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WO2011154871A1 - Inhibiteurs du virus de l'hépatite c - Google Patents

Inhibiteurs du virus de l'hépatite c Download PDF

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Publication number
WO2011154871A1
WO2011154871A1 PCT/IB2011/052392 IB2011052392W WO2011154871A1 WO 2011154871 A1 WO2011154871 A1 WO 2011154871A1 IB 2011052392 W IB2011052392 W IB 2011052392W WO 2011154871 A1 WO2011154871 A1 WO 2011154871A1
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Prior art keywords
mmol
minutes
preparation
pyrrolidin
methyl
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Inventor
Jared Bruce John Milbank
Thien Duc Tran
Florian Wakenhut
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Pfizer Ltd Great Britain
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Pfizer Ltd Great Britain
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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
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/20—Antivirals for DNA viruses
    • A61P31/22—Antivirals for DNA viruses for herpes viruses

Definitions

  • the present invention is directed to certain compounds and pharmaceutically acceptable salts thereof, and their use as inhibitors of the replication of hepatitis C virus (HCV).
  • HCV hepatitis C virus
  • the compounds of the present invention are useful for directly or indirectly inhibiting the activity of one or more HCV proteins and for treating diseases or conditions mediated by HCV such as, for example, hepatitis C.
  • HCV non-structural 5A
  • the compounds of the present invention inhibit HCV replication by direct or indirect inhibition of the non-structural 5A (NS5A) protein.
  • NS5A non-structural 5A
  • HCV inhibitors of HCV replication to treat hepatitis C.
  • HCV inhibitors which show activity against multiple HCV genotypes. Balanced activity against both genotype 1a and 1 b is particularly desirable.
  • HCV inhibitors which retain activity against viral strains which, as a result of mutation, have developed resistance to known HCV inhibitors.
  • a broad range of mutants have been described that result in reduced susceptibility to HCV inhibitors.
  • mutations at Y93 and L31 in particular have been found to give rise to resistance. Resistance mutations associated with HCV inhibitor therapy (other than by NS3 protease or polymerase inhibition) are reviewed in more detail in Holler et al. Expert Opin. Drug Discov. 4(3), 293-314 (2009).
  • preferred compounds should exhibit potent inhibition of the NS5A protein, whilst showing little affinity for other receptors, and show functional activity as inhibitors of HCV replication. They should be well absorbed from the gastrointestinal tract, be metabolically stable and possess favourable pharmacokinetic properties. They should be non-toxic and demonstrate few side-effects. In particular, good cardiovascular, liver and cell based safety profiles are important features of preferred compounds. Furthermore, the ideal drug candidate will exist in a physical form that is stable, non-hygroscopic and easily formulated.
  • the present invention provides compound of formula (I)
  • At each occurrence X * independently represents CR or N, at each occurrence X 1 independently represents C (in which case it is bonded to the imidazole ring), CR or N, and at each occurrence X 2 independently represents C (in which case it is bonded to the Y containing ring), CR or N, provided that the total number of N atoms in the 6-membered ring may not exceed 2 and provided that the total number of R substituents, other than H, on the 6-membered ring may not exceed 2;
  • Y* independently represents CR or N
  • at each occurrence Y independently represents C (in which case it is bonded to the X 2 containing ring), CR or N
  • at each occurrence Y 2 independently represents C (in which case it is bonded to the 9-membered bicyclic ring), CR or N, provided that the total number of N atoms in the 6-membered ring may not exceed 2 and provided that the total number of R substituents, other than H, on the 6-membered ring may not exceed 2;
  • each occurrence Z* independently represents CH or N, and at each occurrence Z independently represents C (in which case it is bonded to the 6-membered Y 2 containing ring), CH or N, provided that the total number of N atoms in this 9-membered bicyclic ring does not exceed 3;
  • R independently represents H, OH, C-i_ 4 alkoxy, CN, NH 2 or C-M alkylsulfonyl; each R is independently selected from H, C-i_ 4 alkyl, halogen, C-M alkoxyalkyl, C 3 . 6 cycloalkyl, phenyl, a 5- or 6-membered monocyclic heteroaryl, and a 4-, 5- or 6-membered monocyclic saturated heterocyclyl;
  • phenyl being optionally substituted with up to 2 halogen atoms
  • C 1- alkyl being optionally substituted with a group selected from OH, C 1- alkoxy, C 1- alkoxybenzyl, C 3 . 6 cycloalkyl, C 1- alkylsulfonyl, -NR a R , -CONR a R , phenyl, pyridinyl and indolyl;
  • R a and R being each independently selected from H , C-i_ 4 alkyl, C-i_ 4 alkoxyalkyl, Ci_4 alkylcarbonyl, and C-i_ 4 alkoxycarbonyl;
  • each R 2 is independently selected from H, C-i_ 4 alkyl, halogen, and C-i_ 4 alkoxyalkyl;
  • Ci_4 alkyl being optionally substituted by OH or NR°R d ;
  • R° and R d being each independently selected from H, C-i_ 4 alkyl, C-i_ 4 alkoxyalkyl, Ci_4 alkylcarbonyl, and C-i_ 4 alkoxycarbonyl; or
  • R and R 2 together with the C atom to which they are attached , form a 4-, 5- or 6-membered saturated ring optionally containing 1 or 2 heteroatoms selected from O, S and NR e ;
  • R e being selected from H, C-i_ 4 alkyl, C-i_ 4 alkylcarbonyl, C-i_ 4 alkoxycarbonyl and C-i_ 4 alkylsulfonyl;
  • each R 3 is independently selected from C 1-4 alkyl, C 1- alkoxy, C 1- alkoxyalkyl, NH 2 , NHiC ⁇ alkyl), N(Ci_4 alkyl) 2 and Ar;
  • Ci_4 alkyl being optionally substituted with Ar or NR f R 9 ;
  • R f and R 9 being each independently selected from H, C-i_ 4 alkyl, C-i_ 4 alkoxyalkyl, Ci_4 alkylcarbonyl, and C-i_ 4 alkoxycarbonyl;
  • each Ar being independently selected from isoxazolyl, pyrazinyl, dihydrobenzimidazolyl, indazolyl, and tetrahydroquinolinyl, optionally substituted with C-i_ 4 alkyl or a carbonyl group.
  • the present invention provides a compound of formula (la)
  • X * , Y * , Z, Z * , R , R 2 and R 3 are as defined above.
  • the present invention provides a compound of formula (lb)
  • X * , Y * , Z * , R , R 2 and R 3 are as defined above.
  • the present invention provides a compound of formula (Ic)
  • the present invention provides a compound of formula (I) selected from:
  • R , R 2 and R 3 are as defined above.
  • the present invention provides a compound of formula (I) selected from:
  • R 2 and R 3 are as defined above. More particularly preferred is the embodiment wherein:
  • R is H
  • each R 2 is independently selected from H, C-i_ 4 alkyl, halogen, and C-i_ 4 alkoxyalkyl;
  • Ci_4 alkyl being optionally substituted by NR°R ; said R° and R d being each independently selected from H, C-i_ 4 alkyl, C-i_ 4 alkoxyalkyl, C 1- alkylcarbonyl, and C 1- alkoxycarbonyl; and
  • each R 3 is independently C 1- alkoxy.
  • the present invention provides a compound of formula (I) selected from:
  • R , R 2 and R 3 are as defined above. More particularly preferred is the embodiment wherein:
  • R is H
  • each R 2 is independently selected from H, C-i_ 4 alkyl, halogen, and C-i_ 4 alkoxyalkyl;
  • Ci_4 alkyl being optionally substituted by NR°R d ;
  • R° and R d being each independently selected from H, C-i_ 4 alkyl, C-i_ 4 alkoxyalkyl,
  • Ci_4 alkylcarbonyl, and C-i_ 4 alkoxycarbonyl are Ci_4 alkylcarbonyl, and C-i_ 4 alkoxycarbonyl
  • each R 3 is independently C-i_ 4 alkoxy.
  • all references to a compound of formula (I) include compounds of formulae (I), (la), and
  • the present invention provides:
  • each occurrence X * independently represents CH or N
  • at each occurrence X 1 independently represents C (in which case it is bonded to the imidazole ring), CH or N
  • at each occurrence X 2 independently represents C (in which case it is bonded to the Y containing ring), CH or N, provided that the total number of N atoms in the 6-membered ring may not exceed 2;
  • each occurrence Y * independently represents CH or N
  • at each occurrence Y independently represents C (in which case it is bonded to the X 2 containing ring), CH or N
  • at each occurrence Y 2 independently represents C (in which case it is bonded to the 9-membered bicyclic ring), CH or N, provided that the total number of N atoms in the 6-membered ring may not exceed 2;
  • the present invention provides a compound of formula (I) selected from:
  • the present invention provides the following compounds: methyl ⁇ (2S)-1 -[(2S)-2- ⁇ 5-[6-(4- ⁇ 2-[(2S)-1- ⁇ (2S)-2-[(methoxycarbonyl)amino]-3-methylbutanoyl ⁇ pyrrolidin-2-yl] 1 H-imidazol-5-yl ⁇ phenyl)pyridazin-3-yl]-1 H-benzimidazol-2-yl ⁇ pyrrolidin-1-yl]-3-methyl-1 -oxobutan-2- yljcarbamate;
  • 'C-i_ 4 alkyl' means a monovalent unsubstituted saturated straight-chain or branched-chain hydrocarbon radical having from 1 to 4 carbon atoms.
  • 'Ci -2 alkyl' and 'Ci -3 alkyl' have analogous meanings.
