HBV inhibitors and uses thereof

Abstract

The present application provides anti-HBV compounds, pharmaceutically acceptable compounds or stereoisomers thereof, as well as methods of making and uses thereof for treating, eradicating or suppressing HBV infection or for slowing liver damage caused by HBV infection, etc.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202080091985.7 (application date: January 20, 2020), the full text of which is incorporated herein by reference. Technical Field

[0002] This application relates to antiviral compounds, and more specifically, to anti-HBV compounds, pharmaceutically acceptable compounds or stereoisomers thereof, methods for their preparation, and their use in treating, eradicating or inhibiting HBV infection or in alleviating liver damage caused by HBV infection. Background Technology

[0003] Hepatitis B (HBV) is a major threat to human health. It is caused by the hepatitis B virus (HBV), primarily affecting the liver and potentially causing damage to multiple organs. HBV is a DNA virus belonging to the hepatoviridae family. HBV is widespread globally, infecting approximately 250 million people worldwide, mainly affecting children and young adults. A significant proportion of these patients develop cirrhosis or liver cancer. Therefore, it has become a serious global disease threatening human health.

[0004] Currently available antiviral nucleoside (acid) drugs for hepatitis B include lamivudine, telbivudine, entecavir, tenofovir disoproxil fumarate, and clavidine. These drugs have several drawbacks, such as inconsistent treatment duration, susceptibility to viral resistance, and a high risk of relapse after discontinuation.

[0005] Furthermore, during hepatitis B virus (HBV) replication, viral DNA enters the host cell nucleus. Under the action of DNA polymerase, the gaps in both strands are filled, forming a supercoiled, covalently closed circular DNA molecule (cccDNA). Extracellular HBV DNA is a relaxed circular DNA (rcDNA) molecule. cccDNA serves as the original template for HBV pregenomic RNA replication. Although its content is relatively low, with only about 5–50 copies per hepatocyte, it is crucial for HBV replication and the establishment of an infectious state. Only by clearing cccDNA from the cell nucleus can the HBV carrier state be completely eliminated, which is the goal of antiviral therapy.

[0006] Unlike nucleoside analogs targeting polymerases, capsid protein inhibitors can reduce the latent form of hepatitis B virus, namely cccDNA. Currently, several publications have reported on the targets of capsid protein inhibitors. For example, patents WO 2015 / 011281, WO 2017 / 156255, WO 2018 / 039531, WO 2018 / 121689, WO 2019 / 165374, WO 2019 / 154343, WO 2019 / 118358, and WO 2019 / 185016 report some capsid protein inhibitors.

[0007] However, the inhibitory activity and cytotoxicity related to drug safety reported by existing technologies vary widely, making it difficult to predict the structural formulas of compounds with good drug efficacy. Based on long-term research experience, the inventors have obtained a series of new anti-HBV compounds. Surprisingly, many of these compounds, whose structures are not obvious, exhibit excellent efficacy and show great promise for drug development. Summary of the Invention

[0008] This invention provides compounds represented by general formula I or general formula II, or pharmaceutically acceptable salts or tautomers or enantiomers or diastereomers thereof:

[0009]

[0010] in:

[0011] X is selected from N or CR3;

[0012] Y is selected from N or CR4;

[0013] Q is selected from O and S;

[0014] W is selected from O, S, NR5;

[0015] R1 is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl;

[0016] R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 saturated or unsaturated heterocycles containing N, O, and S heteroatoms, and aryl.

[0017] Each time R2 appears, it is optionally substituted by one or more substituents selected from the group consisting of: halogen, hydroxyl, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C3 alkoxy, C3-C8 saturated or unsaturated heterocycles containing N, O, or S heteroatoms, aryl, CF3, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)2R, -S(O)2N(R)2, -N(R)C(O)R;

[0018] R3 and R4 are each independently selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl;

[0019] R5 is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, hydroxyl-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl, halogen-substituted C1-C6 alkyl, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)2R, -S(O)2N(R)2; wherein, when B is a monocyclic ring, R5 is not H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl;

[0020] R is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, C1-C3 alkoxy-substituted C1-C6 alkyl.

[0021] Ring A and ring B are each independently selected from 5-12 substituted or unsubstituted monocyclic or bicyclic cyclic rings. The monocyclic or bicyclic cyclic rings are saturated monocyclic or bicyclic cyclic rings, partially unsaturated monocyclic or bicyclic cyclic rings, or aromatic monocyclic or bicyclic cyclic rings. The cyclic carbon atom on the monocyclic or bicyclic cyclic ring is substituted by 0 to 5 heteroatoms, where the heteroatoms refer to O, N, or S.

[0022] In a first aspect, a novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, is characterized in that ring A or ring B is independently selected from:

[0023]

[0024] in:

[0025] m is selected from 0, 1, or 2;

[0026] X1, X2, X3, X4, X5, X6, X7, X8, and X9 are each independently selected from either CR6 or N;

[0027] R6 is selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, aryl, heteroaryl, nitro, cyano, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)2R, -S(O)2N(R)2, -N(R)C(O)R;

[0028] R7 is selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl.

[0029] Each R is independently selected from: H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl.

[0030] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that ring A or ring B is independently selected from:

[0031]

[0032] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that ring A or ring B is independently selected from:

[0033]

[0034] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that ring A or ring B is independently selected from:

[0035]

[0036] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that...

[0037] X1, X2, X3, X5, X6, X8, and X9 are each independently selected from: CR6;

[0038] X4 and X7 are each independently selected from either CR6 or N.

[0039] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that...

[0040] R6 is selected from: H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, hydroxyl-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, nitro, cyano, -OR, -N(R)2, -SR, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)2R, -S(O)2N(R)2, -N(R)C(O)R;

[0041] R7 is selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl;

[0042] Each R is independently selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl.

[0043] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that...

[0044] R6 is selected from: H, halogen, C1-C6 alkyl, C2-C6 alkynyl, halogen-substituted C1-C6 alkyl;

[0045] R7 is selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl.

[0046] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that...

[0047] X is selected from CR3;

[0048] Y is selected from CR4;

[0049] Q is selected from O and S;

[0050] W is selected from NR5;

[0051] R1 is selected from: H;

[0052] R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 saturated or unsaturated heterocycles containing N, O, and S heteroatoms, and aryl.

[0053] Each time R2 appears, it is optionally substituted by one or more substituents selected from the group consisting of: halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with C1-C3 alkoxy, C3-C8 saturated or unsaturated heterocycles containing N, O, or S heteroatoms, aryl, CF3, -OR, -C(O)OR, -C(O)N(R)2;

[0054] R3 and R4 are each independently selected from: H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl;

[0055] R5 is selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl, -C(O)OR, -C(O)N(R)2, -C(O)R, -S(O)R, -S(O)2R, -S(O)2N(R)2; wherein, when B is a monocyclic ring, R5 is not H, C1-C6 alkyl;

[0056] R is selected from: H, C1-C6 alkyl, C3-C8 cycloalkyl, halogen-substituted C1-C6 alkyl.

[0057] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that...

[0058] R2 is selected from: methyl, ethyl, isopropyl, tert-butyl, cyclopentyl

[0059]

[0060] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that...

[0061] R2 is selected from: tert-butyl, cyclopentyl

[0062]

[0063] A novel structural anti-hepatitis B virus (HBV) inhibitor compound, or its pharmaceutically acceptable salt or stereoisomer, characterized in that it is preferably derived from the following compounds:

[0064]

[0065]

[0066]

[0067]

[0068]

[0069] More preferably, novel structural anti-hepatitis B virus (HBV) inhibitor compounds

[0070] Selected from:

[0071]

[0072] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, a solvent compound thereof or an N-oxide thereof, and a pharmaceutically acceptable excipient.

[0073] Preferably, in the pharmaceutical composition of the second aspect of the invention, the pharmaceutically acceptable excipients are selected from at least one of excipients, diluents, disintegrants, glidants and lubricants, and preferably include dicalcium phosphate, cellulose, compressible sugar, dehydrated dicalcium phosphate, lactose mannitol, microcrystalline cellulose, starch and / or tricalcium phosphate.

[0074] Preferably, the pharmaceutical composition of the second aspect of the present invention further includes one or more antiviral agents, preferably selected from at least one of the following: hepatitis B virus (HBV) polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, assembly regulators, reverse transcriptase inhibitors, and TLR-agonists.

[0075] More preferably, in the pharmaceutical composition of the second aspect of the present invention, the reverse transcriptase inhibitor is selected from at least one of: entecavir, tenofovir, HepDirect-tenofovir, emtricitabine, adefovir, HepDirect-adefovir, acyclovir, ganciclovir, GS-7340 (TAF), besifovir, birinapant (HY-16591), ribavirin, and evavirenz, preferably tenofovir.

[0076] In a third aspect, the present invention provides methods for using the compounds of the first aspect of the invention, pharmaceutically acceptable salts thereof, solvent compounds thereof, or N-oxide compounds thereof in the preparation of medicaments for treating hepatitis B virus (HBV) infection or for preparing medicaments for alleviating liver damage caused by hepatitis B virus (HBV) infection.

[0077] In a fourth aspect, the present invention provides a method for treating, eradicating, reducing, slowing down, or inhibiting hepatitis B virus (HBV) infection or for alleviating liver damage caused by hepatitis B virus (HBV) infection, comprising administering to an individual in need an effective amount of a compound of the first aspect of the present invention, a pharmaceutically acceptable salt thereof, a solvent compound thereof, or an N-oxide compound thereof.

[0078] In a fifth aspect, the present invention provides a method for preparing the compound of the first aspect of the present invention, which includes the following four preparation processes:

[0079] Scheme 1: The synthesis of compounds of general formula I can be carried out as described in Scheme 1. Carboxylic acid IA and amine IB are coupled in the presence of a condensing agent to give intermediate amide IC. Intermediate IC can be given intermediate ID in the presence of Lewis acids such as AlCl3 or LDA, n-butyllithium, or tert-butyllithium. Intermediate ID is hydrolyzed under basic conditions to give intermediate IE. The α-keto acid of intermediate IE is coupled with IF in the presence of a condensing agent to give compounds of general formula I.

[0080]

[0081] Scheme 1: Synthetic route for compounds of general formula I

[0082] Option 2: The synthesis of compounds of general formula I can also be carried out via the two routes described in Option 2.

[0083] a) The carboxylic acid ester IG is first hydrolyzed and then directly coupled with the amine IB under the action of a condensing agent to give the amide intermediate IH. Intermediate IH is subjected to Lewis acids such as AlCl3 or LDA, n-butyllithium, or tert-butyllithium to give intermediate ID. Intermediate ID is selectively hydrolyzed with an inorganic base NaOH to give intermediate IE. The α-keto acid of intermediate IE is coupled with the amine IF under the action of a condensing agent to give the compound of general formula I.

[0084] b) The carboxylic acid ester IG reacts with an alkylmethyleneamine to give intermediate II. Intermediate II is hydrolyzed to give intermediate IJ. The carboxylic acid of intermediate IJ is coupled with amine IB under the action of a condensing agent to give a compound of general formula I.

[0085]

[0086] Scheme 2: Synthetic route for compounds of general formula I

[0087] Scheme 3: The synthesis of compounds of general formula II can be carried out via the route described in Scheme 3. Carboxylic acid ester II-A is synthesized in the presence of Lewis acids such as AlCl3 or LDA, n-butyllithium, or tert-butyllithium to give intermediate II-B. Intermediate II-B is selectively hydrolyzed to the corresponding oxalate II-C. Intermediate II-C is coupled with amine IF in the presence of a condensing agent to give intermediate II-D. Intermediate II-D is further hydrolyzed to give II-E. Intermediate II-E is coupled with an amine in the presence of a condensing agent to give compounds of general formula II.

[0088]

[0089] Scheme 3: Synthetic route for compounds of general formula II

[0090] Scheme 4: The synthesis of compounds of general formula II can also be carried out via the route described in Scheme 4. Carboxylic ester II-A is first hydrolyzed to give the corresponding carboxylic acid intermediate II-F. Intermediate II-F is coupled with an amine in the presence of a condensing agent to give intermediate II-G. Intermediate II-G is synthesized in the presence of Lewis acids such as AlCl3 or LDA, n-butyllithium, or tert-butyllithium to give intermediate II-H. Intermediate II-H is further hydrolyzed to give II-I. Intermediate II-I is coupled with amine IF in the presence of a condensing agent to give compounds of general formula II.

[0091]

[0092] Scheme 4: Synthetic route for compounds of general formula II

[0093] Certain embodiments of the present invention will now be described in detail. The present invention is intended to cover all alternatives, modifications, and equivalents, all of which are included within the scope of the invention as defined in these claims. Those skilled in the art will recognize that many similar or equivalent methods and materials can be used to implement the present invention. The present invention is by no means limited to the methods and materials described herein. In the event that one or more of the incorporated documents, patents, and similar materials differ from or contradict this application (including, but not limited to, defined terminology, application of terminology, described techniques, etc.), the present invention shall prevail.

[0094] Unless otherwise defined, the terms used in this invention have the meanings generally accepted in the art. Furthermore, some of the terms used in this invention are defined as follows:

[0095] The term "comprising" is an open-ended expression, meaning it includes the contents specified in this invention, but does not exclude other aspects.

