EP2344487A1 - Composés inhibiteurs de l'hépatite c - Google Patents

Composés inhibiteurs de l'hépatite c

Info

Publication number
EP2344487A1
EP2344487A1 EP09815517A EP09815517A EP2344487A1 EP 2344487 A1 EP2344487 A1 EP 2344487A1 EP 09815517 A EP09815517 A EP 09815517A EP 09815517 A EP09815517 A EP 09815517A EP 2344487 A1 EP2344487 A1 EP 2344487A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
compound
substituted
cycloalkyl
halogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP09815517A
Other languages
German (de)
English (en)
Other versions
EP2344487A4 (fr
Inventor
Jeffrey O'meara
Josée BORDELEAU
Vida Gorys
Mélissa LEBLANC
Kirsten Lenhardt
Montse Llinas-Brunet
Mathieu Parisien
Marc-André Poupart
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim International GmbH
Original Assignee
Boehringer Ingelheim International GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Boehringer Ingelheim International GmbH filed Critical Boehringer Ingelheim International GmbH
Publication of EP2344487A1 publication Critical patent/EP2344487A1/fr
Publication of EP2344487A4 publication Critical patent/EP2344487A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • 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
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0808—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to compounds, processes for their synthesis, compositions and methods for the treatment of hepatitis C virus (HCV) infection.
  • HCV hepatitis C virus
  • the present invention provides novel peptide analogs, pharmaceutical compositions containing such analogs and methods for using these analogs in the treatment of HCV infection.
  • HCV hepatitis C virus
  • HCV is an enveloped positive strand RNA virus in the genus Hepacivirus in the Fiavivm ⁇ ae family
  • the single stran ⁇ HCV RNA genome is approximately 9500 nucleotides in length and has a single open reading frame (ORF), f ⁇ an ⁇ ed by 5' ana 3' non-translated regions
  • the HCV 5' non-translated region is 341 nucleotides in iength and functions as an internal ⁇ bosome entry site for cap-independent translation initiation
  • the open reading frame encodes a single large polyprotein of about 3000 ammo acids which is cleaved at multiple sites by cellular and viral proteases to produce the mature structural and non-structural (NS2 NS3 NS4A, NS4B NS5A, and NS5B) proteins
  • the viral NS2/3 protease cleaves at the NS2- NS3 junction while the viral NS3 protease mediates the cleavages downstream of !
  • HCV NS3 protease inhibitors The first evidence of the clinical antiviral activity of HCV NS3 protease inhibitors is provided by the results of a two day dinical trial, which indicate that the HCV NS3 protease inhibitor BiLN 2081 is effective m rapidly reducing viral loads m patients infected with the hepatitis C virus (Gastioenterology (2004) 127(5) 1347-1355) More recently, in 14- and 28-day dinical trials with the HCV NS3 protease inhibitor VX-95Q, alone (Gastroenterology (2006) 131 (4) 997-1002) or in combination with pegylated interferon with or witnout ribavirin, viral load for most HCV patients rapidly decreased to undetectable levels dunng treatment (Hepatology i 2006) 44(4 s1 ) 532A and 614A)
  • R 2 may be O-R 2 Q and R 2 Q nay be a Het, either unsubstituted or mono-, d ⁇ - or tri-substituted, are described as hepatitis C viral NS3 protease inhibitors, an enzyme essential for the replication of the hepatitis C virus
  • Oral administration is one of the most commonly used drug dosing route.
  • In vitro approaches evaluating absorption distribution, metabolism and excretion have been developed to speed up characterization of the increased number of compounds synthesized in drug discovery programs These experiments are designed to identify candidates that are most likely to have adequate PK profile (Prediction of pharmacokinetic properties using experimental approaches during early drug discovery, Pravin R Chalurvedi * , Caroline J Decker and Aieksandrs Odinecs Current Opinion in Chemical Biology, 2001 , 5 452-463.) but do not yet replace in vivo methods (Pharmacokinetics and metabolism in early drug discovery, Dennis A Smith and Han van de Wate ⁇ eemd. Current Opinion in Chemical Biology, 1999. 3, 373-378) herein incorporated by reference.
  • the rat is among the most commonly used animal in preclinical PK studies and the fraction of oral dose absorbed in rats can be correlated to that observed in humans for many drugs (Lmear correlation of the fraction of oral dose absorbed of 64 drugs between humans and rats. Win L. Chiou and Abhyit Barve Pharmaceutical Research,Mo ⁇ . 15 No. 1 1 , 1792-1795,1998), herein incorporated by reference.
  • the present invention provides a novel series of compounds having at least one of the following surprising advantages:
  • One aspect of the invention provides a racemate, diastereoisomer, or optical isomer of a compound of Formula (I):
  • R 3 is (C 2 - 8 )alkyl, (C ⁇ cycloalkyl or (C 1-3 )alkyl-(C 3-7 )cycloalkyl, wherein each of said alkyl, cycloalkyl, and alkyl-cycloalkyl groups may be mono-, di- or tri- substituted with (C 1-4 )alkyl;
  • L 0 is halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, -NH 2 , -NH(C 1-4 )alkyl or -N((C 1-4 )alkyl) 2 ;
  • L 1 is halogen, (C 1-4 )alkyl, -O-(Ci ⁇ )alkyl, -S-(C 1-4 )alkyl, -SO-(d ⁇ )alkyl, or -SO 2 - (Ci- 4 )alkyl, wherein each of said alkyl groups is optionally substituted with from one to three halogen atoms;
  • R 2 is -NR 22 COR 20 , -NR 22 COOR 20 , -NR 22 R 21 or -NR 22 CONR 21 R 23 , wherein
  • R 20 is (C 1- ⁇ )alkyl, (C ⁇ cycloalkyl or (C 1 . 4 )alkyl-(C 3-7 )cycloalkyl, wherein said alkyl, cycloalkyl or alkyl-cycloalkyl may be mono-, di- or tri-substituted with
  • R 21 is H or R 20 as defined above, R 22 and R 23 are independently H or methyl, R 1 is (C 1-4 )alkyl, (Cjwjalkenyl or (C ⁇ Jcycloalkyl;
  • R c is hydroxy or NHSO 2 R 8 wherein R s is (C 1- ⁇ )alkyl, (C ⁇ Jcycloalkyl, (C 1-6 )alkyl- (C 3-7 )CyClOaI kyl, aryl or Het; each of which optionally being mono-, di- or tri- substituted with substituents selected from halogen, hydroxy, cyano, (C 1-4 )alkyl, O-(C 1-6 )alkyl, -CO-NH 2 , -CO-NHfd ⁇ alkyl, -CO-Ntfd- ⁇ alkylk, -NH 2 , -NH(C 1-4 )alkyl and -N((C 1-4 )alkyl) 2 , wherein (C 1-4 )alkyl and O-(C 1-6 )alkyl are optionally substituted with one to three halogen atoms;
  • alkyl and O-alkyl groups may be optionally substituted with 1 to 3 halogen atoms; and wherein Het is a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O 1 N and S 1 or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 ;
  • compounds according to this invention exhibit one or more of the following surprising advantages: « unexpectedly good cell-based potency; and/or * unexpectedly good DMPK profile.
  • Another aspect of this invention provides compounds of Formula (!) showing at least one of the following surprising advantages:
  • Another aspect of this invention provides a compound of formula (I), or a pharmaceutically acceptable salt or ester thereof, as a medicament.
  • composition comprising an anti-hepatitis C viraliy effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt or ester thereof, in admixture with at least one pharmaceutically acceptable carrier medium or auxiliary agent.
  • the pharmaceutical composition according to this invention further comprises a therapeutically effective amount of at least one other antiviral agent.
  • the invention also provides the use of a pharmaceutical composition as described hereinabove for the treatment of a hepatitis C viral infection in a mammal having or at risk of having the infection.
  • Another important aspect of the invention involves a method of treating or preventing a hepatitis C viral infection m a mammal by administering to the mammal an anti-hepatitis C viraily effective amount of a compound of Formula (! ⁇ , a pharmaceutically acceptable salt or ester thereof, or a composition as described above, alone or in combination with at least one other antiviral agent, administered together or separately.