  • 'C 3 _ 6 cycloalkyl' means an unsubstituted saturated monocyclic hydrocarbon radical having from 3 to 6 carbon atoms.
  • '0 ⁇ 4 alkoxy' means -0-C-i_ 4 alkyl (C-i_ 4 alkyl being as defined above).
  • 'C-i_ 4 alkylsulfonyl' means -(S0 2 )-C 1 . 4 alkyl (C-M alkyl being as defined above).
  • 'C-i_ 4 alkoxyalkyl means C-i_ 3 alkyl-O-C ⁇ alkyl (C-i_ 3 alkyl being as defined above), provided that the total number of C atoms does not exceed 4.
  • 'C-i_ 4 alkoxybenzyl' means PhCH 2 0-C 1 ⁇ ( alkyl.
  • 'Halogen' means a fluorine, chlorine, bromine or iodine atom.
  • '5- or 6-membered monocyclic heteroaryl' means a monocyclic aromatic group with a total of 5 atoms in the ring wherein from 1 to 4 of those atoms are each independently selected from N, O and S; or a monocyclic aromatic group with a total of 6 atoms in the ring wherein from 1 to 3 of those atoms are N.
  • 5-membered monocyclic heteroaromatic groups have from 1 to 3 atoms in the ring which are each independently selected from N, O and S.
  • 5-membered monocyclic heteroaromatic groups include pyrrolyl (also called azolyl), furanyl, thienyl (also called thiophenyl), pyrazolyl (also called 1 H-pyrazolyl and 1 ,2- diazolyl), imidazolyl, oxazolyl (also called 1 ,3-oxazolyl), isoxazolyl (also called 1 ,2-oxazolyl), thiazolyl (also called 1 ,3-thiazolyl), isothiazolyl (also called 1 ,2-thiazolyl), triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, oxatriazolyl and thiatriazolyl.
  • 6-membered monocyclic heteroaromatic groups include pyridiny
  • '4-, 5- or 6-membered monocyclic saturated heterocyclyl' means a saturated monocyclic group with a total of 4 atoms in the ring wherein from 1 to 2 of those atoms are each independently selected from N, O and S, a saturated monocyclic group with a total of 5 atoms in the ring wherein from 1 to 2 of those atoms are each independently selected from N, O and S, or a saturated monocyclic group with a total of 6 atoms in the ring wherein from 1 to 2 of those atoms are each independently selected from N, O and S.
  • 5-membered saturated heterocyclyl groups include tetrahydrofuranyl, pyrrolidinyl, tetrahydrothiophenyl, pyrazolidinyl, imidazolidinyl, dioxolanyl, thiazolidinyl, and isoxazolidinyl.
  • 6-membered saturated heterocyclyl groups include tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, thiomorpholinyl, and thioxanyl.
  • 'Pharmaceutically acceptable salts' of the compounds of formula (I) include the acid addition and base salts thereof.
  • Suitable acid addition salts may be formed from acids which form non-toxic salts. Examples may include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide,
  • hydroiodide/iodide isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2- napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen
  • Suitable base salts may be formed from bases which form non-toxic salts. Examples may include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts.
  • Hemisalts of acids and bases may also be formed, for example, hemisulphate and hemicalcium salts.
  • compositions of formula (I) may be prepared by one or more of three methods:
  • the resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent.
  • the degree of ionisation in the resulting salt may vary from completely ionised to almost non-ionised.
  • the compounds of the invention may exist in a continuum of solid states ranging from fully amorphous to fully crystalline.
  • the term 'amorphous' refers to a state in which the material lacks long range order at the molecular level and, depending upon temperature, may exhibit the physical properties of a solid or a liquid. Typically such materials do not give distinctive X-ray diffraction patterns and, while exhibiting the properties of a solid, are more formally described as a liquid.
  • a change from solid to liquid properties occurs which is characterised by a change of state, typically second order ('glass transition').
  • 'crystalline' refers to a solid phase in which the material has a regular ordered internal structure at the molecular level and gives a distinctive X-ray diffraction pattern with defined peaks. Such materials when heated sufficiently will also exhibit the properties of a liquid, but the change from solid to liquid is
  • phase change characterised by a phase change, typically first order ('melting point').
  • the compounds of the invention may exist in both unsolvated and solvated forms and the definition of said compounds is intended to encompass solvates thereof.
  • the term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol.
  • the term 'hydrate' is employed when said solvent is water.
  • a currently accepted classification system for organic hydrates is one that defines isolated site, channel, or metal-ion coordinated hydrates - see "Polymorphism in Pharmaceutical Solids" by K. R. Morris (Ed. H. G. Brittain, Marcel Dekker, 1995).
  • Isolated site hydrates are ones in which the water molecules are isolated from direct contact with each other by intervening organic molecules.
  • channel hydrates the water molecules lie in lattice channels where they are next to other water molecules.
  • metal- ion coordinated hydrates the water molecules are bonded to the metal ion.
  • the complex When the solvent or water is tightly bound, the complex will have a well-defined stoichiometry independent of humidity.
  • the solvent or water is weakly bound, as in channel solvates and hygroscopic compounds, the water/solvent content will be dependent on humidity and drying conditions. In such cases, non-stoichiometry will be the norm.
  • multi-component complexes other than salts and solvates
  • complexes of this type include clathrates (drug-host inclusion complexes) and co- crystals.
  • the latter are typically defined as crystalline complexes of neutral molecular constituents which are bound together through non-covalent interactions, but could also be a complex of a neutral molecule with a salt.
  • Co-crystals may be prepared by melt crystallisation, by recrystallisation from solvents, or by physically grinding the components together - see Chem Commun, 17, 1889-1896, by O. Almarsson and M. J.
  • the compounds of the invention may also exist in a mesomorphic state (mesophase or liquid crystal) when subjected to suitable conditions.
  • the mesomorphic state is intermediate between the true crystalline state and the true liquid state (either melt or solution).
  • Mesomorphism arising as the result of a change in temperature is described as 'thermotropic' and that resulting from the addition of a second component, such as water or another solvent, is described as 'lyotropic'.
  • references to a compound of formula (I) include references to salts, solvates, polymorphs, crystal habits, multi-component complexes and liquid crystals thereof.
  • Compounds of formula (I) contain at least two asymmetric carbon atoms (on the pyrrolidine rings) and can therefore exist as two or more stereoisomers.
  • Compounds of formula (I) also contain aromatic moieties, such as the imidazole rings, wherein tautomeric isomerism ('tautomerism') can occur. This can take the form of proton tautomerism (for example in the imidazole rings) as well as valence tautomerism (for example in the other aromatic moieties). It follows that a single compound may exhibit more than one type of isomerism.
  • enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC).
  • HPLC high pressure liquid chromatography
  • the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • a suitable optically active compound for example, an alcohol, or, in the case where the compound of formula (I) contains an acidic or basic moiety, an acid or base such as tartaric acid or 1 -phenylethylamine.
  • the resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s)
  • enantiomerically-enriched form using chromatography, typically HPLC, on a resin with an asymmetric stationary phase and with a mobile phase consisting of a hydrocarbon, typically heptane or hexane, containing from 0 to 50% isopropanol, typically from 2 to 20%, and from 0 to 5% of an alkylamine, typically 0.1 % diethylamine. Concentration of the eluant affords the enriched mixture. Mixtures of stereoisomers may be separated by conventional techniques known to those skilled in the art. See, for example, "Stereochemistry of Organic Compounds" by E L Eliel (Wiley, New York, 1994).
  • compounds of the present invention may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about a single bond may permit separation of different conformers. Certain conformers which are preferred for biological activity may also be selected for through intramolecular hydrogen bonding. Included within the scope of the claimed compounds of the present invention are all conformers of the compounds of formula (I), including compounds exhibiting more than one type of conformation, and mixtures of one or more thereof.
  • the compounds of the invention also includes all pharmaceutically acceptable isotopically-labelled compounds of formula (I) wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number which predominates in nature.
  • isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as H and H; carbon, such as C, C and C; chlorine, such as CI; fluorine, such as F; iodine, such as 23 l and 25 l; nitrogen, such as 3 N and 5 N; oxygen, such as 5 0, 7 0 and 8 0; and sulphur,
  • isotopically-labelled compounds of formula (I), for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies.
  • the radioactive isotopes tritium, i.e. 3 H, and carbon-14, i.e. 4 C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.
  • substitution with heavier isotopes such as deuterium, i.e. 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.
  • Isotopically-labelled compounds of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying
  • the compounds of formula (I) are comprised of atoms such that the average atomic mass or mass number for each atom of each element present corresponds to the average atomic mass or mass number for that element as it occurs in nature. In other words, such compounds are not isotopically enriched at any atomic position.
  • solvates in accordance with the invention include those wherein the solvent of crystallization may be isotopically substituted, e.g. D 2 0, d 6 -acetone, and d 6 -DMSO.
  • the present invention also encompasses any one or more of these processes for preparing the compounds of formula (I) or derivatives as herein defined, in addition to any novel intermediates used therein.
  • the acid (1 ) can be converted to the acid chloride (2) using a suitable chlorinating agent, such as oxalyl chloride or thionyl chloride, in a suitable solvent, such as dichloromethane or toluene, optionally in the presence of catalytic DMF, at a suitable temperature, typically of between 0 °C and room temperature.
