WO2018133845A1 - Thiourea and urea compound and use thereof - Google Patents

Abstract

Disclosed are a thiourea and urea compound which can be used as an HBV replication inhibitor or a stereoisomer or a tautomer thereof, or a pharmaceutically acceptable salt, a hydrate or a solvate thereof and a preparation method thereof and a pharmaceutical composition comprising the compound and the use thereof in treating hepatitis B.

Description

Thioureas, urea compounds and uses thereof Technical field

The present invention belongs to the field of medicine, and in particular, the present invention relates to thioureas, urea compounds for use in the treatment of hepatitis B and uses thereof.

Background technique

Hepatitis B virus (HBV) is an enveloped, partially double-stranded DNA (dsDNA), hepatovirus DNA family (Hepadnaviridae) virus. Its genome contains four overlapping reading frames: the pronuclear/nuclear gene, the polymerase gene, the UM and S genes (which encode three envelope proteins), and the X gene. At the time of infection, the partially double-stranded DNA genome is transformed into a covalently closed circular DNA (cccDNA) in the host cell nucleus (open loop DNA, rcDNA) and the viral mRNA is transcribed. Once encapsidated, the pre-genomic RNA (pgRNA), which is also encoded by the core protein and Pol, is used as a template for reverse transcription, which regenerates this portion of the dsDNA genome (rcDNA) in the nucleocapsid.

The spread of hepatitis B virus is derived from exposure to infectious blood or body fluids, while viral DNA is detected in the saliva, tears, and urine of chronic carriers with high-priced DNA in serum. The choice of direct treatment is currently limited to interferon as well as the following antiviral drugs; tenofovir, lamivudine, adefovir, entecavir and telbivudine.

In addition, heteroaryldihydropyrimidines (HAPs) have been identified as a class of HBV inhibitors in tissue culture and animal models (Weber et al., Antiviral Res. 54:69-78) . Also disclosed are WO sulfonyl-aryl amide compounds which are resistant to HBV activity, as disclosed in WO 2013/006394 and WO 2013/096744.

However, these direct HBV antiviral drugs encounter various problems such as toxicity, mutagenicity, lack of selectivity, poor efficacy, poor bioavailability, and difficulty in synthesis.

Therefore, there is a need in the art to develop HBV inhibitors having advantages such as high potency and lower toxicity.

Summary of the invention

It is an object of the present invention to provide a novel class of thiourea and urea compounds useful as HBV inhibitors.

According to a first aspect of the present invention, there is provided a compound of formula A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

among them,

W is C=O or O=S=O;

Q is -CR ₁₃ , N, -CR ₁₃ =CR ₁₃ , -CR ₁₃ =NR ₁₃ , -CR ₁₃ -NR ₁₃ R ₁₄ , wherein R ₁₃ and R ₁₄ are each independently selected from: H, C ₁ -C _{a 6} alkyl group, a halogenated C ₁ -C ₆ alkyl group;

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted having 1- 3 3-10 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted, selected from the group consisting of the following heteroatoms of N, S and O, having 1-3 selected from a 5-10 membered heteroaryl group of the following group of heteroatoms of N, S and O; wherein said substitutions R ₁ and R ₂ are selected from one or more selected from the group consisting of 2, 3, Substituted by four substituents: -OH, halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -O-;

X is CR ₁₁ R ₁₂ or -CR ₁₁ =CR ₁₂ -; wherein R ₁₁ and R ₁₂ are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or not Substituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted, having 1-3 selected from a 3-10 membered heterocycloalkyl group of a hetero atom of N, S and O, a substituted or unsubstituted C ₆ -C ₁₀ aryl group, or a substituted or unsubstituted one or more selected from the group consisting of N, S And a 5- to 10-membered heteroaryl group of a hetero atom of O, C _1-3 alkyl-R ₇ , -C(=O)OC _1-4 alkyl; wherein said R _{7 is} selected from the group consisting of halogen, C _1- C ₃ alkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-2 heteroatoms selected from the group consisting of N, S and O, having 1-3 selected from the group consisting of N, a 3-7 membered heterocycloalkyl of a hetero atom of S and O, -NR ₉ R ₁₀ , wherein said R ₉ and R ₁₀ are each independently selected from the group consisting of: H, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl;

or,

The R ₁₁ and R ₁₂ together with the adjacent C atoms constitute a substituted or unsubstituted 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, wherein The substitution of the 3-7 membered heterocycloalkyl refers to the substitution of one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of -OH, halogen, methoxy, -O. -, -C(=O)OC _1-4 alkyl, benzyl, C _1-4 alkyl, halogenated C _1-4 alkyl,

Further, in the above R ₁₁ and R ₁₂ , the substitution means is substituted by one or more (for example, 2, 3, 4, etc.) substituents selected from the group consisting of -OH, halogen, C ₁ - C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, -OH substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C(=O)OC _1-4 alkyl;

Y is a substituted or unsubstituted C ₁ -C ₇ alkylene group or a C ₂ -C ₇ alkenylene group, and in the Y, the substitution means one or more selected from the group consisting of (for example, 2, 3) Substituted by four, four, etc. substituents: C ₁ -C ₄ alkyl, halogen, -OH, preferably C ₁ -C ₄ alkyl or -OH;

Z is selected from the group consisting of NH, O or a bond;

Ring C is a substituted or unsubstituted C ₆ -C ₁₀ aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O, said ring In C, the substitution is substituted by one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of C ₁ -C ₃ alkyl (preferably methyl), C ₃ -C ₄ cycloalkyl, -CN or halogen;

Ring B is a substituted or unsubstituted C ₆ -C ₁₀ aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O; In B, the substitution refers to being substituted with one or more (e.g., 2, 3, 4, etc.) substituents selected from the group consisting of C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl , -CN or halogen;

R _a , R _b , R _c , R _d are substituents at any position on Ring B, each independently selected from the group consisting of H, halogen, —CN, hydroxy, amino, carboxy, —(C=O)- Substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkyne a substituted, unsubstituted or unsubstituted C ₁ -C ₈ alkylamino group, a substituted or unsubstituted C ₁ -C ₈ alkoxy group, a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, substituted or unsubstituted 3 to 3 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or 1-3 substituted or unsubstituted, selected from the group consisting of the following heteroatoms of N, S and O a 5-10 membered heteroaryl group selected from the group consisting of a hetero atom of N, S and O; in said R _a , R _b , R _c , R _d , said "substituted" means a group selected from the group consisting of Or a plurality of (eg, 2, 3, 4, etc.) substituents substituted: halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, Halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, halogenated C ₃ -C ₈ cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, C ₆ -C ₁₀ Aryl, Substituted C ₆ -C ₁₀ aryl group, having 1-3 heteroatoms selected from the group N, at 5-10 membered heteroaryl, S and O atoms in the aryl group, lower haloalkyl group having 1-3 heteroatoms selected from N, A 5-10 membered heteroaryl of a hetero atom of S and O.

