WO2013095275A1 - Nouveaux inhibiteurs du virus de l'hépatite c - Google Patents

Nouveaux inhibiteurs du virus de l'hépatite c Download PDF

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WO2013095275A1
WO2013095275A1 PCT/SE2012/051426 SE2012051426W WO2013095275A1 WO 2013095275 A1 WO2013095275 A1 WO 2013095275A1 SE 2012051426 W SE2012051426 W SE 2012051426W WO 2013095275 A1 WO2013095275 A1 WO 2013095275A1
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mmol
alkyl
gave
title compound
crc
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PCT/SE2012/051426
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Susana Ayesa
Oscar Belda
Catarina BJÖRKLUND
Magnus Nilsson
Francesco Russo
Christer Sahlberg
Daniel Wiktelius
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Medivir Ab
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/10—Spiro-condensed systems
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 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
    • C07D491/10—Spiro-condensed systems

Definitions

  • the present invention relates to novel derivatives which have antiviral properties.
  • the invention relates to compounds which are effective in inhibiting the replication of hepatitis virus (HCV), particularly functions of the non-structural 5A (NS5A) protein of HCV.
  • HCV hepatitis virus
  • NS5A non-structural 5A
  • the invent further relates to compositions comprising these compounds and the of these compounds in 1 treatment or prophylaxis of HCV.
  • HCV is a single stranded, positive-sense RNA virus belonging to the Flaviviridae family of viruses in the hepacivirus genus.
  • the genome is approximately 9500 nucleotides in length ar has an open reading frame (ORF) encoding a single polyprotein of about 3000 amino acids. I infected cells, this polyprotein is cleaved by a combination of cellular and viral proteases into individual structural and non-structural viral proteins (core, E1 , E2, p7, NS2, NS3, NS4A, NS ⁇ NS5A, NS5B).
  • the structural proteins E1 and E2 are embedded into a viral lipid envelope forming stable heterodimers and that the structural core protein interacts with t viral RNA genome to form the nucleocapsid.
  • the non-structural proteins, designated NS2 to NS5, include proteins with enzymatic functions involved in virus replication and protein processing.
  • the protein NS5A is a membrane anchored phosphoprotein that exists either in
  • hypophosphorylated (56 kDa) or hyperphosphorylated (58 kDa) form Although the function o NS5A has not yet been fully elucidated, no enzymatic function has been ascribed to the prote NS5A is implicated in multiple aspects of the viral lifecycle including viral replication and the assembly of infectious particles and it is reported to interact with numerous viral and cellular factors.
  • HCV genotype 1 is the predominant genotype in Europe and in th( US.
  • the extensive genetic heterogeneity of HCV has important diagnostic and clinical implications, perhaps explaining difficulties in vaccine development and the lack of response current therapy.
  • HCV therapies are based on (pegylated) interferon-alpha (IFN-a) in combination with ribavirin.
  • IFN-a interferon-alpha
  • This combination therapy yields a sustained virologic response in more than 40% of patients infected by genotype 1 viruses and about 80% of those infected by genotypes 2 and Beside the limited efficacy on HCV genotype 1 , this combination therapy has significant side effects and is poorly tolerated in many patients.
  • Major side effects include influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Hence there is a nee for more effective, convenient and better-tolerated treatments.
  • HCV inhibitors that may overcome the disadvantages of current HCV therapy such as side effects e.g. toxicity, limited efficacy, the emerging of resistance, and compliance failures, as well as improve the sustained viral response.
  • side effects e.g. toxicity, limited efficacy, the emerging of resistance, and compliance failures, as well as improve the sustained viral response.
  • compound which are effective to inhibit the function of the NS5A protein are desired.
  • the present invention provides new of HCV inhibiting compounds which have useful propertii regarding one or more of the following parameters: antiviral efficacy, favourable profile of resistance development, efficacy on emerging resistant mutants, lack of toxicity and genotoxicity, favourable pharmacokinetics and pharmacodynamics, and ease of formulation ⁇ administration.
  • Compounds of the invention may also be attractive due to the fact that they lack activity agair other viruses, in particular against HIV. HIV infected patients often suffer from co-infections si as HCV. Treatment of such patients with an HCV inhibitor that also inhibits HIV may lead to tl emergence of resistant HIV strains.
  • Rings A and A' are each independently an optionally substituted 5-membered aromatic heterocyclyl comprising 1 , 2, 3 or 4 heteroatoms independently selected from N, S and O;
  • R 1 is H, CrC 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylCrC 3 alkyl, C 3 -C 7 heterocyclyl, C 3 -
  • R 1 is H or C C 6 alkyl
  • R 2 is C C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 3 -C 6 cycloalkyl, C 3 -C 7 cycloalkylC C 3 alkyl, phenyl, heteroaryl;
  • R y is H, CrC 6 alkyl, CrC 6 alkylcarbonyl or phenyl, or Ry and R 3 together with the atoms to which they are attached form a C 3 -C 6 cycloalkyl or a 3 to 6 membered heterocyclyl;
  • R 3 is C C 6 alkyl, CrC 6 haloalkyl, CrC 6 hydroxyalkyl, d-C 6 alkoxy, Crdalkoxyd-dalkyl, hydroxy, halo or CrC 6 alkylcarbonyl; or two R 3 , together with the carbon atom(s) to which they are attached, form an optionally substituted 3 to 6 membered cycloalkyl, 3-6 membered heterocyclyl or phenyl; or two geminal R 3 , together with the carbon atom to which they are attached, form a keto group;
  • p 0, 1 , 2, 3 or 4;
  • r and r' are independently 0, 1 or 2;
  • R 12 is hydroxy, CrC 3 alkoxy, azido, cyano or fluoro; or two R 12 together with the carbon atom(s) to which they are attached, form an optionally substituted 3 to 7 membered cycloalkyl or a 3 to 7 membered heterocyclyl;
  • R x is H, C C 6 alkyl, phenyl, d-C 6 alkylcarbonyl or d-C 6 alkoxycarbonyl;
  • R 4 is at each time independently selected from H, d-C 6 alkyl, C C 6 alkoxy, halo, hydroxy, amino, d-C 6 alkylamino and did-C 6 alkylamino; or
  • R u is, each independently, H, C C 3 alkyl, halo, phenyl or heteroaryl;
  • R 5a and R 5b are independently selected from H, CrC 6 alkyl, CrC 6 alkoxy, halo, hydroxy, amino, d-C 6 alkylamino, did-C 6 alkylamino, phenyl, C 3 -C 6 cycloalkyl, and 4-6 membered heterocyclyl, or
  • R 6 is NR 7 R 7 , OR 8 , CR 9 R 9 NRaR 10 , wherein
  • R 7 is H, CrC 6 alkyl, Ci-C 3 alkoxycarbonylCi-C 6 alkyl, C 3 -C 6 cycloalkoxycarbonylCrC 6 alkyl,
  • R 7' is H or CrC 6 alkyl
  • R 7 and R 7 together with the nitrogen atom to which they are attached form a 5- or 6- membered optionally substituted heterocyclyl
  • R 8 is C C 6 alkyl or C 2 -C 6 alkyleneNRaR 11 ;
  • R 9 is H, C C 6 alkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 cycloalkylCi-C 3 alkyl;
  • R 9' is H, C C 6 alkyl, or
  • R 9 and R 9 together with the carbon atom to which they are attached form a 3, 4 or 5- membered ring;
  • R 10 is C C 3 alkoxycarbonyl, d-C 3 alkylaminocarbonyl, (d-C 3 alkyl) 2 aminocarbonyl, C 3 -
  • R 11 is C C 3 alkoxycarbonyl, d-C 3 alkylaminocarbonyl or (d-C 3 alkyl) 2 aminocarbonyl; Ra at each occurrence is independently H or CrC 3 alkyl;
  • q 0, 1 or 2;
  • n 0, 1 , 2 or 3;
  • n 0, 1 , 2 or 3;
  • each Ci-C 4 alkyl and CrC 6 alkyl on its own and in composite expressions such as d- C 6 alkylcarbonyl, CrC 6 alkylamino, etc. is optionally substituted with one or two or, where valence permits, up to three substituents independently selected from CrC 3 alkoxy; hydroxy and halo;
  • each C 3 -C 7 cycloalkyl is optionally substituted with one or two or, where valence permits, up to three substituents independently selected from CrC 3 alkyl, CrC 3 alkoxy, Ci-C 3 alkoxyCi-C 3 alkyl, hydroxy, halo, trifluoromethyl and trifluoromethoxy;
  • heterocyclyl is a saturated, partly unsaturated or aromatic ring comprising 1 , 2, 3 or 4 heteroatoms independently selected from N, O and S, which ring is optionally substituted with one, two or, where valence permits, up to three substituents independently selected from d- C 3 alkyl, C C 3 alkoxy, d-C 3 alkoxyd-C 3 alkyl, hydroxy, halo, trifluoromethyl and trifluoromethoxy; each phenyl is optionally substituted with one, two or three substituents independently selected from d-C 3 alkyl, C r C 3 alkoxy, d-Csalkoxyd-Csalkyl, halo, trifluoromethyl and trifluoromethoxy; heteroaryl is an aromatic heterocyclyl;
  • the invention concerns the use of compounds of formula I or any subgroup of formula I as specified herein for inhibiting HCV.
