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WO2013021344A1 - Nouveaux dérivés de quercétine utiles comme agents antiviraux - Google Patents

Nouveaux dérivés de quercétine utiles comme agents antiviraux Download PDF

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Publication number
WO2013021344A1
WO2013021344A1 PCT/IB2012/054020 IB2012054020W WO2013021344A1 WO 2013021344 A1 WO2013021344 A1 WO 2013021344A1 IB 2012054020 W IB2012054020 W IB 2012054020W WO 2013021344 A1 WO2013021344 A1 WO 2013021344A1
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Prior art keywords
imidazol
amino
methyl
alkyl
cyclopentyl
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PCT/IB2012/054020
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English (en)
Inventor
Vidya Ramdas
Advait Arun JOSHI
Moloy Manoj BANERJEE
Amit Kumar DAS
Deepak Sahebrao WALKE
Venkata P. Palle
Rajender Kumar Kamboj
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Lupin Ltd
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Lupin Ltd
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Priority to PH1/2014/500312A priority Critical patent/PH12014500312A1/en
Publication of WO2013021344A1 publication Critical patent/WO2013021344A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • the present invention is related to novel compounds of the general formula I,
  • HCV Persistent hepatitis C virus
  • HCV chronic infection is often asymptomatic with latent periods lasting for decades before manifestation by which time extensive liver damage has occurred.
  • HCV is spread primarily by unscreened blood transfusions and use of contaminated needles and syringes; the highest risk groups are intravenous drug users and people who received blood transfusions (mainly haemophiliacs) before 1990 when screening for HCV was introduced.
  • Factors that have been reported to influence the rate of HCV disease progression include age (increasing age is associated with more rapid progression), gender (males have more rapid disease progression than females), alcohol consumption (associated with an increased rate of disease progression), HIV co-infection (associated with a markedly increased rate of disease progression), and fatty liver.
  • HCV exists as many closely related viral sequences, termed as quasi-species, in the infected individual, making specific pharmaceutical targeting of HCV proteins challenging due to the rapid evolution of escape mutants. It is increasingly evident that a broad collection of specific, pan genotypic anti- viral drugs targeting multiple essential viral functions, in addition to the current viral therapies will be required for effective global control of HCV.
  • the present invention provides a pharmaceutical composition, containing the compound of the general formula (I) as defined herein, its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its N-oxides, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates, or its co-crystals in combination with the usual pharmaceutically employed carriers, diluents and the like are useful for the treatment of HCV infection.
  • HCV is a member of the Flaviviridae family of enveloped, positive stranded RNA viruses belonging to the genus Hepacivirus.
  • the genome is a single ⁇ 9.6kb strand of RNA and consists of one open reading frame that encodes for a polyprotein of -3000 amino acids flanked by untranslated regions at both 5' and 3' ends.
  • This precursor polyprotein is then processed by viral and cellular proteases to yield 10 separate mature viral proteins critical for replication and assembly of progeny viral particles.
  • the organization of the structural and non-structural proteins in the HCV polyprotein is as follows: C-E1 -E2-P7-NS2-NS3- NS4a-NS4b-NS5a-NS5b.
  • NS2 is a zinc dependent metalloproteinase that functions in conjunction with a part of NS3 protein.
  • NS3 protein has two catalytic activities associated with it: a serine protease at the N-terminal end which requires NS4A as a cofactor, and an ATPase dependent helicase activity at the C-terminal end.
  • NS5A is a membrane anchored phosphoprotein that is present in basally phosphorylated (56kDa) and hyperphosphorylated (58kDa) forms.
  • NS5A plays an important role in replication and infectivity of HCV.
  • the NS5B protein encodes an RNA dependent RNA polymerase activity, key to the generation of progeny viruses. While the pathology of HCV infection mainly affects the liver, the virus is found in other cell types in the body including peripheral blood lymphocytes [Thomson BJ et al., Clin Microbial Infect. 2005, 1J., 86-94; Moriishi K et al., Antivir. Chem. Chemother. 2003, 14, 285-297].
  • Characterization of the replicase machinery required for HCV RNA synthesis has defined the protease/helicase NS3 protein, the NS4A cofactor, the NS4B integral membrane protein, the NS5A protein and the RNA dependent RNA polymerase NS5B as being its essential components.
  • Ring 'A' is a saturated carbocycle, which may be a monocyclic system or may be a fused carbocycle or may be a bridged carbocycle, the said ring A may contain 5 to 10 carbons; Ring 'D' is selected from 5 to 10 membered carbocycle and 5 to 10 membered
  • the ring 'D' may be monocyclic, fused bicyclic, bridged bicyclic or spiro bicyclic;
  • Y is selected from -CH(R 2a )- and -N(R 2 )-;
  • R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are independently selected as hydrogen, or R 5 and R 6 together, R 7 and R 10 together, or R 8 and R 9 together independently along with the carbon atoms to which they are attached forming 5 to 8 membered substituted- or unsubstituted- carbocycle, 5 to 8 membered substituted- or unsubstituted- heterocycle, 6 membered substituted- or unsubstituted- aryl, or 5 to 6 membered substituted- or unsubstituted- heteroaryl; with a proviso that the compound of formula I must have at least one cyclic system formed out of either R 5 and R 6 , R 8 and R 9 , or R 7 and R 10 ; also provided that R 7 and R 10 take part in formation of cyclic system only when n is 0;
  • R 11 and R 12 are independently selected from a group consisting of hydrogen, halogen, substituted- or unsubstituted- Ci- 6 alkyl, R 13b O-, and (R 13 )(R 14 )N-; wherein, R 13 , R 14 , R 14a and R 15 are independently selected from hydrogen, substituted- or unsubstituted- Ci -6 alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl; R 13a is selected from substituted- or unsubstituted- Ci -6 alkyl, perhaloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstitute
  • R 13b is selected from hydrogen, substituted- or unsubstituted- Ci -6 alkyl, perhaloalkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl;
  • R 16 is selected from hydrogen or substituted- or unsubstituted alkyl group
  • R a , R b , R c and R d are independently selected from hydrogen, halogen, substituted- or unsubstituted- Ci -6 alkyl, substituted- or unsubstituted- aryl, substituted- or unsubstituted- heteroaryl, substituted- or unsubstituted- cycloalkyl, and substituted- or unsubstituted- heterocyclyl, or R a , R b , R c and R d together with the carbon atom(s) to which they are attached forming substituted- or unsubstituted- carbocycle, substituted- or unsubstituted- heterocycle; m is an integer ranging between 0 to 2, selected independently at each occurrence; n is an integer ranging between 0 and 2; 'alkyl' may be substituted with 1 to 4 substituents selected from the group consisting of halogen, oxo, Ci- 6 alkyl, haloalkyl,
  • R 17 , R 18 and R 19 are independently selected from hydrogen and alkyl;
  • R 17a is selected from alkyl and perhaloalkyl;
  • R 17b is selected from the group consisting of hydrogen, alkyl, and perhaloalkyl
  • any sub-range or individual number of carbon atoms falling within the indicated range also can be used.
