-6 alkoxy, and C 1-6 alkylamino.

优选地，所述环状α-羟基酰亚胺化合物的结构式为式(2)或式(3)所示：
Preferably, the structural formula of the cyclic α-hydroxyimide compound is shown in formula (2) or formula (3):

R4是氢、氘、C1-6烷基、C3-7环烷基、C3-7杂环烷基、C1-6烷氧基、C1-6烷基氨基、任选取代的芳基或任选取代的杂芳基中的任一种； R4 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;

Z是CH2、NH、O、S中的任一种。Z is any one of CH 2 , NH, O and S.

优选地，所述结构通式中，R1是芳基或杂芳基取代的C1-6烷基；Preferably, in the general structural formula, R 1 is a C 1-6 alkyl substituted with an aryl or heteroaryl group;

R2是任选取代的芳基或任选取代的杂芳基； R2 is optionally substituted aryl or optionally substituted heteroaryl;

X是CH、N中的任一种；X is any of CH and N;

Y如式(1)所示的基团；所述式(1)中，R3是氨基或C1-6烷氧基；Y is a group represented by formula (1); in formula (1), R 3 is an amino group or a C 1-6 alkoxy group;

Z是CH2。Z is CH2 .

优选地，所述环状α-羟基酰亚胺化合物的结构式为式(4)-式(20)中的任意一种。Preferably, the structural formula of the cyclic α-hydroxyimide compound is any one of formula (4) to formula (20).

式(4)-式(20)具体如下：

Formula (4) to Formula (20) are as follows:

式(4)——3-羟基-2-氧代-1H-喹啉-4-甲酸乙酯。Formula (4) - 3-hydroxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester.

式(5)——1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-羟基-2-氧代喹啉-4-甲酸。Formula (5) - 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-hydroxy-2-oxoquinoline-4-carboxylic acid.

式(6)——3-羟基-2-氧代-1H-1,5-萘啶-4-甲酰胺。Formula (6)—3-hydroxy-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

式(7)——3-羟基-6-{[4-(4-羟基苯基)吡啶-2-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。Formula (7)—3-Hydroxy-6-{[4-(4-hydroxyphenyl)pyridin-2-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

式(8)——3-羟基-6-{[3-(4-羟基苯基)苯基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。Formula (8)—3-Hydroxy-6-{[3-(4-hydroxyphenyl)phenyl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

式(9)——3-羟基-6-{[5-(3-羟基苯基)噻吩-2-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。Formula (9)—3-Hydroxy-6-{[5-(3-hydroxyphenyl)thiophen-2-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

式(10)——3-羟基-6-{[4-(1H-吡咯并[2,3-b]吡啶-3-基)吡唑-1-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。Formula (10)—3-hydroxy-6-{[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazol-1-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

式(11)——3-羟基-6-{2-[(4-羟基苯基)氨基]-2-氧代乙基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。Formula (11)—3-hydroxy-6-{2-[(4-hydroxyphenyl)amino]-2-oxoethyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

式(12)——3-羟基-2-氧代-6-{[4-(2-氧代-1H-吡啶-4-基)吡啶-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺。Formula (12)—3-hydroxy-2-oxo-6-{[4-(2-oxo-1H-pyridin-4-yl)pyridin-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide.

式(13)——3-羟基-2-氧代-6-{[5-(4-甲酰胺基苯基)噻吩-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺。Formula (13)—3-Hydroxy-2-oxo-6-{[5-(4-formamidophenyl)thiophen-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide.

式(14)——3-羟基-2-氧代-6-{[3-(4-甲酰胺基苯基)苯基]甲基}-1H-1,5-萘啶-4-甲酰胺。Formula (14)—3-Hydroxy-2-oxo-6-{[3-(4-formamidophenyl)phenyl]methyl}-1H-1,5-naphthyridine-4-carboxamide.

式(15)——3-羟基-2-氧代-6-{[4-(5-甲酰胺基-1H-吡咯-3-基)吡唑-1-基]甲基}-1H-1,5-萘啶-4-甲酰胺。Formula (15)—3-Hydroxy-2-oxo-6-{[4-(5-carboxamido-1H-pyrrol-3-yl)pyrazol-1-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide.

式(16)——3-羟基-2-氧代-6-{[6-(1H-吡咯并[2,3-b]吡啶-3-基)吡啶-3-基]甲基-1H-1,5-萘啶-4-甲酰胺。Formula (16)—3-Hydroxy-2-oxo-6-{[6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]methyl-1H-1,5-naphthyridine-4-carboxamide.

式(17)——3-羟基-2-氧代-6-{[5-(1H-吡咯并[2,3-b]吡啶-3-基)噻吩-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺。Formula (17)—3-Hydroxy-2-oxo-6-{[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide.

式(18)——3-羟基-2-氧代-6-({5-[3-(4-甲基哌嗪-1-基)苯基]噻吩-2-基}甲基)-1H-1,5-萘啶-4-甲酰胺。Formula (18)—3-Hydroxy-2-oxo-6-({5-[3-(4-methylpiperazin-1-yl)phenyl]thiophen-2-yl}methyl)-1H-1,5-naphthyridine-4-carboxamide.

式(19)——4-{3-[(8-甲酰胺基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)甲基]苯基}苯甲酸。Formula (19)—4-{3-[(8-Formamido-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)methyl]phenyl}benzoic acid.

式(20)——3-羟基-2-氧代-6-({3-[(4-羟基苯基)甲基]苯基}甲基)-1H-1,5-萘啶-4-甲酰胺。Formula (20)—3-Hydroxy-2-oxo-6-({3-[(4-hydroxyphenyl)methyl]phenyl}methyl)-1H-1,5-naphthyridine-4-carboxamide.

此外，所述环状α-羟基酰亚胺化合物还可以是3-羟基-2-氧代-1H-喹啉-4-甲酸、6-{[4-(3-氯-4-羟基苯基)哌嗪-1-基]甲基}-3-羟基-2-氧代-1H-1,5-萘啶-4-甲酰胺、3-羟基-6-[2-(5-羟基苯并[d]噻唑-2-基)乙基]-2-氧代-1H-1,5-萘啶-4-甲酰胺中的任意一种。In addition, the cyclic α-hydroxyimide compound can also be any one of 3-hydroxy-2-oxo-1H-quinoline-4-carboxylic acid, 6-{[4-(3-chloro-4-hydroxyphenyl)piperazine-1-yl]methyl}-3-hydroxy-2-oxo-1H-1,5-naphthyridine-4-carboxamide, and 3-hydroxy-6-[2-(5-hydroxybenzo[d]thiazol-2-yl)ethyl]-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

综上所述，本申请具有以下有益效果：In summary, this application has the following beneficial effects:

本申请提供的环状α-羟基酰亚胺化合物，具有较强的FEN-1抑制活性，在细胞水平上能够抑制乙肝表面抗原、乙肝E抗原、乙肝总DNA和cccDNA的生成，有望开发成为新型抗乙肝药物。The cyclic α-hydroxyimide compound provided in the present application has strong FEN-1 inhibitory activity and can inhibit the production of hepatitis B surface antigen, hepatitis B E antigen, hepatitis B total DNA and cccDNA at the cellular level, and is expected to be developed into a new anti-hepatitis B drug.

附图说明BRIEF DESCRIPTION OF THE DRAWINGS

图1为式(3)所示的某一具体化合物的合成路线图。FIG1 is a synthetic route diagram of a specific compound represented by formula (3).

图2为式(2)所示的某一具体化合物的合成路线图。 FIG2 is a synthetic route diagram of a specific compound represented by formula (2).

图3为本申请实施例13提供的化合物对HbeAg的抑制率。FIG3 shows the inhibition rate of HbeAg by the compound provided in Example 13 of the present application.

图4为本申请实施例13提供的化合物对cccDNA的抑制作用(Southern-blot结果)。Figure 4 shows the inhibitory effect of the compound provided in Example 13 of the present application on cccDNA (Southern-blot results).

具体实施方式DETAILED DESCRIPTION

术语解释Explanation of terms

为了更为清晰地描述本申请的内容，本申请中所涉及的术语解释如下。本领域技术人员可以结合相关技术对以下术语进行理解。In order to describe the content of this application more clearly, the terms involved in this application are explained as follows. Those skilled in the art can understand the following terms in combination with relevant technologies.

术语“C1-6烷基”单独或者以组合方式表示包含1-6个、特别是1-4个碳原子的饱和直链或支链的烷基，包括甲基、乙基、丙基、异丙基、丁基、仲丁基、异丁基、叔丁基、正戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、正己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基等。The term "C 1-6 alkyl" alone or in combination means a saturated straight or branched alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, including methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-dimethyl-2-butyl and the like.

优选地，“C1-6烷基”是甲基、乙基、正丙基、异丙基、叔丁基中的任一种。Preferably, the "C 1-6 alkyl group" is any one of methyl, ethyl, n-propyl, isopropyl and tert-butyl.

术语“C3-7环烷基”单独或者以组合方式表示包含3-7个、特别是3-6个碳原子的饱和环烷基，包括环丙基、环丁基、环戊基、环己基、环庚基等。The term "C 3-7 cycloalkyl" alone or in combination means a saturated cycloalkyl group containing 3 to 7, especially 3 to 6 carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

优选地，“C3-7环烷基”是环丙基、环戊基、环己基中的任一种。Preferably, the "C 3-7 cycloalkyl group" is any one of cyclopropyl, cyclopentyl and cyclohexyl.

术语“C3-7杂环烷基”是指单环杂环烷基中包含3-7个碳原子和杂原子的环烷基，包括氮丙烷基、氮杂环丁基、氧杂环丁基、吡咯烷基、四氢呋喃基、四氢噻吩基、哌啶基、吗啉基、哌嗪基等。The term "C 3-7 heterocycloalkyl" refers to a cycloalkyl group containing 3 to 7 carbon atoms and heteroatoms in a monocyclic heterocycloalkyl group, including aziridine, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, morpholinyl, piperazinyl and the like.

术语“C1-6烷氧基”单独或者以组合方式表示基团C1-6烷基-O-，其中“C1-6烷基”的定义如上所述。“C1-6烷氧基”包括(但不限于)甲氧基(-OCH3)、乙氧基(-OCH2CH3)、正丙氧基(-OCH2CH2CH3)、异丙氧基(-OCH(CH3)2)、正丁氧基(-OCH2CH2CH2CH3)、仲丁氧基(-OCH(CH3)CH2CH3)、异丁氧基(-OCH2CH(CH3)2)、叔丁氧基(-OC(CH3)3)、正戊氧基(-OCH2CH2CH2CH2CH3)、新戊氧基(-OCH2C(CH3)3)等。The term "C 1-6 alkoxy" alone or in combination refers to the group C 1-6 alkyl-O-, wherein "C 1-6 alkyl" is as defined above. "C 1-6 alkoxy" includes, but is not limited to, methoxy (-OCH 3 ), ethoxy (-OCH 2 CH 3 ), n-propoxy (-OCH 2 CH 2 CH 3 ), isopropoxy (-OCH(CH 3 ) 2 ), n-butoxy (-OCH 2 CH 2 CH 2 CH 3 ), sec-butoxy (-OCH(CH 3 )CH 2 CH 3 ), isobutoxy (-OCH 2 CH(CH 3 ) 2 ), tert-butoxy (-OC(CH 3 ) 3 ), n-pentoxy (-OCH 2 CH 2 CH 2 CH 2 CH 3 ), neopentoxy (-OCH 2 C(CH 3 ) 3 ), and the like.

术语“C1-6烷基氨基”单独或者以组合方式表示基团C1-6烷基-N-，其中“C1-6烷基”的定义如上所述。“C1-6烷基氨基”包括甲基氨基、乙基氨基、丙基氨基、异丙基氨基、正丁基氨基、异丁基氨基、2-丁基氨基、叔丁基氨基、正戊基氨基、2-戊基氨基、3-戊基氨基、2-甲基2-丁基氨基、3-甲基-2-丁基氨基、3-甲基-1-丁基氨基、2-甲基-1-丁基氨基、正己基氨基、2-己基氨基、3-己基氨基、2-甲基-2-戊基氨基、3-甲基-2-戊基氨基、4-甲基-2-戊基氨基、3-甲基-3-戊基氨基、2-甲基-3-戊基氨基、2,3-二甲基-2-丁基氨基、3,3-二甲基-2-丁基氨基等。 The term "C 1-6 alkylamino" alone or in combination refers to the group C 1-6 alkyl-N-, wherein "C 1-6 alkyl" is as defined above. "C 1-6 alkylamino" includes methylamino, ethylamino, propylamino, isopropylamino, n-butylamino, isobutylamino, 2-butylamino, tert-butylamino, n-pentylamino, 2-pentylamino, 3-pentylamino, 2-methyl 2-butylamino, 3-methyl-2-butylamino, 3-methyl-1-butylamino, 2-methyl-1-butylamino, n-hexylamino, 2-hexylamino, 3-hexylamino, 2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino, 3-methyl-3-pentylamino, 2-methyl-3-pentylamino, 2,3-dimethyl-2-butylamino, 3,3-dimethyl-2-butylamino, and the like.

优选地，“C1-6烷基氨基”是甲基氨基、乙基氨基、异丙基氨基、叔丁基氨基中的任一种。Preferably, the "C 1-6 alkylamino group" is any one of methylamino, ethylamino, isopropylamino and tert-butylamino.

术语“杂芳基”单独或以组合方式表示基团具有5-20个原子的一个或多个环，其中一个环中的至少一个原子是选自氮、氧、硫的杂原子；且，其中包含杂原子的至少一个环是芳香族。在包括2个或更多个稠环的杂芳基中，带有非杂原子的环可以是碳环。杂芳基可以被取代。The term "heteroaryl" alone or in combination means a group having one or more rings of 5 to 20 atoms, wherein at least one atom in one ring is a heteroatom selected from nitrogen, oxygen, sulfur; and wherein at least one ring containing heteroatoms is aromatic. In heteroaryl groups comprising 2 or more fused rings, the ring with non-heteroatoms may be a carbocyclic ring. Heteroaryl groups may be substituted.

术语“药学上可接受的盐”表示本申请的化合物以它们的药用盐的形式存在，包括酸加成盐和碱加成盐。“药学上可接受的盐”在S.M.Berge在J.Pharmaceutical Sciences(66卷：1-19页，1977年)中描述的pharmaceutically salts中有所描述。在本申请中，“药学上可接受的、无毒的酸加成盐”表示本申请中的化合物与有机酸或无机酸形成的盐，有机酸或无机酸包括但不限于盐酸、硫酸、氢溴酸、氢碘酸、磷酸、硝酸、高氨酸、乙酸、草酸、马来酸、富马酸、酒石酸、苯磺酸、甲磺酸、水杨酸、琥珀酸、柠檬酸、乳酸、丙酸、苯甲酸、对甲苯磺酸、苹果酸等。“药学上可接受的、无毒的碱加成盐”表示本申请中的化合物与有机碱或无机碱所形成的盐，包括但不限于碱金属盐，例如鲤、钠或钾盐：碱土金属盐，例如钙或镁盐：有机碱盐，例如通过与含N基团的有机碱形成的接盐或N+(C1-6烷基)4盐；优选地，包括氢氧化锂、氢氧化钠、氢氧化钾、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾、碳酸镁、碳酸钙、氨水、三乙胺、四丁基氢氧化铵等。“药学上可接受的盐”可通过一般的化学方法合成。The term "pharmaceutically acceptable salt" means that the compounds of the present application exist in the form of their pharmaceutical salts, including acid addition salts and base addition salts. "Pharmaceutically acceptable salts" are described in pharmaceutically salts described by SM Berge in J. Pharmaceutical Sciences (Volume 66: 1-19, 1977). In the present application, "pharmaceutically acceptable, non-toxic acid addition salts" means salts formed by the compounds in the present application with organic acids or inorganic acids, and organic acids or inorganic acids include but are not limited to hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, peramic acid, acetic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, benzenesulfonic acid, methanesulfonic acid, salicylic acid, succinic acid, citric acid, lactic acid, propionic acid, benzoic acid, p-toluenesulfonic acid, malic acid, etc. "Pharmaceutically acceptable, non-toxic base addition salts" refer to salts formed by the compounds in the present application with organic bases or inorganic bases, including but not limited to alkali metal salts, such as carbimethylenetetramine, sodium or potassium salts: alkaline earth metal salts, such as calcium or magnesium salts: organic base salts, such as salts formed with organic bases containing N groups or N + (C 1-6 alkyl) 4 salts; preferably, including lithium hydroxide, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, calcium carbonate, ammonia water, triethylamine, tetrabutylammonium hydroxide, etc. "Pharmaceutically acceptable salts" can be synthesized by general chemical methods.

术语“水合物”是指水与本申请中的化合物形成的缔合物。The term "hydrate" refers to an association formed between water and a compound in the present application.

术语“溶剂化物”表示一个或多个溶剂分子与本申请中的化合物所形成的缔合物。形成溶剂化物的溶剂包括但不限于水、甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜等。The term "solvate" refers to an association formed by one or more solvent molecules and the compound in the present application. Solvents that form solvates include, but are not limited to, water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide, and the like.

术语“异构体”包含所有的同分异构形式，包括对映异构体、非对映异构体、互变异构体和几何异构体(包括顺反异构体)。因此，本申请中所涉及的化合物的单个立体化学异构体或其对映异构体、非对映异构体、互变异构体或几何异构体(顺反异构体)的混合物都属于本申请要求保护的范围。The term "isomer" includes all isomeric forms, including enantiomers, diastereomers, tautomers and geometric isomers (including cis-trans isomers). Therefore, the single stereochemical isomers of the compounds involved in the present application or mixtures of their enantiomers, diastereomers, tautomers or geometric isomers (cis-trans isomers) all fall within the scope of protection claimed in the present application.

术语“前药”表示作为本申请的化合物的化学衍生物，该衍生物在体内通过发生化学反应转换成如式(1)所示的化合物。The term "prodrug" refers to a chemical derivative of the compound of the present application, which is converted into the compound represented by formula (1) through a chemical reaction in vivo.

