Intracyclic thiamidinoamide-arylamide compounds and their use for treating hepatitis B - Patents.com

Abstract

The present invention relates to endocyclic thiamidinoamide-arylamide compounds and their use for treating hepatitis B. Specifically, the present invention discloses a compound having the structure shown in chemical formula (L) or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate, or solvate thereof, which can be used as an HBV replication inhibitor. For details of the definition of each group, please refer to the specification. The present invention further relates to a pharmaceutical composition comprising the above compound and its use for treating hepatitis B. [Formula 1] JPEG2022517984000188.jpg4875

Description

[Technical field]

[0001] The present invention relates to the medical field, specifically, the present invention relates to endocyclic thiamidinoamide-arylamide compounds and their use as drugs for treating Hepatitis B. [Background technology]

[0002] Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA), virus of the family Hepadnaviridae. Its genome contains four overlapping reading frames: the pronuclear / nuclear gene, the polymerase gene, the UM and S genes (which code for three envelope proteins), and the X gene. Before infection, this partially double-stranded DNA genome is converted into covalently closed circular DNA (cccDNA) in the host cell nucleus (open-loop DNA, rcDNA), from which the viral mRNA is transcribed. Once encapsidated, this pregenomic RNA (pgRNA) (which also codes for the core protein and Pol) serves as a template for reverse transcription to regenerate a portion of the dsDNA genome (rcDNA) within the nucleocapsid.

[0003] HBV causes epidemics in parts of Asia and Africa and is endemic in China. HBV has infected approximately 2 billion people worldwide, of which approximately 350 million have developed chronic infection. The virus causes hepatitis B disease, and chronic infection is associated with a high increased risk of developing cirrhosis and liver cancer.

[0004] Spread of hepatitis B virus results from exposure to infectious blood or body fluids, with viral DNA being detected in the saliva, tears, and urine of chronic carriers with high titers of DNA in serum. Although an effective and well-tolerated vaccine currently exists, direct treatment options are currently limited to interferon and antiviral drugs such as tenofovir, lamivudine, adefovir, entecavir, and telbivudine.

[0005] Furthermore, heteroaryldihydropyrimidines (HAPs) have been identified as HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78). WO2013 / 006394 (published January 10, 2013) and WO2013 / 096744 (published June 27, 2013) further disclosed sulfamoyl-arylamides that are involved in anti-HBV activity.

[0006] However, problems encountered with these direct HBV antivirals are toxicity, mutagenicity, lack of selectivity, low efficacy, poor bioavailability, and difficulty in synthesis. Therefore, in order to overcome the above drawbacks, it is necessary to develop HBV inhibitors with advantages such as high potency and low toxicity. Summary of the Invention [Problem to be solved by the invention]

[0007] It is an object of the present invention to provide structurally novel compounds which can be used as HBV inhibitors. [Means for solving the problem]

[0008] According to a first aspect of the present invention, there is provided a compound according to formula L, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof: [ka] where n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; [ka] is a substituted or unsubstituted 5- or 6-membered ring, wherein said 5- or 6-membered ring optionally contains one or more heteroatoms selected from the group consisting of O, S, N or P, said substitution meaning that the hydrogen atoms of the group are replaced by one or more substituents selected from the group consisting of C1-C3 alkyl groups (particularly methyl groups), C3-C4 cycloalkyl groups, cyano groups or halogens;

[0009] [ka] is a substituted or unsubstituted 5- or 6-membered aromatic ring or a substituted or unsubstituted 5- or 6-membered heteroaromatic ring,

[0010] X is -CR a R b - and Y is a substituted or unsubstituted C1-C7 alkylene group or a substituted or unsubstituted C2-C7 alkenylene group, wherein the substituents are selected from the group consisting of C1-C4 alkyl groups and hydroxyl groups; Z is selected from the group consisting of O, S, N, or P, or Z is a C-C single bond (i.e., Z is absent);

[0011] W is NRc or None; R1, R2, R3 and R4 are each independently selected from the group consisting of H, halogen, cyano, substituted or unsubstituted C3-C4 cycloalkyl, substituted or unsubstituted C1-C4 alkyl, and substituted or unsubstituted C1-C4 alkoxy, where the term "substitution" means that a hydrogen atom of the group is substituted with one or more substituents selected from the group consisting of halogen, C1-C4 alkyl (e.g., difluoromethyl, difluoroethyl, monofluoromethyl, trifluoromethyl, trifluoromethoxy);

[0012] R5 and R6 each independently represent H, a halogen, -CN, a hydroxyl group, an amino group, a carboxyl group, -(C=O)-substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C8 alkylamine group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C3-C 10 cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C 10 aryl groups, or substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from the group consisting of N, S and O;

[0013] R a , R b are each independently H, a halogen, -CN, a hydroxyl group, an amino group, a carboxyl group, -(C=O)-substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C8 alkylamine group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C1-C6 alkoxy-alkyl group, a substituted or unsubstituted C3-C 10 cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C 10 an aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S and O;

[0014] Rc is H, halogen, -CN, hydroxyl group, amino group, carboxyl group, -(C=O)-substituted or unsubstituted C1-C8 alkyl group, substituted or unsubstituted C1-C8 alkyl group, substituted or unsubstituted C2-C6 alkenyl group, substituted or unsubstituted C2-C6 alkynyl group, substituted or unsubstituted C1-C8 alkylamine group, substituted or unsubstituted C1-C8 alkoxy group, substituted or unsubstituted C3-C 10 cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C 10 an aryl group or a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S and O;

[0015] Unless otherwise specified, the term "substituted" includes halogen, C1-C6 alkyl group, halogenated C1-C6 alkyl group, C1-C6 alkoxy group, halogenated C1-C6 alkoxy group, C3-C8 cycloalkyl group, halogenated C3-C8 cycloalkyl group, oxo, -CN, hydroxyl group, amino group, carboxyl group, and C6-C 10 Aryl groups, halogenated C6-C 10 It means that the aryl group is unsubstituted or substituted by one or more substituents selected from the group consisting of an aryl group, a 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S, and O, and a halogenated 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S, and O, and the substituents are selected from the group consisting of halogen and C1-C6 alkoxy groups.

[0016] In another preferred example, Y is selected from the group consisting of a C1-C4 alkylene group, or a substituted or unsubstituted C2-C4 alkenylene group. In another preferred example, Ra and Rb are each independently a substituted or unsubstituted C1-C8 alkyl group or a substituted or unsubstituted C1-C8 alkoxy group, wherein the substituents are selected from the group consisting of halogen, a hydroxyl group, and a cyano group.

[0017] In another preferred embodiment, the compound has a structure shown in the following formula L-1, L-2, L-3, or L-4: [ka] In each formula, n is 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10; The definitions of A ring, B ring, X, R1, R2, R3, R4, R5, and R6 are as described in the first aspect of the present invention.

[0018] In another preferred example, Ra and Rb are each independently a substituted or unsubstituted C1-C8 alkyl group or a substituted or unsubstituted C1-C8 alkoxy group, wherein the substituents are selected from the group consisting of halogen, a hydroxyl group, and a cyano group.

[0019] In another preferred embodiment, the compound of formula I has the structure shown in formula II: [ka] Here, X1 is -CR= or -N=, X2 is -NR-, and R is H or a C1-C4 alkyl group. In another preferred example, X2 is -NCH3-.

[0020] In another preferred embodiment, the compound of formula I has the following structure: [ka] In another preferred embodiment, the compound of formula I has the structure shown in formula IV-1 or formula IV-2 below. [ka]

[0021] In another preferred embodiment, n is 1. In another preferred embodiment, Ra is selected from the group consisting of substituted or unsubstituted C1-C8 alkyl groups, substituted or unsubstituted C1-C8 alkoxy groups, substituted or unsubstituted C1-C6 alkoxy-alkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted or unsubstituted C3-C6 cycloalkyl groups, substituted C1-C4 alkyl groups, halogenated phenyl groups, and substituted or unsubstituted C1-C alkoxy-phenyl groups; Rb is H.