  • An additional aspecl oi this invention refers to an article o1 man ⁇ _1aclure comprising a composition effective to treat a hepatitis C virai infection, and packaging material comprising a labei which indicates that the composition can be used to treat infection by the hepatitis C virus, wherein the composition comprises a compound of formula (i) according to this invention or a pharmaceutically acceptable salt or ester thereof
  • Still another aspect of this invention reiates to a method of inhibiting the replication of hepatitis C virus comprising exposing the virus to an effective amount of the compound of formula (I) or a salt or ester thereof, under conditions where replication of hepatitis C virus is inhibited
  • the invention is the use of a compound of formula (I), or a salt or ester thereof, to inhibit the replication of hepatitis C virus
  • Yet another aspect of this invention provides a method of inhibiting HCV NS3 protease activity in a mammal by administering a compound of Formula (I), including a pharmaceutically acceptable salt or ester thereof
  • Another aspect of this invention provides a method of decreasing the NS3 protease activity of the hepatitis C virus infecting a mammal by administering a compound of Formula (!), including a pharmaceutically acceptable salt or ester thereof
  • 'vinyl-AGCA refers to a compound of formula
  • ethyl-ACCA refers to a compound of formula
  • cyclopropyl-ACCA refers to a comoound of formula
  • (C 1 )a!k ⁇ i means acyclic, straight or branched chain aikyi suDstiluents containing from 1 to n carbon atoms
  • "(C & )alkyl” includes, but is not iimite ⁇ to, methyl, ethyl, n- propyi n-bulyl, 1-melhy!ethyl (i-propyl), 1-methylpropyl 2-methylpropyl, 1 ,1- dimethylethyl (te/f-butyl), penty! and hexyi
  • Me and Pr denote a methyl group and n-propy! respectively
  • C 0 -jcycloalkyi as used herein, either aione or in combination with another substituent, ⁇ eans a cycloalkyl substituent containing from 3 to n carbon atoms and includes, but is not limited to cyciopropyl cyciobutyi cyciopentyl, cyclohexyi and cycloheptyi
  • (C 3 )cyc!oa!kenyl as used herein, either alone or in combination with another substituent, means an unsaturated cychc radicai containing from 3 to n carbon atoms and includes, but is not limited to, cyclopropenyl, cyclobutenyi, cyclopentenyi, cyciohexenyl and cycloheptenyl
  • (C 1 -)a!kyi-(C u P )cycloalkyr as used nerein means an alkylene radical containing 1 to n carbon atoms to which a cycioaikyi radical containing from 3 to n carbon atoms is directly linked, and includes, but is not limited to, cyclopropyimethyi, cyclobutylmethyl, cyclopentylmetnyi, 1-cycio ⁇ entyiethyi. 2-cydopentyiethy!, cyciohexyimethyl, 1-cyciohexyiethyi, 2-cyclohexyiethyi and cycloheptyi propyl
  • (Ci n )aikyi-(C 3 r )cycloalkeny! as used herein means an aikylene radical containing 1 to n carbon atoms to which a cycloalkenyl radicai containing from 3 to n carbon atoms is directly linked and includes, but is not limited to, cyclopropenylmethyl, cyclobutenyimethyl, cyclopentenylmethyi, 1- cyclopenlenyielhy!, 2-cyclopentenylethyi, cyclohexenylmethyl, 1-cyclohexenylethyl, 2-cyc ⁇ onexenylethy ⁇ and cycloheptenylpropyl
  • O-(C. n )aikyi ' or "(C 1 n )a!koxy' as used nerein, eitner alone or in combination with another radical, means the radical -O-(Ci n )aikyl wherein aikyi is as defined above containing from 1 to n carbon atoms, and includes methoxy, ethoxy.
  • (C 2 -,)aikeny!' is understood to encompass individual stereoisomers where possible, including but not limited to (E) and (Z) isomers, and mixtures thereof
  • a (C 2 n )alkeny! group is substituted it is understood to be substituted on any carbon atom thereof which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by those skilled in the art
  • aryl as usec herein, either aione or in combination with another radicai, is intended to mean a carbocyclic aromatic monocyclic group containing 8 carbon atoms which may be further fused to a second 5- or 6-membered carbocyciic group which may be aromatic, saturated or unsaturated
  • Aryl includes, but is not limited to, phenyl, mda ⁇ yl, indenyl, 1-naphthyl, 2-na ⁇ hthyi, tetrahydronaphthyl and dihydronaphthyl
  • cyano or "CN” as used herein is intended to mean a nitrogen atom attached to a carbon atom by a triple bond (C ⁇ N)
  • haio or “haiogen” as used herein means a halogen substituent selected from fluoro, chioro bromo or iodo
  • carbocyde or “caroocyclic” as usec herein, either aione or in combination with another radical, is intended to mean a cyclic compound, either aromatic or non- aromatic, saturated or unsaturated, in which all of the ring members are carbon atoms
  • the earboeyde group may contain 5 or 6 carbon atoms and may be further fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated
  • the carbocyde may be substituted When the carbocycie is substituted, it is understood that substituents may be attached to any carbon atom whicn would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound, such as are recognized by tnose skilled in the art
  • Net as used herein, either alone or in combination with another radical, is intended to mean a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated unsaturated or aromatic heteropoiycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, H and S, wherein each N heteroatom may, independently and where possibie exist in an oxidized state such that it is further bonded to an oxygen atom to form an N- oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 , unless specified otherwise
  • substituents may De attached to any- carbon atom or heteroatom tnereof which would otherwise bear a hydrogen atom, unless specified otherwise, such that the substitution would give rise to a chemically stable compound
  • (C 1 -)a!kyi-Het as used herein and unless specified otherwise, wherein n is an integer, either alone or in combination with another radical, is intended to mean an alky! radical having 1 to n carbon atoms as defined above which is itself substituted with a Net substituent as defined above
  • Examples of (C 1 ,)a!ky!-Het include, but are not limited to, thienylmethyl, furyimethyi, pipendinyiethyi 2- pyndinyimethyi, 3-pyr ⁇ d ⁇ nylmethyl, 4-pyr ⁇ d ⁇ nyimethyl, quinolinylpropyl, and the hke
  • substituents may be attached to either the Net or the alky! portion tnereof or both, unless specified otherwise, sucn that tne substitution would give rise to a chemically stable compound, sucn as are recognized by those skilled in the art
  • heteroatom as used herein is intended to mean O. S or N
  • heterocyde as used herein and unless specified otherwise, either alone or in combination with another radical, is intended to mean a 3- to 7-membered saturated, unsaturated or aromatic neterocyde containing from 1 to 4 neteroatoms each independently selected from O, N ana S, or a monovalent radical denve ⁇ by- removal of a hy ⁇ rogen atom lhereirom
  • Examples o! sucn heterocycie ⁇ include but are not limited to.
  • n is an integer, either alone or in combination with another radical, is intended to mean an sulfur atom further bonded to an alky! radical having 1 to n carbon atoms as defme ⁇ above
  • Examples o1 -S-(C- r )a ⁇ kyi include but are not limited to methylthio (CH 3 S-), ethyllhiQ (CH 3 CH 2 S-), propyithio (CHJDH 2 CH 2 S-), 1-methyietnyith ⁇ o
  • esters of the compound of Formula (I) m which any of the carboxyl functions of the molecule, but preferably the carboxy terminus, is replaced by an alkoxycarbonyi function in which the R moiety of the ester is selected from alkyl (including, but not limited to, methyl, ethyl, n-propyi, t-butyl, n-butyl).
  • aikoxyaikyl including, but not limited to methoxymethyi
  • alkoxyacyl including, but not limited to acetoxymethyi
  • alkyl-aryi including, but not limited to benzyl
  • aryloxyaikyl including, but not limited to phenoxymethyi
  • esters advantageously contains 1 to 16 carbon atoms, particularly 1 to 8 carbon atoms
  • Any aryl moiety present in such esters advantageously comprises a phenyl group
  • the esters may be a C ⁇ ⁇ 6 a'kyi ester an unsubstituted benzyl ester or a benzyl ester substituted with at least one halogen, C 1 6 alkyi, C, R aikoxy, nitro or tnfluoromethyl
  • pnarmaceutica ⁇ y acceptable salt means a salt of a compound of formula (!) which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, ana the hke, commensurate with a reasonable benefit/risk ratio generally water or oil-soluble or cispersible, and effective for their intended use
  • the term includes pnarmaceuticaily-acceptabie acid addition salts and pharmaceuticaliy-acceptable base addition salts Usts of suitable salts are found in, e g , S M Berge et ai , J Pharm Sc* , 1977, 66, pp 1-19, herein incorporated by reference
  • pharmaceuticaily-acceptabie acd addition salt means those salts which retam the biological effectiveness and properties of the free bases and which are not biologically or otherwise undesirable formed with inorgamc acids such as hydrochloric acid hy ⁇ robromic acid sulfuric a& ⁇ , sulfamic acid, nitnc acid, phosphoric aciCi, and the like, and organic aci ⁇ s such as acetic acid, tnfluoroacetic acid, adipic acid ascorbic acid, aspartic acid, benzenesuifomc acid, benzoic acid, butyric acid, camphoric a ⁇ , eamphorsuilonic acic, cinnamic acid, citric aod, digiuconic acid, ethanesulfonic aod, glutamic acid, glycolic acic, giycerophosphoric acid, nemisuliic acid, hexanoic acid, 1
  • pharmaceuticalaily-acceptaDle base a ⁇ dilion salt means tnose salts which retain the biological effectiveness and properties of the free acids and which are not biologically or otherwise undesirable, formed with inorganic bases such as ammonia or hydroxide, carbonate, or bicarbonate of ammonium or a metal cation such as sodium, potassium lithium calcium, magnesium, iron, zinc, copper, manganese, aluminum and the like Particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts.