In another preferred embodiment, the compound of formula A is a compound of formula A1:

Wherein each group is as defined above.

In another preferred embodiment, R ₁ is H, unsubstituted C ₁ -C ₁₀ alkyl, -OH, -O- or halogen-substituted C ₁ -C ₁₀ alkyl.

In another preferred embodiment, R _{11 is} selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, -C(=O)OC _1-4 alkyl, C _1-3 alkyl-R _a substituted or unsubstituted C _2-4 alkynyl group, a 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, or a substituted or unsubstituted one having 1 Three 5-10 membered heteroaryl groups selected from the group consisting of the following heteroatoms of N, S and O.

In another preferred embodiment, R _{12 is} selected from the group consisting of H, substituted or unsubstituted C ₁ -C ₁₀ alkyl, preferably H, substituted or unsubstituted C ₁ -C ₆ alkyl, more preferably The ground is H or methyl.

In another preferred embodiment, ring C is a substituted or unsubstituted 5 or 6 membered heteroaryl group, said substitution being selected from one or more selected from the group consisting of (eg, 2, 3, 4, etc.) Substituted by a substituent: methyl, -CN or halogen.

In another preferred embodiment, the ring C is selected from the group consisting of:

In another preferred embodiment, Ring B is phenyl or a substituted or unsubstituted 6-membered heteroaryl group, preferably a phenyl or pyridyl group.

In another preferred embodiment, the ring B is selected from the group consisting of:

In another preferred embodiment, the R _a , R _b , R _c , R _d are each independently selected from the group consisting of H, halogen, —CHF ₂ , —CF ₂ —methyl, —CH ₂ F, —CF. ₃ , -OCF ₃ , -CN, -C ₃ -C ₄ cycloalkyl, or -C ₁ -C ₄ alkyl.

In another preferred embodiment, the ring C is

among them,

R ₄ is H, -C ₁ -C ₃ alkyl (preferably methyl), -C ₃ -C ₄ cycloalkyl;

R ₅ is H or halogen (preferably F);

R _{6 is} selected from H, methyl, -CN or halogen.

In another preferred embodiment, the Z is O or a bond.

In another preferred embodiment, the R ₇ is a substituted or unsubstituted 5-10 membered heteroaryl group having 1-2 heteroatoms selected from the group consisting of N, S and O.

In another preferred embodiment, the compound of formula A is selected from the group consisting of:

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 invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, The compound of formula A is a compound of formula VII-1, and the method comprises the step (I):

or,

The compound of formula A shown is a compound of formula IX-1, said method comprising step (II):

or,

The compound of formula A shown is a compound of formula VII-1, said process comprising step (III):

or,

The compound of formula A shown is a compound of formula VII-2, said method comprising step (IV):

or;

The compound of formula A shown is a compound of formula VIII-1, and the method comprises the step (V):

In the methods (I)-(V), the R ₁ , R ₂ , R _a , R _b , R _c , R _{d are} as defined in the first aspect of the invention, and m is an integer of 0-5.

And, R _{3 is} selected from the group consisting of H, halogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkyne a substituted, unsubstituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, substituted or Unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted 5-10 membered heteroaryl, _1-3 alkyl group having 1-3 heteroatoms selected from the group consisting of N, S and O - R ₇ , —C(=O)OC _1-4 alkyl; wherein said R _{7 is} selected from the group consisting of halogen, C ₁ -C ₃ alkyl, substituted or unsubstituted, and 1-2 selected from the group consisting of a 5-10 membered heteroaryl group of a hetero atom of N, S and O, a 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, -NR ₉ R ₁₀ Wherein R ₉ and R ₁₀ are each independently selected from the group consisting of: H, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl.

According to a third aspect of the present invention, a pharmaceutical composition comprising the compound of the first aspect, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt or hydrate thereof, Or a solvate; (2) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition further comprises other drugs for preventing and/or treating hepatitis B virus infection.

In another preferred embodiment, the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of an immunomodulator (eg, interferon-α (IFN-α), PEGylation interference) Au-α) or a stimulant of the innate immune system (such as Toll-like receptor 7 and/or 8 agonists).

In another preferred embodiment, the other drug for preventing and/or treating hepatitis B virus infection may be selected from the group consisting of tenofovir, lamivudine, adefovir, entecavir, and telbiv. Set, or a combination thereof.

In a fourth aspect of the invention, there is provided a compound as shown below:

A fifth aspect of the invention, according to the first aspect of the invention, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a third aspect of the invention Use of the pharmaceutical composition described for the preparation of a medicament for the prevention and/or treatment of hepatitis B virus infection.

It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.

detailed description

The inventors have conducted extensive and intensive research and found a novel class of compounds having excellent therapeutic effects on hepatitis B. The compounds of the present invention have novel cores in structure, especially those having thiourea or urea, and therefore have not only excellent anti-HBV activity but also lower cytotoxicity (especially for liver cells). On this basis, the inventors completed the present invention.

definition

The term "alkyl" as used herein includes a straight or branched alkyl group. For example, C ₁ -C ₈ alkyl represents a straight or branched alkyl group having 1-8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl. Wait.

The term "alkenyl" as used herein, includes a straight or branched alkenyl group. For example, C ₂ -C ₆ alkenyl refers to a straight or branched alkenyl group having 2 to 6 carbon atoms, such as ethenyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2 a butenyl group, or a similar group.

