WO2018082503A1 - Composé hétérocyclique, son procédé de préparation et son application - Google Patents

Composé hétérocyclique, son procédé de préparation et son application Download PDF

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WO2018082503A1
WO2018082503A1 PCT/CN2017/108016 CN2017108016W WO2018082503A1 WO 2018082503 A1 WO2018082503 A1 WO 2018082503A1 CN 2017108016 W CN2017108016 W CN 2017108016W WO 2018082503 A1 WO2018082503 A1 WO 2018082503A1
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group
alkyl
compound
pharmaceutically acceptable
cycloalkyl
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PCT/CN2017/108016
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English (en)
Chinese (zh)
Inventor
蔡家强
宋帅
邓汉文
曾宏
宋宏梅
唐祖建
刘瑶
田强
黄海涛
王利春
王晶翼
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四川科伦博泰生物医药股份有限公司
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Priority to CN201780005344.3A priority Critical patent/CN108602842B/zh
Publication of WO2018082503A1 publication Critical patent/WO2018082503A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a heterocyclic compound having antiviral activity, a pharmaceutical composition comprising the same, a process for the preparation thereof, and its prevention or treatment including but not limited to hepatitis A virus, hepatitis B virus, hepatitis C virus, Use in influenza, herpes, and viral diseases of acquired immunodeficiency syndrome (AIDS).
  • a heterocyclic compound having antiviral activity a pharmaceutical composition comprising the same, a process for the preparation thereof, and its prevention or treatment including but not limited to hepatitis A virus, hepatitis B virus, hepatitis C virus, Use in influenza, herpes, and viral diseases of acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • a virus consists of a nucleic acid molecule (DNA or RNA) or a protein (such as a prion).
  • the virus can cause a variety of infectious diseases. Common diseases caused by viruses include, but are not limited to, viral hepatitis A, hepatitis B, hepatitis C, influenza, herpes and acquired immunodeficiency syndrome. (AIDS).
  • antiviral drugs play a role by inhibiting virus attachment, uncoating, viral gene duplication, maturation or release, or by affecting the host's immune system, including reverse transcriptase inhibitors and capsid protein assembly inhibitors. Wait.
  • Hepatitis B virus is a common hepadnavirus-like viral pathogen. Such viruses can cause diseases such as acute hepatitis, chronic hepatitis, liver fibrosis, cirrhosis and liver cancer.
  • Hepatitis B can be treated with the following nucleoside analogues:
  • Tenofovir is a nucleoside analog reverse transcriptase inhibitor, which is effective against human immunodeficiency virus (HIV) and hepatitis B virus (HBV) infection (Antivir Ther, 2004, 9, 57- 65; J Viral Hepat, 2000, 7, 161-165). Its principle of action is to inhibit reverse transcriptase activity by competing with the natural substrate deoxyadenosine-5'-triphosphate to integrate DNA into HBV and then terminate DNA strand synthesis. But tenofovir is hardly absorbed by the gastrointestinal tract.
  • the esterified prodrug tenofovir disoproxil fumarate (TDF) and the amidated prodrug tenofovir alafenamide fumarate (TAF) are well-soluble (Nucleosides Nucleotides Nucleic Acids. 2001, 20, 1085-1090; Antimicrob Agents Chemother. 2005, 49, 1898-1906; Antimicrob Agents Chemother. 2015, 59, 3563-3569; Journal of Hepatology. 2015, 62, 533-540).
  • hepatitis B can also be treated with non-nucleoside analogs.
  • heteroaryldihydropyrimidines Boy 41-4109
  • dihydropyrimidines induce misassembly of core proteins, resulting in unstable capsid proteins that accelerate the degradation of core proteins (Biochem. Pharmacol., 2003, 66, 2273-2279).
  • the heteroaryl dihydropyrimidine compound HAP1 (Proc. Natl. Acad. Sci., 2005, 102, 8138-8143) discovered by Zlotnick et al.
  • the present invention provides an antiviral heterocyclic compound which exerts an antiviral action by inhibiting the assembly of reverse transcriptase and/or capsid protein.
  • preferred compounds of the invention can simultaneously exhibit inhibition of reverse transcriptase and capsid protein assembly, thereby achieving superior antiviral effects at lower doses.
  • the compounds of the invention also have better physicochemical properties (e.g., solubility, physical and/or chemical stability), improved pharmacokinetic properties (e.g., improved bioavailability, suitable half-life, and duration of action). , improved safety (lower toxicity and / or fewer side effects), less susceptible to drug resistance and other superior properties.