[0096] The term "patient" as used in this invention can include humans (adults and children) or other animals. In some embodiments, "patient" refers to a human.

[0097] The term "halogen" refers to fluorine, chlorine, bromine, and iodine. Specifically, halogens refer to fluorine, chlorine, and bromine.

[0098] The term "cyano" refers to the -CN group.

[0099] The term "hydroxyl group" refers to the -OH group.

[0100] The term "carbonyl" refers to the group -C(=O)-.

[0101] The term "oxalate group" refers to a group.

[0102] The term "carboxyl group" refers to the group -COOH.

[0103] The term "alkynyl" refers to a group.

[0104] The term "amino" refers to a primary (-NH2), secondary (-NH-), or tertiary amino group.

[0105] "alkyl" refers to a straight-chain or branched saturated aliphatic hydrocarbon group. In this application, the alkyl group is preferably a C1-6 alkyl group, meaning a saturated straight-chain or branched alkyl group comprising 1 to 6 carbon atoms; particularly preferred alkyl groups in this application are C1-4 alkyl groups, meaning saturated straight-chain or branched alkyl groups comprising 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, 1-butyl, 2-butyl, and tert-butyl.

[0106] "Alkoxy" refers to an (alkyl-O-) group. Alkyl groups are defined above. Preferred alkoxy groups are C1-6 alkoxy groups, and particularly preferred alkoxy groups are C1-4 alkoxy groups. The term C1-6 alkoxy includes methoxy, ethoxy, n-propoxy, and isopropoxy groups, etc.

[0107] The term "cycloalkyl" refers to a saturated carbon ring with 3 to 12 carbon atoms, particularly 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0108] "Haloalkyl" or "haloalkoxy" means that the alkyl or alkoxy group is replaced by one or more of the same or different halogen atoms. Examples include, but are not limited to, difluoromethyl, trifluoromethyl, and trifluoromethoxy.

[0109] The term "tautomer" refers to a structural isomer of an organic compound that readily interconverts through a chemical reaction called tautomerization. This reaction typically results in the migration of hydrogen atoms or protons, accompanied by the conversion of single bonds and adjacent double bonds.

[0110] The term "chirality" refers to a molecule that has the property that it cannot be superimposed on its mirror image; while "chirality" refers to a molecule that can be superimposed on its mirror image.

[0111] The term "enantiomer" refers to two non-overlapping but mirror-image isomers of a compound.

[0112] The term "diastereomer" refers to a stereoisomer with two or more chiral centers whose molecules are not mirror images of each other. Diastereomers generally have different physical properties, such as boiling point, melting point, spectral properties, and reactivity.

[0113] As described in this invention, the compounds of this invention may optionally be substituted with one or more substituents, such as the general formula compounds above, the specific compounds of this invention, or the specific examples, subclasses, and classes of compounds included in this invention, as described in the embodiments. It should be understood that the terms "optionally substituted" and "substituted or unsubstituted" are used interchangeably. Generally, the term "substituted" means that one or more hydrogen atoms in the given structure are substituted by a specific substituent. Unless otherwise indicated, an optional substituent may be substituted at any substituted position of the group. When more than one position in the given structural formula can be substituted by one or more substituents selected from a specific group, the substituents may be substituted at the same or different positions. The substituents may be, but are not limited to: fluorine, chlorine, bromine, iodine, methylene. Oxygenation Alkyl, alkoxy, cyano, nitro, alkylamino, mercapto, and amino groups, etc.

[0114] The term "pharmaceutically acceptable salt" refers to certain salts of the aforementioned compounds that retain their original biological activity and are suitable for pharmaceutical use. Pharmaceutically acceptable salts of compounds represented by general formulas I and II can be salts formed with suitable acids, including inorganic and organic acids such as acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, hydroxyethanesulfonic acid, lactic acid, malic acid, maleic acid, mandelic acid, mesylate, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, and p-toluenesulfonic acid.

[0115] For ease of understanding, the present invention will be described in detail below with reference to specific embodiments and accompanying drawings. It should be particularly noted that these descriptions are merely exemplary and do not constitute a limitation on the scope of the invention. Many variations and modifications of the invention will be apparent to those skilled in the art based on the discussion in this specification. Furthermore, the present invention references publicly available documents, which are incorporated herein by reference in their entirety for the purpose of more clearly describing the invention, as if their entirety had been repeated and expressly described herein. Attached Figure Description

[0116] Figure 1This is a graph showing the blood concentrations of compounds 36, 52, 53 and 54 of the present invention, and the control Cpd 7a, administered to rats by gavage (20 mg / kg). Detailed Implementation

[0117] The following reactions are generally performed under positive nitrogen pressure. All reaction flasks are sealed with suitable rubber stoppers, and the substrate is injected using a syringe. All glassware is dried. Silica gel columns are used. NMR data are determined using a Bruker Advance 400 NMR spectrometer, with concentrations of CDCl₃, DMSO-d... 6 Alternatively, CD3OD can be used as the solvent (reported in ppm), with TMS (0 ppm) or chloroform (7.25 ppm) as the reference standard. When multiplets are observed, the following abbreviations are used: s (singlet), s,s (singlet, singlet), d (doublet), t (triplet), m (multiple), br (broadened), dd (doublet of doublets), ddd (doublet of doublets), ddt (doublet of doublets), dddd (doublet of doublets), td (triple doublet), brs (broadened singlet). The coupling constant is expressed in Hertz (Hz).

[0118] Low-resolution mass spectrometry (MS) data were obtained using an Agilent 1100 series LC-MS spectrometer. An ESI source was used in the LC-MS spectrometer.

[0119] Compound purity was evaluated using Agilent 1100 series high-performance liquid chromatography (HPLC), with UV detection at 220 nm and 254 nm, Zorbax SB-C18 column (2.1 x 30 mm, 4 μm), 10 min, flow rate 0.6 mL / min, 5-95% (0.1% formic acid acetonitrile solution) and (0.1% formic acid aqueous solution), and column temperature maintained at 40 °C.

[0120] The following abbreviations are used throughout this invention:

[0121]

[0122]

[0123] Preparation Example:

[0124] The compounds of the present invention can be synthesized using the following synthetic schemes (Schemes 1-4). The methods described are illustrative schemes for easier understanding of the embodiments and do not constitute a limitation on the scope of the present invention.

[0125] Option 1

[0126]

[0127] Option 2

[0128]

[0129] Option 3

[0130]

[0131] Option 4

[0132]

[0133] The present invention will be further described below with reference to embodiments, but these embodiments are not intended to limit the scope of protection of the present invention.

[0134] Examples 1 to 17 are synthesized according to the specific route shown in the diagram below in Scheme 1.

[0135]

[0136] Example 1: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 1)

[0137]

[0138] Step 1a: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-furan (compound I-2)

[0139] 2-Methylfuran-3-carboxylic acid (I-1, 10.1 g, 1.0 eq.) was dissolved in 300 mL of dichloromethane. Triethylamine (24.2 g, 3.0 eq.) and HATU (36.5 g, 1.2 eq.) were added with stirring. After reacting at room temperature for 5 min, 3-chloro-4-fluoroaniline (13.9 g, 1.2 eq.) was added, and the reaction was continued at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was terminated by adding water, and the mixture was washed three times with 30 mL of saturated brine. The organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 12.7 g of the target compound, with a yield of 63%. (ES, m / z): [M+1] + =254.

[0140] Step 1b: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-oxalate ethyl-furan (compound I-3) was dissolved in dichloromethane under nitrogen protection. The reaction solution was cooled to 0°C, and oxaloyl chloride ethyl ester (17.4 g, 4.0 eq.) was added with stirring. The mixture was stirred at 0°C for 30 min. Then, I-2 (8.1 g, 1.0 eq.) was added to the above reaction solution, and the mixture was allowed to return to room temperature for 16 h. The reaction was monitored by TLC until completion. The reaction was quenched with dilute hydrochloric acid, and the mixture was washed with water and saturated brine, respectively. The organic phase was dried and concentrated under reduced pressure. Separation was performed by silica gel column chromatography to obtain 5.0 g of the target compound, with a yield of 44%. (ES, m / z): [M+1] + =354.

[0141] Step 1c: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-oxaloyl-furan (compound I-4)

[0142] I-3 (353 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water. The reaction solution was cooled to 0 °C, and LiOH (84 mg, 2.0 eq.) was added. The reaction was carried out for 5 min, and the reaction was monitored by TLC until completion. The tetrahydrofuran was removed by concentration under reduced pressure. The pH was adjusted to 3 with 1 M dilute hydrochloric acid in an ice bath, and the mixture was extracted twice with 10 times the volume of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly for the next step. (ES, m / z): [M+1] + =326.

[0143] Step 1d: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (compound 1)

[0144] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), tert-butylamine (110 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 90 mg of the target compound as a white solid, with a yield of 24%. (ES, m / z): [M+1] + =381, 1 H-NMR: (400MHz, DMSO-d) 6,ppm): δ10.33(s,1H),8.49(s,1H),8.24(s,1H),8.05(dd,J=6.8,2.4Hz,1H),7. 70(ddd,J=6.8,4.0,2.4Hz,1H),7.42(t,J=9.2Hz,1H),2.70(s,3H),1.38(s,9H).

[0145] Example 2: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-propargylamino-oxalyl)-furan (Compound 2)

[0146]

[0147] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), propargylamine (83 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 109 mg of the target compound as a white solid, with a yield of 30%. (ES, m / z): [M+1] + =363, H-NMR: (300MHz, CDCl3, ppm): δ8.45 (s, 1H), 7.87 (dd, J = 6.6, 2.4Hz, 1H), 7.80 (s, 1H), 7.60 (b, 1H ),7.39(m,1H),7.15(t,J=2.4Hz,1H),4.19(dd,J=5.7,2.4Hz,2H),2.80(s,3H),2.34(t,J=2.4Hz,1H).

[0148] Example 3: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1-methylpropynylamino)-oxaloyl)-furan (Compound 3)

[0149]

[0150] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), 1-methylpropyneamine (104 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 85 mg of the target compound as a pale yellow solid, with a yield of 23%. (ES, m / z): [M+1] +=377, H-NMR: (400MHz, CDCl3, ppm): δ8.43(s,1H),8.88(dd,J=6.4,2.4Hz,1H),7.57(s,1H),7.52(m,1H),7.43(d,J= 3.2Hz,1H),7.17(t,J=8.4Hz,1H),4.84(m,1H),2.83(d,J=12.4Hz,3H),2.38(d,J=2.4Hz,1H),2.34(t,J=6.8Hz,3H).

[0151] Example 4: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1,1-dimethylpropynyl)-oxalyl)-furan (Compound 4)

[0152]

[0153] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1,1-dimethylpropynylamine (124 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.) were added sequentially. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 58 mg of the target compound as a white solid, with a yield of 15%. (ES, m / z): [M+1] + =391, H-NMR: (300MHz, CDCl3, ppm): δ8.50 (s, 1H), 7.88 (dd, J = 6.6, 2.7Hz, 1H), 7.70 (s, 1H), 7.44 (s,1H),7.37(m,1H),7.16(t,J=8.4Hz,1H),2.81(s,3H),2.45(s,1H),1.75(s,3H),1.70(s,3H).

[0154] Example 5: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(2-alkynylbutylamino)-oxalyl)-furan (Compound 5)

[0155]

[0156] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1,1-dimethylpropynylamine (104 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.) were added sequentially. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 74 mg of the target compound as a white solid, with a yield of 20%. (ES, m / z): [M+1] + =377, H-NMR:(400MHz, DMSO-d 6 ,ppm): δ10.33(s,1H),9.35(t,J=5.6Hz,1H),8.59(s,1H),8.05(dd,J=6.8,2.4Hz,1H),7.70( m,1H),7.43(t,J=9.2Hz,1H),3.97(dd,J=5.6,2.4Hz,2H),2.71(s,3H),1.79(t,J=2.4Hz,3H).

[0157] Example 6: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(4-methyl-2-ynylpentanyl)-oxaloyl)-furan (Compound 6)

[0158]

[0159] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 2-(4-methyl-2-ynylpentanylamine) (146 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.) were added sequentially. The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 102 mg of the target compound as a white solid, with a yield of 25%. (ES, m / z): [M+1] + =405, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.33(s,1H),9.33(t,J=5.4Hz,1H),8.58(s,1H),8.05(dd,J=6.9,2.4Hz,1H),7.70(m,1H),7 .42(t,J=9.0Hz,1H),4.00(dd,J=5.7,1.8Hz,2H),2.71(s,3H),2.60(m,1H),1.12(s,3H),1.10(s,3H).

[0160] Example 7: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(3-phenyl-2-ynylpropylamino)-oxalyl)-furan (Compound 7)

[0161]

[0162] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), 3-phenyl-2-ynylpropylamine (196 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 86 mg of the target compound as a white solid, with a yield of 20%. (ES, m / z): [M+1] + =439, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.33(s,1H),9.53(t,J=5.7Hz,1H),8.62(s,1H),8.05(dd,J=6.9 ,2.4Hz,1H),7.70(m,1H),7.42(m,6H),4.29(d,J=5.7Hz,2H),2.72(s,3H).