  • the invention provides the use of compounds of formula I or any subgroup thereof as specified herein, for the treatment or prophylaxis of HCV infection in a host.
  • the invention provides the use of compounds of formula I or any subgroup thereof as specified herein, for the treatment of HCV.
  • the invention further relates to a method for manufacturing compounds of formula I or any subgroup of formula I.
  • the invention provides pharmaceutical compositions, comprising an anti- virally effective amount of a compound of formula I or any subgroup thereof as specified herein.
  • One embodiment of the invention provides compounds of formula I wherein Q is a group of the formula:
  • Y is CH 2 , O and NR y wherein R y is CrC 6 alkyl or CrC 6 alkylcarbonyl,
  • R 3 is CrC 6 alkyl, CrC 6 haloalkyl, CrC 6 hydroxyalkyl, C C 6 alkoxy, hydroxy or halo;
  • p 0, 1 , 2 or 3;
  • r and r' are independently 0, 1 or 2.
  • Y is O
  • r and r' are both 1
  • p is 1
  • R 3 is d-C 6 alkyl, such as ethyl or isopropyl.
  • a typical configuration of Q according to this embodiment is represented by the formula:
  • r and r' are both 1 , thus providing compounds of formula I comprising the group: wherein Y, R 3 and p are as defined above.
  • p is 0, 1 or 2. i.e. the ring is unsubstituted or substituted with one or two substituents.
  • R 3 is CrC 3 alkyl, such as methyl.
  • Y in this group include CH 2 , O and NR y , thus forming an optionally substituted piperidinyl, morpholinyl or piperazinyl group.
  • the piperidine, morpholine or piperazine moiety is unsubstituted or substituted with two or preferably one substituent.
  • substituents are CrC 3 alkyl, such as methyl, ethyl and isopropyl, and C C 3 alkyl substituted with fluoro, methoxy or ethoxy, e.g.
  • a typical configuration for Q is morpholine-4-carbonyl which is unsubstituted or substituted with one CrC 3 alkyl, such as methyl, or CrC 3 alkyl, such as methyl or ethyl which is substituted with fluoro, methoxy or ethoxy.
  • a further typical configuration for Q is morpholine-4-carbonyl which is substituted with haloalkyl, such as fluoroalkyl, especially fluoroethyl.
  • a further typical configuration for Q is morpholine-4-carbonyl which is or substituted with Ci-C 4 alkoxyCrC 3 alkyl, such as methoxyCi-C 3 alkyl, especially methoxymethyl.
  • R 1 is H or CrC 6 alkyl
  • Typical structures for Q according to this embodiment are illustrated in the partial structures ia, ib, ic and id:
  • R 2 is H, C r C 6 alkyl, such as isopropyl, 1-propyl or 2- butyl.
  • R 2 include C 3 -C 6 cycloalkyl for example cyclopentyl and cyclohexyl, and C 3 -C 6 cycloalkylCrC 3 alkyl such as cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl, wherein in each case, the cycloalkyl moiety is optionally substituted as defined above.
  • substituents include CrC 3 alkyl such as methyl and ethyl, halo such as one or two fluoro, CrC 3 alkoxy such as methoxy and ethoxy, and Ci-C 3 alkoxyCi-C 3 alkyl such as methoxymethyl, methoxyethyl, ethoxyethyl.
  • a further alternative configuration for R 2 is phenyl.
  • each C C 6 alkyl is independently optionally substituted.
  • R 2 as C C 6 alkyl the C C 6 alkyl moiety is typically unsubstituted or substitute once with methoxy or F.
  • R 1 and R 1 are both optionally substituted CrC 6 alkyl.
  • one of R 1 and R 1 is unsubstituted CrC 6 alkyl and the other is CrC 6 alkyl which is substituted with C C 3 alkoxy such as methoxy, or with halo such as one, two or three fluoro.
  • R 1 is H
  • R 1 is heterocyclyl or CrC 3 alkylheterocyclyl wherein the heterocyclyl moiety is optionally substituted.
  • R 1 according to this embodiment include methylheterocyclyl.
  • R 1 is heteroaryl or C C 3 alkylheteroaryl wherein the heteroaryl moiety is optionally substituted.
  • Q according to this embodiment include methylheteroaryl.
  • the invention provides compounds wherein one of ring A and A' is imidazolylene, oxazolylene or thiazolylene, and the other is as described above.
  • Representative compounds according to this embodiment are those wherein rings A and A' are independently imidazolylene, oxazolylene or thiazolylelene, which rings are linked via carbon atoms thus providing compounds of formula lla:
  • the invention provides compounds wherein one of ring A and A' is optionally substituted imidazolylene, oxazolylene or thiazolylene, and the other is as described above.
  • Representative compounds according to this embodiment are those wherein ring A and A' are independently optionally substituted imidazolylene, oxazolylene or thiazolylelene, thus providing compounds of formula lib:
  • R A and R A are independently H, F, CI or Br.
  • a typical configuration according to this embodiment are compounds wherein both ring A and A' are optionally substituted imidazolylene, thus providing compounds of the formula lie:
  • both R A and R A are H, or one of R A and R A is H and the other is CI, or both R A and R A' are CI.
  • rings A and A' are triazolylene and tetrazolylene.
  • X is typically CH 2 .
  • X is CR R , wherein one R is H and the other is F, or both R >12 are F.
  • X is CR 12 R 12 and the two R 12 together with the carbon atom to which they are attached form a cycloalkyl group, such as a cyclopropyl group.
  • the stereoche is typically trans, as indicated in the
  • One embodiment of the invention provides the compound as a diastereomeric mixture. In an alternative embodiment, the invention provides the compound as a single stereoisomer.
  • the invention provides compounds wherein the group:
  • X is CH 2 and R 12 , m, n and q are as defined above.
  • X is typically CH 2 .
  • X is CR R , wherein one R is H and the other is F, or both R >12 are F.
  • X is CR 12 R 12 and the two R 12 together with the carbon atom to which they are attached form a cycloalkyl group, such as a cyclopropyl group.
  • X is CH 2 , m is 1 , n is 0, 1 or 2 and q is 0.
  • the invention provides compounds wherein the group:
  • X is CH 2 and m and n are both 1.
  • X is CH 2 and m and n are both 1.
  • the stereochemistry of the cyclopentylene is trans as indicated in the substructures:
  • the R,R-configuration is preferred.
  • m and n are both 1 , q is 0,
  • X is CR 12 R 12 , and both R 12 together with the carbon atom to which they are attached form an optionally substituted 3 to 6 membered heterocyclic moiety, preferably a 5 to 6-membered heterocyclic moiety wherein the heteroatoms are sulphur or oxygen.
  • the thus formed spirocyclic moiety has the structure:
  • the thus formed heterocyclyl is 1 ,3-dioxolane or 1 ,3- dithiolane. Accordingly, the group: ctively.
  • the invention in one embodiment, the invention
  • bicyclic moiety i.e. two carbon atoms of the ring are substituted with R 12 , and the two R 12 together with the carbon atoms to which they are attached form cycloalkyl.
  • R 12 represents a bicyclic moiety, i.e. two carbon atoms of the ring are substituted with R 12 , and the two R 12 together with the carbon atoms to which they are attached form cycloalkyl.
  • a typical bicyclic moiety according to this embodiment is illustrated below:
  • X is CH
  • the invention provides compounds of formula I or II or any subgroup thereof, wherein the substructure: represents one of the following groups:
  • the invention provides compounds of formula I or II or any subgroup thereof wherein the substructure
  • the invention provides compounds of formula I or II or any subgroup thereof, wherein the substructure
  • the invention provides compounds wherein U is C(R 4 ) 2 , and both R 4 together with the carbon atom to which they are attached form an optionally substituted 3 to 6 membered heterocyclic moiety, preferably a 5 to 6-membered heterocyclic moiety wherein the heteroatoms are sulphur or oxygen.
  • the substructure R 3 * Ra represents the group:
  • the thus formed heterocyclyl is 1 ,3-dioxolane or 1 ,3- dithiolane. Accordingly, the group: respectively.
  • the invention provides compounds of formula I or any subgroup of formula I wherein R 6 is NR 7 R 7 .
  • R 7 and R 7 together with the nitrogen atom to which they are attached combine to form a
  • heterocyclyl which heterocyclyl is optionally substituted.
  • exemplary heterocycles include morpholinyl, piperidinyl or piperazinyl.
  • a preferred configuration for R 6 according to this embodiment is morpholinyl or morpholinyl substituted with C C 3 alkyl such as methyl or ethyl, d-C 3 haloalkyl such as mono-, di- or tri-fluoromethyl preferably monofluoromethyl, or C
  • the invention provides compounds of formula I or any subgroup of formula I wherein R 6 is CR 9 R 9 NRaR 10 wherein R 9 , R 9' and R 10 are as stated above.
  • R 9 and Ra are both H, thus providing compounds including the partial formula ii:
  • R 10 is typically CrC 3 alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl. Preferably R 10 is methoxycarbonyl.
  • R 10 is C 3 -C 4 cycloalkylaminocarbonyl.
  • R 10 is C C 3 alkylaminocarbonyl, (CrC 3 alkyl) 2 aminocarbonyl or C 3 - C 4 cyclolkylaminocarbonyl.