[0022] In another preferred embodiment, the Ra is selected from the group consisting of substituted or unsubstituted C1-C8 alkyl groups, where the substitution means a C6-C6 alkyl group in which one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of a C1-C4 alkoxy group, a hydroxyl group, a halogen, or a C1-C6 alkoxy group. 10 It is meant to be substituted with a substituent selected from the group consisting of aryl groups. In another preferred embodiment, the R a is selected from the group consisting of a substituted or unsubstituted C3-C6 cycloalkyl group, a substituted or unsubstituted C3-C6 cycloalkyl group substituted with a C1-C4 alkyl group, and a halogenated phenyl group.

[0023] In another preferred embodiment, the R a is selected from the group consisting of a cyclopropyl group, a methylene-cyclopropyl group, a 4-fluorophenyl group, and a 4-methoxyphenyl group. In another preferred embodiment, the compound has the structure shown in the formula: [ka]

[0024] In another preferred embodiment, the B ring is a benzene ring or a pyridine ring. In another preferred embodiment, the A ring is a pyrrole ring. In another preferred embodiment, [ka] teeth, [ka] It is.

[0025] In another preferred embodiment, R1, R2, R3 and R4 are each independently selected from the group consisting of H, halogen and cyano. In another preferred embodiment, R5 is H, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups are selected from the group consisting of: In another preferred embodiment, R6 is H, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C3-C 10 Cycloalkyl groups are selected from the group consisting of:

[0026] In another preferred embodiment, the compound is compound 10a1-100c20 in Table 1, where Peak 1 and Peak 2 are the order in which the enantiomers peak in reverse phase HPLC, Peak 1 being the enantiomer that peaked earlier and Peak 2 being the enantiomer that peaked later. In another preferred example, in the above table, HPLC is reverse-phase HPLC, where peak 1 refers to a compound with high polarity and peak 2 refers to a compound with low polarity.

[0027] According to a second aspect of the present invention there is provided a process for the preparation of a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharma-ceutically acceptable salt, hydrate or solvate thereof, said process comprising the steps of: [ka] In an inert solvent, using a compound of formula L1 [ka] to obtain a compound of formula L, wherein R is a leaving group and the remaining groups are defined as described in the first aspect of the invention.

[0028] In another preferred embodiment, the compound of formula L is a compound of formula VII-1, and the method comprises: [ka] The method includes the steps of: Here, Rg is H, halogen, -CN, a hydroxyl group, an amino group, a carboxyl group, -(C=O)- a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C8 alkylamine group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C3-C 10 cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C 10 aryl groups, or substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from the group consisting of N, S and O; The definition of each group is as above.

[0029] In another preferred embodiment, the compound of formula L is a compound of formula II-2, and the method comprises: [ka] The method includes the steps of: In each formula, the definitions of each group are as above. In another preferred embodiment, the compound of formula L is a compound of formula VII-3, and the method comprises: [ka] The method includes the steps of: In each formula, the definitions of each group are as above.

[0030] In another preferred embodiment, the compound of formula L is a compound of formula II-4, and the method comprises: [ka] The method includes the steps of: In each formula, the definitions of each group are as above. According to a third aspect of the present invention there is provided a compound selected from the group consisting of: [ka] In each formula, Rg is H, halogen, -CN, a hydroxyl group, an amino group, a carboxyl group, -(C=O)- a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C1-C8 alkyl group, a substituted or unsubstituted C2-C6 alkenyl group, a substituted or unsubstituted C2-C6 alkynyl group, a substituted or unsubstituted C1-C8 alkylamine group, a substituted or unsubstituted C1-C8 alkoxy group, a substituted or unsubstituted C3-C 10 cycloalkyl groups, substituted or unsubstituted 3-10 membered heterocycloalkyl groups having 1-3 heteroatoms selected from the group consisting of N, S and O, substituted or unsubstituted C6-C 10 aryl groups, or substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from the group consisting of N, S and O; The definition of each group is as described in the first aspect of the present invention.

[0031] According to a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising: (1) a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof; and (2) a pharma- ceutically acceptable carrier.

[0032] According to a fifth aspect of the present invention there is provided the use of a compound according to the first aspect of the present invention or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof or a pharmaceutical composition according to the fourth aspect of the present invention for use in the manufacture of a medicament for the prophylaxis and / or treatment of Hepatitis B viral infection.

[0033] According to a sixth aspect of the present invention, there is provided a Hepatitis B virus inhibitor comprising a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

[0034] According to a seventh aspect of the present invention there is provided a method of preventing and / or treating Hepatitis B comprising the step of administering to a patient in need thereof a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to the fourth aspect of the present invention.

[0035] According to an eighth aspect of the present invention there is provided a method of inhibiting replication of Hepatitis B virus comprising the step of contacting a compound according to the first aspect of the present invention, or a stereoisomer or tautomer thereof, or a pharma-ceutically acceptable salt, hydrate or solvate thereof with Hepatitis B virus to inhibit replication of Hepatitis B virus. Effect of the Invention

[0036] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0037] After extensive and in-depth research, the present inventors have discovered a novel compound with excellent therapeutic effect against hepatitis B. Based on this, the present inventors have completed the present invention.

[0038] definition The term "alkyl group" as used herein includes straight or branched chain alkyl groups. For example, C1-C8 alkyl means straight or branched chain alkyl groups having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc.

[0039] The term "alkenyl group" as used herein includes straight-chain or branched alkenyl groups. For example, a C2-C6 alkenyl group refers to a straight-chain or branched alkenyl group having 2-6 carbon atoms, such as vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-butenyl, or similar groups.

[0040] The term "alkynyl group" as used herein includes straight-chain or branched-chain alkynyl groups. For example, C2-C6 alkynyl refers to straight-chain or branched-chain alkynyl groups having 2-6 carbon atoms, such as ethynyl, propynyl, butynyl, or similar groups.

[0041] As used herein, the term "C3-C 10 "Cycloalkyl group" refers to a cycloalkyl group having from 3 to 10 carbon atoms. It may be a monocyclic ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or similar groups, or it may be in the form of a bicyclic ring, such as a bridged or spirocycle.

[0042] The term "C1-C8 alkylamine group" as used herein refers to an amine group substituted with a C1-C8 alkyl group, which may be mono- or di-substituted methylamino, ethylamino, propylamino, isopropylamine, butylamine, isobutylamine, tert-butylamine, dimethylamine, diethylamine, dipropylamine, diisopropylamine, dibutylamineamino, diisobutylamino, di-tert-butylamino, and the like.

[0043] The term "C1-C8 alkoxy group" as used herein refers to a straight or branched chain alkoxy group having 1 to 8 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, and the like.

[0044] The term "3-10 membered heterocycloalkyl group having 1-3 heteroatoms selected from the group consisting of N, S and O" as used herein refers to a saturated or partially saturated ring group having 3-10 atoms, of which 1-3 atoms are heteroatoms selected from the group consisting of N, S and O. It may be monocyclic or bicyclic, such as a bridged or spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl.

[0045] As used herein, the term "C6-C 10 "Aryl group" refers to an aryl group having 6-10 carbon atoms, for example, phenyl or naphthyl and similar groups. The term "5-10 membered heteroaryl group having 1-3 heteroatoms selected from the group consisting of N, S and O" as used herein refers to a cyclic aromatic group having 5-10 atoms in its ring and 1-3 atoms being heteroatoms selected from the group consisting of N, S and O. It may be a monocyclic or fused ring system. Specific examples are pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-triazole, tetrazolyl, furanyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, and the like.

