Compounds, Pharmacologically Acceptable Salts or Stereoisomers Thereof, and Uses Thereof

Abstract

To provide anti-HBV compounds, pharmaceutically acceptable compounds or stereoisomers thereof, and preparation methods and uses for treating, eradicating or inhibiting HBV infection or for alleviating liver injury caused by HBV infection, and so on.SOLUTION: For example, a compound having the following structure is illustrated.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present application relates to antiviral compounds, in particular anti-HBV compounds, pharma- ceutically acceptable compounds or stereoisomers thereof, methods for their preparation, and uses thereof for treating, eradicating or inhibiting HBV infection, or reducing liver damage due to HBV infection. [Background technology]

[0002] Viral hepatitis B (abbreviated as hepatitis B) is one of the major "killers" of human health. It is caused by the hepatitis B virus (HBV) and is a disease that mainly causes inflammatory lesions in the liver and can damage multiple organs. Hepatitis B virus is a DNA virus that belongs to the family Hepadnaviridae. Hepatitis B is widespread in countries around the world, and approximately 250 million people, mainly children and young adults, are infected with hepatitis B virus worldwide, and a significant number of patients may develop cirrhosis or liver cancer. It has therefore become a global disease that seriously threatens human health.

[0003] Anti-hepatitis B virus nucleoside (acid) drugs currently available on the market include lamivudine, telbivudine, entecavir, tenofovir disoproxil, clevudine, etc. These drugs have many drawbacks, such as an unstable treatment course, a tendency for the virus to develop drug resistance, and a tendency for the disease to recur after the drug is stopped.

[0004] In addition, during the replication process of hepatitis B virus, viral DNA invades the host cell nucleus, and the missing double-stranded parts are complemented by the action of DNA polymerase, forming a superhelical, closed, circular DNA molecule (covalently closed circular DNA (cccDNA)). Extracellular hepatitis B virus DNA is a type of incomplete double-stranded DNA (relaxed circular DNA (rcDNA)) molecule. cccDNA is the initial template of the precursor of the pregenomic RNA replication of hepatitis B virus, and although its content is small and there are only about 5-50 copies in each hepatocyte, it is of sufficient significance to satisfy the replication of hepatitis B virus and the establishment of an infectious state. Only by removing the cccDNA in the cell nucleus can the carriage of hepatitis B virus be thoroughly eliminated, which is the purpose of antiviral treatment.

[0005] Unlike polymerase-targeting nucleoside drugs, capsid protein-targeting inhibitors can reduce the latent form of Hepatitis B virus, i.e., cccDNA. At present, some literature has reported the target of capsid protein-targeting 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 have reported several capsid protein-targeting inhibitors.

[0006] However, the inhibitory activity and cytotoxicity related to drug safety reported by existing technology are heterogeneous, making it difficult to predict the structural formula of a compound with good drug effect.Based on the long-term research experience, the present inventor has obtained a series of new anti-HBV compounds, and it is particularly surprising that many compounds with unknown structures have excellent effects and are expected to be used in drugs. Summary of the Invention

[0007] The present invention provides compounds according to general formula I or general formula II, or a pharma- ceutically acceptable salt or tautomer or enantiomer or non-enantiomer thereof: [ka]

[0008] Where: X is selected from N or CR3.

[0009] Y is selected from N or CR4.

[0010] Q is selected from O and S.

[0011] W is selected from O, S, and NR5.

[0012] R1 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl.

[0013] 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, S heteroatoms, and aryl.

[0014] wherein each occurrence of R2 is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, 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, 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.

[0015] R3 and R4 are each independently selected from H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, and C1-C6 alkyl substituted with halogen.

[0016] R5 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with C1-C3 alkoxy, C1-C6 alkyl substituted with halogen, -C(O)OR, -C(O)N(R), -C(O)R, -S(O)R, -S(O)R, -S(O)N(R), where R5 is not H, C1-C6 alkyl, C2-C6 alkenyl, or C2-C6 alkynyl if B is a monocyclic ring.

[0017] R is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkyl substituted with hydroxy, and C1-C6 alkyl substituted with C1-C3 alkoxy.

[0018] Ring A and Ring B are each independently selected from a 5-12 membered substituted or unsubstituted monocyclic or bicyclic ring, said monocyclic or bicyclic ring being a saturated monocyclic or bicyclic ring, a partially unsaturated monocyclic or bicyclic ring or an aromatic monocyclic or bicyclic ring, and the ring carbon atoms on said monocyclic or bicyclic ring are replaced with 0-5 heteroatoms, which heteroatoms are O, N or S.

[0019] In a first aspect, a compound of an anti-Hepatitis B virus (HBV) inhibitor having a new structure, characterized in that ring A or ring B is independently selected from the following, or a pharma- ceutically acceptable salt or stereoisomer thereof: [ka]

[0020] Where: m is selected from 0, 1 or 2.

[0021] X1, X2, X3, X4, X5, X6, X7, X8, and X9 are each independently selected from CR6 or N.

[0022] R6 is selected from H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with alkoxy, 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.

[0023] R7 is selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkyl substituted with hydroxy, and C1-C6 alkyl substituted with alkoxy.

[0024] Each R is independently selected from H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkyl substituted with hydroxy, and C1-C6 alkyl substituted with alkoxy.

[0025] A compound of an anti-hepatitis B virus (HBV) inhibitor having a new structure, characterized in that ring A or ring B is independently selected from the following: [ka]

[0026] A compound of an anti-hepatitis B virus (HBV) inhibitor having a new structure, characterized in that ring A or ring B is independently selected from the following: [ka]

[0027] A compound of an anti-hepatitis B virus (HBV) inhibitor having a new structure, characterized in that ring A or ring B is independently selected from the following: [ka]

[0028] An anti-Hepatitis B virus (HBV) inhibitor compound having a new structure, characterized in that X1, X2, X3, X5, X6, X8, and X9 are each independently selected from CR6, and X4 and X7 are each independently selected from CR6 or N, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0029] R6 is H, halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, C1-C6 alkyl substituted with hydroxy, C1-C6 alkyl substituted with alkoxy, 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( A compound of an anti-hepatitis B virus (HBV) inhibitor having a new structure, characterized in that R is selected from -N(R)C(O)R, -N(R)C(O)R, -R7 is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, and each R is independently selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0030] A compound of an anti-Hepatitis B virus (HBV) inhibitor having a new structure, characterized in that R6 is selected from H, halogen, C1-C6 alkyl, C2-C6 alkynyl, and C1-C6 alkyl substituted with halogen, and R7 is selected from H, C1-C6 alkyl, and C3-C8 cycloalkyl, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0031] A compound of an anti-hepatitis B virus (HBV) inhibitor having a new structure, characterized in that X is selected from CR3, Y is selected from CR4, Q is selected from O and S, W is selected from NR5, R1 is selected from H, and R2 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, C3-C8 saturated or unsaturated heterocycle containing N, O, or S heteroatoms, and aryl, or a pharma- ceutically acceptable salt or stereoisomer thereof.

[0032] wherein each occurrence of R2 is optionally substituted with 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, S heteroatoms, aryl, CF3, -OR, -C(O)OR, -C(O)N(R)2.

[0033] R3 and R4 are each independently selected from H, halogen, C1-C6 alkyl, C3-C8 cycloalkyl, and C1-C6 alkyl substituted with halogen.

[0034] R5 is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen, -C(O)OR, -C(O)N(R), -C(O)R, -S(O)R, -S(O)R, -S(O)N(R), where if B is a monocyclic ring then R5 is not H, C1-C6 alkyl.

[0035] R is selected from H, C1-C6 alkyl, C3-C8 cycloalkyl, C1-C6 alkyl substituted with halogen.

[0036] A compound of an anti-hepatitis B virus (HBV) inhibitor having a new structure, characterized in that R2 is selected from methyl, ethyl, isopropyl, tert-butyl, and cyclopentyl, or a pharma- ceutically acceptable salt or stereoisomer thereof. [ka]

[0037] A compound of an anti-hepatitis B virus (HBV) inhibitor having a new structure, characterized in that R2 is selected from tert-butyl and cyclopentyl, or a pharma- ceutically acceptable salt or stereoisomer thereof. [ka]

[0038] A compound of an anti-Hepatitis B virus (HBV) inhibitor having a new structure, characterized in that it is selected from the following compounds, or a pharma- ceutically acceptable salt or stereoisomer thereof: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5]

[0039] More preferably, the compound of the anti-Hepatitis B virus (HBV) inhibitor has a novel structure selected from the following: [ka]

[0040] In a second aspect, the present invention provides a pharmaceutical composition comprising a compound of the first aspect of the present invention, a pharma- ceutically acceptable salt thereof, a solvate thereof or an N-oxygen compound thereof, and a pharma- ceutically acceptable excipient.

[0041] Preferably, in the pharmaceutical composition of the second aspect of the present invention, the pharma- ceutically acceptable excipient is selected from at least one of excipients, diluents, disintegrants, glidants, lubricants, and preferably, the pharma-ceutically acceptable excipients include dicalcium phosphate, cellulose, compressible sugar, calcium hydrogen phosphate dehydrate, lactose mannitol, microcrystalline cellulose, starch and / or tricalcium phosphate.

[0042] Preferably, the pharmaceutical composition according to the second aspect of the present invention also comprises one or more antiviral agents, preferably the antiviral agents are selected from at least one of Hepatitis B Virus (HBV) polymerase inhibitors, interferons, viral entry inhibitors, viral maturation inhibitors, assembly modulators, reverse transcriptase inhibitors, TLR-agonists.

[0043] 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, Entricitabine, Adefovir, HepDirect-Adefovir, Acyclovir, Ganciclovir, GS-7340 (TAF), Besifovir, Birinapant (HY-16591), Ribavirin, Efavirenz, preferably Tenofovir.

[0044] In a third aspect, the present invention provides the use and method of a compound of the first aspect of the invention, a pharma- ceutically acceptable salt thereof, a solvent compound thereof or an N-oxygen compound thereof in the preparation of a medicament for the treatment of Hepatitis B Virus (HBV) infection or for the alleviation of liver damage due to Hepatitis B Virus (HBV) infection.

[0045] In a fourth aspect, the present invention provides a method for treating, eradicating, reducing, ameliorating or inhibiting Hepatitis B Virus (HBV) infection or alleviating liver damage due to Hepatitis B Virus (HBV) infection comprising administering an effective amount of a compound of the first aspect of the invention, a pharma- ceutically acceptable salt thereof, a solvent compound thereof, or an N-oxygen compound thereof to an individual in need thereof.