  • One of the embodiments of the present invention is compound of formula (I) as described above, wherein, ring A is particularly selected as cyclopentane;
  • Y is particularly selected as - N(R 2 )-;
  • m is particularly selected as 0 at all the occurrences
  • R 3 is particularly selected from NH and O;
  • n is particularly selected as 0;
  • R 5 and R 6 are independently selected from hydrogen and halogen, or R 5 and R 6 together with the carbon atoms to which they are attached form a six membered carbocycle;
  • R 7 and R 10 are particularly selected as hydrogen, or R 7 and R 10 together with the carbon atoms to which they are attached form a five or six membered carbocycle, the said carbocycle is unsubstituted or substituted with one or two alkyl groups;
  • R 9 and R 8 are particularly selected as hydrogen, or R 9 and R 8 together with the carbon atoms to which they are attached form a six or seven membered carbocycle, or R 9 and R 8 together with the carbon atoms to which they are attached form a seven membered heterocycle containing one heteroatom;
  • R 11 and R 12 are particularly selected as hydrogen; In any of the embodiments of the invention described above, ring D is particularly selected as
  • ring A is particularly selected
  • m is particularly selected as 0 at all the occurrences
  • R 3 is particularly selected from NH and O
  • n is particularly selected as 0,
  • R 5 and R 6 are independently selected from hydrogen and halogen, or R 5 and R 6 together with the carbon atoms to which they are attached form a six membered carbocycle
  • R 7 and R 10 are particularly selected as hydrogen, or R 7 and R 10 together with the carbon atoms to which they are attached form a five or six membered carbocycle, the said carbocycle is unsubstituted or substituted with one or two alkyl groups
  • R 9 and R 8 are particularly selected as hydrogen, or R 9 and R 8 together with the carbon atoms to which they are attached form a six or seven membered carbocycle, or R 9 and R 8 together with the carbon
  • alkyl means a straight chain or branched hydrocarbon containing from 1 to 20 carbon atoms. Preferably the alkyl chain may contain 1 to 10 carbon atoms. More preferably alkyl chain may contain up to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, and n- hexyl.
  • haloalkyl used herein means an alkyl group as defined hereinabove wherein at least one of the hydrogen atoms of the said alkyl group is substituted with halogen.
  • the haloalkyl group is exemplified by monofluoromethyl, 1 ,2-dichloroethyl and the like.
  • perhaloalkyl means an alkyl group as defined hereinabove wherein all the hydrogen atoms of the said alkyl group are substituted with halogen.
  • the perhaloalkyl group is exemplified by trifluoromethyl, pentafluoroethyl and the like.
  • cycloalkyi means a monocyclic, bicyclic, or tricyclic non- aromatic ring system containing from 3 to 14 carbon atoms, preferably monocyclic cycloalkyi ring containing 3 to 6 carbon atoms.
  • monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • Bicyclic ring systems are also exemplified by a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge.
  • bicyclic ring systems include, but are not limited to, bicyclo[3.1 .1 ]heptane, bicyclo[2.2.1 ]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1 ]nonane, and bicyclo[4.2.1 ]nonane, bicyclo[3.3.2]decane, bicyclo[3.1 .0]hexane, bicyclo[410]heptane, bicyclo[3.2.0]heptanes, octahydro-1 H-indene.
  • Tricyclic ring systems are also exemplified by a bicyclic ring system in which two non- adjacent carbon atoms of the bicyclic ring are linked by a bond or an alkylene bridge.
  • Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1 .0 3 7 ]nonane and tricyclo[3.3.1 .1 3 7 ]decane (adamantane).
  • cycloalkyl also include spiro systems wherein one of the ring is annulated on a single carbon atom such ring systems are exemplified by spiro[2.5]octane, spiro[4.5]decane, spiro[bicyclo[4.1 .0]heptane-2,1 '-cyclopentane], hexahydro-2'H-spiro[cyclopropane-1 ,1 '- pentalene].
  • cycloalkenyl as used herein, means a cycloalkyl group as defined above containing at least one double bond.
  • carrier means a cyclic system made up of carbon atoms, which includes cycloalkyl, cycloalkenyl and aryl.
  • aryl refers to a monovalent monocyclic, bicyclic or tricyclic aromatic hydrocarbon ring system.
  • aryl groups include phenyl, naphthyl, anthracenyl, fluorenyl, indenyl, azulenyl, and the like.
  • Aryl group also include partially saturated bicyclic and tricyclic aromatic hydrocarbons such as tetrahydro-naphthalene.
  • the said aryl group also includes aryl rings fused with heteroaryl or heterocyclic rings such as 2,3-dihydro- benzo[1 ,4]dioxin-6-yl, 2,3-dihydro-benzo[1 ,4]dioxin-5-yl, 2,3-dihydro-benzofuran-5-yl, 2,3- dihydro-benzofuran-4-yl, 2,3-dihydro-benzofuran-6-yl, 2,3-dihydro-benzofuran-6-yl, 2,3- dihydro-1 H-indol-5-yl, 2,3-dihydro-1 H-indol-4-yl, 2,3-dihydro-1 H-indol-6-yl, 2,3-dihydro-1 H- indol-7-yl, benzo[1 ,3]dioxol-4-yl, benzo[1 ,3]dioxol-5-yl
  • substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, alkyl-O-,
  • heteroaryl refers to a 5-14 membered monocyclic, bicyclic, or tricyclic ring system having 1 -4 ring heteroatoms selected from O, N, or S, and the remainder ring atoms being carbon (with appropriate hydrogen atoms unless otherwise indicated), wherein at least one ring in the ring system is aromatic.
  • Heteroaryl groups may be optionally substituted with one or more substituents. In one embodiment, 0, 1 , 2, 3, or 4 atoms of each ring of a heteroaryl group may be substituted by a substituent.
  • heteroaryl groups include pyridyi, 1 -oxo-pyridyl, furanyi, thienyi, pyrroiyl, oxazolyi, oxadiazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyi, pyrazinyl, triazinyl. triazolyl.
  • thiadiazolyl isoquinolinyl, benzoxazolyl, benzofuranyl, indolizinyl, imidazopyridyl, tetrazolyi, benzimidazolyi, benzothiazolyl. benzothiadiazolyl, benzoxadiazolyl, indolyl. azaindolyl, imidazopyridyl. quinazolinyl.
  • substituents selected independently from the group consisting of halogen, nitro, cyano, hydroxy, alkyl, perhaloalkyl, alkyl
  • heterocycle or “heterocyclic” as used herein, means a 'cycloalkyl' group wherein one or more of the carbon atoms replaced by -0-, -S-, -S(0 2 )-, -S(O)-, -N(R m )-, - Si(R m )R n -, wherein, R m and R n are independently selected from hydrogen, alkyl, aryl, heteroaryl, cycloalkyi, and heterocyclyl.
  • the heterocycle may be connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the heterocycle.
  • monocyclic heterocycle include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1 ,3-dioxanyl, 1 ,3-dioxolanyl, 1 ,3- dithiolanyl, 1 ,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl.
  • oxadiazolidinyl oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl.
  • thiopyranyl, and trithianyl thiopyranyl, and trithianyl.
  • bicyclic heterocycle include, but are not limited to 1 ,3-benzodioxolyl, 1 ,3-benzodithiolyl, 2,3-dihydro-1 ,4-benzodioxinyl, 2,3- dihydro-1 -benzofuranyl, 2,3-dihydro-1 -benzothienyl, 2,3-dihydro-1 H-indolyl and 1 ,2,3,4- tetrahydroquinolinyl.
  • the term heterocycle also include bridged heterocyclic systems such as azabicyclo[3.2.1 ]octane, azabicyclo[3.3.1 ]nonane and the like.