[0046] Unless specifically described as "substituted or unsubstituted", the groups described in the present invention include halogen, nitrile, nitro, hydroxyl, amino, C1-C6 alkyl-amine, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy, halogenated C1-C6 alkyl, halogenated C2-C6 alkenyl, halogenated C2-C6 alkynyl, halogenated C1-C6 alkoxy, allyl, benzyl, C6-C6 alkyl, C1-C6 alkoxy, C1-C6 alkyl group, C1-C6 alkenyl, C2-C6 alkynyl, C1-C6 alkoxy ... 12 It may be substituted with a substituent selected from the group consisting of an aryl group, a C1-C6 alkoxy group-C1-C6 alkyl group, a C1-C6 alkoxy group-carbonyl group, a phenoxycarbonyl group, a C2-C6 alkynyl group-carbonyl group, a C2-C6 alkenyl group-carbonyl group, a C3-C6 cycloalkyl group-carbonyl group, a C1-C6 alkyl group-sulfonyl group, and the like.

[0047] As used herein, the term "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from F, Cl, and Br. "Halogenated" refers to substitution with an atom selected from F, Cl, Br, and I.

[0048] Unless otherwise stated, the structural formulae depicted in the present invention are intended to include all isomeric forms (enantiomers, diastereomers, geometric (or conformational) isomers, etc.), including, for example, R,S configurations having asymmetric centers, (Z), (E) isomers of double bonds, etc. Thus, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric (or conformational) isomers are within the scope of the present invention.

[0049] The term "tautomers" as used herein means that structural isomers with different energies can cross a low energy barrier and thereby be converted into each other. For example, proton tautomers (i.e., proton shift) include interconversions by proton migration such as 1H-indazole and 2H-indazole. Valence tautomers include interconversions by rearrangement of some bond electrons.

[0050] The term "solvate" as used herein refers to a complex of a specific ratio formed when a compound of the present invention coordinates with solvent molecules to form a specific ratio. As used herein, the term "hydrate" refers to a complex formed by coordinating a compound of the present invention with water.

[0051] active ingredient As used herein, the term "compounds of the invention" refers to compounds of formula L, and further includes various crystal forms, pharma- ceutically acceptable salts, hydrates or solvates of the compounds of formula L. [ka]

[0052] The term "pharmaceutical acceptable salt" as used herein refers to a salt suitable for use as a drug formed by the compound of the present invention and an acid or base. Pharmaceutically acceptable salts include inorganic salts and organic salts. One preferred salt is a salt formed by the compound of the present invention and an acid. The acid suitable for forming a salt includes, but is not limited to, inorganic acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid, and acidic amino acids such as aspartic acid, glutamic acid, and the like.

[0053] In another preferred example, the A ring, the B ring, R1, R2, R3, R4, R5, and R6 are each independently a group corresponding to each compound in Table 1. Preferred compounds of the present invention are as shown in Table 1. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

Table 1-10

Table 1-11

Table 1-12

Table 1-13

Table 1-14

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

Table 1-32

Table 1-33

Table 1-34

Table 1-35

Table 1-36

Table 1-37

Table 1-38

Table 1-39

Table 1-40

Table 1-41

Table 1-42

Table 1-43

[0054] Pharmaceutical Compositions and Methods of Administration Since the compound of the present invention has excellent inhibitory activity against hepatitis B virus (HBV), the compound of the present invention and its various crystal forms, pharma- ceutically acceptable inorganic or organic salts, hydrates or solvates, and pharmaceutical compositions containing the compound of the present invention as a main active ingredient can be used to prevent and / or treat (stabilize, alleviate or cure) hepatitis B virus infection, or can be used to prevent and / or treat (stabilize, alleviate or cure) hepatitis B virus-related diseases (e.g., hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, ethyl hepatoma).

[0055] The pharmaceutical composition of the present invention comprises a safe and effective amount of the compound of the present invention and a pharma- ceutical acceptable excipient or carrier. Here, "safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention / drug, more preferably 10-200 mg of the compound of the present invention / drug. More preferably, the "drug" is a capsule or tablet.

[0056] "Pharmaceutically acceptable carrier" refers to one or more compatible solid or liquid fillers or gel substances that must be of sufficient purity and sufficiently low toxicity to be suitable for human use. In this context, "compatible" means that each component of the composition can be blended with the compound of the present invention without significantly reducing the pharmacological effect of the compound. Examples of pharmaceutically acceptable carriers include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate, etc.), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., TweenR), wetting agents (e.g., sodium lauryl sulfate), colorants, flavors, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0057] The method of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative administration methods include, but are not limited to, oral and parenteral (intravenous, intramuscular, or subcutaneous). Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or the following ingredients: (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, silicic acid, (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, gum arabic, (c) humectants, such as glycerol, (d) disintegrants, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate, (e) slow solvents, such as paraffin, (f) absorption enhancers, such as quaternary amine compounds, (g) wetting agents, such as cetyl alcohol and glyceryl monostearate, (h) adsorbents, such as kaolin, and (i) lubricants, such as talc, calcium stearate, magnesium stearate, solid, polyethylene glycol, sodium lauryl sulfate, solid polyethylene glycol, sodium lauryl sulfate, or mixtures thereof. For capsules, tablets, and pills, the dosage forms may also comprise buffering agents.

[0058] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using shell materials such as coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound of such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and wax-based substances. If necessary, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0059] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups or tinctures.In addition to the active compound, liquid dosage forms can contain water or other solvents, solubilizers, and emulsifiers, and other inert diluents conventionally used in the art, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures thereof.

[0060] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In addition to the active compounds, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar, or mixtures thereof.

[0061] Compositions for parenteral injection can include physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients can include water, ethanol, polyols, and suitable mixtures thereof.

[0062] The compounds of the present invention can be administered alone or in combination with other pharma- ceutically acceptable compounds (eg, anti-HBV agents). When administered in combination, the pharmaceutical composition also contains one or more (2, 3, 4, or more) other pharma- ceutically acceptable compounds (e.g., anti-HBV agents). One or more (2, 3, 4, or more) of the other pharma- ceutically acceptable compounds (e.g., anti-HBV agents) can be used simultaneously, separately, or sequentially with the compounds of the present invention to prevent and / or treat HBV infection or HBV-related diseases.

[0063] When using a pharmaceutical composition, a safe and effective amount of the compound of the present invention is applied to a mammal (e.g., human) in need of treatment, and the dose administered is a pharmacologic effective dose. For a person weighing 60 kg, the daily dose is usually 1 mg to 2000 mg, preferably 20 mg to 500 mg. Of course, the specific dose must also take into account factors such as the route of administration and the health of the patient, all of which are within the skill of a skilled physician.

[0064] The present invention includes the following main advantages: (1) The compound of the present invention has a novel structure and has excellent anti-HBV infection effect. In this application, the existing sulfoxide amide-aryl amide compound is converted into an intracyclic thiamidino amide-aryl amide compound, which can better interfere with the assembly process of capsid protein, thereby inhibiting the activity or expression of HBV.

[0065] (2) The compounds of the present invention have extremely low toxicity to normal cells and can therefore be applied to therapeutic subjects over a wide range of doses.

[0066] (3) The compounds of the present invention have good drug manufacturing properties, and compared with existing compounds, the compounds of the present invention have better solubility and show good bioavailability in in vivo experiments, and the availability of some compounds is more than 70%. In addition, the compounds of the present invention are very easy to be converted into pharma- ceutically acceptable salts compared with existing compounds, which contributes to the further formation of formulations.

[0067] (4) The compounds of the present invention and pharmaceutical compositions containing the compounds of the present invention as a main active ingredient can be used to prevent and / or treat hepatitis B virus-related diseases (e.g., hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, ethyl hepatoma).

[0068] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. Experimental methods without specific conditions in the following examples are usually based on conventional conditions or conditions recommended by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight. Unless otherwise specified, raw materials or equipment used in the examples of the present invention can be purchased commercially.

[0069] The synthesis of compounds in the 10 series is given below. Example 1: Synthesis of Compound 10a [ka]

[0070] Step 1: Synthesis of compound 2 [ka] Compound 1 (10 g) was dissolved in dichloromethane (40 mL), and aqueous ammonia (30 mL) was added dropwise to the reaction system at room temperature. The reaction was allowed to proceed for 5 hours at room temperature, and the mixture was filtered under suction. The filter cake was washed with water (5 mL) to obtain 5 g of a pale yellow solid of 2. MS (M+1=267).