  • One aspect of the invention provides a compound or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof Or a solvate, metabolite or prodrug, wherein the compound has the structure of formula (I):
  • B is selected from:
  • A is selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, optionally substituted by one or more R b , said alkylene, alkenylene or sub
  • An alkynyl group is optionally interrupted by one or more -O-, -NR- or -S-;
  • X, Y and Z are each independently selected from CH 2 , O, S and NR at each occurrence;
  • R a and R b are each independently selected from the group consisting of halogen, -OH, -CN, -NO 2 , -N(R) 2 , -N 3 , C 1-6 alkyl and C 3-6 ring at each occurrence. alkyl;
  • i and q are each independently 1, 2, 3, 4, 5 or 6 at each occurrence;
  • n is any integer selected from 0-50, preferably 0-20, particularly preferably 0-6;
  • R 1 is selected from:
  • Ar 1 and Ar 2 are each independently selected from a C 6-14 aryl group and a 5-14 membered heteroaryl group, which are optionally selected from one or more selected from the group consisting of halogen, -OH, -CN, -NO 2 , -N Substituent substitution of (R) 2 , C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkylthio and C 3-6 cycloalkyl;
  • L is absent or selected from -O-, -S-, and -NR-;
  • R 3 and R 4 are each independently selected from the group consisting of H, C 1-4 alkyl and C 3-6 cycloalkyl;
  • R 5 is attached to the remainder of the molecule with a single or double bond at each occurrence;
  • R 5 and R 6 are each independently selected from the group consisting of halogen, -OH, -COOH, -CN, -NO 2 , -N(R) 2 , C 1-6 alkyl, halogenated C 1-6 Alkyl, -WC 1-6 alkyl, -C 1-6 alkylene-WR, -WC 1-6 alkylene-W'-R, -WC 2-6 alkenyl, -C 2-6 Alkenyl-WR, -WC 2-6 alkenylene-W'-R and C 3-6 cycloalkyl, wherein the alkylene and alkenylene are optionally further separated by one or more W;
  • R is each independently selected from the group consisting of H, C 1-6 alkyl and C 3-6 cycloalkyl;
  • n each independently is 0, 1, 2, 3, 4 or 5, with the proviso that n is not greater than the number of positions on the corresponding group that can be substituted;
  • each R a may be the same or different, and each R b may be the same or different, and each R 5 may be the same or different, and each R 6 may be the same or different.
  • Another aspect of the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable compound thereof Accepted salts, esters, stereoisomers, tautomers, polymorphs, solvates, metabolites or prodrugs and one or more pharmaceutically acceptable carriers.
  • Another aspect of the invention provides a method of preparing a pharmaceutical composition
  • a method of preparing a pharmaceutical composition comprising administering a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, The solvate, metabolite or prodrug is combined with one or more pharmaceutically acceptable carriers.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the invention
  • a pharmaceutical composition for the preparation of a medicament for the prevention or treatment of a viral disease.
  • Another aspect of the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, or the invention
  • a pharmaceutical composition for preventing or treating a viral disease is also provided.
  • Another aspect of the invention provides a method of preventing or treating a viral disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer thereof, Tautomers, polymorphs, solvates, metabolites or prodrugs or pharmaceutical compositions of the invention.
  • the above viral diseases include, but are not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome (AIDS).
  • viral hepatitis A hepatitis A
  • hepatitis B virus hepatitis B virus
  • hepatitis C virus influenza
  • herpes and acquired immunodeficiency syndrome (AIDS).
  • AIDS acquired immunodeficiency syndrome
  • Another aspect of the invention provides a method of preparing a compound of the invention, the method comprising the steps of:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate and borate;
  • PG is selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonate Acyl, p-nitrophenylsulfonyl, formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, phenyl, benzoyl, trityl, benzyl, 2,4-dimethoxy Benzyl and p-methoxybenzyl;
  • the first step is carried out in the presence of an organic base or an inorganic base and/or a condensation reagent (particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP) in an aprotic solvent or without solvent;
  • a condensation reagent particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP
  • the second step is carried out under conditions suitable for removal of the PG group
  • the third step is carried out in an aprotic solvent in the presence of an organic or inorganic base
  • the fourth step is carried out in an aprotic solvent, preferably in the presence of an organic base or an inorganic base and/or a condensation reagent, particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP.
  • a condensation reagent particularly preferably DCC, DIC, EDC, BOP, PyAOP or PyBOP.
  • Another aspect of the invention provides a method of preparing a compound of the invention, the method comprising the steps of:
  • R 12 is selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate, and borate;
  • LG is a leaving group, which is preferably a pentafluorophenyl group and a p-nitrophenyl group;
  • the first step is carried out in an aprotic solvent in the presence of an organic or inorganic base;
  • the second step is carried out in an aprotic solvent in the presence of an organic or inorganic base;
  • the third step is carried out in an aprotic solvent in the presence of an organic or inorganic base.
  • alkylene denotes a saturated divalent hydrocarbon group, preferably a saturated divalent hydrocarbon group having 1, 2, 3, 4, 5 or 6 carbon atoms, such as methylene, ethylene, Propylene or butylene.
  • alkenylene denotes a divalent hydrocarbon radical containing one or more double bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethenylene, propenylene or Allylene.
  • alkenylene groups the compounds may exist in pure E (ent ought) form, pure Z (zusammen) form, or any mixture thereof.
  • alkynylene denotes a divalent hydrocarbon radical containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, for example ethynylene or propynylene. .
  • alkyl is defined as a straight or branched saturated aliphatic hydrocarbon group.
  • an alkyl group has from 1 to 12 carbon atoms, such as from 1 to 6 carbon atoms.
  • C1-6 alkyl refers to a straight or branched saturated aliphatic hydrocarbon group having from 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, isopropyl) , n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl or n-hexyl), which are optionally substituted by one or more (such as 1 to 3) suitable substituents such as halogen (this This group is referred to as "haloalkyl” (for example, CF 3 , C 2 F 5 , CHF 2 , CH 2 F, CH 2 CF 3 , CH 2 Cl or
  • C 1-4 alkyl refers to a straight or branched saturated aliphatic hydrocarbon group having 1 to 4 carbon atoms (ie, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl) , sec-butyl or tert-butyl).