[0163] Example 8: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1-methyl-imidazol-2-yl)methylamino)-oxalyl)-furan (Compound 8)

[0164]

[0165] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), (1-methyl-imidazol-2-yl)methylamine (166 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) to obtain 16 mg of the target compound as a pale yellow solid, with a yield of 4%. (ES, m / z): [M+1] + =419, H-NMR:(300MHz, DMSO-d 6,ppm): δ10.36(s,1H),9.36(t,J=6.0Hz,1H),8.58(s,1H),8.05(dd,J=6.9,2.4Hz,1H),7.70(m,1H) ,7.46(d,J=9.2Hz,1H),7.09(s,1H),6.80(s,1H),4.47(d,J=5.7Hz,2H),3.89(s,3H),2.71(s,3H).

[0166] Example 9: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-anilino-oxaloyl)-furan (Compound 9)

[0167]

[0168] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), aniline (140 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) to obtain 35 mg of the target compound as a pale yellow solid, with a yield of 9%. (ES, m / z): [M+1] + =401, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.89(s,1H),10.36(s,1H),8.63(s,1H),8.05(dd,J=6.9,2.7Hz,1H),7. 78(d,J=7.8Hz,1H),7.70(m,1H),7.40(m,3H),7.18(t,J=7.2Hz,2H),2.74(s,3H).

[0169] Example 10: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1-allyl-1H-[1,2,3]triazol-4-ylmethylamino)-oxalyl)-furan (Compound 10)

[0170]

[0171] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), 1-allyl-1H-[1,2,3]triazol-4-yl)methylamine (207 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and prepared by high-performance liquid chromatography (HPLC) to give 35 mg of the target compound as a pale yellow solid, with a yield of 8%. (ES, m / z): [M+1] + =446, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.33(s,1H),9.47(d,J=6.0Hz,1H),8.60(s,1H),8.06(dd,J=6.9,2.4Hz,1H),8.04(s,1H),7.71(m,1 H),7.42(t,J=9.0Hz,1H),6.04(m,1H),5.23(m,2H),5.00(d,J=2.7Hz,2H),4.48(d,J=6.0Hz,2H),2.71(s,3H).

[0172] Example 11: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1-cyclopropyl-1H-[1,2,3]triazol-4-ylmethylamino)-oxalyl)-furan (Compound 11)

[0173]

[0174] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), 1-cyclopropyl-1H-[1,2,3]triazol-4-yl)methylamine (207 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) to obtain 5 mg of the target compound as a pale yellow solid, with a yield of 1%. (ES, m / z): [M+1] + =446.H-NMR:(300MHz,DMSO-d 6,ppm): δ10.34(s,1H),9.47(s,1H),8.60(s,1H),8.05(dd,J=6.9,2.4Hz,1H),7.95(s,1H),7.71(m,1 H),7.42(t,J=9.0Hz,2H),6.04(m,1H),5.25(m,2H),5.00(m,2H),4.49(d,J=6.0Hz,2H),2.71(s,3H).

[0175] Example 12: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(thiazol-2-amino)-oxaloyl)-furan (Compound 12)

[0176]

[0177] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), 2-aminothiazole (150 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and purified by high-performance liquid chromatography (HPLC) to obtain 7 mg of the target compound as a pale yellow solid, with a yield of 2%. (ES, m / z): [M+1] + =408.

[0178] Example 13: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(3-methyl-3-oxetane)-oxaloyl)-furan (Compound 13)

[0179]

[0180] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), 3-methyl-3-oxetanediamine (130 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 40 mg of the target compound as a pale yellow solid, with a yield of 10%. (ES, m / z): [M+1] + =395.

[0181] Example 14: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-cyclopentanamino-oxalyl)-furan (14)

[0182]

[0183] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), cyclopentylamine (128 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 36 mg of the target compound as a pale off-white solid, with a yield of 9%. (ES, m / z): [M+1] + =393.

[0184] Example 15: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-((S)-1,1,1-trifluoroprop-2-amino)-oxalyl)-furan (15)

[0185]

[0186] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), (S)-1,1,1-trifluoropropane-2-amine (170 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 53 mg of the target compound as a pale yellow solid, with a yield of 13%. (ES, m / z): [M+1] + =421.

[0187] Example 16: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1-trifluoromethyl-cyclopropylamino)-oxalyl)-furan (16)

[0188]

[0189] Intermediate I-4 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (387 mg, 3.0 eq.), 1-trifluoromethyl-cyclopropylamine (188 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 76 mg of the target compound as a pale yellow solid, with a yield of 18%. (ES, m / z): [M+1] + =433.

[0190] Example 17: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1H-1,2,3-triazol-4-methylamino)-oxalyl)-furan (Compound 17)

[0191]

[0192] Compound 2 (300 mg, 1.0 eq.) was dissolved in 5 mL of acetonitrile. NaN3 (376 mg, 7.0 eq.) was added to the reaction solution, and the mixture was heated to 60 °C for 1 h. After cooling to room temperature, CuSO4 and sodium ascorbate were added, and the mixture was reacted at 80 °C for 1 h. The reaction solution was then injected into saturated NH4Cl. The organic phase was extracted three times with EA, dried, and concentrated under reduced pressure. Separation by silica gel column chromatography yielded 40 mg of the target compound as a white solid, with a yield of 10%. (ES, m / z): [M+1] + =406, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ14.80(b,1H),10.33(s,1H),9.49(b,1H),8.60(s,1H),8.05(dd,J=6.9,2 .7Hz,1H),7.70(m,2H),7.42(t,J=9.0Hz,1H),4.50(d,J=5.4Hz,2H),2.71(s,3H).

[0193] Examples 18 to 28 are synthesized according to the specific route shown in the diagram below in Scheme 1.

[0194]

[0195] Example 18: 2-Methyl-3-amide-N-(4-fluorophenyl)-5-(2-tert-butylamino-oxaloyl)-furan (Compound 18)

[0196]

[0197] Step 18a: 2-Methyl-3-amide-N-(2-fluorophenyl)-furan (Compound I-2-18)

[0198] 2-Methylfuran-3-carboxylic acid (I-1, 3.7 g, 1.0 eq.) was dissolved in 150 mL of DCM. TEA (8.1 mL, 3.0 eq.) and HATU (13.4 g, 1.2 eq.) were added with stirring. The mixture was reacted at room temperature for 15 min, followed by the addition of 4-fluoroaniline (6.5 g, 2.0 eq.). The reaction was allowed to proceed for 2 h at room temperature, and the reaction was confirmed by LCMS. The reaction solution was washed with brine and then with water. The solution was dried, evaporated to dryness, stirred, and passed through a normal-phase column. 5.8 g of the product, a white solid, was obtained. (ES, m / z): [M+1] + =220.

[0199] Step 18b: 2-Methyl-3-amide-N-(2-fluorophenyl)-5-oxalate ethyl-furan (Compound I-3-18)

[0200] Under nitrogen protection, AlCl3 (2.7 g, 4.0 eq.) was dissolved in dichloromethane. The reaction solution was cooled to 0 °C, and oxaloyl chloride (2.7 g, 4.0 eq.) was added with stirring. The mixture was stirred at 0 °C for 30 min. Then, I-2-18 (1.1 g, 1.0 eq.) was added to the above reaction solution, and the mixture was allowed to return to room temperature for 16 h. The reaction was monitored by TLC until completion. The reaction was quenched with dilute hydrochloric acid, and the mixture was washed with water and saturated brine, respectively. The organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 1.1 g of the target compound. (ES, m / z): [M+1] + =320.

[0201] Step 18c: 2-Methyl-3-amide-N-(2-fluorophenyl)-5-oxaloyl-furan (Compound I-4-18)

[0202] I-3-18 (300 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water. The reaction solution was cooled to 0 °C, and LiOH (48 mg, 2.0 eq.) was added. The reaction was carried out for 5 min, and the reaction was monitored by TLC until completion. The tetrahydrofuran was removed by concentration under reduced pressure. The pH was adjusted to 3 with 1 M dilute hydrochloric acid in an ice bath, and the mixture was extracted twice with 10 times the volume of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly in the next step. (ES, m / z): [M+1] + =292.

[0203] Step 18d: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (compound 18)

[0204] Intermediate I-4-18 was dissolved in 5 mL of DMF, followed by the sequential addition of DIPEA (365 mg, 3.0 eq.), tert-butylamine (104 mg, 1.5 eq.), and then HATU (396 mg, 1.1 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 90 mg of the target compound as a white solid. (ES, m / z): [M+1] +=347, H-NMR: (300MHz, CDCl3, ppm): δ8.42 (s, 1H), 7.57 (dt, J = 6.9, 4.2Hz, 2H), 7.50 (s, 1H), 7.09 (t, J = 4.2Hz, 2H), 2.84 (s, 3H), 1.48 (s, 9H).

[0205] Example 19: 2-Methyl-3-amide-N-(3,4-difluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 19)

[0206]

[0207] Following the synthetic route and reaction conditions of Example 18, in step 19a, the starting material was changed to 3,4-difluoroaniline to synthesize compound 19. Overall yield: 15%. (ES, m / z): [M+1] + =365, H-NMR: (400MHz, CDCl3, ppm): δ8.43 (s, 1H), 7.76 (dt, J = 11.2, 7.6Hz, 1H), 7.62 (s, 1H), 7.24 (s, 1H), 7.17 (m, 2H), 2.82 (s, 3H), 1.48 (s, 9H).

[0208] Example 20: 2-Methyl-3-amide-N-(3,4,5-trifluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 20)

[0209]

[0210] Following the synthetic route and reaction conditions of Example 18, in step 20a, the starting material was changed to 3,4,5-trifluoroaniline to synthesize compound 20. Overall yield: 19%. (ES, m / z): [M+1] + =383, H-NMR: (300MHz, CDCl3, ppm): δ8.37 (s, 1H), 8.36 (s, 1H), 7.38 (dd, J = 9.0, 6.0Hz, 2H), 6.84 (m, 1H), 2.82 (s, 3H), 1.48 (s, 9H).

[0211] Example 21: 2-Methyl-3-amide-N-(3-cyano-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 21)

[0212]

[0213] Following the synthetic route and reaction conditions of Example 18, in step 21a, the starting material was changed to 3-cyano-4-fluoroaniline to synthesize compound 21. Overall yield: 11%. (ES, m / z): [M+1] + =372, H-NMR: (400MHz, CDCl3, ppm): δ8.43 (s, 1H), 7.75 (dt, J = 8.4, 4.8Hz, 1H), 7.60 (s, 1H), 7.22 (m, 1H), 7.17 (m, 2H), 2.82 (s, 3H), 1.48 (s, 9H).

[0214] Example 22: 2-Methyl-3-amide-N-(4-trifluoromethylphenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 22)

[0215]

[0216] Following the synthetic route and reaction conditions of Example 18, in step 22a, the starting material was changed to 4-trifluoromethylaniline to synthesize compound 22. Overall yield: 11%. (ES, m / z): [M+1] + =397, H-NMR: (300MHz, CDCl3, ppm): δ8.46 (s, 1H), 7.76 (d, J = 8.4Hz, 1H), 7.65 (d, J = 8.4Hz, 1H), 7.23 (s, 1H), 2.82 (s, 3H), 1.48 (s, 9H).

[0217] Example 23: 2-Methyl-3-amide-N-(3-bromo-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 23)

[0218]

[0219] Following the synthetic route and reaction conditions of Example 18, in step 23a, the starting material was changed to 3-bromo-4-fluoroaniline to synthesize compound 23. Overall yield: 12%. (ES, m / z): [M+1] + =425,427.

[0220] Example 24: 2-Methyl-3-amide-N-(3-iodophenyl)-5-(2-tert-butylamino-oxaloyl)-furan (Compound 24)

[0221]

[0222] Following the synthetic route and reaction conditions of Example 18, in step 24a, the starting material was changed to 3-iodoaniline to synthesize compound 24. Overall yield: 12%. Overall yield: 13%. (ES, m / z): [M+1]+ =455.

[0223] Example 25: 2-Methyl-3-amide-N-(3-trimethylsilylethynyl-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 25)

[0224]

[0225] Compound 23 (681 mg, 1.0 eq.) was dissolved in 15 mL of triethylamine, and trimethylsilylacetylene (441 mg, 3.0 eq.), Ph3P (157 mg, 0.4 eq.), and Pd(OAc)2 (101 mg, 0.3 eq.) were added. The mixture was purged with nitrogen and heated to 100 °C under reflux overnight. The reaction was monitored by LCMS until complete. The reaction solution was filtered, evaporated to dryness, and purified by silica gel column chromatography. 88 mg of the product, a yellow solid, was obtained as compound 25. (ES, m / z): [M+1] + =443.

[0226] Example 26: 2-Methyl-3-amide-N-(3-trimethylsilylethynylphenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 26)

[0227]

[0228] Compound 24 (600 mg, 1.0 eq.) was dissolved in 15 mL of triethylamine, and trimethylsilylacetylene (415 mg, 3.0 eq.), Ph3P (148 mg, 0.4 eq.), and Pd(OAc)2 (94 mg, 0.3 eq.) were added. The mixture was purged with nitrogen and heated to 100 °C under reflux overnight. The reaction was monitored by LCMS until complete. The reaction solution was filtered, evaporated to dryness, and purified by silica gel column chromatography. 67 mg of the product, an off-white solid, was obtained as compound 26. (ES, m / z): [M+1] + =425.