  • Salts derived from pharmaceuticaliy- acceptable organic nontoxic bases include salts of primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines including naturally occurring substituted amines cyclic amines and basic ion-exchange resins, such as methylamine dimethylamine, tnmethylamme, ethylamme, diethylamine, triethylamine, isopropylamine tripropylamine, t ⁇ butylamine, ethanoiamine, diethanoiamine, 2-d ⁇ methylam ⁇ noethanol, 2-d ⁇ etnyiam ⁇ noethano ⁇ , dicyciohexylamine, lysine, arginme, histidine, caffeine, hydrabamine, cnohne, betaine, ethylenediamine, glucosamine, methyiglucamme, theobromine, purines, piperazine, piperidine, N- ethylpipe
  • Particularly preferred organic nontoxic bases are isopropylamine. diethylamine, ethanoiamine, t ⁇ methylamme, dicyciohexylamine, choline, and caffeine.
  • mammal as it is used herem is meant to encompass humans, as well as non-human mammals which are susceptible to infection by hepatitis C virus inducing domestic animals, such as cows, pigs, horses, dogs and cats, and non- domestic animals
  • antiviral agent means an agent (compound or Dioiogical) that is effective to inhibit the formation and/or replication of a virus in a mammal This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of a virus in a mammal. Such agents can be selected from another anti-HCV agent, HiV inhibitor.
  • HAV inhibitor and HBV inhibitor Antiviral agents include, for example ribavirin, amantadine, VX-497 (me ⁇ mepodib, Vertex Pharmaceuticals), VX-498 (Vertex Pharmaceuticals), Levovi ⁇ n, Virami ⁇ ine, Cepiene (maxarnine), XTL-001 and XTL-002 (XTL Biopnarmaceuticals)
  • other anti-HCV agent means those agents that are effective for diminishing or preventing the progression of hepatitis C related symptoms of disease
  • agents can be selected from immunomodulatory agents inhibitors of HCV NS3 protease, inhibitors of HCV polymerase or inhibitors of another target in the HCV life cycle
  • Immunomodulatory agent includes those agents (compounds or biologicais) that are effective to enhance or potentiate the immune system response in a mammal
  • Immunomodulatory agents include, but are not limited to, inosine monophosphate dehydrogenase inhibitors sucn as VX-497 (menmepodib, Vertex Pharmaceuticals), rouge I interferons, rouge M interferons, consensus interferons, asialo-interferons pegylated interferons and conjugated interferons, including but not limited to interferons conjugated with other proteins including but not limited to human albumin
  • Class I interferons are a group of interferons that all bind to receptor type I, including both naturally and synthetically produced class I interferons, while class M interferons ail bind to receptor type M.
  • class i interferons include, but are not limited to, ⁇ -, ⁇ , ⁇ -. to-, and ⁇ -mterferons
  • class Il interferons include, but are not limited to, -> ⁇ interferons
  • inhibitor of HCV NS3 protease means an agent (compound or biological) that is effective to inhibit the function of HCV NS3 protease in a mammal
  • Inhibitors of HCV NS3 protease include, for example, those compounds described in VVO 99/07733, WO 99/07734. WO 00/09558, WO 00/09543.
  • WO 00/59929 WO 03/064416, WO 03/064455, WO 03/064456, WO 2004/030670, WO 2004/037855, WO 2004/039833, WO 2004/101602, WO 2004/101605, WO 2004/103996, WO 2005/028501 , WO 2005/070955, WO 2006/000085, WO 2006/007700, WO 2006/007708, WO 2007/009227 (all by Boehringer Ingelheim), WO 02/080926 WO 03/053349 WO 03/099274, WO 03/099316, WO 2004/032827, WO 2004/043339, WO 2004/094452, WO 2005/046712, WO 2005/051410, WO 2005/054430, WO 2006/122188, WO 2007/056120, WO 2007/044933, WO 2007/008657, WO 2008/008776, WO 2008/064066, WO 2008
  • inhibitor of HCV polymerase means an agent (compound or biological) that is effective to inhibit the function of an HCV polymerase in a mammal
  • WO 2007/033175 WO 03/026587 WO 2007/143521 WO 2007/140109 WO 2007/140200, VVO 2007/140254, WO 2007/136982, WO 2007/092000, WO 2007/092888, WO 2006/020082, US 2005/01 19318, WO 2005/034850 (all by Bristol-Myers Squibb), VVO 2007/034127 (Arrow Therapeutics Limited), WO 2005/063734 (Bayer), VVO 03/093290, WO 2005/012288, WO 2008/01 1521 , VVO 2008/008907, WO 2008/008912, WO 2007/084157, WO 2007/019397, WO 2006/138744, WO 2006/121468, WO 2006/1 16557, WO 2006/102594, WO 2006/076529, WO 2006/075993, US 2006/01 1131 1 , WO 2005/054268, WO 2005/042556, US 2005/009046
  • WO 02/094289 WO 02/18404 (ail by F. Hoffmann-La Roche).
  • WO 2007/039142 WO 2007/039145, VVO 2007/039144, VVO 2006/045613, VVO 2006/045615, WO 2005/103045, VVO 2005/092863, VVO 2005/079799, VVO 2004/096774, WO 2004/096210, VVO 2004/076415, VVO 2004/060889, VVO
  • US 2004/0229840 (all by Merck and Co.), WO 2006/018725, WO 2004/073599. WO 2004/074270.
  • WO 03/095441 , WO 03/082848 (ail by Pfizer).
  • WO 2004/002940 (all by Pharmacia & Upjohn Company), WO 00/04141 (Ribozyme).
  • WO 2006/050035 (Sche ⁇ ng), WO 2006/050034 (Sche ⁇ ngj, US 2003/0203948 (Shionogi).
  • WO 02/20497 (Shionogi), WO 2005/121132 (Shionogi) EP 1321463 (Shire Biochem).
  • WO 02/100851 (Shire Biochem), WO 02/100846 (Shire Bioche ⁇ ), WO 03/061385, WO 03/062256, WO 03/062255, US 6,906.190, WO 2004/080466 (all by Ribapharm), WO 2007/026024 (Tibotec), WO 2006/065590 (XTL Biopharmaceuticals), WO 2008/051244, WO 2007/092558, WO 2006/034337, WO 03/099275, WO 03/099824 (ail by Wyeth). WO 03/059356, WO 01/85172, WO 01/85720.
  • inhibitor of another target in the HCV life cycle means an agent (compound or biologicai) that is effective to inhibit the formation and/or replication of HCV in a mammal other than by inhibiting the function of the HCV NS3 protease.