术语“同位素衍生物”表示如式(1)所示的化合物中的氢原子被1-6个氘原子所取代得到的同位素衍生物、如式(1)所示的化合物中的碳原子被1-3个碳14原子所取代得到的同位素衍生物。The term "isotopic derivative" refers to an isotopic derivative obtained by replacing hydrogen atoms in the compound represented by formula (1) with 1 to 6 deuterium atoms, or an isotopic derivative obtained by replacing carbon atoms in the compound represented by formula (1) with 1 to 3 carbon 14 atoms.

本申请提供了一种环状α-羟基酰亚胺化合物，所述环状α-羟基酰亚胺化合物的结构通式以下：
The present application provides a cyclic α-hydroxyimide compound, and the general structural formula of the cyclic α-hydroxyimide compound is as follows:

所述结构通式中，R1是氢、C1-6烷基、C3-7环烷基、C3-7杂环烷基、芳基或杂芳基取代的C1-6烷基中的任一种；In the general structural formula, R1 is any one of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, aryl or heteroaryl-substituted C1-6 alkyl;

R2是氢、氘、C1-6烷基、C3-7环烷基、C3-7杂环烷基、C1-6烷氧基、C1-6烷基氨基、任选取代的芳基或任选取代的杂芳基中的任一种； R2 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;

X是CH、N中的任一种；X is any of CH and N;

Y是氢、氘、卤素、羟基、氨基、氰基、如式(2)所示的基团中的任一种；
Y is any one of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and a group as shown in formula (2);

所述式(1)中，R3是氢、羟基、氨基、C1-6烷氧基、C1-6烷基氨基中的任一种。In the formula (1), R 3 is any one of hydrogen, hydroxy, amino, C 1-6 alkoxy, and C 1-6 alkylamino.

优选地，所述环状α-羟基酰亚胺化合物的结构式为式(2)或式(3)所示：
Preferably, the structural formula of the cyclic α-hydroxyimide compound is shown in formula (2) or formula (3):

R4是氢、氘、C1-6烷基、C3-7环烷基、C3-7杂环烷基、C1-6烷氧基、C1-6烷基氨基、任选取代的芳基或任选取代的杂芳基中的任一种； R4 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl;

Z是CH2、NH、O、S中的任一种。Z is any one of CH 2 , NH, O and S.

本申请还提供了上述环状α-羟基酰亚胺化合物的制备方法。以下通过描述本申请提供的环状α-羟基酰亚胺化合物的合成路线，以进一步描述本申请的技术方案。The present application also provides a method for preparing the above-mentioned cyclic α-hydroxyimide compound. The following describes the synthesis route of the cyclic α-hydroxyimide compound provided by the present application to further describe the technical solution of the present application.

如图1所示的合成路线中的产物8，为上述式(3)的一个具体化合物。The product 8 in the synthetic route shown in FIG1 is a specific compound of the above formula (3).

当式(3)中的X为N、Y为CONH2、Z为CH2时，式(3)即为图1中所示的合成路线中的产物8。When X in formula (3) is N, Y is CONH 2 , and Z is CH 2 , formula (3) is product 8 in the synthesis route shown in FIG1 .

参考图1，产物8的合成路线具体包括以下步骤：Referring to Figure 1, the synthetic route of product 8 specifically includes the following steps:

(1)化合物1与氰乙酸叔丁酯反应得到产物2；(1) Compound 1 reacts with tert-butyl cyanoacetate to obtain product 2;

(2)产物2在酸性条件下脱去酰基得到产物3；(2) Product 2 is deacylated under acidic conditions to obtain product 3;

(3)产物3还原硝基得到产物4；(3) Reducing the nitro group of product 3 to obtain product 4;

(4)产物4与草酰氯单乙酯反应得到产物5；(4) product 4 reacts with ethyl oxalyl chloride to obtain product 5;

(5)产物5在碱性条件下关环得到产物6；(5) Product 5 is cyclized under alkaline conditions to obtain product 6;

(6)产物6与取代的乙硼酸或取代的Boc-甲烷反应得到产物7；(6) Product 6 is reacted with substituted ethylboronic acid or substituted Boc-methane to obtain product 7;

(7)产物7与多聚磷酸(PPA)水解得到产物8。(7) Product 7 is hydrolyzed with polyphosphoric acid (PPA) to obtain product 8.

如图2所示的合成路线中的产物18，为上述式(2)的一个具体化合物。The product 18 in the synthetic route shown in FIG2 is a specific compound of the above formula (2).

当式(2)中的X为CH、Y为式(1)所示的结构时，式(2)即为图2中所示的合成路线中的产物12。When X in formula (2) is CH and Y is the structure shown in formula (1), formula (2) is the product 12 in the synthesis route shown in FIG. 2 .

参考图2，产物12的合成路线具体包括以下步骤：Referring to Figure 2, the synthetic route of product 12 specifically includes the following steps:

(1)化合物9与三甲基硅烷化重氮甲烷反应得到产物10；(1) Compound 9 reacts with trimethylsilylated diazomethane to obtain product 10;

(2)产物10在与溴化物反应得到产物11；(2) Product 10 reacts with bromide to obtain product 11;

(3)产物11在BBr3脱甲基得到产物12。(3) Product 11 is demethylated with BBr 3 to give product 12.

本申请中常涉及到的物料缩写如表1所示。The abbreviations of materials commonly involved in this application are shown in Table 1.

表1本申请常涉及到的物料缩写
Table 1 Abbreviations of materials commonly involved in this application

通过以下实施例对本申请做进一步的描述，然而这些实施例不应作为对本申请的范围的限制。The present application is further described by the following examples, however, these examples should not be construed as limiting the scope of the present application.

实施例Example

以下描述本申请实施例中的通用实验条件。The following describes the general experimental conditions in the examples of this application.

首先，本申请实施例中的反应均是在氮气保护下进行的。First, the reactions in the examples of the present application were all carried out under nitrogen protection.

进一步地，本申请实施例中的中间体和最终产物通过薄层层析硅胶板(青岛邦凯)、快速制备液相系统(Biotage Isolera Flash)和制备型高效液相色谱系统(Agilent 1290 Infinity II LC System，搭配Welch Xtimate C18反相色谱柱)分离纯化。Furthermore, the intermediates and final products in the examples of the present application were separated and purified by thin layer chromatography silica gel plates (Qingdao Bangkai), rapid preparative liquid chromatography system (Biotage Isolera Flash) and preparative high performance liquid chromatography system (Agilent 1290 Infinity II LC System, with Welch Xtimate C18 reverse phase chromatography column).

进一步地，液质联用色谱仪(LC-MS)使用Waters公司ACQUITY Arc配备QDa Detector。质谱(MS)采用ESI源，仅指示母体分子的分子量M，通常汇报[M+H]+。注射体积是通过样品浓度来确定：流速为mL/min。高效液相色谱(HPLC)的峰值是通过在220nm和254nm处的UV Vis波长来记录读取的。流动相为A和B，梯度洗脱条件如下表2所示，表2中提到的洗脱条件均可以实现对以下实施例中的α-羟基酮含氮稠环化合物的洗脱。Further, the liquid chromatography-mass spectrometry (LC-MS) uses Waters ACQUITY Arc equipped with QDa Detector. The mass spectrometer (MS) uses an ESI source, which only indicates the molecular weight M of the parent molecule, usually reporting [M+H] + . The injection volume is determined by the sample concentration: the flow rate is mL/min. The peak of the high performance liquid chromatography (HPLC) is recorded and read by UV Vis wavelengths at 220nm and 254nm. The mobile phases are A and B, and the gradient elution conditions are shown in Table 2 below. The elution conditions mentioned in Table 2 can all achieve the elution of the α-hydroxy ketone nitrogen-containing fused ring compounds in the following examples.

表2梯度洗脱条件
Table 2 Gradient elution conditions

进一步地，核磁共振(NMR)谱图采用400MHz核磁共振谱仪获得数据，常以CDCl3、DMSO-d6作为溶剂，以ppm(百万分之一)报告化学位移(δ)。各种峰的描述如下：s(单峰)、d(双峰)、t(三重峰)、q(四重峰)、m(多重峰)、dd(双二重峰)。偶合常数使用Hz(赫兹)表示。Further, the nuclear magnetic resonance (NMR) spectra are obtained using a 400 MHz NMR spectrometer, often using CDCl 3 and DMSO-d6 as solvents, and reporting chemical shifts (δ) in ppm (parts per million). The descriptions of the various peaks are as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet of doublets). Coupling constants are expressed in Hz (Hertz).

实施例1-9提供的环状α-羟基酰亚胺化合物的名称、结构式及制备过程具体如表3、表4所示。The names, structural formulas and preparation processes of the cyclic α-hydroxyimide compounds provided in Examples 1-9 are specifically shown in Tables 3 and 4.

表3各步骤中间产物的名称和结构式



Table 3 Names and structural formulas of intermediates in each step



表4实施例提供的环状α-羟基酰亚胺化合物的名称、结构式及制备过程(一)


Table 4 Name, structural formula and preparation process of cyclic α-hydroxyimide compounds provided in the examples (I)


实施例1Example 1

本实施例提供了3-羟基-2-氧代-1H-喹啉-4-甲酸乙酯。其结构式如式(4)所示，制备方法具体如下。
This embodiment provides 3-hydroxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester, the structural formula of which is shown in formula (4), and the specific preparation method is as follows.

靛红(4.42g，10mmol)溶于48mL EtOH/DMF(体积比为5：1)中，快速加入的1,8-二氮杂二环十一碳-7-烯(DBU)(0.7mL，1.5mmol)，室温搅拌均匀，随后在氮气保护下加入重氮乙酸乙酯(7.5mL，20mmol)，室温反应15h。将反应液减压浓缩除去大部分的EtOH，缓慢加入35mL 1M的稀盐酸，搅拌2h。反应液过滤，收集滤饼，分别用40mL水和40mL EtOH洗涤，通过反相高效液相色谱(Pre-HPLC)纯化并在真空干燥箱干燥得到白色固体——3-羟基-2-氧代-1H-喹啉-4-甲酸乙酯(产量42g，46％)。Indigo carmine (4.42 g, 10 mmol) was dissolved in 48 mL EtOH/DMF (volume ratio of 5:1), 1,8-diazabicycloundec-7-ene (DBU) (0.7 mL, 1.5 mmol) was quickly added, and the mixture was stirred evenly at room temperature. Then, ethyl diazoacetate (7.5 mL, 20 mmol) was added under nitrogen protection, and the mixture was reacted at room temperature for 15 h. The reaction solution was concentrated under reduced pressure to remove most of the EtOH, and 35 mL 1 M dilute hydrochloric acid was slowly added and stirred for 2 h. The reaction solution was filtered, the filter cake was collected, and washed with 40 mL water and 40 mL EtOH, respectively. It was purified by reverse phase high performance liquid chromatography (Pre-HPLC) and dried in a vacuum oven to obtain a white solid - 3-hydroxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (yield 42 g, 46%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝234.1[M+H]+。MS (ESI) m/z = 234.1 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ12.30(s，1H)，10.22(s，1H)，7.43-7.29(m，3H)，7.24-7.12(m，1H)，4.40(q，J＝7.2Hz，2H)，1.33(t，J＝7.2Hz，3H)。 1 H NMR (DMSO-d6, 400MHz): δ12.30 (s, 1H), 10.22 (s, 1H), 7.43-7.29 (m, 3H), 7.24-7.12 (m, 1H), 4.40 (q, J =7.2Hz, 2H), 1.33 (t, J=7.2Hz, 3H).

实施例2Example 2

本实施例提供了1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-羟基-2-氧代喹啉-4-甲酸，其结构式如式(5)所示，制备方法具体如下，具体见表3和表4。This embodiment provides 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-hydroxy-2-oxoquinoline-4-carboxylic acid, whose structural formula is shown in formula (5). The specific preparation method is as follows, see Table 3 and Table 4 for details.

(1)制备3-甲氧基-2-氧代-1H-喹啉-4-甲酸乙酯(2A)，其结构式如式(21)所示。(1) Prepare 3-methoxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (2A), the structural formula of which is shown in formula (21).

3-羟基-2-氧代-1H-喹啉-4-甲酸乙酯(实施例1制得的产物)溶于THF/MeOH中；然后向溶液中加入TMSCHN2((三甲基硅基)重氮甲烷)，室温搅拌1h。反应结束后减压浓缩，将粗产品通过硅胶柱层析纯化得到白色固体——3-甲氧基-2-氧代-1H-喹啉-4-甲酸乙酯(2A)。3-Hydroxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (the product prepared in Example 1) was dissolved in THF/MeOH; TMSCHN 2 ((trimethylsilyl)diazomethane) was then added to the solution and stirred at room temperature for 1 hour. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a white solid, 3-methoxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (2A).

(2)制备1-(3-溴苄基)-3-甲氧基-2-氧代喹啉-4-甲酸乙酯(2B)，其结构式如式(22)所示。(2) Preparation of ethyl 1-(3-bromobenzyl)-3-methoxy-2-oxoquinoline-4-carboxylate (2B), the structural formula of which is shown in formula (22).

3-甲氧基-2-氧代-1H-喹啉-4-甲酸乙酯(2A)溶于5mL DMF中，在冰水浴下缓慢加入氢化钠，继续搅拌20min，然后加入3-溴苄溴，继续反应1h。反应结束后加入50mL水并用EA(20mL×3)萃取，饱和食盐水洗涤有机相，然后将有机相浓缩，将粗产品通过硅胶柱层析纯化得到白色固体——1-(3-溴苄基)-3-甲氧基-2-氧代喹啉-4-甲酸乙酯(2B)。3-Methoxy-2-oxo-1H-quinoline-4-carboxylic acid ethyl ester (2A) was dissolved in 5 mL DMF, sodium hydride was slowly added in an ice-water bath, stirring was continued for 20 min, and then 3-bromobenzyl bromide was added and the reaction was continued for 1 h. After the reaction, 50 mL of water was added and extracted with EA (20 mL × 3), the organic phase was washed with saturated brine, and then the organic phase was concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid - 1-(3-bromobenzyl)-3-methoxy-2-oxoquinoline-4-carboxylic acid ethyl ester (2B).

(3)制备1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-甲氧基-2-氧代喹啉-4-羧酸乙酯(2C)，其结构式如式(23)所示。(3) Preparation of ethyl 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-methoxy-2-oxoquinoline-4-carboxylate (2C), the structural formula of which is shown in formula (23).

1-(3-溴苄基)-3-甲氧基-2-氧代喹啉-4-甲酸乙酯(2B)溶于1,4-二氧六环中，向溶液中加入3-乙酰氨基苯硼酸频那醇酯和碳酸铯，搅拌混合后加入Pd(dppf)Cl2(催化剂)，然后升温至100℃反应16h。反应结束后减压浓缩，将粗产品通过硅胶柱层析纯化得到无色油状物——1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-甲氧基-2-氧代喹啉-4-羧酸乙酯(2C)。1-(3-Bromobenzyl)-3-methoxy-2-oxoquinoline-4-carboxylic acid ethyl ester (2B) was dissolved in 1,4-dioxane, 3-acetamidophenylboronic acid pinacol ester and cesium carbonate were added to the solution, and Pd(dppf)Cl 2 (catalyst) was added after stirring and mixing, and then the temperature was raised to 100°C for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography to obtain a colorless oily substance, 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-methoxy-2-oxoquinoline-4-carboxylic acid ethyl ester (2C).

(4)制备1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-羟基-2-氧代喹啉-4-羧酸乙酯(2D)，其结构式如式(24)所示。(4) Preparation of ethyl 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-hydroxy-2-oxoquinoline-4-carboxylate (2D), the structural formula of which is shown in formula (24).

1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-甲氧基-2-氧代喹啉-4-羧酸乙酯(2C)溶于DCM中，向溶液中加入1M的BBr3溶液，然后在室温下搅拌反应10min。反应结束后加入40mL水淬灭，然后加入DCM萃取(10mL×3)，收集有机相，用无水硫酸钠干燥，浓缩后得到——1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-羟基-2-氧代喹啉-4-羧酸乙酯(2D)粗品。1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-methoxy-2-oxoquinoline-4-carboxylic acid ethyl ester (2C) was dissolved in DCM, 1M BBr 3 solution was added to the solution, and then stirred at room temperature for 10 minutes. After the reaction was completed, 40 mL of water was added to quench, and then DCM was added for extraction (10 mL×3), and the organic phase was collected, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product of 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-hydroxy-2-oxoquinoline-4-carboxylic acid ethyl ester (2D).

(5)制备1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-羟基-2-氧代喹啉-4-甲酸，其结构式如式(5)所示。(5) Prepare 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-hydroxy-2-oxoquinoline-4-carboxylic acid, the structural formula of which is shown in formula (5).

1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-羟基-2-氧代喹啉-4-羧酸乙酯(2D)溶于THF中，在室温下向溶液中加入LiOH的水溶液，然后室温反应16h。反应结束后减压浓缩，通过Pre-HPLC纯化得到白色固体——1-({3-[3-(乙酰基氨基)苯基]苯基}甲基)-3-羟基-2-氧代喹啉-4-甲酸。Ethyl 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-hydroxy-2-oxoquinoline-4-carboxylate (2D) was dissolved in THF, and an aqueous solution of LiOH was added to the solution at room temperature, and then reacted at room temperature for 16 hours. After the reaction was completed, the solution was concentrated under reduced pressure and purified by Pre-HPLC to obtain a white solid, 1-({3-[3-(acetylamino)phenyl]phenyl}methyl)-3-hydroxy-2-oxoquinoline-4-carboxylic acid.

实施例3Example 3

本实施例提供了3-羟基-2-氧代-1H-1,5-萘啶-4-甲酰胺。其结构式如式(6)所示，制备方法具体如下，具体见表3和表4。This embodiment provides 3-hydroxy-2-oxo-1H-1,5-naphthyridine-4-carboxamide, the structural formula of which is shown in formula (6), and the specific preparation method is as follows, as shown in Table 3 and Table 4.

(1)制备(2-溴吡啶-3-基)氨基甲酸叔丁酯(3A)，其结构式如式(25)所示。(1) Preparation of tert-butyl (2-bromopyridin-3-yl)carbamate (3A), the structural formula of which is shown in formula (25).