The term "alkynyl", as used herein, includes a straight or branched alkynyl group. For example, C ₂ -C ₆ alkynyl refers to a straight or branched alkynyl group having 2 to 6 carbon atoms, such as an ethynyl group, a propynyl group, a butynyl group, or the like.

As used herein, the term "C ₃ -C ₁₀ cycloalkyl" means a cycloalkyl group having 3-10 carbon atoms. It may be a monocyclic ring such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, or the like. It may also be in the form of a double loop, such as a bridged or spiro ring.

As used herein, the term "C ₁ -C ₈ alkylamino" refers to an amine group substituted by a C ₁ -C ₈ alkyl group, which may be monosubstituted or disubstituted; for example, methylamino, ethylamino, Alanine, isopropylamino, butylamino, isobutylamino, tert-butylamino, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino, diisobutylamino, two Tert-butylamine and the like.

As used herein, the term "C ₁ -C ₈ alkoxy" refers to a straight or branched alkoxy group having from 1 to 8 carbon atoms; for example, methoxy, ethoxy, propoxy, iso Propyloxy, butoxy, isobutoxy, tert-butoxy and the like.

As used herein, the term "3-10 membered heterocycloalkyl having 1-3 heteroatoms selected from the group consisting of N, S and O" means having from 3 to 10 atoms and wherein 1-3 of the atoms are A saturated or partially saturated cyclic group selected from the group consisting of heteroatoms of N, S and O. It may be a single ring or a double ring form, such as a bridge ring or a spiro ring. Specific examples may be oxetane, azetidine, tetrahydro-2H-pyranyl, piperidinyl, tetrahydrofuranyl, morpholinyl, pyrrolidinyl and the like.

As used herein, the term "C ₆ -C ₁₀ aryl" refers to an aryl group having 6 to 10 carbon atoms, for example, a phenyl or naphthyl group or the like.

As used herein, the term "5-10 membered heteroaryl having 1-3 heteroatoms selected from the group consisting of N, S and O" refers to having 5-10 atoms and wherein 1-3 atoms are selected from A cyclic aromatic group of the following group of heteroatoms of N, S and O. It may be a single ring or a fused ring. Specific examples may be pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl and (1,2, 4)-Triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl and the like.

The groups of the present invention may be substituted with a substituent selected from the group consisting of halogen, nitrile group, nitro group, hydroxyl group, amino group, unless otherwise specified as "substituted or unsubstituted". , C ₁ -C ₆ alkyl-amino, C ₁ -C ₆ alkyl, C ₂ -C ₆ alkenyl, C ₂ -C ₆ alkynyl, C ₁ -C ₆ alkoxy, halogenated C ₁ - C ₆ alkyl, halo C ₂ -C ₆ alkenyl, halo C ₂ -C ₆ alkynyl, halo C ₁ -C ₆ alkoxy, allyl, benzyl, C ₆ -C ₁₂ aryl , C ₁ -C ₆ alkoxy-C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy-carbonyl, phenoxycarbonyl, C ₂ -C ₆ alkynyl-carbonyl, C ₂ -C ₆ alkenyl a carbonyl group, a C ₃ -C ₆ cycloalkyl-carbonyl group, a C ₁ -C ₆ alkyl-sulfonyl group or the like.

As used herein, "halogen" or "halogen atom" refers to F, Cl, Br, and I. More preferably, the halogen or halogen atom is selected from the group consisting of F, Cl and Br. "Halo" means substituted with an atom selected from the group consisting of F, Cl, Br, and I.

Unless otherwise stated, the structural formulae described herein are intended to include all isomeric forms (such as enantiomeric, diastereomeric, and geometric isomers (or conformational isomers): for example, containing asymmetry The central R, S configuration, the (Z) and (E) isomers of the double bond. Thus, a single stereochemical isomer of a compound of the invention, or a mixture of enantiomers, diastereomers or geometric isomers (or conformational isomers) thereof, is within the scope of the invention.

As used herein, the term "tautomer" means that structural isomers having different energies can exceed the low energy barrier and thereby transform each other. For example, proton tautomers (ie, proton shifts) include interconversions by proton transfer, such as 1H-carbazole and 2H-carbazole. Valence tautomers include interconversion through some bonding electron recombination.

As used herein, the term "solvate" refers to a complex of a compound of the invention that is coordinated to a solvent molecule to form a particular ratio.

As used herein, the term "hydrate" refers to a complex formed by the coordination of a compound of the invention with water.

Active ingredient

As used herein, "a compound of the invention" refers to a compound of formula (A), and also includes various crystalline forms, pharmaceutically acceptable salts, hydrates or solvates of the compounds of formula (A).

As used herein, "pharmaceutically acceptable salt" refers to a salt of the compound of the invention formed with an acid or base suitable for use as a medicament. Pharmaceutically acceptable salts include inorganic and organic salts. A preferred class of salts are the salts of the compounds of the invention with acids. Suitable acids for forming salts include, but are not limited to, mineral acids such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, Organic acids such as maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzoic acid, and benzenesulfonic acid; and acidic amino acids such as aspartic acid and glutamic acid.

Pharmaceutical composition and method 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 various crystal forms thereof, pharmaceutically acceptable inorganic or organic salts, hydrates or solvates, and the present invention The pharmaceutical composition wherein the compound is the main active ingredient can be used for preventing and/or treating (stabilizing, alleviating or curing) hepatitis B virus infection or for preventing and/or treating (stabilizing, alleviating or curing) a hepatitis B virus-related disease ( For example, hepatitis B, progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, terminal liver disease, ethyl liver cancer).

The pharmaceutical compositions of the present invention comprise a safe and effective amount of a compound of the invention and a pharmaceutically acceptable excipient or carrier. By "safe and effective amount" it is meant that the amount of the compound is sufficient to significantly improve the condition without causing serious side effects. In general, the pharmaceutical compositions contain from 1 to 2000 mg of the compound of the invention per agent, more preferably from 10 to 200 mg of the compound of the invention per agent. Preferably, the "one dose" is a capsule or tablet.

"Pharmaceutically acceptable carrier" means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity. By "compatibility" it is meant herein that the components of the composition are capable of intermixing with the compounds of the invention and between them without significantly reducing the potency of the compound. Examples of pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid). , magnesium stearate), calcium sulfate, vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier (such as Tween

), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a pyrogen-free water, and the like.