[0229] Example 27: 2-Methyl-3-amide-N-(3-ynyl-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 27)

[0230]

[0231] Compound 25 (85 mg, 1.0 eq.) was dissolved in 5 mL of methanol, and KOH (13 mg, 1.2 eq.) was added. The mixture was reacted overnight at room temperature. The reaction was completed by LCMS, and purified by silica gel column chromatography. A white solid, compound 27, was given. The yield of this step was 14%. (ES, m / z): [M+1] + =419, H-NMR:(300MHz, DMSO-d6 , ppm): δ10.27(s,1H),8.53(s,1H),8.48(s,1H),7.99(m,1H),7.78(m,1H),7.31(t,J=9.0Hz,1H),4.52(s,1H),2.70(s,3H),1.38(s,9H).

[0232] Example 28: 2-Methyl-3-amide-N-(3-alkynylphenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 28)

[0233]

[0234] Compound 26 (67 mg, 1.0 eq.) was dissolved in 5 mL of methanol, and KOH (10 mg, 1.2 eq.) was added. The mixture was reacted overnight at room temperature. The reaction was monitored by LCMS until complete, and the solution was purified by silica gel column chromatography. Compound 28 was given as a white solid. The yield of this step was 17%. (ES, m / z): [M+1] + =353, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.24(s,1H),8.50(s,1H),8.23(s,1H),7.93(s,1H),7.78(d,J=8.1Hz,1H), 7.37(t,J=7.8Hz,1H),7.22(d,J=7.8Hz,1H),4.20(s,1H),2.70(s,3H),1.39(s,9H).

[0235] Examples 29 to 41 are synthesized according to the specific route shown in the diagram below in Scheme 1.

[0236]

[0237] Example 29: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-thiophene (Compound 29)

[0238]

[0239] Step 29a: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-thiophene (Compound I-7-29)

[0240] 2-Methylthiophene-3-carboxylic acid (I-6, 3.3 g, 1.0 eq.) was dissolved in 300 mL of dichloromethane. Triethylamine (7.0 g, 3.0 eq.) and HATU (10.6 g, 1.2 eq.) were added with stirring. After reacting at room temperature for 5 min, 3-chloro-4-fluoroaniline (4.0 g, 1.2 eq.) was added, and the reaction was continued at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was terminated by adding water, and the mixture was washed three times with 30 mL of saturated brine. The organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 1.9 g of the target compound as a white solid, in 30% yield. (ES, m / z): [M+1] + =270.

[0241] Step 29b: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-oxalate ethyl-thiophene (compound I-8-29) was dissolved in dichloromethane under nitrogen protection. The reaction solution was cooled to 0°C, and oxaloyl chloride ethyl ester (1.1 g, 4.0 eq.) was added with stirring. The mixture was stirred at 0°C for 30 min. Then, I-7-29 (538 g, 1.0 eq.) was added to the above reaction solution, and the reaction was allowed to proceed naturally at room temperature for 16 h. The reaction was monitored by TLC until completion. The reaction was quenched with dilute hydrochloric acid, and the mixture was washed with water and saturated brine, respectively. The organic phase was dried and concentrated under reduced pressure. Separation was performed by silica gel column chromatography to obtain 521 mg of the target compound as a pale yellow solid, with a yield of 70%. (ES, m / z): [M+1] + =370.

[0242] Step 29c: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-oxaloyl-thiophene (compound I-9-29) I-8-29 (369 mg, 1.0 eq.) was dissolved in 6 mL tetrahydrofuran and 2 mL water. The reaction solution was cooled to 0 °C, and LiOH (84 mg, 2.0 eq.) was added. The reaction was carried out for 5 min, and the reaction was monitored by TLC until completion. The tetrahydrofuran was removed by concentration under reduced pressure. The pH was adjusted to 3 with 1 M dilute hydrochloric acid in an ice bath. The mixture was extracted twice with 10 times the volume of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly in the next step. (ES, m / z): [M+1] + =341.

[0243] Step 29d: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-thiophene (compound 29)

[0244] Intermediate I-9-29 was dissolved in 5 mL of DMF. DIPEA (387 mg, 3.0 eq.) and tert-butylamine (110 mg, 1.5 eq.) were added sequentially, followed by HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 106 mg of the target compound as a white solid, with a yield of 27%. (ES, m / z): [M+1] + =397, H-NMR: (400MHz, CDCl3, ppm): δ8.56 (s, 1H), 7.86 (dd, J = 8.8, 3.2Hz, 1H), 7.23 (s, 1H), 7.42 (b, 1H), 7.14 (m, 2H), 2.86 (s, 3H), 1.48 (s, 9H).

[0245] Example 30: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-propargylamino-oxalyl)-thiophene (Compound 30)

[0246]

[0247] Following the synthetic route and reaction conditions of Example 29, propyneamine was replaced with a different starting material in step 30d to synthesize compound 30. Overall yield: 25%. (ES, m / z): [M+1] + =379, H-NMR: (300MHz, CDCl3, ppm): δ8.44(s,1H),7.86(dd,J=7.2,3.6Hz,1H),7.80(s,1H),7.61(b,1H ),7.38(m,1H),7.14(t,J=3.2Hz,1H),4.19(dd,J=6.6,3.6Hz,2H),2.80(s,3H),2.33(t,J=3.6Hz,1H).

[0248] Example 31: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(3-methyl-3-oxetane)-oxaloyl)-thiophene (Compound 31)

[0249]

[0250] Following the synthetic route and reaction conditions of Example 29, in step 31d, the starting material was changed to 3-methyl-3-oxetanebutylamine to synthesize compound 31. Overall yield: 25%. Overall yield: 9%. (ES, m / z): [M+1] + =411.

[0251] Example 32: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-cyclopentanamino-oxalyl)-thiophene (Compound 32)

[0252]

[0253] Following the synthetic route and reaction conditions of Example 29, cyclopentylamine was used as the starting material in step 32d to synthesize compound 32. Overall yield: 10%. (ES, m / z): [M+1] + =409.

[0254] Example 33: 2-Methyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-((S)-1,1,1-trifluoroprop-2-amino)-oxalyl)-thiophene (Compound 33)

[0255]

[0256] Following the synthetic route and reaction conditions of Example 29, in step 33d, the starting material was changed to (S)-1,1,1-trifluoropropane-2-amine, resulting in compound 33. Overall yield: 10%. (ES, m / z): [M+1] + =437.

[0257] Example 34: 2-Methyl-3-amide-N-(3,4-difluorophenyl)-5-(2-tert-butylamino-oxaloyl)-thiophene (Compound 34)

[0258]

[0259] Following the synthetic route and reaction conditions of Example 29, in step 34a, the starting amine was replaced with 3,4-difluoroaniline to synthesize compound 34. Overall yield: 17%. (ES, m / z): [M+1] + =381, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.45(s,1H),8.44(s,1H),8.27(s,1H),7.90(m,1H),7.48(m,2H),2.74(s,3H),1.38(s,9H).

[0260] Example 35: 2-Methyl-3-amide-N-(3,4,5-trifluorophenyl)-5-(2-tert-butylamino-oxalyl)-thiophene (Compound 35)

[0261]

[0262] Following the synthetic route and reaction conditions of Example 29, in step 35a, the starting amine was replaced with 3,4,5-trifluoroaniline to synthesize compound 35. Overall yield: 21%. (ES, m / z): [M+1] + =399, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.35(s,1H),8.48(s,1H),8.28(s,1H),7.39(m,2H),2.75(s,3H),1.38(s,9H).

[0263] Example 36: 2,4-Dimethyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-tert-butylamino-oxalyl)-thiophene (Compound 36)

[0264]

[0265] Following the synthetic route and reaction conditions of Example 29, in step 36a, the starting material 2,4-dimethylthiophene-3-carboxylic acid (I-6-36) was replaced to synthesize compound 36. Overall yield: 16%. (ES, m / z): [M+1] + =411, H-NMR: (300MHz, CDCl3, ppm): δ7.90 (dd, J = 6.3, 2.4Hz, 1H), 7.56 (s, 1H), 7. 51(m,1H),7.32(s,1H),7.17(t,J=8.7Hz,1H),2.62(d,J=5.4Hz,3H),1.46(s,9H).

[0266] Example 37: 2,4-Dimethyl-3-amide-N-(3,4-difluorophenyl)-5-(2-(3-methoxymethyl-3-oxetane)-oxaloyl)-thiophene (Compound 37)

[0267]

[0268] Following the synthetic route and reaction conditions of Example 29, in step 37a, the starting material was changed to 2,4-dimethylthiophene-3-carboxylic acid (I-6-37), and the starting amine was changed to 3-methoxymethyl-3-oxacyclobutamine, to synthesize compound 37. Overall yield: 11%. (ES, m / z): [M+1] + =455.

[0269] Example 38: 2,4-Dimethyl-3-amide-N-(3-chloro-4-fluorophenyl)-5-(2-(1,1-dimethylpropynylamino)-oxalyl)-thiophene (Compound 38)

[0270]

[0271] Following the synthetic route and reaction conditions of Example 29, in step 38a, the starting material was changed to 2,4-dimethylthiophene-3-carboxylic acid (I-6-38), and the starting amine was changed to 1,1-dimethylpropynylamine, to synthesize compound 38. The overall yield was 26%. (ES, m / z): [M+1] + =421, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.66(s,1H),8.88(s,1H),8.04(dd,J=6.9,2.4Hz,1H),7.61(m,1H) ,7.44(t,J=9.0Hz,1H),3.25(s,1H),2.73(s,3H),2.28(s,3H),1.58(s,6H).

[0272] Example 39: 2,4-Dimethyl-3-amide-N-(benzofuran-5-yl)-5-(2-(1,1-dimethylpropynyl)-oxalyl)-thiophene (Compound 39)

[0273]

[0274] Following the synthetic route and reaction conditions of Example 29, in step 39a, the starting material was changed to 2,4-dimethylthiophene-3-carboxylic acid (I-6-39), and the starting amine was changed to 1,1-dimethylpropynylamine; in step 39d, the starting amine was changed to 5-benzofuranamine, resulting in compound 39. The overall yield was 14%. (ES, m / z): [M+1] + =409.

[0275] Example 40: 2,4-Dimethyl-3-amide-N-(benzofuran-5-yl)-5-(2-(1-ethynylcyclopropane-1-amino)-oxalyl)-thiophene (Compound 40)

[0276]

[0277] Following the synthetic route and reaction conditions of Example 29, in step 40a, the starting material was changed to 2,4-dimethylthiophene-3-carboxylic acid (I-6-40), and the starting amine was changed to 1-acetylenecyclopropane-1-amine; in step 40d, the starting amine was changed to 5-benzofuranamine, yielding compound 40. The overall yield was 14%. (ES, m / z): [M+1] + =407.

[0278] Example 41: 2,4-Dimethyl-3-amide-N-(benzofuran-5-yl)-5-(2-(3-methoxymethyl-3-oxetane)-oxaloyl)-thiophene (Compound 41)

[0279]

[0280] Following the synthetic route and reaction conditions of Example 29, in step 41a, the starting material was changed to 2,4-dimethylthiophene-3-carboxylic acid (I-6-41), and the starting amine was changed to 3-methoxymethyl-3-oxacyclobutamine; in step 41d, the starting amine was changed to 5-benzofuranamine, yielding compound 41. Overall yield: 15%. (ES, m / z): [M+1] + =443.

[0281] Examples 42 and 43 are synthesized according to the specific route shown in the diagram below in Scheme 1.

[0282]

[0283] Example 42: 3-Amino-N-(4-fluorophenyl)-5-(2-tert-butylamino-oxaloyl)-furan (Compound 42)

[0284]

[0285] Step 42a: 3-Amino-N-(4-fluorophenyl)-furan (Compound I-11-42)

[0286] 3-Carboxyfuran (I-10-42, 2.6 g, 1.0 eq.) was dissolved in 120 mL of DCM. TEA (6.5 mL, 3.0 eq.) and HATU (10.7 g, 1.2 eq.) were added with stirring. The mixture was reacted at room temperature for 15 min, followed by the addition of 4-fluoroaniline (5.2 g, 2.0 eq.). The reaction was allowed to proceed for 2 h at room temperature, and the reaction was confirmed by LCMS. The reaction solution was washed with brine and then with water. The solution was dried, evaporated to dryness, stirred, and passed through a normal-phase column. 4.3 g of the product, a white solid, was obtained. (ES, m / z): [M+1] + =206.

[0287] Step 42b: 3-Amino-N-(4-fluorophenyl)-5-oxalate ethyl-furan (Compound I-12-42)

[0288] Under nitrogen protection, AlCl3 (1.8 g, 4.0 eq.) was dissolved in dichloromethane. The reaction solution was cooled to 0°C, and oxaloyl chloride ethyl ester (1.8 g, 4.0 eq.) was added with stirring. The mixture was stirred at 0°C for 30 min. Then, I-11-42 (0.71 g, 1.0 eq.) was added to the above reaction solution, and the mixture was allowed to return to room temperature for 16 h. The reaction was monitored by TLC until completion. The reaction was quenched with dilute hydrochloric acid, and the mixture was washed with water and saturated brine, respectively. The organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to obtain 756 mg of the target compound. (ES, m / z): [M+1] + =306.