  • Inhibitors of another target in the HCV life cycle include, for example, agents that inhibit viral targets such as Core E1 , E2, p7, NS2/3 protease, NS3 nehcase, NS4A NS5A, NS5B polymerase, and internal ⁇ bo ⁇ ome entry site (IRES), or host targets such as cyclophilin B, phosphatidylmositoi 4-k ⁇ nase IHu, CD81 , SR-B1 Ciaudin 1 VAP-A, VAP-B Specific examples of inhibitors of another target in the HCV life cycle include !SIS-14803 (ISIS Pharmaceuticals), GS9190 (G'lead), GS9132 (G ⁇ ead), A-831 (AstraZeneca) NM-811 (Novartis), and DEBIO-0
  • HIV inhibitor means an agent (compound or biological) that is effective to inhibit the formation and/or replication of HIV in a mamma! This induces agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HIV in a mammal HIV inhibitors include, for example nucleoside inhibitors, non- ⁇ iideoside inhibitors, protease inhibitors, fusion inhibitors and integrase inhibitors
  • HAV inhibitor means an agent (compound or bioiogica!) that is effective to inhibit the formation and/or replication of HAV in a mammal This includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HAV in a mammal HAV inhibitors include Hepatitis A vaccines, for example, HaVnX* (GlaxoSmithKlme), VAQT A* (Merck) and Avaxim ⁇ (Aventis Pasteur)
  • HBV inhibitor' as used herein means an agent (compound or bioiogical) that is effective to inhibit the formation and/or replication of HBV in a mammal Tlrs includes agents that interfere with either host or viral mechanisms necessary for the formation and/or replication of HBV in a mammal HBV inhibitors include, for example, agents that inhibit HBV viral DNA polymerase or HBV vaccines Specific examples of HBV inhibitors include Lamivudi ⁇ e (Epivir-HBV 3 ), Adefovir Dipivoxil, Entecavir.
  • FTC (Coviracil '5 '), DAPD (DXG), L-FMAU (Cievudine * ) AM365 (Amrad), Ldt (Teibivudine), monovai-LdC (Valtorcitabme) ACH-126,443 (L-Fd4C) (Achilhon).
  • MCC478 (Eh Lilly), Racivir (RCV) Fluoro-L and D nucleosides Robustallavone, ICN 2001-3 (ICN).
  • Bam 205 Novels
  • XTL-001 XTL
  • Immo-Sugars Nonyi-DNJ
  • HepBzyme and immunomoduiator products such as interferon alpha 2b, HE2000 (HoHis-Eden), Theradigm (Epimmune).
  • EHT899 (Enzo Biochem)
  • Thymosin alpha- 1 Zadaxin*
  • HBV DNA vaccine PowderJect
  • HBV DNA vaccme Jefferon Center
  • HBV antigen OraGen
  • BayHep B' s Bayer
  • Nabi-HB ⁇ Nabi
  • Anti-hepatitis B Cangene
  • HBV vaccme products such as the following Enge ⁇ x B, Recombivax HB, GenHevac B, Hepacare, Bio-Hep B, TwinRix, Comvax, Hexavac
  • antiviral agents ribavirin or amantadine
  • immunomodulatory agents class I interferons, class Ii interferons or pegylated forms tnere ⁇ f,
  • HCV polymerase inhibitors nucleoside analogs or non-nucleosides, 5 1 inhibitor of another target in the HCV hie cycie that inhibits a target selected from NS3 hehcase, NS2/3 protease, interna* ⁇ bosome entry site (IRES), NS ⁇ A, NS5A, NS5B polymerase, or host targets such as cyclophilin A or B,
  • HIV inhibitors nucleoside inhibitors, non-n ⁇ cleosidic inhibitors, protease inhibitors, fusion inhibitors or mtegrase inhibitors, or * HBV inhibitors agents that inhibit virai DMA polymerase or is an HBV vaccine
  • a compound of formula (! ⁇ , or a pharmaceutically acceptable salt thereof is co-ad ministered witn at least one additional agent selected from an antiviral agent, an immunomodulatory agent, another inhibitor of HCV NS3 protease, an inhibitor of HCV polymerase an innibitor of another target in the HCV life cycie, an HIV mniDilor, an HAV inhibitor and an HBV inhibitor Examples of such agents are provided in the Definitions section above
  • additional agents may be combined witn the compounds of this invention to create a single pharmaceutical dosage form Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a kit Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of formula (i), or a pharmaceutically acceptable salt thereof
  • the term 'treatment means the administration of a compound or composition according to the present invention to alleviate or eliminate symptoms of the hepatitis C disease and/or to reduce viral load in a patient
  • prevention means tne administration of a compound or composition according to the present invention post-exposure of the individual to the virus Dut before the appearance ot symptoms oi the disease and/or prior to the detection o1 the virus in the blood, to prevent the appearance of symptoms ot the disease
  • terapéuticaally effective amount means an amount of a compound according to the invention which when administered to a patient in need thereof, is sufficient to effect treatment for disease-states, conditions, or disorders for which the compounds have utility. Such an amount would be sufficient to elicit the biological or medical response of a tissue system, or patient that is sought by a researcher or clinician.
  • the amount of a compound according to the invention which constitutes a therapeutically effective amount will vary depending on such factors as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type of disease-state or disorder being treated and its severity, drugs used in combination with or coincidentally with the compounds of the invention, and the age, body weight, general health, sex and diet of the patient.
  • a therapeutically effective amount can be determined routinely by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.
  • B is aryl or Het, optionally mono-, di- or tri-substituted with halogen, hydroxy, (d-ejalkyl, O-tC ⁇ alkyl, O-aryl, O-Het, S-(C 1-6 )alkyl, -CO-(C ⁇ )alkyl, -CO-NH 2 , -CO-NH(C ⁇ )alkyl, -CO-N((C 1-4 )alkyl) 2 , -NH 2 , -NHfC ⁇ Jalkyl and -N((C 1 _ 4 )alkyl) 2l wherein said alky!
  • O-alkyl groups may be optionally substituted with 1 to 3 halogen atoms; and wherein Het is defined as a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 5 heteroatoms, each independently selected from O, N and S, wherein each N heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to an oxygen atom to form an N-oxide group and wherein each S heteroatom may, independently and where possible, exist in an oxidized state such that it is further bonded to one or two oxygen atoms to form the groups SO or SO 2 .
  • Het is defined as a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 4 heteroatoms each independently selected from O, N and S, or a 7- to 14-membered saturated, unsaturated or aromatic
  • B is aryl or Het, optionally mono-, di- or tri-substituted with halogen, hydroxy, (C ⁇ alkyl, O-(C ⁇ )alkyl, O-aryl, O-H ⁇ t, S-(C 1-6 )alkyl, -CO-(C ⁇ )alkyl, -NH 2 , -NH(C 1-4 )alkyl and -N((C ⁇ )alkyl) 2 , wherein said alkyl and O-alkyl groups may be optionally substituted with 1 to 3 halogen atoms; and wherein Het is defined as a 4- to 7-membered saturated, unsaturated or aromatic heterocycle having 1 to 3 heteroatoms each independently selected from O 1 N and S, or a 7- to 14-membered saturated, unsaturated or aromatic heteropolycycle having wherever possible 1 to 3 heteroatoms, each independently selected from O, N and S.
  • B is aryl or Net, optionally mono-, di ⁇ or tri-substituted with halogen, (Ci_ 6 )a!kyi, O-(Ci -6 )alkyl, O-aryl, O-Het or S-(Ci_ 6 )a!kyi. wherein said aikyl and O-alkyl groups may be optionally substituted with 1 to 3 halogen atoms; and wherein the Net group is defined as:
  • B is C( ⁇ Q)-R 4 : wherein R 4 is (Chalky!, (C 3 . 5)cycloalkyi, (Ci.?)a!kyl-(C3.5)cycloalky!, (Ci.2)alky!-(C 3 ⁇ )cyc!oaikenyl or G 6 - aryl; ail of which being optionally substituted 1 to 3 times with (Ci ⁇ )alkyl; or B is aryi or Het, optionally mono-, di- or tn-substituted with halogen, hydroxy, (Ci. 4 )aikyl, O-(C 1 .
  • B-F In another embodiment, B is C( ⁇ Q)-R 4 wherein R 4 is (Chalky!, (C 3
  • B is aryi or Het, optionally mono- or di-substituted with halogen, (Chalky!, O-(Ci_6)alkyl, O-phenyi, O-tetrahydropyranyl, S-(Ci_6)a!kyl, wherein said aikyl and O-alkyl groups may be optionally substituted with 1 to
  • B is aryl or Het, optionally mono-, di- or tri-substituted with halogen, hydroxy, (C ⁇ alkyl, O- (C 1-4 )alkyl, O-phenyl, O-tetrahydropyranyl, S-(C 1 ⁇ )alkyl, wherein said alkyl and O-aikyi groups may be optionally substituted with 1 to 3 halogen atoms' and wherein tne Het group is ⁇ eimed as
  • R 3 is (C ? e )alky! (C , ,.)cyc!oa!kyi or (C 1 ,)alky!-(C 3 , ' )cye!oaiky!, wherein each of said alkyl, cycloalky!, and alkyl-cydoaikyl groups may De mono-, di- or tn-suDstiluted with (C 1 4 )a!kyi R 3 -B- In another embo ⁇ iment, R 3 is (C 2 6 )alkyl (C 3 ,-)cycloalky ⁇ or (C 1 3 )alky!-(C , ' )cycloaiky ⁇ , wherein each of said alkyl, cycloalky!, and alkyl-cydoaikyl groups may De mono- or di-suDsMuted with (C- 3 )a ⁇ kyl
  • R 3 is ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyciopentyi or eydohexyl, each of which optionaliy being substituted with 1 or 2 substituents selected from methyl, ethyl and propyl
  • R 3 is 1-methylethyl, 1 1-d ⁇ methylethyl, 1-methyipropyl, 2-methyl propyl, 1 ,1-d ⁇ methyipropyl, 1.2-d ⁇ methylpropyi
  • R J -E I n another embodiment, R 3 is
  • R J any and each individual definition of R J as set out herein may be combined with any and each individual definition of R 1 R 2 , R c , B, L s and L 1 as set out herein
  • L 0 L°-A In one embodiment, L 0 is halogen, (C 1-4 )alkyl, -OH, -O-(C 1-4 )alkyl, " NH 2 . -
  • L 0 is halogen, (C 1-4 )alkyl or -0-(C 1 ⁇ JaI kyl.
