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WO2010033466A1 - Inhibiteurs macrocycliques de la protéase du virus de l'hépatite c - Google Patents

Inhibiteurs macrocycliques de la protéase du virus de l'hépatite c Download PDF

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Publication number
WO2010033466A1
WO2010033466A1 PCT/US2009/056859 US2009056859W WO2010033466A1 WO 2010033466 A1 WO2010033466 A1 WO 2010033466A1 US 2009056859 W US2009056859 W US 2009056859W WO 2010033466 A1 WO2010033466 A1 WO 2010033466A1
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compound
substituted
groups
group
alkyl
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PCT/US2009/056859
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English (en)
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Juan Manuel Betancort
Michael E. Hepperle
David Alan Campbell
David T. Winn
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Phenomix Corporation
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Publication of WO2010033466A1 publication Critical patent/WO2010033466A1/fr

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    • 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
    • C07K5/0821—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp
    • C07K5/0823—Tripeptides with the first amino acid being heterocyclic, e.g. His, Pro, Trp and Pro-amino acid; Derivatives thereof

Definitions

  • Hepatitis C virus is the causative agent for hepatitis C, a chronic infection characterized by jaundice, fatigue, abdominal pain, loss of appetite, nausea, and darkening of the urine.
  • HCV belonging to the hepacivirus genus of the Flaviviriae family, is an enveloped, single-stranded positive-sense RNA-containing virus.
  • the long-term effects of hepatitis C infection as a percentage of infected subjects include chronic infection (55-85%), chronic liver disease (70%), and death (1-5%).
  • HCV is the leading indication for liver transplant. In chronic infection, there usually presents progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma.
  • the HCV genome (Choo et al, Science 1989, 244, 359-362; Simmonds et al., Hepatology 1995, 21, 570-583) is a highly variable sequence exemplified by GenBank accession NC_004102 as a 9646 base single-stranded RNA comprising the following constituents at the parenthetically indicated positions: 5' NTR (i.e., non-transcribed region) (1-341); core protein (i.e., viral capsid protein involved in diverse processes including viral morphogenesis or regulation of host gene expression) (342-914); El protein (i.e., viral envelope) (915-1490); E2 protein (i.e., viral envelope) (1491-2579); p7 protein (2580- 2768); NS2 protein (i.e., non-structural protein 2) (2769-3419); NS3 protease (3420-5312); NS4a protein (5313-5474); NS4b protein (5475-6257); NS
  • the present invention is directed to compounds of Formula I, the compounds being adapted to inhibit the viral protease NS3 of the Hepatitis C Virus (HCV), to the use of compounds of compounds of Formula I in the treatment of malconditions for which inhibition of HCV protease is medically indicated, such as in the treatment of HCV infections, and to pharmaceutical compositions and combinations including a compound of Formula I as defined herein.
  • the compounds of Formula I are adapted to bind to, and thus block the action of, an HCV-encoded protease enzyme that is required by the virus for the production of intact, mature, functional viral proteins from the viral polyprotein as translated from the viral RNA, and therefore for the formation of infectious particles, and ultimately for viral replication.
  • the compounds of the invention are mimics or analogs of the peptide domain immediately N-terminal of the substrate site where the viral protease cleaves its native substrate viral polyprotein, and are believed to bind to and inhibit the protease by virtue of this mimicry or analogy.
  • Various embodiments of the invention provide a compound of Formula I:
  • R c at each occurrence is independently H, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl; wherein any carbon atom or nitrogen atom can be substituted with a J group; or two R c groups together with a nitrogen atom to which they are bound form together with the nitrogen atom a 5- 11 membered mono- or bicyclic heterocyclic ring system that is unsubstituted or is substituted with 1-3 J groups;
  • B is CH 2 ;
  • R 1 , R la , R 2 and R 2a are independently H , halo, or alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any carbon atom or nitrogen atom can be substituted with J;
  • X is a bond, O, S, CH(R 3 ) or N(R 4 );
  • Y is a bond, CH 2 , C(O), C(O)C(O), S(O), S(O) 2 or S(O)(NR 4 ); provided that when X and Y are both bonds, taken together they form a single bond: and
  • Z is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, OR 5 , or N(R 5 ) 2 , wherein a heterocyclyl or heteroaryl group can be bonded by a carbon atom or by a heteroatom, wherein any carbon atom or nitrogen atom is unsubstituted or is substituted with J;
  • R 3 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any carbon atom or nitrogen atom can be substituted with J;
  • R 4 is independently at each occurrence hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any carbon atom or nitrogen atom can be substituted with J, or aralkanoyl, heteroaralkanoyl, C(O)R 3 , SO 2 R 3 or carboxamido, wherein any aralkanoyl or heteroaralkanoyl is substituted with 0-3 J groups;
  • R 5 is independently at each occurrence hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J, or two R groups which are bound to a nitrogen atom can form together with the nitrogen atom a 5-11 membered mono- or bicyclic heterocyclic ring system where
  • M is O, S, S(O), S(O) 2 ;
  • J is halogen, R', OR', CN, CF 3 , OCF 3 , O, S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH 2 ) 0 - p N(R') 2 , (CH 2 ) 0 - p SR', (CH 2 ) 0 - p S(O)R', (CH 2 V p S(O) 2 R', (CH 2 )o- p S(0) 2 N(R') 2 , (CH 2 V p SO 3 R', (CH 2 V p C(O)R', (CH 2 V p C(O)C(O)R, (CH 2 VpC(O)CH 2 C(O)R, (CH 2 VpC(S)R', (CH 2 VpC(O)OR', (CH 2 VpOC(O)R, (CH 2 V p C(O)N(R) 2 , (CH 2 V p OC(O
  • T is R 6 , alkyl-R 6 , alkenyl-R 6 , or alkynyl-R 6 ;
  • R 6 is independently at each occurrence hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkenyl, [cycloalkyl or cycloalkenyl]- [alkyl or alkenyl], heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any R 6 except hydrogen is substituted with 0-3 J groups.
  • compositions comprising a compound of Formula I and a suitable excipient.
  • Various embodiments of the invention are further directed to pharmaceutical combinations comprising a compound of Formula I in a therapeutically effective amount and a second medicament in a therapeutically effective amount.
  • a pharmaceutical combination of the invention may be formulated as a pharmaceutical composition of the invention.
  • Various embodiments of the invention are further directed to methods of treatment of a HCV infection in a patient in need thereof, or in a patient when inhibition of an HCV viral protease is medically indicated, comprising administering a therapeutically effective amount of a compound of Formula I to the patient.
  • Various embodiments of the invention are further directed to methods of treatment of a HCV infection in a patient in need thereof, or in a patient when inhibition of an HCV viral protease is medically indicated, comprising administering a therapeutically effective amount of a compound of Formula I to the patient in conjunction with administering an effective amount of a second medicament to the patient.
  • the second medicament can include another antiviral agent, an antibiotic, or a medicament for alleviating symptoms of a Hepatitis C infection.
  • Various embodiments of the invention are directed to use of an inventive compound in preparation of a medicament for the treatment of an HCV infection in a patient.
  • an effective amount of a second bioactive agent can be used in preparation of a medicament for treatment of an HCV infection in a patient.
  • Various embodiments of the invention provide an inventive compound for use in combination with an effective amount of a second medicament in treatment of an HCV infection in a patient.
  • HCV NS3 serine protease denotes all active forms of the serine protease encoded by the NS3 region of the hepatitis C virus, including all combinations thereof with other proteins in either covalent or non-covalent association.
  • other proteins in this context include without limitation the protein encoded by the NS4a region of the hepatitis C virus. Accordingly, the terms “NS3/4a” and “NS3/4a protease” denote the NS3 protease in combination with the HCV NS4a protein.
  • other type(s) of therapeutic agents refers to one or more antiviral agents, other than HCV NS3 serine protease inhibitors of the invention.
  • Subject as used herein, includes mammals such as humans, non-human primates, rats, mice, dogs, cats, horses, cows and pigs.
  • treatment is defined as the management and care of a patient for the purpose of combating the disease, condition, or disorder and includes administering a compound of the present invention to prevent the onset of the symptoms or complications, or alleviating the symptoms or complications, or eliminating the disease, condition, or disorder.
  • Treating within the context of the instant invention means an alleviation of symptoms associated with a disorder or disease, or inhibition of further progression or worsening of those symptoms, or prevention or prophylaxis of the disease or disorder.
  • treating a hepatitis C viral infection includes slowing, halting or reversing the growth of the virus and/or the control, alleviation or prevention of symptoms of the infection.
  • an "effective amount” or a “therapeutically effective amount” of a compound of the invention refers to an amount of the compound that alleviates, in whole or in part, symptoms associated with the disorder or condition, or halts or slows further progression or worsening of those symptoms, or prevents or provides prophylaxis for the disorder or condition.