  • oxo attached to carbon forms a carbonyl
  • oxo substituted on cyclohexane forms a cyclohexanone
  • 'annulated' means the ring system under consideration is either annulated with another ring at a carbon atom of the cyclic system or across a bond of the cyclic system as in the case of fused or spiro ring systems.
  • bridged' means the ring system under consideration contain an alkylene bridge having 1 to 4 methylene units joining two non adjuscent ring atoms.
  • the compounds of general formula I where all the symbols are as defined earlier can be prepared by methods given in Schemes given below or example. Representative procedures are shown below, however; the disclosure should not be construed to limit the scope of the invention arriving at compound of formula I as disclosed hereinabove.
  • Cyclization of 4 using NH 4 OAc could lead to the formation of 5 which may be deprotected and coupled with (S)-2-((methoxycarbonyl)amino)-3-methylbutanoic acid using amide coupling reagents like carbodiimides, phosphonium salts, uronium salts, carbonyldiimidazole in presence of a mild base like triethylamine, 4-methylmorpholine, diisopropylethylamine in a solvent like DMF, 1 ,4-dioxane, THF, dichloromethane leading to the formation of 6.
  • de-protected form of 5 can be coupled to similar moieties by methods known in the literature to furnish compounds of formula I.
  • oxime 35 On treatment with isoamyl nitrite in an appropriate solvent, oxime 35 might be generated from 34 which upon reaction with Boc-L-prolinal under basic conditions may lead to formation of 36. Treatment of 36 with triethyl phosphite might lead to the formation of either 37 or 38. Pd-catalyzed C-C coupling of either 37 or 38 with 25 followed by de-protection and coupling with (S)-2- ((methoxycarbonyl)amino)-3-methylbutanoic acid might lead to the formation of 39 or 40.
  • Symmetrical compounds could be prepared by coupling 42 (generated from 34) with the boronate/boronic acid of 42 through the use of Pd catalyzed C-C coupling reactions to yield 44 or compounds of formula I.
  • a further embodiment of the present invention includes pharmaceutical compositions comprising any single compound, a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, with a pharmaceutically acceptable carrier or excipient.
  • a further embodiment of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising any single compound or a combination of two or more compounds delineated herein, or a pharmaceutically acceptable salt thereof, in combination with one or more agents known in the art, with a pharmaceutically acceptable carrier or excipient.
  • compounds of the present invention can be administered as the sole active pharmaceutical agent, or used in combination with one or more agents to treat or prevent hepatitis C infections or the symptoms associated with HCV infection.
  • Other agents to be administered in combination with a compound or combination of compounds of the present invention include therapies for diseases caused by HCV infection that suppresses HCV viral replication by direct or indirect mechanisms.
  • agents include, but not limited to, host immune modulators (for example, interferon-alpha, pegylated interferon-alpha, consensus interferon, interferon-beta, interferon-gamma, CpG oligonucleotides and the like); antiviral compounds that inhibit host cellular functions such as inosine monophosphate dehydrogenase (for example, ribavirin and the like); cytokines that modulate immune function (for example, interleukin 2, interleukin 6, and interleukin 12); a compound that enhances the development of type 1 helper T cell response; interfering RNA; anti-sense RNA; vaccines comprising HCV antigens or antigen adjuvant combinations directed against HCV; agents that interact with host cellular components to block viral protein synthesis by inhibiting the internal ribosome entry site (IRES) initiated translation step of HCV viral replication or to block viral particle maturation and release with agents targeted toward the viroporin family of membrane proteins such as, for example
  • compositions of the present invention may further comprise inhibitor(s) of other targets in the HCV life cycle, including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • inhibitor(s) of other targets in the HCV life cycle including, but not limited to, helicase, polymerase, metalloprotease, NS4A protein, NS5A protein, and internal ribosome entry site (IRES).
  • one embodiment of the present invention is directed to a method for treating or preventing an infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • Examples of the host immune modulator are, but not limited to, interferon-alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • Example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • a further embodiment of the present invention is directed to a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment an agent or combination of agents that treat or alleviate symptoms of HCV infection including cirrhosis and inflammation of the liver, with a therapeutically effective amount of a compound or combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • Yet another embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by hepatitis B (HBV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • An agent that treats patients for disease caused by hepatitis B (HBV) infection may be for example, but not limited thereto, L-deoxythymidine, adefovir, lamivudine or tenfovir, or any combination thereof.
  • Example of the RNA-containing virus includes, but not limited to, hepatitis C virus (HCV).
  • a further embodiment of the present invention provides a method of treating or preventing infection caused by an RNA-containing virus comprising co-administering to a patient in need of such treatment one or more agents that treat patients for disease caused by human immunodeficiency virus (HIV) infection, with a therapeutically effective amount of a compound or a combination of compounds of the present invention, or a pharmaceutically acceptable salt thereof.
  • HIV human immunodeficiency virus
  • the agent that treats patients for disease caused by human immunodeficiency virus (H IV) infection may include, but is not limited thereto, ritonavir, lopinavir, indinavir, nelfmavir, saquinavir, amprenavir, atazanavir, tipranavir, TMC-1 14, fosamprenavir, zidovudine, lamivudine, didanosine, stavudine, tenofovir, zalcitabine, abacavir, efavirenz, nevirapine, delavirdine, TMC-125, L-870812, S-1360, enfuvirtide (T- 20) or T-1249, or any combination thereof.
  • RNA-containing virus includes, but not limited to, hepatitis C virus (HCV). It can occur that a patient may be co-infected with hepatitis C virus and one or more other viruses, including but not limited to human immunodeficiency virus (HIV), hepatitis A virus (HAV) and hepatitis B virus (HBV). Thus also contemplated is combination therapy to treat such co-infections by co-administering a compound according to the present invention with at least one of an HIV inhibitor, an HAV inhibitor and an HBV inhibitor.
  • HCV human immunodeficiency virus
  • HAV hepatitis A virus
  • HBV hepatitis B virus
  • the present invention provides the use of a compound or a combination of compounds of the invention, or a therapeutically acceptable salt thereof, and one or more agents selected from the group consisting of a host immune modulator and a second or more antiviral agents, or a combination thereof, to prepare a medicament for the treatment of an infection caused by an RNA-containing virus in a patient, particularly hepatitis C virus.
  • host immune modulators include, but are not limited to, interferon- alpha, pegylated-interferon-alpha, interferon-beta, interferon-gamma, a cytokine, a vaccine, and a vaccine comprising an antigen and an adjuvant, and said second antiviral agent inhibits replication of HCV either by inhibiting host cellular functions associated with viral replication or by targeting proteins of the viral genome.
  • combination of compound or compounds of the present invention, together with one or more agents as defined herein above can be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt thereof.
  • combination of therapeutic agents can be administered as a pharmaceutical composition containing a therapeutically effective amount of the compound or combination of compounds of interest, or their pharmaceutically acceptable salt thereof, in combination with one or more agents as defined hereinabove, and a pharmaceutically acceptable carrier.
  • Such pharmaceutical compositions can be used for inhibiting the replication of an RNA-containing virus, particularly Hepatitis C virus (HCV), by contacting said virus with said pharmaceutical composition.
  • such compositions are useful for the treatment or prevention of an infection caused by an RNA-containing virus, particularly Hepatitis C virus (HCV).
  • a still further embodiment of the invention is directed to a method of treating or preventing infection caused by an RNA-containing virus, particularly a hepatitis C virus (HCV), comprising administering to a patient in need of such treatment a pharmaceutical composition comprising a compound or combination of compounds of the invention or a pharmaceutically acceptable salt thereof, and one or more agents as defined hereinabove, with a pharmaceutically acceptable carrier.
