WO2017015451A1 - Agents antiviraux de l'hépatite b - Google Patents

Agents antiviraux de l'hépatite b Download PDF

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Publication number
WO2017015451A1
WO2017015451A1 PCT/US2016/043324 US2016043324W WO2017015451A1 WO 2017015451 A1 WO2017015451 A1 WO 2017015451A1 US 2016043324 W US2016043324 W US 2016043324W WO 2017015451 A1 WO2017015451 A1 WO 2017015451A1
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optionally substituted
compound
group
compounds
alkyl
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PCT/US2016/043324
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English (en)
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Yao-Ling Qui
Wei Li
Hui Cao
Meizhong Jin
Jorden Kass
Xuri Gao
Xiaowen Peng
Yat Sun Or
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Enanta Pharmaceuticals, Inc.
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Publication of WO2017015451A1 publication Critical patent/WO2017015451A1/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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/265—Esters, e.g. nitroglycerine, selenocyanates of carbonic, thiocarbonic, or thiocarboxylic acids, e.g. thioacetic acid, xanthogenic acid, trithiocarbonic acid
    • 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
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/66—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates generally to novel antiviral agents. Specifically, the present invention relates to compounds which can inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the function of the HBV life cycle, compositions comprising such compounds, methods for inhibiting HBV viral replication, methods for treating or preventing HBV infection, and processes for making the compounds.
  • HBV hepatitis B virus
  • HBV infection remains a major public health problem, affecting approximately 2 billion people worldwide. Among them, 350 million people worldwide and 1.4 million in the US develop a chronic infection, which can lead to chronic persistent hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Every year 500,000 to 1 million people die from the end stage of liver diseases caused by HBV infection.
  • HBV Despite the availability of a prophylactic HBV vaccine, the burden of chronic HBV infection continues to be a significant unmet worldwide medical problem, due to suboptimal treatment options and sustained rates of new infections in most parts of the developing world.
  • Current treatments do not provide a cure and are limited to only two classes of agents (interferon and nucleoside analogues/inhibitors of the viral polymerase); drug resistance, low efficacy, and tolerability issues limit their impact.
  • the low cure rates of HBV are attributed at least in part to the presence and persistence of covalently closed circular DNA (cccDNA) in the nucleus of infected hepatocytes.
  • cccDNA covalently closed circular DNA
  • persistent suppression of HBV DNA slows liver disease progression and helps to prevent HCC.
  • the HBV is an enveloped, partially double-stranded DNA (dsDNA) virus of the hepadnavirus family (Hepadnaviridae) .
  • HBV capsid protein (CP) plays essential roles in HBV replication. The predominant biological function of capsid protein is to act as a structural protein to encapsidate pre-genomic RNA and form immature capsid particles, which spontaneously self-assemble from many copies of core dimers in the cytoplasm. Capsid protein also regulates viral DNA synthesis through different phosphorylation status of its C-terminal phosphorylation sites.
  • capsid protein might facilitate the nuclear translocation of viral relaxed circular genome by means of the nuclear localization signals located in the Arginine-rich domain of the C-terminal region of capsid protein.
  • capsid protein could play a structural and regulatory role in the functionality of cccDNA minichromosomes.
  • Capsid protein also interacts with viral large envelope protein in endoplasmic reticulum (ER) and triggers the release of intact viral particles from hepatocytes.
  • ER endoplasmic reticulum
  • phenylpropen-amide derivatives including compounds named AT-61 and AT-130 (Feld J. et al. Antiviral Res. 2007, 76, 168), and a class of thiazolidin-4-ones from Valeant (W02006/033995), have been shown to inhibit pregenomic RNA (pgRNA) packaging.
  • pgRNA pregenomic RNA
  • Heteroaryldihydropyrimidines or HAPs were discovered in a tissue culture-based screening (Weber et al, Antiviral Res. 2002, 54, 69). These HAP analogs act as synthetic allosteric activators and are able to induce aberrant capsid formation that leads to degradation of the core protein.
  • a subclass of sulphamoyl-arylamides also shows activity against HBV (WO2013/006394, WO2013/ 096744, and WO 2014/184365). It was also shown that the small molecule bis-ANS acts as a molecular 'wedge' and interferes with normal capsid-protein geometry and capsid formation (Zlotnick A. et al. J. Virol. 2002, 4848).
  • the present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, as well as methods to treat or prevent viral (particularly HBV) infection in a subject in need of such therapy with said compounds.
  • Compounds of the present invention inhibit the protein(s) encoded by hepatitis B virus (HBV) or interfere with the life cycle of HBV and are also useful as antiviral agents.
  • the present invention includes the process for the preparation of the said compounds.
  • X is an optionally substituted aryl or optionally substituted heteroaryl; preferably X is an optionally substituted phenyl;
  • Ai is absent, or selected from the group consisting of -NH-, -NHC(O)-,
  • Y is an optionally substituted aryl or optionally substituted heteroaryl; preferably Y is an optionally substituted phenyl, optionally substituted thiophenyl, or optionally substituted azolyl;
  • A2 is absent or -NR4-;
  • Z is -CR a R b -; wherein R a and R b are each independently selected from the group consisting of hydrogen, OH, OMe, halogen, and methyl optionally substitituted with 1 to 3 substituents selected from the group consisting of fluoro, chloro, OH, and OMe; wherein at least one of R a and R b is not hydrogen; preferably, Z is -CF2-, -C(CH2F)2-, or - CH(CF 3 )-;
  • R a , R b , and the carbon atom to which they are attached to form an oxetanyl, 5- to 6-membered cyclic ketal, or -C( CF2)-;
  • L is -NRi-, O or -CR1R2-;
  • R, Ri, R2, R3 and R4 at each occurrence are independently selected from the group consisting of hydrogen, optionally substituted -Ci-Cs alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl and optionally substituted heteroaryl; alternatively, Ri and R2 or Ri and R are taken together with the atom to which they are attached to form an optionally substituted C3-C8 cycloalkyl or an optionally substituted 3- to 8-membered heterocyclic.
  • R is terminally substituted Ci-C4-alkyl, more preferably terminally substituted C2-alkyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is optionally substituted phenyl.
  • X is a phenyl optionally substituted with one or more substituents selected from halo, CN, OH, OMe, Me, -C02Me, and cyclopropyl.
  • substituents selected from halo, CN, OH, OMe, Me, -C02Me, and cyclopropyl.
  • X is a fluoro- or cyano-substituted phenyl. In yet another embodiment, X is 3,4,5-trifluorophenyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is optionally substituted monocyclic heteroaryl. In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is optionally substituted bicyclic heteroaryl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is benzimidazolyl,
  • benzothiazolyl benzoxazolyl, indazolyl, quinolyl, isoquinolyl or quinazolyl; each optionally substituted.
  • the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein X is a bicyclic heteroaryl group derived from the groups set forth below:
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Ai is absent.
  • Ai is absent.
  • the present invention relates to compounds of Formula (I), and
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Ai is -NH-. In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Ai is -NHC(0)NR3-. In certain embodiments, the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Ai is an optionally substituted azolyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Ai is an optionally substituted imidazolyl, optionally substituted pyrazolyl, or optionally substituted triazolyl.
  • the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein Ai is an azolyl group derived from one of the following, or a tautomer thereof, by removal of two hydrogen atoms:
  • each of the above shown azole groups is optionally substituted when possible and it may be connected to groups X and Y through either carbon or, when possible, nitrogen.
  • Ai is selected from the groups set forth below, and can optionally be substituted when possible:
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Ai is an optionally substituted azolyl and is connected to groups X and Y in a relative 1,3-meto-substitution position pattern.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salt thereof, wherein Y is optionally substituted phenyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Y is optionally substituted monocyclic heteroaryl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Y is optionally substituted bicyclic heteroaryl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Y is optionally substituted azolyl.