  • a “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result by inhibition of HCV NS3 serine protease activity.
  • a therapeutically effective amount is also one in which any toxic or detrimental effects of compounds of the invention are outweighed by the therapeutically beneficial effects.
  • a therapeutically effective amount of a HCV NS3 serine protease inhibitor of the invention is an amount sufficient to control HCV viral infection.
  • chemically feasible is meant a bonding arrangement or a compound where the generally understood rules of organic structure are not violated; for example a structure within a definition of a claim that would contain in certain situations a pentavalent carbon atom that would not exist in nature would be understood to not be within the claim.
  • amino protecting group or "N-protected” as used herein refers to those groups intended to protect an amino group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine. Commonly used amino protecting groups are disclosed in Protective Groups in Organic Synthesis, Greene, T. W.; Wuts, P. G. M., John Wiley & Sons, New York, NY, (3rd Edition, 1999).
  • Amino protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2- bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, ⁇ - chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; alkoxy- or aryloxy-carbonyl groups (which form urethanes with the protected amine) such as benzyloxycarbonyl (Cbz), p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbony
  • Amine protecting groups also include cyclic amino protecting groups such as phthaloyl and dithiosuccinimidyl, which incorporate the amino nitrogen into a heterocycle.
  • amino protecting groups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl, phenylsulfonyl, Alloc, Teoc, benzyl, Fmoc, Boc and Cbz. It is well within the skill of the ordinary artisan to select and use the appropriate amino protecting group for the synthetic task at hand.
  • hydroxyl protecting group or "O-protected” as used herein refers to those groups intended to protect an OH group against undesirable reactions during synthetic procedures and which can later be removed to reveal the amine.
  • Hydroxyl protecting groups include acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2- chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4- bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; acyloxy groups (which form urethanes with the protected amine) such as benz
  • substituted refers to an organic group as defined herein in which one or more bonds to a hydrogen atom contained therein are replaced by one or more bonds to a non-hydrogen atom such as, but not limited to, a halogen (i.e., F, Cl, Br, and I); an oxygen atom in groups such as hydroxyl groups, alkoxy groups, aryloxy groups, aralkyloxy groups, oxo(carbonyl) groups, carboxyl groups including carboxylic acids, carboxylates, and carboyxlate esters; a sulfur atom in groups such as thiol groups, alkyl and aryl sulfide groups, sulfoxide groups, sulfone groups, sulfonyl groups, and sulfonamide groups; a nitrogen atom in groups such as amines, hydroxylamines, nitriles, nitro groups, N-oxides, hydrazides, azides, and enamines
  • Non-limiting examples of substituents that can be bonded to a substituted carbon (or other) atom include F, Cl, Br, I, OR', OC(O)N(R') 2 , CN, CF 3 , OCF 3 , R', O, S, C(O), S(O), methylenedioxy, ethylenedioxy, N(R') 2 , SR', SOR, SO 2 R, SO 2 N(R) 2 , SO 3 R, C(O)R, C(O)C(O)R, C(O)CH 2 C(O)R, C(S)R', C(O)OR, OC(O)R, C(O)N(R) 2 , 0C(0)N(R') 2 , C(S)N(R') 2 , (CH 2 V 2 NHC(O)R, N(R)N(R)C(O)R, N(R')N(R')C(0)0R', N(R')N(
  • a substituent When a substituent is monovalent, such as, for example, F or Cl, it is bonded to the atom it is substituting by a single bond.
  • a divalent substituent such as O, S, C(O), S(O), or S(O) 2 can be connected by two single bonds to two different carbon atoms.
  • O a divalent substituent
  • the O can be bonded to each of two adjacent carbon atoms to provide an epoxide group, or the O can form a bridging ether group between adjacent or non-adjacent carbon atoms, for example bridging the 1,4-carbons of a cyclohexyl group to form a [2.2.1]- oxabicyclo system.
  • any substituent can be bonded to a carbon or other atom by a linker, such as (CH 2 ) n or (CR 2 ) n wherein n is 1, 2, 3, or more, and each R' is independently selected.
  • Substituted alkyl, alkenyl, alkynyl, cycloalkyl, and cycloalkenyl groups as well as other substituted groups also include groups in which one or more bonds to a hydrogen atom are replaced by one or more bonds, including double or triple bonds, to a carbon atom, or to a heteroatom such as, but not limited to, oxygen in carbonyl (oxo), carboxyl, ester, amide, imide, urethane, and urea groups; and nitrogen in imines, hydroxyimines, oximes, hydrazones, amidines, guanidines, and nitriles.
  • Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and fused ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups can also be substituted with alkyl, alkenyl, and alkynyl groups as defined herein.
  • ring system as the term is used herein is meant a moiety comprising one, two, three or more rings, which can be substituted with non-ring groups or with other ring systems, or both, which can be fully saturated, partially unsaturated, fully unsaturated, or aromatic, and when the ring system includes more than a single ring, the rings can be fused, bridging, or spirocyclic.
  • spirocyclic is meant the class of structures wherein two rings are fused at a single tetrahedral carbon atom, as is well known in the art.
  • Alkyl groups include straight chain and branched alkyl groups and cycloalkyl groups having from 1 to about 20 carbon atoms, and typically from 1 to 12 carbons or, in some embodiments, from 1 to 8 carbon atoms.
  • straight chain alkyl groups include those with from 1 to 8 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups.
  • branched alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec -butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.
  • Representative substituted alkyl groups can be substituted one or more times with any of the groups listed above, for example, amino, hydroxy, cyano, carboxy, nitro, thio, alkoxy, and halogen groups.
  • Cycloalkyl groups are cyclic alkyl groups such as, but not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups.
  • the cycloalkyl group can have 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include poly cyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like. Cycloalkyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above. Representative substituted cycloalkyl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2,2-, 2,3-, 2,4- 2,5- or
  • cycloalkenyl alone or in combination denotes a cyclic alkenyl group.
  • carbocyclic and “carbocycle” denote a ring structure wherein the atoms of the ring are carbon. In some embodiments, the carbocycle has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms is 4, 5, 6, or 7.
  • the carbocyclic ring can be substituted with as many as N-I substituents wherein N is the size of the carbocyclic ring with, for example, alkyl, alkenyl, alkynyl, amino, aryl, hydroxy, cyano, carboxy, heteroaryl, heterocyclyl, nitro, thio, alkoxy, and halogen groups, or other groups as are listed above.
  • (Cycloalkyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.
  • Cycloalkenyl groups include cycloalkyl groups having at least one double bond between 2 carbons.
  • cycloalkenyl groups include but are not limited to cyclohexenyl, cyclopentenyl, and cyclohexadienyl groups.
  • Cycloalkenyl groups can have from 3 to about 8-12 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 6, or 7.
  • Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like, provided they include at least one double bond within a ring.
  • Cycloalkenyl groups also include rings that are substituted with straight or branched chain alkyl groups as defined above.
  • (Cycloalkenyl)alkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkenyl group as defined above.
  • Alkynyl groups include straight and branched chain alkyl groups, except that at least one triple bond exists between two carbon atoms. Thus, alkynyl groups have from 2 to about 20 carbon atoms, and typically from 2 to 12 carbons or, in some embodiments, from 2 to 8 carbon atoms.
  • Examples include, but are not limited to -C ⁇ CH, -OC(CH 3 ), -C ⁇ C(CH 2 CH 3 ), -CH 2 C ⁇ CH, -CH 2 C ⁇ C(CH 3 ), and -CH 2 C ⁇ C(CH 2 CH 3 ) among others.
  • Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
  • aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
  • aryl groups contain about 6 to about 14 carbons in the ring portions of the groups.
  • Aryl groups can be unsubstituted or substituted, as defined above.
  • Representative substituted aryl groups can be mono-substituted or substituted more than once, such as, but not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or 2-8 substituted naphthyl groups, which can be substituted with carbon or non-carbon groups such as those listed above.
  • Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Representative aralkyl groups include benzyl and phenylethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-ethyl-indanyl.
  • Aralkenyl group are alkenyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above.
  • Heterocyclyl groups include aromatic and non-aromatic ring compounds containing 3 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, heterocyclyl groups include 3 to about 20 ring members, whereas other such groups have 3 to about 15 ring members.
  • Ring systems can be monocyclic, bicyclic, or tricyclic; for example a 10-membered heterocyclyl within the meaning herein can be composed of two fused six-membered rings, a least one of which must contain at least one heteroatom such as N, O, or S.
  • a heterocyclyl group designated as a C 2 -heterocyclyl can be a 5 -ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 - heterocyclyl can be a 5-ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • a heterocyclyl ring can also include one or more double bonds.