将2-溴烟酸溶解在叔丁醇中，加入三乙胺、叠氮磷酸二苯酯，升温至80℃反应3h。浓缩得到粗产物，粗产物通过柱色谱纯化得到白色固体——(2-溴吡啶-3-基)氨基甲酸叔丁酯(3A)。2-Bromonicotinic acid was dissolved in tert-butyl alcohol, triethylamine and diphenylphosphoryl azide were added, and the temperature was raised to 80°C for reaction for 3 hours. The crude product was concentrated to obtain a crude product, which was purified by column chromatography to obtain a white solid - tert-butyl (2-bromopyridin-3-yl)carbamate (3A).

(2)制备(2-甲酰基吡啶-3-基)氨基甲酸叔丁酯(3B)，其结构式如式(26)所示。(2) Preparation of tert-butyl (2-formylpyridin-3-yl)carbamate (3B), the structural formula of which is shown in formula (26).

将(2-溴吡啶-3-基)氨基甲酸叔丁酯(3A)溶解在THF中，氮气保护下，降温至-68℃，滴加正丁基锂，滴毕在该温度下搅拌10min后加入DMF，加毕保持该温度反应2h。反应结束后加入200mL饱和食盐水和600mL EA，分液，有机相干燥浓缩，粗产物通过柱色谱纯化得到淡黄色油状物——(2-甲酰基吡啶-3-基)氨基甲酸叔丁酯(3B)。Dissolve tert-butyl (2-bromopyridin-3-yl)carbamate (3A) in THF, cool to -68°C under nitrogen protection, add n-butyl lithium dropwise, stir at this temperature for 10 min, then add DMF, and keep the temperature for 2 h. After the reaction, add 200 mL of saturated saline and 600 mL of EA, separate the liquids, dry and concentrate the organic phase, and purify the crude product by column chromatography to obtain a light yellow oily substance - tert-butyl (2-formylpyridin-3-yl)carbamate (3B).

(3)制备3-氨基吡啶甲醛(3C)，其结构式如式(27)所示。(3) Prepare 3-aminopyridinecarboxaldehyde (3C), whose structural formula is shown in formula (27).

将(2-甲酰基吡啶-3-基)氨基甲酸叔丁酯(3B)溶于DCM中，加入TFA。30℃反应4h，反应完成后浓缩。再加DCM稀释，加饱和碳酸氢钠溶液调pH＝7-8，分液收集有机相，无水硫酸钠干燥有机相，浓缩得黄色固体——3-氨基吡啶甲醛(3C)。Dissolve tert-butyl (2-formylpyridin-3-yl)carbamate (3B) in DCM, add TFA, react at 30°C for 4 hours, and concentrate after the reaction is complete. Dilute with DCM, add saturated sodium bicarbonate solution to adjust pH to 7-8, separate and collect the organic phase, dry the organic phase over anhydrous sodium sulfate, and concentrate to obtain a yellow solid - 3-aminopyridinecarboxaldehyde (3C).

(4)制备3-[(4-甲氧基苄基)氧基]-1H-1,5-萘啶-2-酮(3D)，其结构式如式(28)所示。(4) Prepare 3-[(4-methoxybenzyl)oxy]-1H-1,5-naphthyridin-2-one (3D), the structural formula of which is shown in formula (28).

将3-氨基吡啶甲醛(3C)溶于THF中，加入2-[(4-甲氧基苄基)氧基]乙酸乙酯，-10℃下滴加LiHMDS(六甲基二硅基氨基锂)，滴完室温反应16h，反应完成后过滤得黄色固体——3-[(4-甲氧基苄基)氧基]-1H-1,5-萘啶-2-酮(3D)。3-Aminopyridinecarboxaldehyde (3C) was dissolved in THF, ethyl 2-[(4-methoxybenzyl)oxy]acetate was added, and LiHMDS (lithium hexamethyldisilazide) was added dropwise at -10°C. The mixture was reacted at room temperature for 16 hours. After the reaction was completed, a yellow solid was obtained by filtration, namely 3-[(4-methoxybenzyl)oxy]-1H-1,5-naphthyridine-2-one (3D).

(5)制备3-羟基-1H-1,5-萘啶-2-酮(3E)，其结构式如式(29)所示。(5) Prepare 3-hydroxy-1H-1,5-naphthyridin-2-one (3E), whose structural formula is shown in formula (29).

将3-[(4-甲氧基苄基)氧基]-1H-1,5-萘啶-2-酮(3D)溶于DCM中，加入TFA，加毕室温反应16h，反应完成后浓缩，加入200mL乙醚打浆，得到棕色固体——3-羟基-1H-1,5-萘啶-2-酮(3E)。3-[(4-methoxybenzyl)oxy]-1H-1,5-naphthyridine-2-one (3D) was dissolved in DCM, TFA was added, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the mixture was concentrated and 200 mL of ether was added to slurry to obtain a brown solid, 3-hydroxy-1H-1,5-naphthyridine-2-one (3E).

(6)制备4-溴-3-羟基-1H-1,5-萘啶-2-酮(3F)，其结构式如式(30)所示。(6) Prepare 4-bromo-3-hydroxy-1H-1,5-naphthyridin-2-one (3F), the structural formula of which is shown in formula (30).

将3-羟基-1H-1,5-萘啶-2-酮(3E)溶于醋酸中，加入NBS，室温反应2h。反应完成后过滤得到黄色固体——4-溴-3-羟基-1H-1,5-萘啶-2-酮(3F)。3-Hydroxy-1H-1,5-naphthyridin-2-one (3E) was dissolved in acetic acid, and NBS was added to react at room temperature for 2 hours. After the reaction was completed, a yellow solid, 4-bromo-3-hydroxy-1H-1,5-naphthyridin-2-one (3F), was obtained by filtration.

(7)制备4-溴-1-(4-甲氧基苄基)-3-[(4-甲基苄基)氧基]-1H-1,5-萘啶-2-酮(3G)，其结构式如式(31)所示。(7) Prepare 4-bromo-1-(4-methoxybenzyl)-3-[(4-methylbenzyl)oxy]-1H-1,5-naphthyridin-2-one (3G), the structural formula of which is shown in formula (31).

将4-溴-3-羟基-1H-1,5-萘啶-2-酮(3F)溶于DMF中，加入4-甲氧基苄氯、碳酸铯、碘化钾，室温反应3h。反应完成后加100mL水稀释，用EA(100mL×3)萃取，合并有机相，并用饱和食盐水洗涤，干燥浓缩，粗产物通过柱色谱纯化得到白色固体——4-溴-1-(4-甲氧基苄基)-3-[(4-甲基苄基)氧基]-1H-1,5-萘啶-2-酮(3G)。4-Bromo-3-hydroxy-1H-1,5-naphthyridine-2-one (3F) was dissolved in DMF, and 4-methoxybenzyl chloride, cesium carbonate, and potassium iodide were added, and the mixture was reacted at room temperature for 3 hours. After the reaction was completed, 100 mL of water was added for dilution, and the mixture was extracted with EA (100 mL × 3). The organic phases were combined, washed with saturated brine, dried, and concentrated. The crude product was purified by column chromatography to obtain a white solid, 4-bromo-1-(4-methoxybenzyl)-3-[(4-methylbenzyl)oxy]-1H-1,5-naphthyridine-2-one (3G).

(8)制备3-[(4-甲氧基苄基)氧基]-2-氧代-1,2-二氢-1,5-萘啶-4-腈(3H)，其结构式如式(32)所示。(8) Prepare 3-[(4-methoxybenzyl)oxy]-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (3H), the structural formula of which is shown in formula (32).

将4-溴-1-(4-甲氧基苄基)-3-[(4-甲基苄基)氧基]-1H-1,5-萘啶-2-酮(3G)溶于二甲基乙酰胺(DMA)中，加入氰化锌、锌粉、1,1-双(二苯基膦)二茂铁、Pd2(Dba)3，135℃反应16h。反应完成后浓缩，通过反相柱色谱纯化得到白色固体——3-[(4-甲氧基苄基)氧基]-2-氧代-1,2-二氢-1,5-萘啶-4-腈(3H)。4-Bromo-1-(4-methoxybenzyl)-3-[(4-methylbenzyl)oxy]-1H-1,5-naphthyridin-2-one (3G) was dissolved in dimethylacetamide (DMA), and zinc cyanide, zinc powder, 1,1-bis(diphenylphosphino)ferrocene, and Pd 2 (Dba) 3 were added, and the mixture was reacted at 135°C for 16 hours. After the reaction was completed, the mixture was concentrated and purified by reverse phase column chromatography to obtain a white solid, 3-[(4-methoxybenzyl)oxy]-2-oxo-1,2-dihydro-1,5-naphthyridin-4-carbonitrile (3H).

(9)制备3-羟基-2-氧代-1H-1,5-萘啶-4-甲酰胺，其结构式如式(6)所示。(9) Prepare 3-hydroxy-2-oxo-1H-1,5-naphthyridine-4-carboxamide, the structural formula of which is shown in formula (6).

将3-[(4-甲氧基苄基)氧基]-2-氧代-1,2-二氢-1,5-萘啶-4-腈(3H)溶于浓硫酸中，加热至60℃反应2h。反应完成后过滤，滤饼用3mL MeOH打浆得到黑色固体——3-羟基-2-氧代-1H-1,5-萘啶-4-甲酰胺。3-[(4-methoxybenzyl)oxy]-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (3H) was dissolved in concentrated sulfuric acid and heated to 60°C for 2 hours. After the reaction was completed, the mixture was filtered and the filter cake was slurried with 3 mL MeOH to obtain a black solid, 3-hydroxy-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

实施例4Example 4

本实施例提供了3-羟基-6-{[4-(4-羟基苯基)吡啶-2-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺，其结构式如式(7)所示，制备方法具体如下，具体见表3和表4。This embodiment provides 3-hydroxy-6-{[4-(4-hydroxyphenyl)pyridin-2-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide, whose structural formula is shown in formula (7). The specific preparation method is as follows, see Table 3 and Table 4 for details.

(1)制备2-(6-氯-3-硝基吡啶-2-基)-2-氰基乙酸叔丁酯(4A)，其结构式如式(33)所示。(1) Preparation of tert-butyl 2-(6-chloro-3-nitropyridin-2-yl)-2-cyanoacetate (4A), the structural formula of which is shown in formula (33).

将2,6-二氯-3-硝基吡啶溶于THF中，然后依次加入无水碳酸钾和氰基乙酸叔丁酯，搅拌均匀升温至70℃反应12h。反应完成后过滤并浓缩滤液，得到棕色油状物——2-(6-氯-3-硝基吡啶-2-基)-2-氰基乙酸叔丁酯(4A)。2,6-Dichloro-3-nitropyridine was dissolved in THF, and then anhydrous potassium carbonate and tert-butyl cyanoacetate were added in sequence, stirred evenly, and heated to 70°C for 12 hours. After the reaction was completed, the filtrate was filtered and concentrated to obtain a brown oily substance, tert-butyl 2-(6-chloro-3-nitropyridine-2-yl)-2-cyanoacetate (4A).

(2)制备2-(6-氯-3-硝基吡啶-2-基)乙腈(4B)，其结构式如式(34)所示。(2) Preparation of 2-(6-chloro-3-nitropyridin-2-yl)acetonitrile (4B), the structural formula of which is shown in formula (34).

在2-(6-氯-3-硝基吡啶-2-基)-2-氰基乙酸叔丁酯(4A)的MeCN溶液中，缓慢加入6M的盐酸溶液，搅拌均匀升温至70℃反应6h。反应结束后加入饱和碳酸钠溶液调节pH至8，然后用EA萃取(300mL×2)，有机相用饱和食盐水洗涤3次，无水硫酸钠干燥有机相并浓缩，得到棕色油状物——2-(6-氯-3-硝基吡啶-2-基)乙腈(4B)。Slowly add 6M hydrochloric acid solution to the MeCN solution of tert-butyl 2-(6-chloro-3-nitropyridin-2-yl)-2-cyanoacetate (4A), stir evenly and heat to 70°C for 6 hours. After the reaction, add saturated sodium carbonate solution to adjust the pH to 8, then extract with EA (300mL×2), wash the organic phase with saturated brine 3 times, dry the organic phase with anhydrous sodium sulfate and concentrate to obtain a brown oily substance - 2-(6-chloro-3-nitropyridin-2-yl)acetonitrile (4B).

(3)制备2-(6-氯-3-氨基吡啶-2-基)乙腈(4C)，其结构式如式(35)所示。(3) Preparation of 2-(6-chloro-3-aminopyridin-2-yl)acetonitrile (4C), the structural formula of which is shown in formula (35).

将2-(6-氯-3-硝基吡啶-2-基)乙腈(4B)和氯化铵加入1L圆底烧瓶中，加入MeOH和水溶解，在冰水浴下缓慢加入锌片，加毕撤去冰水浴，继续反应2h。反应结束后加入饱和碳酸钠溶液调节pH至8，然后用EA萃取(300mL×2)，有机相用饱和食盐水洗涤3次，无水硫酸钠干燥有机相并浓缩，将粗产品通过硅胶柱层析纯化得到黄色固体——2-(6-氯-3-氨基吡啶-2-基)乙腈(4C)。2-(6-chloro-3-nitropyridin-2-yl)acetonitrile (4B) and ammonium chloride were added to a 1L round-bottom flask, MeOH and water were added to dissolve, zinc flakes were slowly added in an ice-water bath, the ice-water bath was removed after the addition, and the reaction was continued for 2 hours. After the reaction was completed, a saturated sodium carbonate solution was added to adjust the pH to 8, and then EA was extracted (300mL×2), the organic phase was washed 3 times with saturated brine, the organic phase was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow solid, 2-(6-chloro-3-aminopyridin-2-yl)acetonitrile (4C).

(4)制备{[6-氯-2-(氰基甲基)吡啶-3-基]氨基甲酰基}甲酸乙酯(4D)，其结构式如式(36)所示。(4) Preparation of ethyl {[6-chloro-2-(cyanomethyl)pyridin-3-yl]carbamoyl}carboxylate (4D), the structural formula of which is shown in formula (36).

将2-(6-氯-3-氨基吡啶-2-基)乙腈(4D)和吡啶加入500mL圆底烧瓶中，加入DCM溶解，在冰水浴下缓慢加入草酰氯单乙酯，加毕撤去冰水浴，继续反应1h。反应结束后浓缩反应液，将粗产品通过硅胶柱层析纯化得到黄色固体——{[6-氯-2-(氰基甲基)吡啶-3-基]氨基甲酰基}甲酸乙酯(4D)。2-(6-chloro-3-aminopyridin-2-yl)acetonitrile (4D) and pyridine were added to a 500 mL round-bottom flask, DCM was added to dissolve, and ethyl oxalyl chloride was slowly added under an ice-water bath. After the addition, the ice-water bath was removed and the reaction was continued for 1 hour. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow solid, ethyl {[6-chloro-2-(cyanomethyl)pyridin-3-yl]carbamoyl}carboxylate (4D).

(5)制备6-氯-3-羟基-2-氧代-1,2-二氢-1,5-萘啶-4-甲腈(4E)，其结构式如式(37)所示。(5) Prepare 6-chloro-3-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (4E), the structural formula of which is shown in formula (37).

将{[6-氯-2-(氰基甲基)吡啶-3-基]氨基甲酰基}甲酸乙酯(4D)溶于THF中，在冰水浴下加入t-BuOK(叔丁醇钾)，加毕撤去冰水浴，继续反应2h。反应结束后浓缩反应液并过滤，分别用水和EtOH洗涤滤饼，得到白色固体——6-氯-3-羟基-2-氧代-1,2-二氢-1,5-萘啶-4-甲腈(4E)。Ethyl {[6-chloro-2-(cyanomethyl)pyridin-3-yl]carbamoyl}carboxylate (4D) was dissolved in THF, and t-BuOK (potassium tert-butoxide) was added under an ice-water bath. After the addition, the ice-water bath was removed and the reaction was continued for 2 hours. After the reaction was completed, the reaction solution was concentrated and filtered, and the filter cake was washed with water and EtOH respectively to obtain a white solid - 6-chloro-3-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (4E).

(6)制备2-(4-溴吡啶-2-基)乙酸叔丁酯(4F)，其结构式如式(38)所示。(6) Preparation of tert-butyl 2-(4-bromopyridin-2-yl)acetate (4F), the structural formula of which is shown in formula (38).

将4-溴-2甲基吡啶溶于THF中，冷却至-70℃，在氮气保护下缓慢滴加二异丙基氨基锂，加毕搅拌1.5h。然后向上述溶液中缓慢滴加Boc酸酐THF溶液，加毕缓慢升温至室温并反应过夜。反应完成后加入饱和氯化铵溶液淬灭，然后用EA萃取(100mL×2)，有机相用饱和食盐水洗涤3次，无水硫酸钠干燥有机相并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——2-(4-溴吡啶-2-基)乙酸叔丁酯(4F)。Dissolve 4-bromo-2-methylpyridine in THF, cool to -70°C, slowly add lithium diisopropylamide under nitrogen protection, and stir for 1.5h after addition. Then slowly add Boc anhydride THF solution to the above solution, slowly warm to room temperature after addition and react overnight. After the reaction is completed, add saturated ammonium chloride solution to quench, then extract with EA (100mL×2), wash the organic phase with saturated brine 3 times, dry the organic phase with anhydrous sodium sulfate and concentrate, and purify the crude product by silica gel column chromatography to obtain a yellow oily substance - tert-butyl 2-(4-bromopyridin-2-yl)acetate (4F).

(7)制备2-(4-(4-甲氧基苯基)吡啶-2-基)乙酸叔丁酯(4G)，其结构式如式(39)所示。(7) Preparation of tert-butyl 2-(4-(4-methoxyphenyl)pyridin-2-yl)acetate (4G), the structural formula of which is shown in formula (39).