  • Y is preferably selected from the groups set forth below, which can be optionally substituted; wherein the second connection point of Y can be at any available carbon atom of a phenyl ring or any available carbon or nitrogen atom of a heteroaryl ring:
  • Y is preferably selected from the groups set forth below, which can be optionally substituted; wherein the second connection point of Y is preferably at any available carbon atom of the fused benzo ring:
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is optionally substituted phenyl; and Y is optionally substituted phenyl or optionally substituted monocyclic heteroaryl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is optionally substituted monocyclic heteroaryl; and Y is optionally substituted phenyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X and Y are each independently phenyl optionally substituted with one to more substituents selected from the group consisting of halo, CN, and optionally substituted methyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is optionally substituted phenyl;
  • Y is optionally substituted phenyl or optionally substituted azolyl; and Ai is -NHC(O)- or
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein X is optionally substituted phenyl;
  • Y is optionally substituted phenyl or optionally substituted azolyl; and Ai is independently an optionally substituted azolyl.
  • Ai is an optionally substituted azolyl, and is preferably carbon-connected to groups X and Y; and X, Y, L, R3, R4, R, R a , and R b are as previously defined.
  • the compound of Formula (I) is represented by Formula (IIa-1), (IIb-1), (IIc-1), (IId-1), (IIe-1), or (IIf-1), or a pharmaceutically acceptable salt thereof:
  • R14 at each occurrence is independently selected from the group consisting of hydrogen, OH, protected OH, halo, -CN, -NO2, amino, protected amino, optionally substituted -C1-C6 alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2- C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8- membered heterocyclic, optionally substituted -C1-C6 alkoxy, -C(0)-0-Ci-C6 alkyl, - C(0)NH-Ci-C6 alkyl, and -C(0)-Ci-C6 alkyl; m at each occurrence is each independently 0, 1, 2, 3 or 4; Ai is optionally substituted azolyl; and X, L, R, R3, R4, R a , and R b are as previously defined.
  • the compound of Formula (I) is represented by Formula (Ilia), (Illb), (IIIc), (Hid), (Hie), (Illf), (Illg), or (Illh), or a pharmaceutically acceptable salt thereof:
  • W at each occurrence is independently selected from N or CRu each Q is independently N, NRn, CR12, O or S, preferably one Q is N or CR12 and the other Q is O, S, or NRn;
  • R11 at each occurrence is each independently selected from the groups consisting of hydrogen, optionally substituted -C1-C6 alkyl and optionally substituted -C3- C8 cycloalkyl;
  • R12 at each occurrence is independently selected from the groups consisting of hydrogen, halo, -CN, -NO2, optionally substituted -Ci-C 6 alkyl, optionally substituted - Ci-C 6 alkoxy and optionally substituted -C3-C8 cycloalkyl; and
  • X, L, R, R a , R b , R3, R4, and Ri4 are as previously defined.
  • each Q is independently N, NR11, O, S or CR12; m, Y, L, R, R a , R b , R 3 , R4, R11, R12 and R14 are as previously defined.
  • one Q is N or CR12 and the other Q is NRn, O or S.
  • the compound of Formula (I) is represented by Formula (IVa-1), (IVb-1), (IVc-1), (IVd-1), (IVe-1), (IVf-1), (IVg-1), or (IVh-1), or a
  • Q is NRn, O, S or CR12, provided that when Q is CR12, N in the five- membered ring represents NR11; m, L, R, R a , R b , Ri, R3, R4, R11, R12 and R14 are as previously defined. It is to be understood that the positions of Q and N in the ring in each formula can be switched.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein Ai-Y are taken to
  • each of the above shown core groups is optionally substituted and each CH in each phenyl or heteroaryl ring can be independently replaced with an N if possible.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein Ai-Y are taken together to represent a system selected from the following:
  • each of the above shown core groups is optionally substituted and each CH in each phenyl or heteroaryl ring can be independently replaced with an N if possible.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein Ai-Y are taken together to represent a poly cyclic system selected from the following:
  • each of the above shown core groups is optionally substituted and each CH in each phenyl or heteroaryl ring can be independently replaced with an N if possible.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein X-Ai-Y are taken together to form a poly cyclic system selected from the following:
  • each of the above shown core groups is optionally substituted and up to three CHs in each phenyl or heteroaryl ring can be independently replaced with an N if possible.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein X-Ai-Y are taken together to form a poly cyclic system selected from the following:
  • each of the above shown core groups is optionally substituted and up to three CHs in each phenyl or heteroaryl ring can be replaced with an N if possible.
  • the invention relates to compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein X-Ai-Y are taken together to form a poly cyclic system selected from the following:
  • each of the above shown core group is optionally substituted and up to three CHs in each phenyl or heteroaryl ring can be replaced with a N if possible.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein L is -NRi, wherein Ri is as previously defined.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein L is O.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein L is -NRi, wherein Ri is -Ci-Cs alkyl, -C3-C8 cycloalkyl, or 3- to 8-membered heterocyclic, each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, -CN, amino, protected amino, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted -C1-C3 alkoxy, -C(0)2-Ci-C6 alkyl, - C(0)NH-Ci-Ce alkyl, and -C(0)-Ci-Ce alkyl.
  • L is -NRi
  • Ri is -Ci-Cs alkyl, -C3-C8 cycloalkyl, or 3- to 8-membered heterocyclic, each optionally substituted with one,
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein Ris -Ci-Cs alkyl, -C2-C8 alkenyl, -C2-C8 alkynyl, -C3-C8 cycloalkyl, or 3- to 8-membered heterocyclic, each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, -CN, amino, protected amino, optionally substituted -C1-C6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted -C1-C3 alkoxy, -C(0)ORi5, -OC(0)NH- Ri5, -C(0)NH- R15, and -C(O)- R15.
  • R is optionally substituted Ci-C4-alkyl, for example, optionally substituted C2-alkyl.
  • R is 2-substituted ethyl.
  • R15 is optionally substituted -Ci-Ce alkyl, optionally substituted -C2-C8 alkenyl, optionally substituted -C2-C8 alkynyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl.
  • the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R is optionally substituted -Ci-C 6 alkyl.
  • the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R is -Ci-C 6 alkyl optionally substituted with -C(0)OCi-Ce alkyl, -OC(0)NH-Ci-Ce alkyl, -C(0)NH-Ci-Ce alkyl, and - C(0)-Ci-C6 alkyl, wherein said -Ci-C 6 alkyl is optionally substituted.
  • the present invention relates to compounds of Formula (I), or a
  • R is -C1-C6 alkyl optionally substituted with aryl or heteroaryl, wherein said aryl or heteroaryl is optionally substituted.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein L is -NH or -CH 2 .
  • the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein L is -NH; R is optionally substituted arylalkyl or optionally substituted heteroarylalkyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein L is -NH; R is arylalkyl or heteroarylalkyl, each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, -CN, amino, protected amino, optionally substituted -Ci-C 6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted - C1-C3 alkoxy, -C(0) 2 -Ci-C 6 alkyl, -C(0)NH-Ci-Ce alkyl, and -C(0)-Ci-Ce alkyl.
  • L is -NH
  • R is arylalkyl or heteroarylalkyl, each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, -CN, amino, protected amino, optionally substituted -Ci-C 6 alkyl, optionally substituted -
  • the present invention relates to compounds of Formula (I), or a pharmaceutically acceptable salt thereof, wherein L is -NRi and Ri is optionally substituted arylalkyl or optionally substituted heteroarylalkyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein L is -NRi, and Ri is arylalkyl or heteroarylalkyl, each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, -CN, amino, protected amino, optionally substituted -Ci-C 6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted - C1-C3 alkoxy, -C(0) 2 -Ci-C 6 alkyl, -C(0)NH-Ci-Ce alkyl, and -C(0)-Ci-Ce alkyl.
  • L is -NRi
  • Ri is arylalkyl or heteroarylalkyl, each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, -CN, amino, protected amino, optionally substituted -Ci-C 6 alkyl, optionally substitute
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein -L-R taken together represents a C3-C8 cycloalkyl or optionally substituted 3- to 8-membered heterocyclic.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein -L-R taken together represents a C3-C8 cycloalkyl or 3- to 8-membered heterocyclic containing one or two heteroatoms selected from N, O and S; each optionally substituted with one, two or three groups independently selected from hydroxy, protected hydroxy, halo, -CN, amino, protected amino, optionally substituted -Ci-C 6 alkyl, optionally substituted -C3-C8 cycloalkyl, optionally substituted -C1-C3 alkoxy, -C(0)2-Ci-Ce alkyl, -C(0)NH-Ci-Ce alkyl, and - C(0)-Ci-Ce alkyl.