  • R 9 is H and R 9 is CrC 6 alkyl.
  • the C C 6 alkyl moiety corresponds to the side chain of a natural or non-natural amino acid. Examples are the side chains of glycine (Gly), alanine (Ala), valine (Val) and isoleucine (lie) , i.e. methyl, isopropyl and isobutyl respectively.
  • Gly glycine
  • Al alanine
  • valine valine
  • lie isoleucine
  • the configuration at the asymmetric carbon atom to which C C 6 alkyl is attached is that of an L-amino acid, in particular L-Ala, L-Val and L-lle.
  • the C C 6 alkyl moiety corresponds to the side chain of L-valine, i.e. R 9 is 2-propyl.
  • R 9 is H and R 9 is C 3 -C 7 cycloalkyl, such as cyclobutyl, cyclopentyl or cyclohexyl.
  • R 9 is C 3 -C 7 cycloalkylCrC 6 alkyl.
  • Representative values for R 9 according to this embodiment include cyclobutylmethyl, cyclopentylmethyl and cyclohexylmethyl wherein in each case, the cycloalkyl moiety is optionally substituted as defined above.
  • Representative substituents include C C 3 alkyl such as methyl and ethyl, halo such as one or two fluoro, C C 3 alkoxy such as methoxy and ethoxy, and d-Csalkoxyd-Csalkyl such as methoxymethyl, methoxyethyl, ethoxyethyl, etc.
  • Typical values for R 10 include methylaminocarbonyl, cyclopropylaminocarbonyl,
  • R 9 is H
  • R 9 is isopropyl
  • Ra is H
  • R 10 is methyl
  • R 3 and R 6 are as defined in above;
  • both R 4 are hydrogen or fluoro
  • R 5a and R 5b are hydrogen or
  • R 5a , R 5b and one R 4 are H, the other R 4 is hydroxy, C C 3 alkoxy, C C 3 alkyl or fluoro, or R 5b and one R 4 are H, the other R 4 and R 5a together with the carbon atoms to which they are attached form a fused cyclopropyl, or R 5a and one R 4 are H, the other R 4 and R 5b together with the carbon atoms to which they are attached form a fused cyclopropyl;
  • R 12 is H or OH
  • Y is CH 2 , O or NR y ;
  • R y is H or C C 6 alkyl
  • n 0, 1 or 2;
  • p 0 or 1.
  • R 5a , R 5b and both R 4 are all hydrogen.
  • the invention concerns the use of compounds of formula I, II or III, or any subgroup thereof.
  • the invention provides a compound of formula I, II or III, or any subgroup thereof, or a pharmaceutically acceptable salt or hydrate thereof, for use in the treatment of HCV infection.
  • a further aspect of the invention provides the use of a compound of formula I, II or III, or any subgroup thereof, or a pharmaceutically acceptable salt or hydrate thereof, in combination with at least one immune system modulator and/or one or more further antiviral agent(s) that inhibits replication of HCV in the treatment or prophylaxis of HCV infection.
  • the combination is used in the treatment of HCV infection.
  • Embodiments of the invention concern the use as HCV inhibitors of formula I, II or III, or any subgroup thereof and the pharmaceutically acceptable addition salts thereof. Of particular interest are the free forms of the compounds.
  • HCV genotypes in the context of treatment or prophylaxis in accordance with the invention include genotype 1 b (prevalent in Europe) and 1a (prevalent in North America).
  • the invention also provides a method for the treatment or prophylaxis of HCV infection, in particular of the genotype 1 a or 1 b.
  • the invention provides a method for the treatment of HCV infection, in particular of the genotype 1 a and/or 1 b.
  • any substituent or variable e.g. R 1 , R 2 , R 3 , etc. at a particular location in a molecule is independent of its definitions elsewhere in that molecule.
  • R 1 , R 2 , R 3 , etc. at a particular location in a molecule is independent of its definitions elsewhere in that molecule.
  • each of the two R 3 groups may be the same or different.
  • compositions in accordance with the invention will preferably comprise substantially stereoisomerically pure preparations of the indicated stereoisomer.
  • stereoisomerically pure concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%.
  • 80% i.e. minimum 90% of one isomer and maximum 10% of the other possible isomers
  • a stereoisomeric excess of 100% i.e. 100% of one isomer and none of the other
  • Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures.
  • enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids or bases. Examples thereof are tartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulphonic acid.
  • enantiomers may be separated by chromatographic techniques using chiral stationary phases.
  • Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
  • said compound is synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials.
  • the diastereomeric racemates of the compounds of formula I, II or III, or any subgroup thereof can be obtained separately by conventional methods.
  • Appropriate physical separation methods that may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography.
  • the present invention also includes isotope-labelled compounds of formula I, II or III, or any subgroup thereof, wherein one or more of the atoms is replaced by an isotope of that atom, i.e. an atom having the same atomic number as, but an atomic mass different from, the one(s) typically found in nature.
  • isotopes that may be incorporated into the compounds of formula I or any subgroup of formula I, include but are not limited to isotopes of hydrogen, such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively), carbon, such as 11 C, 13 C and 14 C, nitrogen, such as 13 N and 15 N, oxygen, such as 15 0, 17 0 and 18 0, phosphorus, such as 31 P and 32 P, sulphur, such as 35 S, fluorine, such as 18 F, chlorine, such as 36 CI, bromine such as 75 Br, 76 Br, 77 Br and 82 Br, and iodine, such as 123 l, 124 l, 125 l and 131 1.
  • isotopes of hydrogen such as 2 H and 3 H (also denoted D for deuterium and T for tritium, respectively)
  • carbon such as 11 C, 13 C and 14 C
  • nitrogen such as 13 N and 15 N
  • oxygen such as 15 0, 17 0 and 18
  • isotope included in an isotope-labelled compound will depend on the specific application of that compound. For example, for drug or substrate tissue distribution assays, compounds wherein a radioactive isotope such as 3 H or 14 C is incorporated will generally be most useful. For radio-imaging applications, for example positron emission tomography (PET) a positron emitting isotope such as 11 C, 18 F, 13 N or 15 0 will be useful.
  • PET positron emission tomography
  • a heavier isotope such as deuterium, i.e. 2 H, may provide greater metabolic stability to a compound of formula I or any subgroup of formula I, which may result in, for example, an increased in vivo half-life of the compound or reduced dosage requirements.
  • Isotope-labelled compounds of the invention can be prepared by processes analogous to those described in the Schemes and/or Examples herein below by using the appropriate isotope- labelled reagent or starting material instead of the corresponding non-isotope-labelled reagent or starting material, or by conventional techniques known to those skilled in the art.
  • the pharmaceutically acceptable addition salts comprise the therapeutically active non-toxic acid and base addition salt forms of the compounds of formula I, II or III, or any subgroup of formula thereof. Of interest are the free, i.e. non-salt forms of the compounds of the invention, specified herein.
  • the pharmaceutically acceptable acid addition salts can conveniently be obtained by treating the base form with such appropriate acid.
  • Appropriate acids comprise, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids; or organic acids such as, for example, acetic, propionic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric, malic (i.e.
  • inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and the like acids
  • organic acids such as, for example, acetic, propionic, hydroxyacetic, lactic, pyruvic, oxalic (i.e. ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic, fumaric
  • salt forms can be converted by treatment with an appropriate base into the free base form.
  • the compounds of the invention containing an acidic proton may also be converted into their non-toxic metal or amine addition salt forms by treatment with appropriate organic and inorganic bases.
  • Appropriate base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, /V-methyl-D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like.
  • solvates covers any pharmaceutically acceptable solvates that the compounds of the invention as well as the salts thereof, are able to form.
  • Such solvates are for example hydrates, alcoholates, e.g. ethanolates, propanolates, and the like.
  • Such forms although not explicitly indicated in the structural formulae represented herein, are intended to be included within the scope of the present invention.
  • C m -C n alkyl on its own or in composite expressions such as C m -C n haloalkyl, C m - dalkylcarbonyl, C m -C n alkylamine etc. represents a straight or branched alkyl radical having the number of carbon atoms designated, e.g. CrC 4 alkyl means an alkyl radical having from 1 to 4 carbon atoms.
  • Preferred alkyl radicals for use in the present invention are C C 4 alkyl and includes methyl, ethyl, n-propyl, isopropyl, t-butyl, n-butyl and isobutyl. Methyl and isopropyl are typically preferred.
  • C C 6 alkyl has a corresponding meaning, including also all straight and branched chain isomers of pentyl and hexyl.
  • C m -C n alkylene represents a divalent straight or branched saturated carbon radical having the number of carbon atoms indicated, for example, dalkylene means methylene i.e. -CH 2 -, C 2 alkylene means ethylene, i.e. -CH 2 CH 2 - etc.
  • Me means methyl
  • Et means ethyl
  • MeO means methoxy
  • EtO means ethoxy
  • Ac means acetyl
  • C m -C n alkoxy represents a radical C m -C n alkyl-0- wherein C m -C n alkyl is as defined above.
  • C C 4 alkoxy which includes methoxy, ethoxy, n-propoxy, isopropoxy, t- butoxy, n-butoxy and isobutoxy. Methoxy and isopropoxy are typically preferred.