向100mL圆底烧瓶中加入2-(4-溴吡啶-2-基)乙酸叔丁酯(4F)、4-甲氧基苯基硼酸、碳酸钾，分别加入1,4-二氧六环和水，搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯，在氮气保护下升温至85℃，并反应2h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——2-(4-(4-甲氧基苯基)吡啶-2-基)乙酸叔丁酯(4G)。Add tert-butyl 2-(4-bromopyridin-2-yl)acetate (4F), 4-methoxyphenylboronic acid, potassium carbonate to a 100 mL round-bottom flask, add 1,4-dioxane and water respectively, and stir to dissolve. Then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride to the solution, heat to 85°C under nitrogen protection, and react for 2 hours. After the reaction is completed, filter and collect the filtrate and concentrate it. The crude product is purified by silica gel column chromatography to obtain a yellow oily substance - tert-butyl 2-(4-(4-methoxyphenyl)pyridin-2-yl)acetate (4G).

(8)制备3-羟基-6-{[4-(4-甲氧基苯基)吡啶-2-基]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-腈(4H)，其结构式如式(40)所示。(8) Prepare 3-hydroxy-6-{[4-(4-methoxyphenyl)pyridin-2-yl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (4H), the structural formula of which is shown in formula (40).

向50mL圆底烧瓶中加入2-(4-(4-甲氧基苯基)吡啶-2-基)乙酸叔丁酯(4G)、6-氯-3-羟基-2-氧代-1,2-二氢-1,5-萘啶-4-甲腈(4E)、叔丁醇锂、[1,1'-双(二苯基膦)二茂铁]二氯化钯、imid-phos配体，加入1,4-二氧六环溶解，在氮气保护下升温至130℃，并反应16h。反应结束后浓缩，将粗产品通过Prep-HPLC纯化得到棕黄色固体——3-羟基-6-{[4-(4-甲氧基苯基)吡啶-2-基]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-腈(4H)。To a 50 mL round-bottom flask, tert-butyl 2-(4-(4-methoxyphenyl)pyridin-2-yl)acetate (4G), 6-chloro-3-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (4E), lithium tert-butoxide, [1,1'-bis(diphenylphosphino)ferrocene] dichloropalladium, and imid-phos ligand were added, 1,4-dioxane was added to dissolve, and the temperature was raised to 130°C under nitrogen protection and reacted for 16 hours. After the reaction was completed, the reaction was concentrated, and the crude product was purified by Prep-HPLC to obtain a brown-yellow solid - 3-hydroxy-6-{[4-(4-methoxyphenyl)pyridin-2-yl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (4H).

(9)制备3-羟基-6-{[4-(4-甲氧基苯基)吡啶-2-基]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-甲酰胺(4I)，其结构式如式(41)所示。 (9) Prepare 3-hydroxy-6-{[4-(4-methoxyphenyl)pyridin-2-yl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxamide (4I), the structural formula of which is shown in formula (41).

向50mL圆度烧瓶中加入3-羟基-6-{[4-(4-甲氧基苯基)吡啶-2-基]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-腈(4H)，同时加入PPA，升温至110℃搅拌1h。反应完成后加水淬灭并过滤，用EtOH洗涤滤饼得到黄色固体——3-羟基-6-{[4-(4-甲氧基苯基)吡啶-2-基]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-甲酰胺(4I)。3-Hydroxy-6-{[4-(4-methoxyphenyl)pyridin-2-yl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (4H) was added to a 50 mL round flask, and PPA was added at the same time. The temperature was raised to 110°C and stirred for 1 hour. After the reaction was completed, water was added to quench the reaction and the mixture was filtered. The filter cake was washed with EtOH to obtain a yellow solid, 3-hydroxy-6-{[4-(4-methoxyphenyl)pyridin-2-yl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxamide (4I).

(10)制备3-羟基-6-{[4-(4-羟基苯基)吡啶-2-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺，其结构式如式(7)所示。(10) Prepare 3-hydroxy-6-{[4-(4-hydroxyphenyl)pyridin-2-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide, the structural formula of which is shown in formula (7).

向50mL圆度烧瓶中加入3-羟基-6-{[4-(4-甲氧基苯基)吡啶-2-基]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-甲酰胺(4I)，加入DCM溶解，然后在冰水浴下加入2M的BBr3的DCM溶液，加毕撤去冰水浴反应1h。反应完成后浓缩，将粗产品通过Prep-HPLC纯化得到淡黄色固体——3-羟基-6-{[4-(4-羟基苯基)吡啶-2-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。3-Hydroxy-6-{[4-(4-methoxyphenyl)pyridin-2-yl]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxamide (4I) was added to a 50 mL round flask, and DCM was added to dissolve it. Then, a 2M solution of BBr 3 in DCM was added under an ice-water bath. After the addition, the ice-water bath was removed and the reaction was continued for 1 hour. After the reaction was completed, the mixture was concentrated, and the crude product was purified by Prep-HPLC to obtain a light yellow solid, 3-hydroxy-6-{[4-(4-hydroxyphenyl)pyridin-2-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide.

实施例5Example 5

本实施例提供了3-羟基-6-{[3-(4-羟基苯基)苯基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。其结构式如式(8)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-6-{[3-(4-hydroxyphenyl)phenyl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (8). The specific preparation method is as follows, as shown in Table 3.

(1)制备2-(3-溴苯基)乙酸叔丁酯(5A)，其结构式如式(42)所示。(1) Preparation of tert-butyl 2-(3-bromophenyl)acetate (5A), the structural formula of which is shown in formula (42).

向250mL圆底烧瓶中加入2-(3-溴苯基)乙酸(5g，23.25mmol)和DMAP(1.42g，11.63mmol)，分别加入叔丁醇(50mL)和THF(50mL)，搅拌溶解。然后向溶液中加入Boc酸酐(10.15g，46.50mmol)，在30℃下反应12h。反应结束后浓缩反应液，将粗产品通过硅胶柱层析纯化得到无色油状物——2-(3-溴苯基)乙酸叔丁酯(5A)(产量6.3g，产率99.93％)。2-(3-bromophenyl)acetic acid (5 g, 23.25 mmol) and DMAP (1.42 g, 11.63 mmol) were added to a 250 mL round-bottom flask, and tert-butyl alcohol (50 mL) and THF (50 mL) were added respectively, and stirred to dissolve. Then Boc anhydride (10.15 g, 46.50 mmol) was added to the solution, and the reaction was carried out at 30° C. for 12 h. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oil - tert-butyl 2-(3-bromophenyl)acetate (5A) (yield 6.3 g, yield 99.93%).

(2)制备2-(4'-甲氧基-[1，1'-联苯]-3-基)乙酸叔丁酯(5B)，其结构式如式(43)所示。(2) Preparation of tert-butyl 2-(4'-methoxy-[1,1'-biphenyl]-3-yl)acetate (5B), the structural formula of which is shown in formula (43).

向100mL圆底烧瓶中依次加入2-(3-溴苯基)乙酸叔丁酯(5A)(3.30g，12.17mmol)、4-甲氧基苯基硼酸(2.22g，14.60mmol)和碳酸钾(5.05g，36.51mmol)，分别加入1,4-二氧六环(55mL)和水(11mL)，搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(994mg，1.22mmol)，在氮气保护下升温至90℃，并反应12h。反应结束后过滤收集滤液，用EA萃取(20mL×3)，并用10mL饱和食盐水洗涤有机相，无水硫酸钠干燥有机相并浓缩。将粗产品通过硅胶柱层析纯化得到无色油状物——2-(4'-甲氧基-[1，1'-联苯]-3-基)乙酸叔丁酯(5B)(产量1.6g，产率44.06％)。To a 100 mL round-bottom flask, tert-butyl 2-(3-bromophenyl)acetate (5A) (3.30 g, 12.17 mmol), 4-methoxyphenylboronic acid (2.22 g, 14.60 mmol) and potassium carbonate (5.05 g, 36.51 mmol) were added in sequence, and 1,4-dioxane (55 mL) and water (11 mL) were added respectively, and stirred to dissolve. Then, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (994 mg, 1.22 mmol) was added to the solution, and the temperature was raised to 90°C under nitrogen protection, and the reaction was carried out for 12 h. After the reaction was completed, the filtrate was collected by filtration, extracted with EA (20 mL×3), and the organic phase was washed with 10 mL of saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain a colorless oily substance, tert-butyl 2-(4'-methoxy-[1,1'-biphenyl]-3-yl)acetate (5B) (yield 1.6 g, yield rate 44.06%).

然后以2-(4'-甲氧基-[1，1'-联苯]-3-基)乙酸叔丁酯(5B)(200mg，0.902mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到黄色固体——3-羟基-6-{[3-(4-羟基苯基)苯基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺(产量23mg，产率52.50％)。Then, using tert-butyl 2-(4'-methoxy-[1,1'-biphenyl]-3-yl)acetate (5B) (200 mg, 0.902 mmol) as raw material, a yellow solid, 3-hydroxy-6-{[3-(4-hydroxyphenyl)phenyl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide, was prepared in a manner similar to steps (8)-(10) of Example 4 (yield 23 mg, yield rate 52.50%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝388.2[M+H]+。MS (ESI) m/z = 388.2 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ16.21(s，1H)，12.25-11.97(m，1H)，10.78(s，1H)，10.08-9.88(m，1H)，9.65-9.54(m，1H)，8.73(s，1H)，7.79-7.34(m，5H)，7.25-6.82(m，4H)，4.26(d，2H)。 1 H NMR (DMSO-d6, 400MHz): δ16.21 (s, 1H), 12.25-11.97 (m, 1H), 10.78 (s, 1H), 10.08-9.88 (m , 1H), 9.65-9.54(m, 1H), 8.73(s, 1H), 7.79-7.34(m, 5H), 7.25-6.82(m, 4H), 4.26(d, 2H).

实施例6Example 6

本实施例提供了3-羟基-6-{[5-(3-羟基苯基)噻吩-2-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。其结构式如式(9)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-6-{[5-(3-hydroxyphenyl)thiophen-2-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (9). The specific preparation method is as follows, as shown in Table 3.

(1)制备2-(5-溴噻吩-2-基)乙酸叔丁酯(6A)，其结构式如式(44)所示。(1) Preparation of tert-butyl 2-(5-bromothiophen-2-yl)acetate (6A), the structural formula of which is shown in formula (44).

向250mL圆底烧瓶中加入5-溴-2-噻吩乙酸(2g，9.05mmol)和DMAP(533mg，4.52mmol)，分别加入叔丁醇(20mL)和THF(20mL)，搅拌溶解。然后向溶液中加入Boc酸酐(3.95g，18.09mmol)，在30℃下反应12h。反应结束后浓缩反应液，将粗产品通过硅胶柱层析纯化得到黄色固体——2-(5-溴噻吩-2-基)乙酸叔丁酯(6A)(产量1.6g，产率63.81％)。5-Bromo-2-thiopheneacetic acid (2 g, 9.05 mmol) and DMAP (533 mg, 4.52 mmol) were added to a 250 mL round-bottom flask, and tert-butyl alcohol (20 mL) and THF (20 mL) were added respectively, and stirred to dissolve. Then Boc anhydride (3.95 g, 18.09 mmol) was added to the solution, and the reaction was carried out at 30 ° C for 12 h. After the reaction was completed, the reaction solution was concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow solid - tert-butyl 2-(5-bromothiophene-2-yl)acetate (6A) (yield 1.6 g, yield 63.81%).

(2)制备2-[5-(3-甲氧基苯基)噻吩-2-基]乙酸叔丁酯(6B)，其结构式如式(45)所示。(2) Preparation of tert-butyl 2-[5-(3-methoxyphenyl)thiophen-2-yl]acetate (6B), the structural formula of which is shown in formula (45).

向100mL圆底烧瓶中依次加入2-(5-溴噻吩-2-基)乙酸叔丁酯(6A)(1.60g，5.77mmol)、3-甲氧基苯基硼酸(1.32g，8.66mmol)和碳酸钾(2.39g，17.32mmol)，分别加入1,4-二氧六环(30mL)和水(6mL)，搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(466.74mg，0.58mmol)，在氮气保护下升温至90℃，并反应12h。反应结束后过滤收集滤液，用EA萃取(20mL×3)，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相并浓缩。将粗产品通过硅胶柱层析纯化得到黄色油状物——2-[5-(3-甲氧基苯基)噻吩-2-基]乙酸叔丁酯(6B)(产量1.15g，产率65.45％)。To a 100 mL round-bottom flask, tert-butyl 2-(5-bromothiophene-2-yl)acetate (6A) (1.60 g, 5.77 mmol), 3-methoxyphenylboronic acid (1.32 g, 8.66 mmol) and potassium carbonate (2.39 g, 17.32 mmol) were added in sequence, and 1,4-dioxane (30 mL) and water (6 mL) were added respectively, and stirred to dissolve. Then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (466.74 mg, 0.58 mmol) was added to the solution, and the temperature was raised to 90 ° C under nitrogen protection, and the reaction was carried out for 12 h. After the reaction was completed, the filtrate was collected by filtration, extracted with EA (20 mL × 3), and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow oily substance - tert-butyl 2-[5-(3-methoxyphenyl)thiophen-2-yl]acetate (6B) (yield 1.15 g, yield rate 65.45%).

然后以2-[5-(3-甲氧基苯基)噻吩-2-基]乙酸叔丁酯(6B)(350mg，1.15mmol)为原料，按照类似于实施例4步骤(8)-(10)制备得到黄色固体——3-羟基-6-{[5-(3-羟基苯基)噻吩-2-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺(产量6.41mg，产率6.17％)。Then, using tert-butyl 2-[5-(3-methoxyphenyl)thiophen-2-yl]acetate (6B) (350 mg, 1.15 mmol) as raw material, a yellow solid, 3-hydroxy-6-{[5-(3-hydroxyphenyl)thiophen-2-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide (yield 6.41 mg, yield rate 6.17%), was prepared in a manner similar to steps (8)-(10) of Example 4.

检测结果如下：The test results are as follows:

MS(ESI)m/z＝394.1[M+H]+。MS (ESI) m/z = 394.1 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ12.23(brs，1H)，10.79(s，1H)，9.57(s，1H)，8.83(s，1H)，8.37(s，1H)，7.72-7.61(m，1H)，7.35-7.20(m，3H)，7.01-6.80(m，4H)，4.42(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ12.23 (brs, 1H), 10.79 (s, 1H), 9.57 (s, 1H), 8.83 (s, 1H), 8.37 (s, 1H), 7.72-7.61 (m, 1H), 7.35-7.20 (m, 3H), 7.01-6.80 (m, 4H), 4.42 (s, 2H).

实施例7Example 7

本实施例提供了3-羟基-6-{[4-(1H-吡咯并[2,3-b]吡啶-3-基)吡唑-1-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。其结构式如式(10)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-6-{[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazol-1-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (10). The specific preparation method is as follows, as shown in Table 3.

(1)制备3-溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚(7A)，其结构式如式(46)所示。(1) Preparation of 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindole (7A), the structural formula of which is shown in formula (46).

向500mL圆底烧瓶中加入3-溴-7-氮杂吲哚(10g，50.75mmol)和DBU(23.18g，152.25mmol)，加入DMF(200mL)搅拌溶解。然后在冰水浴下向溶液中缓慢滴加SEM-Cl(10.15g，60.90mmol)，滴毕撤去冰水浴，反应16h。反应结束后加EA和水分液，水相用EA萃取，合并有机相，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到无色油状物——3-溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚(7A)(7.6g，产率45.75％)。3-Bromo-7-azaindole (10 g, 50.75 mmol) and DBU (23.18 g, 152.25 mmol) were added to a 500 mL round-bottom flask, and DMF (200 mL) was added and stirred to dissolve. SEM-Cl (10.15 g, 60.90 mmol) was then slowly added dropwise to the solution under an ice-water bath, and the ice-water bath was removed after the addition, and the reaction was continued for 16 h. After the reaction was completed, EA and water were added to separate the mixture, the aqueous phase was extracted with EA, the organic phases were combined, and the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a colorless oil - 3-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindole (7A) (7.6 g, yield 45.75%).

(2)制备3-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚(7B)，其结构式如式(47)所示。 (2) Preparation of 3-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindole (7B), the structural formula of which is shown in formula (47).

向250mL圆底烧瓶中加入3-溴-1-((2-(三甲基硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚(7A)(2.5g，7.64mmol)和1H-吡唑-4-硼酸(1.28g，11.46mmol)，加入1,4-二氧六环(40mL)搅拌溶解，然后加入8mL碳酸钠水溶液(2.43g，22.91mmol)和[1,1'-双(二苯基膦)二茂铁]二氯化钯(556.59mg，0.76mmol)。在氮气保护下升温至90℃，并反应16h。反应结束后加水稀释，用EA萃取，合并有机相，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到棕色固体——3-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚(7B)(产量276mg，产率11.49％)。3-Bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindole (7A) (2.5 g, 7.64 mmol) and 1H-pyrazole-4-boric acid (1.28 g, 11.46 mmol) were added to a 250 mL round-bottom flask, 1,4-dioxane (40 mL) was added and stirred to dissolve, and then 8 mL of sodium carbonate aqueous solution (2.43 g, 22.91 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (556.59 mg, 0.76 mmol) were added. The temperature was raised to 90 ° C under nitrogen protection and reacted for 16 h. After the reaction was completed, it was diluted with water, extracted with EA, the organic phases were combined, and the organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a brown solid - 3-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindole (7B) (yield 276 mg, yield rate 11.49%).

(3)制备{4-[1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚-3-基]-1H-吡唑-1-基}甲基硼酸(7C)，其结构式如式(48)所示。(3) Preparation of {4-[1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindol-3-yl]-1H-pyrazol-1-yl}methylboronic acid (7C), the structural formula of which is shown in formula (48).