  • an RNA-containing virus particularly a hepatitis C virus (HCV)
  • HCV hepatitis C virus
  • the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or within a predetermined period of time, or the therapeutic agents can be given as a single unit dosage form.
  • Antiviral agents contemplated for use in such combination therapy include agents (compounds or biologicals) that are effective to inhibit the formation and/or replication of a virus in a mammal, including but not limited to agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal.
  • agents can be selected from another anti-HCV agent; an HIV inhibitor; an HAV inhibitor; and an HBV inhibitor.
  • agents to be administered in combination with a compound of the present invention include a cytochrome P450 monooxygenase inhibitor, which is expected to inhibit metabolism of the compounds of the invention. Therefore, the cytochrome P450 monooxygenase inhibitor would be in an amount effective to inhibit metabolism of the compounds of the present invention. Accordingly, the CYP inhibitor is administered in an amount such that the bioavailability of the compounds of the present invention is increased in comparison to the bioavailability in the absence of the CYP inhibitor.
  • room temperature used in the specification denotes any temperature ranging between about 20 °C to about 40 °C, except and otherwise it is specifically mentioned in the specification.
  • the intermediates and the compounds of the present invention may obtained in pure form in a manner known per se, for example, by distilling off the solvent in vacuum and re- crystallizing the residue obtained from a suitable solvent, such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations or subjecting it to one of the purification methods, such as column chromatography (e.g., flash chromatography) on a suitable support material such as alumina or silica gel using eluent such as dichloromethane, ethyl acetate, hexane, methanol, acetone and their combinations.
  • a suitable solvent such as pentane, diethyl ether, isopropyl ether, chloroform, dichloromethane, ethyl acetate, acetone or their combinations
  • the purification methods such as column chromatography (e.g., flash
  • Salts of compound of formula I can be obtained by dissolving the compound in a suitable solvent, for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol, which was then treated with the desired acid or base as described in Berge S.M. et al. "Pharmaceutical Salts, a review article in Journal of Pharmaceutical sciences volume 66, page 1 -19 (1977)" and in handbook of pharmaceutical salts properties, selection, and use by P.H.Einrich Stahland Camille G.wermuth, Wiley- VCH (2002).
  • a suitable solvent for example in a chlorinated hydrocarbon, such as methyl chloride or chloroform or a low molecular weight aliphatic alcohol, for example, ethanol or isopropanol
  • salts can also be found in Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, PA, 1990, p. 1445, and Journal of Pharmaceutical Science, 66, 2-19 (1977).
  • they can be a salt of an alkali metal (e.g., sodium or potassium), alkaline earth metal (e.g., calcium), or ammonium of salt.
  • the compound of the invention or a composition thereof can potentially be administered as a pharmaceutically acceptable acid-addition, base neutralized or addition salt, formed by reaction with inorganic acids, such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid, and organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, malonic acid, succinic acid, maleic acid, and fumaric acid, or by reaction with an inorganic base, such as sodium hydroxide, potassium hydroxide.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, perchloric acid, nitric acid, thiocyanic acid, sulfuric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, glycolic acid, lactic acid, pyruvic acid, oxalic acid, mal
  • the conversion to a salt is accomplished by treatment of the base compound with at least a stoichiometric amount of an appropriate acid.
  • the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol, methanol, and the like, and the acid is added in a similar solvent.
  • the mixture is maintained at a suitable temperature (e.g., between 0 °C and 50 °C).
  • the resulting salt precipitates spontaneously or can be brought out of solution with a less polar solvent.
  • the stereoisomers of the compounds of formula I of the present invention may be prepared by stereospecific syntheses or resolution of the achiral compound using an optically active amine, acid or complex forming agent, and separating the diastereomeric salt/complex by fractional crystallization or by column chromatography.
  • prodrug denotes a derivative of a compound, which derivative, when administered to warm-blooded animals, e.g. humans, is converted into the compound (drug).
  • the enzymatic and/or chemical hydrolytic cleavage of the compounds of the present invention occurs in such a manner that the proven drug form (parent carboxylic acid drug) is released, and the moiety or moieties split off remain nontoxic or are metabolized so that nontoxic metabolic products are produced.
  • a carboxylic acid group can be esterified, e.g., with a methyl group or ethyl group to yield an ester.
  • an ester is administered to a subject, the ester is cleaved, enzymatically or non- enzymatically, reductively, oxidatively, or hydrolytically, to reveal the anionic group.
  • An anionic group can be esterified with moieties (e.g., acyloxymethyl esters) which are cleaved to reveal an intermediate compound which subsequently decomposes to yield the active compound.
  • the prodrugs can be prepared in situ during the isolation and purification of the compounds, or by separately reacting the purified compound with a suitable derivatizing agent.
  • hydroxy groups can be converted into esters via treatment with a carboxylic acid in the presence of a catalyst.
  • cleavable alcohol prodrug moieties include substituted or unsubstituted, branched or unbranched lower alkyl ester moieties, e.g., ethyl esters, di-lower alkylamino lower-alkyl esters, e.g., dimethylaminoethyl ester, acylamino lower alkyl esters, acyloxy lower alkyl esters (e.g., pivaloyloxymethyl ester), aryl esters, e.g., phenyl ester, aryl-lower alkyl esters, e.g., benzyl ester, optionally substituted, e.g., with methyl, halo, or methoxy substituents aryl and aryl- lower alkyl esters, amides, lower-alkyl amides, di-lwer alkyl amides, and hydroxy amides.
  • lower alkyl ester moieties
  • the present invention further provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its stereoisomers, its analogues, its prodrugs, its isotopically substituted analogues, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates and its co-crystals in combination with the usual pharmaceutically acceptable carriers, diluents and the like.
  • the pharmaceutically acceptable carrier is preferably one that is chemically inert to the compound of the invention and one that has no detrimental side effects or toxicity under the conditions of use.
  • Such pharmaceutically acceptable carriers preferably include saline (e.g., 0.9% saline), Cremophor EL (which is a derivative of castor oil and ethylene oxide available from Sigma Chemical Co., St.
  • a preferred pharmaceutical carrier is polyethylene glycol, such as PEG 400, and particularly a composition comprising 40% PEG 400 and 60% water or saline. The choice of carrier will be determined in part by the particular compound chosen, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intraarterial, intramuscular, interperitoneal, rectal, and vaginal administration are merely exemplary and are in no way limiting.
  • compositions for parenteral administration that comprise a solution of the compound of the invention dissolved or suspended in an acceptable carrier suitable for parenteral administration, including aqueous and non-aqueous, isotonic sterile injection solutions.
  • compositions include solutions containing anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol (for example in topical applications), or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-1 ,3-dioxolane- 4-methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carb
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, and synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oil. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-3-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5% or less to about 25% or more by weight of a compound of the invention in solution. Preservatives and buffers can be used. In order to minimize or eliminate irritation at the site of injection, such compositions can contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets.
  • Topical formulations including those that are useful for transdermal drug release, are well known to those of skill in the art and are suitable in the context of the present invention for application to skin.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of a compound of the invention dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a pre-determined amount of the compound of the invention, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations can include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • diluents such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the compound ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising a compound of the invention in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the compound of the invention, such excipients as are known in the art.
  • An compound of the present invention can be made into aerosol formulations to be administered via inhalation.