  • a heteroaryl ring is an embodiment of a heterocyclyl group.
  • the phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups.
  • a dioxolanyl ring and a benzdioxolanyl ring system are both heterocyclyl groups within the meaning herein.
  • the phrase also includes polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl.
  • Heterocyclyl groups can be unsubstituted, or can be substituted as discussed above.
  • Heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquino
  • Representative substituted heterocyclyl groups can be mono-substituted or substituted more than once, such as, but not limited to, piperidinyl or quinolinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or disubstituted with groups such as those listed above.
  • Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S; for instance, heteroaryl rings can have 5 to about 8-12 ring members.
  • a heteroaryl group designated as a C 2 -heteroaryl can be a 5 -ring with two carbon atoms and three heteroatoms, a 6-ring with two carbon atoms and four heteroatoms and so forth.
  • a C 4 -heteroaryl can be a 5 -ring with one heteroatom, a 6-ring with two heteroatoms, and so forth.
  • the number of carbon atoms plus the number of heteroatoms sums up to equal the total number of ring atoms.
  • Ring systems can be monocyclic, bicyclic, or tricyclic; for example a 10- membered heteroaryl within the meaning herein can be composed of two fused six-membered aromatic rings, a least one of which must contain at least one heteroatom such as N, O, or S.
  • Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups can be
  • aryl and heteroaryl groups include but are not limited to phenyl, biphenyl, indenyl, naphthyl (1-naphthyl, 2-naphthyl), N- hydroxytetrazolyl, N-hydroxytriazolyl, N-hydroxyimidazolyl, anthracenyl (1- anthracenyl, 2-anthracenyl, 3-anthracenyl), thiophenyl (2-thienyl, 3-thienyl), furyl (2-furyl, 3-furyl) , indolyl, oxadiazolyl, isoxazolyl, quinazolinyl, fluorenyl, xanthenyl, isoindanyl, benzhydryl, acridinyl, thiazolyl, pyrrolyl (2-pyrrolyl), pyrazolyl (3-pyrazolyl), imidazolyl (1-imidazolyl, 2-
  • Heterocyclylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group as defined above is replaced with a bond to a heterocyclyl group as defined above.
  • Representative heterocyclyl alkyl groups include, but are not limited to, furan-2-yl methyl, furan-3-yl methyl, pyridine-3-yl methyl, tetrahydrofuran-2-yl ethyl, and indol-2-yl propyl.
  • Heteroarylalkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to a heteroaryl group as defined above.
  • alkoxy refers to an oxygen atom connected to an alkyl group, including a cycloalkyl group, as are defined above.
  • linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, and the like.
  • branched alkoxy include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentyloxy, isohexyloxy, and the like.
  • cyclic alkoxy include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • An alkoxy group can include one to about 12-20 carbon atoms bonded to the oxygen atom, and can further include double or triple bonds, and can also include heteroatoms.
  • an allyloxy group is an alkoxy group within the meaning herein.
  • a methoxyethoxy group is also an alkoxy group within the meaning herein.
  • Halo as the term is used herein includes fluoro, chloro, bromo, and iodo.
  • a "haloalkyl” group includes mono-halo alkyl groups, and poly-halo alkyl groups wherein all halo atoms can be the same or different. Examples of haloalkyl include trifluoromethyl, 1,1-dichloroethyl, 1,2-dichloroethyl, 1,3- dibromo-3,3-difluoropropyl and the like.
  • aryloxy and arylalkoxy refer to, respectively, an aryl group bonded to an oxygen atom and an aralkyl group bonded to the oxygen atom at the alkyl moeity. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy.
  • An "acyl” group as the term is used herein refers to a group containing a carbonyl moiety wherein the group is bonded via the carbonyl carbon atom.
  • the carbonyl carbon atom is also bonded to another carbon atom, which can be part of an alkyl, aryl, aralkyl cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl group or the like.
  • the group is a "formyl" group, an acyl group as the term is defined herein.
  • An acyl group can include 0 to about 12-20 additional carbon atoms bonded to the carbonyl group.
  • An acyl group can include double or triple bonds within the meaning herein.
  • An acryloyl group is an example of an acyl group.
  • An acyl group can also include heteroatoms within the meaning here.
  • a nicotinoyl group (pyridyl-3 -carbonyl) group is an example of an acyl group within the meaning herein.
  • Other examples include acetyl, benzoyl, phenylacetyl, pyridylacetyl, cinnamoyl, and acryloyl groups and the like.
  • the group containing the carbon atom that is bonded to the carbonyl carbon atom contains a halogen, the group is termed a "haloacyl" group.
  • An example is a trifluoroacetyl group.
  • amine includes primary, secondary, and tertiary amines having, e.g., the formula N(group)3 wherein each group can independently be H or non-H, such as alkyl, alkenyl, or alkynyl as defined herein, cycloalkyl or heterocyclyl as defined herein, aryl or heteroaryl as defined herein,, and the like.
  • Amines include but are not limited to R-NH 2 , for example, alkylamines, arylamines, alkylarylamines; R 2 NH wherein each R is independently selected, such as dialkylamines, diarylamines, aralkylamines, heterocyclylamines and the like; and R3N wherein each R is independently selected, such as trialkylamines, dialkylarylamines, alkyldiarylamines, triarylamines, and the like.
  • amine also includes ammonium ions as used herein.
  • amino group is a substituent of the form -NH 2 , -NHR, -NR 2 , -NR 3 + , wherein each R is independently selected, and protonated forms of each. Accordingly, any compound substituted with an amino group can be viewed as an amine.
  • ammonium ion includes the unsubstituted ammonium ion NH 4 + , but unless otherwise specified, it also includes any protonated or quaternarized forms of amines. Thus, trimethylammonium hydrochloride and tetramethylammonium chloride are both ammonium ions, and amines, within the meaning herein.
  • amide includes C- and N-amide groups, i.e., -C(O)NR 2 , and -NRC(O)R groups, respectively.
  • Amide groups therefore include but are not limited to carbamoyl groups (-C(O)NH 2 ) and formamide groups (-NHC(O)H).
  • a "carboxamido” group is a group of the formula C(O)NR 2 , wherein R can be H, alkyl, aryl, etc.
  • urethane (or “carbamyl”) includes N- and O-urethane groups, i.e., -NRC(O)OR and -OC(O)NR 2 groups, respectively.
  • sulfonamide (or “sulfonamido”) includes S- and N- sulfonamide groups, i.e., -SO 2 NR 2 and -NRSO 2 R groups, respectively.
  • Sulfonamide groups therefore include but are not limited to sulfamoyl groups (- SO 2 NH 2 ).
  • An organosulfur structure represented by the formula -S(O)(NR)- is understood to refer to a sulfoximine, wherein both the oxygen and the nitrogen atoms are bonded to the sulfur atom, which is also bonded to two carbon atoms.
  • the term "amidine” or “amidino" includes groups of the formula
  • an amidino group is -C(NH)NH 2 .
  • guanidine or "guanidino” includes groups of the formula -NRC(NR)NR 2 .
  • a guanidino group is -NHC(NH)NH 2 .
  • a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
  • acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
  • a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
  • a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
  • a “zwitterion” is a salt within the meaning herein.
  • a “hydrate” is a compound that exists in a composition with water molecules.
  • the composition can include water in stoichiometic quantities, such as a monohydrate or a dihydrate, or can include water in random amounts.
  • a “solvate” is a similar composition except that a solvent other that water replaces the water. For example, methanol or ethanol can form an "alcoholate", which can again be stoichiometic or non-stoichiometric.
  • “Tautomers” are two forms of a substance differing only by the position of a hydrogen atom in the molecular structures.
  • prodrug as is well known in the art is a substance that can be administered to a patient where the substance is converted in vivo by the action of biochemicals within the patients body, such as enzymes, to the active pharmaceutical ingredient.
  • examples of prodrugs include esters of carboxylic acid groups, which can be hydrolyzed by endogenous esterases as are found in the bloodstream of humans and other mammals.
  • the compound or set of compounds, such as are used in the inventive methods can be any one of any of the combinations and/or sub-combinations of the above-listed embodiments.