向50mL圆底烧瓶中加入3-(1H-吡唑-4-基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚(7B)(200mg，0.64mmol)和碳酸钾(264mg，1.91mmol)，加入MeCN(5mL)在室温下搅拌1h，然后加入4mL溴甲基硼酸频哪醇酯的MeCN溶液(169mg,0.76mmol)，加毕室温反应24h。反应结束后过滤，用MeCN洗涤滤饼，得到棕色油状物——{4-[1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚-3-基]-1H-吡唑-1-基}甲基硼酸(7C)(产量210mg，产率88.68％)。3-(1H-pyrazol-4-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindole (7B) (200 mg, 0.64 mmol) and potassium carbonate (264 mg, 1.91 mmol) were added to a 50 mL round-bottom flask, and MeCN (5 mL) was added and stirred at room temperature for 1 h, and then 4 mL of bromomethylboronic acid pinacol ester in MeCN (169 mg, 0.76 mmol) was added, and the reaction was continued at room temperature for 24 h. After the reaction was completed, the mixture was filtered and the filter cake was washed with MeCN to obtain a brown oily substance, {4-[1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindole-3-yl]-1H-pyrazol-1-yl}methylboronic acid (7C) (yield 210 mg, yield 88.68%).

然后以{4-[1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1H-7-氮杂吲哚-3-基]-1H-吡唑-1-基}甲基硼酸(7C)(252mg，0.677mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到黄色固体——3-羟基-6-{[4-(1H-吡咯并[2,3-b]吡啶-3-基)吡唑-1-基]甲基}-2-氧代-1H-1,5-萘啶-4-甲酰胺(产量15mg，产率13.81％)。Then, using {4-[1-((2-(trimethylsilyl)ethoxy)methyl)-1H-7-azaindol-3-yl]-1H-pyrazol-1-yl}methylboronic acid (7C) (252 mg, 0.677 mmol) as raw material, a yellow solid - 3-hydroxy-6-{[4-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyrazol-1-yl]methyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide (yield 15 mg, yield 13.81%) was prepared according to a method similar to steps (8)-(10) of Example 4.

检测结果如下：The test results are as follows:

MS(ESI)m/z＝402.2[M+H]+。MS (ESI) m/z = 402.2 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ12.28(s，1H)，11.72(s，1H)，10.46(s，1H)，8.72(s，1H)，8.32-8.21(m，3H)，7.73-7.68(m，1H)，7.31-7.22(m，3H)，7.15-6.96(m，2H)，5.61(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ12.28 (s, 1H), 11.72 (s, 1H), 10.46 (s, 1H), 8.72 (s, 1H), 8.3 2-8.21 (m, 3H), 7.73-7.68 (m, 1H), 7.31-7.22 (m, 3H), 7.15-6.96 (m, 2H), 5.61 (s, 2H).

实施例8Example 8

本实施例提供了3-羟基-6-{2-[(4-羟基苯基)氨基]-2-氧代乙基}-2-氧代-1H-1,5-萘啶-4-甲酰胺。其结构式如式(11)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-6-{2-[(4-hydroxyphenyl)amino]-2-oxoethyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (11). The specific preparation method is as follows, as shown in Table 3.

(1)制备2-氰基-2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)乙酸(8A)，其结构式如式(49)所示。(1) Prepare 2-cyano-2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)acetic acid (8A), the structural formula of which is shown in formula (49).

向50mL圆底烧瓶中加入氰基乙酸叔丁酯(255mg，1.81mmol)、6-氯-3-羟基-2-氧代-1,2-二氢-1,5-萘啶-4-甲腈(4E)(200mg，0.90mmol)、叔丁醇锂(361mg，4.51mmol)、双(三环己基膦)二氯化钯(67mg，0.09mmol)、imid-phos配体(71mg，0.18mmol)，加入15mL 1,4-二氧六环溶解，在氮气保护下升温至130℃，并反应12h。反应结束后浓缩，将粗产品通过Prep-HPLC纯化得到棕色固体——2-氰基-2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)乙酸(8A)(产量487mg，产率99.78％)。To a 50 mL round-bottom flask, tert-butyl cyanoacetate (255 mg, 1.81 mmol), 6-chloro-3-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carbonitrile (4E) (200 mg, 0.90 mmol), lithium tert-butoxide (361 mg, 4.51 mmol), bis(tricyclohexylphosphine)palladium dichloride (67 mg, 0.09 mmol), imid-phos ligand (71 mg, 0.18 mmol) were added, 15 mL 1,4-dioxane was added to dissolve, the temperature was raised to 130 ° C under nitrogen protection, and the reaction was continued for 12 h. After the reaction was completed, the reaction was concentrated, and the crude product was purified by Prep-HPLC to obtain a brown solid - 2-cyano-2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridine-2-yl)acetic acid (8A) (yield 487 mg, yield 99.78%).

(2)制备2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)乙酸(8B)，其结构式如式(50)所示。(2) Prepare 2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)acetic acid (8B), the structural formula of which is shown in formula (50).

向50mL圆度烧瓶中加入2-氰基-2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)乙酸(8A)(480mg，1.8mmol)，加入10mL水，然后加入12M的盐酸(10mL)，搅拌均匀，然后升温至100℃反应3h。反应完成后，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到黄色油状物——2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)乙酸(8B)(286mg，产率65.50％)。2-cyano-2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)acetic acid (8A) (480 mg, 1.8 mmol) was added to a 50 mL round flask, 10 mL of water was added, and then 12 M hydrochloric acid (10 mL) was added, stirred evenly, and then heated to 100 ° C for 3 h. After the reaction was completed, EA was extracted, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow oil - 2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)acetic acid (8B) (286 mg, yield 65.50%).

(3)制备2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)-N-(4-甲氧基苯基)乙酰胺(8C)，其结构式如式(51)所示。(3) Prepare 2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)-N-(4-methoxyphenyl)acetamide (8C), the structural formula of which is shown in formula (51).

向50mL圆度烧瓶中加入2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)乙酸(8B)(270mg，1.1mmol)，4-茴香胺(163mg，1.32mmol)和HOBt(1-羟基苯并三唑，149mg，1.1mmol)，加入3mL DMF溶解，在冰水浴下加入N,N-二异丙基乙胺(DIPEA，427mg，3.3mmol)、EDCI(1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐，274mg，1.43mmol)，加毕撤去冰水浴反应2h。反应结束后浓缩，将粗产品通过Prep-HPLC纯化得到黄色固体——2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)-N-(4-甲氧基苯基)乙酰胺(8C)(产量250mg，产率64.80％)。To a 50 mL round flask, add 2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)acetic acid (8B) (270 mg, 1.1 mmol), 4-anisidine (163 mg, 1.32 mmol) and HOBt (1-hydroxybenzotriazole, 149 mg, 1.1 mmol), add 3 mL of DMF to dissolve, and add N,N-diisopropylethylamine (DIPEA, 427 mg, 3.3 mmol) and EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 274 mg, 1.43 mmol) in an ice-water bath. After the addition, remove the ice-water bath and react for 2 h. After the reaction, the reaction mixture was concentrated and the crude product was purified by Prep-HPLC to obtain a yellow solid - 2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)-N-(4-methoxyphenyl)acetamide (8C) (yield 250 mg, yield rate 64.80%).

(4)制备3-羟基-6-{[4-(4-甲氧基苯基)甲酰胺]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-甲酰胺(8D)，其结构式如式(52)所示。(4) Preparation of 3-hydroxy-6-{[4-(4-methoxyphenyl)carboxamide]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxamide (8D), the structural formula of which is shown in formula (52).

向50mL圆度烧瓶中加入2-(8-氰基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)-N-(4-甲氧基苯基)乙酰胺(8C)(250mg，0.713mmol)，同时加入3mL多聚磷酸，升温至110℃搅拌1h。反应完成后加水淬灭并过滤，用乙醇洗涤滤饼得到黄色固体3-羟基-6-{[4-(4-甲氧基苯基)甲酰胺]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-甲酰胺(201mg，产率：63.72％)。2-(8-cyano-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)-N-(4-methoxyphenyl)acetamide (8C) (250 mg, 0.713 mmol) was added to a 50 mL round flask, and 3 mL of polyphosphoric acid was added at the same time, and the temperature was raised to 110°C and stirred for 1 hour. After the reaction was completed, water was added to quench and filter, and the filter cake was washed with ethanol to obtain a yellow solid 3-hydroxy-6-{[4-(4-methoxyphenyl)formamide]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxamide (201 mg, yield: 63.72%).

(5)制备3-羟基-6-{2-[(4-羟基苯基)氨基]-2-氧代乙基}-2-氧代-1H-1,5-萘啶-4-甲酰胺(实施例8)(5) Preparation of 3-hydroxy-6-{2-[(4-hydroxyphenyl)amino]-2-oxoethyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide (Example 8)

向50mL圆度烧瓶中加入3-羟基-6-{[4-(4-甲氧基苯基)甲酰胺]甲基}-2-氧代-1,2-二氢-1,5-萘啶-4-甲酰胺(8D，100mg，0.27mmol)，加入5mLDCM溶解，然后在冰水浴下加入0.68mL 2M的三溴化硼二氯甲烷溶液，加毕撤去冰水浴反应1h。反应完成后浓缩，将粗产品通过Prep-HPLC纯化得到黄色固体——3-羟基-6-{2-[(4-羟基苯基)氨基]-2-氧代乙基}-2-氧代-1H-1,5-萘啶-4-甲酰胺(产量5.8g，产率5.85％)。3-Hydroxy-6-{[4-(4-methoxyphenyl)formamide]methyl}-2-oxo-1,2-dihydro-1,5-naphthyridine-4-carboxamide (8D, 100 mg, 0.27 mmol) was added to a 50 mL round flask, 5 mL DCM was added to dissolve, and then 0.68 mL 2M boron tribromide dichloromethane solution was added under an ice-water bath. After the addition, the ice-water bath was removed and reacted for 1 hour. After the reaction was completed, it was concentrated, and the crude product was purified by Prep-HPLC to obtain a yellow solid - 3-hydroxy-6-{2-[(4-hydroxyphenyl)amino]-2-oxoethyl}-2-oxo-1H-1,5-naphthyridine-4-carboxamide (yield 5.8 g, yield 5.85%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝355.2[M+H]+。MS (ESI) m/z = 355.2 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ12.15(d，1H)，10.84(s，1H)，10.16-10.00(m，2H)，9.24(d，1H)，7.74-7.66(m，2H)，7.41-7.34(m，2H)，7.22-7.09(m，2H)，6.97-6.67(m，1H)，3.91(d，2H)。 1 H NMR (DMSO-d6, 400MHz): δ12.15 (d, 1H), 10.84 (s, 1H), 10.16-10.00 (m, 2H), 9.24 (d, 1H), 7.74-7.66 (m, 2H), 7.41-7.34 (m, 2H), 7.22-7.09 (m, 2H), 6.97-6.67 (m, 1H), 3.91 (d, 2H).

实施例9Example 9

本实施例提供了3-羟基-2-氧代-6-{[4-(2-氧代-1H-吡啶-4-基)吡啶-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺，其结构式如式(12)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-{[4-(2-oxo-1H-pyridin-4-yl)pyridin-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide, whose structural formula is shown in formula (12). The specific preparation method is as follows, see Table 3 for details.

(1)制备2-(4-溴吡啶-2-基)乙酸叔丁酯(9A)，其结构式如式(53)所示。(1) Preparation of tert-butyl 2-(4-bromopyridin-2-yl)acetate (9A), the structural formula of which is shown in formula (53).

向100mL圆底烧瓶中加入2-(4-溴吡啶-2-基)乙酸叔丁酯(4F)(1.5g，5.51mmol)、(2-甲氧基吡啶-4-基)硼酸(1.01g，6.61mmol)、碳酸钾(1.52g，11.02mmol)，分别加入25mL1,4-二氧六环和5mL水，搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(305.57mg，0.55mmol)，在氮气保护下升温至85℃，并反应2h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到无色油状物——2-(4-溴吡啶-2-基)乙酸叔丁酯(9A)(产量1.44g，产率86.98％)。To a 100 mL round-bottom flask, tert-butyl 2-(4-bromopyridin-2-yl)acetate (4F) (1.5 g, 5.51 mmol), (2-methoxypyridin-4-yl)boric acid (1.01 g, 6.61 mmol), potassium carbonate (1.52 g, 11.02 mmol) were added, and 25 mL of 1,4-dioxane and 5 mL of water were added, respectively, and stirred to dissolve. Then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (305.57 mg, 0.55 mmol) was added to the solution, and the temperature was raised to 85 ° C under nitrogen protection, and the reaction was carried out for 2 h. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oily substance-tert-butyl 2-(4-bromopyridin-2-yl)acetate (9A) (yield 1.44 g, yield 86.98%).

然后以2-(4-溴吡啶-2-基)乙酸叔丁酯(9A)(488mg，1.62mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到淡黄色固体——3-羟基-2-氧代-6-{[4-(2-氧代-1H-吡啶-4-基)吡啶-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺(产量13mg，产率30.23％)。Then, using tert-butyl 2-(4-bromopyridin-2-yl)acetate (9A) (488 mg, 1.62 mmol) as raw material, a method similar to steps (8)-(10) of Example 4 was used to prepare a light yellow solid - 3-hydroxy-2-oxo-6-{[4-(2-oxo-1H-pyridin-4-yl)pyridin-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide (yield 13 mg, yield rate 30.23%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝390.2[M+H]+。MS (ESI) m/z = 390.2 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ12.00(br，1H)，10.70(s，1H)，9.98(s，1H)，8.70-8.61(m，2H)，7.88-7.73(m，1H)，7.66-7.63(m，1H)，7.57-7.50(m，2H)，7.44-7.42(m，1H)，6.77-6.73(m，1H)，6.61-6.53(m，1H)，4.06(d，2H)。 1 H NMR (DMSO-d6, 400MHz): δ12.00 (br, 1H), 10.70 (s, 1H), 9.98 (s, 1H), 8.70-8.61 (m, 2H), 7.88-7.73 (m, 1H), 7 .66-7.63(m, 1H), 7.57-7.50(m, 2H), 7.44-7.42(m, 1H), 6.77-6.73(m, 1H), 6.61-6.53(m, 1H), 4.06(d, 2H).

实施例10Example 10

本实施例提供了3-羟基-2-氧代-6-{[5-(4-甲酰胺基苯基)噻吩-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺，其结构式如式(13)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-{[5-(4-formamidophenyl)thiophen-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide, whose structural formula is shown in formula (13). The specific preparation method is as follows, see Table 3 for details.

(1)制备2-[5-(4-氰基苯基)噻吩-2-基]乙酸叔丁酯(10A)，其结构式如式(54)所示。(1) Preparation of tert-butyl 2-[5-(4-cyanophenyl)thiophen-2-yl]acetate (10A), the structural formula of which is shown in formula (54).

向100mL圆底烧瓶中加入2-(5-溴噻吩-2-基)乙酸叔丁酯(2.0g，7.22mmol)、4-氰基苯基硼酸(1.27g，8.66mmol)、碳酸钾(2.99g，21.60mmol)，分别加入20mL1,4-二氧六环和4mL水，搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(589mg，0.72mmol)，在氮气保护下升温至90℃，并反应2h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——2-[5-(4-氰基苯基)噻吩-2-基]乙酸叔丁酯(10A)(产量1.30g，产率60.00％)。Add tert-butyl 2-(5-bromothiophen-2-yl)acetate (2.0 g, 7.22 mmol), 4-cyanophenylboronic acid (1.27 g, 8.66 mmol), potassium carbonate (2.99 g, 21.60 mmol) to a 100 mL round-bottom flask, add 20 mL of 1,4-dioxane and 4 mL of water, respectively, and stir to dissolve. Then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (589 mg, 0.72 mmol) to the solution, heat to 90 ° C under nitrogen protection, and react for 2 h. After the reaction is completed, filter and collect the filtrate and concentrate it. The crude product is purified by silica gel column chromatography to obtain a yellow oily substance - tert-butyl 2-[5-(4-cyanophenyl)thiophen-2-yl]acetate (10A) (yield 1.30 g, yield 60.00%).

然后以2-(4-溴吡啶-2-基)乙酸叔丁酯(10A)(405mg，1.35mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到淡黄色固体——3-羟基-2-氧代-6-{[5-(4-甲酰胺基苯基)噻吩-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺(产量5.47mg，总收率1.30％)。Then, using tert-butyl 2-(4-bromopyridin-2-yl)acetate (10A) (405 mg, 1.35 mmol) as raw material, a method similar to steps (8)-(10) of Example 4 was used to prepare a light yellow solid - 3-hydroxy-2-oxo-6-{[5-(4-formamidophenyl)thiophen-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide (yield 5.47 mg, total yield 1.30%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝421.0[M+H]+。MS (ESI) m/z = 421.0 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ10.78(s，1H)，9.96(s，1H)，8.84(s，1H)，7.98-7.66(m，5H)，7.48-6.67(m，6H)，4.49(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ10.78 (s, 1H), 9.96 (s, 1H), 8.84 (s, 1H), 7.98-7.66 (m, 5H), 7.48-6.67 (m, 6H) ), 4.49 (s, 2H).

实施例11Embodiment 11

本实施例提供了3-羟基-2-氧代-6-{[3-(4-甲酰胺基苯基)苯基]甲基}-1H-1,5-萘啶-4-甲酰胺。其结构式如式(14)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-{[3-(4-formamidophenyl)phenyl]methyl}-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (14). The specific preparation method is as follows, as shown in Table 3.

(1)制备2-(3-溴苯基)乙酸叔丁酯(11A)，其结构式如式(55)所示。(1) Preparation of tert-butyl 2-(3-bromophenyl)acetate (11A), the structural formula of which is shown in formula (55).

向100mL圆底烧瓶中加入(3-溴苯基)乙酸(5.0g，23.3mmol)、DMAP(1.42g，11.6mmol)，分别加入50mL叔丁醇和50mL THF，搅拌溶解。然后向溶液中加入Boc酸酐(10.2g，46.50mmol)，室温反应12h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——2-(3-溴苯基)乙酸叔丁酯(11A)(产量5.80g，产率92.00％)。Add (3-bromophenyl)acetic acid (5.0 g, 23.3 mmol) and DMAP (1.42 g, 11.6 mmol) to a 100 mL round-bottom flask, add 50 mL of tert-butyl alcohol and 50 mL of THF, respectively, and stir to dissolve. Then add Boc anhydride (10.2 g, 46.50 mmol) to the solution and react at room temperature for 12 h. After the reaction is completed, filter and collect the filtrate and concentrate it. The crude product is purified by silica gel column chromatography to obtain a yellow oil - tert-butyl 2-(3-bromophenyl)acetate (11A) (yield 5.80 g, yield 92.00%).