[0046] In a fifth aspect, the present invention provides a process for the preparation of a compound according to the first aspect of the present invention, comprising the preparation flows of the following four scenarios:

[0047] Scenario 1: The synthesis of compounds of general formula I can be carried out as described in Scenario 1. Carboxylic acid IA and amine IB are combined under the action of a condensing agent to give intermediate amide IC. Intermediate IC is hydrolyzed under alkaline conditions with Lewis acid such as AlCl3 or LDA, N-butyllithium and tert-butyllithium to give intermediate ID, which is then hydrolyzed under alkaline conditions to give intermediate IE, α-ketone acid of intermediate IE and IF are combined under the action of a condensing agent to give compounds of general formula I. [ka]

[0048] Scenario 2: The synthesis of compounds of general formula I can also be carried out via two routes, which are illustrated in Scenario 2.

[0049] a) Carboxylic acid ester IG is first hydrolyzed and then directly coupled with amine IB under the action of a condensing agent to obtain amide intermediate IH. Intermediate IH is selectively hydrolyzed with inorganic base NaOH to obtain intermediate IE, and α-ketone acid of intermediate IE and amine IF are coupled under the action of a condensing agent to obtain compound of general formula I.

[0050] b) A carboxylic acid ester IG is reacted with an alkylmethyleneamine to give an intermediate II, which is hydrolyzed to give an intermediate of general formula IJ, and the carboxylic acid of intermediate IJ and an amine IB are combined under the action of a condensing agent to give a compound of general formula I. [ka]

[0051] Scenario 3: The synthesis of compounds of general formula II can be carried out by the route described in scenario 3. Carboxylic acid ester II-A is synthesized in the presence of Lewis acid such as AlCl3 or LDA, N-butyllithium, or tert-butyllithium to obtain intermediate II-B, which is selectively hydrolyzed to the corresponding oxalic acid II-C, intermediate II-C and amine IF are combined under the action of a condensing agent to obtain intermediate II-D, which is further hydrolyzed to obtain II-E, and intermediate II-E and amine are combined under the action of a condensing agent to obtain compounds of general formula II. [ka]

[0052] Scenario 4: The synthesis of compounds of general formula II can also be carried out by the route described in Scenario 4. Carboxylic acid ester II-A is first hydrolyzed to obtain the corresponding carboxylic acid intermediate II-F, which is then combined with an amine under the action of a condensing agent to obtain intermediate II-G, which is synthesized under the action of a Lewis acid such as AlCl3 or LDA, N-butyllithium, or tert-butyllithium to obtain intermediate II-H, which is further hydrolyzed to obtain II-I, which is then combined with an amine IF under the action of a condensing agent to obtain compounds of general formula II. [ka]

[0053] Hereinafter, some embodiments of the present invention will be described in detail. The present invention is intended to cover all alternatives, modifications and equivalent technical solutions falling within the scope of the present invention as defined in the claims. Those skilled in the art should recognize that many methods and materials similar or equivalent to those described herein can be used to realize the present invention. The present invention is in no way limited to the methods and materials described herein. In the event that one or more of the literature, patents and similar materials mentioned herein are different or inconsistent with this application (including but not limited to defined terms, application of terms, described techniques, etc.), the present invention shall prevail.

[0054] Unless otherwise defined, the terms used in the present invention have the meanings generally accepted in the art. In addition, some terms used in the present invention are defined as follows:

[0055] The term "comprises" is an open expression, ie includes the subject matter specified in the present invention, but does not exclude other subject matter.

[0056] As used herein, the term "patient" can include humans (adults and children) or animals. In some embodiments, "patient" refers to a human.

[0057] The term "halogen" refers to fluorine, chlorine, bromine and iodine. In particular, halogen refers to fluorine, chlorine and bromine.

[0058] The term "cyano" refers to a cyano group (-CN).

[0059] The term "hydroxy" refers to the hydroxy group (-OH).

[0060] The term "carbonyl" refers to the carbonyl group -(C(=O)-).

[0061] The term "oxalic acid" refers to the oxalic acid group [ka] Refers to...

[0062] The term "carboxyl" refers to the carboxyl group (-COOH).

[0063] The term "alkynyl" refers to an alkynyl group. [ka] Refers to...

[0064] The term "amino" refers to a primary amino group (-NH), a secondary amino group (-NH-) or a tertiary amino group. [ka] Refers to...

[0065] "Alkyl" refers to a saturated aliphatic hydrocarbon group with a straight or branched chain. In the present application, alkyl is preferably C1-6 alkyl, i.e., saturated straight or branched alkyl containing 1 to 6 carbon atoms, and particularly preferred alkyl in the present application is C1-4 alkyl, i.e., saturated straight or branched alkyl of 1 to 4 carbon atoms, such as methyl, ethyl, N-propyl, isopropyl, 1-butyl, 2-butyl, tert-butyl, etc.

[0066] "Alkoxy" refers to the group (alkyl-O-), where alkyl is as defined above. Preferred alkoxy is C1-6 alkoxy, and particularly preferred alkoxy is C1-4 alkoxy. The term C1-6 alkoxy includes methoxy, ethoxy, N-propoxy, isopropoxy, and the like.

[0067] The term "cycloalkyl" refers to a saturated carbocyclic ring of 3 to 12 carbon atoms, especially 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0068] "Haloalkyl" or "haloalkoxy" means an alkyl or alkoxy group substituted with one or more halogen atoms, which may be the same or different. Examples include, but are not limited to, difluoromethyl, trifluoromethyl, trifluoromethoxy, and the like.

[0069] The term "tautomers" refers to structural isomers of organic compounds that are susceptible to conversion between each other by a chemical reaction called tautomerization, which usually results in the formal migration of a hydrogen atom or a proton accompanied by the interchange of a single bond and an adjacent double bond.

[0070] The term "chiral" refers to a molecule having the property of not being superimposable on its mirror image, while "achiral" refers to a molecule that can be superimposed on its mirror image.

[0071] The term "enantiomers" refers to two isomers of a compound that are non-superimposable mirror images of one another.

[0072] The term "non-enantiomer" refers to a stereoisomer that has two or more chiral centers and whose molecules are not mirror images of one another. Non-enantiomers generally have different physical properties, such as boiling points, melting points, spectral properties, reactivity, etc.

[0073] As described in the present invention, the compounds of the present invention, such as the general formula compounds above, the specific compounds of the present invention, or the specific examples, subclasses, and classes of compounds in the examples, may be optionally substituted with one or more substituents. It should be understood that the terms "optionally substituted" and "substituted or unsubstituted" can be used interchangeably. Generally speaking, the term "substituted" means that one or more hydrogen atoms in a given structure are replaced with a specified substituent. Unless otherwise specified, any substituent may be substituted at each substitutable position of the group. When multiple positions in a given structural formula may be substituted with one or more substituents selected from a specified group, the substituent may be the same or different at each position. The substituents herein may be, but are not limited to, fluorine, chlorine, bromine, iodine, methylene (=CH2), oxo (=O), alkyl, alkoxy, cyano, nitro, alkylamino, mercapto, amino, and the like.

[0074] The term "pharmaceutical acceptable salt" refers to a specific salt that can maintain the original biological activity of the above-mentioned compound and is suitable for pharmaceutical use.The pharmaceutical acceptable salt of the compound shown in general formula I or general formula II can be a salt formed with a suitable acid.The suitable acid includes 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, isethionic acid, lactic acid, malic acid, maleic acid, mandelic acid, methanesulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, etc.

[0075] In order to facilitate understanding, the present invention will be described in detail below through specific examples and drawings. Although it is specifically described, these descriptions are limited to illustrative descriptions and do not limit the scope of the present invention. Based on the discussion in this specification, many changes and modifications of the present invention will be apparent to those skilled in the art. It should be noted that the present invention cites publications for the purpose of more clearly explaining the present invention, and the entire text of those publications is incorporated herein by reference by repeating and clearly stating in this specification. [Brief description of the drawings]

[0076] [Figure 1] FIG. 1 shows the blood concentration of compounds 36, 52, 53, and 54 of the present invention and the control Cpd 7a after intragastric administration (20 mg / kg) to rats. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0077] The following reaction is typically carried out under a positive nitrogen pressure. The reaction flask is fitted with a suitable rubber stopper and the substrate can be introduced with a syringe. The glassware used is desiccated. The chromatography column is a silica gel column. Nuclear magnetic resonance data is obtained using CDCl3, DMSO-d 6 or CD3OD as the solvent (reported in ppm) and TMS (0 ppm) or chloroform (7.25 ppm) as reference standards measured on a Bruker Advance 400 nuclear magnetic resonance instrument. When multiplets occur, the abbreviations s (singlet), s, s (singlet, singlet, singlet), d (doublet), t (triplet), m (multiple), br (broadened), dd (doublet of doublets), ddd (doublet of doublet of doublets), ddt (doublet of doublet of triplets), dddd (doublet of doublet of doublet of doublets), td (triplet of doublets), and brs (broadened singlet). Coupling constants are expressed in Hertz (Hz).

[0078] Low resolution mass spectrometry (MS) data was measured on an Agilent 1100 series LC-MS spectrometer. An ESI source was applied to the LC-MS spectrometer.

[0079] The purity of the compounds is evaluated by Agilent 1100 series high performance liquid chromatography (HPLC), where UV detection is performed at 220 nm and 254 nm, Zorbax SB-C18 column specifications are 2.1X30 mm, 4 μm, 10 min, flow rate is 0.6 ml / min, and column temperature is maintained at 40°C for 5-95% (0.1% formic acid in acetonitrile) and (0.1% formic acid in water).

[0080] The following abbreviations are used throughout this application: [Table 2-1] [Table 2-2]

[0081] Preparation Example: The synthesis of the compounds of the present invention can utilize the following synthesis scenarios (Scenarios 1-4). The methods described are illustrative scenarios for easier understanding of the examples, and are not intended to limit the scope of the present invention.

[0082] Scenario 1 [ka]

[0083] Scenario 2 [ka]

[0084] Scenario 3 [ka]

[0085] Scenario 4 [ka]

[0086] The present invention will be further described below with reference to examples, which are not intended to limit the scope of protection of the present invention:

[0087] Examples 1 to 17 were synthesized according to the route shown in Scenario 1 in the diagram below. [ka]

[0088] Example 1: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 1) [ka]

[0089] Step 1a: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-furan (compound I-2)

[0090] 2-Methylfuran-3-formic acid (I-1, 10.1 g, 1.0 eq.) was dissolved in 300 mL of dichloromethane, and triethylamine (24.2 g, 3.0 eq.) and HATU (36.5 g, 1.2 eq.) were added while stirring. After reacting at room temperature for 5 min, 3-chlorine-4-fluoroaniline (13.9 g, 1.2 eq.) was added and reacted at room temperature for 2 h, and TLC showed the completion of the reaction. The reaction was terminated by adding water, and the mixture was washed three times with 30 mL of saturated saline. After the organic phase was dried, it was concentrated under reduced pressure, and after separation with a silica gel column, 12.7 g of the target compound was obtained in 63% yield. (ES, m / z): [M+1] + =254.