[0289] Step 42c: 3-Amino-N-(4-fluorophenyl)-5-oxaloyl-furan (Compound I-13-42)

[0290] I-12-42 (305 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water. The reaction solution was cooled to 0 °C, and LiOH (84 mg, 2.0 eq.) was added. The reaction was carried out for 5 min, and the reaction was monitored by TLC until completion. The tetrahydrofuran was removed by concentration under reduced pressure. The pH was adjusted to 3 with 1 M dilute hydrochloric acid in an ice bath. The mixture was extracted twice with 10 times the volume of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly for the next step. (ES, m / z): [M+1] + =278.

[0291] Step 42d: 3-Amino-N-(4-fluorophenyl)-5-(2-tert-butylamino-oxaloyl)-furan (compound 42)

[0292] Intermediate I-13-42 was dissolved in 5 mL of DMF. DIPEA (387 mg, 3.0 eq.) and tert-butylamine (110 mg, 1.5 eq.) were added sequentially, followed by HATU (456 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 79 mg of the target compound as a white solid. (ES, m / z): [M+1] + =333, H-NMR: (300MHz, CDCl3, ppm): δ8.48(s,1H),8.37(s,1H),7.71(s,1H),7.60(m,2H),7.18(s,1H),7.10(t,J=8.7Hz,2H),1.48(s,9H).

[0293] Example 43: 2-tert-butyl-3-amide-N-(4-fluorophenyl)-5-(2-tert-butylamino-oxaloyl)-furan (Compound 43)

[0294]

[0295] Following the synthetic route and reaction conditions of Example 42, in step 42a, the starting material was changed to 2-tert-butylthiophene-3-carboxylic acid (I-6-43), resulting in the synthesis of compound 43. Overall yield: 13%. (ES, m / z): [M+1] + =389, H-NMR: (300MHz, CDCl3, ppm): δ8.35(s,1H),7.61(s,1H),7.56(m,2H),7.19(s,1H),7.08(t,J=8.7Hz,2H),1.52(s,9H),1.46(s,9H).

[0296] Examples 44 to 48 are synthesized according to the specific route shown in the diagram below in Scheme 2.

[0297]

[0298] Example 44: 2-(2-tert-butylamino-oxalyl)-4-amide-N-(3-chloro-4-fluoro-phenyl)-thiazole (44)

[0299]

[0300] Step 44a: 2-Bromo-4-amido-N-(3-chloro-4-fluorophenyl)-thiazole (Compound I-15-44)

[0301] 2-Bromothiazol-4-carboxylic acid (I-14-44, 1.04 g, 1.0 eq.) was dissolved in 300 mL of dichloromethane. Triethylamine (1.5 g, 3.0 eq.) and HATU (2.3 g, 1.2 eq.) were added with stirring. After reacting at room temperature for 5 min, 3-chloro-4-fluoroaniline (0.9 g, 1.2 eq.) was added, and the reaction was continued at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was terminated by adding water, and the mixture was washed three times with 30 mL of saturated brine. The organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 1.1 g of the target compound, in 65% yield. (ES, m / z): [M+1] + =335,337.

[0302] Step 44b: 2-Ethyl oxalate-4-amide-N-(3-chloro-4-fluorophenyl)-thiazole (I-16-44)

[0303] Under nitrogen protection, I-15-44 (1.0 g, 1.0 eq.) was dissolved in THF. The reaction solution was cooled to -78°C, and 1N n-BuLi solution (3.6 mL, 1.2 eq.) was slowly added dropwise with stirring. The mixture was kept at -78°C and stirred for 30 min. Then, diethyl oxalate (0.9 g, 2.0 eq.) was slowly added dropwise to the above reaction solution. The mixture was kept at -78°C and stirred for 30 min, and then allowed to warm naturally to room temperature. The reaction was quenched with saturated ammonium chloride solution, and the organic phase was extracted with ethyl acetate. After drying, the organic phase was concentrated under reduced pressure and separated by silica gel column chromatography to obtain 250 mg of the target compound, with a yield of 23%. (ES, m / z): [M+1] + =357.

[0304] Step 44c: 2-oxaloyl-4-amide-N-(3-chloro-4-fluorophenyl)-thiazole (I-17-44)

[0305] I-16-44 (240 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran and 2 mL of water. The reaction mixture was cooled to 0 °C, and LiOH (32 mg, 2.0 eq.) was added. The reaction was carried out for 5 min, and the reaction was monitored by TLC until completion. The tetrahydrofuran was removed by concentration under reduced pressure. The pH was adjusted to 3 with 1 M dilute hydrochloric acid in an ice bath, and the mixture was extracted twice with 10 times the volume of ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and used directly in the next step. (ES, m / z): [M+1] + =329.

[0306] Step 44d: 2-(2-tert-butylamino-oxalyl)-4-amide-N-(3-chloro-4-fluoro-phenyl)-thiazole (compound 44) ​​Intermediate I-17-44 was dissolved in 5 mL of DMF. DIPEA (259 mg, 3.0 eq.) and tert-butylamine (73 mg, 1.5 eq.) were added sequentially, followed by HATU (305 mg, 1.2 eq.). The reaction was carried out at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried and concentrated under reduced pressure. High-performance liquid chromatography (HPLC) was used to prepare 51 mg of the target compound as a pale yellow solid, with a two-step yield of 20%. (ES, m / z): [M+1] + =384 H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.60(s,1H),8.92(s,1H),8.55(s,1H),8.13(dd,J=6.9,2.7Hz,1H),7.81(m,1H),7.44(t,J=9.0Hz,1H),1.40(s,9H).

[0307] Example 45: 2-(2-tert-butylamino-oxalyl)-4-amide-N-(3-chloro-4-fluoro-phenyl)-5-methyl-thiazole (Compound 45)

[0308]

[0309] Following the synthetic route and reaction conditions of Example 44, in step 45a, the starting material was changed to 2-bromo-5-methylthiazol-4-carboxylic acid (I-14-45), yielding compound 51. Overall yield: 4%. (ES, m / z): [M+1] + =398.

[0310] Example 46: 2-(2-tert-butylamino-oxalyl)-4-amide-N-(3-chloro-4-fluoro-phenyl)-oxazole (Compound 46)

[0311]

[0312] Following the synthetic route and reaction conditions of Example 44, in step 46a, the starting material was changed to 2-bromo-oxazol-4-carboxylic acid (I-14-46), yielding compound 46. Overall yield: 3%. (ES, m / z): [M+1] + =368.

[0313] Example 47: 2-(2-tert-butylamino-oxalyl)-4-amide-N-(3-chloro-4-fluoro-phenyl)-5-methyl-oxazole (Compound 47)

[0314]

[0315] Following the synthetic route and reaction conditions of Example 44, in step 47a, the starting material was changed to 2-bromo-5-methyloxazol-4-carboxylic acid (I-14-47), yielding compound 47. Overall yield: 5%. (ES, m / z): [M+1] + =382.

[0316] Example 48: 3-Amino-N-(3-chloro-4-fluoro-phenyl)-5-(2-tert-butylamino-oxalyl)-isoxazole (Compound 48)

[0317]

[0318] Following the synthetic route and reaction conditions of Example 44, in step 48a, the starting material was changed to 2-bromoisoxazole-4-carboxylic acid (I-14-48), resulting in compound 48. Overall yield: 5% (ES, m / z): [M+1) + =368.

[0319] Examples 49 to 51 are synthesized according to the specific route shown in the diagram below in Scheme 2.

[0320]

[0321] Example 49: 2-Methyl-3-amide-N-(3,4,5-trifluorophenyl)-4-chloro-5-(2-tert-butylamino-oxalyl)-furan (Compound 49)

[0322]

[0323] Step 49a: 2-Methyl-3-carboxylic acid ethyl ester-4-chloro-5-(2-tert-butylamino-oxaloyl)-furan (I-19-49)

[0324] Under nitrogen protection, ZnCl2 (2.0 g, 3.0 eq.) was added to a reaction flask, followed by 20 mL of THF. After the addition was complete, 2-methyl-3-carboxylic acid ethyl ester-4-chloro-5-aldehyde-furan (I-18-49, 1.0 g, 1.0 eq.), MeNHOH.HCl (0.7 g, 1.6 eq.), and NaHCO3 (0.7 g, 1.6 eq.) were added. The mixture was stirred for 30 minutes, then n-tert-butylmethylimine (0.8 g, 2.0 eq.) and AcOH (0.9 g, 3 eq.) were added. The mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with 10 times its volume of ethyl acetate, filtered through a diatomaceous earth filter, and the filtrate was evaporated to dryness. Purification by normal-phase column chromatography yielded 550 mg of a yellow oily substance, with a yield of 38%. (ES, m / z): [M+1] + =316.

[0325] Step 49b: 2-Methyl-3-carboxylic acid-4-chloro-5-(2-tert-butylamino-oxaloyl)-furan (I-20-49)

[0326] I-19-49 (450 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran, 6 mL of methanol, and 2 mL of water. NaOH (120 mg, 2.0 eq.) was added. The reaction was allowed to proceed for 30 min, and TLC was used to monitor the reaction until completion. After the reaction was complete, 10 volumes of water and 10 volumes of ethyl acetate were added to the reaction solution for separation. The pH of the aqueous phase was adjusted to approximately 3 with 1N HCl. The solution was extracted twice with 10 volumes of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was then evaporated to dryness to obtain the crude product. The crude product was used directly in the next step. (ES, m / z): [M+1] + =288.

[0327] Step 49c: 2-Methyl-3-amide-N-(3,4,5-trifluorophenyl)-4-chloro-5-(2-tert-butylamino-oxalyl)-furan (compound 49)

[0328] 2-Methyl-3-carboxylic acid-4-chloro-5-(2-tert-butylamino-oxalyl)-furan (I-20-49, 3.3 g, 1.0 eq.), 3,4,5-trifluoroaniline (194 mg, 2.0 eq.), DMF (2 mL), and TEA (133 mg, 2.0 eq.) were added sequentially to a reaction flask. The mixture was cooled to 0°C, and HATU (377 mg, 1.5 eq.) was added. The mixture was allowed to return to room temperature and stirred overnight. After the reaction was complete, the mixture was purified by reverse-phase chromatography and sent to a reagent preparation to obtain 70 mg of a yellow solid, with a yield of 12%. (ES, m / z): [M+1] + =417.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.98(b,1H),8.58(s,1H),7.66(m,2H),2.74(s,3H),1.35(s,9H).

[0329] Example 50: 3-Amino-N-(3-chloro-4-fluoro-phenyl)-4-chloro-5-(2-tert-butylamino-oxalyl)-furan (Compound 50)

[0330]

[0331] Following the synthetic route and reaction conditions of Example 49, in step 50a, the starting material was changed to ethyl 3-carboxylate-4-chloro-5-aldehyde furan (I-18-50), and in step 50c, the starting material was changed to 3-chloro-4-fluoroaniline, to synthesize compound 50. Overall yield: 6%. (ES, m / z): [M+1] + =401.H-NMR: (300MHz, CDCl3, ppm): δ8.40(s,1H),8.31(s,1H),7.81(dd,J=6 .9,3.9Hz,1H),7.48(m,1H),7.21(t,J=8.7Hz,1H),6.82(s,1H),1.48(s,9H).

[0332] Example 51: 2-Chloro-3-amide-N-(3-chloro-4-fluoro-phenyl)-5-(2-tert-butylamino-oxalyl)-furan (Compound 51)

[0333]

[0334] Following the synthetic route and reaction conditions of Example 49, in step 51a, the starting material was changed to 2-chloro-3-carboxylic acid ethyl ester-5-aldehyde furan (I-18-51), and in step 51c, the starting material was changed to 3-chloro-4-fluoroaniline, to synthesize compound 51. Overall yield: 5%. (ES, m / z): [M+1] + =401.

[0335] Examples 52 to 78 are synthesized according to the specific route shown in the diagram below for Scheme 3.

[0336]

[0337] Example 52: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-tert-butylamino-oxaloyl)-pyrrole (Compound 52)

[0338]

[0339] Step 52a: 1,3,5-Trimethyl-2-carboxylic acid ethyl ester-4-oxalate ethyl ester-pyrrole (II-2)

[0340] Under nitrogen protection, AlCl3 (5.3 g, 4.0 eq.) was dissolved in dichloromethane. The reaction solution was cooled to 0 °C, and oxaloyl chloride ethyl ester (5.5 g, 4.0 eq.) was added with stirring. The mixture was stirred at 0 °C for 30 min. Then, 1,3,5-trimethyl-2-carboxylic acid ethyl ester-pyrrole (II-1, 1.8 g, 1.0 eq.) was added to the above reaction solution, and the mixture was allowed to return to room temperature for 16 h. The reaction was monitored by TLC until completion. The reaction was quenched with dilute hydrochloric acid, and the mixture was washed with water and saturated brine, respectively. The organic phase was dried and concentrated under reduced pressure. Separation was performed by silica gel column chromatography to obtain 2.1 g of the target compound, with a yield of 74%. (ES, m / z): [M+1] + =282.

[0341] Step 52b: 1,3,5-Trimethyl-2-carboxylic acid ethyl ester-4-oxaloyl-pyrrole (II-3)

[0342] Dissolve II-2 (2.1 g, 1.0 eq.) in 60 mL of tetrahydrofuran and 20 mL of water. Cool the reaction mixture to 0 °C and add LiOH (357 mg, 2.0 eq.). React for 5 min, and monitor the reaction until complete using TLC. Concentrate under reduced pressure to remove tetrahydrofuran. Adjust the pH to 3 with 1 M dilute hydrochloric acid in an ice bath. Extract twice with 10 times the volume of ethyl acetate. Combine the organic phases, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and use directly in the next step. (ES, m / z): [M+1] + =254.