  • L 0 is (C 1-4 )alkyl or -O-(C 1 ⁇ )alkyl.
  • L°-D In another embodiment, L 0 is -O-tC ⁇ alkyl.
  • L 0 is -O-(Ci -2 )alkyl.
  • L 0 is -OCH 3 .
  • L 0 any and each individual definition of L 0 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R 3 , R c , B and L 1 as set out herein.
  • L 1 is halogen, (C 1-4 )alkyl, -O-(C 1-4 )alkyl, -S-(C 1 ⁇ JaI kyl, -
  • L 1 -B In another embodiment, L 1 is halogen, (C 1-4 )alkyl or -O-(C 1-4 )alkyl.
  • L 1 -C In another embodiment, L 1 is -CH 3 , -C 2 H 5 , -C 3 H 7 , -F, -Cl, -Br 1 -OCH 3 , -OC 2 H 5 or -OC 3 H 7 .
  • L 1 -D In another embodiment, L 1 is -CH 3 , -C 2 H 5 , -Cl or -Br.
  • L 1 -E In another embodiment, L 1 is CH 3 , -Cl or -Br.
  • L 1 any and each individual definition of L 1 as set out herein may be combined with any and each individual definition of R 1 , R 2 , R c , R 3 , B and L 0 as set out herein.
  • R 2 -A In one embodiment, R 2 is -NR 22 COR 20 , -NR 22 COOR 20 , -NR 22 R 21 or -
  • R 20 is (C 1- ⁇ )alkyl, (C ⁇ Jcycloalkyl or (C 1 ⁇ )alkyl-(C 3-7 )cycloalkyl, wherein said alkyl, cycloalkyl or alkyl-cycloalkyl may be mono-, di- or tri-substituted with (C 1-3 )alkyl or -O(C 1-3 )alkyl;
  • R 21 is H or R 20 as defined above,
  • R 22 and R 23 are independently H or methyl.
  • R 2 -B In another embodiment, R 2 is -NR 22 COR 20 , -NR 22 COOR 20 or -NR 22 R 21 , wherein R 20 is (C 1 6 )aikyi, (C 3 . 7 )cycloalky! or (C,.,:)aikyl ⁇ (C 3 7 )cydoa!kyl, wherein said alkyi, cycloalkyl or alkyl-cycioaikyl may be mono-, di- or tri-subslituled With (C 1 3 )alkyl or -O(C 1 3 )alkyl; R 21 is H or R 20 as defined above, R 22 is H or methyl.
  • R 2 -C in another embodiment, R 2 is -N(H)COR 28 , -N(H)COOR 20 or -N(H)R 21 , wherein
  • R 20 is (Ci_ 6 )alkyl or (C 3 - 7 )cycioaikyl, wherein said alkyi or cydoalky! may be mono- or di-substituted with (Ci. 3 )alkyl or -O(Ci. 3 )alkyl;
  • R 21 is R 20 as defined above.
  • R 2 -D in another embodiment, R 2 is -N(H)COR 20 , -N(H)COOR 20 or -N(H)R 21 , wherein
  • R 20 is is (C- M )aikyi or (C 3-5 )cyc!oa!kyi, wherein said aikyi or cycioaikyi nay be mono- or di-substituted with (Ci -3 )alkyl or -O(Ci -3 )alkyl; and R 21 is R 20 as defined above.
  • R ? -E In another embodiment, R 2 is -N(H)CQR ?0 , -N(H)COOR 20 or -N(H)R 21 , wherein
  • R 20 is (Ci.i)alkyl or (C 3 . 5 )cycioaikyl, wherein said aikyi may be mono- or di- substituted with (C 1 3 )a!ky! or -0(C 1 3 )a!ky!: and R 21 is R 28 as defined above.
  • R 2 -F in st ⁇ l another embodiment, R 2 is
  • R c is hydroxy or NHSO 2 R 8 wherein R s is (C ⁇ Jalkyl,
  • R c -B In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R s is (C 1- ⁇ )alkyl,
  • R c -C In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is (C 1-e )alkyl,
  • R c -D In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is (Ci- ⁇ )alkyl,
  • R c -E In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is (C 1-6 )alkyl,
  • R c -F In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is
  • R c -G In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is cyclopropyl optionally being mono-substituted with (C M )alkyl.
  • R c -H In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 is
  • R c -I In another embodiment, R c is hydroxy or NHSO 2 R 8 wherein R 8 cyclopropyl.
  • R c -J In another embodiment, R c is hydroxy. Any and each individual ⁇ eiinition of R c as sel out herein may be combined witn any ana each individual definition o1 R 1 , R 2 , R 3 L 0 L 1 and B as sel out herein
  • R 1 is (C- i)alkyl, (C 24 )ai ⁇ enyi or (C 3 7 )cycloalkyi.
  • R 1 -B In another embodiment, R 1 is (C 2 i )alkyl, (C 2 4 )al ⁇ eny! or (C 3 5 )cycloal ⁇ yi. R 1 -C in another embodiment, R 1 is ethyl, vinyi or cyciopropyl
  • R 1 any and each individual definition of R 1 as set out herein may be combined with any and each individual definition of R 2 , R 3 R c L 0 L 1 and B as set out herein
  • R 1 is cyciopropyl
  • the asymmetric carbon atoms in the cyciopropy! group take the R, S configuration according to the subformula'
  • the pharmaceutical composition o! this invention nay additionally comp ⁇ se at least one other anti-HCV agent.
  • anti-HCV agents include, ⁇ - (alpha), ⁇ - (beta), ⁇ - (delta), y- (gamma), ⁇ - (omega) or ⁇ (tau) interferon, pegylated ⁇ 'nterferon, ribavirin and amantadine
  • the pharmaceutical composition of this invention may additionally comprise at least one otner inhibitor of HCV NS3 protease
  • the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of HCV polymerase
  • the pharmaceutical composition of this invention may additionally comprise at least one inhibitor of other targets in the HCV life cycle, including but not limited to, hehcase NS2/3 protease or internal ⁇ bosome entry site (IRES).
  • at least one inhibitor of other targets in the HCV life cycle including but not limited to, hehcase NS2/3 protease or internal ⁇ bosome entry site (IRES).
  • the pharmaceutical composition of this invention may be administered orally parenteraliy or via an implanted reservoir Orai administration or administration by iniection is preferred
  • the pharmaceutical composition of this invention may contain any conventional non-toxic pharmaceiilicaliy-acceptable carriers, adjuvants or venicles
  • the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases or buffers to enhance tne stability of the formulated compound c its delivery form.
  • parenteral as used herein ⁇ eludes subcutaneous, intracutaneous, intravenous, intramuscular, intra-articuiar, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques
  • the pharmaceutical composition may be in the form of a stenle injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension
  • This suspension may be formulated according to techniques known m the art using suitable dispersing or wettmg agents (such as, for example Tween 80) and suspending agents
  • the pharmaceutical composition of this invention may be orally administered in any oraily acceptable dosage form including, but not limited to, aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets
  • aqueous suspensions and solutions including, but not limited to, aqueous suspensions and solutions, capsules, powders, syrups, elixirs or tablets
  • earners which are commonly used include iactose and corn starch Lubricating agents such as magnesium stearate are aiso typically added For orai administration !