  • a suitable chlorinating agent such as oxalyl chloride or thionyl chloride
  • a suitable solvent such as dichloromethane or toluene
  • catalytic DMF catalytic DMF
  • the acid (1 ) can be converted to a suitable activated species with a coupling agent, such as EDCI.HCI, EDCI.Mel, HBTU, HATU, PyBop, DCC, or CDI, in a suitable solvent, such as dichloromethane, acetonitrile or DMF.
  • a suitable solvent such as dichloromethane, acetonitrile or DMF.
  • HOBT is optionally added.
  • a suitable base such as triethylamine or diisopropylethylamine, is also used and the reaction is typically carried out at room temperature.
  • Amine (4) may be formed from protected amine (5), wherein one or more of the N moieties are protected by a suitable protecting group (PG).
  • PG protecting group
  • Suitable protecting groups for the pyrrolidine N moiety include, for example, t-butyloxycarbonyl (t-BOC).
  • Suitable protecting groups for the imidazole N moiety include, for example, (trimethylsilyl)ethoxymethyl (SEM). Deprotection is carried out using known literature methods such as reaction with an acid (e.g. hydrochloric acid or trifluoracetic acid), in a suitable solvent, such as methanol, ethanol or 1 ,4-dioxane, at a temperature typically of between room temperature and reflux.
  • M MgX',ZnX',SnR 3 ,B(OR) 2
  • R H,alkyl
  • X' CI,Br,l
  • R H,alkyl
  • X' CI,Br,l
  • a suitable palladium catalyst is tris(dibenzylideneacetone)dipalladium, bis (dibenzylideneacetone) palladium, palladium acetate or (1 ,1 '-bis(diphenylphosphino) ferrocene) dichloropalladium.
  • a suitable phosphine base is tncyclohexylphosphine or 2-dicyclohexylphosphino-2',6'-dimethoxylbiphenyl.
  • a suitable base is potassium carbonate, potassium phosphate or sodium hydrogen carbonate and solvents are DME, 1 ,4-dioxane or THF/water.
  • a suitable catalyst such as tetrakis(triphenylphosphine)palladium
  • an optional copper (I) source such as copper (I) chloride
  • a suitable base such as cesium fluoride
  • a suitable solvent such as ⁇ , ⁇ -dimethylformamide
  • Suitable palladium catalysts are tris(dibenzylideneacetone)dipalladium, bis(dibenzylidene acetone)palladium, palladium acetate or (1 ,1 '-bis(diphenylphosphino) ferrocene) dichloropalladium.
  • Suitable phosphine bases are tricyclohexylphosphine or 2-dicyclohexylphosphino-2',6'-dimethoxylbiphenyl.
  • a suitable copper (I) source is copper (I) chloride.
  • Suitable bases are potassium carbonate or sodium hydrogen carbonate.
  • Suitable solvents are DME, 1 ,4-dioxane or THF/water.
  • R H,alkyl
  • X' CI,Br,l
  • a suitable palladium catalyst such as (1 ,1 - bis(diphenylphosphino)ferrocen
  • Aryl-LGi i.e. LG ⁇ OS0 2 CF 3 or Cl/Br/I
  • R H,alkyl
  • X' CI,Br,l
  • Organometallated derivative (9) may be formed from derivative (1 1 ) (when
  • organometallic reagent such as butyllithium or isopropylmagnesium chloride (optionally used as the lithium chloride complex)
  • a suitable solvent such as THF or diethylether
  • the resulting species can be further converted into an organoboronate by reaction with a trialkyl borate (such as trimethylborate) followed by hydrolysis with water or dilute base/acid.
  • a suitable boron source such as bis(pinacolato)diboron or 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
  • a suitable palladium catalyst such as palladium acetate or (1 ,1 '-bis(diphenylphosphino)ferrocen
  • it may also be made by palladium cross coupling of a suitable organo stannane source, such as hexamethylditin, using a suitable palladium catalyst, such as tetrakis(triphenylphosphine)palladium, in a suitable solvent, such as 1 ,4-dioxane or toluene, at a temperature of typically around 80 °C to 120 °C.
  • a suitable organo stannane source such as hexamethylditin
  • a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium
  • solvent such as 1 ,4-dioxane or toluene
  • conversion of amide derivative (16) to derivative (1 1 ) can be carried out using phosphorus oxychloride at a temperature of typically around 120 °C.
  • Amide derivative (16) is prepared from aniline (14) and carboxylic acid (15) using suitable coupling conditions as detailed above in Scheme 1.
  • derivative of general formula (1 1 ) can be synthesised directly from aniline (14) and aldehyde (17) in a suitable acidic solvent, such as acetic acid, or in a solvent, such as acetonitrile, methanol or ethanol, in the presence of an acid catalyst, such as acetic acid or p-toluenesulfonic acid, at a suitable temperature of typically between room temperature and reflux and in the presence of a suitable oxidant, such as 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone (DDQ), iron (III) chloride or manganese dioxide.
  • a suitable acidic solvent such as acetic acid
  • a solvent such as acetonitrile, methanol or ethanol
  • an acid catalyst such as acetic acid or p-toluenesulfonic acid
  • DDQ 2,3-dichloro-5,6-dicyano-1 ,4-benzoquinone
  • Aniline (14) can be prepared by reduction of the corresponding nitro derivative (13) under hydrogen at a pressure of typically between 50psi and 100psi, in the presence of a catalyst, such as Raney Nickel, and a solvent, such as methanol or ethanol.
  • a catalyst such as Raney Nickel
  • a solvent such as methanol or ethanol.
  • aniline derivative (14) is prepared by reaction with a reductive agent, such as sodium dithionite (Na 2 S 2 0 4 ), in a mixture of water and an organic solvent, such as dichloromethane, methanol or ethanol.
  • a reductive agent such as sodium dithionite (Na 2 S 2 0 4 )
  • an organic solvent such as dichloromethane, methanol or ethanol.
  • a phase transfer catalyst may also be added.
  • Metallated imidazole (21 ) is formed from haloimidazole derivative (20) using a suitable organometallic reagent, such as butyllithium or isopropylmagnesium chloride (optionally used as the lithium chloride complex), in a suitable solvent, such as THF or diethyl ether, at a temperature of between -78 °C and room temperature.
  • a suitable organometallic reagent such as butyllithium or isopropylmagnesium chloride (optionally used as the lithium chloride complex)
  • a suitable solvent such as THF or diethyl ether
  • Haloimidazole (20) is formed from derivative (19) using a source of halogen, such as bromine, N- bromosuccinimide, iodine or N-iodosuccinimide, in a suitable solvent, such as dichloromethane or acetonitrile at a temperature of typically between 0 °C and reflux.
  • a source of halogen such as bromine, N- bromosuccinimide, iodine or N-iodosuccinimide
  • a suitable solvent such as dichloromethane or acetonitrile at a temperature of typically between 0 °C and reflux.
  • the imidazole (19) is protected, preferentially with a SEM group, using standard literature methods, such as reaction with a suitable base (e.g. sodium hydride), in a solvent, such as NMP or DMF, followed by addition of 2-(triethylsilyl)ethoxymethyl chloride at a temperature of typically between 0 °C and room temperature.
  • a suitable base e.g. sodium hydride
  • a solvent such as NMP or DMF
  • Formation of imidazole (18) from derivative (17) is carried out with glyoxal and ammonium hydroxide in a suitable solvent, such as methanol, at a temperature of typically between 0 °C and room temperature (the pyrrolidine nitrogen is preferably protected as a Boc or CBZ derivative).
  • a suitable solvent such as methanol
  • R H,alkyl
  • X' CI,Br,l
  • a suitable organometallic reagent such as butyllithium or isopropylmagnesium chloride (optionally used as the lithium chloride complex)
  • a suitable solvent such as THF or diethylether
  • a suitable boron source such as bis(pinacolato)diboron or 4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane
  • a suitable palladium catalyst such as palladium acetate or (1 ,1 - bis(diphenylphosphino)ferrocen
  • derivative (6b) may also be made by a palladium coupling of derivative (24) with a suitable stannane source, such as hexamethylditin, using a suitable palladium catalyst, such as tetrakis(triphenylphosphine)palladium, in a suitable solvent, such as 1 ,4-dioxane or toluene, at a temperature of typically around 80 °C to 120 °C.
  • stannane source such as hexamethylditin
  • a suitable palladium catalyst such as tetrakis(triphenylphosphine)palladium
  • solvent such as 1 ,4-dioxane or toluene
  • Formation of imidazole derivative (24) from ester (23) is carried out using a suitable ammonia source, typically ammonium acetate, in a solvent, such as toluene, tnfluorotoluene or xylene, at a temperature of typically around 100 °C to 150 °C.
  • a suitable ammonia source typically ammonium acetate
  • a solvent such as toluene, tnfluorotoluene or xylene
  • Ester (23) may be prepared using bromoketone (22) and protected carboxylic acid (15) with a suitable base, such as triethylamine or diisopropylethylamine, in a suitable solvent, such as dichloromethane, acetonitrile or methyl-THF, at a temperature of typically between 0 °C and room temperature (the pyrrolidine protecting group is preferably BOC or CBZ).
  • a suitable base such as triethylamine or diisopropylethylamine
  • a suitable solvent such as dichloromethane, acetonitrile or methyl-THF
  • the reaction is typically carried out using a suitable palladium catalyst, such as palladium acetate, a suitable phosphine base, such as tricyclohexylphosphine (typically used as the tetrafluoroborate salt), an acid source, such as 2,2- dimethylpropionic acid (pivalic acid), and a suitable base, such as potassium carbonate, in the presence of a suitable solvent, such as A/,A/-dimethylacetamide or A/,A/-dimethylformamide, at a temperature of typically around 140 °C.