  • CrC 6 alkoxy has a corresponding meaning, expanded to include all straight and branched chain isomers of pentoxy and hexoxy.
  • C 3 -C n cycloalkyl represents a saturated cycloalkyl radical having the number of carbons indicated, e.g. C 3 -C 6 cycloalkyl means a cycloalkyl radical having from 3 to 6 carbon atoms, i.e. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • C 3 -C n cycloalkoxy represents a radical C 3 -C n cycloalkyl-0- wherein C 3 -C n cycloalkyl is as defined above. Of particular interest are cyclopropoxy and cyclobutoxy.
  • C 3 -C n cycloalkylC m -C n alkyl represents a straight or branched C m -C n alkyl group which is substituted with a C 3 -C n cycloalkyl wherein C m -C n alkyl and C 3 -C n cycloalkyl are as defined above and each m and n are independent of each other.
  • C m -C n alkoxyC m -C n alkyl represents a C m -C n alkyl group which is substituted with a C m -C n alkoxy wherein C m -C n alkyl and C m -C n alkoxy are as defined above and each m and n are independent of each other.
  • amino represents the radical -NH 2 .
  • aminoC m -C n alkyl represents a C m -C n alkyl radical as defined above which is substituted with an amino group, i.e. one hydrogen atom of the alkyl moiety is replaced by an NH 2 -group.
  • aminoC m -C n alkyl is aminoCrC 6 alkyl.
  • aminoC m -C n alkylcarbonyl represents a C m -C n alkylcarbonyl radical as defined above, wherein one hydrogen atom of the alkyl moiety is replaced by an NH 2 -group.
  • aminoC m -C n alkylcarbonyl is aminoCi-C 6 alkylcarbonyl.
  • heterocycle represents a stable, monocyclic or bicyclic, saturated, partially saturated or aromatic ring, containing 1-4 hetero atoms independently selected from O, S and N, each ring having 4, 5 or 6 ring atoms.
  • exemplary saturated heterocycle include morpholine, piperidine, piperazine, pyrrolidine, tetrahydrofuran, pyran, 1 ,4-dioxane, 1 ,3-dioxane, oxetane and azetidine.
  • exemplary unsaturated heterocyclyl include dihydropyran,
  • tetrahydrothiopyran tetrahydrothiophene
  • 2-H-pyrrole pyrroline
  • pyrazoline imidazoline
  • thiazolidine imidazoline
  • Exemplary aromatic heterycycles include furan, thiophene, pyrrole, imidazole, pyrazole, triazole, tetrazole, thiazole, oxazole, isoxazole, oxadiazole, thiadiazole, isothiazole, pyridine, pyridazine, pyrazine, pyrimidine, quinoline, isoquinoline, benzofuran, benzothiophene, indole, indazole and the like.
  • heterocyclyl and “heterocyclylene” represents a monovalent or divalent heterocycle radical respectively.
  • a monovalent heterocycle radical having an aromatic character may also be referred to as heteroaryl.
  • a divalent heterocycle radical having an aromatic character may also be referred to as heteroarylene.
  • heteroaryl/heteroarylene moiety is optionally substituted with one or two or, where valence permits up to three substituents independently selected from halo, hydroxy, nitro, cyano, carboxy, d-C 3 alkyl, d-C 3 alkoxy, d-C 3 alkoxyd-C 3 alkyl, d-C 3 alkanoyl, amino, azido, nitro, C 3 - dcarbocyclyl .
  • radical positions on any molecular moiety used in the definitions may be anywhere on such a moiety as long as it is chemically stable. When any variable is present occurs more than once in any moiety, each definition is independent.
  • the names of compounds used in this application are generated using ChemDraw Ultra 12.0.2. If there is discrepancy between a depicted structure and a name given to that structure, the depicted structure is to be accorded more weight. In addition, if the
  • stereochemistry of a structure or a portion of a structure is not indicated with for example bold or dashed lines, the structure or portion of that structure is to be interpreted as encompassing all stereoisomers of it.
  • R" is R 6 or a group that is
  • a-Bromination of p-bromoacetophenon effected by treatment with a source of bromonium ion such as Br 2 , N-bromosuccinimide (NBS) or CBr 4 provides a-bromo keton (1 b).
  • the afforded compound can then either be reacted with a desired suitably protected cyclic alkylene carboxylic acid (1d) in the presence of a base such as potassium carbonate or sodium bicarbonate or similar, thus affording ⁇ -keto ester (1e), or it can be transformed into the corresponding a-amino keton (1c) which subsequently is reacted with a desired suitably protected cyclic alkylene carboxylic acid (1d) under standard amide formation conditions such as using a coupling agent like HATU in the presence of a base such as DIPEA in e.g.
  • the phenyl bromide derivative (1j) for use in the biphenyl formation step of Scheme 1 can be prepared according to the procedure described in e.g. WO2008/021927 as schematically illustrated in Scheme 2.
  • R" is R 6 or a group that is subsequently transformed to R 6
  • cyclic amino acids (2a) to be used in the preparation of the phenyl bromide derivative are commercially available, others can be prepared from commercially available starting materials using literature procedures well known to a person skilled in the art.
  • cyclopentylene moiety can be prepared according to the method described in Scheme 3.
  • ethyl 2-oxocyclohexanecarboxylate (3a) Subjecting commercially available ethyl 2-oxocyclohexanecarboxylate (3a) to Favorskii conditions, i.e. a-bromination and ring contraction effected by treatment with bromine, followed by treatment with potassium hydroxide or equivalent provides the cyclopentane-1 ,2-dicarboxylic acid (3b).
  • a protecting strategy is required, accordingly, ring closure of the diacid effected by treatment with acetic anhydride to provide the intramolecular anhydride (3c) followed by opening of the anhydride using methanol provides the cis mono ester (3d).
  • the cis compound can be isomerised by treatment with LDA, t.BuOK or the like, thus providing the trans mono ester (3e).
  • a building block for the preparation of compounds of the invention wherein the X-containing cyclic moiety is hydroxy substituted cyclopentylene, i.e. X is CH 2 , m, n and q are all 1 and R 12 is OH, can be prepared as illustrated in Scheme 4.
  • Opening of the bicyclic acid (5a) using LiOH or equivalent provides the diacid (5b).
  • Ring closure effected by treatment with DIAD and triphenylphosphine or similar conditions followed by esterification and ring opening as described above, provides the hydroxy substituted dicarboxylic cyclopentane derivative (5e).
  • a building block for the preparation of compounds of the invention wherein X is O and m and n are both 1 , i.e. compounds comprising a tetrahydrofuran moiety, can be prepared according to the metho
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene.
  • N-protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o- nitrophenoxyacetyl, a-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulphonyl groups such as benzenesulphonyl, p-toluenesulphonyl, and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxy-carbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,
  • cyclopentyloxycarbonyl adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl, and the like; alkyl groups such as benzyl, triphenylmethyl, benzyloxymethyl and the like; and silyl groups such as trimethylsilyl and the like.
  • Favoured N-protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, benzyl, t-butoxycarbonyl (BOC) and
  • Hydroxy and/or carboxy protecting groups are also extensively reviewed in Greene ibid and include ethers such as methyl, substituted methyl ethers such as methoxymethyl,
  • silyl ethers such as trimethylsilyl (TMS), t-butyldimethylsilyl (TBDMS) tribenzylsilyl, triphenylsilyl, t- butyldiphenylsilyl, triisopropyl silyl and the like, substituted ethyl ethers such as 1-ethoxymethyl, 1 -methyl- 1-methoxyethyl, t-butyl, allyl, benzyl, p-methoxybenzyl, diphenylmethyl,
  • Ester hydroxy protecting groups include esters such as formate, benzylformate, chloroacetate, methoxyacetate, phenoxyacetate, pivaloate,
  • Carbonate hydroxy protecting groups include methyl vinyl, allyl, cinnamyl, benzyl and the like.
  • the present invention concerns a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or any subgroup of formula I, as specified herein, and a pharmaceutically acceptable carrier.
  • a therapeutically effective amount in this context is an amount sufficient to stabilize or to reduce viral infection, and in particular HCV infection, in infected subjects.
  • the "therapeutically effective amount” will vary depending on individual requirements in each particular case. Features that influence the dose are e.g. the severity of the disease to be treated, age, weight, general health condition etc. of the subject to be treated, route and form of administration.
  • the invention relates to the use of a compound of formula I or any subgroup of formula I, for the treatment of "treatment naive" patients, i.e. patients infected with HCV that are not previously treated against the infection.
  • the invention relates to the use of a compound of formula I or any subgroup of formula I, the treatment of "treatment experienced" patients, i.e. patients infected with HCV that are previously treated against the infection and have subsequently relapsed.
  • the invention relates to the use of a compound of formula I or any subgroup of formula I, the treatment of "non-responders", i.e. patients infected with HCV that are previously treated but have failed to respond to the treatment.
  • the present invention concerns a pharmaceutical composition comprising a prophylactically effective amount of a compound of formula I or any subgroup of formula I, as specified herein, and a pharmaceutically acceptable carrier.
  • a prophylactically effective amount in this context is an amount sufficient to act in a prophylactic way against HCV infection, in subjects being at risk of being infected.