(2)制备2-[3-(4-氰基苯基)苯基]乙酸叔丁酯(11B)，其结构式如式(56)所示。(2) Preparation of tert-butyl 2-[3-(4-cyanophenyl)phenyl]acetate (11B), the structural formula of which is shown in formula (56).

向100mL圆底烧瓶中加入2-(3-溴苯基)乙酸叔丁酯(11A)(3.0g，11.1mmol)、4-氰基苯基硼酸(2.11g，14.4mmol)、碳酸钾(4.59g，33.2mmol)，Pd(dppf)Cl2(催化剂)(809mg,1.11mmol)，加入40mL1,4-二氧六环搅拌溶解。在氮气保护下升温至90℃，并反应12h。反应完成后，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到白色固体——2-[3-(4-氰基苯基)苯基]乙酸叔丁酯(11B)(产量3.2g，产率98.00％)。To a 100 mL round-bottom flask, tert-butyl 2-(3-bromophenyl)acetate (11A) (3.0 g, 11.1 mmol), 4-cyanophenylboronic acid (2.11 g, 14.4 mmol), potassium carbonate (4.59 g, 33.2 mmol), Pd(dppf)Cl2 (catalyst) (809 mg, 1.11 mmol) were added, and 40 mL of 1,4-dioxane was added and stirred to dissolve. The temperature was raised to 90 ° C under nitrogen protection and reacted for 12 h. After the reaction was completed, EA was extracted, and the organic phase was washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate and concentrated. The crude product was purified by silica gel column chromatography to obtain a white solid - tert-butyl 2-[3-(4-cyanophenyl)phenyl]acetate (11B) (yield 3.2 g, yield 98.00%).

然后以2-[3-(4-氰基苯基)苯基]乙酸叔丁酯(11B)(298mg，1.02mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到黄色固体——3-羟基-2-氧代-6-{[3-(4-甲酰胺基苯基)苯基]甲基}-1H-1,5-萘啶-4-甲酰胺(产量91.18mg，总收率21.57％)。Then, using tert-butyl 2-[3-(4-cyanophenyl)phenyl]acetate (11B) (298 mg, 1.02 mmol) as raw material, a method similar to steps (8)-(10) of Example 4 was used to prepare a yellow solid - 3-hydroxy-2-oxo-6-{[3-(4-formamidophenyl)phenyl]methyl}-1H-1,5-naphthyridine-4-carboxamide (yield 91.18 mg, total yield 21.57%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝415.1[M+H]+。MS (ESI) m/z = 415.1 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ11.99(s，1H)，10.73(s，1H)，9.96(s，1H)，8.03-7.95(m，3H)，7.80-7.57(m，9H)，7.50-7.18(m，1H)，4.31(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ11.99 (s, 1H), 10.73 (s, 1H), 9.96 (s, 1H), 8.03-7.95 (m, 3H), 7.80-7.57 (m, 9H) ), 7.50-7.18(m, 1H), 4.31(s, 2H).

实施例12 Example 12

本实施例提供了3-羟基-2-氧代-6-{[4-(5-甲酰胺基-1H-吡咯-3-基)吡唑-1-基]甲基}-1H-1,5-萘啶-4-甲酰胺。其结构式如式(15)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-{[4-(5-carboxamido-1H-pyrrol-3-yl)pyrazol-1-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (15). The specific preparation method is as follows, as shown in Table 3.

(1)制备4-溴-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯-2甲酸甲酯(12A)，其结构式如式(57)所示。(1) Preparation of 4-bromo-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrole-2-carboxylic acid methyl ester (12A), the structural formula of which is shown in formula (57).

向100mL圆底烧瓶中加入4-溴-1H-吡咯-2甲酸甲酯(10.0g，49.0mmol)、DBU(22.4g，147mmol)，加入150mL DCM搅拌溶解，在冰水浴下滴加SEM-Cl(12.3g,73.5mmol)，滴毕在室温下反应12h。反应完成后加水稀释，用DCM萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到无色油状物——4-溴-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯-2甲酸甲酯(12A)(产量9.70g，产率59.00％)。Add 4-bromo-1H-pyrrole-2-carboxylic acid methyl ester (10.0 g, 49.0 mmol) and DBU (22.4 g, 147 mmol) to a 100 mL round-bottom flask, add 150 mL DCM and stir to dissolve, add SEM-Cl (12.3 g, 73.5 mmol) dropwise under an ice-water bath, and react at room temperature for 12 h. After the reaction is completed, dilute with water, extract with DCM, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate. The crude product was purified by silica gel column chromatography to obtain a colorless oil - 4-bromo-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrole-2-carboxylic acid methyl ester (12A) (yield 9.70 g, yield 59.00%).

(2)制备4-(1H-吡唑-4-基)-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯-2甲酸甲酯(12B)，其结构式如式(58)所示。(2) Preparation of 4-(1H-pyrazol-4-yl)-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrole-2-carboxylic acid methyl ester (12B), the structural formula of which is shown in formula (58).

向100mL圆底烧瓶中加入4-溴-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯-2甲酸甲酯(12A)(7.5g，22.4mmol)、1H-吡唑-4-频哪醇硼酸酯(6.53g，33.7mmol)、碳酸钾(9.30g，67.3mmol)、Pd(dppf)Cl2(催化剂)(1.64g,2.24mmol)，分别加入140mL DMF和35mL水搅拌溶解，在氮气保护下升温至80℃，并反应12h。反应完成后加水稀释，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到黄色油状物——4-(1H-吡唑-4-基)-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯-2甲酸甲酯(12B)(产量2.60g，产率36.00％)。4-Bromo-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrole-2-carboxylic acid methyl ester (12A) (7.5 g, 22.4 mmol), 1H-pyrazole-4-pinacol borate (6.53 g, 33.7 mmol), potassium carbonate (9.30 g, 67.3 mmol), Pd(dppf)Cl 2 (catalyst) (1.64 g, 2.24 mmol) were added to a 100 mL round-bottom flask, and 140 mL of DMF and 35 mL of water were added to stir and dissolve, and the temperature was raised to 80° C. under nitrogen protection, and the reaction was carried out for 12 hours. After the reaction was completed, the mixture was diluted with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow oily substance - 4-(1H-pyrazol-4-yl)-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrole-2-carboxylic acid methyl ester (12B) (yield 2.60 g, yield rate 36.00%).

(3)制备4-[1-(硼酸甲基)吡唑-4-基]-1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯-2甲酸甲酯(12C)，其结构式如式(59)所示。(3) Prepare 4-[1-(boronic acid methyl)pyrazol-4-yl]-1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrole-2-carboxylic acid methyl ester (12C), the structural formula of which is shown in formula (59).

向100mL圆底烧瓶中加入4-(1H-吡唑-4-基)-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯-2甲酸甲酯(12B)(2.6g，8.09mmol)、碳酸钾(3.35g，24.3mmol)，加入50mL乙腈搅拌溶解，然后加入溴甲基苯甲酸频那酯(2.14g，9.71mmol)。在室温下反应12h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——4-[1-(硼酸甲基)吡唑-4-基]-1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯-2甲酸 甲酯(12C)(产量3.0g，产率97.00％)。4-(1H-pyrazol-4-yl)-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrole-2-carboxylic acid methyl ester (12B) (2.6 g, 8.09 mmol), potassium carbonate (3.35 g, 24.3 mmol) were added to a 100 mL round-bottom flask, 50 mL of acetonitrile was added and stirred to dissolve, and then bromomethylbenzoic acid pinacol (2.14 g, 9.71 mmol) was added. The reaction was carried out at room temperature for 12 h. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow oily substance - 4-[1-(boronic acid methyl) pyrazol-4-yl]-1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrole-2-carboxylic acid methyl ester (12C) (yield 3.0 g, yield 97.00%).

然后以4-[1-(硼酸甲基)吡唑-4-基]-1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯-2甲酸甲酯(12C)(385mg，1.02mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到淡黄色固体——3-羟基-2-氧代-6-{[4-(5-甲酰胺基-1H-吡咯-3-基)吡唑-1-基]甲基}-1H-1,5-萘啶-4-甲酰胺(产量4.59mg，产率6.0％)。Then, using 4-[1-(boronic acid methyl) pyrazol-4-yl]-1-(2-trimethylsilyl) ethoxy) methyl-1H-pyrrole-2-carboxylic acid methyl ester (12C) (385 mg, 1.02 mmol) as raw material, a method similar to steps (8)-(10) of Example 4 was used to prepare a light yellow solid - 3-hydroxy-2-oxo-6-{[4-(5-formamido-1H-pyrrol-3-yl) pyrazol-1-yl] methyl}-1H-1,5-naphthyridine-4-carboxamide (yield 4.59 mg, yield rate 6.0%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝394.1[M+H]+。MS (ESI) m/z = 394.1 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ11.38(s，1H)，10.51(s，1H)，8.75(s，1H)，8.17(s，1H)，7.92-7.90(m，1H)，7.69-7.46(m，5H)，7.06-6.87(m，3H)，5.53(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ11.38(s, 1H), 10.51(s, 1H), 8.75(s, 1H), 8.17(s, 1H), 7.92-7.90(m, 1H), 7.69-7.46(m, 5H), 7.06-6.87(m, 3H), 5.53(s, 2H).

实施例13Embodiment 13

本实施例提供了3-羟基-2-氧代-6-{[6-(1H-吡咯并[2,3-b]吡啶-3-基)吡啶-3-基]甲基-1H-1,5-萘啶-4-甲酰胺。其结构式如式(16)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-{[6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]methyl-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (16). The specific preparation method is as follows, as shown in Table 3.

(1)制备3-溴-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯并[2,3-b]吡啶(13A)，其结构式如式(60)所示。(1) Prepare 3-bromo-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (13A), the structural formula of which is shown in formula (60).

向100mL圆底烧瓶中加入3-溴-1H-吡咯并[2,3-b]吡啶(30g，156mmol)、DBU(70g，457mmol)，加入300mL THF搅拌溶解，在冰水浴下滴加SEM-Cl(38g,228mmol)，滴毕在室温下反应16h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到无色油状物——3-溴-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯并[2,3-b]吡啶(13A)(产量21g，产率42％)。3-Bromo-1H-pyrrolo[2,3-b]pyridine (30 g, 156 mmol) and DBU (70 g, 457 mmol) were added to a 100 mL round-bottom flask, and 300 mL THF was added and stirred to dissolve. SEM-Cl (38 g, 228 mmol) was added dropwise under an ice-water bath, and the mixture was reacted at room temperature for 16 h. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a colorless oil - 3-bromo-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (13A) (yield 21 g, yield 42%).

(2)制备3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯并[2,3-b]吡啶(13B)，其结构式如式(61)所示。(2) Prepare 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (13B), the structural formula of which is shown in formula (61).

向100mL圆底烧瓶中加入3-溴-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯并[2,3-b]吡啶(13A)(19.2g,58.6mmol)、联硼酸频那醇酯(22.3g，88.0mmol)、醋酸钾(17.3g，199.4mmol)、Pd(dppf)Cl2(催化剂)(5.3g,7.2mmol)，分别加入240mL DMF和60mL水搅拌溶解，在氮气保护下升温至80℃，并反应12h。反应完成后加水稀释，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到黄色油状物——3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯并[2,3-b]吡啶(13B)(产量11.9g，产率78.00％)。3-Bromo-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (13A) (19.2 g, 58.6 mmol), biboronic acid pinacol ester (22.3 g, 88.0 mmol), potassium acetate (17.3 g, 199.4 mmol), Pd(dppf)Cl 2 (catalyst) (5.3 g, 7.2 mmol) were added to a 100 mL round-bottom flask, and 240 mL of DMF and 60 mL of water were added to stir and dissolve, and the temperature was raised to 80°C under nitrogen protection, and the reaction was carried out for 12 hours. After the reaction was completed, it was diluted with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow oil - 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (13B) (yield 11.9 g, yield rate 78.00%).

(3)制备2-(6-氯吡啶-3基)乙酸叔丁酯(13C)，其结构式如式(62)所示。(3) Preparation of tert-butyl 2-(6-chloropyridin-3-yl)acetate (13C), the structural formula of which is shown in formula (62).

向100mL圆底烧瓶中加入2-(6-氯吡啶-3基)乙酸(5.0g，29.14mmol)、DMAP(1.78g，14.57mmol)，分别加入50mL THF和50mL叔丁醇搅拌溶解，然后在冰水浴下加入Boc酸酐(12.72g，58.28mmol)，在室温下反应6h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到淡黄色油状物——2-(6-氯吡啶-3基)乙酸叔丁酯(13C)(产量6.3g，产率95.00％)。2-(6-chloropyridin-3-yl)acetic acid (5.0 g, 29.14 mmol) and DMAP (1.78 g, 14.57 mmol) were added to a 100 mL round-bottom flask, and 50 mL THF and 50 mL tert-butyl alcohol were added and stirred to dissolve, and then Boc anhydride (12.72 g, 58.28 mmol) was added under an ice-water bath and reacted at room temperature for 6 h. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a light yellow oily substance - tert-butyl 2-(6-chloropyridin-3-yl)acetate (13C) (yield 6.3 g, yield 95.00%).

(4)制备2-{6-[(1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯并[2,3-b]吡啶-3-基]吡啶-3-基}乙酸叔丁酯(13D)，其结构式如式(63)所示。(4) Preparation of tert-butyl 2-{6-[(1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}acetate (13D), the structural formula of which is shown in formula (63).

向100mL圆底烧瓶中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯并[2,3-b]吡啶(13B)(7.4g，19.76mmol)、2-(6-氯吡啶-3基)乙酸叔丁酯(13C)(3.0g，13.18mmol)，分别加入100mL 1,4-二氧六环和20mL水搅拌溶解，然后加入碳酸钾(5.46g，39.53mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(964.07mg，1.32mmol)，在氮气保护下升温至90℃反应16h。反应完成后加水稀释，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到淡黄色油状物——2-{6-[(1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯并[2,3-b]吡啶-3-基]吡啶-3基}乙酸叔丁酯(13D)(产量2.4g，产率41.00％)。3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (13B) (7.4 g, 19.76 mmol) and tert-butyl 2-(6-chloropyridin-3-yl)acetate (13C) (3.0 g, 13.18 mmol) were added to a 100 mL round-bottom flask, and 100 mL 1,4-dioxane and 20 mL water were added to stir and dissolve, and then potassium carbonate (5.46 g, 39.53 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (964.07 mg, 1.32 mmol) were added, and the temperature was raised to 90 ° C under nitrogen protection for 16 h. After the reaction was completed, it was diluted with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a light yellow oil - tert-butyl 2-{6-[(1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}acetate (13D) (yield 2.4 g, yield rate 41.00%).

然后以2-{6-[(1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯并[2,3-b]吡啶-3-基]吡啶-3-基}乙酸叔丁酯(13D)(505.89mg，1.15mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到黄色固体——3-羟基-2-氧代-6-{[6-(1H-吡咯并[2,3-b]吡啶-3-基)吡啶-3-基]甲基-1H-1,5-萘啶-4-甲酰胺(产量17.3mg，总收率3.65％)。Then, using tert-butyl 2-{6-[(1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]pyridin-3-yl}acetate (13D) (505.89 mg, 1.15 mmol) as raw material, a method similar to steps (8)-(10) of Example 4 was used to prepare a yellow solid - 3-hydroxy-2-oxo-6-{[6-(1H-pyrrolo[2,3-b]pyridin-3-yl)pyridin-3-yl]methyl-1H-1,5-naphthyridine-4-carboxamide (yield 17.3 mg, total yield 3.65%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝413.1[M+H]+。MS (ESI) m/z = 413.1 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ11.99(s，1H)，10.75(s，1H)，9.95(s，1H)，8.75-8.55(m，2H)，8.26-8.18(m，2H)，7.89-7.65(m，5H)，7.42-7.16(m，2H)，6.54(s，1H)，4.27(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ11.99 (s, 1H), 10.75 (s, 1H), 9.95 (s, 1H), 8.75-8.55 (m, 2H) , 8.26-8.18(m, 2H), 7.89-7.65(m, 5H), 7.42-7.16(m, 2H), 6.54(s, 1H), 4.27(s, 2H).

实施例14Embodiment 14

本实施例提供了3-羟基-2-氧代-6-{[5-(1H-吡咯并[2,3-b]吡啶-3-基)噻吩-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺。其结构式如式(17)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-{[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (17). The specific preparation method is as follows, as shown in Table 3.

(1)制备2-{5-[(1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯并[2,3-b]吡啶-3-基]噻吩-2-基}乙酸叔丁酯(14A)，其结构式如式(64)所示。(1) Preparation of tert-butyl 2-{5-[(1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]thiophen-2-yl}acetate (14A), the structural formula of which is shown in formula (64).

向100mL圆底烧瓶中加入3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)-1-[(2-三甲基硅烷基)乙氧基]甲基-1H-吡咯并[2,3-b]吡啶(13B)(3.0g，8.01mmol)、2-(5-溴噻吩-2-基)乙酸叔丁酯(2.2g，8.01mmol)、磷酸钾(5.1g，24.04mmol)，分别加入30mL1,4-二氧六环和6mL水，搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(293.18mg，0.53mmol)，在氮气保护下升温至100℃，并反应10h。反应结束后分液收集有机相并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——2-{5-[(1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯并[2,3-b]吡啶-3-基]噻吩-2-基}乙酸叔丁酯(14A)(产量600mg，产率16.84％)。3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-1-[(2-trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (13B) (3.0 g, 8.01 mmol), tert-butyl 2-(5-bromothiophen-2-yl)acetate (2.2 g, 8.01 mmol), potassium phosphate (5.1 g, 24.04 mmol) were added to a 100 mL round-bottom flask, and 30 mL of 1,4-dioxane and 6 mL of water were added respectively, and stirred to dissolve. Then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (293.18 mg, 0.53 mmol) was added to the solution, and the temperature was raised to 100 ° C under nitrogen protection, and the reaction was carried out for 10 hours. After the reaction, the organic phase was collected and concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow oil - tert-butyl 2-{5-[(1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]thiophen-2-yl}acetate (14A) (yield 600 mg, yield 16.84%).