[0091] Procedure 1b: 2-Methyl-3-amido-N-(3-chloro-4-fluorophenyl)-5-ethyl oxalate-furan (compound I-3)

[0092] Under nitrogen protection, AlCl3 (17.1g, 4.0eq.) was dissolved in dichloromethane, the reaction solution was cooled to 0℃, and ethyl chloroglyoxylate (17.4g, 4.0eq.) was added while stirring, and the mixture was stirred at 0℃ for 30 min. Then I-2 (8.1g, 1.0eq.) was added to the reaction solution, and the mixture was allowed to react naturally for 16h. TLC showed the reaction was complete. The mixture was then washed with dilute hydrochloric acid and then washed with water and saturated saline, respectively. After the organic phase was dried, the mixture was concentrated under reduced pressure, and separated by silica gel column to obtain 5.0g of the target compound with a yield of 44%. (ES, m / z): [M+1] + =354.

[0093] Procedure 1c: 2-Methyl-3-amido-N-(3-chloro-4-fluorophenyl)-5-oxalate-furan (compound I-4)

[0094] I-3 (353 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 (84 mg, 2.0 eq.) was added. The mixture was allowed to react for 5 min. TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, adjusted to PH=3 with 1M dilute hydrochloric acid in an ice bath, extracted twice with 10x ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then used directly in the next step. (ES, m / z): [M+1] + =326.

[0095] Step 1d: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 1)

[0096] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), tert-butylamine (110 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.) were added in sequence, followed by reaction at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 90 mg of the target compound as a white solid in 24% yield. (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, 2.4 Hz, 1H), 7.42(t, J=9.2 Hz, 1H), 2.70(s, 3H), 1.38(s, 9H).

[0097] Example 2: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-propargylamino-oxalyl)-furan (compound 2) [ka]

[0098] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), propargylamine (83 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 109 mg of the target compound as a white solid in 30% yield. (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).

[0099] Example 3: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(1-methylpropargylamine)-oxalyl)-furan (compound 3) [ka]

[0100] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1-propargylamine (104 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 85 mg of the target compound as a pale yellow solid in 23% yield. (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).

[0101] Example 4: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(1,1-dimethylpropargylamino)-oxalyl)-furan (compound 4) [ka]

[0102] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1,1-dimethylpropargylamine (124 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 58 mg of the target compound as a white solid in 15% yield. (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, 1 H), 7.16(t, J=8.4Hz, 1H), 2.81(s, 3H), 2.45(s, 1H), 1.75(s, 3H), 1.70(s, 3H).

[0103] Example 5: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(2-alkynylbutylamino)-oxalyl)-furan (compound 5) [ka]

[0104] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1,1-dimethylpropargylamine (104 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the mixture was allowed to react at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated using a silica gel column to obtain 74 mg of the target compound as an off-white solid in 20% yield. (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, 1 H), 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).

[0105] Example 6: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(4-methyl-2-alkynylamylamino)-oxalyl)-furan (compound 6) [ka]

[0106] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 2-(4-methyl-2-alkynyl amyl amino (146 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 102 mg of the target compound as a white solid in 25% yield. (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).

[0107] Example 7: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(3-phenyl-2 alkynylpropylamino)-oxalyl)-furan (compound 7) [ka]

[0108] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 3-phenyl-2-alkynylpropylamine (196 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated using a silica gel column to obtain 86 mg of the target compound as a white solid in 20% yield. (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).

[0109] Example 8: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(1-methyl-imidazole-2-group)methylamino)-oxalyl)-furan (compound 8) [ka]

[0110] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), (1-methyl-imidazole-2-group)methylamine (166 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The organic phase was then dried, concentrated under reduced pressure, and purified by HPLC (high efficiency liquid phase), to obtain 16 mg of the target compound as a pale yellow solid in 4% yield. (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).

[0111] Example 9: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-anilino-oxalyl)-furan (compound 9) [ka]

[0112] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), aniline (140 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the mixture was allowed to react at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and purified by HPLC (high efficiency liquid phase), to obtain 35 mg of the target compound as a pale yellow solid in 9% yield. (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).

[0113] Example 10: 2-Methyl-3-amido-N-(3-chloro-4-fluorophenyl)-5-(2-(1-allyl-1H-[1,2,3]triazole-4-methylamino)-oxalyl)-furan (compound 10) [ka]

[0114] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1-allyl-1H-[1,2,3]triazole-4-methylamine (207 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.) were added in sequence, and the mixture was allowed to react at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The organic phase was then dried, concentrated under reduced pressure, and purified by HPLC (high efficiency liquid phase), to obtain 35 mg of the target compound as a pale yellow solid in 8% yield. (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, 1H), 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).

[0115] Example 11: 2-Methyl-3-amido-N-(3-chloro-4-fluorophenyl)-5-(2-(1-cyclopropyl-1H-[1,2,3]triazole-4-methylamino)-oxalyl)-furan (compound 11) [ka]

[0116] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1-cyclopropyl-1H-[1,2,3]triazole-4-methylamine (207 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.) were added in sequence, and the mixture was allowed to react at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and purified by HPLC (high efficiency liquid phase), to obtain 5 mg of the target compound as a pale yellow solid in 1% yield. (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, 1H), 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).

[0117] Example 12: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-(thiazol-2-amino)-oxalyl)-furan (compound 12) [ka]

[0118] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 2-aminothiazole (150 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the mixture was allowed to react at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and purified by HPLC (high efficiency liquid phase), to obtain 7 mg of the target compound as a pale yellow solid in 2% yield. (ES, m / z): [M+1] + =408.

[0119] Example 13: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(3-methyl-3-oxetanamine group)-oxalyl)-furan (compound 13) [ka]

[0120] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 3-methyl-3-oxetanamine (130 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 40 mg of the target compound as a pale yellow solid in 10% yield. (ES, m / z): [M+1] + =395.

[0121] Example 14: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-cyclopentylamino-oxalyl)-furan (14) [ka]

[0122] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), cyclopentylamino (128 mg, 1.5 eq.), HATU (456 mg, 1.2 eq.) were added in sequence, and the mixture was allowed to react at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 36 mg of the target compound as a pale off-white solid in 9% yield. (ES, m / z): [M+1] + =393.

[0123] Example 15: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-((S)-1,1,1-trifluoropropane-2-amino)-oxalyl)-furan (15) [ka]

[0124] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), (S)-1,1,1-trifluoropropan-2-amine (170 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 53 mg of the target compound as a pale yellow solid in 13% yield. (ES, m / z): [M+1] + =421.

[0125] Example 16: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-(1-trifluoromethyl-cyclopropylamino)-oxalyl)-furan (16) [ka]

[0126] Intermediate I-4 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), 1-trifluoromethyl-cyclopropylamine (188 mg, 1.5 eq.) were added in sequence, followed by HATU (456 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 76 mg of the target compound as a pale yellow solid in 18% yield. (ES, m / z): [M+1] + =433.

[0127] Example 17: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(1H-1,2,3-triazole-4-methylamino)-oxalyl)-furan (compound 17) [ka]

[0128] Compound 2 (300mg, 1.0eq.) was dissolved in 5mL of acetonitrile, NaN3 (376mg, 7.0eq.) was added to the reaction solution, heated to 60℃, reacted for 1h, cooled to room temperature, CuSO4 and sodium ascorbate were added, reacted at 80℃ for 1h, poured into saturated NH4Cl, extracted three times with EA, the organic phase obtained was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 40mg of the target compound as a white solid in 10% yield. (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, 2.7H z, 1H), 7.70(m, 2H), 7.42(t, J=9.0Hz, 1H), 4.50(d, J=5.4Hz, 2H), 2.71(s, 3H).

[0129] Examples 18 to 28 were synthesized according to the route shown in Scenario 1 in the diagram below. [ka]

[0130] Example 18: 2-Methyl-3-amido-N-(4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (compound 18) [ka]

[0131] Procedure 18a: 2-Methyl-3-amido-N-(2-fluorophenyl)-furan (Compound I-2-18)

[0132] 2-Methylfuran-3-formic acid (I-1, 3.7 g, 1.0 eq.) was dissolved in 150 mL of DCM, and TEA (8.1 mL, 3.0 eq.) and HATU (13.4 g, 1.2 eq.) were added with stirring. The reaction was allowed to proceed at room temperature for 15 min, and then 4-fluoroaniline (6.5 g, 2.0 eq.) was added. The reaction was allowed to proceed at room temperature for 2 h, and LCMS showed the reaction was complete. The reaction solution was washed with brine and then with water. The mixture was dried, spun dry, mixed, and passed through a normal phase column. 5.8 g of product was obtained as a white solid. (ES, m / z): [M+1] + =220.

[0133] Procedure 18b: 2-Methyl-3-amido-N-(2-fluorophenyl)-5-oxalate ethyl-furan (compound I-3-18)

[0134] Under nitrogen protection, AlCl3 (2.7g, 4.0eq.) was dissolved in dichloromethane, the reaction solution was cooled to 0℃, and ethyl chloroglyoxylate (2.7g, 4.0eq.) was added while stirring, and the mixture was stirred at 0℃ for 30 min. I-2-18 (1.1g, 1.0eq.) was then added to the reaction solution, and the mixture was allowed to naturally react for 16h. TLC showed the completion of the reaction. The mixture was quenched by adding dilute hydrochloric acid, and then washed with water and saturated saline, respectively. The organic phase was dried, concentrated under reduced pressure, and separated using a silica gel column to obtain 1.1g of the target compound. (ES, m / z): [M+1] + =320.

[0135] Procedure 18c: 2-Methyl-3-amido-N-(2-fluorophenyl)-5-oxalic acid-furan (compound I-4-18)

[0136] I-3-18 (300 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 (48 mg, 2.0 eq.) was added. The reaction was allowed to proceed for 5 min, and TLC showed the reaction was complete. The tetrahydrofuran was removed by vacuum concentration, and the pH was adjusted to 3 with 1M dilute hydrochloric acid in an ice bath. The mixture was extracted twice with 10 times ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure before being used directly in the next step. (ES, m / z): [M+1] + =292.

[0137] Step 18d: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 18)

[0138] Intermediate I-4-18 was dissolved in 5 mL of DMF, and DIPEA (365 mg, 3.0 eq.), Tert-butylamine (104 mg, 1.5 eq.) were added in sequence, followed by HATU (396 mg, 1.1 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated using a silica gel column 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).