  • this invention relates to a process of preparing a pharmaceutical composition as specified herein, which comprises intimately mixing a pharmaceutically acceptable carrier with a therapeutically or prophylactically effective amount of a compound of formula I or any subgroup of formula I, as specified herein.
  • the compounds of formula I or any subgroup of formula I may be formulated into various pharmaceutical forms for administration purposes.
  • compositions there may be cited all compositions usually employed for systemically administering drugs.
  • an effective amount of the particular compound, optionally in addition salt form or metal complex, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • a pharmaceutically acceptable carrier which carrier may take a wide variety of forms depending on the form of preparation desired for administration.
  • These pharmaceutical compositions are desirable in unitary dosage form suitable, particularly, for administration orally, rectally, percutaneously, or by parenteral injection.
  • any of the usual pharmaceutical media may be employed such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs, emulsions and solutions; or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules, and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit forms, in which case solid pharmaceutical carriers are obviously employed.
  • the carrier will usually comprise sterile water, at least in large part, though other ingredients, for example, to aid solubility, may be included.
  • Injectable solutions may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution.
  • Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. Also included are solid form preparations intended to be converted, shortly before use, to liquid form preparations.
  • the carrier optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not introduce a significant deleterious effect on the skin.
  • the compounds of the present invention may also be administered via oral inhalation or insufflation in the form of a solution, a suspension or a dry powder using any art- known delivery system.
  • Unit dosage form refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • unit dosage forms are tablets (including scored or coated tablets), capsules, pills, suppositories, powder packets, wafers, injectable solutions or suspensions and the like, and segregated multiples thereof.
  • the compounds of formula I or any subgroup of formula I show activity against HCV and can be used in the treatment and/or prophylaxis of HCV infection or diseases associated with HCV.
  • the compounds of formula I or any subgroup thereof can be used in the treatment of HCV infection or diseases associated with HCV.
  • Diseases associated with HCV include progressive liver fibrosis, inflammation and necrosis leading to cirrhosis, end-stage liver disease, and HCC.
  • a number of the compounds of this invention moreover are believed to be active against mutated strains of HCV. Additionally, many of the compounds of this invention show a favourable pharmacokinetic profile and have attractive properties in terms of
  • bioavailability including an acceptable half-life, AUC (area under the curve) and peak values and lacking unfavourable phenomena such as insufficient quick onset and tissue retention.
  • Appropriate cell types can be equipped by stable transfection with a luciferase reporter gene whose expression is dependent on a constitutively active gene promoter, and such cells can be used as a counter-screen to eliminate non-selective inhibitors. Due to their antiviral properties, particularly their anti-HCV properties, the compounds of formula I, including any possible stereoisomers, the pharmaceutically acceptable addition salts or solvates thereof, are useful in the treatment of warm-blooded animals, in particular humans, infected with HCV. The compounds of formula I are further useful for the prophylaxis of HCV infections.
  • the present invention furthermore relates to a method of treating a warm-blooded animal, in particular human, infected by HCV, or being at risk of infection by HCV, said method comprising the administration of an anti-HCV effective amount of a compound of formula I, as specified herein.
  • the compounds of the present invention may therefore be used as a medicine, in particular as an anti HCV medicine.
  • Said use as a medicine or method of treatment comprises the systemic administration to HCV infected subjects or to subjects susceptible to HCV infection of an amount effective to combat the conditions associated with HCV infection.
  • the present invention also relates to the use of the present compounds in the manufacture of a medicament for the treatment or the prevention of HCV infection.
  • the present invention relates to the use of the compounds of formula I or any subgroups thereof, in the manufacture of a medicament for the treatment of HCV infection.
  • an antiviral effective daily amount would be from about 0.01 to about 700 mg/kg, or about 0.5 to about 400 mg/kg, or about 1 to about 250 mg/kg, or about 2 to about 200 mg/kg, or about 10 to about 150 mg/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day. Said sub-doses may be formulated as unit dosage forms, for example, containing about 1 to about 5000 mg, or about 50 to about 3000 mg, or about 100 to about 1000 mg, or about 200 to about 600 mg, or about 100 to about 400 mg of active ingredient per unit dosage form.
  • the invention also relates to a combination of a compound of formula I or any subgroup of formula I,, a pharmaceutically acceptable salt or solvate thereof, and another antiviral compound, in particular another anti-HCV compound.
  • the term "combination" may relate to a product containing (a) a compound of formula I, as specified above, and (b) optionally another anti-HCV compound, as a combined preparation for simultaneous, separate or sequential use in treatment of HCV infections.
  • Anti-HCV compounds that can be used in such combinations include HCV polymerase inhibitors, HCV protease inhibitors, inhibitors of other targets in the HCV life cycle, and an immunomodulatory agents, and combinations thereof.
  • HCV polymerase inhibitors include, NM283 (valopicitabine), R803, JTK-109, JTK-003, HCV-371 , HCV-086, HCV-796 and R-1479, R-7128, MK-0608, VCH-759, PF-868554, GS9190, XTL-2125, NM-107, GSK625433, R-1626, BILB-1941 , ANA-598, IDX-184, IDX-375, MK-3281 , MK-1220, ABT-333, PSI-7851 , PSI-6130, VCH-916.
  • Inhibitors of HCV proteases include BILN-2061 , VX-950 (telaprevir), GS-9132 (ACH-806), SCH-503034 (boceprevir), TMC435350 (also referred to as TMC435), TMC493706, ITMN-191 , MK-7009, BI-12202, BILN-2065, Bl- 201335, BMS-605339, R-7227, VX-500, BMS650032, VBY-376, VX-813, SCH-6, PHX-1766, ACH-1625, IDX-136, IDX-316.
  • An example of an HCV NS5A inhibitor is BMS790052.
  • Inhibitors of other targets in the HCV life cycle including NS3 helicase; metalloprotease inhibitors; antisense oligonucleotide inhibitors, such as ISIS-14803 and AVI-4065; siRNA's such as SIRPLEX-140-N; vector-encoded short hairpin RNA (shRNA); DNAzymes; HCV specific ribozymes such as heptozyme, RPI.13919; entry inhibitors such as HepeX-C, HuMax-HepC; alpha glucosidase inhibitors such as celgosivir, UT-231 B and the like; KPE-02003002; and BIVN 401.
  • siRNA's such as SIRPLEX-140-N
  • shRNA vector-encoded short hairpin RNA
  • DNAzymes HCV specific ribozymes such as heptozyme, RPI.13919
  • entry inhibitors such as HepeX-C, HuMax-HepC
  • Immunomodulatory agents include, natural and recombinant interferon isoform compounds, including a-interferon, ⁇ -interferon, ⁇ -interferon, and ⁇ -interferon, such as Intron A®, Roferon- A®, Canferon-A300®, Advaferon®, Infergen®, Humoferon®, Sumiferon MP®, Alfaferone®, IFN- beta®, and Feron®; polyethylene glycol derivatized (pegylated) interferon compounds, such as PEG interferon-a-2a (Pegasys®), PEG interferon-a-2b (PEG-lntron®), and pegylated IFN- a-con1 ; long acting formulations and derivatizations of interferon compounds such as the albumin-fused interferon albuferon a; compounds that stimulate the synthesis of interferon in cells, such as resiquimod; interleukins; compounds that enhance the development of
  • propagermanium propagermanium; tetrachlorodecaoxide; ampligen; IMP-321 ; KRN-7000; antibodies, such as civacir and XTL-6865; and prophylactic and therapeutic vaccines such as InnoVac C and HCV E1 E2/MF59.
  • antiviral agents include, ribavirin, amantadine, viramidine, nitazoxanide; telbivudine; NOV- 205; taribavirin; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors, and mycophenolic acid and derivatives thereof, and including, but not limited to, VX-497 (merimepodib), VX-148, and/or VX- 944); or combinations of any of the above.
  • interferon-a IFN-a
  • pegylated interferon- a or ribavirin as well as therapeutics based on antibodies targeted against HCV epitopes
  • small interfering RNA Si RNA
  • ribozymes DNAzymes
  • DNAzymes antisense RNA
  • small molecule antagonists of for instance NS3 protease, NS3 helicase and NS5B polymerase for instance NS3 protease, NS3 helicase and NS5B polymerase.
  • combinations of a compound of formula I as specified herein and an anti-HIV compound preferably are those HIV inhibitors that have a positive effect on drug metabolism and/or pharmacokinetics that improve bioavailability.
  • An example of such an HIV inhibitor is ritonavir.
  • this invention further provides a combination comprising (a) a compound of formula I or a pharmaceutically acceptable salt or solvate thereof; and (b) ritonavir or a pharmaceutically acceptable salt thereof.
  • the compound ritonavir, its pharmaceutically acceptable salts, and methods for its preparation are described in WO 94/14436. US 6,037, 157, and references cited therein: US 5,484,801 , US 08/402,690, WO 95/07696, and WO 95/09614, disclose preferred dosage forms of ritonavir.
  • the invention also concerns a process for preparing a combination as described herein, comprising the step of combining a compound of formula I, as specified above, and another agent, such as an antiviral, including an anti-HCV or anti-HIV agent, in particular those mentioned above.
  • the said combinations may find use in the manufacture of a medicament for treating HCV infection in a mammal infected therewith, said combination in particular comprising a compound of formula I, as specified above and interferon-a (IFN-a), pegylated interferon-a, or ribavirin.