The mode of administration of the compound or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, 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 mixed with: (a) a filler or compatibilizer, for example, Starch, lactose, sucrose, glucose, mannitol and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; (c) humectants, For example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) a slow solvent such as paraffin; (f) Absorbing accelerators, for example, quaternary amine compounds; (g) wetting agents, such as cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, hard Calcium citrate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, or a mixture thereof. In capsules, tablets and pills, the dosage form may also contain a buffer.

Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active compound or compound in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active compound may also be in microencapsulated form with one or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.

In addition to these inert diluents, the compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.

In addition to the active compound, the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.

Compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.

The compounds of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds (e.g., anti-HBV agents).

When administered in combination, the pharmaceutical composition further comprises one or more (2, 3, 4, or more) other pharmaceutically acceptable compounds (e.g., anti-HBV agents). One or more (2, 3, 4, or more) of the other pharmaceutically acceptable compound (eg, an anti-HBV agent) may be used simultaneously, separately or sequentially with the compound of the present invention. For the prevention and / or treatment of HBV infection or HBV related diseases.

When a pharmaceutical composition is used, a safe and effective amount of a compound of the invention is administered to a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage, for a 60 kg body weight, The dose to be administered is usually from 1 to 2000 mg, preferably from 20 to 500 mg. Of course, specific doses should also take into account factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.

The compound of the invention:

The main advantages of the invention include:

1. The compound of the present invention is novel in structure and has an excellent anti-HBV infection effect.

2. The compounds of the invention are very toxic to normal cells.

3. The compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus infection.

4. The compound of the present invention and a pharmaceutical composition containing the compound of the present invention as a main active ingredient can be used for the prevention and/or treatment of hepatitis B virus-related diseases (for example, hepatitis B, progressive liver fibrosis, inflammation leading to cirrhosis, and Necrosis, terminal liver disease, ethyl liver cancer).

Terminology

All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined.

As used herein, when used in reference to a particular recited value, the term "about" means that the value can vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).

As used herein, the terms "containing" or "including" may be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of," or "consisting of."

The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight and parts by weight.

The experimental materials and reagents used in the following examples are available from commercially available sources unless otherwise specified.

The following is the synthesis of 10 compounds:

Example 1: Synthesis of Compound 10a

step 1:

Compound 1 (1.5 g) and propylene bromide (1 g) were dissolved in acetonitrile (15 mL), then cesium carbonate (3.5 g) was added to the reaction system, the temperature was raised to 85 degrees for 2 h, and the reaction system was added to 30 (mL), acetic acid. Ethyl acetate (3*20 mL) was extracted and dried over anhydrous sodium sulfate. ESI-MS, (M+H=273.02)

Step 2:

Compound (1.0 g), ethylene boron anhydride pyridine complex (1.1 g), tetrakistriphenylphosphine palladium (120 mg), potassium carbonate (2.5 g) were dissolved in ethylene glycol dimethyl ether (25 mL) and 4 mL of water. The temperature of the system was raised to 120 °C under nitrogen atmosphere for 10 h. The reaction system was added with water (40 mL), ethyl acetate (3*40 mL), and dried over anhydrous sodium sulfate. (800mg), ESI-MS, (M+H=221.12)

Step 3:

Compound 3 (800 mg) was dissolved in 1,2-dichloroethane (800 mL), nitrogen was introduced into the reaction system, and a second-generation Grubbs catalyst (80 mg) was added to the reaction system, and reacted at 60 degrees for 4 hours to add silica gel to the reaction system. The organic phase was dried and the crude was purified by column chromatography to afford compound 4 (450mg), ESI-MS, (M+H=193.09)

Step 4:

Compound 4 (450 mg) and isopropylaminesulfonyl chloride (300 mg) were dissolved in acetonitrile (6 mL), then pyridine (100 mg) was added to the reaction system, reacted at 85 ° C for 5 h, then 15 mL of water was added to the reaction system, ethyl acetate (3*20 mL) was extracted, dried over anhydrous sodium sulfate and evaporated to dryness.

Step 5:

Compound 5 (100 mg) was dissolved in tetrahydrofuran (3 mL), water (0.6 mL), methanol (0.6 mL), then lithium hydroxide monohydrate (120 mg) was added to the reaction system at room temperature, reacted at 40 °C for 5 h, then the system was The pH was adjusted to 3-4 with 1N EtOAc (EtOAc) (EtOAc (EtOAc)

Step 6:

Compound 6 (40 mg), triethylamine (70 mg), 3,4-difluoroaniline (22 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 degrees, then TBTU (70 mg) was added The reaction system was reacted at room temperature for 12 h, extracted with water (15 mL), dichloromethane (3*20 mL), dried over anhydrous sodium sulfate, and the organic phase was evaporated to dryness to give compound 10a (10 mg)

Example 2: Synthesis of Compound 10b

The preparation of compound 6b is carried out by referring to steps 1-5 of Example 1, except that in step 4, trifluoromethyl-substituted isopropylaminesulfonyl chloride is used in place of isopropylaminesulfonyl chloride.

According to the step 6 of Example 1, only the compound 6b was used instead of the compound 6, and the other conditions were unchanged, and the objective product 10b (12 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).

Example 3: Synthesis of Compound 10c

The procedure for the preparation of compound 6c is as described in Steps 1-5 of Example 1, except that in step 4, t-butylamine sulfonyl chloride is used in place of isopropylamine sulfonyl chloride.

According to the step 6 of Example 1, only the compound 6c was used instead of the compound 6, and the other conditions were unchanged, and the objective product 10c (22 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).

Example 4: Synthesis of Compound 10d

The preparation of the compound 6d was carried out in the same manner as in the step 1-5 of Example 1, except that in the step 4, butyl sulfonamide chloride was used instead of isopropyl sulfonyl chloride.

According to the step 6 of Example 1, it was only necessary to replace the compound 6 with the compound 6d, and the other conditions were unchanged, and the objective product was obtained by column chromatography (n-heptane: ethyl acetate = 1:1) 10d (9mg).

Example 5: Synthesis of Compound 10e

According to the step 6 of the embodiment 1, it is only necessary to replace the compound 3,4-difluoroaniline with the compound 4-fluoro-3-cyanoaniline, and the other conditions are unchanged, and the column chromatography (n-heptane: ethyl acetate = 2) :1) Target product 10e (11 mg).