  • R c at each occurrence is independently H, or a substituted or unsubstituted alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl; wherein any carbon atom or nitrogen atom can be substituted with a J group; or two R c groups together with a nitrogen atom to which they are bound form together with the nitrogen atom a 5- 11 membered mono- or bicyclic heterocyclic ring system that is unsubstituted or is substituted with 1-3 J groups;
  • B is CH 2 ;
  • R 1 , R la , R 2 and R 2a are independently H , halo, or alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any carbon atom or nitrogen atom can be substituted with J;
  • X is a bond, O, S, CH(R 3 ) or N(R 4 );
  • Z is hydrogen, alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, OR 5 , or N(R 5 ) 2 , wherein a heterocyclyl or heteroaryl group can be bonded by a carbon atom or by a heteroatom, wherein any carbon atom or nitrogen atom is unsubstituted or is substituted with J;
  • R 3 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any carbon atom or nitrogen atom can be substituted with J;
  • R 4 is independently at each occurrence hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkylalkenyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any carbon atom or nitrogen atom can be substituted with J, or aralkanoyl, heteroaralkanoyl, C(O)R 3 , SO 2 R 3 or carboxamido, wherein any aralkanoyl or heteroaralkanoyl is substituted with 0-3 J groups;
  • R 5 is independently at each occurrence hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl, wherein any alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, or heteroarylalkyl is substituted with 0-3 J, or two R groups which are bound to a nitrogen atom can form together with the nitrogen atom a 5-11 membered mono- or bicyclic heterocyclic ring system where
  • M is O, S, S(O), S(O) 2 ;
  • J is halogen, R', OR', CN, CF 3 , OCF 3 , O, S, C(O), S(O), methylenedioxy, ethylenedioxy, (CH 2 ) 0 - p N(R') 2 , (CH 2 ) 0 - p SR', (CH 2 ) 0 - p S(O)R', (CH 2 V p S(O) 2 R', (CH 2 )o- p S(0) 2 N(R') 2 , (CH 2 V p SO 3 R', (CH 2 V p C(O)R', (CH 2 V p C(O)C(O)R, (CH 2 VpC(O)CH 2 C(O)R, (CH 2 VpC(S)R', (CH 2 VpC(O)OR', (CH 2 VpOC(O)R, (CH 2 V p C(O)N(R) 2 , (CH 2 V p OC(O
  • T is R 6 , alkyl-R 6 , alkenyl-R 6 , or alkynyl-R 6 ;
  • R 6 is independently at each occurrence hydrogen, alkyl, alkoxy, aryl, aralkyl, cycloalkyl, cycloalkenyl, [cycloalkyl or cycloalkenyl]- [alkyl or alkenyl], heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroarylalkyl, or heteroarylalkenyl, wherein any R 6 except hydrogen is substituted with 0-3 J groups.
  • a compound of the invention is as shown in Table 1, or a compound as shown in Table 2, below.
  • M is O.
  • D is CH or C(CH 3 ).
  • X-Y is O, thus forming an ether linkage between Z and the pyrrolidine ring.
  • T is R 6 and R 6 is alkyl.
  • R 6 is methyl.
  • T and the CR of D form a spirocyclic ring comprising 3-6 atoms including 0-2 heteroatoms selected from the set consisting of O, NR, S, S(O), and S(O) 2 .
  • a compound of the invention can have the formula
  • the spirocyclic ring formed by T and the CR' of D is a 3, 4, or 5 membered ring that is carbocyclic or that contains a single oxygen atom.
  • B is CH 2 . In various embodiments, B is absent, such that a single bond exists between the carbon atom bearing A and the adjacent carbon atom.
  • a carbon atom bearing T is of an R absolute configuration, or is of an S absolute configuration, or is a mixture thereof.
  • A is a group of formula
  • A is a group of formula
  • X is O, or X is a bond.
  • Y is a bond, or C(O).
  • both X and Y are bonds, taken together forming a single bond.
  • Z can be an unsubstituted heteroaryl group or is a heteroaryl group mono- or independently pluri- substituted with J.
  • Z can be a substituted quinolyl group, a substituted triazolyl group, a substituted tetrazolyl group, or a substituted isoindolidinyl group, wherein any group is mono- or independently pluri-substituted with J.
  • Z can be a thiazolyl-substituted quinolyl group, or a pyrazolyl-substituted quinolyl group, wherein any group is mono- or independently pluri-substituted with J.
  • X-Y-Z comprises a group of the formula
  • n is O- 1.
  • n is 1-4.
  • Z is a group of formula
  • L is C 2 H 2 . More specifically, the C 2 H 2 group of L can be in a cis configuration in the macrocyclic ring.
  • the compound of formula I is any of the compounds shown below in Table 1 or Table 2, or any Example herein, provided that the definition of A falls within the limitations of claim 1, or any stereoisomer, solvate, hydrate, tautomer, prodrug, salt, or pharmaceutically acceptable salt, or mixture thereof.
  • the invention provides a method of preparation of a compound of formula I of claim 1. More specifically, in various embodiments the invention provides a method of preparation of a compound of formula (Ha) wherein L is C 2 H 2 , comprising contacting a compound of formula II
  • the olefin metathesis catalyst can be dichloro(o- isopropoxyphenylmethylene) (tricyclohexylphosphine)ruthenium(II), also known as Hoveyda-Grubbs 1st generation catalyst.
  • the invention provides methods of inhibiting HCV NS3 protease.
  • the methods include contacting the hepatitis C viral serine protease with a compound as described herein.
  • the methods of inhibiting HCV NS3 protease include administering a compound as described herein to a subject infected with hepatitis C virus.
  • the invention provides methods for treating hepatitis C viral infection.
  • the methods include administering to a subject in need of such treatment an effective amount of a compound of the invention as described herein.
  • a compound can refer to a single compound or a plurality of compounds.
  • the methods for treating hepatitis C viral infection include administering to a subject in need of such treatment an effective amount of a composition comprising a compound of the invention and a pharmaceutically acceptable carrier.
  • the invention provides methods for treating hepatitis C viral infection comprising administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with another medicament, such as another anti-viral agent.
  • anti-viral agent denotes a compound which interferes with any stage of the viral life cycle to slow or prevent HCV reproduction.
  • anti-viral agents include, without limitation, INTRON-A, (interferon alfa-2b available from Schering Corporation, Kenilworth, N.J.), PEG-INTRON (peginteferon alfa-2b, available from Schering Corporation, Kenilworth, N.J.), ROFERON-A (recombinant interferon alfa-2a available Hoffmann-La Roche, Nutley, N.J.), PEGASYS (peginterferon alfa-2a available Hoffmann-La Roche, Nutley, N.J.), INFERGEN A (Schering Plough, inteferon-alpha 2B+Ribavirin), WELLFERON (interferon alpha-nl), cyclophilin inhibitors, nucleoside analogues, IRES inhibitors, El inhibitors, E2 inhibitors, IMPDH inhibitors, NS5B polymerase inhibitors such as R- 1626, R-7128, MK-0608, A837093, GS9190 and PF-
  • the methods of treating HCV infection include administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with another NS3/4A inhibitor.
  • NS3/4A inhibitors which can be administered in combination with compounds of the present invention include, without limitation, telaprevir (VX950), boceprevir (SCH503034), ITMN191, TMC 435350, MK7009, and PHXl 766.
  • Still other antiviral agents that may be used in conjunction with inventive compounds for the treatment of HCV infection include, but are not limited to, ribavirin (l-beta-D-ribofuranosyl-lH-l,2,- 4-triazole-3-carboxamide, available from ICN Pharmaceuticals, Inc., Costa Mesa, Calif.; described in the Merck Index, entry 8365, Twelfth Edition); REBETROL.RTM. (Schering Corporation, Kenilworth, N.J.), COPEGASUS. RTM. (Hoffmann-La Roche, Nutley, N.J.); BEREFOR.RTM.
  • interleukin 2 (Davis, G. L. et al., "Future Options for the Management of Hepatitis C.” Seminars in Liver Disease, 19, pp. 103-112 (1999); Interleukin 6 (Davis et al. "Future Options for the Management of Hepatitis C.” Seminars in Liver Disease 19, pp. 103-112 (1999); interleukin 12 (Davis, G.
  • the invention provides a method for treating hepatitis C viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with an anti-proliferative agent.
  • antiproliferative agent denotes a compound which inhibits cellular proliferation. Cellular proliferation can occur, for example without limitation, during carcinogenesis, metastasis, and immune responses.
  • Representative anti-proliferative agents include, without limitation, 5-fluorouracil, daunomycin, mitomycin, bleomycin, dexamethasone, methotrexate, cytarabine, and mercaptopurine.
  • Representative anti-IL-1 compounds in this context include without limitation anakinra.
  • Representative immune suppressants include without limitation cyclosporin and FK506.
  • the invention provides a method for treating hepatitis C viral infection, comprising administering to a subject in need of such treatment an effective amount of a compound of the invention in combination with an antibiotic.
  • an antibiotic includes an anti-bacterial or anti-fungal agent. Agents of this type are useful in combating, for example, secondary bacterial or fungal infections that may accompany a hepatitis C infection. Examples include beta-lactam antibiotics, macrocyclic antibiotics, triazole anti-fungal agents, and the like.