  • the present invention relates to compounds of Formula (I), and pharmaceutically acceptable salts thereof, wherein -L-R is selected from the following:
  • the compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic, diastereoisomeric, and optically active forms. It will still be appreciated that certain compounds of the present invention may exist in different tautomeric forms. All tautomers are contemplated to be within the scope of the present invention.
  • the compounds of the invention are useful in HBV treatment by disrupting, accelerating, reducing, delaying and/or inhibiting normal viral capsid assembly and/or disassembly of immature or mature particles, thereby inducing aberrant capsid morphology and leading to antiviral effects such as disruption of virion assembly and/or disassembly, virion maturation, and/or virus egress.
  • a disruptor of capsid assembly interacts with mature or immature viral capsid to perturb the stability of the capsid, thus affecting assembly and/or disassembly.
  • a disruptor of capsid assembly perturbs protein folding and/or salt bridges required for stability, function and/or normal morphology of the viral capsid, thereby disrupting and/or accelerating capsid assembly and/or disassembly.
  • the compounds of the invention bind capsid and alter metabolism of cellular polyproteins and precursors, leading to abnormal accumulation of protein monomers and/or oligomers and/or abnormal particles, which causes cellular toxicity and death of infected cells.
  • the compounds of the invention cause failure of the formation of capsid of optimal stability, affecting efficient uncoating and/or disassembly of viruses (e.g., during infectivity).
  • the compounds of the invention disrupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is immature. In another embodiment, the compounds of the invention disrupt and/or accelerate capsid assembly and/or disassembly when the capsid protein is mature. In yet another embodiment, the compounds of the invention disrupt and/or accelerate capsid assembly and/or disassembly during vial infectivity. In yet another embodiment, the disruption and/or acceleration of capsid assembly and/or disassembly attenuates HBV viral infectivity and/or reduces viral load. In yet another embodiment, disruption, acceleration, inhibition, delay and/or reduction of capsid assembly and/or disassembly eradicates the virus from the host organism. In yet another embodiment, eradication of the HBV from a host advantageously obviates the need for chronic long-term therapy and/or reduces the duration of long-term therapy.
  • the compounds of the invention disrupt, reduce, delay and/or inhibit viral DNA synthesis, viral relaxed circular genome translocation, and/or viral cccDNA stability or transcription.
  • the compounds described herein are suitable for
  • the compounds described herein are suitable for use in combination therapy.
  • the compounds of the invention can be used in methods of modulating (e.g., inhibit, disrupt or accelerate) the activity of HBV cccDNA. In yet another embodiment, the compounds of the invention can be used in methods of diminishing or preventing the formation of HBV cccDNA.
  • the additional therapeutic agent is selected from immune modulator or immune stimulator therapies, which includes T-cell response activator AIC649 and biological agents belonging to the interferon class, such as interferon alpha 2a or 2b or modified interferons such as pegylated interferon, alpha 2a, alpha 2b, lamda; or TLR modulators such as TLR-7 agonists or TLR-9 agonists; or therapeutic vaccines to stimulate an HBV-specific immune response such as virus-like particles composed of HBcAg and HBsAg, immune complexes of HBsAg and HBsAb, or recombinant proteins comprising HBx, HBsAg and HBcAg in the context of a yeast vector; or immunity activator such as SB-9200 of certain cellular viral RNA sensors such as RIG-I, NOD2, and MDA5 protein, or RNA interence (RNAi) or small interfering RNA (siRNA) such as ARC-520, ARC-521
  • Lamivudine Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine, or Etravirine.
  • the TLR-7 agonist is selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad- enine), AZD 8848 (methyl [3-( ⁇ [3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9- yl)propyl] [3-(4-morpholinyl) propyl] amino Imethyl)phenyl] acetate), GS-9620 (4-Amino- 2-butoxy-8-[3-(l-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone), and RO6864018.
  • SM360320 9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)ad- enine
  • AZD 8848 methyl [3-( ⁇ [3-(6-amino-2-butoxy-8-oxo-7,8-
  • the additional therapeutic agent is a modulator of viral capsid protein and/or its assembly.
  • the capsid modulator is selected from the group consisting of NVR3-778, AB-423, GLS4, ABI-H0731, ABI-H0808, ABI-H0986, GLP-26, Bay 41-4109, and AT-130.
  • the compound and the additional therapeutic agent are co-formulated. In another embodiment, the compound and the additional therapeutic agent are co-administered.
  • administering the compound of the invention allows for administering of the additional therapeutic agent at a lower dose or frequency as compared to the administering of the at least one additional therapeutic agent alone that is required to achieve similar results in prophylactically treating an HBV infection in an individual in need thereof.
  • the individual before administering the therapeuticly effective amount of the compound of the invention, is known to be refractory to a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • administering the compound of the invention reduces viral load in the individual to a greater extent compared to the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • administering of the compound of the invention causes a lower incidence of viral mutation and/or viral resistance than the administering of a compound selected from the group consisting of a HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • aryl refers to a mono- or poly cyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl.
  • a poly cyclic aryl is a poly cyclic ring system that comprises at least one aromatic ring.
  • Poly cyclic aryls can comprise fused rings, covalently attached rings or a combination thereof.
  • heteroaryl refers to a mono- or poly cyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized.
  • Heteroaryl includes, but is not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl.
  • a poly cyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof.
  • aromatic groups can be substituted or unsubstituted.
  • bicyclic aryl or "bicyclic heteroaryl” refers to a ring system consisting of two rings wherein at least one ring is aromatic; and the two rings can be fused or covalently attached.
  • azole group refers to 5-membered heteroaromatic ring containing at least one nitrogen atom.
  • Preferred azole groups contain a nitrogen atom and at least one additional heteroatom, preferably a nitrogen, oxygen or sulfur atom.
  • Azole groups include, but are not limited to pyrazole, imidazole, thiazole, oxazole, isoxazole, 1,2,3-triazole, 1,2,4- triazole, tetrazole.
  • An azole group is termed "ortho" substituted in reference to two substituents which are on adjacent ring atoms.
  • An azole group is termed "meta" substituted in reference to two substituents which are not on adjacent ring positions.
  • azolyl is a univalent or bivalent group derived from an azole group by removal of one or two hydrogen atoms.
  • Azolyl groups include, but are not limited to, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, 1,2,3-triazolyl, 1,2,4- triazolyl, tetrazolyl.
  • bicyclic azole or "bicyclic azole group” refers to an aromatic ring system consisting of two rings wherein at least one ring is azole group; and the two rings can be fused or covalently attached.
  • Preferred bicyclic azole groups are those in which an azole ring is fused to a six-membered aromatic or heteroaromatic ring.
  • Such groups include, but are not limited to, benzimidazole, benzopyrazole, benzotriazole, benzoxazole, benzisoxazole benzothiazole, imidazolopyridine, pyrazolopyridine, thiazolopyridine, oxazolopyridine, isoxazolopyridine, triazolopyridine, and tetrazolopyridine.
  • a bicyclic azolyl group is a univalent or bivalent group derived from a biclyclic azole group by removal of one or two hydrogen atoms.
  • Such groups include, but are not limited to, benzimidazolyl, benzopyrazolyl, benzotriazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, imidazolopyridyl, pyrazolopyridyl, thiazolopyridyl, oxazolopyridyl, isoxazolopyridyl, triazolopyridyl, and tetrazolopyridyl.
  • a univalent bicyclic azolyl group can be derived from the corresponding bicyclic azole group by removal of a hydrogen atom from either ring.
  • a bivalent bicyclic azolyl group can be derived from the corresponding bicyclic azole group by removal of two hydrogen atoms from the same ring or one hydrogen atom from each ring.
  • alkyl refers to saturated, straight- or branched-chain hydrocarbon radicals.
  • Ci-C 4 alkyl refers to alkyl groups containing from one to four, one to six, one to eight carbon atoms, 2 to 4 and 3 to 6 carbon atoms respectively.
  • Ci-Cs alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, w-butyl, fert-butyl, neopentyl, n-hexyl, heptyl and octyl radicals.
  • alkenyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • C 2 -C 8 alkenyl refers to alkenyl groups containing from two to eight, two to four, three to four or three to six carbon atoms respectively.
  • Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l -methyl-2-buten-l-yl, heptenyl, octenyl, and the like.
  • alkynyl refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond by the removal of a single hydrogen atom.
  • C 2 -C 8 alkynyl refers to alkynyl groups containing from two to eight, two to four, three to four or three to six carbon atoms respectively.
  • alkynyl groups include, but are not limited to, for example, ethynyl, 1 -propynyl, 1 -butynyl, heptynyl, octynyl, and the like.
  • cycloalkyl refers to a monocyclic or poly cyclic saturated carbocyclic ring compound, and the carbon atoms may be optionally oxo- substituted.
  • Preferred cycloalkyl groups include C3-C8 cycloalkyl and C4-C7 cycloalkyl.
  • C3-C8 cycloalkyl examples include, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl and cyclooctyl; and examples of C4-C7 cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, bicyclo [2.2.1] heptyl, and the like.
  • cycloalkenyl refers to monocyclic or poly cyclic carbocyclic ring compound having at least one carbon-carbon double bond and the carbon atoms may be optionally oxo-substituted.
  • Preferred cycloalkenyl groups include C3-C8 cycloalkenyl or C5-C7 cycloalkenyl groups.
  • C3-C8 cycloalkenyl examples include, but not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, and the like; and examples of C5-C7 cycloalkenyl include, but not limited to, cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.
  • arylalkyl means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -CH 2 CH 2 -phenyl.
  • substituted arylalkyl means an arylalkyl functional group in which the aryl group is substituted.
  • heteroarylalkyl means a functional group wherein an alkylene chain is attached to a heteroaryl group.
  • substituted heteroarylalkyl means a heteroarylalkyl functional group in which the heteroaryl group is substituted.
  • alkoxy employed alone or in combination with other terms means, unless otherwise stated, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule via an oxygen atom, such as, for example, methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers.
  • Preferred alkoxy are (C1-C3) alkoxy.
  • any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic and cycloalkenyl moiety described herein can also be an aliphatic group or an alicyclic group.
  • an "aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen or other atoms, and optionally contains one or more units of unsaturation, e.g., double and/or triple bonds.
  • Examples of aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(0) 2 , C(0)0, C(0)NH, OC(0)0, OC(0)NH, OC(0)NH 2 ,
  • Carbon atoms of an aliphatic group can be optionally oxo-substituted.
  • An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms.
  • aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls, such as polyalkylene glycols, polyamines, and
  • Aliphatic groups may be optionally substituted.
  • heterocyclic or “heterocycloalkyl” can be used interchangeably and referred to a non-aromatic ring or a bi- or tri-cyclic group fused or bridged system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quatemized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo-substituted.
  • heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]heptyl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or heterocyclic groups can be C-attached or N-attached (where possible).
  • any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like, described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s).
  • One of skill in the art can readily determine the valence of any such group from the context in which it occurs.
  • substituted refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -CI, -Br, -I, -OH, Ci-Ci2-alkyl; C2-Ci2-alkenyl, C2-Ci2-alkynyl, protected hydroxy, - NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-Ci-Ci2-alkyl, -NH-C2-C8- alkenyl, -NH-C 2 -C8-alkynyl, -NH-C 3 -Ci 2 -cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH- heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -0-Ci-C
  • aryls, heteroaryls, alkyls, cycloalkyls and the like can be further substituted.
  • halo or “halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.
  • the term "optionally substituted”, as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.
  • hydrox includes hydrogen and deuterium.
  • recitation of an atom includes other isotopes of that atom so long as the resulting compound is pharmaceutically acceptable.
  • hydroxy activating group refers to a labile chemical moiety which is known in the art to activate a hydroxyl group so that it will depart during synthetic procedures such as in a substitution or an elimination reaction.
  • hydroxyl activating group include, but not limited to, mesylate, tosylate, triflate, /?- nitrobenzoate, phosphonate and the like.
  • activated hydroxyl refers to a hydroxy group activated with a hydroxyl activating group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example.
  • hydroxy protecting group refers to a labile chemical moiety which is known in the art to protect a hydroxyl group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the hydroxy protecting group as described herein may be selectively removed. Hydroxy protecting groups as known in the art are described generally in T.H. Greene and P.G. M. Wuts, Protective Groups in Organic Synthesis. 3rd edition, John Wiley & Sons, New York (1999).
  • hydroxyl protecting groups include benzyloxycarbonyl, 4- methoxybenzyloxycarbonyl, tert-butoxy-carbonyl, isopropoxycarbonyl,
  • protected hydroxy refers to a hydroxy group protected with a hydroxy protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl groups, for example.
  • hydroxy prodrug group refers to a promoiety group which is known in the art to change the physicochemical, and hence the biological properties of a parent drug in a transient manner by covering or masking the hydroxy group. After said synthetic procedure(s), the hydroxy prodrug group as described herein must be capable of reverting back to hydroxy group in vivo. Hydroxy prodrug groups as known in the art are described generally in Kenneth B. Sloan, Prodrugs. Topical and Ocular Drug Delivery. (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992).
  • amino protecting group refers to a labile chemical moiety which is known in the art to protect an amino group against undesired reactions during synthetic procedures. After said synthetic procedure(s) the amino protecting group as described herein may be selectively removed.
  • Amino protecting groups as known in the art are described generally in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, t- butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and the like.
  • protected amino refers to an amino group protected with an amino protecting group as defined above.
  • leaving group means a functional group or atom which can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction.
  • representative leaving groups include chloro, bromo and iodo groups; sulfonic ester groups, such as mesylate, tosylate, brosylate, nosylate and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and the like.
  • aprotic solvent refers to a solvent that is relatively inert to proton activity, i.e., not acting as a proton-donor.
  • examples include, but are not limited to, hydrocarbons, such as hexane and toluene, for example, halogenated hydrocarbons, such as, for example, methylene chloride, ethylene chloride, chloroform, and the like, heterocyclic compounds, such as, for example, tetrahydrofuran and N- methylpyrrolidinone, and ethers such as diethyl ether, bis-methoxymethyl ether.
  • protic solvent refers to a solvent that tends to provide protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like.
  • solvents are well known to those skilled in the art, and it will be obvious to those skilled in the art that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending upon such factors as the solubility of reagents, reactivity of reagents and preferred temperature ranges, for example. Further discussions of protogenic solvents may be found in organic chemistry textbooks or in specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification. 4th ed., edited by John A. Riddick et al , Vol. II, in the Techniques of Chemistry Series. John Wiley & Sons, NY, 1986.
  • stable refers to compounds which possess stability sufficient to allow manufacture and which maintains the integrity of the compound for a sufficient period of time to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject).
  • the synthesized compounds can be separated from a reaction mixture and further purified by a method such as column chromatography, high pressure liquid
  • subject refers to an animal.
  • the animal is a mammal. More preferably, the mammal is a human.
  • a subject also refers to, for example, dogs, cats, horses, cows, pigs, guinea pigs, fish, birds and the like.
  • the compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties.
  • modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • the compounds described herein contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or as (D)- or (L)- for amino acids.
  • the present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms.
  • Optical isomers may be prepared from their respective optically active precursors by the procedures described above, or by resolving the racemic mixtures. The resolution can be carried out in the presence of a resolving agent, by chromatography or by repeated crystallization or by some combination of these techniques which are known to those skilled in the art.
  • any carbon-carbon double bond appearing herein is selected for convenience only and is not intended to designate a particular configuration unless the text so states; thus a carbon-carbon double bond or carbon- heteroatom double bond depicted arbitrarily herein as trans may be cis, trans, or a mixture of the two in any proportion.
  • Certain compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present invention includes each conformational isomer of these compounds and mixtures thereof.
  • pharmaceutically acceptable salt refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al.
  • salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977).
  • the salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid.
  • suitable organic acid examples include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange.
  • salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate,
  • alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like.
  • Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate and aryl sulfonate.
  • ester refers to esters which hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof.
  • Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited.
  • compositions of the present invention comprise a
  • the term "pharmaceutically acceptable carrier or excipient” means a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid;
  • compositions of this invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir, preferably by oral administration or administration by injection.