[0343] Step 52c: 1,3,5-Trimethyl-2-carboxylic acid ethyl ester-4-(2-tert-butylamino-oxaloyl)-pyrrole (II-4-52)

[0344] Intermediate II-3 was dissolved in 10 mL of DMF, followed by the sequential addition of DIPEA (2.9 g, 3.0 eq.), tert-butylamine (810 mg, 1.5 eq.), and then HATU (3.4 g, 1.2 eq.). The reaction was carried out at room temperature for 6 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried and concentrated under reduced pressure. High-performance liquid chromatography (HPLC) was used to prepare 1.5 g of the target compound as a pale yellow solid, with a two-step yield of 66%. (ES, m / z): [M+1) + =309.

[0345] Step 52d: 1,3,5-Trimethyl-2-carboxylic acid-4-(2-tert-butylamino-oxaloyl)-pyrrole (II-5-52)

[0346] Dissolve II-4-52 (308 mg, 1.0 eq.) in 6 mL tetrahydrofuran, 6 mL methanol, and 2 mL water, then add NaOH (80 mg, 2.0 eq.). React for 30 min, monitoring the reaction complete by TLC. After the reaction is complete, add 10 volumes of water and 10 volumes of ethyl acetate to the reaction solution for separation. Adjust the pH of the aqueous phase to approximately 3 with 1N HCl. Extract twice with 10 volumes of ethyl acetate, combine the organic phases, and dry them over anhydrous sodium sulfate. Rotate the organic phase to dryness to obtain the crude product. The crude product is used directly in the next step. (ES, m / z): [M+1] + =281.

[0347] Step 52e: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-tert-butylamino-oxaloyl)-pyrrole (Compound 52)

[0348] II-5-52, benzofuran-5-amine (266 mg, 2.0 eq.), DMF (2 mL), and TEA (202 mg, 2.0 eq.) were added sequentially to a reaction flask. The mixture was cooled to 0°C, and then HATU (570 mg, 1.5 eq.) was added. The mixture was allowed to return to room temperature and stirred overnight. After the reaction was complete, the product was purified by reverse-phase chromatography and sent to the preparation stage to give 95 mg of a pale yellow solid, with a yield of 24%. (ES, m / z): [M+1] + =396.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.23(s,1H),8.24(s,1H),8.11(s,1H),7.98(s,1H),7.62(s,1H),7 .56(s,1H),6.97(s,1H),3.75(s,3H),2.51(s,3H),2.43(s,3H),1.41(s,9H).

[0349] Example 53: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 53)

[0350]

[0351] Following the synthetic route and reaction conditions of Example 52, in step 53c, the starting amine was replaced with propyneamine to synthesize compound 53. Overall yield: 11%. (ES, m / z): [M+1] + =378.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.26(s,1H),9.14(t,J=5.7Hz,1H),8.11(s,1H),7.98(s,1H),7.56(s,2H),6.97 (s,1H),4.01(dd,J=5.7,3.3Hz,2H),3.61(s,3H),3.18(s,1H),2.41(s,3H),2.57(s,3H).

[0352] Example 54: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(1,1-dimethylpropynyl)-oxaloyl)-pyrrole (Compound 54)

[0353]

[0354] Following the synthetic route and reaction conditions of Example 52, in step 54c, the starting amine was replaced with 1,1-dimethylpropynylamine to synthesize compound 54. Overall yield: 10%. (ES, m / z): [M+1] + =406 H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.26(s,1H),8.76(s,1H),8.11(s,1H),7.99(s,1H),7.56(s,2H),6 .97(s,1H),3.61(s,3H),3.22(s,1H),2.44(s,3H),2.29(s,3H),1.57(s,6H).

[0355] Example 55: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(1-ethynylcyclopropane-1-amino)-oxaloyl)-pyrrole (Compound 55)

[0356]

[0357] Following the synthetic route and reaction conditions of Example 52, in step 55c, the starting amine was replaced with 1-acetylenecyclopropaneamine to synthesize compound 55. Overall yield: 11%. (ES, m / z): [M+1] + =404 H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.26(s,1H),9.29(s,1H),8.11(s,1H),7.98(s,1H),7.56(s,2H),6.97(s,1H ),3.61(s,3H),2.41(s,3H),2.32(s,3H),1.18(t,J=4.2Hz,2H),1.06(t,J=4.2Hz,2H).

[0358] Example 56: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-((S)-1,1,1-trifluoroprop-2-amino)-oxalyl)-pyrrole (Compound 56)

[0359]

[0360] Following the synthetic route and reaction conditions of Example 52, in step 56c, the starting amine was replaced with (S)-1,1,1-trifluoropropane-2-amine to synthesize compound 56. Overall yield: 10%. (ES, m / z): [M+1] + =436.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.29(s,1H),9.36(d,J=9.0Hz,1H),8.11(s,1H),7.99(s,1H),7.56(s,2H),6 .97(s,1H),4.74(m,1H),3.74(s,3H),2.41(s,3H),2.36(s,3H),1.32(d,J=6.9Hz,3H).

[0361] Example 57: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(3-methyl-3-oxetane)-oxaloyl)-pyrrole (Compound 57)

[0362]

[0363] Following the synthetic route and reaction conditions of Example 52, in step 57c, the starting amine was replaced with 3-methyl-3-oxetanebutylamine to synthesize compound 57. Overall yield: 11%. (ES, m / z): [M+1] + =410 H-NMR:(300MHz,DMSO-d 6,ppm): δ10.26(s,1H),9.20(s,1H),8.11(s,1H),7.99(d,J=2.1Hz,1H),7.56(s,2H),6.97(d,J=2.1Hz, 1H),4.68(d,J=6.3Hz,2H),4.38(d,J=6.3Hz,2H),3.62(s,3H),2.42(s,3H),2.28(s,3H),1.60(s,3H).

[0364] Example 58: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-cyclopentanamino-oxaloyl)-pyrrole (Compound 58)

[0365]

[0366] Following the synthetic route and reaction conditions of Example 52, in step 58c, the starting amine was replaced with cyclopentylamine to synthesize compound 58. Overall yield: 13%. (ES, m / z): [M+1] + =408.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.25(s,1H),8.65(d,J=2.1Hz,1H),8.11(s,1H),7.98(d,J=2.1Hz,1H),7.56(s,2H),6.97(d,J=2.1 Hz,1H),4.11(d,J=6.3Hz,1H),3.83(s,3H),2.41(s,3H),2.26(s,3H),1.86(m,2H),1.71(m,2H),1.65(m,4H).

[0367] Example 59: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(thiazo-2-amino)-oxaloyl)-pyrrole (Compound 59)

[0368]

[0369] Following the synthetic route and reaction conditions of Example 52, in step 59c, the starting amine was replaced with thiazole-2-amine to synthesize compound 59. Overall yield: 7%. (ES, m / z): [M+1] + =423.H-NMR:(300MHz,DMSO-d 6,ppm): δ13.00(b,1H),10.36(s,1H),8.11(s,1H),7.98(s,1H),7.58(m,3H) ,7.38(d,J=3.6Hz,1H),7.01(s,1H),3.74(s,3H),2.41(s,3H),2.22(s,3H).

[0370] Example 60: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(N-methyl-1-carboxamide-3,3-difluorocyclobutane-1-amine)-oxalyl)-pyrrole (Compound 60)

[0371]

[0372] Following the synthetic route and reaction conditions of Example 52, in step 60c, the starting amine was replaced with N-methyl-1-carboxamide-3,3-difluorocyclobutane-1-amine to synthesize compound 60. Overall yield: 8%. (ES, m / z): [M+1] + =487.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.25(s,1H),9.52(s,1H),8.11(s,1H),7.99(d,J=2.4Hz,1H),7.72(t,J=4.8Hz,1H),7.59 (s,2H),6.97(s,1H),3.62(s,3H),3.32(m,2H),2.98(m,2H),2.73(s,3H),2.39(s,3H),2.26(s,3H).

[0373] Example 61: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(1-ethynyl-3,3-difluorocyclobutane-1-amine)-oxalyl)-pyrrole (Compound 61)

[0374]

[0375] Following the synthetic route and reaction conditions of Example 52, in step 61c, the starting amine was replaced with 1-ethynyl-3,3-difluorocyclobutane-1-amine to synthesize compound 61. Overall yield: 9%. (ES, m / z): [M+1] + =454.

[0376] Example 62: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetane)-oxalyl)-pyrrole (Compound 62)

[0377]

[0378] Following the synthetic route and reaction conditions of Example 52, in step 62c, the starting amine was replaced with 3-methoxymethyl-3-oxetanebutylamine to synthesize compound 62. Overall yield: 11%. (ES, m / z): [M+1] + =440.H-NMR: (300MHz, CDCl3, ppm): δ8.02(s,1H),7.67(s,1H),7.52(m,2H),7.42(m,2H),6.93(s,1H ),4.96(d,J=6.9Hz,2H),4.63(d,J=6.9Hz,2H),3.98(s,2H),3.70(s,3H),3.53(s,3H),2.45(s,6H).

[0379] Example 63: 1,3,5-Trimethyl-2-amide-N-(benzothiophene-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 63)

[0380]

[0381] Following the synthetic route and reaction conditions of Example 52, in step 63c, the starting amine was replaced with propyneamine; in step 63e, the starting amine was replaced with 5-benzothiopheneamine, yielding compound 63. Overall yield: 8%. (ES, m / z): [M+1] + =394 H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.35(s,1H),9.16(t,J=5.7Hz,1H),8.38(s,1H),7.95(d,J=8.4Hz,1H),7.78(d,J=5.4Hz,1H),7.60( dd,J=8.7,1.8Hz,1H),7.46(d,J=5.4Hz,1H),4.01(m,2H),3.76(s,3H),3.12(s,1H),2.41(s,3H),2.26(s,3H).

[0382] Example 64: 1,3,5-Trimethyl-2-amide-N-(1-methyl-1H-indol-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 64)

[0383]

[0384] Following the synthetic route and reaction conditions of Example 52, in step 64c, the starting amine was replaced with propyneamine; in step 64e, the starting amine was replaced with 1-methyl-1H-5-indoleamine, resulting in compound 64. Overall yield: 10%. (ES, m / z): [M+1]+ =391.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.07(s,1H),9.14(s,1H),7.98(s,1H),7.39(s,2H),7.31(s,1H),6.40(s, 1H),4..01(s,2H),3.78(s,3H),3.61(s,3H),3.18(s,1H),2.40(s,3H),2.26(s,3H).

[0385] Example 65: 1,3,5-Trimethyl-2-amide-N-(benzofuran-6-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 65)

[0386]

[0387] Following the synthetic route and reaction conditions of Example 52, in step 65c, the starting amine was replaced with propyneamine; in step 65c, the starting amine was replaced with 6-benzofuranamine, resulting in compound 65. Overall yield 6%. (ES, m / z): [M+1] + =378.

[0388] Example 66: 1,3,5-Trimethyl-2-amide-N-(naphth-2-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 66)

[0389]

[0390] Following the synthetic route and reaction conditions of Example 52, in step 66c, the starting amine was replaced with propyneamine; in step 66e, the starting amine was replaced with 2-naphthylamine, resulting in compound 66. Overall yield: 13%. (ES, m / z): [M+1] + =388.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.45(s,1H),9.17(t,J=5.7Hz,1H),8.42(s,1H),7.87(m,3H),7.37(dd,J=8.7,1.8Hz,1 H),7.46(m,2H),4.01(dd,J=5.7,2.4Hz,2H),3.87(s,3H),3.20(s,1H),2.42(s,3H),2.28(s,3H).

[0391] Example 67: 1,3,5-Trimethyl-2-amide-N-(quinoxalo-6-yl)-4-(2-propargyl-oxaloyl)-pyrrole (Compound 67)

[0392]

[0393] Following the synthetic route and reaction conditions of Example 52, in step 67c, the starting amine was replaced with propyneamine; in step 67e, the starting amine was replaced with 6-quinoxalineamine, resulting in compound 67. Overall yield: 4%. (ES, m / z): [M+1] + =390.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.74(s,1H),9.18(t,J=5.7Hz,1H),8.91(d,J=2.1Hz,1H),8.50(d,J=2.1Hz,1H),8.60(s,1H), 8.09(s,2H),4.01(dd,J=5.4,3.0Hz,2H),3.65(s,3H),3.19(t,J=2.4Hz,1H),2.43(s,3H),2.29(s,3H).

[0394] Example 68: 1,3,5-Trimethyl-2-amide-N-(quinoline-6-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 68)

[0395]

[0396] Following the synthetic route and reaction conditions of Example 52, in step 68c, the starting amine was replaced with propyneamine; in step 68e, the starting amine was replaced with 6-quinolinamine, resulting in compound 68. Overall yield: 3%. (ES, m / z): [M+1] + =389.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.68(s,1H),9.16(m,1H),8.94(d,J=3.0Hz,1H),8.61(s,1H),8.07(m,2 H),7.69(m,1H),4.01(m,2H),3.70(s,3H),3.19(s,1H),2.43(s,3H),2.35(s,3H).