  • Compounds of the invention include mixtures of stereoisomers such as mixtures of diastereomers and/or enantiomers.
  • the compound e.g. of Formula I, is 90 weight percent (wt %) or greater of a single diastereomer of enantiomer.
  • the compound is 92, 94, 96, 98 or even 99 wt % or more of a single diastereomer or single enantiomer.
  • a variety of uses of the invention compounds are possible along the lines of the various methods of treating a subject as described above.
  • Exemplary uses of the invention methods include, without limitation, use of a compound of the invention in a medicament or for the manufacture of a medicament for treating a condition that is regulated or normalized via inhibition of the HCV NS3 serine protease.
  • An embodiment of the invention is directed to use of an inventive compound in preparation of a medicament for the treatment of an HCV infection in a patient.
  • an effective amount of a second bioactive agent such as described above, can be used in preparation of a medicament for treatment of an HCV infection in a patient.
  • An embodiment of the invention provides an inventive compound for use in combination with an effective amount of a second medicament, such as described above, in treatment of an HCV infection in a patient.
  • Fluorescence resonance energy transfer (FRET; see e.g., Heim et al, (1996) Curr. Biol. 6: 178-182; Mitra et al., (1996) Gene 173: 13-17; and Selvin et al., (1995) Meth. Enzymol. 246:300-345) is an extremelyly sensitive method for detecting energy transfer between two fluorophoric probes.
  • probes are given the designations "donor” and "acceptor” depending on the relative positions of the maxima in the absorption and emission spectra characterizing the probes. If the emission spectrum of the acceptor overlaps the absorption spectrum of the donor, energy transfer can occur.
  • FRET measurements correlate with distance. For example, when the probes are in proximity, such as when the probes are attached to the N- and C- termini of a peptide substrate, and the sample is illuminated in a spectrofluorometer, resonance energy can be transferred from one excited probe to the other resulting in observable signal. Upon scission of the peptide linking the probes, the average distance between probes increases such that energy transfer between donor and accept probe is not observed.
  • the degree of hydrolysis of the peptide substrate, and the level of activity of the protease catalyzing hydrolysis of the peptide substrate can be quantitated. Accordingly, using methods known in the arts of chemical and biochemical kinetics and equilibria, the effect of inhibitor on protease activity can be quantitated.
  • compositions of the compounds of the invention alone or in combination with another NS3 protease inhibitor or another type of antiviral agent and/or another type of therapeutic agent.
  • compounds of the invention include stereoisomers, tautomers, solvates, prodrugs, pharmaceutically acceptable salts and mixtures thereof.
  • Compositions containing a compound of the invention may be prepared by conventional techniques, e.g. as described in Remington: The Science and Practice of Pharmacy, 21st Ed., (2005).
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions or topical applications.
  • compositions include a compound of the invention which inhibits the enzymatic activity of the HCV NS3 protease, and a pharmaceutically acceptable excipient which may be a carrier or a diluent.
  • a pharmaceutically acceptable excipient which may be a carrier or a diluent.
  • the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of an ampoule, capsule, sachet, paper, or other container.
  • the active compound When the active compound is mixed with a carrier, or when the carrier serves as a diluent, it may be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.
  • the active compound can be adsorbed on a granular solid carrier, for example contained in a sachet.
  • suitable carriers are water, salt solutions, alcohols, polyethylene glycols, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose and polyvinylpyrrolidone.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate
  • the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
  • auxiliary agents which do not deleteriously react with the active compounds.
  • Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances preserving agents, sweetening agents or flavoring agents.
  • the compositions can also be sterilized if desired.
  • the route of administration may be any route which effectively transports the active compound of the invention which inhibits the enzymatic activity of the HCV NS3 protease to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal or parenteral, e.g., rectal, depot, subcutaneous, intravenous, intraurethral, intramuscular, intranasal, ophthalmic solution or an ointment, the oral route being preferred.
  • a solid carrier is used for oral administration, the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • injectable dosage forms generally include aqueous suspensions or oil suspensions which may be prepared using a suitable dispersant or wetting agent and a suspending agent Injectable forms may be in solution phase or in the form of a suspension, which is prepared with a solvent or diluent.
  • Acceptable solvents or vehicles include sterilized water, Ringer's solution, or an isotonic aqueous saline solution.
  • sterile oils may be employed as solvents or suspending agents.
  • the oil or fatty acid is non-volatile, including natural or synthetic oils, fatty acids, mono-, di- or tri-glycerides.
  • the formulation may also be a powder suitable for reconstitution with an appropriate solution as described above. Examples of these include, but are not limited to, freeze dried, rotary dried or spray dried powders, amorphous powders, granules, precipitates, or particulates.
  • the formulations may optionally contain stabilizers, pH modifiers, surfactants, bioavailability modifiers and combinations of these.
  • the compounds may be formulated for parenteral administration by injection such as by bolus injection or continuous infusion.
  • a unit dosage form for injection may be in ampoules or in multi-dose containers.
  • the formulations of the invention may be designed to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing procedures well known in the art.
  • the formulations may also be formulated for controlled release or for slow release.
  • compositions contemplated by the present invention may comprise, for example, micelles or liposomes, or some other encapsulated form, or may be administered in an extended release form to provide a prolonged storage and/or delivery effect. Therefore, the formulations may be compressed into pellets or cylinders and implanted intramuscularly or subcutaneous Iy as depot injections or as implants such as stents. Such implants may employ known inert materials such as silicones and biodegradable polymers, e.g., polylactide-polyglycolide. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides).
  • injectable solutions or suspensions preferably aqueous solutions with the active compound dissolved in polyhydroxylated castor oil.
  • Tablets, dragees, or capsules having talc and/or a carbohydrate carrier or binder or the like are particularly suitable for oral application.
  • Preferable carriers for tablets, dragees, or capsules include lactose, corn starch, and/or potato starch.
  • a syrup or elixir can be used in cases where a sweetened vehicle can be employed.
  • a typical tablet that may be prepared by conventional tabletting techniques may contain:
  • a typical capsule for oral administration contains, for example, compounds of the invention (250 mg), lactose (75 mg) and magnesium stearate (15 mg). The mixture is passed through a 60 mesh sieve and packed into a No. 1 gelatin capsule.
  • a typical injectable preparation is produced by aseptically placing, for example, 250 mg of compounds of the invention into a vial, aseptically freeze-drying and sealing. For use, the contents of the vial are mixed with 2 mL of sterile physiological saline, to produce an injectable preparation.
  • the compounds of the invention may be administered to a mammal, especially a human in need of such treatment, prevention, elimination, alleviation or amelioration of the various diseases as mentioned above, e.g., HCV infection.
  • mammals include also animals, both domestic animals, e.g. household pets, farm animals, and non-domestic animals such as wildlife.
  • the compounds of the invention are effective over a wide dosage range.
  • daily dosages ranging from about 1 to about 3000 mg may be used. Doses of about 1 mg to about 1000 mg can be provided to the patient up to three times per day. In choosing a regimen for patients it may frequently be necessary to begin with a higher dosage and when the condition is under control to reduce the dosage. The exact dosage will depend upon the activity of the compound, mode of administration, on the therapy desired, form in which administered, the subject to be treated and the body weight of the subject to be treated, and the preference and experience of the physician or veterinarian in charge.
  • HCV NS3 protease inhibitor activity of the compounds of the invention may be determined by use of an in vitro assay system which measures the potentiation of inhibition of the HCV NS3 protease.
  • Inhibition constants i.e., K 1 or IC50 values as known in the art
  • K 1 or IC50 values as known in the art
  • the invention also encompasses prodrugs of a compound of the invention which on administration undergo chemical conversion by metabolic or other physiological processes before becoming active pharmacological substances. Conversion by metabolic or other physiological processes includes without limitation enzymatic (e.g, specific enzymatically catalyzed) and non- enzymatic (e.g., general or specific acid or base induced) chemical transformation of the prodrug into the active pharmacological substance.
  • prodrugs will be functional derivatives of a compound of the invention which are readily convertible in vivo into a compound of the invention. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • compositions of a compound described herein comprising formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent.
  • the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
  • the methods may further comprise the step of formulating the composition into a tablet or capsule.
  • the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
  • the methods further comprise the step of lyophilizing the composition to form a lyophilized preparation.
  • the compounds of the invention may be used in combination with i) one or more other NS3 protease inhibitors and/or ii) one or more other types of antiviral agents (employed to treat viral infection and related diseases) and/or one or more other types of therapeutic agents which may be administered orally in the same dosage form, in a separate oral dosage form (e.g., sequentially or non-sequentially) or by injection together or separately (e.g., sequentially or non- sequentially).