  • cycloalkyl refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, or bicyclic, including spiro, fused or bridged systems (such as bicyclo [1.1.1] pentyl, bicyclo [2.2.1] heptyl, bicyclo [ 3.2.1] Octyl or bicyclo [5.2.0] anthracenyl, decalinyl, etc.)), which is optionally substituted by one or more (such as 1 to 3) suitable substituents.
  • bicyclic hydrocarbon ring eg, a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, Cyclohe
  • the cycloalkyl group has 3 to 15 carbon atoms.
  • C 3-6 cycloalkyl refers to a saturated or unsaturated, non-aromatic monocyclic or polycyclic (such as bicyclic) hydrocarbon ring having from 3 to 6 ring-forming carbon atoms (eg, cyclopropyl, cyclobutyl) A group, a cyclopentyl group or a cyclohexyl group, which is optionally substituted by one or more (such as 1 to 3) suitable substituents, such as a methyl-substituted cyclopropyl group.
  • aryl refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system.
  • C6-14 aryl means an aromatic group containing from 6 to 14 carbon atoms, such as phenyl or naphthyl.
  • the aryl group is optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO 2 , C 1-6 alkyl, etc.).
  • aralkyl denotes an alkyl group substituted with an aryl group, wherein the aryl group and the alkyl group are as defined herein.
  • the aryl group can have from 6 to 14 carbon atoms and the alkyl group can have from 1 to 6 carbon atoms.
  • Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.
  • heteroaryl refers to a monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contain at least one hetero atom which may be the same or different (the hetero atom is, for example, oxygen, nitrogen or sulfur), and additionally In one case, it may be benzo-fused.
  • the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia A oxazolyl group or the like, and a benzo derivative thereof; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group or the like, and a benzo derivative thereof.
  • halo or halogen group, as used herein, is defined to include F, Cl, Br or I.
  • alkylthio refers to an alkyl group, as defined above, appended to the parent molecular moiety through a sulfur atom.
  • Representative examples of C1-6 alkylthio include, but are not limited to, methylthio, ethylthio, tert-butylthio, and hexylthio.
  • the 3 to 14 membered nitrogen heterocycle is a cyclic group having 3 to 14 carbon atoms and a hetero atom (at least one of which is a nitrogen atom) in the ring, including but not limited to aziridine, nitrogen Heterocyclic butane, pyrrolyl, pyrrolidinyl, pyrrolinyl, pyrrolidinyl, imidazolyl, imidazolidinyl, imidazolinyl, pyrazolyl, pyrazolinyl, piperidinyl, morpholinyl, sulfur? A phenyl group, a piperazinyl group, a fluorenyl group, a porphyrin group or the like.
  • substituted means that one or more (eg, one, two, three or four) hydrogens on the designated atom are replaced by the selection of the indicated group, provided that the specified atom is not present at present.
  • the normal valence in the case and the substitution form a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • substituent may be unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the carbon (to the extent of any hydrogen present) may be independently and/or together independently The optional substituents selected are substituted. If the nitrogen of the substituent is described as being optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) may each be independently selected. Substitute substitution.
  • each substituent is selected independently of the other.
  • each substituent may be the same or different from another (other) substituent.
  • one or more means 1 or more than 1, such as 2, 3, 4, 5 or 10 under reasonable conditions.
  • a point of attachment of a substituent may come from any suitable position of the substituent.
  • the invention also includes all pharmaceutically acceptable isotopically-labeled compounds which are identical to the compounds of the invention, except that one or more atoms are of the same atomic number but the atomic mass or mass number differs from the atomic mass prevailing in nature. Or atomic substitution of mass.
  • isotopes suitable for inclusion in the compounds of the invention include, but are not limited to, isotopes of hydrogen (e.g., 2 H, 3 H); isotopes of carbon (e.g., 11 C, 13 C, and 14 C); isotopes of chlorine (e.g.
  • isotope of fluorine eg 18 F
  • isotopes of iodine eg 123 I and 125 I
  • isotopes of nitrogen eg 13 N and 15 N
  • isotopes of oxygen eg 15 O, 17 O and 18 O
  • isotope of phosphorus eg, 32 P
  • isotope of sulfur eg, 35 S.
  • Certain isotopically-labeled compounds of the invention e.g., those incorporating radioisotopes
  • are useful in drug and/or substrate tissue distribution studies e.g., assays).
  • the radioisotope ruthenium (i.e., 3 H) and carbon-14 (i.e., 14 C) are particularly useful for this purpose because of their ease of incorporation and ease of detection.
  • Substitution with positron emitting isotopes eg, 11 C, 18 F, 15 O, and 13 N
  • PET positron emission tomography
  • Isotopically labeled compounds of the invention can be prepared by replacing the previously employed non-labeled reagents with suitable isotopically labeled reagents by methods analogous to those described in the accompanying routes and/or examples and preparations.
  • the pharmaceutically acceptable solvates of the present invention include those in which the crystallization solvent can be substituted with an isotope, for example, D 2 O, acetone-d 6 or DMSO-d 6 .
  • stereoisomer denotes an isomer formed by at least one asymmetric center.
  • a compound having one or more (eg, one, two, three or four) asymmetric centers it can produce a racemic mixture, a single enantiomer, a mixture of diastereomers, and Diastereomers.
  • Specific individual molecules can also exist as geometric isomers (cis/trans).