[0071] Step 2: Synthesis of compound 3 [ka] Substrate 2 (5 g) was dissolved in DMF (10 mL), sodium hydride (1.5 g) was added to the reaction system at 0 degrees, stirred for 15 minutes, TBDPSCl was added to the reaction system, reacted for 18 hours, poured into ice water, extracted with ethyl acetate (3*30 mL), dried the organic phase, spun dry, and the crude product was subjected to column chromatography (N-heptane:ethyl acetate=1:4) to obtain product 3 (3 g). MS (M+1=505).

[0072] Step 3: Synthesis of compound 4 [ka] After cooling PPh3Cl2 chloroform solution (80 mL) to 0 degrees, triethylamine (7 mL) was added and stirred for 10 minutes, compound 3 was added at 0 degrees, and after stirring for 20 minutes, 2-isopropyl-3-propenylamine was added to the reaction system and reacted at room temperature for 18 hours, water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3*25 mL), the organic phase was dried, spin-dried, and the crude product was subjected to column chromatography (N-heptane:ethyl acetate=1:5) to obtain product 4 (1.9g). MS (M+1=586).

[0073] Step 4: Synthesis of compound 5 [ka] Compound 4 (1.8 g), tetratriphenylphosphine palladium (100 mg), vinyl borate (900 g), and cesium carbonate (2.7 g) were dissolved in DMF (410 mL), and reacted at 100 degrees for 15 hours under nitrogen gas protection, quenched with an aqueous solution, extracted with ethyl acetate, dried the organic phase, spun dry, and the resulting crude product was subjected to column chromatography (N-heptane:ethyl acetate=1:5) to obtain compound 5 (1.0 g). MS (M+1=340).

[0074] Step 5: Synthesis of compound 6 [ka] Compound 5 (1.0 g) was dissolved in dichloromethane (500 mL), and Zhan Catalysts (0.1 g) was added to the reaction system, stirred overnight, the reaction solution was spun dry, and the crude product was purified by column chromatography (N-heptane:ethyl acetate=1:3) to obtain compound 6. TLC showed bottom point 6-1 (0.22 g), TLC showed top point 6-2 (0.27 g) MS (M+1=312).

[0075] Step 6: Synthesis of compound 10a1 [ka] Compound 6-1 (30 mg) and 4-fluoro-3-cyanoaniline (20 mg) were dissolved in tetrahydrofuran (5 mL), and the temperature was lowered to 0 degrees. NaHMDS (0.2 mL) was added to the reaction system, and the reaction was allowed to proceed with stirring at room temperature for 16 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate (3*15 mL). The organic phase was dried over anhydrous sodium sulfate and spin-dried. The crude product was subjected to column chromatography (N-heptane:ethyl acetate=1:3) to obtain the target product 10a1 (11 mg). 1 H nMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.89 - 7.83 (m, 1H), 7.71 (s, 1H), 7.44 (qd, J = 4.7, 4.2, 2.5 Hz, 2H), 6.54 (dd, J = 12.4, 2.7 Hz, 1H), 5.75 (dd, J = 12.4, 2.8 Hz, 1H), 4.0 (dq, J = 7.8, 2.6 Hz, 1H), 3.74 (s, 3H), 1.97-1.89 (m, 1H), 0.98 (dd, J = 12.6, 6.7 Hz, 6H). MS(M+1=395).

[0076] Example 2: Synthesis of Compound 10a2 [ka] According to step 6 of Example 1, only compound 6-2 was used instead of compound 6-1, and other conditions were not changed, and the target product 10a2 (8 mg) was obtained by column chromatography (N-heptane:ethyl acetate=1:1). 1H nMR (400 MHz, DMSO-d6) δ 10.69 (s, 1H), 7.89 - 7.83 (m, 1H), 7.51 (s, 1H), 7.44 (qd, J = 4.7, 4.2, 2.5 Hz, 2H), 6.53 (dd, J = 12.4, 2.7 Hz, 1H), 5.72 (dd, J = 12.4, 2.8 Hz, 1H), 3.87 (dq, J = 7.8, 2.6 Hz, 1H), 3.72 (s, 3H), 1.91-1.85 ( m, 1H), 0.96 (dd, J = 12.6, 6.7 Hz, 6H). MS(M+1=395).

[0077] Example 3: Synthesis of Compound 10b1 [ka]

[0078] Step 1: Synthesis of compound 7 [ka] 2 (2.5 g), vinyl borate (1.5 g), sodium carbonate (3.5 g), palladium acetate (120 mg) and Xphos (500 mg) were dissolved in DMF, and the reaction system was reacted in an oil bath at 100 degrees for 6 hours under nitrogen gas protection, water (50 mL) was added to the reaction system, and the reaction system was extracted with ethyl acetate (3*60 mL), dried over anhydrous sodium sulfate, spin-dried, and column chromatography was performed to obtain 1.2 g of a yellow solid. MS (M+1=259).

[0079] Step 2: Synthesis of compound 8 [ka] The temperature of the reaction system was lowered to 0 degrees, sodium hydride (180 mg) was added to DMF, and the mixture was stirred for 10 minutes. At 0 degrees, a DMF solution of TBDPSCl (2.7 g) and 7 (1.1 g) was added dropwise to the reaction system, and the mixture was reacted at room temperature for 1.5 hours. The reaction solution was added dropwise to a mixed solution of 1NHCl and saturated ammonium chloride, extracted with ethyl acetate (3*50 mL), dried over anhydrous sodium sulfate, and the organic phase was spin-dried. 800 mg of a white solid was obtained by column chromatography. MS (M+1=497). 1 H nMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.62 - 7.59 (m, 1H), 7.45 - 7.41(m, 1H), 7.33 - 7.29 (m, 3H), 7.13 (qd, J = 4.7, 4.2, 2.5 Hz, 2H), 6.16 (dd, J = 12.4, 2.7 Hz, 1H), 5.58 (dd, J = 12.4, 2.8 Hz, 1H), 5.09 (s, 1H), 4.35-4.40 (m, 2 ), 3.56 (s, 3H), 1.45-1.40 (m,3), 1.04 (s, 9H).

[0080] Step 3: Synthesis of compound 11 [ka] The temperature of the PPh3Cl2 mixture was lowered to 0 degrees, and triethylamine (3 mL) was added to the reaction system after completion of the dropwise addition, and the reaction was allowed to proceed at 0 degrees for 10 minutes. Then, solid 8 (500 mg) was added to the reaction system at once, and the reaction was allowed to proceed at 0 degrees for 20 minutes. Finally, a solution of isopropylallylamine (200 mg) in chloroform was added to the reaction system, and the reaction was allowed to proceed at room temperature for 18 hours. Silica gel was added directly to the reaction system, and after spin drying, 650 mg of pale yellow oil was obtained by column chromatography. MS (M+1=578) 1H nMR (400 MHz, DMSO-d6) δ 7.81 - 7.73 (m, 4H), 7.38-7.32 (m, 7H), 7.06 - 6.91 (m, 2H), 6.01-5.89 (m, 1 H), 5.48-5.33 (m, 2 H), 4.92-4.70 (m, 2 H), 4.36-4.30 (m, 2 H), 3.79 (s, 1.55H), 3.76 (s, 1.36H), 3.50-3.41(m, 1H ),1.71-1.66 (m, 0. 5H ),1.56-1.51 (m, 0.5H), 1.40-1.35 (m, 3 ),1.14 (s, 4.2H), 1.12 (s, 4.5H),0.76-0.73 (m,3H), 0.68-0.64 (m,3H).