  • a suitable solvent such as A/,A/-dimethylacetamide or A/,A/-dimethylformamide
  • the reaction can be carried out using a suitable palladium catalyst, such as palladium acetate, palladium bis(triphenylphosphine)dichloride, tetrakis(triphenylphosphine)palladium, or (1 ,1 '-bis(diphenylphosphino)ferrocene)dichloropalladium, and a suitable base, such as sodium carbonate, sodium hydrogen carbonate, potassium acetate or potassium phosphate, in a suitable solvent, such as 1 ,4-dioxane or DME, at a temperature of typically around 80 °C to 120 °C.
  • a suitable palladium catalyst such as palladium acetate, palladium bis(triphenylphosphine)d
  • ketone (27) can typically be carried out via formation of an enol ether (26) followed by hydrolysis under acidic conditions.
  • Formation of the enol ether (26) is typically carried out using tributyl(1-ethoxy)vinyltin and a palladium catalyst, such as palladium bis(triphenylphosphine)dichloride or tetrakis(triphenylphosphine)palladium, in a suitable solvent such as DMF, 1 ,4-dioxane or acetonitrile, at a temperature of typically between 80 °C and 120 °C.
  • a palladium catalyst such as palladium bis(triphenylphosphine)dichloride or tetrakis(triphenylphosphine)palladium
  • bromination of (27) may also be carried out using standard literature methods, such as using bromine in acetic acid, with either hydrochloric or hydrobromic acid present.
  • the reaction is typically carried out at room temperature.
  • the reaction can be carried out with tetrabutylammonium tribromide, in a suitable solvent, such as acetonitrile or methanol, at a temperature of typically between room temperature and 70 °C.
  • the reaction can also be carried out using copper (II) bromide in a suitable solvent, such as 1 ,4-dioxane, typically at reflux.
  • the reaction can be carried out using a suitable palladium catalyst, a suitable base, in a suitable solvent such as 1 ,4-dioxane or DME at a temperature of typically around 80 °C to 120 °C.
  • Suitable palladium catalysts are palladium acetate, palladium bis(triphenylphosphine)dichloride, tetrakis(triphenylphosphine)palladium, or (1 ,1 '-bis(diphenylphosphino)ferrocene)dichloropalladium
  • Suitable bases are sodium carbonate, sodium hydrogen carbonate, potassium acetate or potassium phosphate.
  • the compound of formula ( ⁇ ) may be prepared from amine (29), according to Scheme 11 , using suitable coupling conditions such as those described in Scheme 1.
  • Amine (29) may be formed from protected amine (30), according to Scheme 12, using known literature methods such as reaction with an acid (e.g. hydrochloric acid or trifluoracetic acid), in a suitable solvent, such as methanol, ethanol or 1 ,4-dioxane, at a temperature typically of between room temperature and reflux.
  • an acid e.g. hydrochloric acid or trifluoracetic acid
  • a suitable solvent such as methanol, ethanol or 1 ,4-dioxane
  • a suitable palladium catalyst such as (1 ,1 '-bis(diphenylphosphino)fer
  • Aryl-LG ! i.e. LG ⁇ OS0 2 CF 3 or Cl/Br/I
  • LG 2 OS0 2 CF 3 or Cl/Br/I
  • M MgX',ZnX',SnR 3 ,B(OR) 2
  • LG 2 OS0 2 CF 3 ,CI,Br or I
  • R H,alkyl
  • X' CI,Br,l
  • protected amine (30) may be formed by a palladium catalysed coupling between a metallated imidazole (31 ) and derivative (7).
  • a suitable palladium catalyst is tris(dibenzylideneacetone)dipalladium, bis (dibenzylideneacetone) palladium, palladium acetate or (1 ,1 '-bis(diphenylphosphino) ferrocene) dichloropalladium.
  • a suitable phosphine base is tricyclohexylphosphine or 2-dicyclohexylphosphino-2',6'-dimethoxylbiphenyl.
  • a suitable base is potassium carbonate, potassium phosphate or sodium hydrogen carbonate and solvents are DME, 1 ,4-dioxane or THF/water.
  • R H,alkyl
  • X' CI,Br,l
  • LG 2 OS0 2 CF 3 ,CI,Br or I
  • Organometallated derivative (31 ) may be formed from derivative (33) by palladium coupling with a suitable boron source, such as bis(pinacolato)diboron or 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, using a suitable palladium catalyst, such as palladium acetate or (1 ,1 '-bis(diphenylphosphino) ferrocene)dichloropalladium, and a suitable base, such as sodium carbonate, sodium hydrogen carbonate, potassium acetate or potassium phosphate, in a suitable solvent, such as 1 ,4-dioxane or DME, at a temperature of typically around 80 °C to 120 °C.
  • a suitable boron source such as bis(pinacolato)diboron or 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
  • a suitable palladium catalyst such as palladium acetate or (1 ,1 '-bis
  • Amide derivative (33) may be formed using standard literature conditions.
  • the acid (1 ) can be converted to the acid chloride (2) using a suitable chlorinating agent, such as oxalyl chloride or thionyl chloride, in a suitable solvent, such as dichloromethane or toluene, optionally in the presence of catalytic DMF, at a suitable temperature, typically of between 0 °C and room temperature.
  • a suitable chlorinating agent such as oxalyl chloride or thionyl chloride
  • a suitable solvent such as dichloromethane or toluene
  • catalytic DMF catalytic DMF
  • the acid (1 ) can be converted to a suitable activated species with a coupling agent, such as EDCI.HCI, EDCI.Mel, HBTU, HATU, PyBop, DCC, or CDI, in a suitable solvent, such as dichloromethane, acetonitrile or DMF.
  • a suitable solvent such as dichloromethane, acetonitrile or DMF.
  • HOBT is optionally added.
  • a suitable base such as triethylamine or diisopropylethylamine, is also used and the reaction is typically carried out at room temperature.
  • Amine (32) may be formed from protected amine (24) using known literature methods such as reaction with an acid (e.g. hydrochloric acid or trifluoracetic acid), in a suitable solvent, such as methanol, ethanol or 1 ,4-dioxane, at a temperature typically of between room temperature and reflux.
  • an acid e.g. hydrochloric acid or trifluoracetic acid
  • a suitable solvent such as methanol, ethanol or 1 ,4-dioxane
  • the compound of formula ( ⁇ ) may be prepared from amine (34), according to Scheme 16, using suitable coupling conditions such as those described in Scheme 1.
  • Amine (34) may be formed from protected amine (35), according to Scheme 17, using known literature methods such as reaction with an acid (e.g. hydrochloric acid or trifluoracetic acid), in a suitable solvent, such as methanol, ethanol or 1 ,4-dioxane, at a temperature typically of between room temperature and reflux.
  • an acid e.g. hydrochloric acid or trifluoracetic acid
  • a suitable solvent such as methanol, ethanol or 1 ,4-dioxane
  • R H,alkyl
  • X' CI,Br,l
  • LG 2 OS0 2 CF 3 ,CI,Br or I
  • Protected amine (35) may be formed by a palladium catalysed coupling between a metallated imidazole (6b) and derivative (36).
  • a suitable palladium catalyst is tris(dibenzylideneacetone)dipalladium, bis (dibenzylideneacetone) palladium, palladium acetate or (1 ,1 '-bis(diphenylphosphino) ferrocene) dichloropalladium.
  • a suitable phosphine base is tricyclohexylphosphine or 2-dicyclohexylphosphino-2',6'-dimethoxylbiphenyl.
  • a suitable base is potassium carbonate, potassium phosphate or sodium hydrogen carbonate and solvents are DME, 1 ,4-dioxane or THF/water.
  • R H,alkyl
  • X' CI,Br,l
  • LG LG 2 OS0 2 CF 3 ,CI,Br or I
  • Suitable palladium catalysts are tris(dibenzylideneacetone)dipalladium, bis(dibenzylidene acetone)palladium, palladium acetate or (1 ,1 '-bis(diphenylphosphino) ferrocene) dichloropalladium.
  • Suitable phosphine bases are tricyclohexylphosphine or 2-dicyclohexylphosphino-2',6'-dimethoxylbiphenyl.
  • Suitable bases are potassium carbonate or sodium hydrogen carbonate.
  • Suitable solvents are DME, 1 ,4-dioxane or THF/water.
  • LG 2 OS0 2 CF 3 ,CI,Br or I
  • a suitable palladium catalyst such as (1 ,1 - bis(diphenylphosphino)ferrocene
  • R H,alkyl
  • X' CI,Br,l
  • LG 2 OS0 2 CF 3 ,CI,Br or I
  • Organometallated derivative (37) may be formed from derivative (39) by palladium coupling with a suitable boron source, such as bis(pinacolato)diboron or 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, using a suitable palladium catalyst, such as palladium acetate or (1 ,1 '-bis(diphenylphosphino) ferrocene)dichloropalladium, and a suitable base, such as sodium carbonate, sodium hydrogen carbonate, potassium acetate or potassium phosphate, in a suitable solvent, such as 1 ,4-dioxane or DME, at a temperature of typically around 80 °C to 120 °C.
  • a suitable boron source such as bis(pinacolato)diboron or 4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane
  • a suitable palladium catalyst such as palladium acetate or (1 ,1 '-bis(dip
  • Amide derivative (39) may be formed using standard literature conditions.
  • the acid (1 ) can be converted to the acid chloride (2) using a suitable chlorinating agent, such as oxalyl chloride or thionyl chloride, in a suitable solvent, such as dichloromethane or toluene, optionally in the presence of catalytic DMF, at a suitable temperature, typically of between 0 °C and room temperature.