  • the pharmaceutical compositions of this invention may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance the stability of the formulated compound or its delivery form.
  • parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, intraarticular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional and intracranial injection or infusion techniques.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • the oral compositions can also include adjuvants such as wetting agents, e
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P. and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectable.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non- irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and g
  • compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or
  • embedding compositions that can be used include polymeric substances and waxes.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body.
  • dosage forms can be made by dissolving or dispensing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin.
  • the rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration e.g., inhalation into the respiratory system.
  • Solid or liquid particulate forms of the active compound prepared for practicing the present invention include particles of respirable size: that is, particles of a size sufficiently small to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs.
  • Delivery of aerosolized therapeutics, particularly aerosolized antibiotics is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al, U.S. Pat. No. 5,508,269 to Smith et al, and WO 98/43650 by Montgomery, all of which are incorporated herein by reference).
  • ANTIVIRAL ACTIVITY is known in the art (see, for example U.S. Pat. No. 5,767,068 to Van Devanter et al, U.S. Pat. No. 5,508,2
  • An inhibitory amount or dose of the compounds of the present invention may range from about 0.01 mg/Kg to about 500 mg/Kg, alternatively from about 1 to about 50 mg/Kg. Inhibitory amounts or doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents.
  • viral infections, conditions are treated or prevented in a patient such as a human or another animal by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such time as is necessary to achieve the desired result.
  • a therapeutically effective amount of a compound of the invention is meant an amount of the compound which confers a therapeutic effect on the treated subject, at a reasonable benefit/risk ratio applicable to any medical treatment.
  • the therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., subject gives an indication of or feels an effect).
  • an effective amount of the compound described above may range from about 0.1 mg/Kg to about 500 mg/Kg, preferably from about 1 to about 50 mg/Kg. Effective doses will also vary depending on route of administration, as well as the possibility of co-usage with other agents. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or contemporaneously with the specific compound employed; and like factors well known in the medical arts.
  • the total daily dose of the compounds of this invention administered to a human or other animal in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg/kg body weight or more usually from 0.1 to 25 mg/kg body weight.
  • Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.
  • treatment regimens according to the present invention comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of this invention per day in single or multiple doses.
  • the compounds of the present invention described herein can, for example, be administered by injection, intravenously, intra-arterial, subdermally, intraperitoneally, intramuscularly, or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation, or by inhalation, with a dosage ranging from about 0.1 to about 500 mg/kg of body weight, alternatively dosages between 1 mg and 1000 mg/dose, every 4 to 120 hours, or according to the requirements of the particular drug.
  • the methods herein contemplate administration of an effective amount of compound or compound composition to achieve the desired or stated effect.
  • the pharmaceutical compositions of this invention will be administered from about 1 to about 6 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
  • compositions or carriers to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w).
  • such preparations may contain from about 20% to about 80% active compound.
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary.
  • the dosage or frequency of administration, or both may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level.
  • Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • compositions of this invention comprise a combination of a compound of the Formula described herein and one or more additional therapeutic or prophylactic agents
  • both the compound and the additional agent should be present at dosage levels of between about 1 to 100%, and more preferably between about 5 to 95% of the dosage normally administered in a monotherapy regimen.
  • the additional agents may be administered separately, as part of a multiple dose regimen, from the compounds of this invention. Alternatively, those agents may be part of a single dosage form, mixed together with the compounds of this invention in a single composition.
  • the said "additional therapeutic or prophylactic agents” includes but not limited to, immune therapies (eg. interferon), therapeutic vaccines, antifibrotic agents, antiinflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g. theophylline), mucolytic agents, anti-muscarinics, anti-leukotrienes, inhibitors of cell adhesion (e.g. ICAM antagonists), anti-oxidants (eg N- acetylcysteine), cytokine agonists, cytokine antagonists, lung surfactants and/or antimicrobial and anti-viral agents (e.g. ribavirin and amantidine).
  • immune therapies eg. interferon
  • therapeutic vaccines e.g. interferon
  • antifibrotic agents such as corticosteroids or NSAIDs
  • bronchodilators such as beta-2 adrene
  • Drug resistance most typically occurs by mutation of a gene that encodes for a protein such as an enzyme used in viral replication, and most typically in the case of HIV, reverse transcriptase, protease, or DNA polymerase, and in the case of HBV, DNA polymerase, or in the case of HCV, RNA polymerase, protease, or helicase.
  • the compounds can be used for combination are selected from the group consisting of a HBV polymerase inhibitor, interferon, TLR modulators such as TLR-7 agonists or TLR-9 agonists, therapeutic vaccines, immune activator of certain cellular viral RNA sensors, viral entry inhibitor, viral maturation inhibitor, distinct capsid assembly modulator, antiviral compounds of distinct or unknown mechanism, and combination thereof.
  • TLR modulators such as TLR-7 agonists or TLR-9 agonists
  • therapeutic vaccines immune activator of certain cellular viral RNA sensors
  • viral entry inhibitor viral maturation inhibitor
  • distinct capsid assembly modulator distinct capsid assembly modulator
  • antiviral compounds of distinct or unknown mechanism and combination thereof.
  • the pharmacokinetics, biodistribution, or other parameter of the drug can be altered by such combination or alternation therapy.
  • combination therapy is typically preferred over alternation therapy because it induces multiple simultaneous stresses on the virus.
  • Preferred compounds for combination or alternation therapy for the treatment of HBV include 3TC, FTC, L-FMAU, interferon, adefovir dipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3'-valinyl L-dC), ⁇ -D-dioxolanyl-guanine (DXG), ⁇ -D-dioxolanyl- 2,6-diaminopurine (DAPD), and -D-dioxolanyl-6-chloropurine (ACP), famciclovir, penciclovir, lobucavir, ganciclovir, and ribavirin.
  • azobisisobutyronitrile BINAP for 2,2'-bis(diphenylphosphino)-l, -binaphthyl; B0C2O for di-fer/-butyl-dicarbonate; Boc for /-butoxycarbonyl; Bpoc for 1 -methyl- 1 -(4- biphenylyl)ethyl carbonyl; Bz for benzoyl; Bn for benzyl; BocNHOH for fert-butyl N- hydroxy carbamate; t-BuOK for potassium fert-butoxide; Bu3SnH for tributyltin hydride; BOP for (benzotriazol-l-yloxy)tris(dimethylamino)phospho-nium Hexafluorophosphate; Brine for sodium chloride solution in water; BS A for N,0-bis(trimethylsilyl)acetamide; CDI for carbonyldiimidazole; CH2CI2 for
  • EDC for N-(3-dimethylaminopropyl)-N'-ethylcarbodiirnide
  • EDC HCl for N-(3-dimethylaminopropyl)-N'-ethylcarbodiirnide hydrochloride
  • EtOAc for ethyl acetate
  • EtOH for ethanol
  • Et20 for diethyl ether
  • HATU for 0-(7-azabenzotriazol-l- yl)-N,N,N',N',-tetramethyluronium Hexafluoro-phosphate
  • HCl for hydrogen chloride
  • HOBT for 1 -hydroxy benzotriazole
  • K2CO3 for potassium carbonate
  • «-BuLi for w-butyl lithium
  • z-BuLi for z-butyl lithium
  • /-BuLi for /-butyl lithium
  • PhLi for phenyl lithium
  • TMEDA for ⁇ , ⁇ , ⁇ ', ⁇ '-tetramethylethylene-diamine
  • TPP or PPh3 for triphenyl-phosphine
  • Troc for 2,2,2-trichloroethyl carbonyl
  • Ts for tosyl or -SO2- C6H4CH3
  • TS2O for tolylsulfonic anhydride or tosyl-anhydride
  • TsOH for p-tolylsulfonic acid
  • Pd for palladium
  • Ph for phenyl
  • POPd for dihydrogen dichlorobis(di-tert- butylphosphinito-KP)palladate(II);
  • Pd2(dba)3 for tris(dibenzylideneacetone) dipalladium (0)
  • Pd(PPh 3 )4 for tetrakis(triphenylphosphine)palladium (0)
  • the compounds of the present invention may be prepared via several different synthetic strategies and routes from a variety of phenyl, 5- and 6-membered heteroaryl or fused bicyclic aryl or heteroaryl precursors using the reactions that are known to those skilled in the art.