  • a compound or epimer of the invention is preferably supplied in finely divided form along with a surfactant and propellant.
  • Typical percentages of the compounds of the invention can be about 0.01 % to about 20% by weight, preferably about 1 % to about 10% by weight.
  • the surfactant must, of course, be nontoxic, and preferably soluble in the propellant.
  • Such surfactants are the esters or partial esters of fatty acids containing from 6 to 22 carbon atoms, such as caproic, octanoic, lauric, palmitic, stearic, linoleic, linolenic, olesteric and oleic acids with an aliphatic polyhydric alcohol or its cyclic anhydride.
  • Mixed esters such as mixed or natural glycerides can be employed.
  • the surfactant can constitute from about 0.1 % to about 20% by weight of the composition, preferably from about 0.25% to about 5%.
  • the balance of the composition is ordinarily propellant.
  • a carrier can also be included as desired, e.g., lecithin, for intranasal delivery.
  • aerosol formulations can be placed into acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations can be used to spray mucosa.
  • acceptable pressurized propellants such as dichlorodifluoromethane, propane, nitrogen, and the like.
  • non-pressured preparations such as in a nebulizer or an atomizer.
  • Such spray formulations can be used to spray mucosa.
  • the compound of the invention can be made into suppositories by mixing with a variety of bases, such as emulsifying bases or water-soluble bases.
  • bases such as emulsifying bases or water-soluble bases.
  • Formulations suitable for vaginal administration can be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the compound ingredient, such carriers as are known in the art to be appropriate.
  • the concentration of the compound in the pharmaceutical formulations can vary, e.g., from less than about 1 % to about 10%, to as much as 20% to 50% or more by weight, and can be selected primarily by fluid volumes, and viscosities, in accordance with the particular mode of administration selected.
  • a typical pharmaceutical composition for intravenous infusion could be made up to contain 250 ml of sterile Ringer's solution, and 100 mg of at least one compound of the invention.
  • Actual methods for preparing parenterally administrable compounds of the invention will be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Science (17 th ed., Mack Publishing Company, Easton, PA, 1985). It will be appreciated by one of ordinary skill in the art that, in addition to the aforedescribed pharmaceutical compositions, the compound of the invention can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • Liposomes can serve to target a compound of the invention to a particular tissue, such as lymphoid tissue or cancerous hepatic cells. Liposomes can also be used to increase the half-life of a compound of the invention. Many methods are available for preparing liposomes, as described in, for example, Szoka et al., Ann. Rev. Biophys. Bioeng., 9, 467 (1980) and U.S. Patents 4,235,871 , 4,501 ,728, 4,837,028, and 5,019,369.
  • the present invention also provides a pharmaceutical composition, containing the compounds of the general formula (I) as defined above, its tautomeric forms, its stereoisomers, its analogs, its prodrugs, its isotopes, its metabolites, its pharmaceutically acceptable salts, its polymorphs, its solvates, its optical isomers, its clathrates and its co- crystals in combination with the usual pharmaceutically employed carriers, diluents and the like, and for use in any of the methods described herein.
  • the compounds of the invention can be administered in a dose sufficient to treat the disease, condition or disorder.
  • doses are known in the art (see, for example, the Physicians' Desk Reference (2004)).
  • the compounds can be administered using techniques such as those described in, for example, Wasserman et al., Cancer, 36, pp. 1258-1268 (1975) and Physicians' Desk Reference, 58th ed., Thomson PDR (2004).
  • Suitable doses and dosage regimens can be determined by conventional range-finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages that are less than the optimum dose of the compound of the present invention. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
  • the present method can involve the administration of about 0.1 ⁇ g to about 50 mg of at least one compound of the invention per kg body weight of the individual. For a 70 kg patient, dosages of from about 10 ⁇ g to about 200 mg of the compound of the invention would be more commonly used, depending on a patient's physiological response.
  • the dose of the pharmaceutically active agent(s) described herein for methods of treating or preventing a disease or condition as described above can be about 0.001 to about 1 mg/kg body weight of the subject per day, for example, about 0.001 mg, 0.002 mg, 0.005 mg, 0.010 mg, 0.015 mg, 0.020 mg, 0.025 mg, 0.050 mg, 0.075 mg, 0.1 mg, 0.15 mg, 0.2 mg, 0.25 mg, 0.5 mg, 0.75 mg, or 1 mg/kg body weight per day.
  • the dose of the pharmaceutically active agent(s) described herein for the described methods can be about 1 to about 1000 mg/kg body weight of the subject being treated per day, for example, about 1 mg, 2 mg, 5 mg, 10 mg, 15 mg, 0.020 mg, 25 mg, 50 mg, 75 mg, 100 mg, 150 mg, 200 mg, 250 mg, 500 mg, 750 mg, or 1000 mg/kg body weight per day.
  • the present invention provides methods of treating, preventing, ameliorating, and/or inhibiting a hepatitis C virus infection comprising administering a compound of formula (I) or a salt thereof.
  • the compounds of the present invention can inhibit multiple genotypes of HCV.
  • compound of the present invention are active against the 1 a, 1 b, 2a, 2b, 3a, 4a and 5a genotypes.
  • the terms “treat,” “prevent,” “ameliorate,” and “inhibit,” as well as words stemming therefrom, as used herein, do not necessarily imply 100% or complete treatment, prevention, amelioration, or inhibition. Rather, there are varying degrees of treatment, prevention, amelioration, and inhibition of which one of ordinary skill in the art recognizes as having a potential benefit or therapeutic effect.
  • the inventive methods can provide any amount of any level of treatment, prevention, amelioration, or inhibition of the disorder in a mammal.
  • a disorder, including symptoms or conditions thereof may be reduced by, for example, 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, or 10%.
  • the treatment, prevention, amelioration, or inhibition provided by the inventive method can include treatment, prevention, amelioration, or inhibition of one or more conditions or symptoms of the disorder, e.g., cancer.
  • "treatment,” “prevention,” “amelioration,” or “inhibition” can encompass delaying the onset of the disorder, or a symptom or condition thereof.
  • the term subject includes an "animal” which in turn includes a mammal such as, without limitation, the order Rodentia, such as mice, and the order Lagomorpha, such as rabbits.
  • the mammals are from the order Carnivora, including Felines (cats) and Canines (dogs). It is more preferred that the mammals are from the order Artiodactyla, including Bovines (cows) and Swine (pigs) or of the order Perssodactyla, including Equines (horses). It is most preferred that the mammals are of the order Primates, Ceboids, or Simoids (monkeys) or of the order Anthropoids (humans and apes). An especially preferred mammal is the human.
  • viral infection refers to the introduction of a virus into cells or tissues, e.g., hepatitis C virus (HCV). In general, the introduction of a virus is also associated with replication. Viral infection may be determined by measuring virus antibody titer in samples of a biological fluid, such as blood, using, e.g., enzyme immunoassay. Other suitable diagnostic methods include molecular based techniques, such as RT-PCR, direct hybrid capture assay, nucleic acid sequence based amplification, and the like. A virus may infect an organ, e.g., liver, and cause disease, e.g., hepatitis, cirrhosis, chronic liver disease and hepatocellular carcinoma.
  • HCV hepatitis C virus
  • immune modulator refers to any substance meant to alter the working of the humoral or cellular immune system of a subject.
  • immune modulators include inhibitors of mast cell-mediated inflammation, interferons, interleukins, prostaglandins, steroids, cortico-steroids, colony-stimulating factors, chemotactic factors, etc.