  • the compounds of the invention may exist as mixtures (often referred to as tautomers) of two or more different forms in a rapidly balanced structure.
  • tautomers include keto-enol tautomers, phenol-keto tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait.
  • a dihydropyrimidinyl group can exist in equilibrium in the following tautomeric forms: It is to be understood that the scope of the present application covers all such ratios in any ratio (eg, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99). %) isomer or a mixture thereof.
  • Solid lines can be used in this article Solid wedge Virtual wedge
  • the carbon-carbon bonds of the compounds of the invention are depicted.
  • the use of solid lines to delineate linkages bonded to an asymmetric carbon atom is intended to include all possible stereoisomers at the carbon atom (eg, specific enantiomers, racemic mixtures, etc.).
  • the use of a solid or virtual wedge to characterize a bond to an asymmetric carbon atom is intended to indicate the presence of the stereoisomers shown.
  • solid and virtual wedges are used to define relative stereochemistry rather than absolute stereochemistry.
  • the compounds of the invention are intended to be stereoisomers (including cis and trans isomers, optical isomers (eg, R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the invention may exhibit more than one type of isomerism and consist of a mixture thereof (e.g., a racemic mixture and a diastereomeric pair).
  • the invention encompasses all possible crystalline forms or polymorphs of the compounds of the invention, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the invention may exist in free form for treatment or, where appropriate, in the form of their pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, esters, solvates, metabolites or prodrugs, which are capable of being administered directly to a patient in need thereof
  • the compound of the invention or a metabolite or residue thereof is provided indirectly or indirectly.
  • a compound of the invention it is also intended to encompass the various derivative forms described above for the compound.
  • the pharmaceutically acceptable salts of the compounds of the present invention include the acid addition salts and base addition salts thereof.
  • Suitable acid addition salts are formed from acids which form pharmaceutically acceptable salts. Examples include aspartate, bicarbonate/carbonate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hydrobromide/bromide, hydrogen Iodate/iodide, naphthylate, nicotinate, nitrate, orotate, palmitate and other similar salts.
  • Suitable base addition salts are formed from bases which form pharmaceutically acceptable salts. Examples include aluminum salts, arginine salts, choline salts, lysine salts, magnesium salts, meglumine salts, tromethamine salts, and other similar salts.
  • esters means an ester derived from a compound of the formulae herein, which includes a physiologically hydrolyzable ester (which can be hydrolyzed under physiological conditions to release the free acid or alcohol form of the invention). Compound).
  • the compounds of the invention may also be esters per se.
  • the compound of the present invention may exist in the form of a solvate (preferably a hydrate) wherein the compound of the present invention contains a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly such as water, methanol or ethanol.
  • the amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios.
  • metabolites of the compounds of the invention i.e., substances formed in vivo upon administration of a compound of the invention. Such products may be produced, for example, by oxidation, reduction, hydrolysis, amidation, deamidation, esterification, delipidization, enzymatic hydrolysis, and the like of the administered compound. Accordingly, the invention includes metabolites of the compounds of the invention, including compounds prepared by contacting a compound of the invention with a mammal for a time sufficient to produce a metabolic product thereof.
  • the invention further includes within its scope prodrugs of the compounds of the invention which are certain derivatives of the compounds of the invention which may themselves have less or no pharmacological activity, when administered to or into the body It can be converted to a compound of the invention having the desired activity by, for example, hydrolytic cleavage.
  • prodrugs will be functional group derivatives of the compounds which are readily converted in vivo to the desired therapeutically active compound. Additional information on the use of prodrugs can be found in "Pro-drugs as Novel Delivery” Systems, Vol. 14, ACS Symposium Series (T. Higuchi and V. Stella) and "Bioreversible Carriers in Drug Design," Pergamon Press, 1987 (EB Roche, ed., American Pharmaceutical Association).
  • Prodrugs of the invention can be passed, for example, Substituting certain parts of the compounds of the invention as known to the "pro-moiety" (for example “Design of Prodrugs", H. Bundgaard (Elsevier, 1985)" by those skilled in the art Prepare with appropriate functional groups.
  • the invention also encompasses compounds of the invention containing a protecting group.