  • a suitable chlorinating agent such as oxalyl chloride or thionyl chloride
  • a suitable solvent such as dichloromethane or toluene
  • catalytic DMF catalytic DMF
  • the acid (1 ) can be converted to a suitable activated species with a coupling agent, such as EDCI.HCI, EDCI.Mel, HBTU, HATU, PyBop, DCC, or CDI, in a suitable solvent, such as dichloromethane, acetonitrile or DMF.
  • a suitable solvent such as dichloromethane, acetonitrile or DMF.
  • HOBT is optionally added.
  • a suitable base such as triethylamine or diisopropylethylamine, is also used and the reaction is typically carried out at room temperature.
  • Amine (38) may be formed from protected amine (11 ) using known literature methods such as reaction with an acid (e.g. hydrochloric acid or trifluoracetic acid), in a suitable solvent, such as methanol, ethanol or 1 ,4-dioxane, at a temperature typically of between room temperature and reflux.
  • an acid e.g. hydrochloric acid or trifluoracetic acid
  • a suitable solvent such as methanol, ethanol or 1 ,4-dioxane
  • the protected amine (5) may be prepared in such a way that the two pyrrolidine ring N atoms are differentially protected with two orthogonal protecting groups, PG1 and PG2.
  • Suitable protecting groups include, but are not limited to, t-butyloxycarbonyl (t-BOC), allyloxycarbonyl (alloc) and benzyloxycarbonyl (Cbz).
  • the t-BOC protecting group may be selectively removed using a suitable reagent described in the literature for this purpose such as a strong acid (e.g. hydrochloric acid or trifluoroacetic acid) in a suitable solvent, such as methanol, ethanol or 1 ,4-dioxane, at a temperature typically of between room temperature and reflux, to give the amine (5-1 ).
  • a strong acid e.g. hydrochloric acid or trifluoroacetic acid
  • a suitable solvent such as methanol, ethanol or 1 ,4-dioxane
  • the acid (5-2) can be converted to a suitable activated species with a coupling agent, such as EDCI.HCI, EDCI.Mel, HBTU, HATU, PyBop, DCC, or CDI, in a suitable solvent, such as dichloromethane, acetonitrile or DMF.
  • a suitable solvent such as dichloromethane, acetonitrile or DMF.
  • HOBT is optionally added.
  • a suitable base such as triethylamine or diisopropylethylamine, is also used and the reaction is typically carried out at room temperature to give the amide derivative (5-3).
  • the t- BOC protecting group may then be removed using standard methodology to give the amine (5-4), and then reacted with a suitable reagent for the formation of the methyl carbamate (5-5), for example methyl chloroformate.
  • a suitable reagent for the formation of the methyl carbamate (5-5), for example methyl chloroformate for example methyl chloroformate.
  • a range of amino acid methyl esters (5-6) may be they commercially available or prepared using methods described in the literature, may be converted into the corresponding methyl carbamate (5-7) using a suitable reagent, for example methyl chloroformate.
  • Ester hydrolysis carried out according to standard methods, for example by using a strong base such as lithium or sodium hydroxide, may then provide the corresponding acid (5-8). This can then be coupled directly to the amine (5-1 ) using the methods indicated above.
  • the second protecting group may then be removed.
  • the Cbz group may be removed using a suitable reagent described in the literature for this purpose such as hydrogen gas in the presence of a heterogeneous palladium or platinum catalyst, which would provide a derivative that is entirely analogous to intermediate (29) described in Scheme 1 1. This could then be treated in exactly the same ways described above to provide compounds of the general formula ( ⁇ ).
  • compounds of general formula (5-1 ) or (29) can be reacted with an acid of general formula (5-2) and the reaction mixture extracted with a suitable solvent, for example ethyl acetate or t-butyl methyl ether.
  • a suitable solvent for example ethyl acetate or t-butyl methyl ether.
  • the extract may then be dried over a suitable reagent, for example sodium or magnesium sulfate, and the solvent evaporated.
  • the crude material may then be dissolved in a suitable solvent, for example methanol or 1 ,4-dioxane, and treated with a strong acid such as hydrochloric acid or trifluoroacetic acid.
  • the mixture may be evaporated under reduced pressure and then immediately treated with a mixture of methyl chloroformate in a suitable solvent such as dichloromethane or dichloroethane and a suitable base such as triethylamine or A/-methyl morpholine.
  • a suitable solvent such as dichloromethane or dichloroethane
  • a suitable base such as triethylamine or A/-methyl morpholine.
  • the mixture may then be finally concentrated under reduced pressure and purified by preparative HPLC to provide compounds of the formula (5-6) or ( ⁇ ).
  • the amine (5-6) may be converted into the acid (5-8) in a telescoped procedure, before reaction with the amine (5-1 ) according to the standard methods described above to provide derivatives (5-6) or (l').
  • Cyclic cores of derivatives of generic formula (8),(10),(13), (22) and (25) can be prepared by one skilled in the art and carried out according to literature methods detailed in suitable reference books such as Heterocyclic Chemistry, J. A. Joule and K. Mills, 4 th edition, Wiley-Blackwell (2000) or Heterocyclic Chemistry, T.L. Gilchrist, 3 rd edition, Prentice-Hall, 1997.
  • the present invention provides a pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
  • a pharmaceutical composition including a compound of formula (I) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient.
  • excipient is used herein to describe any ingredient other than the compound of the invention. The choice of excipient will to a large extent depend on factors such as the particular mode of administration, the effect of the excipient on solubility and stability, and the nature of the dosage form.
  • compositions suitable for the delivery of compounds of the present invention and methods for their preparation will be readily apparent to those skilled in the art. Such compositions and methods for their preparation may be found, for example, in "Remington's Pharmaceutical Sciences", 19th Edition (Mack Publishing Company, 1995).
  • the compounds of the invention may be administered orally.
  • Oral administration may involve swallowing, so that the compound enters the gastrointestinal tract, or buccal or sublingual administration may be employed by which the compound enters the blood stream directly from the mouth.
  • Formulations suitable for oral administration include both solid and liquid formulations.
  • Solid formulations include tablets, capsules (containing particulates, liquids, or powders), lozenges (including liquid-filled lozenges), chews, multi- and nano-particulates, gels, solid solutions, liposomal preparations, films, ovules, and sprays.
  • Liquid formulations include suspensions, solutions, syrups and elixirs. Such formulations may be employed as fillers in soft or hard capsules and typically comprise a carrier, for example, water, ethanol, polyethylene glycol, propylene glycol, methylcellulose, or a suitable oil, and one or more emulsifying agents and/or suspending agents. Liquid formulations may also be prepared by the reconstitution of a solid, for example, from a sachet.
  • the compounds of the invention may also be used in fast-dissolving, fast-disintegrating dosage forms such as those described in Expert Opinion in Therapeutic Patents, 11 (6), 981-986, by Liang and Chen (2001 ).
  • the drug may make up from 1 weight % to 80 weight % of the dosage form, more typically from 5 weight % to 60 weight % of the dosage form.
  • tablets In addition to the drug, tablets generally contain a disintegrant.
  • disintegrants include sodium starch glycolate, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, croscarmellose sodium, crospovidone, polyvinylpyrrolidone, methyl cellulose, microcrystalline cellulose, lower alkyl- substituted hydroxypropyl cellulose, starch, pregelatinised starch and sodium alginate.
  • the disintegrant will comprise from 1 weight % to 25 weight %, preferably from 5 weight % to 20 weight % of the dosage form.
  • Binders are generally used to impart cohesive qualities to a tablet formulation. Suitable binders include microcrystalline cellulose, gelatin, sugars, polyethylene glycol, natural and synthetic gums, polyvinylpyrrolidone, pregelatinised starch, hydroxypropyl cellulose and hydroxypropyl methylcellulose.
  • Tablets may also contain diluents, such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • diluents such as lactose (monohydrate, spray-dried monohydrate, anhydrous and the like), mannitol, xylitol, dextrose, sucrose, sorbitol, microcrystalline cellulose, starch and dibasic calcium phosphate dihydrate.
  • Tablets may also optionally comprise surface active agents, such as sodium lauryl sulfate and polysorbate 80, and glidants such as silicon dioxide and talc.
  • surface active agents such as sodium lauryl sulfate and polysorbate 80
  • glidants such as silicon dioxide and talc.
  • surface active agents may comprise from 0.2 weight % to 5 weight % of the tablet, and glidants may comprise from 0.2 weight % to 1 weight % of the tablet.
  • Tablets also generally contain lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • lubricants such as magnesium stearate, calcium stearate, zinc stearate, sodium stearyl fumarate, and mixtures of magnesium stearate with sodium lauryl sulphate.
  • Lubricants generally comprise from 0.25 weight % to 10 weight %, preferably from 0.5 weight % to 3 weight % of the tablet.
  • ingredients include anti-oxidants, colourants, flavouring agents, preservatives and taste-masking agents.
  • Exemplary tablets contain up to about 80% drug, from about 10 weight % to about 90 weight % binder, from about 0 weight % to about 85 weight % diluent, from about 2 weight % to about 10 weight % disintegrant, and from about 0.25 weight % to about 10 weight % lubricant.
  • Tablet blends may be compressed directly or by roller to form tablets. Tablet blends or portions of blends may alternatively be wet-, dry-, or melt-granulated, melt congealed, or extruded before tabletting.
  • the final formulation may comprise one or more layers and may be coated or uncoated; it may even be encapsulated.