[0081] Step 4: Synthesis of compound 12 [ka] Compound 11 (650 mg) was dissolved in 1,2-dichloroethane, and zhan1B was added to the reaction system. Under nitrogen gas protection, the temperature of the system was raised to 70°C and stirred for 24 hours. Silica gel was added directly to the reaction system, and after spin drying, pale yellow oil 12 was obtained by column chromatography. TLC showed bottom point 12-1 (0.22 g), TLC showed top point 12-2 (0.27 g) MS (M+1=550). 1 H nMR (400 MHz, DMSO-d6) δ 7.81 - 7.74 (m, 5H), 7.40-7.37 (m, 7H), 7.28-7.21 (m, 1H), 6.01-5.89 (m, 1H), 6.99 (s, 1H), 5.77-5.73 (m, 1 H), 4.42-4.35 (m, 2 H), 4.15-4.11 (m, 1 H), 3.80 (s, 3H), 1.91-1.86 (m, 1H ), 1.43-1.39 (m, 3 ), 1.14 (s, 9H), 0.87-0.78 (m,6H).

[0082] Step 5: Synthesis of compound 13 [ka] 12-1 (90 mg) (TLC bottom point) and 3,4-difluoroaniline (43 mg) were dissolved in THF (8 mL), the temperature of the system was lowered to 0 degrees, 6 equivalents of NaHMDS were added to the reaction system, and the reaction was allowed to proceed at 0 degrees for 1 hour. Water (20 mL) was added to the reaction system, and the reaction system was extracted with ethyl acetate (3*30 mL), dried over anhydrous sodium sulfate, spin-dried, and subjected to column chromatography to obtain 80 mg of a yellow oil. MS (M+1=640).

[0083] Step 6: Synthesis of Compound 10b1 [ka] 13-1 (40 mg) (TLC bottom point) was dissolved in THF (3 mL), 120 equivalents of 3HF.TEA was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 3 days. The preparation plate was separated and lyophilized to obtain a white solid 10b1 (4.5 mg). 1 H nMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 8.18 (dd, J = 5.8, 2.7 Hz, 1H), 7.99(ddd, J = 9.2, 4.8, 2.7 Hz, 1H), 7.78- 7.70 (m, 2H), 7.57 (d, J = 10.3 Hz, 1H), 6.57 (dd, J = 12.4, 2.7 Hz, 1H), 5.77 (dd, J = 12.4, 2.8 Hz, 1H), 4.07 (ddt, J = 10.6, 5.4, 2.7 Hz, 1H), 3.76 (s, 3H), 1.92 (tq, J = 12.1, 6.7, 5.6 Hz, 1H), 0.99 (dd, J = 12.0, 6.7 Hz, 6H). Ms(ESI) m / z = 402(M+1)

[0084] Example 4: Synthesis of Compound 10b2 [ka] According to step 6 of Example 3, only compound 13-2 (top point as shown by TLC) was used instead of compound 13-1 (bottom point as shown by TLC), and other conditions were not changed, and the target product 10b2 (8 mg) was obtained by column chromatography (N-heptane:ethyl acetate=1:1). 1 H nMR (400 MHz, DMSO-d6) δ 10.89 (s, 1H), 8.20 (dd, J = 5.8, 2.7 Hz, 1H), 7.97(ddd, J = 9.2, 4.8, 2.7 Hz, 1H), 7.90- 7.88 (m, 2H), 7.56 (d, J = 10.3 Hz, 1H), 6.65(dd, J = 12.4, 2.7 Hz, 1H), 5.91 (dd, J = 12.4, 2.8 Hz, 1H), 3.80 (s, 3H), 3.69-3.63(m, 1H), 1.95 (tq, J = 12.1, 6.7, 5.6 Hz, 1H), 0.99 (dd, J = 12.0, 6.7 Hz, 6H). Ms(ESI) m / z = 402(M+1)

[0085] According to the synthesis method of Example 3, the following 10 and 30 series compounds were also synthesized. [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18] [Table 2-19] [Table 2-20] The following is the synthesis of 20 series compounds.

[0086] Example 72: Synthesis of Compound 20a1 [ka]

[0087] Step 1 [ka] Compound 10a1 (20 mg) was dissolved in methanol (5 mL), palladium on carbon (5 mg) was added to the reaction system, and the reaction was carried out at room temperature for 6 hours under the protection of hydrogen gas. The crude product was subjected to column chromatography (n-heptane:ethyl acetate=1:3) to obtain the target product 20a1 (11 mg). 1 H nMR (400 MHz, DMSO-d6) δ 10.56 (s, 1H), 7.88- 7.83 (m, 1H), 7.63 (s, 2H), 7.46- 7.42 (m, 1H), 7.21- 6.96 (m, 1H), 3.72 (s, 3H), 3.12 - 3.09 (m, 1H), 3.00 (dd, J = 15.0, 6.7 Hz, 1H), 2.89 - 2.78(m, 1H), 1.89-1.85 (m, 1H), 1.69-1.50 (m, 1H), 1.43 (q, J = 12.0 Hz, 1H), 0.92 (dd, J = 6.8, 3.5 Hz, 6H). MS(M+1=397).

[0088] Example 73: Synthesis of Compound 20a2 [ka] According to step 6 of Example 1, only compound 10a2 was used instead of compound 10a1, and other conditions were not changed, and the target product 20a2 (8 mg) was obtained by column chromatography (N-heptane:ethyl acetate=1:1). 1H nMR (400 MHz, DMSO-d6) δ 10.67 (s, 1H), 8.20- 8.18 (m, 1H), 7.97 (d, J = 3.7 Hz, 1H), 7.68- 7.59 (m, 1H), 7.55 (d, J = 10.3 Hz, 1H), 3.76 (s, 3H), 3.04 - 2.92 (m, 2H), 2.85 (dd, J = 15.0, 6.7 Hz, 1H), 1.90 - 1.83 (m, 1H), 1.73 (dd, J = 14.3, 6.7 Hz, 1H), 1.69-1.50 (m, 1H), 1.45 (q, J = 12.0 Hz, 1H), 0.89 (dd, J = 6.8, 3.5 Hz, 6H). MS(M+1=397).

[0089] Example 74: Synthesis of Compound 20b1 [ka]

[0090] Step 1 [ka] Compound 1 (150 mg) was dissolved in methanol (8 mL), Pd / C (30 mg) was added to the reaction system, and the system was ventilated with nitrogen gas three times and with hydrogen gas three times. The system was reacted under hydrogen gas balloon conditions at room temperature (25 degrees) for 18 hours, and the reaction of the raw material was detected to be complete by TLC. The system was suction filtered, the solvent was spin-dried, and the target product was obtained by column chromatography (N-heptane: ethyl acetate = 5: 1) in an amount of 130 mg. MS (M+1 = 552).

[0091] Step 2 [ka] 12-1 (45 mg) and 3-cyano-4-fluoroaniline (23 mg) were dissolved in THF (6 mL), the temperature of the system was lowered to 0 degrees, 8 equivalents of NaHMDS were added to the reaction system, and the reaction was allowed to proceed at 0 degrees for 1 hour. Water (20 mL) was added to the reaction system, and the reaction system was extracted with ethyl acetate (3*30 mL), dried over anhydrous sodium sulfate, spin-dried, and 18 mg of a yellow oil was obtained by column chromatography. MS (M+1=640).