  • the invention provides a method of treating a mammal, in particular a human, infected with HCV comprising the administration to said mammal of an effective amount of a combination as specified herein.
  • said treating comprises the systemic administration of the said combination, and an effective amount is such amount that is effective in treating the clinical conditions associated with HCV infection.
  • the above-mentioned combinations are formulated in the form of a pharmaceutical composition that includes the active ingredients described above and a carrier, as described above.
  • Each of the active ingredients may be formulated separately and the formulations may be co-administered, or one formulation containing both and if desired further active ingredients may be provided.
  • the combinations may also be formulated as a combined preparation for simultaneous, separate or sequential use in HCV therapy.
  • the said composition may take any of the forms described above.
  • both ingredients are formulated in one dosage form such as a fixed dosage combination.
  • the present invention provides a pharmaceutical composition comprising (a) a therapeutically effective amount of a compound of formula I, including a possible stereoisomeric form thereof, or a pharmaceutically acceptable salt thereof, or a
  • the individual components of the combinations of the present invention can be administered separately at different times during the course of therapy or concurrently in divided or single combination forms.
  • the present invention is meant to embrace all such regimes of simultaneous or alternating treatment and the term "administering" is to be interpreted accordingly.
  • the separate dosage forms are administered simultaneously.
  • the combinations of the present invention contain an amount of ritonavir, or a pharmaceutically acceptable salt thereof, that is sufficient to clinically improve the
  • the combinations of the present invention contains an amount of ritonavir, or a pharmaceutically acceptable salt thereof, which is sufficient to increase at least one of the pharmacokinetic variables of the compound of formula I selected from t 1 2 , Cmin, C max , C ss , AUC at 12 hours, or AUC at 24 hours, relative to said at least one
  • the combinations of this invention can be administered to humans in dosage ranges specific for each component comprised in said combinations, e.g. the compound of formula I as specified above, and ritonavir or a pharmaceutically acceptable salt, may have dosage levels in the range of 0.02 to 5.0 g/day.
  • the weight ratio of the compound of formula I to ritonavir may be in the range of from about 30:1 to about 1 :15, or about 15: 1 to about 1 : 10, or about 15: 1 to about 1 : 1 , or about 10: 1to about 1 : 1 , or about 8: 1 to about 1 : 1 , or about 5: 1 to about 1 : 1 , or about 3: 1 to about 1 : 1 , or about 2: 1 to 1 : 1.
  • the compound formula I and ritonavir may be co-administered once or twice a day, preferably orally, wherein the amount of the compound of formula I per dose is as described above; and the amount of ritonavir per dose is from 1 to about 2500 mg, or about 50 to about 1500 mg, or about 100 to about 800 mg, or about 100 to about 400 mg, or 40 to about 100 mg of ritonavir.
  • the amount of the compound of formula I per dose is as described above; and the amount of ritonavir per dose is from 1 to about 2500 mg, or about 50 to about 1500 mg, or about 100 to about 800 mg, or about 100 to about 400 mg, or 40 to about 100 mg of ritonavir.
  • Hexamethyleneteramine (urotropin) 13 g, 93 mmol was added to a solution of 2-bromo-1-(4- bromophenyl)ethanone (25 g, 91 mmol) in chloroform (300 ml) and the mixture was stirred for at RT. After 4 hours the precipitated hexamine adduct was filtered, dissolved in a mixture of methanol and cone. HCI and heated at reflux for 3 hours, then cooled and filtered. The filtered cake was washed with methanol which gave the title compound (15 g, 66%).
  • BB1-f Pd(PPh 3 ) 4 (0.04 eq.) was added under N 2 to a mixture of the aryl bromide BB1-e (17 g, 37.9 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (28.9 g, 113.8 mmol) and KOAc (1 1.1 g, 1 14 mmol) in 1 ,4-dioxane (30 ml). The resulting mixture was stirred at 80 °C overnight, filtered and
  • Step b) (1 ,2-trans)-2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cvclobutanecarboxylic acid (BB3-b)
  • BB3-b A mixture of the keto ester BB3-a (1.6 g, 4.7 mmol) and NH 4 OAc (7.3 g, 94 mmol) in xylene (60 ml) was heated in a sealed tube at 120 °C for 6h.
  • the reaction mixture was then partitioned between EtOAc (100 ml) and H 2 0 (20 ml).
  • the organic layer was dried over Na 2 S0 4 , filtered and concentrated in vacuo and the residue was purified by column chromatography
  • Step c) ((1 ,2-trans)-2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cvclobutyl)((R)-3- methylmorpholino)methanone (BB3-c) DIPEA (1.3 g, 9.93mmol) was added at rt under N 2 to a mixture of the acid BB3-b (1 g, 3.31 mmol), the HCI salt of the amine BB4-f (642 mg, 4.69 mmol) and HATU (1.26 g, 3.31 mmol) in DCM (30 ml) and the resulting reaction mixture was stirred overnight.
  • Step d) ((R)-3-methylmorpholino)((1 ,2-trans)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-1 H-imidazol-2-yl)cvclobutyl)methanone (BB3)
  • Step f) ((1 ,2-trans)-2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cvclopentyl)((R)-3- methylmorpholino)methanone (BB4)
  • the acid 6a (990 mg, 6.34 mmol) was dissolved in of DCM (15 ml) and then cooled to approximately -10 °C under N 2 . Isobutylene was bubbled into the solution until the total volume had increased to approximately 25 ml. 0.8M BF 3 x Et 2 0 (0.4 ml, 3.17 mmol) was added and the reaction mixture was kept at approximately -10 °C under N 2 . After 70 min. sat. NaHC0 3 (aq, 20 ml) was added and the reaction mixture was stirred vigorously for 10 min and then the layers were separated. The organic layer was washed with sat.
  • Step c) (1 ,2-trans,4S)-2-(tert-butoxycarbonyl)-4-hvdroxycvclopentanecarboxylic acid (BB6) 1M LiOH (aq, 4.7 ml, 4.7 mmol) was added to a stirred solution of the bicyclic compound BB6-b (545 mg, 2.57 mmol) in dioxane at 0 °C. The mixture was stirred at 0 °C for 2h and then diluted with water (50 ml) and acidified to pH2 using aq 2M HCI.
  • Triethylamine (6.47 g, 64.1 mmol) and a solution of CuS0 4 -5H 2 0 (0.8 g, 3.2 mmol) in water (4 ml) were added consecutively to a solution of 4-bromoaniline (3.66 g, 21.4 mmol) in DCM (16 ml), then a freshly prepared solution of TfN 3 (64.1 mmol, 1 eq) was added and the solution was brought to homogeneity by addition of MeOH. The resulting solution was stirred at rt and when TLC indicated complete reaction, the solution was poured into saturated aqueous NaHCO 3 (100 ml) and extracted with DCM (3x50 ml).
  • Step d methyl ((S)-1-((S)-2-(1-(4-bromophenyl)-1 H-1 ,2,3-triazol-4-yl)pyrrolidin-1-yl)-3-methyl-1- oxobutan-2-yl)carbamate (BB7-d)
  • Triethylamine (352 mg, 3.48 mmol) was added at 0 °C to a solution of the anhydride BB8-a and (R)-3-methylmorpholine (238 mg, 1.74 mmol) in DCM (40 ml). After stirring for 30 min at 0 °C the mixture was washed with brine (2x5 ml) and the organic layer was concentrated which gave the title compound (400 mg). MS (ESI): 256 [M+H] + .
  • Step c) ((1 R,2R)-2-(5-(4-Bromophenyl)-1 H-imidazol-2-yl)cvclohexyl)((R)-3- methylmorpholino)methanone (BB8)
  • Step b) (S)-methyl 2-((1.2-cis)-2-((2-(4-bromophenyl)-2-oxoethyl)carbamoyl)- cyclopentanecarboxamido)-3-methylbutanoate (BB10-b)
  • Step d) ((1.2-trans)-2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cvclopentyl)((S)-3-(tert- butoxymethyl)morpholino)methanone (BB12)
  • Step b) (R)-Benzyl 3-(methoxymethyl)morpholine-4-carboxylate (BB13-b) Ag 2 0 (941 mg, 4.06 mol) was added to a solution of the alcohol BB13-a (500 mg, 2.0 mmol) in THF and the resulting mixture was stirred at room temperature. After 30 min, Mel (577 mg, 4.06 mmol) was added and the reaction was stirred at 45 °C for 48h. The formed precipitate was filtered off, the filtrate was concentrated and the residue was purified by column
  • HATU (506 mg, 1.34 mmol) and DIPEA (630 mg, 4.88 mmol) were added at rt to a mixture of BB13-C (160 mg, 1.22 mmol) and the HCI salt of BB2-g (497 mg, 1.34 mmol) in of DMF (20 ml) and the resulting reaction mixture was stirred overnight. The solvent was evaporated and the residue was purified by column chromatography (DCM/MeOH) which gave the title compound (516 mg, 95%). MS (ESI): 448 [M+H] + .