[0397] Example 69: 1,3,5-Trimethyl-2-amide-N-(2,3-dihydrobenzofuran-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 69)

[0398]

[0399] Following the synthetic route and reaction conditions of Example 52, in step 69c, the starting amine was replaced with propyneamine; in step 69e, the starting amine was replaced with 2,3-dihydrobenzofuran-5-amine, yielding compound 69. Overall yield: 8%. (ES, m / z): [M+1] + =380 H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.06(s,1H),9.14(t,J=5.7Hz,1H),7.62(s,1H),7.36(d,J=8.7Hz,1H),6.72(d,J=8.7Hz,1H), 4.51(t,J=8.7Hz,2H),4.00(dd,J=5.4,2.4Hz,2H),3.58(s,3H),3.19(m,3H),2.42(s,3H),2.27(s,3H).

[0400] Example 70: 1,3,5-Trimethyl-2-amide-N-(benzothiazol-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 70)

[0401]

[0402] Following the synthetic route and reaction conditions of Example 52, in step 70c, the starting amine was replaced with propyneamine; in step 70e, the starting amine was replaced with 5-benzothiazolamine, yielding compound 70. Overall yield 2%. (ES, m / z): [M+1] + =395.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.48(s,1H),9.40(s,1H),9.17(t,J=5.4Hz,1H),8.57(s,1H),8.12(d,J=8.7Hz,1H),7.76(d d,J=8.7,1.5Hz,1H),4.01(dd,J=5.4,2.4Hz,2H),3.70(s,3H),3.20(s,1H),2.42(s,3H),2.27(s,3H).

[0403] Example 71: 1,3,5-Trimethyl-2-amide-N-(benzoxazol-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 71)

[0404]

[0405] Following the synthetic route and reaction conditions of Example 52, in step 71c, the starting amine was replaced with propyneamine; in step 71e, the starting amine was replaced with 5-benzoxazoleamine, resulting in compound 71. Overall yield: 2%. (ES, m / z): [M+1] + =379.

[0406] Example 72: 1,3,5-Trimethyl-2-amide-N-(1-methyl-1H-benzimidazol-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 72)

[0407]

[0408] Following the synthetic route and reaction conditions of Example 52, in step 72c, the starting amine was replaced with propyneamine; in step 72e, the starting amine was replaced with 1-methyl-1H-benzimidazole-5-amine, yielding compound 72. Overall yield: 3%. (ES, m / z): [M+1] + =392.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.26(s,1H),9.14(m,1H),8.23(s,1H),8.03(s,1H),7.61(s,2H),4.04(m,5H),3.62(s,3H),3.19(s,1H),2.41(s,3H),2.26(s,3H).

[0409] Example 73: 1,3,5-Trimethyl-2-amide-N-(1-methyl-1H-indazol-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 73)

[0410]

[0411] Following the synthetic route and reaction conditions of Example 52, in step 73c, the starting amine was replaced with propyneamine; in step 73e, the starting amine was replaced with 1-methyl-1H-indazole-5-amine, resulting in compound 73. Overall yield: 2%. (ES, m / z): [M+1] + =392.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.21(s,1H),9.16(t,J=5.7Hz,1H),8.16(s,1H),8.09(s,1H),7.53(t,J=8.7Hz,2H), 4.01(dd,J=5.7,3.0Hz,2H),3.83(s,3H),3.62(s,3H),3.19(s,1H),2.41(s,3H),2.26(s,3H).

[0412] Example 74: 1,3,5-Trimethyl-2-amide-N-(benzisoxazol-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 74)

[0413]

[0414] Following the synthetic route and reaction conditions of Example 52, in step 74c, the starting amine was replaced with propyneamine; in step 74e, the starting amine was replaced with 5-benzisoxazoleamine, resulting in compound 74. Yield: 5%. (ES, m / z): [M+1] + =379.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ9.24(t,J=5.4Hz,1H),7.17(d,J=9.3Hz,1H),6.93(s,1H),6.91(s,1H),5.62(d, J=4.8Hz,2H),4.01(d,J=3.3Hz,2H),3.80(s,3H),3.20(s,1H),2.42(s,3H),2.36(s,3H).

[0415] Example 75: 1,3,5-Trimethyl-2-amide-N-(4-fluorobenzofuran-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 75)

[0416]

[0417] Following the synthetic route and reaction conditions of Example 52, in step 75c, the starting amine was replaced with propyneamine; in step 75e, the starting amine was replaced with 4-fluorobenzofuran-5-amine, yielding compound 75. Overall yield: 9%. (ES, m / z): [M+1] + =396.

[0418] Example 76: 1,3,5-Trimethyl-2-amide-N-(4-chlorobenzofuran-5-yl)-4-(2-propargyl-oxalyl)-pyrrole (Compound 76)

[0419]

[0420] Following the synthetic route and reaction conditions of Example 52, in step 76c, the starting amine was replaced with propyneamine; in step 76e, the starting amine was replaced with 4-chlorobenzofuran-5-amine, resulting in compound 76. Overall yield: 11%. (ES, m / z): [M+1] + =412.

[0421] Example 77: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(3,3-difluoro-1-(1H-1,2,3-triazol-4-yl)cyclobutane-1-amino)-oxalyl)-pyrrole (Compound 77)

[0422]

[0423] Dissolve 1 mL of NaN3 (192 mg, 6.6 eq.) in water and place in a microwave tube. Add compound 61 (203 mg, 1.0 eq.), 1 mL of acetonitrile, 86 mg of CuSO4 (1.2 eq.), and sodium ascorbate (44 mg, 0.5 eq.) sequentially to the above reaction solution. React in a microwave tube at 80 °C for 1 h. Inject the reaction solution into saturated NH4Cl. Extract three times with EA. Dry the resulting organic phase, concentrate under reduced pressure, and separate by high performance liquid chromatography to obtain 40 mg of the target compound as a white solid, yield 18%. (ES, m / z): [M+1] + =497, H-NMR:(300MHz, DMSO-d 6 ,ppm): δ14.90(b,1H),10.26(s,1H),9.73(s,1H),8.10(s,1H),7.98(s,1H),7.81(s ,1H),7.56(s,3H),6.97(s,1H),3.60(s,3H),3.25(m,4H),3.23(s,3H),2.08(s,3H).

[0424] Example 78: 1,3,5-Trimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(2-(1H-1,2,3-triazol-4-yl)-2-propylamino)-oxalyl)-pyrrole (Compound 78)

[0425]

[0426] Following the synthetic route and reaction conditions of Example 77, but replacing the starting material with compound 54, compound 78 was synthesized. Yield: 22%. (ES, m / z): [M+1] + =449, H-NMR: (300MHz, CDCl3, ppm): δ8.01 (s, 1H), 7.98 (b, 1H), 7.65 (s, 1H), 7.62 (d, J = 2.1Hz, 1H), 7 .47(s,1H),7.44(s,1H),7.37(d,J=8.4Hz,2H),3.66(s,3H),2.34(s,3H),2.27(s,3H),1.85(s,6H).

[0427] Examples 79 to 82 are synthesized according to the specific route shown in the diagram below for Scheme 4.

[0428]

[0429] Example 79: 1-Cyclopropyl-2-amide-N-(benzofuran-5-yl)-3,5-dimethyl-4-(2-(1,1-dimethylpropynyl)-oxaloyl)pyrrole (Compound 79)

[0430]

[0431] Step 79a: 1-Cyclopropyl-3,5-Dimethyl-pyrrole-2-carboxylic acid (II-7-79)

[0432] 1-Cyclopropyl-2-carboxylate-3,5-dimethyl-pyrrole (II-6-79, 537 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran, 6 mL of methanol, and 2 mL of water. NaOH (240 mg, 2.0 eq.) was added. The reaction was allowed to proceed for 30 min, and TLC was used to monitor the reaction until completion. After the reaction was complete, 10 volumes of water and 10 volumes of ethyl acetate were added to the reaction solution for separation. The pH of the aqueous phase was adjusted to approximately 3 with 1N HCl. The solution was extracted twice with 10 volumes of ethyl acetate, and the organic phases were combined and dried over anhydrous sodium sulfate. The organic phase was evaporated to dryness to obtain the crude product. The crude product was used directly in the next step. (ES, m / z): [M+1] + =180.

[0433] Step 79b: 1-Cyclopropyl-2-amide-N-(benzofuran-5-yl)-3,5-dimethyl-pyrrole (II-8-79)

[0434] II-7-79, benzofuran-5-amine (798 mg, 2.0 eq.), DMF (20 mL), and TEA (606 mg, 2.0 eq.) were added sequentially to a reaction flask. The mixture was cooled to 0°C, and HATU (1.7 g, 1.5 eq.) was added. The mixture was allowed to return to room temperature and stirred overnight. After the reaction was complete, the product was post-treated, purified by reverse-phase chromatography, and sent to the preparation stage to yield 300 mg of a pale yellow solid, with a yield of 34%. (ES, m / z): [M+1] + =295.

[0435] Step 79c: 1-Cyclopropyl-2-amide-N-(benzofuran-5-yl)-3,5-dimethyl-4-oxalate ethyl pyrrole (II-9-79)

[0436] Under nitrogen protection, AlCl3 (532 mg, 4.0 eq.) was dissolved in dichloromethane. The reaction solution was cooled to 0 °C, and oxaloyl chloride ethyl ester (548 g, 4.0 eq.) was added with stirring. The mixture was stirred at 0 °C for 30 min. Then, 1,3,5-trimethyl-2-carboxylic acid ethyl ester-pyrrole (II-8-79, 295 mg, 1.0 eq.) was added to the above reaction solution, and the mixture was allowed to return to room temperature for 16 h. The reaction was monitored by TLC until completion. The reaction was quenched with dilute hydrochloric acid, and the mixture was washed with water and saturated brine, respectively. The organic phase was dried and concentrated under reduced pressure. Separation was performed by silica gel column chromatography to obtain 213 mg of the target compound, with a yield of 54%. (ES, m / z): [M+1] + =395.

[0437] Step 79d: 1-Cyclopropyl-2-amide-N-(benzofuran-5-yl)-3,5-dimethyl-4-oxaloyl-pyrrole (II-10-79)

[0438] Dissolve II-9-79 (213 mg, 1.0 eq.) in 6 mL of tetrahydrofuran and 2 mL of water. Cool the reaction mixture to 0 °C and add LiOH (26 mg, 2.0 eq.). React for 5 min, and monitor the reaction for completion by TLC. Concentrate under reduced pressure to remove tetrahydrofuran. Adjust the pH to 3 with 1 M dilute hydrochloric acid in an ice bath. Extract twice with 10 times the volume of ethyl acetate. Combine the organic phases, dry to anhydrous sodium sulfate, concentrate under reduced pressure, and use directly in the next step. (ES, m / z): [M+1] + =367.

[0439] Step 79e: 1-Cyclopropyl-2-amide-N-(benzofuran-5-yl)-3,5-dimethyl-4-(2-(1,1-dimethylpropynyl)-oxaloyl)pyrrole (Compound 79)

[0440] Intermediate II-10-79 was dissolved in 5 mL of DMF. DIPEA (209 mg, 3.0 eq.) and 1,1-dimethylpropyneamine (67 mg, 1.5 eq.) were added sequentially, followed by HATU (246 mg, 1.2 eq.). The reaction was allowed to proceed at room temperature for 2 h. The reaction was monitored by TLC until completion. The reaction was quenched with water, followed by the addition of ethyl acetate, and then washed with saturated brine. The resulting organic phase was dried, concentrated under reduced pressure, and separated by silica gel column chromatography to give 48 mg of the target compound as a white solid. The two-step yield was 21%. (ES, m / z): [M+1] + =432.

[0441] Example 80: 1-Difluoromethyl-2-amide-N-(benzofuran-5-yl)-3,5-dimethyl-4-(2-(1,1-dimethylpropynyl)-oxaloyl)pyrrole (Compound 80)

[0442]

[0443] Following the synthetic route and reaction conditions of Example 79, compound 80 was synthesized in step 80a by changing the starting material to 1-difluoromethyl-3,5-dimethyl-pyrrole-2-carboxylic acid (II-7-80). Overall yield: 5%. (ES, m / z): [M+1] + =442.

[0444] Example 81: 1-Methylsulfon-2-amide-N-(3,4-difluorophenyl)-3,5-dimethyl-4-(2-(1,1-dimethylpropynyl)-oxaloyl)pyrrole (Compound 81)

[0445]

[0446] Following the synthetic route and reaction conditions of Example 79, in step 81a, the starting material was changed to 1-methylsulfonyl-3,5-dimethyl-pyrrole-2-carboxylic acid (II-7-81); and in step 81e, the starting amine was changed to 3,4-difluoroaniline, to synthesize compound 81. Overall yield: 1%. (ES, m / z): [M+1] + =466.

[0447] Example 82: 1-(2,2,2-trifluoroethyl)-2-amide-N-(3,4-difluorophenyl)-3,5-dimethyl-4-(2-(1,1-dimethylpropynyl)-oxaloyl)pyrrole (Compound 82)

[0448]

[0449] Following the synthetic route and reaction conditions of Example 79, in step 82a, the starting material was changed to 1-(2,2,2-trifluoroethyl)-3,5-dimethyl-pyrrole-2-carboxylic acid (II-7-82); and in step 81e, the starting amine was changed to 3,4-difluoroaniline, to synthesize compound 82. Overall yield: 2%. (ES, m / z): [M+1] + =470.