  • Consumable oral films are typically pliable water-soluble or water-swellable thin film dosage forms which may be rapidly dissolving or mucoadhesive and typically comprise a compound of formula (I), a film- forming polymer, a binder, a solvent, a humectant, a plasticiser, a stabiliser or emulsifier, a viscosity- modifying agent and a solvent. Some components of the formulation may perform more than one function.
  • the film-forming polymer may be selected from natural polysaccharides, proteins, or synthetic hydrocolloids and is typically present in the range 0.01 to 99 weight %, more typically in the range 30 to 80 weight %.
  • Films in accordance with the invention are typically prepared by evaporative drying of thin aqueous films coated onto a peelable backing support or paper. This may be done in a drying oven or tunnel, typically a combined coater dryer, or by freeze-drying or vacuuming.
  • Solid formulations for oral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • Suitable modified release formulations for the purposes of the invention are described in US Patent No. 6,106,864. Details of other suitable release technologies such as high energy dispersions and osmotic and coated particles are to be found in "Pharmaceutical Technology On-line", 25(2), 1-14, by Verma ef al (2001 ). The use of chewing gum to achieve controlled release is described in WO 00/35298.
  • the compounds of the invention may also be administered directly into the blood stream, into muscle, or into an internal organ.
  • Suitable means for parenteral administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular and subcutaneous.
  • Suitable devices for parenteral administration include needle (including microneedle) injectors, needle-free injectors and infusion techniques.
  • Parenteral formulations are typically aqueous solutions which may contain excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9), but, for some applications, they may be more suitably formulated as a sterile non-aqueous solution or as a dried form to be used in conjunction with a suitable vehicle such as sterile, pyrogen-free water.
  • excipients such as salts, carbohydrates and buffering agents (preferably to a pH of from 3 to 9)
  • a suitable vehicle such as sterile, pyrogen-free water.
  • parenteral formulations under sterile conditions may readily be accomplished using standard pharmaceutical techniques well known to those skilled in the art.
  • solubility of the compound of formula (I) used in the preparation of parenteral solutions may be increased by the use of appropriate formulation techniques, such as the incorporation of solubility-enhancing agents.
  • Formulations for parenteral administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compound of the invention may be formulated as a solid , semi-solid , or thixotropic liquid for administration as an implanted depot providing modified release of the active compound .
  • examples of such formulations include drug-coated stents and poly(d/-lactic-coglycolic)acid (PGLA) microspheres.
  • the compounds of the invention may also be administered topically to the skin or mucosa, that is, dermally or transdermally.
  • Typical formulations for this purpose include gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings, foams, films, skin patches, wafers, implants, sponges, fibres, bandages and microemulsions. Liposomes may also be used .
  • Typical carriers include alcohol, water, mineral oil, liquid petrolatum, white petrolatum, glycerin, polyethylene glycol and propylene glycol. Penetration enhancers may be incorporated - see, for example, J Pharm Sci, 88 (10), 955-958, by Finnin and Morgan (October 1999).
  • topical administration include delivery by electroporation, iontophoresis,
  • phonophoresis e.g. PowderjectTM, BiojectTM, etc.
  • microneedle or needle-free injection e.g. PowderjectTM, BiojectTM, etc.
  • Formulations for topical administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be administered rectally or vaginally, for example, in the form of a suppository, pessary, or enema.
  • Cocoa butter is a traditional suppository base, but various alternatives may be used as appropriate.
  • Formulations for rectal/vaginal administration may be formulated to be immediate and/or modified release.
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the compounds of the invention may be combined with soluble macromolecular entities, such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers, in order to improve their solubility, dissolution rate, taste-masking, bioavailability and/or stability for use in any of the aforementioned modes of administration.
  • soluble macromolecular entities such as cyclodextrin and suitable derivatives thereof or polyethylene glycol-containing polymers
  • Drug-cyclodextrin complexes are found to be generally useful for most dosage forms and administration routes. Both inclusion and non-inclusion complexes may be used.
  • the cyclodextrin may be used as an auxiliary additive, i.e. as a carrier, diluent, or solubiliser. Most commonly used for these purposes are alpha-, beta- and gamma-cyclodextrins, examples of which may be found in International Patent Applications Nos. WO 91/11172, WO 94/02518 and WO 98/55148.
  • the compounds of the invention may have the advantage that they are more potent, have a longer duration of action, have a broader range of activity, are more stable, have fewer side effects or are more selective, or have other more useful properties than the compounds in the art.
  • the compounds of formula (I) are potent inhibitors of HCV replication.
  • the compounds of formula (I) are potent inhibitors of HCV replication which show activity against multiple HCV genotypes. More preferably, the compounds of formula (I) are potent inhibitors of HCV replication which show balanced activity against both genotype 1a and 1 b.
  • the present invention provides a compound of formula (I) or a
  • a specific embodiment of this aspect of the invention is a compound of formula (I) or a
  • Another specific embodiment of this aspect of the invention is a compound of formula (I) or a pharmaceutically acceptable salt thereof, for use in the treatment of HCV infection.
  • the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament to treat a disease for which an inhibitor of HCV replication is indicated.
  • a specific embodiment of this aspect of the invention is the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of HCV infection.
  • the present invention provides a method of treatment of a mammal, including a human being, to treat a disease for which an inhibitor of HCV replication is indicated, including administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • a specific embodiment of this aspect of the invention is a method of treatment of a mammal, including a human being, to treat HCV infection, including administering to said mammal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.
  • treatment includes both preventative and curative treatment of a disease or disorder. It also includes slowing, interrupting, controlling or stopping the progression of a disease or disorder. It also includes preventing, curing, slowing, interrupting, controlling or stopping the symptoms of a disease or disorder.
  • the compound of the present invention may be administered in combination with one or more additional agents for the treatment of a mammal, such as a human, that is suffering from an infection with the HCV virus, or any other disease or condition which is related to infection with the HCV virus.
  • the agents that may be used in combination with the compounds of the present invention include, but are not limited to, cyclophilin inhibitors (such as NIM-811 , Debio-025 and SCY-635), immunomodulators (such as Zadaxin, Ceplene, Cellcept, Civacir and Zadazim), TLR9 agonists (such as Actilon), antisense agents (such as ISIS14803), NS4A inhibitors (such as ACH-806), NS5A inhibitors (such as A831 , BMS-790052 and A689), inosine monophosphate dehydrogenase inhibitors (such as Levovirin, Miremepodib, Viramidine and
  • Ribavirin inhibitors of HCV entry (such as XTL-6865), NS3 serine protease inhibitors (such as Telapravir, Bocepravir, TMC-435350, MK-7009, BI-201335, ABT-450, ITMN-191 and BILN-2061 ; and also compounds described in Reiser and Timm, Expert Rev. Anti Infect. Ther.
  • TLR7 agonists such as N-(4-(4-amino-2-ethyl-1 H-imidazo[4,5-c]quinolin-1-yl)butyl)methanesulfonamide, ANA-971 and ANA-773
  • NS5B RNA-polymerase inhibitors such as Filibuvir, HCV-796, Valopicitabine, GL-59728, GL-60667, PSI- 6130, R1626, R7128, JTK-003 GL-59728 and GS-9190; and also compounds described in Beaulieu, Expert Opin. Ther.
  • the compound of the present invention may be administered in combination with one or more additional agents selected from NS3 serine protease inhibitors (such as
  • NS5B RNA-polymerase inhibitors such as Filibuvir, HCV-796, Valopicitabine, GL-59728, GL-60667, PSI-6130, R1626, R7128, JTK-003 GL-59728 and GS-9190
  • Compounds of the present invention can also be combined with inhibitors of the hepatitis C structural proteins such as nucleocapsid or core proteins.
  • Compounds of the present invention can also be combined with an interferon, or an interferon derivative (such as Albuferon, Alb Interferon, BLX-883 (locteron), Infergen A, Omega IFN, IFN beta, Rebif, Roferon A, Intron A, Rebetron, Actimmune, Multiferon, Wellferon, Omniferon, Pegasys, Pegasys+Ribavirin, and Pegintron+Ribavirin).
  • an interferon or an interferon derivative (such as Albuferon, Alb Interferon, BLX-883 (locteron), Infergen A, Omega IFN, IFN beta, Rebif, Roferon A, Intron A, Rebetron, Actimmune, Multiferon, Wellferon, Omniferon, Pegasys, Pegasys+Ri
  • Such a combination may be administered such that the compound of the present invention is present in the same pharmaceutical composition as the additional agent(s) described above.
  • such a combination may be administered such that the compound of the present invention is present in a pharmaceutical composition that is separate from the pharmaceutical composition in which the additional agent(s) is(are) found. If the compound of the present invention is administered separately from the additional agent(s), such administration may take place concomitantly or sequentially with an appropriate period of time in between.
  • the compound of the present invention may be administered in combination with one or more additional agents that have the effect of increasing the exposure of the mammal to the compound of the invention.
  • 'exposure' refers to the concentration of the compound of the invention in the plasma of a mammal as measured over a period of time.
  • the exposure of a mammal to a particular compound can be measured by administering the compound of the invention to a mammal in an appropriate form, withdrawing plasma samples at predetermined times, and measuring the amount of a compound of the invention in the plasma using an appropriate analytical technique, such as liquid chromatography or liquid chromatography/mass spectroscopy.
  • the amount of the compound of the invention present in the plasma at a certain time is determined and the concentration and time data from all the samples are plotted to afford a curve.