[0139] Example 19: 2-Methyl-3-amido-N-(3,4-difluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 19) [ka]

[0140] Following the synthesis route and reaction conditions of Example 18, compound 19 was synthesized by replacing the raw material with 3,4-difluoroaniline in step 19a. The total yield was 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).

[0141] Example 20: 2-Methyl-3-amido-N-(3,4,5-trifluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 20) [ka]

[0142] Following the synthesis route and reaction conditions of Example 18, compound 20 was synthesized by replacing the raw material with 3,4,5-trifluoroaniline in step 20a. The total yield was 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).

[0143] Example 21: 2-Methyl-3-amido-N-(3-cyano-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 21) [ka]

[0144] Following the synthesis route and reaction conditions of Example 18, compound 21 was synthesized by replacing the raw material with 3-cyano-4-fluoroaniline in step 21a. The total yield was 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).

[0145] Example 22: 2-Methyl-3-amido-N-(4-trifluoromethylphenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 22) [ka]

[0146] Following the synthesis route and reaction conditions of Example 18, compound 22 was synthesized by replacing the raw material with 4-trifluoromethylaniline in step 22a. The total yield was 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).

[0147] Example 23: 2-Methyl-3-amido-N-(3-bromo-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (compound 23) [ka]

[0148] Following the synthesis route and reaction conditions of Example 18, compound 23 was synthesized by replacing the raw material with 3-bromo-4-fluoroaniline in step 23a. The total yield was 12%. (ES, m / z): [M+1] + =425, 427.

[0149] Example 24: 2-Methyl-3-amido-N-(3-iodophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 24) [ka]

[0150] Following the synthesis route and reaction conditions of Example 18, compound 24 was synthesized by replacing the raw material with 3-iodoaniline in step 24a. The total yields were 12% and 13%. (ES, m / z): [M+1] + =455.

[0151] Example 25: 2-Methyl-3-amido-N-(3-trimethylsilylethynyl-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 25) [ka]

[0152] Compound 23 (681 mg, 1.0 eq.) was dissolved in 15 mL of triethylamine, trimethylsilylacetylene (441 mg, 3.0 eq.), Ph3P (157 mg, 0.4 eq.), and Pd(OAc)2 (101 mg, 0.3 eq.) were added, and the mixture was purged with nitrogen, heated to 100°C, and refluxed overnight. LCMS showed the reaction was complete. The reaction solution was filtered, spin-dried, and purified on a silica gel column. 88 mg of compound 25 was obtained as a yellow solid. (ES, m / z): [M+1] + =443.

[0153] Example 26: 2-Methyl-3-amido-N-(3-trimethylsilylethynylphenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 26) [ka]

[0154] Compound 24 (600 mg, 1.0 eq.) was dissolved in 15 mL of triethylamine, trimethylsilylacetylene (415 mg, 3.0 eq.), Ph3P (148 mg, 0.4 eq.), and Pd(OAc)2 (94 mg, 0.3 eq.) were added, and the mixture was purged with nitrogen, heated to 100°C, and refluxed overnight. LCMS showed the reaction was complete. The reaction solution was filtered, spin-dried, and purified with a silica gel column. 67 mg of compound 26 was obtained as an off-white solid. (ES, m / z): [M+1] + =425.

[0155] Example 27: 2-Methyl-3-amido-N-(3-alkynyl-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 27) [ka]

[0156] Compound 25 (85 mg, 1.0 eq.) was dissolved in 5 mL of methanol, KOH (13 mg, 1.2 eq.) was added, and the mixture was allowed to react at room temperature overnight. LCMS showed the reaction was complete, and the mixture was purified by silica gel column. Compound 27 was obtained as an off-white solid. The yield of this procedure was 14%. (ES, m / z): [M+1] + =419, H-NMR: (300MHz, DMSO-d 6 , 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).

[0157] Example 28: 2-Methyl-3-amido-N-(3-alkynylphenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 28) [ka]

[0158] Compound 26 (67 mg, 1.0 eq.) was dissolved in 5 mL of methanol, KOH (10 mg, 1.2 eq.) was added, and the mixture was allowed to react at room temperature overnight. LCMS showed the reaction was complete, and the mixture was purified by silica gel column. Compound 28 was obtained as an off-white solid. The yield of this procedure 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), 7.3 7(t, J=7.8Hz, 1H), 7.22(d, J=7.8Hz, 1H), 4.20(s, 1H), 2.70(s, 3H), 1.39(s, 9H).

[0159] Examples 29 to 41 were synthesized according to the route shown in Scenario 1 in the diagram below. [ka]

[0160] Example 29: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-thiophene (compound 29) [ka]

[0161] Step 29a: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-thiophene (compound I-7-29)

[0162] 2-Methylthiophene-3-formic acid (I-6, 3.3 g, 1.0 eq.) was dissolved in 300 mL of dichloromethane, and triethylamine (7.0 g, 3.0 eq.) and HATU (10.6 g, 1.2 eq.) were added while stirring. After reacting at room temperature for 5 min, 3-chlorine-4-fluoroaniline (4.0 g, 1.2 eq.) was added and reacted at room temperature for 2 h, and TLC showed the completion of the reaction. The reaction was terminated by adding water, washed three times with 30 mL of saturated saline, and the organic phase was dried, concentrated under reduced pressure, and separated with a silica gel column to obtain 1.9 g of the target compound as a white solid in 30% yield. (ES, m / z): [M+1] + =270.

[0163] Procedure 29b: 2-Methyl-3-amido-N-(3-chloro-4-fluorophenyl)-5-ethyl oxalate-thiophene (compound I-8-29)

[0164] Under nitrogen protection, AlCl3 (1.1g, 4.0eq.) was dissolved in dichloromethane, the reaction solution was cooled to 0℃, and ethyl chloroglyoxylate (1.1g, 4.0eq.) was added while stirring, and the mixture was stirred at 0℃ for 30 min. I-7-29 (538g, 1.0eq.) was then added to the reaction solution, and the mixture was allowed to react naturally for 16h. TLC showed the reaction was complete. Dilute hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was washed with water and saturated saline, respectively. The organic phase was dried, concentrated under reduced pressure, and separated by a silica gel column to obtain 521mg of the target compound as a pale yellow solid in 70% yield. (ES, m / z): [M+1] + =370.

[0165] Procedure 29c: 2-Methyl-3-amido-N-(3-chloro-4-fluorophenyl)-5-oxalic acid-thiophene (compound I-9-29)

[0166] I-8-29 (369 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 (84 mg, 2.0 eq.) was added. The reaction was continued for 5 min, and TLC showed the reaction was complete. The tetrahydrofuran was removed by vacuum concentration, and the pH was adjusted to 3 with 1M dilute hydrochloric acid in an ice bath. The mixture was extracted twice with 10 times ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then used directly in the next step. (ES, m / z): [M+1] + =341.

[0167] Step 29d: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-thiophene (compound 29)

[0168] Intermediate I-9-29 was dissolved in 5 mL of DMF, and DIPEA (387 mg, 3.0 eq.), Tert-butylamine (110 mg, 1.5 eq.), and then HATU (456 mg, 1.2 eq.) were added in sequence, followed by reaction at room temperature for 2 h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 106 mg of the target compound as a white solid in 27% yield. (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).

[0169] Example 30: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-propargylamino-oxalyl)-thiophene (compound 30) [ka]

[0170] Following the synthesis route and reaction conditions of Example 29, compound 30 was synthesized by replacing the raw material with propargylamine in step 30d. The overall yield was 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).

[0171] Example 31: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(3-methyl-3-oxetanamine group)-oxalyl)-thiophene (compound 31) [ka]

[0172] Following the synthesis route and reaction conditions of Example 29, compound 31 was synthesized by replacing the raw material with 3-methyl-3-oxetanamine in step 31d. The overall yield was 25%, 9%. (ES, m / z): [M+1] + =411.

[0173] Example 32: 2-Methyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-cyclopentylamino-oxalyl)-thiophene (compound 32) [ka]

[0174] Following the synthesis route and reaction conditions of Example 29, compound 32 was synthesized by replacing the raw material with cyclopentylamino in step 32d. The overall yield was 10%. (ES, m / z): [M+1] + =409.

[0175] Example 33: 2-Methyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-((S)-1,1,1-trifluoropropane-2-amino)-oxalyl)-thiophene (compound 33) [ka]

[0176] Following the synthesis route and reaction conditions of Example 29, compound 33 was synthesized by replacing the raw material with (S)-1,1,1-trifluoropropan-2-amine in step 33d. The total yield was 10%. (ES, m / z): [M+1] + =437.

[0177] Example 34: 2-Methyl-3-amido-N-(3,4-difluorophenyl)-5-(2-Tert-butylamino-oxalyl)-thiophene (Compound 34) [ka]

[0178] Following the synthesis route and reaction conditions of Example 29, compound 34 was synthesized by replacing the starting amine with 3,4-difluoroaniline in step 34a. The total yield was 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).

[0179] Example 35: 2-Methyl-3-amido-N-(3,4,5-trifluorophenyl)-5-(2-Tert-butylamino-oxalyl)-thiophene (Compound 35) [ka]

[0180] Following the synthesis route and reaction conditions of Example 29, compound 35 was synthesized by replacing the starting amine with 3,4,5-trifluoroaniline in step 35a. The overall yield was 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).

[0181] Example 36: 2,4-Dimethyl-3-amido-N-(3-chlor-4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-thiophene (Compound 36) [ka]

[0182] Following the synthetic route and reaction conditions of Example 29, compound 36 was synthesized by replacing the starting material with 2,4-dimethylthiophene-3-formic acid (I-6-36) in step 36a. The overall yield was 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).

[0183] Example 37: 2,4-Dimethyl-3-amido-N-(3,4-difluorophenyl)-5-(2-(3-methoxymethyl-3-oxetanamine group)-oxalyl)-thiophene (compound 37) [ka]

[0184] Following the synthesis route and reaction conditions of Example 29, compound 37 was synthesized in step 37a by replacing the starting material with 2,4-dimethylthiophene-3-formic acid (I-6-37) and simultaneously replacing the starting amine with 3-methoxymethyl-3-oxetanamine. The total yield was 11%. (ES, m / z): [M+1] + =455.

[0185] Example 38: 2,4-Dimethyl-3-amido-N-(3-chlorine-4-fluorophenyl)-5-(2-(1,1-dimethylpropargylamino)-oxalyl)-thiophene (compound 38) [ka]

[0186] Following the synthesis route and reaction conditions of Example 29, compound 38 was synthesized by replacing the starting material with 2,4-dimethylthiophene-3-formic acid (I-6-38) in step 38a and simultaneously replacing the starting amine with 1,1-dimethylpropargylamine. The total 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).