[0092] Step 3: Synthesis of compound 20b1 [ka] 2 (18 mg) was dissolved in THF (3 mL), 50 equivalents of 3HF.TEA was added dropwise to the reaction system, and the reaction was allowed to proceed at room temperature for 3 days. The preparation plate was separated and lyophilized to obtain 4.0 mg of the target product as a white solid. 1 H nMR (400 MHz, DMSO-d6) δ 10.77(s, 1H), 8.20 (dd, J = 5.8, 2.7 Hz, 1H), 7.98 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.90 (s, 1H), 7.51 (t, J = 9.1 Hz, 1H), 3.77 (s, 3H), 3.11 - 3.02 (m, 2H), 2.89 - 2.87 (m, 1H), 1.97-1.92 (m, 1H), 1.78-1.73 (m, 1H), 1.60-1.51 (m, 1H), 0.96 (dd, J = 6.8, 3.4 Hz, 6H).Ms(ESI) m / z = 404(M+1)

[0093] Example 75: Synthesis of Compound 20b2 [ka] According to step 3 of example 74, only compound 19b2 was used instead of compound 19b1, and other conditions were not changed, and the target product 20b2 (8 mg) was obtained by column chromatography (N-heptane:ethyl acetate=1:1). 1H nMR (400 MHz, DMSO-d6)δ 10.67 (s, 1H), 8.19 (dd, J = 5.8, 2.7 Hz, 1H), 7.97 (ddd, J = 9.2, 4.9, 2.7 Hz, 1H), 7.68 (s, 1H), 7.57 (t, J = 9.1 Hz, 1H), 3.76 (s, 3H), 3.04-2.92(m, 2H), 2.85 - 2.83 (m, 1H), 1.90-1.83 (m, 1H), 1.74-1.69 (m, 1H), 1.67-1.46 (m, 1H), 0.89 (dd, J = 6.8, 3.4 Hz, 6H).Ms(ESI) m / z = 404(M+1)

[0094] According to the synthesis method of Example 72 or Example 74, the following 20 and 40 series compounds were also synthesized. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6] [Table 3-7] [Table 3-8] [Table 3-9] [Table 3-10] [Table 3-11] [Table 3-12] [Table 3-13] [Table 3-14] [Table 3-15] [Table 3-16] [Table 3-17] [Table 3-18] [Table 3-19] [Table 3-20] [Table 3-21] The following is the synthesis of the 50 series compounds.

[0095] Example 167: Synthesis of compound 50a1 [ka]

[0096] Step 1: Synthesis of compound 42 [ka] Compound 41 (10 g) was dissolved in dichloromethane (40 mL), and methylamine aqueous solution (30 mL) was added dropwise to the reaction system at room temperature. The reaction was allowed to proceed for 5 hours at room temperature, and the mixture was filtered by suction. The filter cake was washed with water (5 mL) to obtain 5 g of 42, a pale yellow solid. MS (M+1=281).

[0097] Step 2: Synthesis of compound 43 [ka] After cooling PPh3Cl2 chloroform solution (80 mL) to 0 degrees, triethylamine (7 mL) was added and stirred for 10 minutes, and compound 42 was added at 0 degrees. After stirring for 20 minutes, 2-isopropyl-3-propenylamine (5 g) was added to the reaction system and reacted at room temperature for 18 hours. Water (20 mL) was added to the reaction system, and the mixture was extracted with ethyl acetate (3*25 mL). The organic phase was dried, spin-dried, and the crude product was subjected to column chromatography (N-heptane:ethyl acetate=1:5) to obtain product 43 (400 mg). MS (M+1=362).

[0098] Step 3: Synthesis of compound 44 [ka] Compound 43 (1.8 g), tetratriphenylphosphine palladium (100 mg), vinyl borate (900 g), and cesium carbonate (2.7 g) were dissolved in DMF (410 mL), and reacted at 100 degrees for 15 hours under nitrogen gas protection, quenched with an aqueous solution, extracted with ethyl acetate, dried the organic phase, spun dry, and the obtained crude product was subjected to column chromatography (N-heptane:ethyl acetate=1:5) to obtain compound 44 (0.5 g). MS (M+1=354).

[0099] Step 4: Synthesis of compound 45 [ka] Compound 44 (1.0 g) was dissolved in dichloromethane (500 mL), and Zhan Catalysts (0.1 g) was added to the reaction system, stirred overnight, spun dry, and the crude product was purified by column chromatography (N-heptane:ethyl acetate=1:3) to give compound 45. TLC showed bottom point 45-1 (0.22 g), TLC showed top point 45-2 (0.27 g) MS (M+1=312).

[0100] Step 5: Synthesis of compound 50a1 [ka] Compound 45-1 (30 mg) and 4-fluoro-3-cyanoaniline (20 mg) were dissolved in tetrahydrofuran (5 mL), and the temperature was lowered to 0 degrees. Then, NaHMDS (0.2 mL) was added to the reaction system, and the reaction was stirred at room temperature for 16 hours. Water was added to the reaction system, and the mixture was extracted with ethyl acetate (3*15 mL). The organic phase was dried with anhydrous sodium sulfate, spin-dried, and the crude product was subjected to column chromatography (N-heptane:ethyl acetate=1:3) to obtain the target product 50a1 (11 mg). MS (M+1=409). Following the synthesis method of Example 167, the following 50 series compounds were also synthesized. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6] The following is the synthesis of the 60 series compounds.

[0101] Example 186: Synthesis of compound 60a1 [ka] Step 1 [ka] Compound 50a1 (20 mg) was dissolved in methanol (5 mL), palladium on carbon (5 mg) was added to the reaction system, and the mixture was reacted at room temperature for 6 hours under the protection of hydrogen gas. The crude product was subjected to column chromatography (n-heptane:ethyl acetate=1:3) to obtain the target product 60a1 (11 mg). MS (M+1=411). Following the synthesis method of Example 186, the following 60 series compounds were also synthesized. [Table 5-1] [Table 5-2] [Table 5-3] [Table 5-4] [Table 5-5] [Table 5-6] [Table 5-7] Below are the syntheses of the 70, 80 and 90 series compounds.

[0102] Example 234: Synthesis of compound 70a1 Following the synthetic steps of Example 74 and Example 167, the following list of compounds can be obtained by substituting pyrazole-based compounds for pyrrole-based compounds. [Table 6-1] [Table 6-2] [Table 6-3]

[0103] Example 235: Synthesis of Compound 100a03 and Compound 100a04 [ka]

[0104] Step 1: Synthesis of Compound 2 [ka] Compound 1 (10 g) was dissolved in dichloromethane (40 mL), and aqueous ammonia (30 mL) was added dropwise to the reaction system at room temperature. The reaction was allowed to proceed for 5 hours at room temperature, and the mixture was filtered under suction. The filter cake was washed with water (5 mL) to obtain 5 g of a pale yellow solid of 2. MS (M+1=267).

[0105] Step 2: Synthesis of compound 3 [ka] Compound 2 (1.8 g), XPhos Pd G3 (100 mg), vinylboronic acid pinacolate (3.12 g), and cesium carbonate (2.7 g) were dissolved in DMF (180 mL) / water (18 ml), and reacted at 100°C for 15 hours under nitrogen gas protection. The reaction was quenched with an aqueous solution, extracted with ethyl acetate, the organic phase was dried, and the resulting crude product was purified by column chromatography (n-heptane:ethyl acetate=1:5) to obtain compound 5 (0.89 g), MS (M+1=259).

[0106] Step 3: Synthesis of compound 4 [ka]

[0107] Dissolve substrate 3 (5.0 g) in DMF (50 mL), add sodium hydride (560 mg) to the reaction system at 0°C, stir for 15 minutes, then add TBDPSCl (6.38 g) to the reaction system and react for 18 hours. Pour the reaction system into ice water, extract with ethyl acetate (3*30 mL), dry the organic phase, spin-dry, and subject the crude product to column chromatography (n-heptane:ethyl acetate=1:4) to obtain product 4 (9.03 g). 1H NMR (400 MHz, DMSO-d6) δ 10.78 (s, 1H), 7.62 - 7.59 (m, 1H), 7.45 - 7.41(m, 1H), 7.33 - 7.29 (m, 3H), 7.13 (qd, J = 4.7, 4.2, 2.5 Hz, 2H), 6.16 (dd, J = 12.4, 2.7 Hz, 1H), 5.58 (dd, J = 12.4, 2.8 Hz, 1H), 5.09 (s, 1H), 4.35-4.40 (m, 2 ), 3.56 (s, 3H), 1.45-1.40 (m,3), 1.04 (s, 9H). MS(M+1=497).