  • specific aryl or heteroaryl moieties in the target molecules are connected together via suitable reactions from properly functionalized aryl or heteroaryl precursors.
  • These reactions include, but not limited to, organometallics catalyzed cross-coupling, amino nucleophilic displacement reaction, carbodiimide (DCC, EDC) mediated amide formation, Curtius rearrangement, et al.
  • A2 is absent and Y is connected with Z directly. Y is firstly connected with L through a linker, which is transformed into Z through proper functional group manipulation.
  • A2 is -NH-. The A2 amino group is installed on Y or Z at first, and then couples with Z or Y through coupling conditions or substitution.
  • X, Ai, Y, Z, L, R are as defined previously for formula (I); LGi is independently selected from carboxyl acid, ester, amide, nitrile, halogen, triflate and acyl halide; LG2 is independently selected from lithium, magnesium bromide, halogen, triflate and mesylate; LG3 is amino, halo.
  • An optionally substituted aryl or heteroaryl 1-1 reacts with 1-2 to give an intermediate 1-3 in which Y is connected with L through a linker. In most cases, this linker is a carbonyl, which could be transformed into Z through functional group manipulation. This intermediate 1-3 directly would couple with 1-4 to give a compound with general formula la.
  • an optionally substituted aryl or heteroaryl 1-1 would react with 1-4 to give an intermediate 1-3'.
  • This intermediate 1-3' would be coupled with 1-2 through a linker, which would be transformed into Z by functional group manipulation to give a compound with general formula la.
  • amide compound 1-la would be treated with Grignard compound l-2a to afford a ketone intermediate which would be sequentially transformed to give difluoro product l-3a.
  • the bromide on l-3a would be transformed into a carboxyl acid, through a sequence of Suzuki coupling, ozonolysis and Pinnick oxidation, which could react with an arylamino compound l-4a in the present of a suitable dehydrating reagent such as EDC, HATU and an organic base (TEA, DIPEA) in proper organic solvent (CH2CI2, CH3CN, DMF) to give a compound with general formula I
  • an optionally substituted 2-1 reacts with an optionally substituted 2-2 to give the advanced intermediate 2-3.
  • the proper reaction employed here includes, but not limited to, reductive amination and substitution.
  • a compound with general Formula lb would be obtained.
  • the starting material 2-1 could react with 2-4 to give the advanced intermediate 2-3'.
  • a compound with the general formula lb also would be obtained.
  • Another alternative option is starting with 2-2'.
  • Step lb To a solution of the compound from Step la (2.3710 g, 8.513 mmol) in THF (21.3 mL) at 0 °C was added a solution of 0.5 M 3-butenylmagnesium bromide in THF (25.54 mL, 12.77 mmol). Then the solution was stirred at 0 °C for 2 hours, then warmed up to rt and kept for 14 hours. The solution was partitioned (EtOAc-NFUCl aq. solution). The organic was dried (Na2S04), filtered and concentrated. The residue was
  • Step lc To a solution of the compound from Step lb (1.061 g, 3.878 mmol) in DCM (4.0 mL) at rt was added ethanol (179 mg, 3.878 mmol) and DEOXO-FLUORO® (5.147 g, 23.27 mmol). Then the resulting solution was stirred at rt for 5 days. The solution was diluted with DCM (30 mL), then slowly poured into an Erlenmeyer Flask with 150 ml saturated NaHCC aq. solution. NaHCC solid was added into the mixture to neutralize excess DEOXO-FLUORO®. The solution was partitioned (EtOAc-brine).
  • Step Id To a solution of the compound from Step lc (225 mg, 0.761 mmol) in DCM (7.6 mL) at -78 °C was induced ozone until the solution changed into pale blue. Then O2 was induced until the blue color disappeared. The solution was warmed to 0 °C and NaBH4 (57.6 mg, 1.52 mmol) was added. The mixture was kept at 0 °C for 2 hours. The solution was partitioned (EtOAc-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (103.2 mg, 46%).
  • Step le To a solution of the compound from Step Id (103.2 mg, 0.3445 mmol) in DCM (3.4 mL) at 0 °C was added 2,6-lutidine (107.2 mg, 1.034 mmol) and TBSOTf (133.6 mg, 0.5168 mmol). Then the resulting solution was stirred at 0 °C for 4 hours. The solution was partitioned (EtOAc-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (102.7 mg, 72%).
  • Step If To a solution of 1.0M K3PO4 solution (1.165 mL, 1.165 mmol) was added vinylboronic acid pinacol ester (53.9 mg, 0.350 mmol) and toluene (6.0 mL), then the mixture was stirred at rt for 10 minutes. The resulting mixture was transferred into another solution of the compound from Step le (96.6 mg, 0.233 mmol) in toluene (4.0 mL). Then PPh 3 (61.1 mg, 0.233 mmol) and Pd(OAc)2 (10.5 mg, 0.0466 mmol) were added into the mixture. The reaction mixture was degased by bubbling N2 for 5 minutes. The mixture was then heated to 95 °C and kept for 14 hours.
  • Step lh To a solution of the compound from Step lg (51.5 mg, 0.142 mmol) in a mixture of 2-methyl-2-butene (2.0 mL) and /-BuOH (2.0 mL) at 0 °C was added a solution of 1.25 M KH2PO4 solution (0.5 mL) and NaClC (80%, 160 mg, 1.42 mmol). Then the resulting mixture was stirred at 0 °C for 3 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (43.3 mg, 81%).
  • Step li To a solution of the compound from Step lh (34.2 mg, 0.0903 mmol) in DMF (3.0 mL) was added 3,4,5-trifluoroaniline (13,3 mg, 0.0903 mmol), DIPEA (23.3 mg, 0.181 mmol) and HATU (34.3 mg, 0.0903 mmol). Then the resulting solution was stirred at rt for 14 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (16.4 mg, 36%).
  • Step lj To a solution of the compound from Step li (16.4 mg, 0.0323 mmol) in THF (3.2 mL) at 0 °C was added a solution of 1.0 M TBAF (96.9 ⁇ , 0.0969 mmol). Then the resulting solution was stirred at 0°C for 6 hours. The solution was partitioned (EtOAc- brine). The organic was dried Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the title compound as white powder (10.8 mg, 85%).
  • Step 2a A mixture of the title compound 1 (11.2 mg, 0.028), pyridine (258 mg, 2.84 mmol) and methyl chloroformate (4.0 mg, 0.043 mmol) in CH2C12 (1.4 mL) was stirred at rt for overnight. The mixture was concentrated and the residue was chromatographed (silice gel, EtOAc/hexanes) to give the title compound (10.8 mg, 84%).
  • Step 3a To a solution of the compound from Step Id (146 mg, 0.49 mmol) in DCM (4.0 mL) at 0°C was added DAST (0.10 mL, 0.75 mmol) and the resulting solution was stirred at rt overnight. Aqueous Sat. NaHCC was added to the mixture and it was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (100 mg, 68%).
  • Step 7 To a solution of the title compound 4 (20 mg, 0.050 mmol) in DCM (0.4 mL) and DMF (0.1 mL) was added DIPEA (18 ⁇ , 0.100 mmol) and ethyl isocyanate (8 nL, 0.100 mmol). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtOAc-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the title compound as white solid (10 mg, 42%). MS ESI (M+NH4)+ 487.24, 488.27, 489.27, 490.25.
  • Step 8 To a solution of the title compound 4 (20 mg, 0.050 mmol) in DCM (0.4 mL) and DMF (0.1 mL) was added DIPEA (18 ⁇ , 0.100 mmol) and benzyl isocyanate (12 nL, 0.100 mmol). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtOAc-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the title compound as white solid (13 mg, 49%). MS ESI (M+H)+ 532.11, 534.10.
  • Step 9 To a solution of the title compound 4 (23 mg, 0.058 mmol) in DCM (0.45 mL) and DMF (0.12 mL) was added DIPEA (50 ⁇ , 0.288 mmol) and phenyl isocyanate (31 nL, 0.288 mmol). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtOAc-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the title compound as white solid (22 mg, 74%). MS ESI (M+NH4)+ 534.18, 535.18, 536.18, 537.18.