  • the invention provides combinations, comprising: a) a compound of the invention as described herein; and b) one or more compounds comprising: i) other compounds of the present invention ii) anti-viral agents including, but not limited to, other NS3 protease inhibitors iii) anti-proliferative agents iv) immune modulators v) antibiotics.
  • Combinations of the invention include mixtures of compounds from (a) and (b) in a single formulation and compounds from (a) and (b) as separate formulations. Some combinations of the invention may be packaged as separate formulations in a kit. In some embodiments, two or more compounds from (b) are formulated together while a compound of the invention is formulated separately. Combinations of the invention can further comprise a pharmaceutically acceptable carrier. In some embodiments, the compound of the invention is 90 wt % or more of a single diastereomer or single enantiomer.
  • the compound of the invention can be 91, 92, 93, 94, 95, 96, 97, 98, or 99 wt % or more of a single diastereomer or single enantiomer.
  • the dosages and formulations for the other antiviral agent to be employed, where applicable, will be as set out in the latest edition of the
  • a composition may be employed containing the compounds of the invention, with or without another antiviral agent and/or other type therapeutic agent, in association with a pharmaceutical vehicle or diluent.
  • the composition can be formulated employing conventional solid or liquid vehicles or diluents and pharmaceutical additives of a type appropriate to the mode of desired administration.
  • the compounds can be administered to mammalian species including humans, monkeys, dogs, etc. by an oral route, for example, in the form of tablets, capsules, granules or powders, or they can be administered by a parenteral route in the form of injectable preparations.
  • the dose for adult humans is preferably between 1 and 3,000 mg per day, which can be administered in a single dose or in the form of individual doses of about 1 mg to about 1,000 mg up to 3 times per day.
  • Compound 1 was prepared according to the following protocol.
  • Compound 2 was prepared according to the following protocol.
  • the sodium salt of D-lactic acid (1.26 g, 11.2 mmol) was dissolved in DMSO (40 mL) with some sonication.
  • the reaction flask was placed in a water bath at 15-20 0 C and tBuOK (1.26 g, 11.2 mmol) was added in one portion.
  • the reaction was stirred under argon for 90 minutes.
  • 6-bromo-l-hexene (1.66 mL, 11.76 mmol) was added dropwise and the reaction stirred for 21 hours at room temperature.
  • the contents of the flask were added portionwise to distilled water cooled to 0 0 C with vigorous stirring.
  • Et 2 O ( ⁇ 50 mL) was added to the same Erlenmeyer flask.
  • a two-neck round bottom flask was charged with a solution of compound E19 (923 mg, 2.2 mmol) in 1,2 dichloroethane (1 L). After the flask was fitted with a reflux condenser, argon gas was bubbled through the solution for 15 min at room temperature. Then the flask was placed in a 80 0 C oil bath and stirred for 15 min with a continuous flow of argon through the solution. Hoveyda-Grubbs 1 st generation catalyst (40 mg, 3 mol %) was added to the reaction in one portion.
  • Compound 3 was prepared according to the following protocol.
  • Compound E37 was prepared following the procedures described in the synthesis of Compound 2 using 7-methoxy-8-methyl-2-(3-isopropyl-lH-pyrazol- l-yl)quinolin-4-ol in place of the 2-(4-isopropylthiazol-2-yl)-7-methoxy-8- methylquinolin-4-ol. Compound 5.
  • Compound 6 was prepared according to the following protocols.
  • the title compound was prepared following the procedures described in the synthesis of Compound 2 using 7-methoxy-2-(3-methyl-lH-pyrazol-l- yl)quinolin-4-ol in place of the 2-(4-isopropylthiazol-2-yl)-7-methoxy-8- methylquinolin-4-ol.
  • the 7-methoxy-2-(3-methyl-lH-pyrazol-l-yl)quinolin-4-ol was prepared as described in WO 2000/059929 Al
  • the title compound was prepared following the procedures described in the synthesis of Compound 2 using 2-ethoxy-7-methoxy-8-methylquinolin-4-ol in place of the 2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-ol.
  • the 2-ethoxy-7-methoxy-8-methylquinolin-4-ol was prepared as described in WO 2008/059046 Al. Compound 23.
  • the title compound was prepared following the procedures described in the synthesis of Compounds 2 and 4 using 2-(5-(4-methoxyphenyl)-2H-l,2,3- triazol-4-yl)thiazole in place of the 2-(4-isopropylthiazol-2-yl)-7-methoxy-8- methylquinolin-4-ol.
  • the 2-(5-(4-methoxyphenyl)-2H-l,2,3-triazol-4-yl)thiazole was prepared according to WO 2008/021871 A2.
  • the title compound was prepared following the procedures described in the synthesis of Compounds 2 and 4 using 6-methoxy-2-phenylpyrimidin-4-ol in place of the 2-(4-isopropylthiazol-2-yl)-7-methoxy-8-methylquinolin-4-ol.
  • the 6-methoxy-2-phenylpyrimidin-4-ol was prepared as described in WO 2008/095999 Al.
  • the title compound was prepared following the procedures described in the synthesis of Compounds 2 and 4 using 7-methoxy-8-methyl-2-(6- methylpyridin-2-yl)quinolin-4-ol in place of the 2-(4-isopropylthiazol-2-yl)-7- methoxy-8-methylquinolin-4-ol.
  • the 7-methoxy-8-methyl-2-(6-methylpyridin-2- yl)quinolin-4-ol was prepared as described in WO 2007/014926 Al.
  • the title compound was prepared following the procedures described in the synthesis of Compounds 2 and 4 using 2-(6-isopropylpyridin-2-yl)-7-methoxy- 8-methylquinolin-4-ol in place of the 2-(4-isopropylthiazol-2-yl)-7-methoxy-8- methylquinolin-4-ol.
  • the 2-(6-isopropylpyridin-2-yl)-7-methoxy-8- methylquinolin-4-ol was prepared as described in WO 2007/014926 Al.
  • the title compound was prepared following the procedures described in the synthesis of Compound 2 using (R)-2-hydroxy-3-phenylpropanoic acid ethyl ester in place of the (+)-methyl D-lactate.
  • the (R)-2-hydroxy-3-phenylpropanoic acid ethyl ester was prepared according to the following procedure.
  • Triethylsilylchloride (0.2 ml, 1.5 mmol) was added to a solution of acid E51 (2.5 g, 15.0 mmol) in diethoxyethane (24 mL) and EtOH (6 mL). The mixture was stirred for 16 hours at room temperature and the solvent removed under reduced pressure. The residue was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate mixtures to give E52 (2.3 g, 79% yield) as a white solid. Mass (ESI positive): 195 [M+H] +
  • HCV NS3/4A Genotype Ib from strain Con-1, Genotype Ia from strain H77, Genotype 2a from strain HC- J6, and Genotype 3a from strain N2L1 were custom prepared by Protein One (Bethesda, MD).
  • the NS3 protease (amino acids 3 - 181) was expressed with an NS4A fragment (His-NS4A 2 i-3 2 - GSGS-NS3-181) as a single peptide in bacterial cells and purified using immobilized metal ion chromatography followed by additional FPLC methods. Purified HCV proteases were analyzed by Nu-PAGE and confirmed by western blot analysis. Phenomix protease inhibitors were prepared as 10 mM stocks in DMSO and stored at -20 0 C.
  • HCV protease inhibitors were screened using a fluorescence resonance energy transfer (FRET) based assay.
  • FRET fluorescence resonance energy transfer
  • the FRET peptide was derived from the natural cleavage site at the NS4A/NS4B junction of the HCV polypeptide, and dual labeled with 5-carboxyfluorescein (5-FAM) and QXLTM520 dyes. 5-FAM fluorescence is quenched by QXLTM520 when the peptide is intact, only to be recovered upon protease driven cleavage of the substrate.
  • Protease enzymes were diluted in reaction buffer to provide a signal to noise (SfN) ratio above 4 after 10 minutes of substrate turnover at room temperature.
  • SfN signal to noise
  • Test wells in 96-well plates contained 45 uL of diluted protease and 5 uL of compound titrated in DMSO.
  • Enzyme only (max) wells contained 45 uL of diluted protease and 5 uL of DMSO.
  • No enzyme (min) wells contained 45 uL of reaction buffer and 5 uL of DMSO. All compounds were assayed in duplicate.
  • the assay plate was incubated at room temperature for 20 minutes post compound addition to allow for equilibration of test compounds with the enzyme. 50 uL of FRET-substrate diluted in reaction buffer was then added to all wells followed by incubation at room temperature for 10 minutes.
  • IC50/90 calculations were performed from the calculated percent inhibition data by non-linear regression analysis using Prism software (GraphPad).
  • Table 3 lists compounds that were prepared according to any one of the above procedures and their activities in the assays described above.