[0108] Step 4: Synthesis of compound 5 [ka] PPh3Cl2 (3.63 g) was added to chloroform (80 mL) and cooled to 0°C, then triethylamine (7 mL) was added, stirred for 10 minutes, and then compound 4 (5.00 g) was added at 0°C, stirred for 20 minutes, and then (R)-1-cyclopropylprop-2-en-1-amine (962 mg) was added to the reaction system, and reacted at room temperature for 18 hours, water (20 mL) was added to the reaction system, and extracted with ethyl acetate (3*30 mL), the organic phase was dried, spin-dried, and the crude product was separated by column chromatography (n-heptane:ethyl acetate=1:5) to obtain product 5 (3.47 g), which is a mixture of a pair of epimers. MS (M+1=585).

[0109] Step 5: Synthesis of compound 6 [ka] Compound 5 (1.0 g) was dissolved in dichloroethane (500 ml), then Chang's catalyst (0.1 g) was added to the reaction system, and the mixture was stirred overnight under heating and refluxing, the reaction solution was spun dry, and separated by column chromatography (n-heptane:ethyl acetate=1:3) to obtain two compounds which are chiral isomers on the sulfur atom. The upper point shown by TLC is 6-1 (0.35 g) MS (M+1=548), and the lower point shown by TLC is 6-2 (0.35 g) MS (M+1=548).

[0110] Step 6: Synthesis of compound 7-1 [ka] Compound 6-1 (30 mg) and 4-fluoro-3-cyanoaniline (20 mg) are dissolved in tetrahydrofuran (5 mL), cooled to 0°C, then NaHMDS (0.2 mL) is added to the reaction system, and the mixture is stirred at room temperature for 16 hours. Water is added to the reaction system, and the mixture is extracted with ethyl acetate (3*15 mL). The organic phase is dried over anhydrous sodium sulfate and spin-dried. The crude product is purified by column chromatography (n-heptane:ethyl acetate=1:3) to obtain the desired product, compound 7-1 (11 mg). MS (M+1=638). Following the steps above, compound 7-2 can be obtained by substituting compound 6-2 for compound 6-1.

[0111] Step 7: Synthesis of compound 100a04 [ka] Compound 7-1 (40 mg) was dissolved in THF (3 mL), and then 3HF.TEA (1 ml) was added dropwise to the reaction system, and the mixture was reacted at room temperature for 3 days. Compound 100a04 (4.5 mg), m / z=400 (M+1), was obtained as a white solid by preparative TLC separation and purification. Compound 100a03 can be obtained by following the steps above and substituting compound 7-2 for compound 7-1.

[0112] Example 236: Synthesis of compound 100a2 [ka] Step 1: Synthesis of compound 8-1 Compound 6-1 (500 mg) was dissolved in ethyl acetate (10 ml), 10% Pd / C (200 mg) was added, and the mixture was reacted with hydrogen gas at room temperature overnight. After filtering off the Pd / C, the filtrate was concentrated to give 500 mg of compound 8-1, which was used directly in the next reaction.

[0113] Step 2: Synthesis of compound 9-1 With reference to the synthesis method of Step 6 in Example 1, compound 9-1 can be obtained by replacing compound 6-1 with compound 8-1.

[0114] Step 3: Synthesis of compound 100a02 Compound 100a02 can be obtained by referring to the synthesis method of Step 7 in Example 1, substituting compound 9-1 for compound 7-1.

[0115] According to the synthesis methods of Examples 235-236, by replacing the corresponding raw materials, other compounds 100a01-100c20 in the following table were further synthesized. [Table 7-1] [Table 7-2] [Table 7-3] [Table 7-4] [Table 7-5]

[0116] Biological Example--Anti-HBV Activity Experiment Experiment 1: Method for testing in vitro anti-HBV nucleocapsid assembly activity Key reagents and raw materials: The C150 protein was expressed and purified by Yakult Co., Ltd. BoDIPYRFL was purchased from Thermo Fisher Scientific.

[0117] Protein fluorescent labeling: 150 μL of 2% w / v skim milk was added to each well of a 96-well plate and incubated for 2 h at room temperature. The skim milk was absorbed, washed with deionized water, dried, and stored at room temperature. C150 protein (3 mg per tube) was desalted with a 5 mL Hitrap desalting column. Each tube of desalted C150 protein was mixed homogeneously with 20 μl of 50 mM BoDIPYRFL fluorescent dye and incubated overnight at 4°C protected from light. The fluorescent dye not bound to C150 was removed by filtration through Sephadex G-25 gel. The fluorescent labeling efficiency of C150 was calculated as follows:

[0118] [BoDIPYRFL]=A504 / 78,000M -1 , [C150Bo]=(A280-[BoDIPYRFL]×1300M -1 ) / 60900M -1 , Fluorescence labeling efficiency = [BoDIPYRFL] / [C150Bo], Where: [BoDIPYRFL] represents the concentration of the fluorescent label. [C150Bo] represents the concentration of fluorescently labeled protein, A504 represents the absorbance value at a wavelength of 504 nM; A280 represents the absorbance value at a wavelength of 280 nM; M -1 represents the reciprocal of the molar concentration.

[0119] Compound dilution: Compound stock solutions were diluted to 6 mM in DMSO, diluted to 600 μM in 50 mM HEPES, and further serially diluted 3-fold to 8 concentrations in 10% DMSO / 50 mM HEPES. C150Bo was diluted to 2 μM with 50 mM HEPES. 37.5 μL C150Bo and 2.5 μL of each compound concentration were added to a 96-well reaction plate, mixed evenly, and incubated at room temperature for 15 min. 10 μL of 750 mM NaCl / 50 mM HEPES was added to the reaction wells, making the final concentration of NaCl 150 mM. Assemble control wells with 0% protein and add 10 μL of 50 mM HEPES, with a final concentration of NaCl of 0 mM.

[0120] Assemble control wells with 100% protein and add 10 μL of 5 M NaCl / 50 mM HEPES for a final concentration of NaCl of 1 M. The final concentration of DMSO was 0.5%, the highest final concentration of compound was 30 μM, and the final concentration of C150Bo was 1.5 μM. Incubation was carried out at room temperature for 1 hour. The fluorescence signal was measured (excitation 485 nm, emission 535 nm).

[0121] Data analysis % Protein Assembly = [1-(sample fluorescence-1 M NaCl fluorescence) / (0 M NaCl fluorescence-1 M NaCl fluorescence)] x 100. I C 50 The values ​​were calculated by the prism software and the formula is: Y=Bottom+(Top-Bottom) / (1+10 ((LogIC50-X)*HillSlope) ), Where: X represents the logarithm of the concentration, Y represents the effect size, and Y is fitted with an S-shape from the bottom to the top, Bottom represents the bottom of the curve, Top represents the top of the curve, HillSlope represents the absolute value of the maximum slope of the curve.

[0122] Experiment 2: Measurement of anti-HBV activity in HepG2.2.15 cells Main Reagents: QIAamp 96 DNA Blood Kit (12) (Qiagen, Catalog No. 51162); FastStart Universal Probe Master (Roche, Catalog No. 04914058001), Cell-titer Glo detection reagent (Promega, catalog number G7573).

[0123] Compound dilution: For in vitro anti-HBV activity and cytotoxicity experiments, all compounds were serially diluted 3-fold to 8 concentrations. The final starting concentration of the test compound was 30 μM, the final starting concentration of the reference compound GLS4 was 1 μM, and the final concentration of DMSO was 0.5%.

[0124] HepG2.2.15 cells (4 x 10 4 Cells / well) were added to a 96-well plate and cultured at 37C with 5% CO2 overnight. The next day, fresh culture medium containing different concentrations of compounds was added to the wells. On the fifth day, the original culture medium in the culture wells was aspirated and fresh culture medium containing different concentrations of compounds was added. On day 8, the supernatants from the culture wells were collected and used to extract HBV DNA in the supernatants, and qPCR was used to detect the HBV DNA content in the supernatants of HepG2.2.15. After the supernatants were collected, the medium and Cell-titer Glo reagent were added to the culture wells, and the chemiluminescence value of each well was detected by a microplate reader.