  • Hexafluoropropene diethylamine complex (1.25 ml, 6.89 mmol) was added dropwise at -30 ° under N 2 to a solution of BB14-a (1.19 g, 5.74 mmol) in dry DCM (100 ml) and the resulting reaction mixture was stirred at rt for 3h. The solution was then washed with water and sat. aq. NaHC0 3 , dried over Na 2 S0 4 and evaporated in vacuo. The residue was dissolved in methanol (100 ml) and the solution was added to a 30% CH 3 ONa solution in methanol (209 ml).
  • Step d) ((1 ,2-trans)-2-(5-(4-Bromophenyl)-1 H-imidazol-2-yl)cvclopentyl)((S)-3- (fluoromethyl)morpholino)methanone (BB14)
  • Step b) (R)-2-(dimethylamino)-2-phenyl-1-((S)-2-(5-(4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2- yl)phenyl)-1 H-imidazol-2-yl)pyrrolidin-1-yl)ethanone (BB18)
  • BB26-b A mixture of ethylene glycol (8,51 g, 137,07 mmol), PTSA (122,2 mg, 0,64 mmol) and BB26-a (1 ,4 g, 3,4 mmol) in Toluene (50 ml) was refluxed with a Dean Stark trap for 2 h.
  • the reaction mixture was cooled down to r.t., diluted with EtOAc (20 mL), washed with sat. aq. NaHC0 3 (x2), brine and dried (Na 2 S0 4 ) which gave the title compound (1.5 g).
  • BB26-e (121 mg, 0,28 mmol) in MeOH (1 ,5 ml) was treated with NaOH (22,34 mg, 0,56 mmol) in water (0,28 ml). The resulting solution was stirred for 3 h at r.t. The reaction mixture was then concentrated under vacuum and coevaporated with DCM to give a yellowish solid that was mixed with H-Val-OMexHCI (46,82 mg, 0,28 mmol) and DIPEA (108,28 mg, 0,84 mmol) in DMF (3 mL). To the resulting mixture was added HATU (106, 19 mg, 0,28 mmol). The reaction mixture was stirred for 15 min at r.t.
  • Step b) (R)-3-Methyl-1-(3-methylmorpholine-4-carbonyl)-1 H-imidazol-3-ium iodide (BB29-a) Methyl iodide (379 mg, 2.7 mmol) was added to a solution of BB29-a (130 mg, 0.67 mmol) in MeCN (10 ml). The reaction mixture was heated to 30 °C and stirred overnight, then the solvent was removed in vacuo which gave the title compound (220 mg, 98%) as a yellow solid which used in the next step without further purification. MS (ESI): 210[M+H] + .
  • Step c) ((S)-2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)pyrrolidin-1-yl)((R)-3- methylmorpholino)methanone (BB29-C)
  • Step d) ((R)-3-Methylmorpholino)((S)-2-(5-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl)-1 H-imidazol-2-yl)pyrrolidin-1-yl)methanone (BB29)
  • Pd(PPh 3 ) 4 (0.04eq.) was added under N 2 to a mixture of BB29-C (1 eq.), bis(pinacolateo)diboron (2 eq.) and potassium acetate (2.5 eq.) in dioxane. The resulting mixture was stirred at 80 °C. After 16h, the mixture was concentrated and the residue purified by column chromatography, which gave the title compound (500 mg, 61 %).
  • Step b) 1-(isopropyl(2-methoxyethyl)carbamoyl)-3-methyl-1 H-imidazol-3-ium iodide
  • BB30-b Methyl iodide (753 mg, 5.3 mmol) was added to a solution of BB30-a (280 mg, 1.32 mmol) in CH 3 CN (10 ml). The reaction mixture was heated at 30 °C and stirred overnight whereafter the solvent was removed in vacuum which gave the title compound (470 mg, 100%) as a light yellow solid.
  • Step c) (1.2-trans)-2-(5-(4-Bromophenyl)-1 H-imidazol-2-yl)-N-isopropyl-N-(2- methoxyethvDcyclopentanecarboxamide (BB30)
  • DIPEA (1.7g, 13.2) was added dropwise to a heterogeneous mixture of (R)-1-methoxypropan-2- amine, the HCI salt of BB2-g (500 mg, 1.35 mmol) and HATU (616 mg, 1.62 mmol) in a mixture of DMF (20 ml) and DCM (10 ml), and the reaction mixture was stirred at ambient temperature overnight. Most of the volatile components were removed under vacuum, and the residue was partitioned between EtOAc and water, the organic layer was washed with water and brine, dried, filtered and concentrated under vacuum. The residue was purified by column
  • Step a) 1 , 1 , 1-trifluoro-2-methylpropan-2-yl 1 H-imidazole-1-carboxylate (BB36-a)
  • Step b) 3-methyl-1 -(((1 , 1 , 1-trifluoro-2-methylpropan-2-yl)oxy)carbonyl)-1 H-imidazol-3-ium (BB36-b)
  • HATU 857 mg, 2.25 mmol
  • BB45-b were added at 0 °C to a solution of BB1-a (360 mg, 2.05 mmol) in DCM (50 ml), followed by slow addition of DIPEA (1.06 g, 8.2 mmol).
  • DIPEA 1.06 g, 8.2 mmol
  • the resulting mixture was stirred at rt for 2 h and then solvent was removed.
  • the residue was diluted with EtOAc (100 ml) and the organic phase was washed with 1 N HCI (2x20 ml), saturated
  • BB46-C (650 mg, 1.34 mmol) was reacted with 4,4,4',4', 5,5,5', 5'-octamethyl-2,2'-bi(1 , 3,2- dioxaborolane) (1.02g, 4.03mmol) according to the method described in BB1 step f, which gave the title compound (410 mg, 57.4%).
  • BB47-b (800 mg, 1.56 mmol) was reacted with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (1.37 g, 5.39 mmol) according to the method described in BB1 step f, which gave the title compound (500 mg, 57%).
  • BB48-b (600 mg, 1.3 mmol) was reacted with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (838 mg, 3.3 mmol) according to the method described in BB1 step f, which gave the title compound (272 mg, 98%).
  • Step f) ((R)-3-methylmorpholino)((1 R.2R)-2-(5-(4-(4.4.5.5-tetramethyl-1.3.2-dioxaborolan-2- yl)phenyl)-1 H-imidazol-2-yl)cvclopentyl)methanone (BB52)
  • Step b) (1 R,2R)-tert-butyl 2-(5-(4'-(2-((S)-1-((S)-2-((methoxycarbonyl)amino)-3- methylbutanoyl)pyrrolidin-2-yl)-1 H-imidazol-5-yl)-[1 ,1 '-biphenyl1-4-yl)-1 H-imidazol-2- yQcyclopentanecarboxylate (BB53-b)
  • Step c) (1 R,2R)-2-(5-(4'-(2-((S)-1-((S)-2-((methoxycarbonyl)amino)-3-methylbutanoyl)pyrrolidin- 2-yl)-1 H-imidazol-5-yl)-[1 , T-biphenyl1-4-yl)-1 H-imidazol-2-yl)cvclopentanecarboxylic acid (BB53) 3N HCI aq (20 ml) was slowly added to a solution of BB53-b (1.2 g 1eq) in THF (10 ml). The resulting mixture was stirred at room temperature for 2days, then concentrated to dryness which gave the title compound (1.2 g, 96%). MS (ESI): 625 [M+H] + .
  • Step c) methyl ((S)-3-methyl-1-oxo-1-((2S.3aS.7aS)-2-(5-(4-(4.4.5.5-tetramethyl-1.3.2- dioxaborolan-2-yl)phenyl)-1 H-imidazol-2-yl)octahvdro-1 H-indol-1-yl)butan-2-yl)carbamate (BB56)
  • BB56-b (800 mg, 1 eq) was reacted with 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (1.2 g, 3 eq) according to the method described in BB1 step f, which gave the title compound (500 mg, 57%).
  • Cis compound BB58-b (1.06 g, 6.7 mmol) was dissolved under nitrogen at -70 °C in THF (12 ml).
  • the reaction mixture was then poured out in 2 M HCI and EtOAc, dried over MgS0 4 and evaporated.
  • the afforded crude was purified by chromatography on silica eluted with ether/hexanes 1 :1 , which gave the title compound (515 mg, 49%) containing 40% of the cis-
  • Step e) (1 S,2S)-Methyl 2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)cvclobutanecarboxylate (BB58-e)
  • Compound BB58-d (305 mg, 0.859 mmol) and NH 4 OAc (331 mg, 4.29 mmol) were heated at 150 - 160 °C for about 2.5 h using a Dean-Stark apparatus. Then left at room temperature over night. The mixture was evaporated on silica and purified on silica using ether/hexanes 2:1 followed by pure ether, which gave the title compound (136 mg, 47%).
  • HATU (1 14 mg, 0.30 mmol) was added to a stirred mixture of BB58-f (107 mg, 0.30 mmol)), DIPEA (155 mg, 1.20 mmol) and BB4-f (41.2 mg, 0.30) in DCM (5 ml_). The mixture was then stirred at rt overnight. Work up with DCM and NaHC0 3 solution. Evaporation on silica and purification on silica column packed in ether and eluted with 5% MeOH in ether gave the title compound (56 mg, 46 %). MS (ESI) 404.2 & 406.2 [M+H] + .