  • a protecting group In any process for preparing a compound of the invention, it may be necessary and/or desirable to protect a sensitive group or reactive group on any of the molecules of interest, thereby forming a chemically protected form of the compound of the invention. This can be achieved by conventional protecting groups such as those described in Protective Groups in Organic Chemistry, ed. JFW McOmie, Plenum Press, 1973; and TW Greene & P. GM Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991. Protecting groups, which are incorporated herein by reference. The protecting group can be removed at a suitable subsequent stage using methods known in the art.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein
  • the compound has the structure of formula (I):
  • B is selected from:
  • A is selected from C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene, optionally substituted by one or more R b , said alkylene, alkenylene or sub
  • An alkynyl group is optionally interrupted by one or more -O-, -NR- or -S-;
  • X, Y and Z are each independently selected from CH 2 , O, S and NR at each occurrence;
  • R a and R b are each independently selected from the group consisting of halogen, -OH, -CN, -NO 2 , -N(R) 2 , -N 3 , C 1-6 alkyl and C 3-6 ring at each occurrence. alkyl;
  • i and q are each independently 1, 2, 3, 4, 5 or 6 at each occurrence;
  • n is any integer selected from 0-50, preferably 0-20, particularly preferably 0-6;
  • R 1 is selected from:
  • Ar 1 and Ar 2 are each independently selected from a C 6-14 aryl group and a 5-14 membered heteroaryl group, which are optionally selected from one or more selected from the group consisting of halogen, -OH, -CN, -NO 2 , -N Substituent substitution of (R) 2 , C 1-6 alkyl, halo C 1-6 alkyl, C 1-6 alkylthio and C 3-6 cycloalkyl;
  • L is absent or selected from -O-, -S-, and -NR-;
  • R 3 and R 4 are each independently selected from the group consisting of H, C 1-4 alkyl and C 3-6 cycloalkyl;
  • R 5 is attached to the remainder of the molecule with a single or double bond at each occurrence;
  • R 5 and R 6 are each independently selected from the group consisting of halogen, -OH, -COOH, -CN, -NO 2 , -N(R) 2 , C 1-6 alkyl, halogenated C 1-6 Alkyl, -WC 1-6 alkyl, -C 1-6 alkylene-WR, -WC 1-6 alkylene-W'-R, -WC 2-6 alkenyl, -C 2-6 Alkenyl-WR, -WC 2-6 alkenylene-W'-R and C 3-6 cycloalkyl, wherein the alkylene and alkenylene are optionally further separated by one or more W;
  • R is each independently selected from the group consisting of H, C 1-6 alkyl and C 3-6 cycloalkyl;
  • n each independently is 0, 1, 2, 3, 4 or 5, with the proviso that n is not greater than the number of positions on the corresponding group that can be substituted, and
  • each R a may be the same or different, and each R b may be the same or different, and each R 5 may be the same or different, and each R 6 may be the same or different.
  • X, Y, and Z at each occurrence is independently selected from CH 2, O, and NH.
  • X, Y and Z are each independently selected from O and NH at each occurrence.
  • R a and R b are each independently selected from the group consisting of halogen, -OH, -N(R) 2 , -N 3 and C 1-6 alkyl.
  • R a and R b are each independently selected from the group consisting of F, -OH, amino, cyclopropylamino and methyl at each occurrence.
  • B is selected from the group consisting of:
  • B is
  • A is selected from the group consisting of:
  • One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).
  • A is One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).
  • A is One of the positions is connected to B, and the second position is connected to the phosphorus atom (P).
  • It is selected from the group consisting of azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl and piperazinyl.
  • R 1 is selected from the group consisting of
  • Ar 1 and Ar 2 are each independently selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, piperazinyl and phenyl, each of which is optionally one or more The same or different halogen, C 1-6 alkyl, halo C 1-6 alkyl and C 3-6 cycloalkyl are substituted.
  • Ar 1 and Ar 2 are each independently selected from the group consisting of imidazolyl, oxazolyl, thiazolyl, pyridyl, pyrimidinyl, piperazinyl and phenyl, each of which is optionally one or more The same or different halogen, C 1-6 alkyl and C 3-6 cycloalkyl substituted.
  • Ar 1 is selected from the group consisting of
  • R c is each independently selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl, halo C 1-6 alkyl, and C 3-6 cycloalkyl;
  • each occurrence of R c is independently selected from the group consisting of F, Cl, Br, I, C 1-6 alkyl and C 3-6 cycloalkyl;
  • Ar 1 is preferably selected from:
  • Ar 1 is more preferably from:
  • Ar 2 is selected from the group consisting of
  • the above groups are optionally substituted by one or more groups selected from the group consisting of halogen, C1-6 alkyl, halogenated C1-6 alkyl and C3-6 cycloalkyl.
  • Ar 2 is selected from the group consisting of
  • the above groups are optionally substituted by one or more groups selected from the group consisting of halogen, C 1-6 alkyl and C 3-6 cycloalkyl.
  • L is -O-.
  • R 3 and R 4 are each independently selected from the group consisting of methyl, ethyl, n-propyl and isopropyl.
  • R 4 is H.
  • R 2 is selected from the group consisting of: C 1-6 alkyl, -((CH 2 ) i O) m -(CH 2 ) q -OC 1-6 alkyl,
  • i and q are each independently 1, 2, 3, 4, 5 or 6 at each occurrence;
  • n is any integer selected from 0-50, preferably 0-20, particularly preferably 0-6;
  • R 7 , R 8 and R 9 are each independently selected from the group consisting of H, C 1-10 alkyl, C 3-6 cycloalkyl, C 6-20 aryl and C 7-20 aralkyl, said alkyl group,
  • the cycloalkyl, aryl and aralkyl groups are each optionally substituted by one or more substituents selected from the group consisting of halogen, -OH, -CN and -NO 2 ;
  • R 7 and R 8 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group
  • R 10 and R 11 are each independently selected from the group consisting of H, halogen, -OH, -CN, -NO 2 , C 1-10 alkyl, and C 3-6 cycloalkyl.
  • R 2 is selected from the group consisting of: C 1-6 alkyl, -((CH 2 ) i O) m -(CH 2 ) q -OC 1-4 alkyl,
  • i and q are each independently 1, 2, 3 or 4 at each occurrence;
  • n 1, 2, 3, 4, 5 or 6;
  • R 7 and R 9 are each independently selected from H or C 1-4 alkyl, and the alkyl group is optionally substituted with one or more substituents selected from the group consisting of halogen, -OH, -CN, and -NO 2 ;
  • R 10 and R 11 are each independently selected from H, halogen, -OH, -CN, -NO 2 or C 1-4 alkyl.