[0125] The activity calculation formula is as follows: Y=Bottom+(Top-Bottom) / (1+10 ((LogIC50-X)*HillSlope) ); Where: X represents the logarithm of the concentration, Y represents the effect size, and Y is fitted with an S-shape from the bottom to the top, Bottom represents the bottom of the curve, Top represents the top of the curve, HillSlope represents the absolute value of the maximum slope of the curve.

[0126] Experiment 3: Cytotoxicity measurements The cytotoxicity of the test compounds was tested using HepG2 cells, which were incubated in the presence of the test compounds for 4 days. Cell vitality was assessed with resazurin. The results show that the compounds of the present invention have good anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and have low cytotoxicity.

[0127] Activity data from Experiments 1 to 3 are shown in Table 1. [Table 8-1] [Table 8-2] [Table 8-3] In Table 1, [Table 9] This demonstrates that the compounds of the present application have excellent anti-HBV activity.

[0128] It should be noted that, after the compounds of the present invention are resolved by HPLC, the two configuration compounds based on the chiral sulfur atom center (i.e., S in O=S=N-R6) can be effectively separated. The inventors unexpectedly discovered that among the two configuration compounds based on the chiral sulfur atom center, the less polar enantiomer has significantly higher inhibitory activity against HBV nucleocapsid than the more polar enantiomer, and in some embodiments, the difference in activity can reach several fold.

[0129] Experiment 4 Mouse PK Experiment Example: Eighteen male C57 mice (9 intravenously, 9 orally) were randomly divided into groups according to body weight and administered the test compound at 2 mg / kg (intravenously) and 50 mg / kg (orally). Three mice were sampled at each time point in each group for a total of eight time points (5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 8 h, 24 h). The calculation method for oral bioavailability F was AUC po / Dose po / AUC iv / Dose iv It is.

[0130] Administration of the compounds of the present invention resulted in each showing good bioavailability in in vivo experiments, with some compounds showing bioavailability reaching or exceeding 70%.

[0131] All documents mentioned in this application are incorporated by reference into this application as if each document was individually incorporated by reference. Furthermore, after reading the above teachings of the present invention, those skilled in the art will be able to make various changes or modifications to the present invention, and these equivalents are also within the scope defined by the claims appended hereto.

Claims

1. A compound of formula L, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof: [Formula 1] n is 1 or 2; [chemical 2] is a substituted or unsubstituted 5- or 6-membered ring, said 5- or 6-membered ring optionally containing one or more heteroatoms selected from the group consisting of O, S, N or P, said substitution meaning that a hydrogen atom of the group is replaced by a C1-C3 alkyl group, C ３ -C ４ substituted by one or more substituents selected from the group consisting of cycloalkyl groups, cyano groups, or halogens; [C3] is a substituted or unsubstituted 5- or 6-membered aromatic ring or a substituted or unsubstituted 5- or 6-membered heteroaromatic ring; X is -CR ａ R ｂ - and Y is a substituted or unsubstituted C １ -C ７ An alkylene group, or a substituted or unsubstituted C ２ -C ７ alkenylene group, the substituent being C １ -C ４ and a hydroxyl group; Z is a C-C single bond, W is None, R １ , R ２ , R ３ and R ４ are each independently H, a halogen, a cyano group, a substituted or unsubstituted C ３ -C ４ a cycloalkyl group of the formula: １ -C ４ an alkyl group of the formula: １ -C ４and the substitution is selected from the group consisting of a halogen, a C １ -C ４ and wherein the alkyl group is substituted with one or more substituents selected from the group consisting of the alkyl groups R ５ and R ６ are each independently H, a halogen, -CN, a hydroxyl group, an amino group, a carboxyl group, -(C=O)-substituted or unsubstituted C １ -C ８ Alkyl group, substituted or unsubstituted C １ -C ８ Alkyl group, substituted or unsubstituted C ２ -C ６ Alkenyl group, substituted or unsubstituted C ２ -C ６ Alkynyl group, substituted or unsubstituted C １ -C ８ Alkylamine groups, substituted or unsubstituted C １ -C ８ Alkoxy groups, substituted or unsubstituted C ３ -C １０ a cycloalkyl group, a substituted or unsubstituted 3-10 membered heterocycloalkyl group having 1-3 heteroatoms selected from the group consisting of N, S and O; a substituted or unsubstituted C ６ -C １０ aryl groups, or substituted or unsubstituted 5-10 membered heteroaryl groups having 1-3 heteroatoms selected from the group consisting of N, S and O; R ａ is selected from the group consisting of (a) a cyclopropyl group, (b) a methylene-cyclopropyl group, (c) a methyl group substituted with a 4-fluorophenyl group, and (d) a methyl group substituted with a 4-methoxyphenyl group; R ｂ is H, Unless otherwise specified, the term "substituted" means (1) Halogen, C １ -C ６ Alkyl groups, halogenated C １ -C ６ Alkyl group, C １ -C ６ Alkoxy group, halogenated C １ -C ６ Alkoxy group, C ３ -C ８ Cycloalkyl groups, halogenated C ３ -C ８ Cycloalkyl groups, oxo, -CN, hydroxyl groups, amino groups, carboxyl groups, and (2) C ６ -C １０ Aryl group, halogenated C ６ -C １０ a halogenated 5-10 membered heteroaryl group having 1-3 heteroatoms selected from N, S and O, wherein the substituents are selected from the group consisting of halogen, C １ -C ６ alkoxy groups, is meant to be substituted with one or more (e.g., 2, 3, 4, etc.) groups selected from the group consisting of: A compound represented by the above formula L, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

2. R １ , R ２ , R ３ and R ４ are each independently H, a halogen, a cyano group, C １ -C ４ alkyl group, difluoromethyl, difluoroethyl, monofluoromethyl, trifluoromethyl, substituted or unsubstituted C ３ -C ４ a cycloalkyl group of the formula: １ -C ４ and the substitution is selected from the group consisting of a halogen, a C １ -C ４ The alkyl group is characterized in that it is substituted with one or more substituents selected from the group consisting of the alkyl groups 2. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

3. The compound has the structure shown in Formula II: [C4] X １ is -CR= or -N=, and X ２ is -NR-, wherein R is H or C １ -C ４ is an alkyl group represented by the formula:

2. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

4. The compound is characterized in that it has the structure shown in Formula III: [C5] 2. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

5. The compound is as follows: [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] and wherein Peak 1 and Peak 2 refer to the order in which the peaks of the enantiomers appear in reversed-phase HPLC, Peak 1 being the enantiomer that appears first, and Peak 2 being the enantiomer that appears later.

2. A compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

6. 13. A process for preparing a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, comprising the steps of: The method comprises: [C6] In an inert solvent, with a compound of formula L1 [C7] to obtain a compound of formula L, 2. A method for preparing the compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, characterized in that R is a leaving group and the remaining groups are defined as in claim 1.

7. 1. A pharmaceutical composition comprising:

1. The pharmaceutical composition comprising: (1) the compound according to claim 1 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof; and (2) a pharma- ceutically acceptable carrier.

8. 10. Use of a compound according to claim 1 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 7, comprising Use of a compound as defined in claim 1 or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined in claim 11, in the manufacture of a drug for the prevention and / or treatment of Hepatitis B virus infection.

9. 1. A hepatitis B virus inhibitor comprising:

10. The Hepatitis B virus inhibitor, characterized in that the inhibitor comprises a compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof.

10. 1. A method for inhibiting Hepatitis B virus in vitro, comprising:

10. A method for inhibiting Hepatitis B virus in vitro, comprising the step of contacting a compound of claim 1, or a stereoisomer or tautomer thereof, or a pharma- ceutically acceptable salt, hydrate or solvate thereof, with Hepatitis B virus to inhibit replication of the Hepatitis B virus.

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