  • useful diluents include lactose and d ⁇ ed corn stanch
  • the active ingredient is combined with emulsifying and suspending agents
  • certain sweetening and/or flavoring and/or coloring agents may be ad ⁇ ed
  • systemic administration including but not limited to administration Dy subcutaneous intracutaneous, intravenous, intramuscular, intra-articiiiar, intrasynovial, intrasternal intrathecal and intralesional injection or miusion techniques, it is preferred to use a solution of the compound, or a pharmaceutically acceptable salt or ester thereof , in a pharmaceutically acceptable ste ⁇ le aqueous venicle
  • Dosage levels of between about 0 01 and about 100 mg/kg body weight per day preferably between about 0 1 and about 50 mg/kg body weight per day of the protease inhibitor compound described herein are useful in a monotherapy or in combination therapy 1or the prevention and treatment oi HCV mediated disease
  • the pharmaceutical composition of this invention will be administered 1rom about 1 to about 5 times per day or alternatively, as a continuous infusion
  • Such administration can be used as a chronic or acute therapy
  • the amount of active ingredient that may be combined with the earner materials to produce a single dosage form will vary depending upon the host treated and the particular node of administration
  • a typical preparation will contain from about 5% to aoout 95% active compound (w/w)
  • such preparations contain from about 20% to about 80% active compound
  • composition of this invention comprises a combination of a compound of Formula (!) and one or more additional therapeutic or prophylactic agent
  • both the compound and the additional agent should be present at dosage levels of between about 10 to 100%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen
  • the resulting composition may be administered in vivo to mammals, such as man to inhibit HCV NS3 protease or to treat or prevent HCV virus infection
  • mammals such as man to inhibit HCV NS3 protease or to treat or prevent HCV virus infection
  • Preferred other antiviral agents are described within the Delinitions section and the section of preferred pharmaceutical compositions according to this invention and include but are not limited to ⁇ , ⁇ -, ⁇ -, ro ⁇ , y- or ⁇ - mterferon ribavirin, amantadine, other inhibitors of HCV NS3 protease, inhibitors of HCV polymerase, inhibitors of other targets in the HCV life cycle, which include but are not limited to, heiicase, NS2/3 protease or interna! ⁇ bosome entry site (IRES). or combinations thereof
  • the additional agents may be combined with compounds of this invention to create a single dosage form Alternatively
  • another embodiment of this invention provides a method of inhibiting HCV NS3 protease activity in a mammal by administering a compound of the Formula (I) including a pharmaceutically acceptable sait o r ester thereof
  • this metnod is useful in decreasing the NS3 protease activity of the nepatitis C virus infecting a mammal
  • combination therapy is contemplated wherein a compound of formula (I), or a pharmaceutically acceptable sait or ester thereof, is co-administered with at ieast one additional antiviral agent
  • Preferred antiviral agents are described nereinbefore ana examples of such agents are provided in the Definitions section
  • These additional agents may be combined with the compounds of this invention to create a single pharmaceutical dosage form Alternatively these additional agents may be separately administered to the patient as part of a multiple dosage form, for example, using a Kit
  • Such additional agents may be administered to the patient prior to, concurrently with, or following the administration of a compound of formula (i), or a pharmaceutically acceptable salt or ester thereof
  • a compound of formula (!), or a pharmaceutically acceptable sait or ester thereof, set forth herein may also be used as a laboratory reagent
  • a compoun ⁇ of this invention including a pharmaceutically acceptable salt or ester tnereof, may also be used to treat or prevent viral contamination of materials and therefore reduce the risk of viral infection o1 laboratory or medical personnel or patients who come in contact witn such materials (e g biood, tissue, surgical instruments and garments, laboratory instruments and garments, ana biood collection apparatuses and materials)
  • a compound of formula (J), including a pharmaceutically acceptable sait or ester thereof set forth herein may also be used as a research reagent
  • a compound of formula (Ij, including a pharmaceutically acceptable salt or ester thereof, may aiso be used as positive control to validate surrogate cell-based assays or in vitro or in vivo viral replication assays
  • dipeptide 1 The synthesis of dipeptide 1 is carried out by coupling the P1 residue to the properly protected frans-hydroxy proline under standard conditions. The stereochemistry of the hydroxyl group is inverted by the well known Mitsunobu reaction using para- nitrobenzoic acid. Coupling of the dipeptide with the P3 moiety (2a-h) (obtained from commercial sources) yields t ⁇ peplide 3 Introduction of tne quinohne moiety to the hydroxyl group of the tripeptide 3 with inversion of stereochemistry can be earned out using either a Mitsonobu reaction or by converting tne free hydroxy!
  • the qui ⁇ oiine used contains a 2-carbomethoxy group as shown in 5 Conversion of the carboxyiate group to the aminothiazoie derivative !
  • ester is hydrolyzed under basic aqueous conditions to provide compounds oi formula (! in which R1 is vinyl Tne vinyl group can De reduces using hydrazine monohydrale as a source of di ⁇ i ⁇ »de to provide compounds of formula (I) in which R1 is ethyl
  • Scheme 2 describes another reaction sequence for making compounds o1 Formula ⁇ I ⁇
  • the quinohne moiety is introduced to the dipeptide in a similar way as desc ⁇ bed in Scheme 1
  • the PZ moiety (2a-h) is coupled under standard conditions with the dipeptide 17 to provide the corresponding t ⁇ peptide analogs 9
  • Conversion of the resulting t ⁇ peotides (9) to the desired inhibitors (11 and 12) of formula (i) is earned out as described in Scheme 1
  • Scheme 3 demonstrates the reaction sequence used to prepare intermediates 21 and 22 To prepare P3 fragments 19a-h.
  • the commercially available ammo acids (18a-h) were heated in the presence of commercially available aryi halides using copper catalysis and the N-arylated amino acids 19a-h are obtained
  • the N-arylated ammo acids 1 ⁇ a-h can undergo a peptide coupling reaction with the deprotected dipeptide 17 to provide the N-arylated tripeptides 20
  • Basic aqueous hydrolysis of these intermediates provides compounds (21) o1 lormula (!) where R1 is vinyl arse B is aryi Re ⁇ uction of the vinyl group in using hydrazine monohy ⁇ rate as a source oi diimi ⁇ e provides compoun ⁇ s (22) oi Formula (I) where R1 is ethyl and B is aryl
  • B is Het (Met being other than 2-py ⁇ m ⁇ dyi described in Scheme 1 )
  • Scheme A describes an alternative synthetic route for the synthesis of compounds of formula (Ij in which R1 is ethyl
  • the vinyl cyiopropane derivative 23 is reduced using Rh/C under 45 ps* of hydrogen gas to provide the ethyl-cyclopropane derivative 24
  • This compound is then sequentially coupled with protected amino acids 25 and 2a-fo to provide the t ⁇ peptide analog 28
  • the t ⁇ peptide 28 is converted to the quinohne aminothiazoie derivative 30 using similar transformations to those described in Scheme 1 for the conversion of 3 to 9.
  • 30 can be converted to compounds of formula (i) where R1 is ethyl using similar transformations to those described in Scheme 1 for the conversion of 9 to 10,
  • Scheme 5 described a reaction sequence for making compounds of formula (I) where R 1 is cyclopropyi.
  • the vinyl cyclopropane derivative 17 is cyclopropanated using palladium acetate and diazomethane to give intermediate 33 Peptide coupling between the deprotected dipeptide 33 and one of the P3 fragments 2a-h or 19a-h provides tripeptide derivatives which can be converted to compounds of formula (I) using reaction sequences already described m Schemes 1 to 4
  • Scheme 6 describes a reaction sequence which permits the conversion of carboxylic acids of formula (I) to the corresponding acyl sulfonamides.
  • the acid is activated by a peptide coupling agent or a chloroformate and is thereby converted to the corresponding aza-lactone.
  • the azalactone is opened by the nucleophilic addition of a sulfonamide to obtain the corresponding acyl sulfonamide analogs.
  • Scheme 7 describes a reaction sequence for preparing sulfonamide 42-C used in Scheme 6.
  • Compound 42-A is first reacted with sulfur dioxide, then reacted with N- chlorosuccinimide (NCS) in a suitable solvent at a suitable reaction temperature to provide compound 42-B, which is then reacted with ammonia in a suitable solvent, at a suitable reaction temperature, to provide sulfonamide 42-C.