然后以2-{5-[(1-(2-三甲基硅烷基)乙氧基)甲基-1H-吡咯并[2,3-b]吡啶-3-基]噻吩-2-基}乙酸叔丁酯(14A)(231mg，0.52mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到淡黄色固体——3-羟基-2-氧代-6-{[5-(1H-吡咯并[2,3-b]吡啶-3-基)噻吩-2-基]甲基}-1H-1,5-萘啶-4-甲酰胺(产量5.64mg，总收率2.60％)。Then, using tert-butyl 2-{5-[(1-(2-trimethylsilyl)ethoxy)methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]thiophen-2-yl}acetate (14A) (231 mg, 0.52 mmol) as raw material, a method similar to steps (8)-(10) of Example 4 was used to prepare a light yellow solid - 3-hydroxy-2-oxo-6-{[5-(1H-pyrrolo[2,3-b]pyridin-3-yl)thiophen-2-yl]methyl}-1H-1,5-naphthyridine-4-carboxamide (yield 5.64 mg, total yield 2.60%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝418.1[M+H]+。MS (ESI) m/z = 418.1 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ11.93(s，1H)，10.85(s，1H)，9.96(s，1H)，8.90(s，1H)，8.27-8.21(m，2H)，7.78-7.67(m，2H)，7.27-6.96(m，5H)，4.46(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ11.93 (s, 1H), 10.85 (s, 1H), 9.96 (s, 1H), 8.90 (s, 1H), 8.27-8.21(m, 2H), 7.78-7.67(m, 2H), 7.27-6.96(m, 5H), 4.46(s, 2H).

实施例15Embodiment 15

本实施例提供了3-羟基-2-氧代-6-({5-[3-(4-甲基哌嗪-1-基)苯基]噻吩-2-基}甲基)-1H-1,5-萘啶-4-甲酰胺。其结构式如式(18)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-({5-[3-(4-methylpiperazin-1-yl)phenyl]thiophen-2-yl}methyl)-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (18). The specific preparation method is as follows, see Table 3 for details.

(1)制备1-(3-溴苯基)-4-甲基哌嗪(15A)，其结构式如式(65)所示。(1) Preparation of 1-(3-bromophenyl)-4-methylpiperazine (15A), the structural formula of which is shown in formula (65).

向100mL圆底烧瓶中加入1-(3-溴苯基)哌嗪(9.50g，34.22mmol)、甲醛(4.17g，51.33mmol)，加入100mL二氯乙烷搅拌溶解。然后向溶液中加入十八烷基三甲基溴化铵(10.88g，51.33mmol)，加毕室温反应16h。反应结束后用加入饱和碳酸钠溶液调节pH＝9，分液得到有机相旋干，将粗产品通过硅胶柱层析纯化得到无色油状物——1-(3-溴苯基)-4-甲基哌嗪(15A)(产量8.50g，产率97.00％)。1-(3-bromophenyl)piperazine (9.50 g, 34.22 mmol) and formaldehyde (4.17 g, 51.33 mmol) were added to a 100 mL round-bottom flask, and 100 mL of dichloroethane was added to stir and dissolve. Octadecyltrimethylammonium bromide (10.88 g, 51.33 mmol) was then added to the solution, and the reaction was continued at room temperature for 16 h. After the reaction was completed, saturated sodium carbonate solution was added to adjust the pH to 9, and the organic phase was separated and dried by spin drying. The crude product was purified by silica gel column chromatography to obtain a colorless oily substance, 1-(3-bromophenyl)-4-methylpiperazine (15A) (yield 8.50 g, yield 97.00%).

(2)制备1-甲基-4-[3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基]哌嗪(15B)，其结构式如式(66)所示。(2) Prepare 1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (15B), the structural formula of which is shown in formula (66).

向100mL圆底烧瓶中加入1-(3-溴苯基)-4-甲基哌嗪(15A)(8.50g,33.31mmol)、联硼酸频那醇酯(16.92g，66.62mmol)、醋酸钾(9.81g，99.94mmol)、Pd(dppf)Cl2(催化剂)(1.22g,1.67mmol)，加入250mL 1,4-二氧六环搅拌溶解，在氮气保护下升温至90℃，并反应12h。反应完成后加水稀释，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到黑色油状物——1-甲基-4-[3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基]哌嗪(15B)(产量7.60g，产率75.00％)。1-(3-bromophenyl)-4-methylpiperazine (15A) (8.50 g, 33.31 mmol), biboronic acid pinacol ester (16.92 g, 66.62 mmol), potassium acetate (9.81 g, 99.94 mmol), Pd(dppf)Cl 2 (catalyst) (1.22 g, 1.67 mmol) were added to a 100 mL round-bottom flask, and 250 mL of 1,4-dioxane was added and stirred to dissolve, and the temperature was raised to 90°C under nitrogen protection, and the reaction was carried out for 12 hours. After the reaction was completed, the mixture was diluted with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a black oily substance - 1-methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]piperazine (15B) (yield 7.60 g, yield rate 75.00%).

(3)制备{5-[(3-(4-甲基哌嗪-1-基)苯基]噻吩-2-基}乙酸叔丁酯(15C)，其结构式如式(67)所示。(3) Preparation of tert-butyl {5-[(3-(4-methylpiperazin-1-yl)phenyl]thiophen-2-yl}acetate (15C), the structural formula of which is shown in formula (67).

向100mL圆底烧瓶中加入1-甲基-4-[3-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基]哌嗪(15B)(3.05g，10.10mmol)、(5-噻吩-2-基)乙酸叔丁酯(2.80g，10.10mmol)，分别加入50mL 1,4-二氧六环和10mL水搅拌溶解，然后加入碳酸钾(4.19g，30.31mmol)、[1,1'-双(二苯基膦)二茂铁]二氯化钯(824.95mg，1.01mmol)，在氮气保护下升温至90℃反应16h。反应完成后加水稀释，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到黑色油状物——{5-[(3-(4-甲基哌嗪-1-基)苯基]噻吩-2-基}乙酸叔丁酯(15C)(产量2.4g，产率64.00％)。 1-Methyl-4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl]piperazine (15B) (3.05 g, 10.10 mmol) and tert-butyl (5-thiophen-2-yl)acetate (2.80 g, 10.10 mmol) were added to a 100 mL round-bottom flask, and 50 mL of 1,4-dioxane and 10 mL of water were added respectively to stir and dissolve, and then potassium carbonate (4.19 g, 30.31 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (824.95 mg, 1.01 mmol) were added, and the temperature was raised to 90°C under nitrogen protection to react for 16 h. After the reaction was completed, it was diluted with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a black oily substance - tert-butyl {5-[(3-(4-methylpiperazin-1-yl)phenyl]thiophen-2-yl}acetate (15C) (yield 2.4 g, yield rate 64.00%).

然后以{5-[(3-(4-甲基哌嗪-1-基)苯基]噻吩-2-基}乙酸叔丁酯(15C)(1.13g，1.02mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到黄色固体——3-羟基-2-氧代-6-({5-[3-(4-甲基哌嗪-1-基)苯基]噻吩-2-基}甲基)-1H-1,5-萘啶-4-甲酰胺(产量19.70mg，总收率4.07％)。Then, using tert-butyl {5-[(3-(4-methylpiperazin-1-yl)phenyl]thiophen-2-yl}acetate (15C) (1.13 g, 1.02 mmol) as raw material, a yellow solid, 3-hydroxy-2-oxo-6-({5-[3-(4-methylpiperazin-1-yl)phenyl]thiophen-2-yl}methyl)-1H-1,5-naphthyridine-4-carboxamide, was prepared in a manner similar to steps (8)-(10) of Example 4 (yield 19.70 mg, total yield 4.07%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝476.1[M+H]+。MS (ESI) m/z = 476.1 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ12.28(s，1H)，10.78(s，1H)，7.78-7.72(m，3H)，7.43-7.18(m，3H)，7.07-6.85(m，4H)，4.45(s，2H)，3.16(t，4H)，2.45(t，4H)，2.22(s，3H)。 1 H NMR (DMSO-d6, 400MHz): δ12.28 (s, 1H), 10.78 (s, 1H), 7.78-7.72 (m, 3H), 7.43-7. 18(m, 3H), 7.07-6.85(m, 4H), 4.45(s, 2H), 3.16(t, 4H), 2.45(t, 4H), 2.22(s, 3H).

实施例16Example 16

本实施例提供了4-{3-[(8-甲酰胺基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)甲基]苯基}苯甲酸。其结构式如式(19)所示，制备方法具体如下，具体见表3。
This embodiment provides 4-{3-[(8-formamido-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)methyl]phenyl}benzoic acid. Its structural formula is shown in formula (19). The specific preparation method is as follows, as shown in Table 3.

(1)制备3’-甲基-[1,1’-联苯]-4-甲酸甲酯(16A)，其结构式如式(68)所示。(1) Prepare 3'-methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16A), the structural formula of which is shown in formula (68).

向100mL圆底烧瓶中加入3-碘代甲苯(5.0g，22.9mmol)、4-硼酸苯甲酸甲酯(4.95g，27.5mmol)、碳酸钾(9.51g，68.8mmol)，分别加入50mL1,4-二氧六环和10mL水搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(1.68g，2.29mmol)，在氮气保护下升温至90℃，并反应2h。反应完成后加水稀释，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到黄色固体——3’-甲基-[1,1’-联苯]-4-甲酸甲酯(16A)(产量4.9g，产率94％)。3-iodotoluene (5.0 g, 22.9 mmol), methyl 4-boronic acid benzoate (4.95 g, 27.5 mmol), potassium carbonate (9.51 g, 68.8 mmol) were added to a 100 mL round-bottom flask, and 50 mL of 1,4-dioxane and 10 mL of water were added and stirred to dissolve. Then [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (1.68 g, 2.29 mmol) was added to the solution, and the temperature was raised to 90 ° C under nitrogen protection, and the reaction was carried out for 2 h. After the reaction was completed, it was diluted with water, extracted with EA, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by silica gel column chromatography to obtain a yellow solid - 3'-methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16A) (yield 4.9 g, yield 94%).

(2)制备3’-溴代甲基-[1,1’-联苯]-4-甲酸甲酯(16B)，其结构式如式(69)所示。(2) Prepare 3'-bromomethyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16B), the structural formula of which is shown in formula (69).

向100mL圆底烧瓶中加入3’-甲基-[1,1’-联苯]-4-甲酸甲酯(16A)(4.8g，21.2mmol)、NBS试剂(4.15g，23.3mmol)，加入60mL四氯化碳，然后向溶液中加入过氧化二苯甲酰(0.51mg，2.12mmol)，升温至80℃并反应12h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到白色固体——3’-溴代甲基-[1,1’-联苯]-4-甲酸甲酯(16B)(产量4.6g，产率89％)。 3'-Methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16A) (4.8 g, 21.2 mmol), NBS reagent (4.15 g, 23.3 mmol) were added to a 100 mL round-bottom flask, and 60 mL of carbon tetrachloride was added, and then dibenzoyl peroxide (0.51 mg, 2.12 mmol) was added to the solution, and the temperature was raised to 80°C and reacted for 12 hours. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid - 3'-bromomethyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16B) (yield 4.6 g, yield 89%).

(3)制备3’-[(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)]甲基-[1,1’-联苯]-4-甲酸甲酯(16C)，其结构式如式(70)所示。(3) Preparation of 3'-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)]methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16C), the structural formula of which is shown in formula (70).

向100mL圆底烧瓶中加入3’-溴代甲基-[1,1’-联苯]-4-甲酸甲酯(16B)(4.5g，14.8mmol)、联硼酸频那醇酯(4.49g，17.7mmol)、醋酸钾(4.34g，44.2mmol)、Pd(dppf)Cl2(催化剂)(1.08g,1.47mmol)，加入90mL 1,4-二氧六环搅拌溶解，在氮气保护下升温至80℃，并反应2h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到白色固体——3’-[(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)]甲基-[1,1’-联苯]-4-甲酸甲酯(16C)(产量2.8g，产率53％)。3'-Bromomethyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16B) (4.5 g, 14.8 mmol), biboronic acid pinacol ester (4.49 g, 17.7 mmol), potassium acetate (4.34 g, 44.2 mmol), Pd(dppf)Cl 2 (catalyst) (1.08 g, 1.47 mmol) were added to a 100 mL round-bottom flask, and 90 mL of 1,4-dioxane was added and stirred to dissolve, and the mixture was heated to 80°C under nitrogen protection and reacted for 2 h. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a white solid - 3'-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)]methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16C) (yield 2.8 g, yield 53%).

然后以3’-[(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)]甲基-[1,1’-联苯]-4-甲酸甲酯(16C)(405mg，1.15mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到黄色固体——4-{3-[(8-甲酰胺基-7-羟基-6-氧代-5H-1,5-萘啶-2-基)甲基]苯基}苯甲酸(产量9.87mg，总收率2.07％)。Then, using 3'-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)]methyl-[1,1'-biphenyl]-4-carboxylic acid methyl ester (16C) (405 mg, 1.15 mmol) as raw material, a yellow solid - 4-{3-[(8-formamido-7-hydroxy-6-oxo-5H-1,5-naphthyridin-2-yl)methyl]phenyl}benzoic acid (yield 9.87 mg, total yield 2.07%) was prepared according to a method similar to steps (8)-(10) of Example 4.

检测结果如下：The test results are as follows:

MS(ESI)m/z＝416.2[M+H]+。MS (ESI) m/z = 416.2 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ11.95(s，1H)，10.72(s，1H)，9.96(s，1H)，8.72(s，1H)，8.03-8.01(m，2H)，7.82-7.21(m，9H)，4.31(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ11.95 (s, 1H), 10.72 (s, 1H), 9.96 (s, 1H), 8.72 (s, 1H), 8.03-8.01 (m, 2H), 7.82-7.21 (m, 9H), 4.31 (s, 2H).

实施例17Embodiment 17

本实施例提供了3-羟基-2-氧代-6-({3-[(4-羟基苯基)甲基]苯基}甲基)-1H-1,5-萘啶-4-甲酰胺。其结构式如式(20)所示，制备方法具体如下，具体见表3。
This embodiment provides 3-hydroxy-2-oxo-6-({3-[(4-hydroxyphenyl)methyl]phenyl}methyl)-1H-1,5-naphthyridine-4-carboxamide. Its structural formula is shown in formula (20), and its preparation method is as follows, as shown in Table 3.

(1)制备[3-(4-甲氧基苄基)苯基]甲醇(17A)，其结构式如式(71)所示。(1) Preparation of [3-(4-methoxybenzyl)phenyl]methanol (17A), the structural formula of which is shown in formula (71).

向100mL圆底烧瓶中加入(3-溴苯基)甲醇(2.5g，13.3mmol)、4-甲氧基苄基硼酸频哪醇酯(3.98g，16.0mmol)、碳酸钾(5.54g，40.1mmol)，分别加入50mL1,4-二氧六环和10mL水，搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(978mg，1.34mmol)，在氮气保护下升温至90℃，并反应12h。反应完成后加水稀释，用EA萃取，并用饱和食盐水洗涤有机相，无水硫酸钠干燥有机相后浓缩。将粗产品通过硅胶柱层析纯化得到黄色油状物——[3-(4-甲氧基苄基)苯基]甲醇(17A)(产量1.60g，产率52％)。To a 100 mL round-bottom flask, add (3-bromophenyl)methanol (2.5 g, 13.3 mmol), 4-methoxybenzylboronic acid pinacol ester (3.98 g, 16.0 mmol), potassium carbonate (5.54 g, 40.1 mmol), add 50 mL of 1,4-dioxane and 10 mL of water, respectively, and stir to dissolve. Then add [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (978 mg, 1.34 mmol) to the solution, heat to 90 ° C under nitrogen protection, and react for 12 h. After the reaction is completed, dilute with water, extract with EA, wash the organic phase with saturated brine, dry the organic phase with anhydrous sodium sulfate, and concentrate. The crude product is purified by silica gel column chromatography to obtain a yellow oily substance, [3-(4-methoxybenzyl)phenyl]methanol (17A) (yield 1.60 g, yield 52%).

(2)制备1-[3-(4-甲氧基苄基)]溴化苄(17B)，其结构式如式(72)所示。(2) Preparation of 1-[3-(4-methoxybenzyl)]benzyl bromide (17B), the structural formula of which is shown in formula (72).

向100mL圆底烧瓶中加入三苯基膦(2.59g，9.86mmol)，加入50mLTHF搅拌溶解，在冰水浴下缓慢加入四溴化碳(3.27g，9.86mmol)、[3-(4-甲氧基苄基)苯基]甲醇(17A)(1.50g，6.57mmol)溶于10mL THF中，在冰水浴下缓慢滴加至上述溶液中，滴毕室温反应2h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——1-[3-(4-甲氧基苄基)]溴化苄(17B)(产量1.70g，产率89％)。Triphenylphosphine (2.59 g, 9.86 mmol) was added to a 100 mL round-bottom flask, and 50 mL of THF was added and stirred to dissolve. Carbon tetrabromide (3.27 g, 9.86 mmol) and [3-(4-methoxybenzyl)phenyl]methanol (17A) (1.50 g, 6.57 mmol) were slowly added to the above solution under an ice-water bath, and the mixture was slowly added dropwise to the above solution under an ice-water bath. After the addition, the mixture was reacted at room temperature for 2 h. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow oily substance, 1-[3-(4-methoxybenzyl)]benzyl bromide (17B) (yield 1.70 g, yield 89%).

(3)制备2-[3-(4-甲氧基苄基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(17C)，其结构式如式(73)所示。(3) Prepare 2-[3-(4-methoxybenzyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17C), the structural formula of which is shown in formula (73).