  • R 2 is selected from the group consisting of H, methyl, ethyl, propyl, butyl, pentyl, -((CH 2 ) 2 O) 6 -(CH 2 ) 2 -O-CH 3 ,
  • R 2 is selected from the group consisting of methyl, ethyl, propyl, butyl, -((CH 2 ) 2 O) 6 -(CH 2 ) 2 -O-CH 3 ,
  • n 0, 1, 2 or 3.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein
  • the compound has the structure of formula (II) or formula (II)-1:
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein
  • the compound has any structure of the following formula:
  • the present invention encompasses compounds obtained by any combination of the various embodiments.
  • the invention provides a compound, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, wherein Said compound is selected from:
  • One embodiment of the invention provides a method of preparing a compound of the invention, the method comprising the steps of:
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate and borate;
  • PG is selected from the group consisting of tert-butoxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, allyloxycarbonyl, trimethylsilyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl, p-toluenesulfonyl, o-nitrobenzenesulfonate Acyl, p-nitrophenylsulfonyl, formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, phenyl, benzoyl, trityl, benzyl, 2,4-dimethoxy Benzyl and p-methoxybenzyl;
  • the first step is carried out in the presence of an organic base or an inorganic base and/or a condensation reagent in an aprotic solvent or without a solvent;
  • the second step is carried out under conditions suitable for removal of the PG group
  • the third step is carried out in an aprotic solvent in the presence of an organic or inorganic base
  • the fourth step is carried out in an aprotic solvent, preferably in the presence of an organic base or an inorganic base and/or a condensation reagent.
  • Another aspect of the invention provides a method of preparing a compound of the invention, the method comprising the steps of:
  • R 12 is selected from the group consisting of F, Cl, Br, I, -NHR, hydroxy, triflate, p-toluenesulfonate, and borate;
  • LG is a leaving group, which is preferably a pentafluorophenyl group and a p-nitrophenyl group;
  • the first step is carried out in an aprotic solvent in the presence of an organic or inorganic base;
  • the second step is carried out in an aprotic solvent in the presence of an organic or inorganic base;
  • the third step is carried out in an aprotic solvent in the presence of an organic or inorganic base.
  • R 12 , R 13 and R 14 are each independently selected from the group consisting of F, Cl, Br, I, NH 2 or a hydroxyl group.
  • PG may be a tert-butoxycarbonyl group, and the conditions suitable for the removal of the tert-butoxycarbonyl group may be, for example, catalyzed by an acid such as trifluoroacetic acid in a solvent such as dichloromethane at 0. °C to room temperature.
  • LG-OH can be pentafluorophenol, p-nitrophenol.
  • the aprotic solvent which can be used in the method of preparing the compound of the present invention includes, but is not limited to, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, acetonitrile, N,N-dimethyl Formamide (DMF), N-methylpyrrolidone, 1,3-dimethyl-2-imidazolidinone (DMI), dimethyl sulfoxide (DMSO), and hexamethylphosphoric triamide (HMPA).
  • the organic bases which can be used in the preparation of the compounds of the invention include, but are not limited to, sodium t-butoxide, t-butylmagnesium chloride, triethylamine, N,N-diisopropylethylamine (DIPEA) , pyridine or 4-dimethylaminopyridine (DMAP); inorganic bases which can be used in the preparation of the compounds of the invention include, but are not limited to, NaH, NaOH, Na 2 CO 3 or K 2 CO 3 .
  • condensation reagents which can be used in the method of preparing the compounds of the invention include, but are not limited to, dicyclohexylcarbodiimide (DCC), N,N-diisopropylcarbodiimide (DIC).
  • DCC dicyclohexylcarbodiimide
  • DIC N,N-diisopropylcarbodiimide
  • EDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • BOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • PyAOP benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate
  • PyBOP 1H-benzo Triazol-1-yloxytripyrrolidinylphosphonium hexafluorophosphate
  • compositions and methods of treatment are provided.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a prophylactically or therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, or a pharmaceutically acceptable salt thereof A form, solvate, metabolite or prodrug and one or more pharmaceutically acceptable carriers.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents, such as other therapeutic agents for preventing or treating viral diseases.
  • the invention provides a method of preparing a pharmaceutical composition
  • a pharmaceutical composition comprising the compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph thereof, or a pharmaceutically acceptable salt thereof
  • the form, solvate, metabolite or prodrug is combined with one or more pharmaceutically acceptable carriers.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, Or the use of the pharmaceutical composition of the present invention in the preparation of a medicament for preventing or treating a viral disease.
  • the invention provides a compound of the invention, or a pharmaceutically acceptable salt, ester, stereoisomer, tautomer, polymorph, solvate, metabolite or prodrug thereof, Or a pharmaceutical composition of the invention for use in the prevention or treatment of a viral disease.
  • the invention provides a method of preventing or treating a viral disease, the method comprising administering to an individual in need thereof an effective amount of a compound of the invention, or a pharmaceutically acceptable salt, ester, or stereoisod thereof A construct, tautomer, polymorph, solvate, metabolite or prodrug or a pharmaceutical composition of the invention.
  • Preferred compounds of the invention exert an antiviral effect by inhibiting the assembly of reverse transcriptase and/or capsid protein.