[0187] Example 39: 2,4-Dimethyl-3-amido-N-(benzofuran-5-yl)-5-(2-(1,1-dimethylpropargylamino)-oxalyl)-thiophene (compound 39) [ka]

[0188] According to the synthesis route and reaction conditions of Example 29, in step 39a, the starting material was replaced with 2,4-dimethylthiophene-3-formic acid (I-6-39), and at the same time, the raw material amine was replaced with 1,1-dimethylpropargylamine, and in step 39d, the raw material amine was replaced with 5-benzofuranamine to synthesize compound 39. The total yield was 14%. (ES, m / z): [M+1] + =409.

[0189] Example 40: 2,4-Dimethyl-3-amido-N-(benzofuran-5-yl)-5-(2-(1-acetylenecyclopropane-1-amino)-oxalyl)-thiophene (Compound 40) [ka]

[0190] According to the synthesis route and reaction conditions of Example 29, in step 40a, the starting material was replaced with 2,4-dimethylthiophene-3-formic acid (I-6-40), and at the same time, the raw material amine was replaced with 1-acetylenecyclopropan-1-amine, and in step 40d, the raw material amine was replaced with 5-benzofuranamine to synthesize compound 40. The total yield was 14%. (ES, m / z): [M+1] + =407.

[0191] Example 41: 2,4-Dimethyl-3-amido-N-(benzofuran-5-yl)-5-(2-(3-methoxymethyl-3-oxetanamine)-oxalyl)-thiophene (Compound 41) [ka]

[0192] According to the synthesis route and reaction conditions of Example 29, in step 41a, the starting material was replaced with 2,4-dimethylthiophene-3-formic acid (I-6-41), and at the same time, the raw material amine was replaced with 3-methoxymethyl-3-oxetanamine, and in step 41d, the raw material amine was replaced with 5-benzofuranamine to synthesize compound 41. The total yield was 15%. (ES, m / z): [M+1] + =443.

[0193] Examples 42 and 43 were synthesized according to the route shown in Scenario 1 in the diagram below. [ka]

[0194] Example 42: 3-Amido-N-(4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (Compound 42) [ka]

[0195] Step 42a: 3-amido-N-(4-fluorophenyl)-furan (compound I-11-42)

[0196] 3-Furan formate (I-10-42, 2.6 g, 1.0 eq.) was dissolved in 120 mL of DCM, and TEA (6.5 mL, 3.0 eq.) and HATU (10.7 g, 1.2 eq.) were added with stirring. The reaction was allowed to proceed at room temperature for 15 min, and then 4-fluoroaniline (5.2 g, 2.0 eq.) was added. The reaction was allowed to proceed at room temperature for 2 h, and LCMS showed the reaction was complete. The reaction solution was washed with brine and then with water. The mixture was dried, spun dry, mixed, and passed through a normal phase column. 4.3 g of product was obtained as a white solid. (ES, m / z): [M+1] + =206.

[0197] Step 42b: 3-Amido-N-(4-fluorophenyl)-5-ethyl oxalate-furan (compound I-12-42)

[0198] Under nitrogen protection, AlCl3 (1.8g, 4.0eq.) was dissolved in dichloromethane, the reaction solution was cooled to 0℃, and ethyl chloroglyoxylate (1.8g, 4.0eq.) was added while stirring, and the mixture was stirred at 0℃ for 30min. I-11-42 (0.71g, 1.0eq.) was then added to the reaction solution, and the mixture was allowed to react naturally for 16h. TLC showed the completion of the reaction. The mixture was quenched by adding dilute hydrochloric acid, and then washed with water and saturated saline, respectively. The organic phase was dried, concentrated under reduced pressure, and separated by silica gel column to obtain 756mg of the target compound. (ES, m / z): [M+1] + =306.

[0199] Procedure 42c: 3-Amido-N-(4-fluorophenyl)-5-oxalic acid-furan (Compound I-13-42)

[0200] I-12-42 (305 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 (84 mg, 2.0 eq.) was added. The reaction was allowed to proceed for 5 min, and TLC showed the reaction was complete. The tetrahydrofuran was removed by vacuum concentration, and the pH was adjusted to 3 with 1M dilute hydrochloric acid in an ice bath, and the mixture was extracted twice with 10 times ethyl acetate. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then used directly in the next step. (ES, m / z): [M+1] + =278.

[0201] Step 42d: 3-Amido-N-(4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (compound 42)

[0202] Intermediate I-13-42 was dissolved in 5mL DMF, and DIPEA (387mg, 3.0eq.), Tert-butylamine (110mg, 1.5eq.) were added in sequence, followed by HATU (456mg, 1.2eq.), and the reaction was allowed to proceed at room temperature for 2h. TLC showed the completion of the reaction. Water was added to quench the reaction, and ethyl acetate was added. The reaction was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 79mg 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).

[0203] Example 43: 2-Tert-butyl-3-amido-N-(4-fluorophenyl)-5-(2-Tert-butylamino-oxalyl)-furan (compound 43) [ka]

[0204] Following the synthetic route and reaction conditions of Example 42, compound 43 was synthesized by replacing the starting material with 2-Tert-butylthiophene-3-formic acid (I-6-43) in step 42a. The overall yield was 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).

[0205] Examples 44 to 48 were synthesized according to the route shown in Scenario 2 in the diagram below. [ka]

[0206] Example 44: 2-(2-Tert-butylamino-oxalyl)-4-amido-N-(3-chlorine-4-fluorine-phenyl)-thiazole (44) [ka]

[0207] Procedure 44a: 2-bromo-4-amido-N-(3-chloro-4-fluorophenyl)-thiazole (compound I-15-44)

[0208] 2-Bromothiazole-4-carboxylic acid (I-14-44, 1.04 g, 1.0 eq.) was dissolved in 300 mL of dichloromethane, and triethylamine (1.5 g, 3.0 eq.) and HATU (2.3 g, 1.2 eq.) were added while stirring. After reacting at room temperature for 5 min, 3-chlorine-4-fluoroaniline (0.9 g, 1.2 eq.) was added and reacted at room temperature for 2 h, and TLC showed the completion of the reaction. The reaction was terminated by adding water, and the mixture was washed three times with 30 mL of saturated saline. After the organic phase was dried, it was concentrated under reduced pressure and separated by a silica gel column, and 1.1 g of the target compound was obtained in 65% yield. (ES, m / z): [M+1] + =335, 337.

[0209] Step 44b: 2-Ethyl oxalate-4-amido-N-(3-chlor-4-fluorophenyl)-thiazole (I-16-44)

[0210] Under nitrogen protection, I-15-44 (1.0g, 1.0eq.) was dissolved in THF, the reaction solution was cooled to -78℃, 1N n-BuLi solution (3.6mL, 1.2eq.) was slowly added dropwise while stirring, and the mixture was stirred for 30min while maintaining -78℃. Diethyl oxalate (0.9g, 2.0eq.) was slowly added dropwise to the above reaction solution, and the mixture was stirred for 30min while maintaining -78℃, and then allowed to warm to room temperature. Saturated ammonium chloride solution was added to the reaction mixture to quench the reaction, and the organic phase was extracted with ethyl acetate. After the organic phase was dried, it was concentrated under reduced pressure and separated on a silica gel column to obtain 250mg of the target compound in 23% yield. (ES, m / z): [M+1] + =357.

[0211] Procedure 44c: 2-Oxalic-4-amido-N-(3-chloro-4-fluorophenyl)-thiazole (I-17-44)

[0212] 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 allowed to proceed for 5 min, and TLC showed the reaction was complete. The tetrahydrofuran was removed by vacuum concentration, and the pH was adjusted to 3 with 1M dilute hydrochloric acid in an ice bath. The mixture was extracted twice with 10 times ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure before being used directly in the next step. (ES, m / z): [M+1] + =329.

[0213] Step 44d: 2-(2-Tert-butylamino-oxalyl)-4-amido-N-(3-chlorine-4-fluorine-phenyl)-thiazole (compound 44)

[0214] Intermediate I-17-44 was dissolved in 5 mL of DMF, and DIPEA (259 mg, 3.0 eq.), Tert-butylamine (73 mg, 1.5 eq.) were added in sequence, followed by HATU (305 mg, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and purified by HPLC (high efficiency liquid phase) to obtain 51 mg of the target compound as a pale yellow solid. The yield of the two steps was 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).

[0215] Example 45: 2-(2-Tert-butylamino-oxalyl)-4-amido-N-(3-chlorine-4-fluorine-phenyl)-5-methyl-thiazole (compound 45) [ka]

[0216] Following the synthesis route and reaction conditions of Example 44, compound 51 was synthesized by replacing the raw material in step 45a with 2-bromo-5-methylthiazole-4-carboxylic acid (I-14-45). The overall yield was 4%. (ES, m / z): [M+1] + =398.

[0217] Example 46: 2-(2-Tert-butylamino-oxalyl)-4-amido-N-(3-chlorine-4-fluorine-phenyl)-oxazole (compound 46) [ka]

[0218] Following the synthetic route and reaction conditions of Example 44, compound 46 was synthesized by replacing the starting material with 2-bromo-oxazole-4-carboxylic acid (I-14-46) in step 46a. The overall yield was 3%. (ES, m / z): [M+1] + =368.

[0219] Example 47: 2-(2-Tert-butylamino-oxalyl)-4-amido-N-(3-chlorine-4-fluorine-phenyl)-5-methyl-oxazole (compound 47) [ka]

[0220] Following the synthesis route and reaction conditions of Example 44, compound 47 was synthesized by replacing the raw material with 2-bromo-5-methyloxazole-4-carboxylic acid (I-14-47) in step 47a. The overall yield was 5%. (ES, m / z): [M+1] + =382.

[0221] Example 48: 3-Amido-N-(3-chlorine-4-fluorine-phenyl)-5-(2-Tert-butylamino-oxalyl)-isoxazole (compound 48) [ka]

[0222] Following the synthesis route and reaction conditions of Example 44, compound 48 was synthesized by replacing the raw material with 2-bromoisoxazole-4-carboxylic acid (I-14-48) in step 48a. The overall yield was 5%, 4%. (ES, m / z): [M+1] + =368.