  • the area under this curve is calculated and affords the exposure of the mammal to the compound.
  • the terms 'exposure', 'area under the curve', and 'area under the concentration/time curve' are intended to have the same meaning and may be used interchangeably.
  • agents that may be used to increase the exposure of a mammal to a compound of the present invention are those that can act as inhibitors of at least one isoform of the cytochrome P450 (CYP450) enzymes.
  • the isoforms of CYP450 that may be beneficially inhibited include, but are not limited to, CYP1A2, CYP2D6, CYP2C9, CYP2C19 and CYP3A4.
  • Suitable agents that may be used to inhibit CYP3A4 include, but are not limited to, ritonavir, delavirdine, N-(3,4-difluorobenzyl)-2- ⁇ [(4-methoxypyridin-3- yl)amino]sulfonyl ⁇ -N-methylbenzamide, and N-(1-(5-(4-fluorobenzyl)-3-(pyridin-4-yl)-1 H-pyrazole-1- carbonyl)piperidin-4-yl)methanesulfonamide.
  • Such a combination may be administered such that the compound of the present invention is present in the same formulation as the additional agent(s) described above.
  • such a combination may be administered such that the compound of the present invention is present in a pharmaceutical composition that is separate from the pharmaceutical composition in which the additional agent(s) is(are) found. If the compound of the present invention is administered separately from the additional agent(s), such
  • administration may take place concomitantly or sequentially with an appropriate period of time in between.
  • the kit of the invention comprises two or more separate pharmaceutical compositions, at least one of which contains a compound of formula (I) in accordance with the invention, and means for separately retaining said compositions, such as a container, divided bottle, or divided foil packet.
  • a container, divided bottle, or divided foil packet An example of such a kit is the familiar blister pack used for the packaging of tablets, capsules and the like.
  • the kit of the invention is particularly suitable for administering different dosage forms, for example, oral and parenteral, for administering the separate compositions at different dosage intervals, or for titrating the separate compositions against one another.
  • the kit typically comprises directions for administration and may be provided with a so-called memory aid.
  • the invention provides:
  • kits comprising two or more pharmaceutical compositions, at least one of which comprises a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable excipient, and means for separately retaining said compositions;
  • Example 1 Methyl ⁇ (2S)-1 -[(2S)-2- ⁇ 5-[6-(4- ⁇ 2-[(2S)-1- ⁇ (2S)-2-[(methoxycarbonyl)amino]-3- methylbutanoyl ⁇ pyrrolidin-2-yl]-1H-imidazol-5-yl ⁇ phenyl)pyridazin-3-yl]-1 H-benzimidazol-2- yl ⁇ pyrrolidin-1-yl -3-methyl-1 -oxobutan-2-yl ⁇ carbamate
  • A/-(Methoxycarbonyl)-L-valine obtained from Preparation 58 (131 mg, 0.746 mmol), HOBT (1 19 mg, 0.778 mmol) and EDCI.HCI (143 mg, 0.746 mmol) in acetonitrile (5 ml_) were stirred at room temperature for 40 minutes.
  • Example 2 Methyl ⁇ (2S)-1 -[(2S)-2- ⁇ 5-[5-(4- ⁇ 2-[(2S)-1- ⁇ (2S)-2-[(methoxycarbonyl)amino]-3- methylbutanoyl ⁇ pyrrolidin-2-yl]-1H-imidazol-5-yl ⁇ phenyl)pyrazin-2-yl]-1 H-benzimidazo
  • A/-(Methoxycarbonyl)-L-valine obtained from Preparation 58 (47 mg, 0.271 mmol), HOBT (43 mg, 0.283 mmol) and EDCI.HCI (52 mg, 0.271 mmol) in acetonitrile (8 mL) were stirred at room temperature for 40 minutes.
  • A/-(Methoxycarbonyl)-L-valine obtained from Preparation 58 (143 mg, 0.816 mmol), HOBT (130 mg, 0.85 mmol) and EDCI.HCI (156 mg, 0.816 mmol) in acetonitrile (20 ml_) were stirred at room temperature for 40 minutes.
  • A/-(Methoxycarbonyl)-L-valine obtained from Preparation 58 (46 mg, 0.266 mmol), HOBT (42 mg, 0.2775 mmol) and EDCI.HCI (51 mg, 0.266 mmol) in acetonitrile (8 ml_) were stirred at room temperature for 40 minutes.
  • EDCI.HCI (3.82 g, 19.92 mmol) was added in one portion. Once a clear solution was obtained, the reaction mixture was stirred at 0 °C for 40 minutes.
  • the reaction mixture was concentrated under reduced pressure, and then the residue was diluted with dichloromethane (150 mL) and sodium bicarbonate (sat. aq.) (100 mL). The mixture was thoroughly mixed for 30 minutes. The two phases were separated and the organic layer was washed with water (100 mL). The layers were separated and the organic layer was concentrated under reduced pressure to an orange foam.
  • the crude product was purified by flash chromatography (heptane:acetone, 40:60 to
  • Example 7 Methyl ⁇ (2S)-1 -[(2S)-2- ⁇ 4-[4-(5- ⁇ 2-[(2S)-1- ⁇ (2S)-2- [(methoxycarbonyl)amino]butanoyl ⁇ pyrrolidin-2-yl]-1 H-benzimidazol-6-yl ⁇ pyrazin-2-yl)phenyl]-1 H- imidazol-2-yl ⁇ pyrrolidin-1 -yl]-3-methyl-1 -oxobutan-2-yl ⁇ carbamate
  • Example 8 Methyl [(2S)-1 - ⁇ (2S)-2-[5-(5- ⁇ 2-[(2S)-1 - ⁇ (2S)-2-[(methoxycarbonyl)amino]-3- methylbutanoyl ⁇ pyrrolidin-2-yl]-1H-imidazol-5-yl ⁇ -2,3'-bipyridin-6'-yl)-1H-benzimidazol-2
  • A/-(Methoxycarbonyl)-L-valine obtained from Preparation 58 (147 mg, 0.84 mmol), HOBT (134 mg, 0.875 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (161 mg, 0.84 mmol) in acetonitrile (5 mL) were stirred at room temperature for 20 minutes.
  • Example 10 Methyl ⁇ (2S)-1-[(2S)-2- ⁇ 4-[5-(4- ⁇ 2-[(2S)-1 - ⁇ (2S)-2-[(methoxycarbonyl)amino]-3- methylbutanoyl ⁇ pyrrolidin-2-yl]-1H-benzimidazol-5-yl ⁇ phenyl)pyrimidin-2-yl]-1 H-imidazol-2- yl ⁇ pyrrolidin-1-yl -3-methyl-1 -oxobutan-2-yl ⁇ carbamate
  • A/-(Methoxycarbonyl)-L-valine obtained from Preparation 58 (40 mg, 230 ⁇ ), HOBT (37 mg, 240 ⁇ ) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 230 ⁇ ) in acetonitrile (5 ml_) were stirred at room temperature for 20 minutes.
  • the solid was further purified by preparative HPLC (30:70 acetonitrile/ water with ammonium hydrogen carbonate buffer pH 10 over 20 minutes) to a white solid that was loaded on a SCX column (20.0 g), eluting with 7N ammonia in methanol (2 x 20 mL). The elute was concentrated under reduced pressure to give the title compound as an off white solid (90 mg).
  • A/-(Methoxycarbonyl)-L-threonine obtained from Preparation 70 (94 mg, 0.53 mmol), HOBT (169 mg, 1.10 mmol) and 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (101 mg, 0.53 mmol) in acetonitrile (15 mL) were stirred at room temperature for 20 minutes.
  • Example 14 Methyl ⁇ (2S,3R)-3-hydroxy-1-[(2S)-2- ⁇ 4-[4-(5- ⁇ 2-[(2S)-1- ⁇ (2S)-2-[(methoxycarbonyl)amino]- 3-methylbutanoyl ⁇ pyrrolidin-2-yl]-1H-benzimidazol-5-yl ⁇ pyrazin-2-yl)phenyl]-1H-imidazol-2- y I ⁇ pyrrol idi n-1 -yl -1 -oxobutan-2-yl ⁇ carbamate
  • Example 15 Methyl ⁇ (2S)-1-[(2S)-2- ⁇ 5-[4-(5- ⁇ 2-[(2S)-1 - ⁇ (2S)-3-methoxy-2-
  • A/-(Methoxycarbonyl)-0-methyl-L-serine obtained from Preparation 77 (103 mg, 0.583 mmol), HOBT (93 mg, 0.607 mmol), EDCI.HCI (112 mg, 0.583 mmol) and DIPEA (0.508 mL, 2.916 mmol) were stirred in acetonitrile (5 mL) at room temperature for 30 minutes.
  • Example 16 Methyl ⁇ (2S)-3-methoxy-1-[(2S)-2-(5- ⁇ 4-[5-(2- ⁇ (2S)-1-[N-(methoxycarbonyl)-0-methyl-L- seryl]pyrrolidin-2-yl ⁇ -1 H-benzimidazol-6-yl)pyrazin-2-yl]phenyl ⁇ -1 H-imidazol-2-yl)pyrrolidin-1 -yl]-1 - oxopropan-2-yl ⁇ carbamate
  • reaction mixture was then cooled to 0°C and triethylamine (2.0 equivalents) was added dropwise followed by stirring at 0°C for 10 minutes. It was then allowed to warm up to room temperature and stirred at this temperature for 1 hour. 7M Ammonia in methanol (1 ml_) was then added to the reaction mixture and it was stirred at room temperature for a further 16 hours. The resulting mixture was concentrated under reduced pressure and the residue was purified by preparative HPLC to give the pure final compound.