  • the compounds of the invention are useful in the treatment of any virus involved in the assembly of reverse transcriptase and/or capsid proteins in the process of affecting a host, including but not limited to hepatitis A virus (HAV), hepatitis B virus (HBV) ), hepatitis C virus (HCV), influenza virus, herpes virus (HSV) and human immunodeficiency virus (HIV).
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • influenza virus influenza virus
  • HSV herpes virus
  • HSV human immunodeficiency virus
  • viral diseases which can be prevented and treated using the compounds of the present invention include, but are not limited to, viral hepatitis A, hepatitis B virus, hepatitis C virus, influenza, herpes, and acquired immunodeficiency syndrome. (AIDS), and related symptoms or diseases caused by the above diseases (for example, inflammation, liver fibrosis, cirrhosis, liver cancer, etc.).
  • “Pharmaceutically acceptable carrier” in the context of the present invention means a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the composition may also contain minor amounts of wetting agents, emulsifying agents or pH buffering agents as needed.
  • Oral formulations may contain standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, magnesium carbonate, and the like. Examples of suitable pharmaceutically acceptable carriers are as described in Remington's Pharmaceutical Sciences (1990).
  • compositions of the invention may act systemically and/or locally.
  • they may be administered in a suitable route, for example by injection (for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation) or transdermal administration; or by oral, buccal, or oral administration.
  • injection for example intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular, including instillation
  • transdermal administration or by oral, buccal, or oral administration.
  • compositions of the invention may be administered in a suitable dosage form.
  • the dosage forms include, but are not limited to, tablets, capsules, troches, hard candy, powders, sprays, creams, ointments, suppositories, gels, pastes, lotions, ointments, aqueous suspensions. Injectable solutions, elixirs, syrups.
  • an effective amount refers to an amount of a compound that, to a certain extent, relieves one or more symptoms of the condition being treated after administration.
  • the dosing regimen can be adjusted to provide the optimal desired response. For example, a single bolus may be administered, several divided doses may be administered over time, or the dose may be proportionally reduced or increased as indicated by the urgent need for treatment. It is noted that the dose value can vary with the type and severity of the condition to be alleviated and can include single or multiple doses. It is to be further understood that for any particular individual, the particular dosage regimen will be adjusted over time according to the individual needs and the professional judgment of the person administering the composition or the composition of the supervised composition.
  • an effective dose will be from about 0.0001 to about 50 mg per kg body weight per day, for example from about 0.01 to about 10 mg/kg/day (single or divided doses). For a 70 kg person, this would add up to about 0.007 mg/day to about 3500 mg/day, such as from about 0.7 mg/day to about 700 mg/day.
  • a dose level that is not higher than the lower limit of the aforementioned range may be sufficient, while in other cases, a larger dose may still be employed without causing any harmful side effects, provided that the larger The dose is divided into several smaller doses to be administered throughout the day.
  • the amount or amount of the compound of the present invention in the pharmaceutical composition may be from about 0.01 mg to about 1000 mg, suitably from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 150 mg, particularly preferably from 1 to 50 mg, for example, 1.5 mg, 2 mg, 4 mg, 10 mg, 25 mg, and the like.
  • treating means reversing, alleviating, inhibiting the progression of a condition or condition to which such a term applies or one or more symptoms of such a condition or condition, or Prevention of such a condition or condition or one or more symptoms of such condition or condition.
  • “Individual” as used herein includes human or non-human animals.
  • Exemplary human individuals include a human individual (referred to as a patient) or a normal individual having a disease, such as the disease described herein.
  • “Non-human animals” in the present invention include all vertebrates, such as non-mammals (eg, birds, amphibians, reptiles) and mammals, such as non-human primates, domestic animals, and/or domesticated animals (eg, sheep, dogs). , cats, cows, pigs, etc.).
  • compositions of the present invention may further comprise one or more additional therapeutic or prophylactic agents including, but not limited to, lamivudine, telbivudine, entecavir, adefovir Ester, tenofovir, tenofovir disoproxil fumarate, and tenofovir alafenamide fumarate.
  • additional therapeutic or prophylactic agents including, but not limited to, lamivudine, telbivudine, entecavir, adefovir Ester, tenofovir, tenofovir disoproxil fumarate, and tenofovir alafenamide fumarate.
  • LC-MS was detected on an Aglient 1200 liquid chromatograph using an Aglient 6120 Quadrupole mass spectrometer at 214 nm and 254 nm.
  • the following table performs a linear gradient elution:
  • Step 1 Synthesis of 4-(4-hydroxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (Compound 1-2)
  • Step 2 4-(4-((((())))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))))) Synthesis of tert-butyl ester of oxy)phenyl)piperidine-1-carboxylate (Compound 1-3)
  • Step 3 ((((R)-1-(6-amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-4-(piperidin-4-yl)-benzene Synthesis of base-monophosphate (compounds 1-4)
  • Trifluoroacetate salt of compound 1-4 (163 mg, 0.4 mmol) was dissolved in 1,2-dichloroethane (4 mL) at room temperature, followed by (R)-6-(bromomethyl)-4 -(2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (204 mg, 0.4 mmol) and N,N-diiso The propyl ethylamine (0.1 mL) was added and the mixture was evaporated. ESI-MS (m/z): 824.2 [M+H] + .