Example 6: Synthesis of Compound 10f

According to the step 6 of Example 1, only the compound 4-fluoro-3-methylaniline was used instead of the compound 3,4-difluoroaniline, and the other conditions were unchanged, and the column chromatography (n-heptane: ethyl acetate = 2) :1) Target product 10f (9 mg).

Example 7: Synthesis of Compound 10g

According to the step 6 of Example 1, only the compound 4-fluoroaniline was used instead of the compound 3,4-difluoroaniline, and the other conditions were unchanged, and the target product was subjected to column chromatography (n-heptane: ethyl acetate = 2:1). 10 g (7 mg).

Example 8: Synthesis of Compound 10h

According to the step 6 of Example 1, only the compound 4-fluoro-3-chloroaniline was used instead of the compound 3,4-difluoroaniline, and the other conditions were unchanged, and the column chromatography (n-heptane: ethyl acetate = 2: 1) Target product 10 g (7 mg).

Example 9: Synthesis of Compound 20a

Step 11:

The compound 10a (20 mg) was dissolved in ethyl acetate, then palladium carbon (5 mg) was added to the reaction system, and the reaction was carried out at 25 °C for 5 h, and the organic phase was evaporated to dryness.

Example 10: Synthesis of Compound 20b

According to the step 11 of Example 9, only the compound 10b was used instead of the compound 10a, and the other conditions were unchanged, and the objective product 20b (7 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 2:1).

Example 11: Synthesis of Compound 20c

According to the step 11 of Example 9, the compound 10a was replaced with the compound 10e, and the other conditions were unchanged, and the objective product 20c (9 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 2:1).

Example 12: Synthesis of Compound 20d

According to the step 11 of Example 9, the compound 10a was used instead of the compound 10a, and the other conditions were unchanged, and the objective product was 20d (12 mg) by column chromatography (n-heptane: ethyl acetate = 2:1).

Example 13: Synthesis of Compound 30a

Step 12:

Compound 21 (1.5 g) and propylene bromide (1 g) were dissolved in acetonitrile (15 mL), then cesium carbonate (3.5 g) was added to the reaction system, the temperature was raised to 85 degrees for 2 h, and the reaction system was added to 30 (mL), acetic acid. The ethyl ester (3*20 mL) was extracted and dried over anhydrous sodium sulfate. ESI-MS, (M+H=273.02)

Step 13:

Compound (1.0 g), allyl trifluoroborate (1.1 g), tetrakistriphenylphosphine palladium (120 mg), potassium carbonate (2.5 g) were dissolved in ethylene glycol dimethyl ether (25 mL) and 4 mL water. The temperature of the system was raised to 120 °C under nitrogen atmosphere for 10 h. The reaction system was added with water (40 mL), ethyl acetate (3*40 mL), and dried over anhydrous sodium sulfate. (800mg), ESI-MS, (M+H=236.13)

Step 14:

Compound 23 (800 mg) was dissolved in 1,2-dichloroethane (800 mL), nitrogen was introduced into the reaction system, and a second-generation Grubbs catalyst (80 mg) was added to the reaction system, and reacted at 60 degrees for 4 hours to add silica gel to the reaction system. The organic phase was dried and the crude was purified by column chromatography to afford compound 24 (450mg), ESI-MS, (M+H=208.11)

Step 15:

Compound 24 (450 mg) and isopropylamine sulfonyl chloride (300 mg) were dissolved in acetonitrile (6 mL), then pyridine (100 mg) was added to the reaction system, reacted at 85 ° C for 5 h, then 15 mL of water was added to the reaction system, ethyl acetate (3*20 mL), EtOAc (EtOAc) m.

Step 16:

Compound 25 (100 mg) was dissolved in tetrahydrofuran (3 mL), water (0.6 mL), methanol (0.6 mL), then lithium hydroxide monohydrate (120 mg) was added to the reaction system at room temperature, reacted at 40 °C for 5 h, then the system was The pH was adjusted to 3-4 with 1N EtOAc (EtOAc) (EtOAc (EtOAc)

Step 17:

Compound 26 (40 mg), triethylamine (70 mg), 3,4-difluoroaniline (22 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 degrees, then TBTU (70 mg) was added The reaction system was reacted at room temperature for 12 h, extracted with water (15 mL), dichloromethane (3*20 mL), dried over anhydrous sodium sulfate.

Example 14: Synthesis of Compound 30b

The procedure for the preparation of compound 26b is as described in Steps 12-16 of Example 13, except that in Example 15, trifluoromethyl-substituted isopropylaminesulfonyl chloride is used in place of isopropylaminesulfonyl chloride.

According to the step 17 of Example 13, the compound 26b was used instead of the compound 26, and the other conditions were unchanged, and the objective product 30b (12 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).

Example 15: Synthesis of Compound 30c

The procedure for the preparation of compound 26c is as described in Steps 12-16 of Example 13, except that in step 15, t-butylamine sulfonyl chloride was used in place of isopropylamine sulfonyl chloride.

According to the step 17 of Example 13, the compound 26c was used instead of the compound 26, and the other conditions were unchanged, and the objective product 30c (16 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).

Example 16: Synthesis of Compound 30d

The preparation of compound 26d is carried out in the same manner as in the step 12-16 of Example 13, except that in the step 15, butyl sulphonyl chloride was used instead of isopropyl sulfonyl chloride.

According to the step 17 of Example 13, the compound 26d was used instead of the compound 26, and the other conditions were unchanged, and the objective product was 30d (10 mg) by column chromatography (n-heptane: ethyl acetate = 1:1).

Example 17: Synthesis of Compound 30e

According to the step 17 of Example 13, only the compound 4-fluoro-3-cyanoaniline was used instead of the compound 3,4-difluoroaniline, and the other conditions were unchanged, and the column chromatography (n-heptane: ethyl acetate = 2) :1) Target product 30e (8 mg).

Example 18: Synthesis of Compound 30f

According to the step 17 of Example 13, only the compound 4-fluoro-3-methylaniline was used instead of the compound 3,4-difluoroaniline, and the other conditions were unchanged, and the column chromatography (n-heptane: ethyl acetate = 2) :1) Target product 30f (13 mg).