向100mL圆底烧瓶中加入1-[3-(4-甲氧基苄基)]溴化苄(17B)(1.6g，5.49mmol)、联硼酸频那醇酯(1.67g，6.59mmol)、醋酸钾(1.62g，16.5mmol)，加入30mL1,4-二氧六环搅拌溶解。然后向溶液中加入[1,1'-双(二苯基膦)二茂铁]二氯化钯(402mg，0.55mmol)，在氮气保护下升温至80℃，并反应12h。反应结束后过滤收集滤液并浓缩，将粗产品通过硅胶柱层析纯化得到黄色油状物——2-[3-(4-甲氧基苄基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(17C)(产量1.60g，产率86％)。1-[3-(4-methoxybenzyl)]benzyl bromide (17B) (1.6 g, 5.49 mmol), bipyraclostrobin (1.67 g, 6.59 mmol), potassium acetate (1.62 g, 16.5 mmol) were added to a 100 mL round-bottom flask, and 30 mL of 1,4-dioxane was added and stirred to dissolve. Then [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (402 mg, 0.55 mmol) was added to the solution, and the temperature was raised to 80°C under nitrogen protection, and the reaction was carried out for 12 hours. After the reaction was completed, the filtrate was collected by filtration and concentrated, and the crude product was purified by silica gel column chromatography to obtain a yellow oily substance - 2-[3-(4-methoxybenzyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (17C) (yield 1.60 g, yield 86%).

然后以2-[3-(4-甲氧基苄基)苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼烷(17C)(366mg，1.08mmol)为原料，按照类似于实施例4步骤(8)-(10)的方法制备得到黄色固体——3-羟基-2-氧代-6-({3-[(4-羟基苯基)甲基]苯基}甲基)-1H-1,5-萘啶-4-甲酰胺(产量22.2mg，总收率5.1％)。Then, using 2-[3-(4-methoxybenzyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (17C) (366 mg, 1.08 mmol) as raw material, a yellow solid, 3-hydroxy-2-oxo-6-({3-[(4-hydroxyphenyl)methyl]phenyl}methyl)-1H-1,5-naphthyridine-4-carboxamide, was prepared in a manner similar to steps (8)-(10) of Example 4 (yield 22.2 mg, total yield 5.1%).

检测结果如下：The test results are as follows:

MS(ESI)m/z＝402.2[M+H]+。MS (ESI) m/z = 402.2 [M+H] + .

1H NMR(DMSO-d6，400MHz)：δ12.03(br，1H)，10.73(s，1H)，9.17(s，1H)，7.78-7.61(m，3H)，7.34-6.99(m，7H)，6.65-6.63(m，2H)，4.16(s，2H)，3.78(s，2H)。 1 H NMR (DMSO-d6, 400MHz): δ12.03 (br, 1H), 10.73 (s, 1H), 9.17 (s, 1H), 7.78-7 .61 (m, 3H), 7.34-6.99 (m, 7H), 6.65-6.63 (m, 2H), 4.16 (s, 2H), 3.78 (s, 2H).

以下具体描述了上述环状α-羟基酰亚胺化合物进行生物学试验的结果，以进一步阐述本申请的技术方案。The results of biological tests on the cyclic α-hydroxyimide compounds are described in detail below to further illustrate the technical solution of the present application.

检测试验一Test 1

试验对象为本申请实施例1-17提供的环状α-羟基酰亚胺化合物，试验类型为检测上述化合物对FEN-1的抑制能力。 The test subjects are the cyclic α-hydroxyimide compounds provided in Examples 1-17 of the present application, and the test type is to detect the inhibitory ability of the above compounds on FEN-1.

具体如下：The details are as follows:

(1)试验方法(1) Test method

A.野生型人源FEN-1蛋白的表达纯化A. Expression and purification of wild-type human FEN-1 protein

利用大肠杆菌E.coli BL21(DE3)表达系统(Vazyme BL21(DE3)competent cells)构建野生型人源FEN-1蛋白表达系统，并通过大肠杆菌E.coli BL21(DE3)表达系统获得纯化后的FEN-1蛋白。其中，FEN-1质粒由Genscript合成(UniProt Entry:P39748)。The wild-type human FEN-1 protein expression system was constructed using the E. coli BL21 (DE3) expression system (Vazyme BL21 (DE3) competent cells), and the purified FEN-1 protein was obtained through the E. coli BL21 (DE3) expression system. The FEN-1 plasmid was synthesized by Genscript (UniProt Entry: P39748).

B.基于荧光信号的FEN-1酶活性检测体系的构建B. Construction of FEN-1 enzyme activity detection system based on fluorescence signal

含HBV序列的DNA底物的构建：具有HBV的r序列5’-flap结构的DNA底物，同时连接荧光产生基团和荧光淬灭基团结构，由“flap”、“quencher”和“template”寡核苷酸序列经退火制备而成(F为5-TAMRA荧光基团，Q代表BHQ荧光淬灭基团)。各序列具体如表6所示。Construction of DNA substrate containing HBV sequence: DNA substrate with HBV r sequence 5'-flap structure, connected with fluorescence generating group and fluorescence quenching group structure, prepared by annealing "flap", "quencher" and "template" oligonucleotide sequences (F is 5-TAMRA fluorescence group, Q represents BHQ fluorescence quenching group). The specific sequences are shown in Table 6.

表6含HBV序列的DNA底物的构建
Table 6 Construction of DNA substrate containing HBV sequence

退火程序如下：95℃，5min；然后冷却至25℃。The annealing program was as follows: 95°C, 5 min; then cooled to 25°C.

退火得到的DNA底物与上述纯化后获得的FEN-1蛋白(100nM)共孵育，FEN-1剪切下F片段因为与Q片段分离而发出荧光，因此可以通过增加的荧光强度来表示FEN-1对“flap”的切割活性。在此体系中加入不同浓度梯度的待检测化合物(实施例1-17提供的化合物)，通过荧光检测设备收集荧光变化数据。抑制率和IC50(半数抑制浓度)的计算公式如下：The annealed DNA substrate was co-incubated with the purified FEN-1 protein (100 nM). The F fragment cleaved by FEN-1 emits fluorescence because it is separated from the Q fragment. Therefore, the increased fluorescence intensity can be used to indicate the cleavage activity of FEN-1 on the "flap". Different concentration gradients of the compounds to be tested (compounds provided in Examples 1-17) were added to this system, and the fluorescence change data were collected by a fluorescence detection device. The calculation formulas for the inhibition rate and IC 50 (half-maximal inhibitory concentration) are as follows:

抑制率和IC50计算公式如下：

IC50of the compound is calculated by XL fit software-Fit models(205)。The inhibition rate and IC50 calculation formula are as follows:

IC 50 of the compound is calculated by XL fit software-Fit models(205).

(2)检测结果(2) Test results

检测结果如表7所示。IC50(半数抑制浓度)能指示待检测化合物在抑制FEN-1蛋白的半量时的浓度；抑制能力越强，该浓度越低；The test results are shown in Table 7. IC 50 (half-maximal inhibitory concentration) indicates the concentration of the test compound at half the amount of FEN-1 protein inhibition; the stronger the inhibitory ability, the lower the concentration;

表7实施例1-17提供的环状α-羟基酰亚胺化合物抑制FEN-1的活性数据

Table 7 Activity data of cyclic α-hydroxyimide compounds provided in Examples 1-17 for inhibiting FEN-1

由表7可知，本申请提供的环状α-羟基酰亚胺化合物能够有效抑制FEN-1蛋白的活性。It can be seen from Table 7 that the cyclic α-hydroxyimide compound provided by the present application can effectively inhibit the activity of FEN-1 protein.

检测试验二Test 2

试验对象为本申请实施例13提供的环状α-羟基酰亚胺化合物，试验类型为检测该化合物在PHH细胞(人原代肝细胞)上的功能性试验，来评价本申请提供的化合物的体外抗HBV药效。The test subject is the cyclic α-hydroxyimide compound provided in Example 13 of the present application, and the test type is a functional test to detect the compound on PHH cells (primary human hepatocytes) to evaluate the in vitro anti-HBV efficacy of the compound provided in the present application.

试验方法具体如下：The test method is as follows:

(1)试验方法(1) Test method

第0天，复苏冻存的PHH细胞，调整密度6×105个细胞/ml，将PHH细胞铺种到24孔板中，每孔0.45ml。On day 0, thawed frozen PHH cells, adjusted the density to 6×10 5 cells/ml, and plated PHH cells into 24-well plates, with 0.45 ml per well.

第1天，加入D型HBV感染PHH细胞。On day 1, HBV subtype D was added to infect PHH cells.

第2天，开始加入化合物处理PHH细胞。On day 2, compounds were added to treat PHH cells.

测试化合物起始浓度50μM，4倍稀释，5个浓度，双复孔，参考化合物GLS4(乙肝新药)起始浓度5μM，4倍稀释，5个浓度，双复孔。每隔2天更换一次含化合物的新鲜培养基。培养基中DMSO(二甲基亚砜)的终浓度为2％。The test compound had a starting concentration of 50 μM, 4-fold dilution, 5 concentrations, and duplicate wells. The reference compound GLS4 (a new drug for hepatitis B) had a starting concentration of 5 μM, 4-fold dilution, 5 concentrations, and duplicate wells. The fresh medium containing the compound was replaced every 2 days. The final concentration of DMSO (dimethyl sulfoxide) in the medium was 2%.

第8天，24孔板收集PHH细胞上清，用ELISA法检测PHH细胞上清中的HBeAg(乙型肝炎e抗原)，通过荧光检测设备收集荧光变化数据。On the 8th day, the supernatant of PHH cells was collected in a 24-well plate, and HBeAg (hepatitis B e antigen) in the supernatant of PHH cells was detected by ELISA, and the fluorescence change data was collected by a fluorescence detection device.

利用CCK-8法测定PHH细胞活力。收集PHH细胞，提取PHH细胞内Hirt DNA，利用Southern blot检测cccDNA(2个复孔合并作为一个孔进行试验)。The viability of PHH cells was determined using the CCK-8 method. PHH cells were collected, Hirt DNA in PHH cells was extracted, and cccDNA was detected using Southern blot (two replicate wells were combined as one well for the test).

(2)检测结果(2) Test results

抑制活性数据如表8所示。其中，EC50(半致死效应浓度)能指示待检测化合物在引起50％PHH细胞死亡或中毒或病变的浓度；该浓度越高，表明待检测化合物对PHH细胞越安全。CC50(半数抑制浓度)能指示待检测化合物在引起50％PHH细胞死亡或中毒或病变的浓度；抑制能力越强，该浓度越低。 The inhibitory activity data are shown in Table 8. Among them, EC 50 (half lethal effect concentration) can indicate the concentration of the compound to be tested that causes 50% PHH cell death, poisoning or pathology; the higher the concentration, the safer the compound to be tested is for PHH cells. CC 50 (half inhibitory concentration) can indicate the concentration of the compound to be tested that causes 50% PHH cell death, poisoning or pathology; the stronger the inhibitory ability, the lower the concentration.

表8实施例13对HBeAg的抑制活性数据
Table 8 Inhibitory activity data of Example 13 on HBeAg

待检测化合物在第8天对HbeAg的抑制率如图3所示。Southern blot检测cccDNA的检测结果如图4所示。The inhibition rate of HbeAg by the tested compounds on day 8 is shown in FIG3 . The results of Southern blot detection of cccDNA are shown in FIG4 .

由图3、图4和表8可知，本申请实施例13提供的化合物不仅能够在PHH细胞上显著降低HBeAg的产生外，还能够有抑制cccDNA的形成，显示出治愈乙型肝炎的潜力。As can be seen from Figures 3, 4 and Table 8, the compound provided in Example 13 of the present application can not only significantly reduce the production of HBeAg in PHH cells, but also inhibit the formation of cccDNA, showing the potential to cure hepatitis B.

本具体实施例仅仅是对本申请的解释，其并不是对本申请的限制，本领域技术人员在阅读完本说明书后可以根据需要对本实施例做出没有创造性贡献的修改，但只要在本申请的权利要求范围内都受到专利法的保护。 This specific embodiment is merely an explanation of the present application and is not a limitation of the present application. After reading this specification, those skilled in the art may make modifications to the present embodiment without any creative contribution as needed, but such modifications are protected by the patent law as long as they are within the scope of the claims of the present application.

Claims (10)

一种环状α-羟基酰亚胺化合物，其特征在于，所述环状α-羟基酰亚胺化合物的结构通式以下：
A cyclic α-hydroxyimide compound, characterized in that the cyclic α-hydroxyimide compound has the following general structural formula:
所述结构通式中，R1是氢、C1-6烷基、C3-7环烷基、C3-7杂环烷基、芳基或杂芳基取代的C1-6烷基中的任一种；In the general structural formula, R1 is any one of hydrogen, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, aryl or heteroaryl-substituted C1-6 alkyl; R2是氢、氘、C1-6烷基、C3-7环烷基、C3-7杂环烷基、C1-6烷氧基、C1-6烷基氨基、任选取代的芳基或任选取代的杂芳基中的任一种； R2 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl; X是CH、N中的任一种；X is any of CH and N; Y是氢、氘、卤素、羟基、氨基、氰基、如式(2)所示的基团中的任一种；
Y is any one of hydrogen, deuterium, halogen, hydroxyl, amino, cyano, and a group as shown in formula (2);
所述式(1)中，R3是氢、羟基、氨基、C1-6烷氧基、C1-6烷基氨基中的任一种。In the formula (1), R 3 is any one of hydrogen, hydroxy, amino, C 1-6 alkoxy, and C 1-6 alkylamino. 根据权利要求1所述的环状α-羟基酰亚胺化合物，其特征在于，所述环状α-羟基酰亚胺化合物的结构式为式(2)或式(3)所示：
The cyclic α-hydroxyimide compound according to claim 1, characterized in that the structural formula of the cyclic α-hydroxyimide compound is shown in formula (2) or formula (3):
R4是氢、氘、C1-6烷基、C3-7环烷基、C3-7杂环烷基、C1-6烷氧基、C1-6烷基氨基、任选取代的芳基或任选取代的杂芳基中的任一种； R4 is any of hydrogen, deuterium, C1-6 alkyl, C3-7 cycloalkyl, C3-7 heterocycloalkyl, C1-6 alkoxy, C1-6 alkylamino, optionally substituted aryl or optionally substituted heteroaryl; Z是CH2、NH、O、S中的任一种。Z is any one of CH 2 , NH, O and S. 根据权利要求1所述的环状α-羟基酰亚胺化合物，其特征在于，The cyclic α-hydroxyimide compound according to claim 1, characterized in that 所述结构通式中，R1是芳基或杂芳基取代的C1-6烷基；In the general structural formula, R 1 is a C 1-6 alkyl substituted with an aryl or heteroaryl group; R2是任选取代的芳基或任选取代的杂芳基； R2 is optionally substituted aryl or optionally substituted heteroaryl; X是CH、N中的任一种；X is any of CH and N; Y如式(1)所示的基团；所述式(1)中，R3是氨基或C1-6烷氧基； Y is a group represented by formula (1); in formula (1), R 3 is an amino group or a C 1-6 alkoxy group; Z是CH2。Z is CH2 . 根据权利要求1所述的环状α-羟基酰亚胺化合物，其特征在于，所述环状α-羟基酰亚胺化合物的结构式为式(4)-式(20)中的任意一种：

The cyclic α-hydroxyimide compound according to claim 1, characterized in that the structural formula of the cyclic α-hydroxyimide compound is any one of formula (4) to formula (20):

一种权利要求1-4中任一项所述的环状α-羟基酰亚胺化合物在制备用于预防和治疗乙型肝炎病毒感染的药物中的应用。A use of the cyclic α-hydroxyimide compound according to any one of claims 1 to 4 in the preparation of a medicament for preventing and treating hepatitis B virus infection. 一种组合物，其特征在于，所述组合物包括权利要求1-4中任一项所述的环状α-羟基酰亚胺化合物；A composition, characterized in that the composition comprises the cyclic α-hydroxyimide compound according to any one of claims 1 to 4; 优选地，所述组合物为一种制剂；所述制剂还包括药学上可接受的盐；Preferably, the composition is a preparation; the preparation further comprises a pharmaceutically acceptable salt; 优选地，所述药学上可接受的盐包括酸加成盐和碱加成盐。Preferably, the pharmaceutically acceptable salts include acid addition salts and base addition salts. 一种溶剂化物，其特征在于，所述溶剂化物为权利要求1-4中任一项所述的环状α-羟基酰亚胺化合物与一个或多个溶剂分子形成的缔合物；优选地，所述溶剂包括水、甲醇、乙醇、异丙醇、乙酸乙酯、四氢呋喃、N,N-二甲基甲酰胺、二甲亚砜中的任意一种或多种。A solvate, characterized in that the solvate is an association complex formed by the cyclic α-hydroxyimide compound according to any one of claims 1 to 4 and one or more solvent molecules; preferably, the solvent includes any one or more of water, methanol, ethanol, isopropanol, ethyl acetate, tetrahydrofuran, N,N-dimethylformamide, and dimethyl sulfoxide. 一种异构体，其特征在于，所述异构体为权利要求1-4中任一项所述的环状α-羟基酰亚胺化合物的异构体；优选地，所述异构体包括立体异构体、互变异构体、顺反异构体。An isomer, characterized in that the isomer is an isomer of the cyclic α-hydroxyimide compound according to any one of claims 1 to 4; preferably, the isomer includes stereoisomers, tautomers, and cis-trans isomers. 一种同位素衍生物，其特征在于，所述同位素衍生物为权利要求1-4中任一项所述的环状α-羟基酰亚胺化合物中的氢原子被1-6个氘原子所取代或碳原子被1-3个碳14原子所取代得到的同位素衍生物。 An isotope derivative, characterized in that the isotope derivative is an isotope derivative obtained by replacing the hydrogen atoms in the cyclic α-hydroxyimide compound according to any one of claims 1 to 4 with 1 to 6 deuterium atoms or replacing the carbon atoms with 1 to 3 carbon 14 atoms. 一种前药，其特征在于，所述前药为权利要求1-4中任一项所述的环状α-羟基酰亚胺化合物的化学衍生物。 A prodrug, characterized in that the prodrug is a chemical derivative of the cyclic α-hydroxyimide compound according to any one of claims 1 to 4.
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