  • ACN Acetonitrile. Boc: tert-butyloxycarbonyl. Cbz: Carbobenzyloxy.
  • CDCI 3 Deuterochloroform.
  • DCM dichloromethane.
  • DDQ 2,3-Dichloro-5,6-dicyano-p- benzoquinone.
  • DIPEA N, N-diisopropylethylamine.
  • DME 1 , 2-dimethoxyethane.
  • DMF N, N-dimethylformamide.
  • DMSO-c 6 Dimethyl sulfoxide-d 6 .
  • EDCI A/-(3-Dimethylaminopropyl)- /V-ethylcarbodiimide.
  • EtOAc Ethyl acetate.
  • HATU 0-(7-Azabenzotriazol-1 -yl)-A/,A/,A/',/V- tetramethyluronium hexafluorophosphate.
  • HCI hydrochloric acid.
  • HOBt 1 - Hydroxybenzotriazole hydrate.
  • HPLC High Performance Liquid Chromatography.
  • KOAc potassium acetate.
  • MeOD Methanol-d 4 .
  • Na 2 S04 sodium sulphate.
  • NaHC0 3 sodium bicarbonate.
  • NCS N-chlorosuccinimide.
  • PCy 3 Tricyclohexylphosphine.
  • Pd(PPh 3 ) 4 Tetrakis(triphenylphosphine)palladium(0).
  • Pd-C Palladium on charcoal.
  • PdCI 2 (dppf) [1 ,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll).
  • PdCl 2 (dppf)-CH 2 CI 2 [1 ,1 '- Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane.
  • pet-ether petroleum ether.
  • TFA trifluoroacetic acid.
  • THF Tetrahydrofuran
  • Example 1 Preparation of methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H- naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (mixture of trans isomers) (Compound 1):
  • Step 1 2-(4-bromophenyl)-2-oxoethyl-2-((tert- butoxycarbonyl)amino)cyclopentanecarboxylate (trans isomers) (1 a):
  • Step 2 tert-butyl (2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (trans isomers)(1 b):
  • Step 3 tert-butyl (2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)carbamate (trans isomers) (1 c):
  • Step 4 (2S)-tert-butyl 2-(7-(4-(2-(2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H-imidazol- 5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (trans isomers) (1 d):
  • Step 5 methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (mixture of trans isomers) (Compound 1 ):
  • Example 2 methyl ((2S)-1-((2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2- d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2- yl)carbamate (mixture of cis isomers) (Compound 2):
  • Step 1 2-(4-bromophenyl)-2-oxoethyl-2-((tert- butoxycarbonyl)amino)cyclopentanecarboxylate (cis isomers) (2a):
  • Step 2 tert-butyl (2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (cis isomers) (2b):
  • Step 3 tert-butyl (2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)carbamate (cis isomers) (2c):
  • Step 4 (2S)-tert-butyl 2-(8-(4-(2-(2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H-imidazol- 5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-yl)pyrrolidine-1 - carboxylate (2d):
  • Step 5 methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (mixture of cis isomers): (Compound 2)
  • Example 3 Preparation of methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H- naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (mixture of cis isomers) (Compound 3):
  • Step 1 (2S)-tert-butyl 2-(7-(4-(2-(2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H-imidazol- 5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (cis isomers) (3a):
  • Step 2 methyl ((2S)-1 -((2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (mixture of cis isomers): (Compound 3)
  • Step 1 (1 S,2R)-2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)amino) cyclopentanecarboxylate (4a):
  • Step 2 tert-butyl ((1 R,2S)-2-(4-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (4b):
  • Step 3 tert-butyl ((1 R,2S)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)carbamate (4c):
  • Step 4 (S)-tert-butyl 2-(7-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (4d):
  • Step 5 methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 4).
  • Example 5 Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 , 4,5,6- tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Example 5):
  • Step 1 (S)-tert-butyl 2-(8-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2- yl)pyrrolidine-1 -carboxylate (5a):
  • Step 2 methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 5):
  • Step 1 (S)-tert-butyl 2-(8-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-2-yl)pyrrol ⁇ carboxylate (6a):
  • Step 2 methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 6):
  • Example 7 methyl ((S)-1-(((1 S,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 7):
  • Step 1 (1 R,2S)-2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl) amino)cyclopentanecarboxylate (7a):
  • Step 2 tert-butyl- ((1 S,2R)-2-(4-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (7b):
  • Step 3 tert-butyl ((1 S,2R)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)carbamate (7c):
  • Step 4 (S)-tert-butyl 2-(8-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-2-yl)pyrrolidine-1 - carboxylate (7d):
  • Step 5 methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 7):
  • Example 8 Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1 -((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 , 4,5,6- tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 8):
  • Step 1 (S)-tert-butyl 2-(8-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2- yl)pyrrolidine-1 -carboxylate (8a):
  • Step 2 methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8- yl)phenyl)-1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 8):
  • Example 9 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1, 4,5,6- tetrahydrobenzo[3,4]cyclohepta[1,2-d]imidazol-8-yl)phenyl)-1H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 9):
  • Step 1 (1S,2S)-2-(4-bromophenyl)-2-oxoethyl-2-((tertbutoxycarbonyl)amino) cyclopentanecarboxylate (9a):
  • Step 3 tert-butyl ((1 S,2S)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)carbamate (9c):
  • Step 4 (S)-tert-butyl 2-(8-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2- yl)pyrrolidine-1 -carboxylate (9d):
  • Step 5 methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 9):
  • Step 1 (S)-tert-butyl 2-(7-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (10a)
  • Step 2 methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 10):
  • Example 11 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H- benzo[2,3]oxepino[4,5-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)- 3-methyl-1-oxobutan-2-yl)carbamate (Compound 11 ):
  • Step 1 (S)-tert-butyl 2-(8-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-ben ⁇
  • Step 2 methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 1 1 ):
  • Example 12 Preparation of methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 , 4,5,6- tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 12):
  • Step 1 (1 R, 2R)-2-(4-bromophenyl)-2-oxoethyl-2-((tert-butoxycarbonyl)amino) cyclopentane carboxylate (12a):
  • Step 2 tert-butyl ((1 R,2R)-2-(4-(4-bromophenyl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (12b):
  • Step 3 tert-butyl ((1 R,2R)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)carbamate (12c):
  • Step 4 (S)-tert-butyl 2-(8-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2- yl)pyrrolidine-1 -carboxylate (12d):
  • Step 5 methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 ,4,5,6-tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 12):
  • Example 13 Preparation of methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H- benzo[2,3]oxepino[4,5-d]imidazol-8-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)- 3-methyl-1-oxobutan-2-yl)carbamate (Compound 13):
  • Step 1 (S)-tert-butyl 2-(8-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-2-yl)pyrrolidine-1 - carboxylate (13a):
  • Step 2 methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-benzo[2,3]oxepino[4,5-d]imidazol-8- yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 13):
  • Example 14 Preparation of methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H- naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (Compound 14):
  • Step 1 (S)-tert-butyl 2-(7-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (14a):
  • Step 2 methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 14):
  • Example 15 Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H- naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (Compound 15):
  • Step 1 (S)-tert-butyl 2-(7-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (15a):
  • Step 2 methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 15):
  • Example 16 Preparation of methyl ((S)-1-(((1 R,2R)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1H-naphtho[1,2- d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2- yl)carbamate (Compound 16):
  • Step 2 (S)-tert-butyl 2-(7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-3H-naphtho[1 ,2- d]imidazol-2-yl)pyrrolidine-1 -carboxylate (16b):
  • Step 3 (S)-tert-butyl 2-(7-(4-(2-((1 R,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (16c):
  • Step 4 methyl ((S)-1 -(((1 R,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 16):
  • Example 17 Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2- d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2- yl)carbamate (Compound 17):
  • Step 1 (S)-tert-butyl 2-(7-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (17a):
  • Step 2 methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 17):
  • Example 18 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2- d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2- yl)carbamate (Compound 18):
  • Step 1 (S)-tert-butyl 2-(7-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (18a):
  • Step 2 methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 18):
  • Example 19 Preparation of methyl ((S)-1-(((1S,2R)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2- d]imidazol-7-yl)phenyl)-4-chloro-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (Compound 19):
  • Step 1 tert-butyl ((1 S,2R)-2-(5-(4-bromophenyl)-4-chloro-1 H-imidazol-2- yl)cyclopentyl)carbamate (19a):
  • Step 2 (S)-tert-butyl 2-(7-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4- chloro-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate
  • Step 3 methyl ((S)-1 -(((1 S,2R)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-chloro-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 19).