  • Step 2 ((((R)-1-(6-Amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-(3,3-difluoropiperidin-4- Synthesis of mono)triphosphate trifluoroacetate (compound 7-3)
  • Step 4 (4R)-6-((4-(((((((((((()))))))))))) ((S)-1-ethoxy-1-oxopropan-2-yl)oxy)phosphonyl)oxy)-3,3-difluoropiperidin-1-yl)methyl)-4- Synthesis of (2-Chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid ethyl ester (Compound 27)
  • Step 2 ((((R)-1-(6-Amino-9H-indol-9-yl)propan-2-yl)oxy)methyl)-4,4-difluoropyrrolidin-3-yl Synthesis of monophosphate trifluoroacetate (compound 8-3)
  • Step 1 (4R)-4-(2-Chloro-4-fluorophenyl)-6-((4-((dichlorophosphonyl)oxy)-3,3-difluoropyrrolidin-1-yl) Synthesis of ethyl (ethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (Compound 12-2)
  • Step 2 (4R)-4-(2-chloro-4-fluorophenyl)-6-((3,3-difluoro-4-(((()))) Oxopropan-2-yl)amino)(pentafluorophenoxy)phosphonyloxy)pyrrolidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydro Synthesis of pyrimidine-5-carboxylate ethyl ester (compound 12-3)
  • Step 3 (4R)-4-(2-chloro-4-fluorophenyl)-6-((3,3-difluoro-4-((((())))) 5-(5-Methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)tetrahydrofuran-2-yl)methoxy)(((S)-1-iso) Propoxy-1-oxopropan-2-yl)amino)phosphono)oxy)pyrrolidin-1-yl)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine- Synthesis of ethyl 5-carboxylate (Compound 32)
  • telbivudine 50 mg, 0.2 mmol was dissolved in tetrahydrofuran (2 mL), the temperature was lowered to -20 ° C under nitrogen, and t-butyl magnesium chloride (0.4 mL, 1 M) was added dropwise. After 1 h, the temperature was further lowered to -20 ° C under nitrogen atmosphere, and the tetrahydrofuran solution obtained in the second step was added dropwise, and the reaction was carried out overnight under nitrogen atmosphere at room temperature. The title compound (2.0 mg) was obtained after purification. ESI-MS (m/z): 918.0 [M+H] + .
  • HBV hepatitis B virus
  • HepG2 2.2.15 cells in logarithmic growth phase were seeded in 96-well plates at a cell concentration of 40/ ⁇ L. Incubate for 3 days at 37 ° C in a 5% CO 2 incubator; replace with fresh medium (200 ⁇ L/well) before adding the compound.
  • the mother liquor concentration of each test compound was 200 ⁇ M.
  • the highest concentration was 200 ⁇ M, diluted to a number of different concentrations in DMSO, and 1 ⁇ L of the test compound was placed in the corresponding medium well.
  • the final test concentrations of the compounds were 0.06, 0.24, 0.98, 3.9, 15.6, 62.5, 250, 1000 nM (using Calculate the half effective concentration (EC 50 )).
  • each test compound was diluted to 600 ⁇ M and 60 ⁇ M with DMSO, and 1 ⁇ L of each was added to the corresponding medium well, and the final test concentrations of the compounds were 3 ⁇ M and 0.3 ⁇ M (for calculating the percent inhibition).
  • Blank control 1 ⁇ L of DMSO was added to the corresponding medium wells as a control.
  • test compound was added, it was co-cultured for 10 days at 37 ° C in a 5% CO 2 incubator, the medium was changed every two days, and the compound was re-added.
  • the tested compounds showed strong inhibitory activity in the activity test for inhibiting the replication of deoxyribonucleic acid (DNA) of hepatitis B virus (HBV), and some compounds had an EC 50 of ⁇ 60 nM, preferably a compound (for example).
  • the EC 50 of the compounds 29 and 30) was ⁇ 10 nM, indicating that the compound of the present invention has very excellent inhibitory activity.
  • the tested compound exhibited an excellent inhibitory effect in the activity test for inhibiting the deoxyribonucleic acid (DNA) replication of hepatitis B virus (HBV) at a concentration of 3 ⁇ M.
  • the compound tested also exhibited an excellent inhibitory effect at a concentration of 0.3 ⁇ M, indicating that the compound of the present invention has a very excellent inhibitory effect.
  • test compound was diluted to 30 mM with DMSO, diluted to a maximum concentration of 30 mM, and diluted to a plurality of different concentrations. 0.2 ⁇ L of each compound was added to a 384-well plate, and 2000/50 ⁇ L of HepG2 was added to each well. For 15 cells, the highest concentration of the test compound was 150 ⁇ M; 1 ⁇ L of DMSO was added to the corresponding wells as a control.
  • the cells were co-cultured for 4 days at 37 ° C in a 5% CO 2 incubator.
  • Preferred compounds e.g. compound of Example 5
  • CC 50 value of greater than 150 M indicating its low cytotoxicity and high safety.

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Abstract

La présente invention concerne un composé hétérocyclique ayant une activité antivirale, une composition de médicament le comprenant, son procédé de préparation, et une application de celui-ci pour la prévention ou le traitement de maladies virales comprenant, mais sans y être limitées, l'hépatite A virale, l'hépatite B virale, l'hépatite C virale, la grippe, l'herpès et le syndrome d'immunodéficience acquise (SIDA).
PCT/CN2017/108016 2016-11-02 2017-10-27 Composé hétérocyclique, son procédé de préparation et son application WO2018082503A1 (fr)

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