  • imidazol-2-yl ⁇ pyrrolidin-1 -yl]butan-2-yl ⁇ carbamate obtained from Preparation 86, in DMSO (0.7 equivalents of 0.1 M), triethylamine (0.7 equivalents) and HATU (1 .0 equivalents). The reaction mixture was then stirred at 50°C for 16 hours. After this time, it was evaporated under reduced pressure and the residue was purified by preparative HPLC to give pure final compound.
  • 2,4'-dibromoacetophenone (23.7 g, 85.4 mmol) was added to a stirred solution of 1-(ieri-butoxycarbonyl)-L- proline (17.5 g, 81.3 mmol) in dichloromethane (175 mL) at 0 °C.
  • DIPEA (15.6 mL, 89.4 mmol) was added dropwise to the mixture and the resulting yellow solution was allowed to warm to room temperature and stirred for a further 2.5 hours. After this time, the mixture was washed successively with water (200 ml_), sodium bicarbonate solution (sat.)(100 ml_), water (200 ml_) and brine (200 ml_). The organic layer was dried over MgS0 4 and the solvent was evaporated under reduced pressure to give the title compound as a viscous yellow oil (33.6 g).
  • 2,4'-dibromoacetophenone (13.09 Kg, 47.1 mol) was added to a stirring solution of 1-(ieri-butoxycarbonyl)-L- proline (9.67 Kg, 44.9 mol) in dichloromethane (48 L) at 5°C.
  • DIPEA (6.38 Kg, 49.4 mol) was added dropwise to the mixture and the resulting yellow solution was allowed to warm to room temperature and stirred for a further 2.5 hours.
  • the mixture was washed with water (25 L), saturated sodium bicarbonate solution (25 L), water (25 L) and brine (25 L).
  • the organic phase was dried (Na 2 S0 4 ) and evaporated under reduced pressure to give a viscous yellow oil (18.51 Kg).
  • the reaction was purged again with nitrogen before heating at reflux for 2 hours. After this time, the resulting suspension was cooled to room temperature and the reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The pH of the aqueous layer was adjusted to around 8 by addition of a 2N aqueous sodium hydroxide solution and the phases were then separated. The aqueous layer was extracted again with ethyl acetate (100 mL). The combined organic extracts were dried over MgS0 4 and the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography (heptane : ethyl acetate, 50:50 to 40:60) to give the desired compound as a white foam.
  • the organic layer was washed sequentially with 2M aqueous potassium carbonate (1000 mL), 1 M aqueous hydrochloric acid (1000 mL), 0.5M aqueous hydrochloric acid (1000 mL), 2M aqueous potassium carbonate (1000 mL) and water (1000 mL).
  • the solvent was evaporated under reduced pressure to give the title compound as a brown solid (340 g).
  • reaction mixture was cooled to room temperature, diluted with ethyl acetate (30 ml_) and washed with water. The aqueous layer was extracted again with ethyl acetate. The combined organic extracts were dried over MgS0 4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (dichloromethane : methanol, 95:5) to give the title compound as a yellow solid (295 mg).
  • the reaction mixture was heated at 120 °C for 16 hours. After this time, the resulting mixture was cooled to room temperature, diluted with ethyl acetate (15 mL) and washed with water. The aqueous layer was extracted again with ethyl acetate. The combined organic extracts were dried over Na 2 S0 4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (dichloromethane : methanol, 95:5) to give the title compound as a yellow solid (148 mg).
  • the reaction mixture was heated at 60 °C for 16 hours. After this time, the resulting mixture was cooled to room temperature, diluted with ethyl acetate (30 ml_) and washed with water. The aqueous layer was extracted again with ethyl acetate. The combined organic extracts were dried over MgS0 4 and the solvent was evaporated under reduced pressure. The crude product obtained was purified by flash chromatography (ethyl acetate : dichloromethane, 1 : 1 ) to give the title compound as a yellow solid (385 mg).
  • the reaction mixture was heated at 120 °C for 16 hours. After this time, the resulting mixture was cooled to room temperature and diluted with ethyl acetate (15 ml_). It was washed with sodium bicarbonate (sat. aq.), then brine. The organic layer was dried over Na 2 S0 4 and the solvent was evaporated under reduced pressure. The crude product obtained was purified by flash chromatography (acetone : dichloromethane, 1 :1 ) to give the title compound as a yellow solid (103 mg).
  • the reaction mixture was heated at 120 °C for 16 hours. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (15 mL). It was washed with sodium bicarbonate (sat. aq.), then brine. The organic extracts were dried over Na 2 S0 4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (dichloromethane:methanol, 98:2 to 90:10), followed by trituration with hexane and diethyl ether to give the title compound as a yellow solid (230 mg).
  • the reaction mixture was heated at 60 °C under argon for 16 hours. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (30 mL) and washed with water. The aqueous layer was extracted again with ethyl acetate. The combined ethyl acetate extracts were dried over MgS0 4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (ethyl acetate : dichloromethane, 1 :1 ) to give the title compound as a yellow solid
  • the reaction mixture was sparged with nitrogen and heated at 60 °C for 10 hours. After this time, the mixture was cooled to room temperature, diluted with ethyl acetate (400 ml_) and washed with saturated sodium bicarbonate (250 ml_). water. The aqueous layer was extracted again with ethyl acetate. The layers were separated and the organic phase was washed with brine (200ml). It was then dried over Na 2 S0 4 and evaporated under reduced pressure. The pale yellow residue was purified by flash chromatography (redisep 330g, silica preabsorption) eluting heptane:EtOAc (80:20 to 30:70) to give the title compound as a white solid (8.45 g).
  • the reaction mixture was heated at 120 °C for 16 hours. After this time, the resulting mixture was cooled to room temperature, diluted with ethyl acetate (15 ml_) and washed with sodium bicarbonate (sat. aq.), then brine. The ethyl acetate extracts were dried over Na 2 S0 4 and the solvent was evaporated under reduced pressure.
  • the crude product was purified by flash chromatography (dichloromethane : methanol, 98:2 to 90:10) to give the title compound as a yellow solid. A further purification by flash chromatography (dichloromethane : acetone, 60:40) gave the title compound as a pale yellow solid (75 mg).
  • the reaction mixture was purged with nitrogen and a solution of potassium phosphate (96 mg, 0.452 mmol) in water (356 ⁇ _) was added.
  • the resulting reaction mixture was heated at 110 °C for 16 hours. After this time, the suspension was cooled to room temperature and the solvent was evaporated under reduced pressure.
  • the crude product was purified by flash chromatography (ethyl acetate : methanol, 100:0 to 50:50) to give the title compound as a yellow solid (121 mg).
  • the vial was sealed and heated at 120 °C under microwave irradiation for 1 hour. After this time, the reaction mixture was diluted with dichloromethane (20 mL) and filtered through Arbocel ® . The filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography (heptane : ethyl acetate, 70:30 to 30:70) to give the title compound as a white solid (55 mg).
  • the resulting reaction mixture was degassed with nitrogen and stirred at 1 10 °C for 5 hours. After this time, the mixture was cooled to room temperature and diluted with ethyl acetate (50 mL). The resulting suspension was washed with ammonia (0.880 solution, 50 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (4 x 25 mL). The combined organic extracts were dried over Na 2 S0 4 and the solvent was evaporated under reduced pressure. The crude material was purified by flash chromatography (dichloromethane : methanol : ammonia, 98:2:0.3 to 95:5:0.3) to give the title compound as an orange solid (78 mg).
  • Trimethyl borate (1 .92 mL, 17.2 mmol) was added and the resulting mixture was allowed to warm up to room temperature and stirred for 16 hours. After this time, water (60 mL) was added, followed by sodium bicarbonate (sat. solution) (40 mL). The mixture was extracted with ethyl acetate (3 x 60 mL) and the combined organic fractions were washed with brine, dried over MgS0 4 and the solvent was removed under reduced pressure to give 3.4 g of the title compound as a yellow solid.
  • Trimethyl borate (1.19 mL, 10.6 mmol) was added and the resulting mixture was allowed to warm to room temperature and stirred for 16 hours. After this time, water (60 mL) was added, followed by sodium bicarbonate (sat. solution) (40 mL). The mixture was extracted with ethyl acetate (3 x 60mL) and the combined organic fractions were washed with brine, dried over MgS0 4 and the solvent was removed under reduced pressure to give 2.72 g of the title compound as a yellow solid.
  • the resulting mixture was heated at 60 °C for 23 hours. After this time, the reaction was cooled to room temperature and diluted with ethyl acetate (15 mL) and water (15 mL). The layers were separated and the organic phase was washed with sodium bicarbonate (sat. aq.), then brine. The ethyl acetate extracts were dried over MgS0 4 and the solvent was evaporated under reduced pressure. The crude product was purified by flash chromatography (dichloromethane : methanol, 98:2) to give the title compound as a cream foam (538 mg).

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Abstract

Cette invention concerne des composés de formule (I) et leurs sels pharmaceutiquement acceptables; des compositions les contenant; et l'utilisation desdits composés à titre d'inhibiteurs de réplication du VHC.
PCT/IB2011/052392 2010-06-10 2011-05-31 Inhibiteurs du virus de l'hépatite c Ceased WO2011154871A1 (fr)

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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
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US9775831B2 (en) 2013-07-17 2017-10-03 Bristol-Myers Squibb Company Combinations comprising biphenyl derivatives for use in the treatment of HCV
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