  • Benzyl chloroformate (1.01 g, 5.91 mmol) was added at 0 °C to a solution of BB60-a (1.1 g, 5.91 mmol) and triethylamine (0.6 g, 5.91 mmol) in DCM (20 mL). The mixture was stirred for 5 min, then DMAP (0.07 g, 0.59 mmol) was added and the resulting reaction mixture was stirred at 0 °C for 40 min. The reaction mixture was diluted with DCM (20 ml_) and washed with sat. NaHCOs (20 ml_), 2 M HCI (10 ml_) and brine (10 ml_). The organic phase was dried (Na 2 S0 4 ), filtered and concentrated. The afforded residue was purified by flash chromatography
  • 2,4'-Dibromoacetophenone (0.18 g, 0.64 mmol) was coupled to BB60-d (0.15 g, 0.64 mmol) according to the method described in BB2 step e. which gave the linear intermediate bromide (317 mg).
  • a part of the afforded compound (0.18 g, 0.42 mmol) was dissolved in xylenes (10 ml_), ammonium acetate (0.32 g, 4.17 mmol) was added and the resulting mixture was refluxed with a Dean Stark trap for 2 h. More ammonium acetate was added (321 mg) and the heating was continued for 4h , then the mixture was cooled to rt and left overnight..
  • Zinc trifluoromethanesulphonate (436 mg, 1.2 mmol) was added to a solution of (1 R,2R)-1-tert- butyl 2-methyl 4-oxocyclopentane-1 ,2-dicarboxylate (242 mg, 1 mmol) and 1 ,2-ethanediol (188 mg, 2 mmol) in DCM (6 ml_).
  • the reaction mixture was stirred at rt on, then diluted with DCM and washed with NaHC0 3 .
  • BB61-b (7R,8R)-8-(tert-butoxycarbonyl)-1 ,4-dithiaspiror4.4lnonane-7-carboxylic acid
  • 2,4'-dibromoacetophenone (126 mg, 0.45 mmol) was added in portions under nitrogen at rt to a solution of the acid BB61-b (125 mg, 0.41 mmol) and DIPEA (58 mg, 0.45 mmol) in MeCN (4 ml_). The mixture was stirred over night, then diluted with EtOAc and washed with brine. The organic phase was concentrated onto silica and purified on silica using ether/hexanes 1 :3. Appropriate fractions were pooled and concentrated which gave the intermediate linear bromide (140 mg, 68%).
  • HATU 144 mg, 0.38 mmol was added at rt to a solution of the crude compound BB61-d (200 mg, -0.38 mmol), BB4-f (52 mg, 38 mmol), DIPEA (196 mg, 1.52 mmol) in DCM and the mixture was stirred overnight. The mixture was diluted with DCM and washed with NH 4 CI. The organic phase was dried, filtered and concentrated on silica and the afforded residue was purified by column chromatography on silica eluted with ether containing 2% MeOH followed by 5% MeOH, which gave the title compound (140 mg).
  • BB62-b (800 mg, 1.69 mmol) was coupled to 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2- dioxaborolane) (1.29 g, 5.06 mmol) according to the method described in BB1 step f, which gave the title compound (350 mg). MS (ESI): 523 [M+H] + .
  • BB4-f 120 mg, 0.87 mmol was reacted with compound BB65-e (343 mg. 0.79 mmol) according to the method described for the preparation of BB35-f, which gave the title compound as a mixture of diastereomers (337 mg, 95%).
  • HATU (86.97 mg, 0.23 mmol) was added to a solution of the sodium salt BB66-a (100 mg, 0.23 mmol), ammonium chloride (12.24 mg, 0.23 mmol) and DIPEA (1 19.52 ⁇ , 0.69 mmol) in DMF (1 ml_).
  • the reaction mixture was stirred at r.t. for 6 h, then diluted with EtOAc and washed with brine + water.
  • the organic phase was dried (Na 2 S0 4 ), the solvent evaporated and the residue purified by flash chromatography (DCM with 0 to 6% MeOH) which gave the title compound (29 mg, 32%).
  • MS 392.2 & 394.2 [M+H] + MS 392.2 & 394.2 [M+H] + .
  • the title compound was prepared by chlorination of BB44-b with N-chlorosuccinimide according to the method described for the preparation of BB68.
  • Tin(IV)chloride 200 ⁇ , 1 M solution in DCM
  • (1 R.2R)- dimethyl 4-oxocyclopentane-1 ,2-dicarboxylate 400 mg, 2.0 mmol
  • propanedithiol 238 mg, 2.2 mmol
  • 2,4'-dibromoacetophenone (545 mg, 1.79 mmol) was added in portions under nitrogen at rt to a solution of the acid BB61-b (452 mg, 0.41 1.63 mmol) and DIPEA (233 mg, 1.79 mmol) in MeCN (15 mL). The mixture was stirred over night, then diluted with EtOAc and washed with brine. The organic phase was concentrated onto silica and purified on silica using
  • hexafluorophosphate (COMU) (1.14 g, 2.66 mmol) was added to a solution of BB72-b (0.7 g, 2.66 mmol), cyclobutane carboxylic acid (0.25 ml, 2.66 mmol) and DIPEA (1.39 ml, 7.98 mmol) in DMF (5 mL).
  • the reaction mixture was stirred for 10 min, then diluted with EtOAc and washed with aq. NaHC0 3 .
  • the organic phase was dried (Na 2 S0 4 ) filtered and concentrated. The residue was purified by flash chromatography (Hep: EtOAc) which gave the title compound (490 mg, 68%) (R)-Cvclobutyl(3-methylpiperazin-1-yl)methanone (BB72-d)
  • Step c) (5,6-trans)-6-(methoxycarbonyl)spiror2.41heptane-5-carboxylic acid (BB76-C) 1 N NaOH aq (12 mmol) was added dropwise at 0 °C to a solution of BB76-b (1.3 g, 6.1 mmol) in 1 ,4-dioxane/water (1 : 1 , 50 mL). The reaction was stirred at 0 °C for 2 h, then poured into ice- water and acidified with 1 N HCI to pH 2-3.
  • Step a) (1 R,2R)-2-(5-(4-bromophenyl)-1 H-imidazol-2-yl)-N-methylcvclopentanecarboxamide (BB77-a) DIPEA (330 mg, 2.56 mmol) was added to a solution of BB52-d (250 mg, 0.64 mmol) in DMF (3 mL) at to 0° C, followed by addition of HATU, The reaction was stirred for 3 min, then MeNH 2 in EtOH (0.16 mL, 1.3 mmol) was added in one portion and the cooling was removed.
  • the title compound was prepared by chlorination of BB77-b (100 mg, 0.287 mmol) with N- chlorosuccinimide according to the method described for the preparation of BB68. Yield: 38 mg, 35%.
  • BB78-C (160 mg) was reacted with 2, 4'-dibromoacetophenone (302 mg, 1 .1 mmol) according to the procedure described in BB3 step a.
  • the afforded residue was dissolved in toluene (50 mL); NH 4 OAc (2.2 g, 28.6 mmol) was added and the mixture was stirred for 8h at 95
  • Step f) ((3R,4R)-4-(5-(4-Bromophenyl)-1 H-imidazol-2-yl)-1-oxidotetrahydrothiophen-3-yl)((R)-3- methylmorpholino)methanone (BB78-f)
  • Step b) (1 R,3S.5R)-Tert-butyl 3-(5-(4-bromophenyl)-1 H-imidazol-2-yl)-2- azabicyclor3.1.Olhexane-2-carboxylate (BB79-b)
  • Boc 2 0 (1.39 g, 6.42 mmol) were added at 0 °C.
  • the reaction mixture was warmed to rt and stirred for 3h, then concentrated under reduced pressure.
  • Trifluoroacetic acid 5 ml was added to a solution of BB79-b (890 mg, 2.22 mmol) in DCM (5 ml). The mixture stirred for 5 hours at room temperature, then concentrated.
  • Triphenylphosphine (4 g, 16 mmol) and a 40% wt solution of DEAD in toluene (7 ml, 15 mmol) was added at rt to a solution of BB80-C (3 g, 9.4 mmol) in THF (120 mL) The resulting mixture was stirred for 18 h and then concentrated. The residue was purified by column

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Abstract

L'invention concerne des composés de formule (I) : dans laquelle les Cycles A et A' sont indépendamment des hétérocycles aromatiques, éventuellement substitués, à 5 chaînons; Q est C(=O)NR1R1' ou la formule U est C(R4)2, O, S, S(=O)2, C(R4)2C(R4)2, CH2O, OCH2, CH2S, SCH2, CH2S(=O)2, S(=O)CH2 or C=C(Ru )2; X est CH2, CHR12, CR12R12, O, S, S(=O)2 ou NRx; m est 0, 1, 2 ou 3; n est 0, 1, 2 or 3; les autres variables sont telles que définies dans les revendications. Ces composés sont utiles dans le traitement ou la prophylaxie d'une infection par le virus de l'hépatite C, et des aspects apparentés.
PCT/SE2012/051426 2011-12-20 2012-12-19 Nouveaux inhibiteurs du virus de l'hépatite c WO2013095275A1 (fr)

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WO2022264037A1 (fr) * 2021-06-14 2022-12-22 Intrabio Ltd. Dérivés d'acides aminés à chaîne ramifiée pour traiter une maladie

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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
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
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