  • Example 20 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2- d]imidazol-7-yl)phenyl)-4-chloro-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (Compound 20):
  • Step 1 tert-butyl ((1 S,2S)-2-(5-(4-bromophenyl)-4-chloro-1 H-imidazol-2- yl)cyclopentyl)carbamate (20a):
  • Step 2 (S)-tert-butyl 2-(7-(4-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4- chloro-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate (20b):
  • Step 3 methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-4-chloro-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 20):
  • reaction mixture was poured into water (100 mL) and the compound was extracted with ethyl acetate (100 mL ⁇ 2), dried over sodium sulphate, concentrated under reduced pressure and purified by flash column chromatography (45-55% Ethylacetate/Hexane) to get the title compound as side product, orange colored solid (0.7 g, 23 % yield) along with (S)-tert-butyl 2-(8-bromo-1 , 4,5,6- tetrahydrobenzo[3,4]cyclohepta[1 ,2-d]imidazol-2-yl)pyrrolidine-1 -carboxylate as the major compound.
  • Step 2 (S)-tert-butyl 2-(8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5,6-dihydro-4H- benzo[3,4]cyclohepta[1 ,2-d]oxazol-2-yl)pyrrolidine-1 -carboxylate (21 b):
  • Step 3 (S)-tert-butyl 2-(8-(4-(2-((1S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1H- imidazol-5-yl)phenyl)-5,6-dihydro-4H-benzo[3,4]cyclohepta[1,2-d]oxazol-2-yl)pyrrolidine-1- carboxylate (21c):
  • Step 4 methyl ((S)-1-(((1R,2S)-2-(5-(4-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-5,6-dihydro-4H-benzo[3,4]cyclohepta[1,2-d]oxazol-8- yl)phenyl)-1H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 21):
  • Example 22 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5- dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 22):
  • Step 1 (S)-tert-butyl 2-(8-bromo-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2- yl)pyrrolidine-1 -carboxylate (22a):
  • Step 2 (S)-tert-butyl 2-(8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-4,5- dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2-yl)pyrrolidine-1 -carboxylate (22b):
  • Step 3 (S)-tert-butyl 2-(8-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2-yl)pyrrolidine-1 - carboxylate (22c):
  • Step 4 methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 22):
  • Example 23 Preparation of methyl ((S)-1-(((1 R,2S)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5- dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (Compound 23):
  • Step 1 (S)-tert-butyl 2-(8-(4-(2-((1 S,2R)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenyl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-2-yl)pyrrolidine-1 - carboxylate (23a):
  • Step 2 methyl ((S)-1 -(((1 R,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydrobenzo[2,3]oxepino[4,5-d]oxazol-8-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 23):
  • Example 24 Preparation of methyl ((S)-1-(((1S,2S)-2-(7-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)- 4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1- oxobutan-2-yl)carbamate (Compound 24):
  • Step 1 (1 S,2S)-6-bromo-1 -oxo-1 ,2,3,4-tetrahydronaphthalen-2-yl 2-((tert- butoxycarbonyl)amino)cyclopentanecarboxylate (24a):
  • Step 2 tert-butyl ((1 S,2S)-2-(7-bromo-4,5-dihydro-3H-naphtho[1 ,2-d]imidazol-2- yl)cyclopentyl)carbamate (24b):
  • Step 3 (S)-tert-butyl 2-(5-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4,5- dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate (24c).
  • Step 4 methyl ((S)-1 -(((1 S,2S)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2- d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 24):
  • Step 2 tert-butyl ((1 S,2R)-2-(7-bromo-4,5-dihydro-3H-naphtho[1 ,2-d]imidazol-2- yl)cyclopentyl)carbamate (25b):
  • Step 3 (S)-tert-butyl 2-(5-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-4,5- dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate (25c):
  • Title compound was synthesized by following the procedure as described in Step 4 of Example 1 , using the intermediates (25b) from the previous step and (S)-tert-butyl 2-(5-(4- (4,4,5, 5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 - carboxylate [synthesized using procedures described in ref. WO2010/99527A1 ] as starting materials.