  • Example 10 To a solution of the title compound 4 (23 mg, 0.058 mmol) in DCM (0.45 mL) and DMF (0.12 mL) was added DIPEA (50 ⁇ , 0.288
  • Step 10 To a solution of the title compound 4 (24 mg, 0.050 mmol) in DCM (0.48 mL) and DMF (0.12 mL) was added DIPEA (53 ⁇ , 0.300 mmol) and tot-butyl isocyanate (34iL, 0.300 mmol). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the title compound as white solid (3 mg, 5%). MS ESI (M+H)+ 498.12, 500.12.
  • Step 11a To a solution of the compound from Step lh (50 mg, 0.132 mmol) in acetonitrile (1 mL) was added 3-cyclopropyl-4-(trifluoromethyl)aniline (40 mg, 0.198 mmol), DMAP (4 mg, 0.033 mmol) and EDC (51 mg, 0.264 mmol). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (32 mg, 43%).
  • Step lib To a solution of the compound from Step 11 a (32 mg, 0.057 mmol) in MeOH (2 mL) was added cone. HC1 (50 ⁇ , 1.65 mmol). The resulting solution was stirred at rt for 1 hour. The reaction mixture was concentrated. The residue was chromatographed (silica, methanol :dichloromethane) to give the title compound as white solid (22 mg, 86%). MS ESI (M-H)- 446.13, 448.11.
  • Step 12a To a solution of the compound from Step lh (50 mg, 0.132 mmol) in acetonitrile (1 mL) was added 3-chloro-4-cyclopropylaniline (33 mg, 0.198 ⁇ DMAP (4 mg, 0.033 mmol) and EDC (51 mg, 0.264 mmol). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (43 mg, 62%).
  • Step 12b To a solution of the compound from Step 12a (43 mg, 0.081 mmol) in MeOH (2 mL) was added cone. HC1 (50 ⁇ , 1.65 mmol). The resulting solution was stirred at rt for 1 hour. The reaction mixture was concentrated. The residue was chromatographed (silica, methanol :dichloromethane) to give the title compound as white solid (33 mg, 98%). MS ESI (M-H)- 412.08, 414.06.
  • Step 13a To a solution of the compound from Step lh (50 mg, 0.132 mmol) in acetonitrile (1 mL) was added 4-amino-2-fluorobenzonitrile (27 mg, 0.198 mmol), DMAP (4 mg, 0.033 mmol) and EDC (51 mg, 0.264 mmol). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as yellow oil (17 mg, 26%).
  • Step 13b To a solution of the compound from Step 13a (17 mg, 0.034 mmol) in MeOH (2 mL) was added cone. HC1 (50 ⁇ , 1.65 mmol). The resulting solution was stirred at rt for 1 hour. The reaction mixture was concentrated. The residue was chromatographed (silica, methanol :dichloromethane) to give the title compound as white solid (11 mg, 84%). MS ESI (M-H)- 381.09, 383.07.
  • Step 20a To a stirred solution of compound from step lh (60 mg, 0.158 mmol) and 2- bromo-l-(3-bromo-4-fluorophenyl)ethan-l-one (70.3 mg, 0.238 mmol) in acetonitrile (1.0 ml) and DMF (1.0 ml) was addedsodium bicarbonate (39.9 mg, 0.475 mmol) at 0 °C. The resulting mixture was slowly warmed up to rt and stirred at rt overnight. The reaction mixture was then diluted with ethyl acetate (20 ml) and washed with brine (10 mL x 2).
  • Step 20b A stirred mixture of 2-(3-bromo-4-fluorophenyl)-2-oxoethyl 3-(4-((tert-butyl- dimethylsilyl)oxy)-l,l-difluorobutyl)-4-chlorobenzoate (50 mg, 0.084 mmol), ammonium acetate (97 mg, 1.263 mmol) in toluene (2.0 ml) in a sealed heating tube was heated at 120 °C for 2h. The reaction mixture was diluted by DCM (20 mL), and washed with aq. NaHCC solution (lOmL).
  • Step 20c To a stirred solution of 4-(3-bromo-4-fluorophenyl)-2-(3-(4-((tert- butyldimethyl-silyl)oxy)-l,l-difluorobutyl)-4-chlorophenyl)-lH-imidazole (5 mg, 8.71 ⁇ ) in MeOH (2.0 ml) was added concentrated HC1 (0.073 ml, 0.871 mmol) at 0 °C. The reaction was stirred at rt for 30min.The mixture was then concentrated under reduced pressure. The residue was re-dissovled in DCM (30 mL) and was washed with aq. NaHC03 solution (10 mL x 2).
  • Step 21a To a solution of the compound from Step lb (1.265 g, 4.62 mmol) in THF (23 mL) at 0 °C was added methylmagnesium bromide (2.31 mL, 6.94 mmol, 3M in Et ⁇ O). The resulting solution was stirred at rt for 18 hours. The solution was partitioned (EtOAc- NH4CI). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (1.225 g, 91%).
  • Step 21b To a solution of the compound from Step 21a (600 mg, 2.07 mmol) in DCM (2.1 mL) was added DEOXO-FLUORO® (1.91 mL, 5.18 mmol). The resulting solution was stirred at rt for 1.5 hours. The solution was partitioned (DCM-NaHCCb). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (450 mg, 75%). Step 21c.
  • Step 21d To a solution of the compound from Step 21c (144 mg, 0.487 mmol) in DCM (2.4 mL) at 0 °C was added 2,6-lutidine (170 ⁇ ,, 1.46 mmol) and TBSOTf (157 ⁇ xL, 0.974 mmol). Then the resulting solution was stirred at 0 °C for 30 minutes. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (157 mg, 79%).
  • Step 21e To a solution of 1.0M K3PO4 solution (2.68 mL, 2.68 mmol) was added vinylboronic acid pinacol ester (97 , 0.575 mmol) and toluene (7.0 mL), then the mixture was stirred at rt for 10 minutes. The resulting mixture was transferred into another solution of the compound from Step 21d (157 mg, 0.383 mmol) in toluene (5.0 mL). Then PPh 3 (100 mg, 0.383 mmol) and Pd(OAc)2 (17.2 mg, 0.0766 mmol) were added into the mixture. The reaction mixture was degased by bubbling N2 for 5 minutes. The mixture was then heated to 95 °C and kept for 14 hours.
  • Step 21f To a solution of the compound from Step 21e (87 mg, 0.245 mmol) in DCM (5.0 mL) mL) at -78 °C was induced ozone until the solution changed into pale blue. Then O2 was induced until the blue color disappeared. Me2S (1 mL) was added. The mixture was warmed to rt and kept for 14 hours. The mixture was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was used as crude (93 mg).
  • Step 21g To a solution of the compound from Step 21f (93 mg, 0.245 mmol) in a mixture of 2-methyl-2-butene (2.0 mL) and /-BuOH (2.0 mL) at 0 °C was added a solution of 1.25 M KH2PO4 solution (0.5 mL) and NaC10 2 (80%, 160 mg, 1.42 mmol). Then the resulting mixture was stirred at 0 °C for 3 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (85 mg, 87%).
  • Step 21h To a solution of the compound from Step 21g (85 mg, 0.227 mmol) in DMF (1.1 mL) was added 3,4,5-trifluoroaniline (34 mg, 0.227 mmol), DIPEA (79 pL, 0.453 mmol) and HATU (86 mg, 0.227 mmol). Then the resulting solution was stirred at rt for 14 hours. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (105 mg, 92%).
  • Step 21i To a solution of the compound from Step 21h (105 mg, 0.208 mmol) in MeOH (2 mL) at rt was cone. HCl (50 ⁇ , 1.65 mmol). The resulting solution was stirred at rt for 1 hour. The reaction mixture was concentrated. The residue was chromatographed (silica, ethyl acetate :hexanes) to give the title compound as white solid (24 mg, 30%). MS ESI (M-H)- 388.151, 390.153.
  • Step 22a To a solution of the compound from Step lb (500 mg, 1.83 mmol) in MeOH (23 mL) at 0 °C was added NaBEU (84 mg, 2.19 mmol. The resulting solution was stirred at 0 °C for 1 hour. The solution was partitioned (EtO Ac-brine). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (500 mg, 100%).