Example 19: Synthesis of Compound 30g

According to the step 17 of Example 13, only the compound 4-fluoroaniline was used instead of the compound 3,4-difluoroaniline, and the other conditions were unchanged. Column chromatography (n-heptane: ethyl acetate = 2:1) 30 g (7 mg).

Example 20: Synthesis of Compound 30h

According to the step 17 of Example 13, only the compound 4-fluoro-3-chloroaniline was used instead of the compound 3,4-difluoroaniline, and the other conditions were unchanged, and column chromatography (n-heptane: ethyl acetate = 2: 1) Target product 30h (7mg).

Example 21: Synthesis of Compound 40a

Step 20:

The compound 30a (20 mg) was dissolved in ethyl acetate, then palladium carbon (5 mg) was added to the reaction system, and the reaction was carried out at 25 °C for 5 h, and the organic phase was evaporated to dryness.

Example 22: Synthesis of Compound 40b

According to the step 20 of Example 21, the compound 30b (11 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 2:1).

Example 23: Synthesis of Compound 40c

According to the step 20 of Example 21, the compound 30a was used instead of the compound 30a, and the other conditions were unchanged, and the objective product 40c (9 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 2:1).

Example 24: Synthesis of Compound 40d

According to the step 20 of Example 21, the compound 30a was used instead of the compound 30a, and the other conditions were unchanged, and the objective product was 40d (8 mg) by column chromatography (n-heptane: ethyl acetate = 2:1).

Example 25: Synthesis of Compound 50a

Step 21:

Compound 41 (1 g), triethylamine (1.2 g), isopropyl carbamate (1 g) was dissolved in dichloromethane (15 mL), then TBTU (1.5 g) was added to the reaction system, 25 degree reaction for 5 h, water (10 mL) was added to the reaction mixture, dichloromethane (3~20 mL) was evaporated. )

Step 22:

Compound 42 (400 mg) was dissolved in tetrahydrofuran (5 mL), water (1 mL), methanol (1 mL), then lithium hydroxide monohydrate (480 mg) was added to the reaction system at room temperature, reacted at 40 ° C for 5 h, then the pH of the system was The mixture was adjusted to 3-4 with EtOAc (EtOAc) (mjjjjjjjj

Step 23:

Compound 43 (40 mg), triethylamine (70 mg), 4-fluoro-3-cyanoaniline (22 mg) was dissolved in dichloromethane (3 mL), then the temperature was reduced to about 5 degrees, then TBTU (70 mg) Adding to the reaction system, reacting at room temperature for 12h, adding water (15mL), dichloromethane (3*20mL), extracting, drying over anhydrous sodium sulfate, and drying the organic phase, crude column chromatography to give compound 50a (10mg)

Example 26: Synthesis of Compound 50b

According to the step 23 of Example 25, the compound 4-fluoro-3-methylaniline was used instead of the compound 4-fluoro-3-cyanoaniline, and the other conditions were unchanged. Column chromatography (n-heptane: ethyl acetate) = 1:1) target product 50b (10 mg).

Example 27: Synthesis of Compound 50c

The procedure for the preparation of compound 43c is as described in Steps 21-22 of Example 25, except that in step 21, trifluoromethyl substituted isopropylamine is used instead of isopropylamine.

According to the step 23 of Example 25, the compound 43c was used instead of the compound 43, and the other conditions were unchanged, and the objective product 50c (10 mg) was subjected to column chromatography (n-heptane: ethyl acetate = 1:1).

Example 28: Synthesis of Compound 50d

The preparation of the compound 43d was carried out in the same manner as in the step 21-22 of Example 25, except that in the step 21, t-butylaminocarboxylic acid was used instead of the isopropyl carbamic acid.

According to the step 23 of Example 25, the compound 43d was used instead of the compound 43, and the other conditions were unchanged, and the objective product was 50d (10 mg) by column chromatography (n-heptane: ethyl acetate = 1:1).

Example 29: Synthesis of Compound 60a

Step 30:

The compound 50a (20 mg) was dissolved in ethyl acetate, then palladium carbon (5 mg) was added to the reaction system, and the reaction was carried out at 25 ° C for 5 h, and the organic phase was evaporated to dryness.

Example 30: Synthesis of Compound 60b

According to the step 30 of Example 29, the compound 50b (8 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 2:1).

Example 31: Synthesis of Compound 60c

According to the step 30 of Example 29, the compound 50c (7 mg) was obtained by column chromatography (n-heptane: ethyl acetate = 2:1).

Example 32: Synthesis of Compound 60d

According to the step 30 of Example 29, the compound 50d was used instead of the compound 50a, and the other conditions were unchanged. Column chromatography (n-heptane: ethyl acetate = 2:1).

Biological Example--Anti-HBV Activity Experiment

Experiment 1: In vitro anti-HBV nucleocapsid assembly activity test method

Main reagents and raw materials:

C150 protein is expressed and purified by WuXi PharmaTech;

FL was purchased from Thermo Fisher Scientific.

Protein fluorescent label:

150 μL of 2% w/v skim milk was added to each well of a 96-well plate and incubated for 2 hours at room temperature. Aspirate skim milk, wash it with deionized water, dry it, and store at room temperature. C150 protein (3 mg per tube) was desalted using a 5 ml Hitrap desalting column. Add 50 mM to the C150 protein after desalting each tube

20 μl of FL fluorescent dye was mixed well and incubated overnight at 4 ° C in the dark. The fluorescent dye not bound to C150 was removed by filtration with Sephadex G-25 gel. Calculate the fluorescence labeling efficiency of C150, the formula is as follows:

among them,

Indicates the concentration of the fluorescent label;

[C150Bo] represents the concentration of a fluorescently labeled protein;

A504 represents an absorbance value of a wavelength of 504 nM;

A280 represents an absorption value of a wavelength of 280 nM;

M ^-1 represents the reciprocal of the molar concentration.

Compound dilution:

The mother liquor of the compound was diluted to 6 mM with DMSO, diluted to 600 μM with 50 mM HEPES, and then further diluted 8 times with 10% DMSO/50 mM HEPES.