  • Step 4 methyl ((S)-1 -(((1 S,2R)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2- d]imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 25):
  • Step 1 (S)-tert-butyl 2-(5-(4-(2-((1 R,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate (26a):
  • Step 2 methyl ((S)-1 -(((1 S,2R)-2-(7-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2- yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 26):
  • Step 1 (S)-tert-butyl 2-(5-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)pyrrolidine-1 -carboxylate (27a):
  • Step 2 methyl ((S)-1 -(((1 S,2S)-2-(7-(4-(2-((S)-1 -((S)-2-amino-3-methylbutanoyl)pyrrolidin- 2-yl)-1 H-imidazol-5-yl)phenyl)-1 H-naphtho[1 ,2-d]imidazol-2-yl)cyclopentyl)amino)-3- methyl-1 -oxobutan-2-yl)carbamate (Compound 27):
  • Example 28 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(4-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H- naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H-imidazol-2-yl)cyclopentyl)(ethyl)amino)-3- methyl-1 -oxobutan-2-yl)carbamate (Compound 28): Step 1 : (1 S,2S)-ethyl-2-(ethylamino)cyclopentanecarboxylate (28a):
  • Step 2 (1 S,2S)-ethyl 2-((tert-butoxycarbonyl)(ethyl)amino)cyclopentanecarboxylate (28b):
  • Step 3 (1 S,2S)-2-((tert-butoxycarbonyl)(ethyl)amino)cyclopentanecarboxylic acid (28c):
  • Step 4 (1 S, 2S)-2-(4-bromophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)(ethyl) amino) cyclopentane carboxylate (28d):
  • Step 5 tert-butyl ((1 S,2S)-2-(5-(4-bromophenyl)-1 H-imidazol-2- yl)cyclopentyl)(ethyl)carbamate (28e):
  • Step 6 (S)-tert-butyl 2-(7-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)(ethyl)amino) cyclopentyl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2- yl)pyrrolidine-1 -carboxylate (28f):
  • Step 7 methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)(ethyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 28):
  • Step 2 (1 S, 2S)-ethyl 2-((tert-butoxycarbonyl)(methyl)amino) cyclopentanecarboxylate (29b):
  • Step 4 (1 S,2S)-2-(4-bromophenyl)-2-oxoethyl 2-((tert-butoxycarbonyl)(methyl) amino)cyclopentanecarboxylate (29d) :
  • Step 5 tert-butyl ((1 S,2S)-2-(5-(4-bromophenyl)-1 H-imidazol-2- yl)cyclopentyl)(methyl)carbamate (29e):
  • Step 6 (S)-tert-butyl 2-(7-(4-(2-((1 S,2S)-2-((tert-butoxycarbonyl)(methyl)amino) cyclopentyl)-1 H-imidazol-5-yl)phenyl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-2- yl)pyrrolidine-1 -carboxylate (29f):
  • Step 7 methyl ((S)-1 -(((1 S,2S)-2-(5-(4-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-4,5-dihydro-1 H-naphtho[1 ,2-d]imidazol-7-yl)phenyl)-1 H- imidazol-2-yl)cyclopentyl)(methyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 29):
  • Example 30 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9H- fluoren-2-yl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2- yl)carbamate (Compound 30): Step 1 : 1 -(7-bromo-9H-fluoren-2-yl)ethanone (30a):
  • Step 4 (1 S,2S)-2-(7-bromo-9H-fluoren-2-yl)-2-oxoethyl-2-((tert-butoxycarbonyl) amino)cyclopentanecarboxylate (30d) :
  • Step 5 tert-butyl ((1 S,2S)-2-(5-(7-bromo-9H-fluoren-2-yl)-1 H-imidazol-2- yl)cyclopentyl)carbamate (30e):
  • Step 6 tert-butyl ((1 S,2S)-2-(5-(7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-9H-fluoren- 2-yl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (30f):
  • Step 7 (S)-tert-butyl 2-(5-(7-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)-9H-fluoren-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2- yl)pyrrolidine-1 -carboxylate (30g):
  • Step 8 methyl ((S)-1 -(((1 S,2S)-2-(5-(7-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9H-fluoren-2-yl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 30):
  • Example 31 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9,9- dimethyl-9H-fluoren-2-yl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan- 2-yl)carbamate (Compound 31 ):
  • Step 1 1 -(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)ethanone (31 a):
  • Step 2 2,2-dibromo-1 -(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)ethanone
  • Step 3 2-bromo-1 -(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)ethanone (31 c): Title compound was synthesized by following the procedure as described in Step 3 of Example 30, using intermediate (31b) from the previous step.
  • Step 4 (1S,2S)-2-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)-2-oxoethyl 2-((tert- butoxycarbonyl)amino)cyclopentanecarboxylate (31d):
  • Step 5 tert-butyl ((1S,2S)-2-(5-(7-bromo-9,9-dimethyl-9H-fluoren-2-yl)-1 H-imidazol-2- yl)cyclopentyl)carbamate (31 e):
  • Step 6 tert-butyl ((1S,2S)-2-(5-(9,9-dimethyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)-9H-f luoren-2-yl)-1 H-imidazol-2-yl)cyclopentyl)carbamate (31 f)
  • Step 7 (S)-tert-butyl 2-(5-(7-(2-((1S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)-9,9-dimethyl-9H-fluoren-2-yl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H- imidazol-2-yl)pyrrolidine-1-carboxylate (31 g):
  • Step 8 methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-9,9-dimethyl-9H-fluoren-2-yl)-1 H- imidazol-2-yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 31 ):
  • Example 32 Preparation of methyl ((S)-1-(((1S,2S)-2-(5-(7-(2-((S)-1-((S)-2- (methoxycarbonyl)amino-3-methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5- yl)phenanthren-2-yl)-1 H-imidazol-2-yl)cyclopentyl)amino)-3-methyl-1-oxobutan-2- yl)carbamate (Compound 32):
  • Step 1 1 -(7-bromophenanthren-2-yl)ethanone (32a):
  • Step 4 (1S,2S)-2-(7-bromophenanthren-2-yl)-2-oxoethyl 2-((tert- butoxycarbonyl)amino)cyclopentanecarboxylate (32d):
  • Step 5 tert-butyl ((1S,2S)-2-(5-(7-bromophenanthren-2-yl)-1 H-imidazol-2- yl)cyclopentyl)carbamate (32e): Title compound was synthesized by following the procedure as described in Step 5 of Example 30, using intermediate (32d) from the previous step.
  • Step 6 tert-butyl ((1 S,2S)-2-(5-(7-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenanthren-2-yl)-1 H-i )
  • Step 7 (S)-tert-butyl 2-(5-(7-(2-((1 S,2S)-2-((tert-butoxycarbonyl)amino)cyclopentyl)-1 H- imidazol-5-yl)phenanthren-2-yl)-1 -((2-(trimethylsilyl)ethoxy)methyl)-1 H-imidazol-2- yl)pyrrolidine-1 -carboxyla
  • Step 8 methyl ((S)-1 -(((1 S,2S)-2-(5-(7-(2-((S)-1 -((S)-2-(methoxycarbonyl)amino-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)phenanthren-2-yl)-1 H-imidazol-2- yl)cyclopentyl)amino)-3-methyl-1 -oxobutan-2-yl)carbamate (Compound 32):
  • the Huh7.5/ Con1/SG-Neo(l)hRluc2aUb cell line persistently expressing a bicistronic genotype 1 b replicon in Huh 7.5 cells was obtained from Apath LLC. This cell line was used to test inhibition of genotype 1 b replicon levels by test compound using Renilla luciferase enzyme activity readout as a measure of viral replication efficiency. Briefly, 7000 cells were seeded in 96 well black clear bottom plates and allowed to adhere overnight. The next day each compound was added in triplicate to the cells at the desired concentration with a final DMSO concentration of 0.5%.
  • Table 1 shows EC50 values, for inhibition of genotype 1 b replicon, of the compounds of the invention.
  • Group A compounds exhibited EC50 value between 1 pM to 999 pM
  • Group B exhibited EC50 value between 1 nM to 999 nM
  • Goup C exhibited EC50 value of more than 1 ⁇ .

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Abstract

L'invention concerne des composés de formule générale I, leurs formes tautomères, leurs stéréo-isomères, leurs analogues, leurs promédicaments, leurs isotopes, leurs N-oxydes, leurs métabolites, leurs sels pharmaceutiquement acceptables, des polymorphes, des solvates, des isomères optiques, des clathrates, des co-cristaux, des combinaisons avec un médicament approprié, des compositions pharmaceutiques les contenant, des procédés de fabrication des composés précités et leur utilisation comme candidats antiviraux, plus spécifiquement comme anti-VHC.
PCT/IB2012/054020 2011-08-08 2012-08-07 Nouveaux dérivés de quercétine utiles comme agents antiviraux Ceased WO2013021344A1 (fr)

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CN104513147A (zh) * 2014-11-20 2015-04-15 上海众强药业有限公司 芴乙酮衍生物的制备方法
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9326973B2 (en) 2012-01-13 2016-05-03 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9717712B2 (en) 2013-07-02 2017-08-01 Bristol-Myers Squibb Company Combinations comprising tricyclohexadecahexaene derivatives for use in the treatment of hepatitis C virus
US9770439B2 (en) 2013-07-02 2017-09-26 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
CN104513147A (zh) * 2014-11-20 2015-04-15 上海众强药业有限公司 芴乙酮衍生物的制备方法
US10617675B2 (en) 2015-08-06 2020-04-14 Bristol-Myers Squibb Company Hepatitis C virus inhibitors

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