  • the compound numbers correspond to the compound numbers in Table 1.
  • A indicates IC50 of less than 10 nM
  • B indicates 10 nM ⁇ IC50 ⁇ 100
  • C indicates 100 nM ⁇ IC50 ⁇ 1 ⁇ M
  • D indicates IC50 > 1 ⁇ M
  • Huh-luc/neo-ET cells expressing the persistent replicon I ⁇ luc-ubi- neo/NS3-37ET were purchased from Reblikon. Cells were cultured in DMEM media (Invitrogen) containing 10% FBS (Biowhittaker), IX Antibiotic- Antimycotic (Invitrogen), IX nonessential amino acids (Invitrogen), and 1 mg/mL G418 (Invitrogen). Cells were housed in a 37 0 C incubator with 5% CO2 and were passaged regularly. Huh-luc/neo-ET cells (5,000 cells per well) were seeded in a 96-well plate in DMEM media (without phenol red or G418) and were incubated at 37 0 C overnight.
  • Table 4 shows the activity of compounds of this invention in the assay described above.
  • the compound numbers correspond to the compound numbers in Table 1.
  • A indicates IC50 of less than 10 nM
  • B indicates 10 nM ⁇ IC50 ⁇ 100 nM
  • C indicates 100 nM ⁇ IC50 ⁇ 1 ⁇ M
  • D indicates IC50 > 1 ⁇ M
  • the NS3 protease (amino acids 3 - 181) was expressed with an NS4A fragment (His- NS4A 21 -3 2 -GSGS-NS3- 1 8 1 ) as a single peptide in bacterial cells and purified using immobilized metal ion chromatography followed by additional FPLC methods. Purified HCV proteases were analyzed by Nu-PAGE and confirmed by western blot analysis. Phenomix protease inhibitors were prepared as 10 mM stocks in DMSO and stored at -20 0 C. HCV protease inhibitors were screened using a fluorescence resonance energy transfer (FRET) based assay.
  • FRET fluorescence resonance energy transfer
  • the FRET peptide was derived from the natural cleavage site at the NS4A/NS4B junction of the HCV polypeptide, and dual labeled with 5-carboxyfluorescein (5-FAM) and QXLTM520 dyes. 5-FAM fluorescence is quenched by QXLTM520 when the peptide is intact, only to be recovered upon protease driven cleavage of the substrate.
  • Protease enzymes were diluted in reaction buffer to provide a signal to noise (SfN) ratio above 4 after 10 minutes of substrate turnover at room temperature. Compounds were assayed in an 8 dose format using half-log dilutions.
  • Test wells in 96-well plates contained 45 uL of diluted protease and 5 uL of compound titrated in DMSO.
  • Enzyme only (max) wells contained 45 uL of diluted protease and 5 uL of DMSO.
  • No enzyme (min) wells contained 45 uL of reaction buffer and 5 uL of DMSO. All compounds were assayed in duplicate.
  • the assay plate was incubated at room temperature for 20 minutes post compound addition to allow for equilibration of test compounds with the enzyme. 50 uL of FRET-substrate diluted in reaction buffer was then added to all wells followed by incubation at room temperature for 10 minutes.
  • IC50/90 calculations were performed from the calculated percent inhibition data by non-linear regression analysis using Prism software (GraphPad).
  • Table 5 shows the activity of compounds of this invention in the assays described above.
  • the compound numbers correspond to the compound numbers in Table 1.
  • A indicates IC50 of less than 10 nM
  • B indicates 10 nM ⁇ IC50 ⁇ 100
  • C indicates 100 nM ⁇ IC50 ⁇ 1 ⁇ M
  • D indicates IC50 > 1 ⁇ M
  • HCV NS3/4A protease Although the HCV NS3/4A protease is of viral origin, it was identified as a chymotrypsin-like protease with some similarity to human proteases.
  • NS3/4A requires screening against human proteases to assure selectivity.
  • Compounds of the present invention were screened against five human proteases: chymotrypsin, human neutrophil elastase (HNE), cathepsin G, cathepsin B, and chymase.
  • Chymotrypsin (#230900), human neutrophil elastase (HNE) (#324681), cathepsin B (#219362), and cathepsin G (#219373) were purchased from Calbiochem.
  • Chymase (#SE-281) was from Biomol.
  • Suc-Ala-Ala-Pro-Phe-AMC (#230914), MeOSuc-Ala-Ala-Pro-Val-AMC (#324740), and Z-Arg-Arg-AMC (#219392) fluorogenic substrates were purchased from Calbiochem.
  • the reference compounds chymostatin (#230790) and cathepsin G Inhibitor I
  • the chymotrypsin assay was run in 100 mM Hepes pH 7.5, 100 mM NaCl, 20 mM CaCl 2 , and 0.125 mg/mL BSA using 20 uM of the Suc- Ala-Ala-Pro-Phe-AMC substrate.
  • the HNE assay was run in 62.5 mM Hepes pH 7.8, 625 mM NaCl, and 1.25 mg/mL BSA using 200 uM MeOSuc-Ala-Ala- Pro-Val-AMC.
  • the cathepsin B assay was run in 100 mM sodium/potassium phosphate buffer pH 6.8, 1 mM EDTA, and 2 mM DTT using 200 uM of the Z- Arg-Arg-AMC substrate.
  • the cathepsin G assay was run in 100 mM Hepes pH 7.5, 500 mM NaCl, 1 mM DTT, and 0.125 mg/mL BSA using 200 uM Suc-Ala- Ala-Pro-Phe-AMC.
  • the chymase assay was run in 200 mM Hepes pH 8.0, 2 M NaCl, and 0.01% Triton X-100 using 20 uM of the Sue-Ala- Ala-Pro-Phe- AMC substrate.
  • Protease enzymes were diluted in the appropriate assay buffer to provide a signal to noise (SfN) ratio allowing for a sensitive and reproducible assay.
  • SfN signal to noise
  • Chymotrypsin, HNE and cathepsin B were optimized for a S/N ratio above 6 after 10 minutes of substrate turnover at room temperature. Due to the lower activity of cathepsin G and chymase, these enzymes required 25 to 30 minutes of substrate turnover to obtain a S/N ratio greater than 3.
  • Compounds were assayed in an 8 dose format using half-log dilutions.
  • Test wells in 96-well plates contained 45 uL of diluted protease and 5 uL of compound titrated in DMSO.
  • Enzyme only (max) wells contained 45 uL of diluted protease and 5 uL of DMSO.
  • No enzyme (min) wells contained 45 uL of reaction buffer and 5 uL of DMSO. All compounds were assayed in duplicate.
  • the assay plate was incubated at room temperature for 20 minutes post compound addition to allow for equilibration of test compounds with the enzyme. 50 uL of AMC-substrate diluted in reaction buffer was then added to all wells followed by incubation at room temperature for 10 to 30 minutes.
  • the percent inhibition of protease activity was determined using the fluorescence value (FV) at each concentration of a given test compound. Percent inhibition was defined as: 100% X (max- FV) / (max- min) IC50/90 calculations were performed from the calculated percent inhibition data by non-linear regression analysis using Prism software (GraphPad).
  • the plasma pharmacokinetics and liver concentrations of Compound 2 after a single administration of 10 mg/kg in solution (60% PEG 400, 10% ethanol and 30% water) by oral gavage to three male Sprague Dawley rats were determined. Eight time points of plasma and 24 hr liver samples were taken from two rats, and seven time points of plasma and 12 hr liver samples were taken from the third animal for plasma and liver concentration determinations.
  • the PK parameters of Compound 2 were as follows: the mean T max was 1.8 hr; the mean C max was 629 ng/ml; the mean AUCo-mf value was 3590 hr*ng/ml; the mean terminal half-life was 3.7 hr.
  • the mean plasma concentrations of Compound 2 were sustained more than 24 hr above its replicon EC 9 0 (0.19 ng/ml). These data indicated that Compound 2 was orally available, with a bioavailability of 54% (an intravenous PK study served as the reference).
  • the rat 12 hr liver concentration was 216 ng/g of liver, which corresponds to 3.4-fold of the plasma concentration from the same animal at that timepoint.
  • the 12 hr liver concentration was 1137-fold of the replicon EC 9 0 of Compound 2.
  • the mean 24 hr liver concentration was 3.6 ng/g of liver, which corresponds to 5.8-fold of the plasma concentration from the same animal at that timepoint.
  • the 24 hr liver concentration was 19-fold of the replicon EC 9 0 of Compound 2.
  • the plasma pharmacokinetics and liver concentrations of Compounds 18, 19, 20 and 43 after a single administration of 10 mg/kg in solution by oral gavage to male Sprague Dawley rats were determined.