[0223] Examples 49 to 51 were synthesized according to the route shown in Scenario 2 in the diagram below. [ka]

[0224] Example 49: 2-Methyl-3-amido-N-(3,4,5-trifluorophenyl)-4-chlorine-5-(2-Tert-butylamino-oxalyl)-furan (compound 49) [ka]

[0225] Procedure 49a: 2-Methyl-3-carboxylate-4-chlor-5-(2-Tert-butylamino-oxalyl)-furan (I-19-49)

[0226] Under nitrogen protection, ZnCl2 (2.0g, 3.0eq.) was added to the reaction flask, followed by 20mL of THF, followed by 2-methyl-3-ethyl-4-chlorine-5-aldehyde-furan (I-18-49, 1.0g, 1.0eq.), MeNHOH.HCl (0.7g, 1.6eq.), NaHCO3 (0.7g, 1.6eq.), and stirred for 30 minutes. N-tert-butylazomethine (0.8g, 2.0eq.), AcOH (0.9g, 3eq.) were added, and the mixture was stirred overnight at room temperature. After the reaction was complete, the reaction solution was diluted with 10 times the amount of ethyl acetate, filtered through diatomaceous earth, and the filtrate was spin-dried. The mixture was purified by normal phase column to give 550mg of yellow oil in 38% yield. (ES, m / z): [M+1] + =316.

[0227] Procedure 49b: 2-Methyl-3-carboxylic acid-4-chlorine-5-(2-Tert-butylamino-oxalyl)-furan (I-20-49)

[0228] I-19-49 (450 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran, 6 mL of methanol, and 2 mL of water, and NaOH (120 mg, 2.0 eq.) was added. The reaction was allowed to proceed for 30 min, and TLC showed the reaction was complete. After the reaction was complete, 10 volumes of water and 10 volumes of ethyl acetate were added to the reaction solution to separate, and the pH of the aqueous phase was adjusted to about 3 with 1N HCl. The organic phase 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 spun dry to obtain the crude product. This crude product was used directly in the next step. (ES, m / z): [M+1] + =288.

[0229] Procedure 49c: 2-Methyl-3-amido-N-(3,4,5-trifluorophenyl)-4-chlor-5-(2-Tert-butylamino-oxalyl)-furan (Compound 49)

[0230] 2-Methyl-3-carboxylate-4-chlorine-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), TEA (133 mg, 2.0 eq.) were added to the reaction flask in sequence, the temperature was lowered to 0°C, and HATU (377 mg, 1.5 eq.) was added. The mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed, 70 mg of a yellow solid was obtained in 12% yield after purification and further preparation by reverse phase column. (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).

[0231] Example 50: 3-Ami-N-(3-chlorine-4-fluorine-phenyl)-4-chlorine-5-(2-Tert-butylamino-oxalyl)-furan (compound 50) [ka]

[0232] Following the synthesis route and reaction conditions of Example 49, compound 50 was synthesized by replacing the raw material with 3-ethyl carboxylate-4-chlorine-5-aldehyde furan (I-18-50) in step 50a and with 3-chlorine-4-fluoroaniline in step 50c. The total yield was 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).

[0233] Example 51: 2-Chlorine-3-amido-N-(3-chlorine-4-fluorine-phenyl)-5-(2-Tert-butylamino-oxalyl)-furan (compound 51) [ka]

[0234] According to the synthesis route and reaction conditions of Example 49, compound 51 was synthesized by replacing the raw material with 2-chloro-3-ethyl carboxylate-5-aldehyde furan (I-18-51) in step 51a and with 3-chloro-4-fluoroaniline in step 51c. The total yield was 5%. (ES, m / z): [M+1] + =401.

[0235] Examples 52 to 78 were synthesized according to the route shown in Scenario 3 in the diagram below. [ka]

[0236] Example 52: 1,3,5-Trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-Tert-butylamino-oxalyl)-pyrrole (compound 52) [ka]

[0237] Procedure 52a: 1,3,5-trimethyl-2-ethyl carboxylate-4-ethyl oxalate-pyrrole (II-2)

[0238] Under nitrogen protection, AlCl3 (5.3g, 4.0eq.) was dissolved in dichloromethane, the reaction solution was cooled to 0℃, and ethyl chloroglyoxylate (5.5g, 4.0eq.) was added while stirring, and the mixture was stirred at 0℃ for 30min. 1,3,5-trimethyl-2-carboxylate ethyl-pyrrole (II-1, 1.8g, 1.0eq.) was then added to the reaction solution, and the mixture was allowed to react naturally for 16h. TLC showed the end of the reaction. Dilute hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was washed with water and saturated saline, respectively. After the organic phase was dried, the mixture was concentrated under reduced pressure, and separated by a silica gel column, 2.1g of the target compound was obtained in 74% yield. (ES, m / z): [M+1] + =282.

[0239] Procedure 52b: 1,3,5-trimethyl-2-ethyl carboxylate-4-oxalate-pyrrole (II-3)

[0240] II-2 (2.1g, 1.0eq.) was dissolved in 60mL of tetrahydrofuran and 20mL of water, the reaction mixture was cooled to 0℃, and LiOH (357mg, 2.0eq.) was added. The mixture was reacted for 5min, and TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, adjusted to PH=3 with 1M dilute hydrochloric acid in an ice bath, extracted twice with 10x ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then used directly in the next step. (ES, m / z): [M+1] + =254.

[0241] Procedure 52c: 1,3,5-Trimethyl-2-carboxylate Ethyl-4-(2-Tert-butylamino-oxalyl)-pyrrole (II-4-52)

[0242] Intermediate II-3 was dissolved in 10 mL of DMF, and DIPEA (2.9 g, 3.0 eq.) and tert-butylamine (810 mg, 1.5 eq.) were added in sequence, followed by HATU (3.4 g, 1.2 eq.), and the reaction was allowed to proceed at room temperature for 6 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The organic phase obtained was then dried, concentrated under reduced pressure, and purified by HPLC (high efficiency liquid phase) to obtain 1.5 g of the target compound as a pale yellow solid. The yield of the two steps was 66%. (ES, m / z): [M+1] + =309.

[0243] Procedure 52d: 1,3,5-Trimethyl-2-carboxylate-4-(2-Tert-butylamino-oxalyl)-pyrrole (II-5-52)

[0244] II-4-52 (308 mg, 1.0 eq.) was dissolved in 6 mL of tetrahydrofuran, 6 mL of methanol, and 2 mL of water, and NaOH (80 mg, 2.0 eq.) was added. The reaction was allowed to proceed for 30 min, and TLC showed the reaction was complete. After the reaction was complete, 10 volumes of water and 10 volumes of ethyl acetate were added to the reaction solution, and the pH of the aqueous phase was adjusted to about 3 with 1N HCl. The mixture 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 spun dry to obtain the crude product. This crude product was used directly in the next step. (ES, m / z): [M+1] + =281.

[0245] Procedure 52e: 1,3,5-Trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-Tert-butylamino-oxalyl)-pyrrole (Compound 52)

[0246] II-5-52, benzofuran-5-amine (266 mg, 2.0 eq.), DMF (2 mL), TEA (202 mg, 2.0 eq.) were added to the reaction flask in sequence, the temperature was lowered to 0°C, and HATU (570 mg, 1.5 eq.) was added. The mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed, the mixture was purified by reverse phase column and further refined to give 95 mg of a pale yellow solid in 24% yield. (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).

[0247] Example 53: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 53) [ka]

[0248] Following the synthetic route and reaction conditions of Example 52, compound 53 was synthesized by replacing the starting amine with propargylamine in step 53c. The overall yield was 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).

[0249] Example 54: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(1,1-dimethylpropargylamino)-oxalyl)-pyrrole (compound 54) [ka]

[0250] Following the synthetic route and reaction conditions of Example 52, compound 54 was synthesized by replacing the starting amine with 1,1-dimethylpropargylamine in step 54c. The overall yield was 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).

[0251] Example 55: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(1-acetylenecyclopropane-1-amino)-oxalyl)-pyrrole (compound 55) [ka]

[0252] Following the synthetic route and reaction conditions of Example 52, compound 55 was synthesized by replacing the starting amine with 1-acetylenecyclopropanamine in step 55c. The overall yield was 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).

[0253] Example 56: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-((S)-1,1,1-trifluoropropane-2-amino)-oxalyl)-pyrrole (compound 56) [ka]

[0254] Following the synthetic route and reaction conditions of Example 52, compound 56 was synthesized by replacing the starting amine with (S)-1,1,1-trifluoropropan-2-amine in step 56c. The overall yield was 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).

[0255] Example 57: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(3-methyl-3-oxetanamine)-oxalyl)-pyrrole (compound 57) [ka]

[0256] Following the synthetic route and reaction conditions of Example 52, compound 57 was synthesized by replacing the starting amine with 3-methyl-3-oxetanamine in step 57c. The overall yield was 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).

[0257] Example 58: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-cyclopentylamino-oxalyl)-pyrrole (compound 58) [ka]

[0258] Following the synthetic route and reaction conditions of Example 52, compound 58 was synthesized by replacing the starting amine with cyclopentylamino in step 58c. The overall yield was 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=2.1Hz, 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).

[0259] Example 59: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(thiazol-2-amino)-oxalyl)-pyrrole (compound 59) [ka]

[0260] Following the synthetic route and reaction conditions of Example 52, compound 59 was synthesized by replacing the starting amine with thiazol-2-amine in step 59c. The overall yield was 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).

[0261] Example 60: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(N-methyl-1-formamido-3,3-difluorocyclobutane-1-amino)-oxalyl)-pyrrole (compound 60) [ka]

[0262] Following the synthesis route and reaction conditions of Example 52, compound 60 was synthesized by replacing the starting amine with N-methyl-1-formamido-3,3-difluorocyclobutan-1-amine in step 60c. The overall yield was 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).

[0263] Example 61: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(1-ethynyl-3,3-difluorocyclobutane-1-amino)-oxalyl)-pyrrole (compound 61) [ka]

[0264] Following the synthesis route and reaction conditions of Example 52, compound 61 was synthesized by replacing the starting amine with 1-ethynyl-3,3-difluorocyclobutan-1-amine in step 61c. The overall yield was 9%. (ES, m / z): [M+1] + =454.

[0265] Example 62: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetanamine)-oxalyl)-pyrrole (compound 62) [ka]

[0266] Following the synthetic route and reaction conditions of Example 52, compound 62 was synthesized by replacing the starting amine with 3-methoxymethyl-3-oxetanamine in step 62c. The overall yield was 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=6.9H) z, 2H), 4.63(d, J=6.9Hz, 2H), 3.98(s, 2H), 3.70(s, 3H), 3.53(s, 3H), 2.45(s, 6H).

[0267] Example 63: 1,3,5-trimethyl-2-amido-N-(benzothiophene-5-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 63) [ka]

[0268] Following the synthesis route and reaction conditions of Example 52, compound 63 was synthesized by replacing the starting amine with propargylamine in step 63c and with 5-benzothiopheneamine in step 63e. The total yield was 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).

[0269] Example 64: 1,3,5-trimethyl-2-amido-N-(1-methyl-1H-indole-5-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 64) [ka]

[0270] Following the synthesis route and reaction conditions of Example 52, compound 64 was synthesized by replacing the starting amine with propargylamine in step 64c and with 1-methyl-1H-5-indolamine in step 64e. The total yield was 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).