  • NCS N- chlorosuccinimide
  • R s is selected from (C 1- ⁇ )alkyl, (C ⁇ cycloalkyl, (C 1- ⁇ )alkyl-(C 3-7 )cycloalkyl, aryl or Het; each of which optionally being mono-, di- or tri-substituted with substituents selected from halogen, hydroxy, cyano, (C 1-4 JaIkVl 1 O-(C 1 ⁇ )alkyl, -CO-NH 2 , -CO- NH(C 1-4 )alkyl, -CO-N((C M )alkyl) 2 , -NH 2 , -NH(C ⁇ )alkyl and -N((C M )alkyl) 2 , wherein (C 1 _ 4 )alkyl and O-(C 1 ⁇ )alkyl are optionally substituted with one to three halogen atoms.
  • R s is a C 3 - 7 cycloakyl group which is substituted by a group selected from C 1-1(r alkyl, C 3 . 12 -cycloalkyl, aryl, aryl-C 1-10 -alkyl or heteroaryl.
  • Scheme 8 shows an alternative method for preparing sulfonamide 42-C by the reaction of compound 42-A with sulfuryl dichloride, in a suitable solvent, at a suitable reaction temperature to provide compound 42-B, which is then reacted with ammonia in a suitable solvent, at a suitable reaction temperature, to provide sulfonamide 42-C.
  • Scheme 9 describes an alternative method for preparing sulfonamide 42-C via an N -substituted sulfonamide intermediate.
  • the compound 42-B is reacted with a substituted amine compound NHR 1 R 2 to provide compound 42-D wherein R 1 and R 2 are, independently, hydrogen or C 1-10 -alkyl with the proviso that R 1 and R 2 are not both hydrogen.
  • Compound 42-D is then reacted with an acid to provide the sulfonamide 42-C.
  • Scheme 10 describes a reaction sequence for preparing the certain substituted cycloalkyl sulfonamides 42-F wherein R s is a C ⁇ cycloakyl group which is substituted by an R 6 group selected from C 1-10 -alkyl, C 3-12 -CyClOaIkVl 1 aryl, aryl-C 1-10 - alkyl or heteroaryl.
  • R s is a C ⁇ cycloakyl group which is substituted by an R 6 group selected from C 1-10 -alkyl, C 3-12 -CyClOaIkVl 1 aryl, aryl-C 1-10 - alkyl or heteroaryl.
  • Compound 42-D is reacted with a base, followed by a halide R 6 X wherein X is chioro bromo or iodide to provide compound 42-E, which is then reacted with an acid to provide 42-F sulfonamide
  • P1 moieties of compounds of Formula (!) are prepared using the protocols outlined in VVO 00/59929, published October 12, 2000, and WO 00/09543, published on February 24, 2000 herein incorporated by reference in particular reference is made to pages 33-35, Example 1 of WO00/59929 and Pages 58-69 Examples 9 to 20 of WO00/09543 for the preparation of i-ammocyclopropanecarboxyhc acid P1 moieties
  • Amino acids 2a-h and 18a-h are available commercially from various vendors and were used as received
  • Analytical HPLC is carried out under standard conditions using a SunFireTM C18 3.5 ⁇ M reverse phase column, 4.6 x 30 mm and a linear gradient (0 to 100% over 5 or 8 min with 2.5 mL/min) employing 0.1%TFA/acetonitrile and 0.1%TFA/water as solvents.
  • MS mass spectrometry (FiA MS- flow injection analysis mass spectrometry), Me methyl, MeOH methanol, mmoi. rrplhmole, NCS. N- chiorosuccinimide, Ph. phenyl, RT room temperature (18 to 22 0 C), sat saturated, SNAr Nucleophilic aromatic substitution, tert-butyl or t ⁇ buty! 1 ,1-dimethyiethyi. Tbg. terf-buty!
  • the cruce t ⁇ pepti ⁇ e 3a (529 g, 0 79 moi) is dissolved in THF (3L) and water (800 rnL) is added The resulting solution is cooled to 0 'C ana a solution of lithium hydroxide monohy ⁇ rate (1 11 1 g, 0 99 mol) is a ⁇ ded over about 3 mm with vigorous stirring After approximately 3 h at 0°C, the excess base is neutralized with 1 N HCi (final pH -6) and the THF is evaporated, resulting in an aqueous suspension (yellow gum).
  • Tnethyiamme (187 m!_, 1.34 mol) is added dropwise to a cooled solution (O 0 C) of the t ⁇ peptide 4a (18Og, 0 385 moi), 4-bro ⁇ o-benzenesulfonyl chloride (208 6 g. 0 809 mol) and dimethyiaminopyridine (4 7 g. 38 5 mmoi) dissolved in DCM (2 L)
  • the ye ⁇ ow solution is stirred for about 1 h at 0 0 C before slowly warming to RT.
  • the solution is then stirred for about 60 h at RT.
  • the reaction mixture is concentrated to dryness, diluted with EtOAc, washed with saturated sodium bicarbonate solution water and brine, dried over MgSO 4 , filtered and evaporated to dryness to obtain the crude product (50 g)
  • the crude material is purified by flash column chromatography with hexanes EtOAc, 40 80 to 20 80 to provide the pure product 37a (170 g, 84% yield)
  • ⁇ -Bromoketone 7a 700 mg, 0 85 mmoij and thiourea 8h ( 134 mg, 1 02 mmol) are dissolved in isopropanoi (5 mLj and the yellow solution is heated at 75°C lor about 1 n Tne solution is allowed to cooi Io RT and evaporated to dryness Tms crude material 9a is used as such for next step
  • Compound 1003 is prepared using the protocol desc ⁇ oed in Example 8, sleps 1 to 7
  • Compound 15b is prepared using the protocol described in Example 6, steps 1 to 5
  • 15b is converted to 2001 using protocol described in Example 7, steps 6 and 7, using cyclobutyl acetic acid instead of cyclopropyl acetic acid.
  • Compound 1008 is prepared using the protocol described in Example 6, steps 1 to 7
  • Compound 1034 is prepared using the protocol described in Example 6, steps 1 to 7
  • Step 1 Hydrolysis and Synthesis of Aza-lactone Ester 40 was prepares according to tne syntnesis described in Example 6 sleps 1 through 5 using the C8 methyl analog ot 5a in step 1 anc tniourea 8b in step 5 Further details describing the synthesis of tne C8 methyl analogs o1 5a can be found in WO2004/103996 and U S patent 6,323,180. a ⁇ of which are herein incorporated by reference
  • CycloproDyisulfo ⁇ amide 42 is commercially avauabie, or can be prepared according to step 2A below
  • Sulfonamide 42 is dissolved in anhydrous THF (8 5 ml.) in an oven dried flask and cooled to -15 0 C.
  • LiHMDS (0 66 mL of a 1.0 M solution in THF, 0.86 mmoi) is added all at once and the reaction is stirred for about 5 mm, warmed to RT for about 20 mm and then re-cooled to -15 0 C
  • the crude aza-lactone 41 (0 33 mmoi) is dissolved in anhydrous THF (3 mL) and added dropwise to the above solution over about 10 mm
  • the cold bath is removed and the reaction is allowed to warm to RT and stirred for about 16 h
  • the reaction is quenched by the addition of a few drops of giacia!
  • 3002 is reduced using the hydrazine monohydrate procedure described in Example 6, step 8 to provide compound 3004 in 20% yield.
  • Compound 3001 is prepared using the protocol described in Example 6, steps 1 to 7
  • Example 11a In step 3 ⁇ S use ⁇ j j n p
  • Example 11a In step 3 is used in place of cyclopropyl acetic acid.
  • Compound 3006 is reduced to provide 3007 using the protocol described in Example 6, step 8.
  • Compound 9b is prepared according the protocol in Example 6, Steps 1 to 5 using
  • E ⁇ XAMPLE 12b Synthesis of compounds 4003, 4012, 4014 and 4017 These compounds are prepared from 9b using the protocol described in Example 12 steps 6 and 7, but replacing the 5-fluoro-2-chloropyrimidine with the appropriately substituted 2-chloro or 2-bromo pyrimidine.
  • EXAMPLE 12c Synthesis of compounds 4002, 4004, 4005, 4006, 4007, 4008, 4009, 4010, 4011, 4013, 4015, 4016 and 4018
  • EXAMPLE 13 Reduction of vinyl-ACCA
  • EXAMPLE 13a Synthesis of compound 5009 Step 1: Reduction of Vinyl ACCA:
  • the reduction of the vinyl cyclopropane to the ethyl-cyclopropane can be carried out early in the synthesis.