  • the PK parameters were as follows:
  • the PK parameters of Compound 2 were as follows: the mean T max was 1.3 hr; the mean C max was 284 ng/ml; the mean AUCo -mf value was 665 hr*ng/ml; the mean terminal half-life was 3.5 hr.
  • the mean plasma concentrations of Compound 2 were sustained for over 23 hours above its replicon EC 9 0 (0.19 ng/ml). These data indicated that Compound 2 was orally available, with a bioavailability of 26% (an intravenous PK study served as the reference).
  • the plasma pharmacokinetics and the liver concentrations of Compound 2 after a single administration of 6 mg/kg in solution (60% PEG 400, 10% ethanol and 30% water) by oral gavage to 4 male Cynomolgus monkeys were determined. Seven time points of plasma and one 12 hr liver sample from each of two animals, and eight time points of plasma and one 24 hr liver sample from each of the other two animals were taken for plasma and liver concentration determinations.
  • the PK parameters of Compound 2 were as follows: the mean T max was 2.4 hr; the mean C max was 603 ng/ml; the mean AUCo -mf value was 4397 hr*ng/ml; the mean terminal half-life was 5.1 hr.
  • the mean plasma concentrations of Compound 2 were sustained for over 24 hours above its replicon EC 9 0 (0.19 ng/ml). The data indicated that Compound 2 was orally available, with a bioavailability of 57% (an intravenous PK study served as the reference).
  • the mean 12 hr liver concentration was 393 ng/g of liver, which corresponds to 2-fold of the plasma concentration from the same animals at that timepoint.
  • the 12 hr liver concentration was 2066-fold of the replicon EC 9 0 of Compound 2.
  • the mean 24 hr liver concentration was 39 ng/g of liver, which corresponds to 3-fold of the plasma concentration from the same animals at that timepoint.
  • the 24 hr liver concentration was 205-fold of the replicon EC 9 0 of Compound 2.
  • Any compound found to be an effective inhibitor of HCV protease can likewise be tested in animal models and in human clinical studies using the skill and experience of the investigator to guide the selection of dosages and treatment regimens.

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Abstract

Cette invention concerne des composés macrocycliques inhibant la protéase du virus de l'hépatite C, des compositions et des combinaisons contenant ces composés, des méthodes de traitement de pathologies dans lesquelles l'inhibition de la protéase du virus de l'hépatite C est indiquée du point de vue médical, et des méthodes de traitement d'une infection par le virus de l'hépatite C chez l'homme.
PCT/US2009/056859 2008-09-16 2009-09-14 Inhibiteurs macrocycliques de la protéase du virus de l'hépatite c WO2010033466A1 (fr)

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WO2011091757A1 (fr) 2010-01-27 2011-08-04 AB Pharma Ltd. Composés polyhétérocycliques hautement puissants en tant qu'inhibiteurs du vhc
US8232246B2 (en) 2009-06-30 2012-07-31 Abbott Laboratories Anti-viral compounds
CN102617705A (zh) * 2012-02-16 2012-08-01 银杏树药业(苏州)有限公司 抑制丙肝病毒复制的大环类化合物
US8420596B2 (en) 2008-09-11 2013-04-16 Abbott Laboratories Macrocyclic hepatitis C serine protease inhibitors
US8937041B2 (en) 2010-12-30 2015-01-20 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8951964B2 (en) 2010-12-30 2015-02-10 Abbvie Inc. Phenanthridine macrocyclic hepatitis C serine protease inhibitors
US8957203B2 (en) 2011-05-05 2015-02-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8962810B2 (en) 2011-06-16 2015-02-24 AB Pharma Ltd. Macrocyclic heterocyclic compound for inhibiting hepatitis C virus and preparation and use thereof
JP2016508523A (ja) * 2013-02-28 2016-03-22 プロノヴァ・バイオファーマ・ノルゲ・アーエスＰｒｏｎｏｖａ ＢｉｏＰｈａｒｍａ Ｎｏｒｇｅ ＡＳ ２−（（５ｚ，８ｚ，１１ｚ，１４ｚ，１７ｚ）−イコサ−５，８，１１，１４，１７−ペンタエニルオキシ）ブタン酸を調製する方法
US9296782B2 (en) 2012-07-03 2016-03-29 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
US9334279B2 (en) 2012-11-02 2016-05-10 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms
US9409943B2 (en) 2012-11-05 2016-08-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9499550B2 (en) 2012-10-19 2016-11-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9580463B2 (en) 2013-03-07 2017-02-28 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9598433B2 (en) 2012-11-02 2017-03-21 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9617310B2 (en) 2013-03-15 2017-04-11 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
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US9309279B2 (en) 2008-09-11 2016-04-12 Abbvie Inc. Macrocyclic hepatitis C serine protease inhibitors
US8420596B2 (en) 2008-09-11 2013-04-16 Abbott Laboratories Macrocyclic hepatitis C serine protease inhibitors
US8642538B2 (en) 2008-09-11 2014-02-04 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8232246B2 (en) 2009-06-30 2012-07-31 Abbott Laboratories Anti-viral compounds
WO2011091757A1 (fr) 2010-01-27 2011-08-04 AB Pharma Ltd. Composés polyhétérocycliques hautement puissants en tant qu'inhibiteurs du vhc
US8937041B2 (en) 2010-12-30 2015-01-20 Abbvie, Inc. Macrocyclic hepatitis C serine protease inhibitors
US8951964B2 (en) 2010-12-30 2015-02-10 Abbvie Inc. Phenanthridine macrocyclic hepatitis C serine protease inhibitors
US9527885B2 (en) 2011-05-05 2016-12-27 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US8957203B2 (en) 2011-05-05 2015-02-17 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US10201541B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US10201584B1 (en) 2011-05-17 2019-02-12 Abbvie Inc. Compositions and methods for treating HCV
US8962810B2 (en) 2011-06-16 2015-02-24 AB Pharma Ltd. Macrocyclic heterocyclic compound for inhibiting hepatitis C virus and preparation and use thereof
US9321809B2 (en) 2012-02-16 2016-04-26 Ginkgo Pharama Co., Ltd. Macrocyclic compounds for suppressing replication of hepatitis C virus
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CN102617705B (zh) * 2012-02-16 2014-12-31 上海纬诺医药科技有限公司 抑制丙肝病毒复制的大环类化合物
CN104169293A (zh) * 2012-02-16 2014-11-26 银杏树药业(苏州)有限公司 抑制丙肝病毒复制的大环类化合物
US10335409B2 (en) 2012-07-03 2019-07-02 Gilead Pharmasset Llc Inhibitors of hepatitis C virus
US9296782B2 (en) 2012-07-03 2016-03-29 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
US10603318B2 (en) 2012-07-03 2020-03-31 Gilead Pharmasset Llc Inhibitors of hepatitis C virus
US9499550B2 (en) 2012-10-19 2016-11-22 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9643999B2 (en) 2012-11-02 2017-05-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9334279B2 (en) 2012-11-02 2016-05-10 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
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US9409943B2 (en) 2012-11-05 2016-08-09 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
CN107673964B (zh) * 2013-02-28 2021-03-23 普罗诺瓦生物医药挪威公司 制备2-((5z,8z,11z,14z,17z)-二十碳-5,8,11,14,17-五烯基氧基)丁酸的方法
CN107673964A (zh) * 2013-02-28 2018-02-09 普罗诺瓦生物医药挪威公司 制备2‑((5z,8z,11z,14z,17z)‑二十碳‑5,8,11,14,17‑五烯基氧基)丁酸的方法
JP2016508523A (ja) * 2013-02-28 2016-03-22 プロノヴァ・バイオファーマ・ノルゲ・アーエスＰｒｏｎｏｖａ ＢｉｏＰｈａｒｍａ Ｎｏｒｇｅ ＡＳ ２−（（５ｚ，８ｚ，１１ｚ，１４ｚ，１７ｚ）−イコサ−５，８，１１，１４，１７−ペンタエニルオキシ）ブタン酸を調製する方法
US9580463B2 (en) 2013-03-07 2017-02-28 Bristol-Myers Squibb Company Hepatitis C virus inhibitors
US9617310B2 (en) 2013-03-15 2017-04-11 Gilead Sciences, Inc. Inhibitors of hepatitis C virus
US9333204B2 (en) 2014-01-03 2016-05-10 Abbvie Inc. Solid antiviral dosage forms
US10105365B2 (en) 2014-01-03 2018-10-23 Abbvie Inc. Solid antiviral dosage forms
US9744170B2 (en) 2014-01-03 2017-08-29 Abbvie Inc. Solid antiviral dosage forms
WO2023205778A1 (fr) * 2022-04-22 2023-10-26 Vertex Pharmaceuticals Incorporated Composés hétéroaryles pour le traitement de la douleur

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