[0271] Example 65: 1,3,5-trimethyl-2-amido-N-(benzofuran-6-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 65) [ka]

[0272] Following the synthesis route and reaction conditions of Example 52, compound 65 was synthesized by replacing the starting amine with propargylamine in step 65c and with 6-benzofuranamine in step 65c. The total yield was 6%. (ES, m / z): [M+1] + =378. Example 66: 1,3,5-trimethyl-2-amido-N-(naphthalene-2-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 66) [ka]

[0273] Following the synthesis route and reaction conditions of Example 52, compound 66 was synthesized by replacing the starting amine with propargylamine in step 66c and with 2-naphthaleneamine in step 66e. The total yield was 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, 1H), 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).

[0274] Example 67: 1,3,5-trimethyl-2-amido-N-(quinoxaline-6-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 67) [ka]

[0275] Following the synthesis route and reaction conditions of Example 52, compound 67 was synthesized by replacing the starting amine with propargylamine in step 67c and with 6-quinoxalineamine in step 67e. The total yield was 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), 8.0 9(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).

[0276] Example 68: 1,3,5-trimethyl-2-amido-N-(quinoline-6-group)-4-(2-propargylamino-oxalyl)-pyrrole (compound 68) [ka]

[0277] Following the synthesis route and reaction conditions of Example 52, compound 68 was synthesized by replacing the starting amine with propargylamine in step 68c and with 6-quinolineamine in step 68e. The total yield was 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, 2H), 7.69(m, 1H), 4.01(m, 2H), 3.70(s, 3H), 3.19(s, 1H), 2.43(s, 3H), 2.35(s, 3H).

[0278] Example 69: 1,3,5-trimethyl-2-amido-N-(2,3-dihydrobenzofuran-5-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 69) [ka]

[0279] Following the synthesis route and reaction conditions of Example 52, compound 69 was synthesized by replacing the starting amine with propargylamine in step 69c and with 2,3-dihydrobenzofuran-5-amine in step 69e. The total yield was 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), 4.5 1(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).

[0280] Example 70: 1,3,5-trimethyl-2-amido-N-(benzothiazole-5-group)-4-(2-propargylamino-oxalyl)-pyrrole (compound 70) [ka]

[0281] Following the synthesis route and reaction conditions of Example 52, compound 70 was synthesized by replacing the starting amine with propargylamine in step 70c and with 5-benzothiazolamine in step 70e. The total yield was 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(dd, 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).

[0282] Example 71: 1,3,5-trimethyl-2-amido-N-(benzoxazole-5-group)-4-(2-propargylamino-oxalyl)-pyrrole (compound 71) [ka]

[0283] Following the synthesis route and reaction conditions of Example 52, compound 71 was synthesized by replacing the starting amine with propargylamine in step 71c and with 5-benzoxazoleamine in step 71e. The total yield was 2%. (ES, m / z): [M+1] + =379.

[0284] Example 72: 1,3,5-trimethyl-2-amido-N-(1-methyl-1H-benzimidazole-5-group)-4-(2-propargylamino-oxalyl)-pyrrole (compound 72) [ka]

[0285] Following the synthesis route and reaction conditions of Example 52, compound 72 was synthesized by replacing the starting amine with propargylamine in step 72c and with 1-methyl-1H-benzimidazol-5-amine in step 72e. The total yield was 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).

[0286] Example 73: 1,3,5-trimethyl-2-amido-N-(1-methyl-1H-indazole-5-group)-4-(2-propargylamino-oxalyl)-pyrrole (compound 73) [ka]

[0287] Following the synthesis route and reaction conditions of Example 52, compound 73 was synthesized by replacing the starting amine with propargylamine in step 73c and with 1-methyl-1H-indazol-5-amine in step 73e. The total yield was 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), 4.0 1(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).

[0288] Example 74: 1,3,5-trimethyl-2-amido-N-(benzisoxazol-5-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 74) [ka]

[0289] Compound 74 was synthesized according to the synthesis route and reaction conditions of Example 52, except that the starting amine was replaced with propargylamine in step 74c and with 5-benzisoxazolamine in step 74e. The yield was 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).

[0290] Example 75: 1,3,5-trimethyl-2-amido-N-(4-fluorobenzofuran-5-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 75) [ka]

[0291] Following the synthesis route and reaction conditions of Example 52, compound 75 was synthesized by replacing the starting amine with propargylamine in step 75c and with 4-fluorobenzofuran-5-amine in step 75e. The total yield was 9%. (ES, m / z): [M+1] + =396.

[0292] Example 76: 1,3,5-trimethyl-2-amido-N-(4-chlorobenzofuran-5-yl)-4-(2-propargylamino-oxalyl)-pyrrole (compound 76) [ka]

[0293] Following the synthesis route and reaction conditions of Example 52, compound 76 was synthesized by replacing the starting amine with propargylamine in step 76c and with 4-chlorobenzofuran-5-amine in step 76e. The total yield was 11%. (ES, m / z): [M+1] + =412.

[0294] Example 77: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-group)-4-(2-(3,3-difluoro-1-(1H-1,2,3-triazole-4-group)cyclobutane-1-amino)-oxalyl)-pyrrole (compound 77) [ka]

[0295] NaN3 (192mg, 6.6eq.) was dissolved in 1mL of water and placed in a microwave tube. Compound 61 (203mg, 1.0eq.) and 1mL of acetonitrile were added to the above reaction solution in sequence, followed by CuSO4 (86mg, 1.2eq.) and sodium ascorbate (44mg, 0.5eq.), and the reaction was carried out at 80℃ for 1h under microwaves. The reaction solution was poured into saturated NH4Cl, and the organic phase obtained by extracting three times with EA was dried, concentrated under reduced pressure, and separated by high performance liquid chromatography to obtain 40mg of the target compound as a white solid in 18% yield. (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).

[0296] Example 78: 1,3,5-trimethyl-2-amido-N-(benzofuran-5-group)-4-(2-(2-(1H-1,2,3-triazole-4-group)-2-propylamino)-oxalyl)-pyrrole (compound 78) [ka]

[0297] Compound 78 was synthesized by replacing the starting material with compound 54 according to the synthesis route and reaction conditions of Example 77. The yield was 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).

[0298] Examples 79 to 82 were synthesized according to the route shown in Scenario 4 in the diagram below. [ka]

[0299] Example 79: 1-Cyclopropyl-2-amido-N-(benzofuran-5-yl)-3,5-dimethyl-4-(2-(1,1-dimethylpropargylamino)-oxalyl)pyrrole (Compound 79) [ka]

[0300] Procedure 79a: 1-Cyclopropyl-3,5-dimethyl-pyrrole-2-carboxylic acid (II-7-79)

[0301] 1-Cyclopropyl-2-ethyl-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, and NaOH (240 mg, 2.0 eq.) was added. The reaction was allowed to proceed for 30 min, and TLC showed the reaction was complete. After the reaction was complete, 10 volumes of water and 10 volumes of ethyl acetate were added to the reaction solution, and the pH of the aqueous phase was adjusted to about 3 with 1N HCl. The mixture 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 spun dry to obtain the crude product. This crude product was used directly in the next step. (ES, m / z): [M+1] + =180.

[0302] Procedure 79b: 1-Cyclopropyl-2-amido-N-(benzofuran-5-yl)-3,5-dimethyl-pyrrole (II-8-79)

[0303] II-7-79, benzofuran-5-amine (798 mg, 2.0 eq.), DMF (20 mL), TEA (606 mg, 2.0 eq.) were added to the reaction flask in sequence, the temperature was lowered to 0°C, and HATU (1.7 g, 1.5 eq.) was added. The mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed, it was worked up, purified by reverse phase column, and further refined, and 300 mg of pale yellow solid was obtained in 34% yield. (ES, m / z): [M+1] + =295.

[0304] Procedure 79c: 1-Cyclopropyl-2-amido-N-(benzofuran-5-yl)-3,5-dimethyl-4-ethyl oxalate-pyrrole (II-9-79)

[0305] Under nitrogen protection, AlCl3 (532 mg, 4.0 eq.) was dissolved in dichloromethane, the reaction solution was cooled to 0°C, and ethyl chloroglyoxylate (548 g, 4.0 eq.) was added while stirring, and the mixture was stirred at 0°C for 30 min. 1,3,5-trimethyl-2-carboxylate ethyl-pyrrole (II-8-79, 295 mg, 1.0 eq.) was then added to the reaction solution, and the mixture was allowed to react naturally for 16 h. TLC showed the end of the reaction. Dilute hydrochloric acid was added to the reaction mixture to quench the reaction, and the mixture was washed with water and saturated saline, respectively. After the organic phase was dried, the mixture was concentrated under reduced pressure, and separated using a silica gel column, 213 mg of the target compound was obtained in a 54% yield. (ES, m / z): [M+1] + =395.

[0306] Procedure 79d: 1-Cyclopropyl-2-amido-N-(benzofuran-5-yl)-3,5-dimethyl-4-oxalate-pyrrole (II-10-79)

[0307] II-9-79 (213 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 (26 mg, 2.0 eq.) was added. The mixture was allowed to react for 5 min, and TLC showed the reaction was complete. The mixture was concentrated under reduced pressure to remove tetrahydrofuran, and the pH was adjusted to 3 with 1M dilute hydrochloric acid in an ice bath. The mixture was extracted twice with 10 times ethyl acetate, and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and then used directly in the next step. (ES, m / z): [M+1] + =367.

[0308] Procedure 79e: 1-Cyclopropyl-2-amido-N-(benzofuran-5-yl)-3,5-dimethyl-4-(2-(1,1-dimethylpropargylamino)-oxalyl)pyrrole (Compound 79)

[0309] Intermediate II-10-79 was dissolved in 5 mL DMF, and DIPEA (209 mg, 3.0 eq.), 1,1-dimethylpropargylamine (67 mg, 1.5 eq.) were added in sequence, followed by HATU (246 mg, 1.2 eq.), and the mixture was allowed to react at room temperature for 2 h. TLC showed the reaction was complete. Water was added to quench the reaction, and ethyl acetate was added. The mixture was then washed with saturated saline, and the resulting organic phase was dried, concentrated under reduced pressure, and separated on a silica gel column to obtain 48 mg of the target compound as a white solid. The yield of the two steps was 21%. (ES, m / z): [M+1] + =432.

[0310] Example 80: 1-Difluoromethyl-2-amido-N-(benzofuran-5-yl)-3,5-dimethyl-4-(2-(1,1-dimethylpropargylamino)-oxalyl)pyrrole (Compound 80) [ka]

[0311] Following the synthetic route and reaction conditions of Example 79, compound 80 was synthesized by replacing the starting material with 1-difluoromethyl-3,5-dimethyl-pyrrole-2-carboxylic acid (II-7-80) in step 80a. The overall yield was 5%. (ES, m / z): [M+1] + =442.