C150Bo was diluted to 2 μM with 50 mM HEPES. 37.5 μL of C150Bo and 2.5 μL of each concentration of the compound were added to a 96-well reaction plate and mixed, and incubated at room temperature for 15 minutes. 10 μl of 750 mM NaCl/50 mM HEPES was added to the reaction well, and the final concentration of NaCl was 150 mM.

Control wells were assembled with 0% protein, 10 μL of 50 mM HEPES was added, and the final concentration of NaCl was 0 mM.

Control wells were assembled with 100% protein and 10 μL of 5 M NaCl/50 mM HEPES was added with a final concentration of 1 M NaCl.

The final concentration of DMSO was 0.5%, the maximum final concentration of the compound was 30 μM, and the final concentration of C150Bo was 1.5 μM. Incubate for 1 hour at room temperature. The fluorescence signal (excitation light 485 nm; emission light 535 nm) was measured.

data analysis

% protein assembly = [1 - (sample fluorescence value - 1 M NaCl fluorescence value) / (0 M NaCl fluorescence value - 1 M NaCl fluorescence value)] × 100.

The IC ₅₀ value is calculated by the prism software and the equation is as follows:

Y=Bottom+(Top-Bottom)/(1+10 ^{((LogIC50-X)*HillSlope)} );

among them,

X represents the logarithm of the concentration, Y represents the effect value, and Y is fitted from the bottom to the top with an S-shape;

Bottom represents the bottom of the curve;

Top indicates the top of the curve;

HillSlope represents the absolute value of the maximum slope of the curve.

Experiment 2: Determination of anti-HBV activity in HepG2.2.15 cells

Main reagents:

QIAamp 96 DNA Blood Kit (12) (Qiagen, Cat. No. 51162);

FastStart Universal Probe Master (Roche, article number 04914058001);

Cell–titer Glo detection reagent (Promega, Cat. No. G7573).

Compound dilution: in vitro anti-HBV activity assay and cytotoxicity assay All compounds were serially diluted 3 times, 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%.

HepG2.2.15 cells (4 x 10 ⁴ cells/well) were inoculated into 96-well plates and incubated overnight at 37 ° C, 5% CO ₂ . The next day, fresh culture medium containing different concentrations of compounds was added to the culture wells. On the fifth day, the old culture solution in the culture well was aspirated and fresh culture medium containing different concentrations of the compound was added.

On the eighth day, the supernatant in the culture well was collected for extracting HBV DNA from the supernatant, and qPCR was used to detect the HBV DNA content in the supernatant of HepG2.2.15. After collecting the supernatant, the culture medium and the Cell-titer Glo reagent were added to the culture well, and the chemiluminescence value of each well was detected by a microplate reader.

The activity calculation formula is as follows:

Y=Bottom+(Top-Bottom)/(1+10 ^{((LogIC50-X)*HillSlope)} );

among them,

X represents the logarithm of the concentration, Y represents the effect value, and Y is fitted from the bottom to the top with an S-shape;

Bottom represents the bottom of the curve;

Top indicates the top of the curve;

HillSlope represents the absolute value of the maximum slope of the curve.

Experiment 3: Determination of cytotoxicity

The cytotoxicity of the test compounds was tested using HepG2 cells, and these cells were incubated for 4 days in the presence of the test compound. Cell rejuvenation was assessed using the resazurin assay.

The experimental results are shown in the table below.

In the table: a1 indicates that IC50 (μM) is <1; a2 indicates IC50 (μM) is between 1 and 100; a3 indicates IC50 (μM) is >100; b1 indicates EC50 (μM) is between <1; b2 indicates EC50 (μM) is between 1 and 100; b3 means EC50 (μM) is >100; wherein the control compound is:

(See WO2014184350A1).

The results showed that the compound of the present invention was excellent in anti-HBV nucleocapsid assembly activity and anti-HBV activity in vitro, and had lower cytotoxicity.

All documents mentioned in the present application are hereby incorporated by reference in their entirety in their entireties in the the the the the the the the In addition, it should be understood that various modifications and changes may be made by those skilled in the art in the form of the appended claims.

Claims (10)

1. A compound of the formula A, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof,

   

   among them,

   W is C=O or O=S=O;

   Q is -CR ₁₃ , N, -CR ₁₃ =CR ₁₃ , -CR ₁₃ =NR ₁₃ , -CR ₁₃ -NR ₁₃ R ₁₄ , wherein R ₁₃ and R ₁₄ are each independently selected from: H, C ₁ -C _{a 6} alkyl group, a halogenated C ₁ -C ₆ alkyl group;

   R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted having 1- 3 3-10 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted, selected from the group consisting of the following heteroatoms of N, S and O, having 1-3 selected from a 5-10 membered heteroaryl group of the following heteroatoms of N, S and O; wherein in said R ₁ , R ₂ , said substitution is substituted by one or more substituents selected from the group consisting of: -OH, Halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -O-;

   X is CR ₁₁ R ₁₂ or -CR ₁₁ =CR ₁₂ -; wherein R ₁₁ and R ₁₂ are each independently selected from the group consisting of H, halogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or not Substituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkynyl, substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted, having 1-3 selected from a 3-10 membered heterocycloalkyl group of a hetero atom of N, S and O, a substituted or unsubstituted C ₆ -C ₁₀ aryl group, or a substituted or unsubstituted one or more selected from the group consisting of N, S And a 5- to 10-membered heteroaryl group of a hetero atom of O, C _1-3 alkyl-R ₇ , -C(=O)OC _1-4 alkyl; wherein said R _{7 is} selected from the group consisting of halogen, C _1- C ₃ alkyl, substituted or unsubstituted 5-10 membered heteroaryl having 1-2 heteroatoms selected from the group consisting of N, S and O, having 1-3 selected from the group consisting of N, a 3-7 membered heterocycloalkyl of a hetero atom of S and O, -NR ₉ R ₁₀ , wherein said R ₉ and R ₁₀ are each independently selected from the group consisting of: H, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl;

   or,

   The R ₁₁ and R ₁₂ together with the adjacent C atoms constitute a substituted or unsubstituted 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, wherein The substitution of a 3-7 membered heterocycloalkyl group is substituted by one or more substituents selected from the group consisting of -OH, halogen, methoxy, -O-, -C(=O)OC _1-4 Alkyl, benzyl, C _1-4 alkyl, halogenated C _1-4 alkyl,