  • Step 1 Reduction of vinyl cyclopropane amino ester
  • the tosyiate salt of vinyl-ACCA methyl ester 23 (5 0 g) and Rh/C (6 mole %) is dissolved in 50 mL of MeOH letrahydrofuran (1 3) and tne reaction is placed un ⁇ er a hydrogen atmosphere at 45 psi lor 3 5 hours under mechanical stirring (450 rpm) The reaction is complete (by hydrogen consumption monitoring) after 3 hours Alter nitrogen purge the reaction vessel is depressu ⁇ zed and the suspension is filtered through a piug of Cehte ⁇ and the plug is washed with 100 mL methanol The combined filtrates are stnpped of solvent under reduced pressure and the residue is slurried with 20 mL EtOAc and the solid is ⁇ itered off After drymg under vacuum, 4 5 g (90%) of white powdery solid (compound 24) is isolated.
  • Compound 45 can be prepared in a variety of ways One route involves utilizing the procedure for tne synthesis of 37a described in Examples 1 througn 5 and usmg ethyl-ACCA analog 24 instead oi the vinyi-ACCA analog 23 for the preparation of the ⁇ ipeptide described in Example 1
  • Compound 5011 is prepared using the protocol in Example 14a, steps 1 to 3 using (8f) as the thiourea in the aminothiazole forming step (ie. conversion of 46 to 47).
  • Step 3 Deboc. neutralization and SNAr with 2-chloro-5-fluoro pyrimidine These steps are carried out according to the protocol described for Step 2 in Example 14a to provide compound 51.
  • Step 4 Hydrolysis This step is carried out according to the protocol described for Step 3 in Example 14 to provide 5023.
  • the boc-protected amine 55 (1 5g, 1 97 mmol) is dissolved in 4N HCI/dioxanes (30 mL) and stirred for two hours at RT The reaction is concentrated in vacuo and dried under high vacuum to give the amine hydrochloride as a bright yeliow solid In a separate flask the acid 56 (0 49 g, 2 37 mmoi) is dissolved in aceto ⁇ it ⁇ le (20 mL).
  • EXAMPLE 17b Synthesis of compoursd 4021 to 4048 and 6001 to 8008
  • step 5 (8b) is used as the thiourea
  • EXAMPLE 18 CeH ⁇ based iir ⁇ ferase reporter HCV RMA Replication Assay CeH culture
  • Hi ⁇ h-7 cells with a stable subgenomic HCV rephcon that encodes a modified iuciferase reporter gene (expressed as a iuc!ferase-FMDV2A-neomyc ⁇ n phosphotransferase fusion gene) are established as previously described (Lohman et a!., 1999. Science 285 1 10-1 13. Vroljik et al . 2003 J Virol Methods 110 201-209.
  • test compound in 100% DMSO is first diluted in assay medium to a final DMSO concentration of 0 5%
  • the solution is somcate ⁇ for 15 mm
  • assay medium to obtain the starting concentration (2x) to be tested
  • Senal dilutions (1/3) are prepared by transferring 200 ⁇ L from column 3 to coiumn 4, then from column 4 to coiumn 5. serially through to column 1 1
  • Column 12 is the no inhibition control
  • a volume of 70 ⁇ L from each well of the compound dilution plate is transferred to a corresponding well of the Cell Plate (Three columns wil* be used as the "No inhibition control", nine columns are used for the dose response)
  • the ceil culture plate is mcubatec at 37°C with 5% CO 2 for 28 hours
  • the medium is aspirated from the 96-well assay piate and a volume of 50 ⁇ L of 1X Gio Lysis Buffer (Promega) previously warmed to RT was added to each well.
  • the plate is incubated at RT for 10 mm with occasional shaking A black tape was put at the bottom of the plate 50 ⁇ L of Bright- Gio luciferase substrate (Promega) previously warmed to RT is added to each well followed by gentle mixing
  • the luminescence is determined on a Packard Topcount instrument using the Data Mode Luminescence (CPS) with a count delay of 1 mm and a count time of 2 sec
  • CPS Data Mode Luminescence
  • the luminescence determination (CPS) in each well of the culture plate is a measure of the amount of HCV RNA replication m the presence of various concentrations of inhibitor
  • EXAMPLE 19 Pharmacokinetic profiling in rats Oral v ⁇ hse ⁇ arsd compound preparation
  • Compounds are dosed at 5 mg/kg using a suspension consisting of 1 %N ⁇ Methyi-2 ⁇ Pyrr ⁇ hdone, 0 5% aqueous methyiceliuiose and 0.3% of poly ⁇ xyethylene (20) sorbitan monooleafe (Tween ⁇ 80).
  • the dosing volume is 10mL/ ⁇ g via oral gavage.
  • Plasma samples are thawed and standard curves ranging kom 0 01 to 20 ⁇ M are prepared from blank plasma spiked with compound. All samples are extracted by solid phase extraction on Oasis HLB 30 mg/1cc cartridges according to the following method.
  • Residue is reconstituted in 500 ⁇ L of 0 2% NH 4 OH in acetonitnie-water (1.1 )
  • tne pharmacokinetic parameters (Cmax and AUC) are caic ⁇ ated using ToxKin V3 3 and are reported in the following taoie, wherein the values are rounded to one significant digit after tne ⁇ ecima! point

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Abstract

L'invention porte sur des composés représentés par la formule (I) : dans laquelle B, R3, L0, L1, R2, Rc et R1 sont tels que définis dans la description. Les composés sont utiles comme inhibiteurs de la protéase NS3 du VHC pour le traitement d'une infection virale de type hépatite C. En particulier, la présente invention porte sur de nouveaux analogues peptidiques, sur des compositions pharmaceutiques contenant de tels analogues et sur des utilisations de ces analogues dans le traitement d'une infection à VHC.
EP09815517A 2008-09-23 2009-09-14 Composés inhibiteurs de l'hépatite c Withdrawn EP2344487A4 (fr)

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US9929208P 2008-09-23 2008-09-23
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UY32099A (es) 2008-09-11 2010-04-30 Enanta Pharm Inc Inhibidores macrocíclicos de serina proteasas de hepatitis c
AU2009303483A1 (en) * 2008-10-15 2010-04-22 Intermune, Inc. Therapeutic antiviral peptides
US8937041B2 (en) 2010-12-30 2015-01-20 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
BR112013016480A2 (pt) 2010-12-30 2016-09-20 Abbvie Inc macrocíclo da fenantridina inibadores da protease da serina da hepatite c
US8957203B2 (en) 2011-05-05 2015-02-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
JP6154474B2 (ja) 2012-10-19 2017-06-28 ブリストル−マイヤーズ スクイブ カンパニーＢｒｉｓｔｏｌ−Ｍｙｅｒｓ Ｓｑｕｉｂｂ Ｃｏｍｐａｎｙ Ｃ型肝炎ウイルス阻害剤
WO2014070964A1 (fr) 2012-11-02 2014-05-08 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c
US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
EP2914598B1 (fr) 2012-11-02 2017-10-18 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c
EP2914614B1 (fr) 2012-11-05 2017-08-16 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c
EP2964664B1 (fr) 2013-03-07 2017-01-11 Bristol-Myers Squibb Company Inhibiteurs du virus de l'hépatite c
EP3089757A1 (fr) 2014-01-03 2016-11-09 AbbVie Inc. Formes galéniques antivirales solides

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CA2370396A1 (fr) * 2002-02-01 2003-08-01 Boehringer Ingelheim (Canada) Ltd. Tri-peptides inhibiteur de l'hepatite c
CN103204903A (zh) * 2003-05-21 2013-07-17 贝林格尔.英格海姆国际有限公司 丙型肝炎抑制剂化合物
CA2568008C (fr) * 2004-05-25 2014-01-28 Boehringer Ingelheim International Gmbh Processus de preparation d'inhibiteurs de protease hcv acyclique
EP1763531A4 (fr) * 2004-06-28 2009-07-01 Boehringer Ingelheim Int Analogues peptidiques d'inhibiteurs de l'hepatite c
AU2008271116B2 (en) * 2007-06-29 2012-09-20 Gilead Sciences, Inc. Antiviral compounds
CN101801925A (zh) * 2007-06-29 2010-08-11 吉里德科学公司 抗病毒组合物
WO2009076173A2 (fr) * 2007-12-05 2009-06-18 Enanta Pharmaceuticals, Inc. Composés à base de tripeptides fluorés inhibant la sérine protéase du vhc

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WO2010034105A1 (fr) 2010-04-01
TW201016694A (en) 2010-05-01
WO2010034105A8 (fr) 2011-01-06

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