[0312] Example 81: 1-Methylsulfo-2-amido-N-(3,4-difluorophenyl)-3,5-dimethyl-4-(2-(1,1-dimethylpropargylamino)-oxalyl)pyrrole (Compound 81) [ka]

[0313] Following the synthesis route and reaction conditions of Example 79, compound 81 was synthesized by replacing the starting material with 1-methylsulfo-3,5-dimethyl-pyrrole-2-carboxylic acid (II-7-81) in step 81a and the starting amine with 3,4-difluoroaniline in step 81e. The total yield was 1%. (ES, m / z): [M+1] + =466.

[0314] Example 82: 1-(2,2,2-trifluoroethyl)-2-amido-N-(3,4-difluorophenyl)-3,5-dimethyl-4-(2-(1,1-dimethylpropargylamino)-oxalyl)pyrrole (compound 82) [ka]

[0315] Following the synthesis route and reaction conditions of Example 79, compound 82 was synthesized by replacing the starting material with 1-(2,2,2-trifluoroethyl)-3,5-dimethyl-pyrrole-2-carboxylic acid (II-7-82) in step 82a and the starting amine with 3,4-difluoroaniline in step 81e. The total yield was 2%. (ES, m / z): [M+1] + =470.

[0316] Example 83: 2-Ami-N-(3-chlorine-4-fluorine-phenyl)-3-methyl-4-(2-Tert-butylamino-oxalyl)-furan (compound 83) [ka]

[0317] Based on scenario 3, compound 83 was synthesized according to the synthetic route and reaction conditions of example 52, except that the starting material was replaced with 3-methyl-2-ethyl carboxylate-furan in step 83a, and the starting amine was replaced with 3-chlorine-4-fluorine-aniline in step 83e. The total yield was 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).

[0318] Example 84: 2-Ami-N-(3-chlorine-4-fluorine-phenyl)-3,5-dimethyl-4-(2-Tert-butylamino-oxalyl)-furan (compound 84) [ka]

[0319] Based on scenario 3, compound 84 was synthesized according to the synthetic route and reaction conditions of example 52, except that the starting material was replaced with 3,5-dimethyl-2-ethyl carboxylate-furan in step 84a, and the starting amine was replaced with 3-chlorine-4-fluorine-aniline in step 84e. The total yield was 12%. (ES, m / z): [M+1] + =395.

[0320] Example 85: 2-Amido-N-(3-chlorine-4-fluorine-phenyl)-3-methyl-4-(2-Tert-butylamino-oxalyl)-thiophene (Compound 85) [ka]

[0321] Based on scenario 3, compound 85 was synthesized according to the synthetic route and reaction conditions of example 52, by replacing the starting material with 3-methyl-2-ethyl-carboxylate-thiophene in step 85a and the starting amine with 3-chlorine-4-fluorine-aniline in step 85e. The total yield was 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).

[0322] Example 86: 2-Amido-N-(3-chlorine-4-fluorine-phenyl)-3,5-dimethyl-4-(2-Tert-butylamino-oxalyl)-thiophene (Compound 86) [ka]

[0323] Based on scenario 3, compound 84 was synthesized according to the synthetic route and reaction conditions of example 52, except that the starting material was replaced with 3,5-dimethyl-2-ethyl carboxylate-thiophene in step 86a, and the starting amine was replaced with 3-chlorine-4-fluorine-aniline in step 86e. The total yield was 5%. (ES, m / z): [M+1] + =411.

[0324] Example 87: 1,3-Dimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetanamine)-oxalyl)-pyrrole (Compound 90) [ka]

[0325] Based on scenario 3, compound 90 was synthesized according to the synthetic route and reaction conditions of example 52, except that the starting material was replaced with 1,3-dimethyl-2-ethyl-2-carboxylate-pyrrole in step 87a and the starting amine was replaced with 3-methyl-3-oxetanamine in step 87e. The total yield was 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=1.8 Hz, 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).

[0326] Example 88: 1-Methyl-2-amido-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetanamine)-oxalyl)-pyrrole (compound 91) [ka]

[0327] Based on scenario 3, compound 91 was synthesized according to the synthetic route and reaction conditions of example 52, except that the starting material was replaced with 1-methyl-2-ethyl carboxylate-pyrrole in step 88a and the starting amine was replaced with 3-methyl-3-oxetanamine in step 88e. The total yield was 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).

[0328] Example 89: 1,5-Dimethyl-2-amido-N-(benzofuran-5-yl)-4-(2-(3-methoxymethyl-3-oxetanamine)-oxalyl)-pyrrole (Compound 92) [ka]

[0329] Based on scenario 3, compound 92 was synthesized according to the synthetic route and reaction conditions of example 52, except that the starting material was replaced with 1,5-dimethyl-2-ethyl-carboxylate-pyrrole in step 89a and the starting amine was replaced with 3-methyl-3-oxetanamine in step 89e. The total yield was 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), 7.35(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).

[0330] Example of Effect: Biological Activity Test According to in vivo and in vitro biological experiments and tests, the compounds of the present invention, especially the preferred compounds, have strong activity against HBV virus, generally low toxicity, good pharmacokinetic properties in vivo, and obvious superior properties as medicines. According to the structure-activity analysis of all structural molecules in this patent, it can be clearly concluded that the general formula molecules have a class of molecular structures with high activity, low toxicity and high drug discovery potential. 1. Anti-Hepatitis B virus activity and HepG2.2.15 cell activity experiment

[0331] 1. Experimental Method In this experiment, the content of HBV DNA in the supernatant of HepG2.2.15 cells was detected by real-time fluorescent quantitative PCR (qPCR), the anti-hepatitis B virus activity of the compounds in HepG2.2.15 cells was measured, and the effect of the test compounds on HepG2.2.15 cell activity was detected by Cell-titer Blue. In the experiment, entecavir (ETV) was used as a reference compound to monitor the quality of the experiment.

[0332] 1.1 Antiviral experiments Cells were seeded in 96-well plates on day 1, compounds were added to treat cells on day 2, new compound-containing medium was replaced on day 5, and the supernatants were collected and DNA was extracted on day 8. HBV DNA content was detected by quantitative PCR.

[0333] Test and control compounds were serially diluted 3-fold at eight concentration points and assayed in duplicate in parallel. The final concentration of DMSO in the culture medium was 0.5%.

[0334] The formula for calculating the inhibition rate is as follows: %inh.=(1-HBV copy number of sample / HBV copy number of 0.5% DMSO control)×100 EC 50 were analyzed with Graphpad Prism software (four parameter logistic equations).

[0335] 1.2 Cytotoxicity experiment (Cell-titer Blue method) The compound concentration, plate arrangement, and compound treatment process were consistent with the antiviral experiment. Six days after the cells were treated with the compounds, the cell activity was measured by Cell-titer Blue.

[0336] The data was analyzed and the relative cell activity was calculated. The percentage of cell activity was calculated using the following formula: % Cellular activity = (sample fluorescence reading - medium control fluorescence reading) / (DMSO control fluorescence reading - medium control fluorescence reading) x 100.

[0337] Finally, the CC of the compounds was analyzed using GraphPad Prism software. 50 values ​​were calculated.

[0338] 2. Experimental Results The anti-hepatitis B virus (HBV) inhibitor of the present invention can suppress the transcription of the virus to achieve the anti-viral effect. The content of HBV DNA in the supernatant of HepG2.2.15 cells was detected by real-time fluorescent quantitative PCR (qPCR) method, and the anti-hepatitis B virus activity (EC 50 The effect of the test compound on HepG2.2.15 cell activity was measured using Cell-titer Blue (CC 50 The following levels were used: EC50 for anti-hepatitis B virus activity; 50 In the case of I: >50μM, II: ≦50μM and >5μM, III: ≦5μM and >0.5μM, IV: ≦0.5μM and >0.05μM, V: ≦0.05μM. CC of normal HepG2.2.15 cell activity 50 In some cases, a value representing the actual test value or order of magnitude was used. For example, ">100 μM" indicates that the molecule has a CC of cellular activity. 50 This means that the concentration is greater than the maximum concentration in the test relative to the value, and the maximum concentration actually used in this test was 100 μM. The results are shown in Table 1. The literature reports that Cpd 7a (Compound 7a in WO 2017 / 156255 A1) is a highly active anti-Hepatitis B virus (HBV) inhibitor with no obvious effect on the activity of normal cells. Cpd 7a was tested as a control together with the compound of the present invention. The compound of the present invention can effectively inhibit viral transcription and achieve antiviral effects without obvious effects on normal HepG2.2.15 cell activity. [Table 3-1] [Table 3-2]

[0339] 2. Pharmacokinetic (PK) experiments 1. Experimental method Male SD rats weighing 215-343 g were used and fasted overnight before the test. The test compounds were completely dissolved in 5% total DMSO, further diluted to 2 mg / mL with 30% Captisol, and administered intragastrically at 20 mg / kg. At 15 min, 30 min, 1, 2, 4, 6, 8, and 24 h after administration, approximately 0.3 ml of blood was collected by cutting the tail tip at each time point, placed in a centrifuge tube containing K2-EDTA, centrifuged (3500 rpm, 10 min, 4 °C), and then stored in a -80 °C ultra-low temperature refrigerator. 50 μL of blood sample was mixed with 135 ml of acetonitrile (containing internal standard IS), vortexed for 30 s, centrifuged at 15000 rpm at 4 °C for 10 min, and 10 ml of the supernatant was collected and injected into LC-MS / MS for analysis.

[0340] 2. Experimental results Compounds 2, 8, 11, 36, and 42 provided by the present invention were well absorbed and had high blood exposure after oral administration to rats. The results are shown in Figure 1 and Table 2. The Tmax of the compounds of the present invention was 0.5-1.67 hours, the Cmax was 3673-9433ng / ml, and the AUC 0-24h was 17113-87187ng / ml*h, and the AUC of the reference compound Cpd 7a 0-24h Cmax is the maximum blood concentration, T1 / 2 is the half-life, and AUC 0-24 is the area under the time-concentration curve from 0 to 24 hours, AUC 0-inf is the area under the 0-Inf time-concentration curve. [Table 4]

Claims

【Request 1】 【Chemical 1-1】 【Chemistry 1-2】 【Chemistry 1-3】 A compound selected from the group consisting of:

2. 13. Use of the compound of claim 1, or a pharma- ceutically acceptable salt or stereoisomer thereof, in the preparation of a medicament for treating, eradicating, reducing or inhibiting HBV infection, or reducing liver damage due to HBV infection.

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