[0450] Example 83: 2-Amino-N-(3-chloro-4-fluoro-phenyl)-3-methyl-4-(2-tert-butylamino-oxalyl)-furan (Compound 83)

[0451]

[0452] According to Scheme 3, following the synthetic route and reaction conditions of Example 52, in step 83a, the starting material was changed to ethyl 3-methyl-2-carboxylate-furan; in step 83e, the starting amine was changed to 3-chloro-4-fluoro-aniline, resulting in compound 83. Overall yield: 8%. (ES, m / z): [M+1] + =381.H-NMR:(300MHz,DMSO-d 6 , ppm): δ10.67(s,1H),8.91(s,1H),8.12(dd,J=6.9,2.4Hz,1H),8.01(s,1H),7.76(s,1H),7.55(t,J=4.8Hz,1H),2.56(s,3H),1.37(s,9H).

[0453] Example 84: 2-Amino-N-(3-chloro-4-fluoro-phenyl)-3,5-dimethyl-4-(2-tert-butylamino-oxalyl)-furan (Compound 84)

[0454]

[0455] According to Scheme 3, following the synthetic route and reaction conditions of Example 52, in step 84a, the starting material was changed to ethyl 3,5-dimethyl-2-carboxylate-furan; in step 84e, the starting amine was changed to 3-chloro-4-fluoro-aniline, resulting in compound 84. Overall yield: 12%. (ES, m / z): [M+1] + =395.

[0456] Example 85: 2-Amino-N-(3-chloro-4-fluoro-phenyl)-3-methyl-4-(2-tert-butylamino-oxalyl)-thiophene (Compound 85)

[0457]

[0458] According to Scheme 3, following the synthetic route and reaction conditions of Example 52, in step 85a, the starting material was changed to 3-methyl-2-carboxylic acid ethyl ester-thiophene; in step 85e, the starting amine was changed to 3-chloro-4-fluoro-aniline, to synthesize compound 85. Overall yield 7%. (ES, m / z): [M+1]+=397. H-NMR: (300MHz, DMSO-d) 6 , ppm): δ10.55(s,1H),8.37(s,1H),8.01(dd,J=6.9,2.4Hz,1H),7.92(s,1H),7.66(s,1H),7.45(t,J=4.8Hz,1H),2.46(s,3H),1.38(s,9H).

[0459] Example 86: 2-Amino-N-(3-chloro-4-fluoro-phenyl)-3,5-dimethyl-4-(2-tert-butylamino-oxalyl)-thiophene (Compound 86)

[0460]

[0461] According to Scheme 3, following the synthetic route and reaction conditions of Example 52, in step 86a, the starting material was changed to ethyl 3,5-dimethyl-2-carboxylate-thiophene; in step 86e, the starting amine was changed to 3-chloro-4-fluoro-aniline, resulting in compound 84. Overall yield: 5%. (ES, m / z): [M+1] + =411.

[0462] Example 87: 1,3-Dimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetane)-oxaloyl)-pyrrole (Compound 90)

[0463]

[0464] According to Scheme 3, following the synthetic route and reaction conditions of Example 52, in step 87a, the starting material was changed to ethyl 1,3-dimethyl-2-carboxylate-pyrrole; in step 87e, the starting amine was changed to 3-methyl-3-oxacyclobutamine, yielding compound 90. Overall yield 8%. (ES, m / z): [M+1] + =426 H-NMR:(300MHz, DMSO-d 6 ,ppm): δ10.25(s,1H),9.24(s,1H),8.11(s,1H),8.07(s,1H),7.99(d,J=2.1Hz,1H),7.56(m,2H),6.98(d,J= 1.8Hz,1H),4.68(d,J=6.9Hz,2H),4.51(d,J=6.9Hz,2H),3.78(s,3H),3.70(s,2H),3.32(s,3H),2.42(s,3H).

[0465] Example 88: 1-Methyl-2-amide-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetane)-oxaloyl)-pyrrole (Compound 91)

[0466]

[0467] According to Scheme 3, following the synthetic route and reaction conditions of Example 52, in step 88a, the starting material was changed to 1-methyl-2-carboxylic acid ethyl ester-pyrrole; in step 88e, the starting amine was changed to 3-methyl-3-oxacyclobutamine, resulting in compound 91. Overall yield: 10%. (ES, m / z): [M+1] + =412.H-NMR:(300MHz,DMSO-d 6 ,ppm): δ10.16(s,1H),9.32(s,1H),8.16(s,1H),8.11(s,1H),7.98(d,J=2.1Hz,1H),7.61(s,1H),7.57(m,2H ),6.96(s,1H),4.69(d,J=6.6Hz,2H),4.51(d,J=6.6Hz,2H),3.99(d,J=8.4Hz,3H),3.70(s,2H),3.38(s,3H).

[0468] Example 89: 1,5-Dimethyl-2-amide-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetane)-oxaloyl)-pyrrole (Compound 92)

[0469]

[0470] According to Scheme 3, following the synthetic route and reaction conditions of Example 52, in step 89a, the starting material was changed to ethyl 1,5-dimethyl-2-carboxylate-pyrrole; in step 89e, the starting amine was changed to 3-methyl-3-oxacyclobutamine, to synthesize compound 92. Overall yield: 10%. (ES, m / z): [M+1] + =426.H-NMR: (300MHz, CDCl3, ppm): δ8.16(s,1H),8.11(s,1H),7.97(s,1H),7.85(s,1H),7.57(s,1H),7.48(d,J=6.0Hz,1H),7.3 5(d,J=2.1Hz,1H),6.79(m,1H),5.99(d,J=6.9Hz,2H),4.63(d,J=6.9Hz,2H),3.97(s,3H),3.88(s,2H),3.46(s,3H),2.67(s,3H).

[0471] Effect Examples Bioactivity Test

[0472] Based on in vivo and in vitro biological experiments, the compounds of this invention, especially the preferred compounds, not only exhibit strong activity against HBV virus but also generally show very low toxicity. They possess excellent pharmacokinetic characteristics in vivo and demonstrate significant advantages in drug-likeness. Structure-activity analysis of all molecular structures in this patent clearly shows that the general formula represents a class of molecular structures with high activity, low toxicity, and strong drug-likeness.

[0473] I. Anti-hepatitis B virus activity and HepG2.2.15 cell viability assay

[0474] 1. Experimental Methods

[0475] This experiment used real-time quantitative PCR (qPCR) to detect the HBV DNA content in the supernatant of HepG2.2.15 cells and determine the anti-hepatitis B virus activity of the compounds in HepG2.2.15 cells. Cell-titer Blue assay was used to detect the effect of the test compounds on the activity of HepG2.2.15 cells. Entecavir (ETV) was used as a reference compound to monitor experimental quality.

[0476] 1.1 Antiviral Experiment

[0477] On day 1, cells were seeded into 96-well plates. On day 2, the cells were treated with the compound. On day 5, the culture medium containing the compound was replaced. On day 8, the supernatant was collected and DNA was extracted. The HBV DNA content was detected by quantitative PCR.

[0478] Both the test compound and the control compound were serially diluted 3-fold, with 8 concentration points and 2 replicates per well. The final concentration of DMSO in the culture medium was 0.5%.

[0479] The formula for calculating the inhibition percentage is as follows:

[0480] %inh.=(1-HBV copy number of sample / HBV copy number of 0.5% DMSOcontrol)×100

[0481] EC 50 Analysis was performed using Graphpad Prism software (four parameter logistic equations).

[0482] 1.2 Cytotoxicity assay (Cell-titer Blue method)

[0483] The compound concentration, plate arrangement, and compound treatment procedures were consistent with those used in the antiviral experiment. Cell viability was measured using Cell-titer Blue six days after compound treatment.

[0484] Analyze the data and calculate relative cell viability: Calculate the percentage of cell viability using the following formula:

[0485] % cell viability = (sample fluorescence reading - culture medium control fluorescence reading) / (DMSO control fluorescence reading - culture medium control fluorescence reading) × 100.

[0486] Finally, the CC of the compound was calculated using GraphPad Prism software. 50 value.

[0487] 2. Experimental Results

[0488] The anti-hepatitis B virus (HBV) inhibitor of this invention inhibits viral transcription, thereby achieving an antiviral effect. The anti-HBV activity of the compound in HepG2.2.15 cells was determined by real-time quantitative PCR (qPCR) to detect the HBV DNA content in the supernatant of HepG2.2.15 cells (using ECMO). 50 (Indicated), the effect of the test compound on the viability of HepG2.2.15 cells was detected by Cell-titer Blue assay (using CC). 50 (Indicated). Use the following levels: EC for anti-hepatitis B virus activity. 50 For the following concentrations: I: >50 μM; II: ≤50 μM and >5 μM; III: ≤5 μM and >0.5 μM; IV: ≤0.5 μM and >0.05 μM; V: ≤0.05 μM; For normal HepG2.2.15 cell viability, CC 50 In other words, use actual test values ​​or values ​​that express orders of magnitude, such as ">100 μM", to indicate that the molecule has a certain effect on cell activity (CC). 50 The value was greater than the highest concentration tested, while the highest concentration actually used in this test was 100 μM. The results are shown in Table 1. Literature reports that Cpd 7a (Compound 7a in WO 2017 / 156255 A1) is a highly active anti-hepatitis B virus (HBV) inhibitor with no significant effect on the activity of normal cells. We tested Cpd 7a as a control together with the compound of this invention. The compound of this invention can effectively inhibit viral transcription, thereby achieving an antiviral effect, without significantly affecting the activity of normal HepG2.2.15 cells.

[0489] Table 1. Anti-hepatitis B virus activity of some compounds (EC50) 50 ) and HepG2.2.15 cell viability (CC 50 )

[0490]

[0491]

[0492] II. Pharmacokinetic (PK) Experiment

[0493] 1. Experimental Methods

[0494] Male SD rats, weighing 215-343 g, were fasted overnight before the experiment. The test compound was completely dissolved in 5% DMSO and then diluted to 2 mg / mL with 30% Captisol. The solution was administered via gavage at a dose of 20 mg / kg. Blood samples (approximately 0.3 ml) were collected from the tail stump at 15 minutes, 30 minutes, and 1, 2, 4, 6, 8, and 24 hours post-administration. The blood samples were placed in centrifuge tubes containing K2-EDTA and centrifuged (3500 rpm, 10 min, 4°C) to collect plasma, which was then stored at -80°C. 50 μL of plasma sample was mixed with 135 μL of acetonitrile (containing internal standard IS), vortexed for 30 s, centrifuged at 15000 rpm for 10 min at 4°C, and 10 μL of the supernatant was collected and injected into LC-MS / MS for analysis.

[0495] 2. Experimental Results

[0496] Compounds 2, 8, 11, 36, and 42 provided in this invention were well absorbed and showed high blood exposure in rats after oral administration. Results are shown in […]. Figure 1 According to Table 2, the compounds of the present invention have a Tmax of 0.5-1.67 hours and a Cmax of 3673-9433 ng / ml, which are 2.1-5.3 times the Cmax of the reference compound Cpd 7a; AUC 0-24h The value is 17113-87187 ng / ml*h, which is the AUC of the reference compound Cpd 7a. 0-24h 1.4-7.2 times higher. Cmax refers to the maximum plasma concentration, T1 / 2 is the half-life, and AUC is... 0-24 The area under the 0-24 hour time-concentration curve, AUC. 0-inf It refers to the area under the 0-Inf time-concentration curve.

[0497] Table 2. Pharmacokinetics of rats administered via gavage (20 mg / kg)

[0498]

[0499]

Claims

1. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from: 。 2. A pharmaceutical composition comprising the compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

3. The pharmaceutical composition according to claim 2, characterized in that: Pharmaceutically acceptable excipients are selected from at least one of excipients, diluents, disintegrants, glidants, and lubricants.

4. The pharmaceutical composition according to claim 2, characterized in that: Pharmaceutically acceptable excipients include dicalcium phosphate, cellulose, compressible sugar, dehydrated dicalcium phosphate, lactose mannitol, microcrystalline cellulose, starch, and / or tricalcium phosphate.

5. The pharmaceutical composition of claim 2, further comprising one or more antiviral agents.

6. The pharmaceutical composition according to claim 5, characterized in that: The antiviral agents are selected from at least one of the following: hepatitis B virus polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, assembly regulators, reverse transcriptase inhibitors, and TLR-agonists.

7. The pharmaceutical composition according to claim 6, characterized in that: The reverse transcriptase inhibitor mentioned therein is selected from at least one of the following: entecavir, tenofovir, HepDirect-tenofovir, emtricitabine, adefovir, HepDirect-adefovir, acyclovir, ganciclovir, basilin, and ivaveren.

8. The pharmaceutical composition of claim 7, characterized in that: The reverse transcriptase inhibitor mentioned therein is tenofovir.

9. Use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, eradicating, reducing or inhibiting HBV infection or for alleviating liver damage caused by HBV infection.

10. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from: 。 11. Use of the compound of claim 10 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating, eradicating, reducing or inhibiting HBV infection or for alleviating liver damage caused by HBV infection.

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