  • Step 22b-h The title compound was prepared by a procedure similar to that described in example 21. MS ESI (M-H)- 372.080, 374.136.
  • Step 23a To a solution of the compound from Step 22a (250 mg, 1.83 mmol) in DCM (2.1 mL) was added DEOXO-FLUORO® (0.64 mL, 1.73 mmol). The resulting solution was stirred at rt for 1.5 hours. The solution was partitioned (DCM-NaHCCb). The organic was dried (Na2S04), filtered and concentrated. The residue was chromatographed (silica, ethyl acetate/hexanes) to give the desired compound as colorless oil (185 mg, 77%).
  • Step 22b-h The title compound was prepared by a procedure similar to that described in example 21. MS ESI (M-H)- 374.187, 376.081
  • HepAD38 cells are maintained as previously reported (Ladner et al, Antimicrob. Agents Chemother. 1997, 4, 1715). Briefly, cells are passaged upon attaining confluency in DMEM/F12 media in the presence of 10% FBS, Penn/Strep, 250 ⁇ g/mL G418, and 1 ug/ml tetracycline. Novel compounds are screened by first washing cells three times with PBS to remove tetracycline, and plating in 96 well plates at 35,000 cells/well. Compounds dissolved in DMSO are then diluted 1 :200 into wells containing cells. Five days after compound addition, material is harvested for analysis. For an extended 8 day analysis, cells are plated and treated as described above, but media and compound are refreshed on d2 and d5 post initial treatment.
  • virion DNA is obtained by lysing with Sidestep Lysis and Stabilization Buffer and then quantified via quantitative real time PCR.
  • Commercially available ELISA kits are used to quantitate the viral proteins HBsAg (Alpco) or HbeAg (US Biological) by following the manufacturer's recommended protocol after diluting samples to match the linear range of their respective assays. Irrespective of readout, compound concentrations that reduce viral product accumulation in the cell lysates or supematants by 50% relative to no drug controls (EC50) are reported; EC50 ranges are as follows: A ⁇ ⁇ ⁇ ; B l- ⁇ ; C > 10 ⁇ .
  • CC50 Compound concentrations that reduce total ATP levels in wells by 50% relative to no drug controls (CC50) are reported; CC50 ranges are as follows: A > 30 ⁇ ; B 10-30 ⁇ ; C ⁇ 10 ⁇ .

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Abstract

La présente invention concerne des composés de formule (I), ou des sels, des esters ou des promédicaments pharmaceutiquement acceptables de ceux-ci : X-A1-Y-A2-Z-L-R (I) qui inhibent la ou les protéines codées par le virus de l'hépatite B (VHB) ou qui interfèrent avec la fonction du cycle de vie du virus de l'hépatite B et sont également utiles en tant qu'agents antiviraux. La présente invention concerne également des compositions pharmaceutiques comportant lesdits composés, destinées à être administrées à un patient atteint d'une infection à VHB. L'invention concerne également des méthodes de traitement d'une infection à VHB chez un patient, consistant à administrer une composition pharmaceutique comprenant les composés selon la présente invention.
PCT/US2016/043324 2015-07-22 2016-07-21 Agents antiviraux de l'hépatite b WO2017015451A1 (fr)

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WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
WO2018200571A1 (fr) * 2017-04-25 2018-11-01 Arbutus Biopharma Corporation Analogues de 2,3-dihydro-1h-indène substitués et leurs méthodes d'utilisation
WO2019048640A1 (fr) * 2017-09-07 2019-03-14 Aicuris Gmbh & Co. Kg Polythérapies pour des individus atteints d'une infection au virus de l'hépatite b (vhb) utilisant parapoxvirus ovis (ppvo) et au moins un autre médicament antiviral
WO2019086141A1 (fr) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides à substitution amino-thiazole hautement actifs agissant contre le virus de l'hépatite b (vhb)
WO2019086142A1 (fr) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides à substitution pyrazolo-pipéridine hautement actifs agissant contre le virus de l'hépatite b (vhb)
US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
WO2020089459A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020089453A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouveaux 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020089452A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[4,3-c]pyridines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020089455A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg 6,7-dihydro-4 h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020089456A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020089460A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles urée-6,7-dihydro-4 h-thiazolo[5,4-c]pyridines actives contre le virus de l'hépatite b (vhb)
WO2020123674A1 (fr) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Arylméthylurées et hétéroarylméthylurées substituées, analogues de ces dernières et procédés d'utilisation de celles-ci
WO2020221826A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020221824A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouveaux indolizine-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020221811A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouvelles oxalyl pipérazines actives contre le virus de l'hépatite b (vhb)
WO2020221816A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouvelles urées de phényle et de pyridyle actives contre le virus de l'hépatite b (vhb)
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof

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US10328053B2 (en) 2016-08-26 2019-06-25 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10874640B2 (en) 2016-08-26 2020-12-29 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
WO2018085619A1 (fr) 2016-11-07 2018-05-11 Arbutus Biopharma, Inc. Composés tricycliques contenant de la pyridinone substituée, et procédés les utilisant
WO2018172852A1 (fr) 2017-03-21 2018-09-27 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
EP3601216A4 (fr) * 2017-03-21 2021-01-06 Arbutus Biopharma Corporation Dihydroindène-4-carboxamides substitués, leurs analogues et procédés d'utilisation correspondant
US11098010B2 (en) 2017-03-21 2021-08-24 Arbutus Biopharma Corporation Substituted dihydroindene-4-carboxamides and analogs thereof, and methods using same
US11130740B2 (en) 2017-04-25 2021-09-28 Arbutus Biopharma Corporation Substituted 2,3-dihydro-1H-indene analogs and methods using same
WO2018200571A1 (fr) * 2017-04-25 2018-11-01 Arbutus Biopharma Corporation Analogues de 2,3-dihydro-1h-indène substitués et leurs méthodes d'utilisation
CN111093697A (zh) * 2017-09-07 2020-05-01 艾库里斯有限及两合公司 乙肝病毒(hbv)感染的个体的使用绵羊副痘病毒(ppvo)和至少一种另外的抗病毒药物的组合疗法
WO2019048640A1 (fr) * 2017-09-07 2019-03-14 Aicuris Gmbh & Co. Kg Polythérapies pour des individus atteints d'une infection au virus de l'hépatite b (vhb) utilisant parapoxvirus ovis (ppvo) et au moins un autre médicament antiviral
WO2019086142A1 (fr) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides à substitution pyrazolo-pipéridine hautement actifs agissant contre le virus de l'hépatite b (vhb)
WO2019086141A1 (fr) 2017-11-02 2019-05-09 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides à substitution amino-thiazole hautement actifs agissant contre le virus de l'hépatite b (vhb)
US11420974B2 (en) 2018-02-26 2022-08-23 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
US10836769B2 (en) 2018-02-26 2020-11-17 Gilead Sciences, Inc. Substituted pyrrolizine compounds and uses thereof
WO2020089456A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020089460A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles urée-6,7-dihydro-4 h-thiazolo[5,4-c]pyridines actives contre le virus de l'hépatite b (vhb)
WO2020089455A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg 6,7-dihydro-4 h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020089452A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[4,3-c]pyridines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020089453A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouveaux 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazine indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020089459A1 (fr) 2018-11-02 2020-05-07 Aicuris Gmbh & Co. Kg Nouvelles 6,7-dihydro-4h-pyrazolo[1,5-a]pyrazines d'urée actives contre le virus de l'hépatite b (vhb)
WO2020123674A1 (fr) 2018-12-12 2020-06-18 Arbutus Biopharma Corporation Arylméthylurées et hétéroarylméthylurées substituées, analogues de ces dernières et procédés d'utilisation de celles-ci
WO2020221826A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouveaux indole-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020221824A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouveaux indolizine-2-carboxamides actifs contre le virus de l'hépatite b (vhb)
WO2020221811A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouvelles oxalyl pipérazines actives contre le virus de l'hépatite b (vhb)
WO2020221816A1 (fr) 2019-04-30 2020-11-05 Aicuris Gmbh & Co. Kg Nouvelles urées de phényle et de pyridyle actives contre le virus de l'hépatite b (vhb)

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