   And, in R ₁₁ and R ₁₂ , the substitution means being substituted with one or more substituents selected from the group consisting of -OH, halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, -OH substituted C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, -C(=O)OC _1-4 alkyl;

   Y is a substituted or unsubstituted C ₁ -C ₇ alkylene group or a C ₂ -C ₇ alkenylene group, and in the Y, the substitution means being substituted with one or more substituents selected from the group consisting of C: _1- C ₄ alkyl, halogen, -OH, preferably C ₁ -C ₄ alkyl or -OH;

   Z is selected from the group consisting of NH, O or a bond;

   Ring C is a substituted or unsubstituted C ₆ -C ₁₀ aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O, said ring In C, the substitution refers to being substituted with one or more substituents selected from the group consisting of C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, -CN or halogen;

   Ring B is a substituted or unsubstituted C ₆ -C ₁₀ aryl group, a substituted or unsubstituted 5-10 membered heteroaryl group having 1-3 hetero atoms selected from the group consisting of N, S and O; In B, the substitution refers to being substituted with one or more substituents selected from the group consisting of C ₁ -C ₃ alkyl, C ₃ -C ₄ cycloalkyl, -CN or halogen;

   R _a , R _b , R _c , R _d are substituents at any position on Ring B, each independently selected from the group consisting of H, halogen, —CN, hydroxy, amino, carboxy, —(C=O)- Substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₁ -C ₈ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkyne a substituted, unsubstituted or unsubstituted C ₁ -C ₈ alkylamino group, a substituted or unsubstituted C ₁ -C ₈ alkoxy group, a substituted or unsubstituted C ₃ -C ₁₀ cycloalkyl group, substituted or unsubstituted 3 to 3 membered heterocycloalkyl, substituted or unsubstituted C ₆ -C ₁₀ aryl, or 1-3 substituted or unsubstituted, selected from the group consisting of the following heteroatoms of N, S and O a 5-10 membered heteroaryl group selected from the group consisting of a hetero atom of N, S and O; in said R _a , R _b , R _c , R _d , said "substituted" means a group selected from the group consisting of Or substituted with a plurality of substituents: halogen, C ₁ -C ₆ alkyl, halogenated C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy, halogenated C ₁ -C ₆ alkoxy, C ₃ -C ₈ cycloalkyl, halogenated C ₃ -C ₈ cycloalkyl, oxo, -CN, hydroxy, amino, carboxy, C ₆ -C ₁₀ aryl, halogenated C ₆ -C ₁₀ aryl Base 5-10 membered heteroaryl groups having 1-3 hetero atoms selected from the group consisting of N, S and O, halogenated 5-10 having 1-3 hetero atoms selected from the group consisting of N, S and O Meta-heteroaryl.
2. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R _{11 is} selected from the group consisting of H, Substituted or unsubstituted C ₁ -C ₁₀ alkyl, -C(=O)OC _1-4 alkyl, C _1-3 alkyl-R ₇ , substituted or unsubstituted C _2-4 alkynyl, having 1 - 3 3-7 membered heterocycloalkyl selected from the group consisting of the following heteroatoms of N, S and O, or substituted or unsubstituted 5 having 1-3 heteroatoms selected from the group consisting of N, S and O -10 yuan heteroaryl.
3. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein R _{12 is} selected from the group consisting of H, Substituted or unsubstituted C ₁ -C ₁₀ alkyl.
4. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring C is substituted or unsubstituted 5 A meta or 6-membered heteroaryl group, said substitution being substituted by one or more substituents selected from the group consisting of methyl, -CN or halogen.
5. The compound according to claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein ring B is phenyl or substituted or not Substituted 6-membered heteroaryl, preferably phenyl or pyridyl.
6. The compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula A is selected from the group consisting of :

   

   
7. A process for the preparation of a compound according to claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein the compound of formula A is of formula VII-1 The compound shown, the method comprising the step (I):

   

   or,

   The compound of formula A shown is a compound of formula IX-1, said method comprising step (II):

   

   or,

   The compound of formula A shown is a compound of formula VII-1, said process comprising step (III):

   

   or,

   The compound of formula A shown is a compound of formula VII-2, said method comprising step (IV):

   

   or;

   The compound of formula A shown is a compound of formula VIII-1, and the method comprises the step (V):

   

   In the methods (I)-(V), the R ₁ , R ₂ , R _a , R _b , R _c , R _d are as defined in claim 1, and m is an integer of 0-5.

   And, R _{3 is} selected from the group consisting of H, halogen, substituted or unsubstituted C ₁ -C ₁₀ alkyl, substituted or unsubstituted C ₂ -C ₆ alkenyl, substituted or unsubstituted C ₂ -C ₆ alkyne a substituted, unsubstituted or unsubstituted C ₃ -C ₁₀ cycloalkyl, substituted or unsubstituted 3-10 membered heterocycloalkyl having 1 to 3 heteroatoms selected from the group consisting of N, S and O, substituted or Unsubstituted C ₆ -C ₁₀ aryl, or substituted or unsubstituted 5-10 membered heteroaryl, _1-3 alkyl group having 1-3 heteroatoms selected from the group consisting of N, S and O - R ₇ , —C(=O)OC _1-4 alkyl; wherein said R _{7 is} selected from the group consisting of halogen, C ₁ -C ₃ alkyl, substituted or unsubstituted, and 1-2 selected from the group consisting of a 5-10 membered heteroaryl group of a hetero atom of N, S and O, a 3-7 membered heterocycloalkyl group having 1 to 3 hetero atoms selected from the group consisting of N, S and O, -NR ₉ R ₁₀ Wherein R ₉ and R ₁₀ are each independently selected from the group consisting of: H, C ₁ -C ₃ alkyl, halogenated C ₁ -C ₃ alkyl.
8. A pharmaceutical composition comprising (1) the compound of claim 1, or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof; (2) A pharmaceutically acceptable carrier.
9. The compound shown below:

   
10. The use of a compound according to claim 1 or a stereoisomer or tautomer thereof, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition according to claim 8 A medicament for preventing and/or treating hepatitis B virus infection is prepared.