WO2003087092A2 - Inhibitors of serine proteases, particularly hepatitis c virus ns3 - ns4 protease - Google Patents

Inhibitors of serine proteases, particularly hepatitis c virus ns3 - ns4 protease Download PDF

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Publication number
WO2003087092A2
WO2003087092A2 PCT/US2003/011459 US0311459W WO03087092A2 WO 2003087092 A2 WO2003087092 A2 WO 2003087092A2 US 0311459 W US0311459 W US 0311459W WO 03087092 A2 WO03087092 A2 WO 03087092A2
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Prior art keywords
aliphatic
independently
ring
cycloalkyl
aryl
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PCT/US2003/011459
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French (fr)
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WO2003087092A3 (en
Inventor
Janos Pitlik
Kevin M. Cottrell
Luc J. Farmer
Robert B. Perni
Lawrence F. Courtney
John H. Van Drie
Mark A. Murcko
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Vertex Pharmaceuticals Incorporated
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Priority to MXPA04009938A priority Critical patent/MXPA04009938A/en
Priority to CA2481369A priority patent/CA2481369C/en
Priority to EP03719741A priority patent/EP1497282A2/en
Priority to AU2003223602A priority patent/AU2003223602B8/en
Priority to KR10-2004-7016168A priority patent/KR20040099425A/en
Priority to JP2003584048A priority patent/JP2005535574A/en
Application filed by Vertex Pharmaceuticals Incorporated filed Critical Vertex Pharmaceuticals Incorporated
Publication of WO2003087092A2 publication Critical patent/WO2003087092A2/en
Publication of WO2003087092A3 publication Critical patent/WO2003087092A3/en
Priority to IL16445504A priority patent/IL164455A0/en
Priority to NO20044889A priority patent/NO20044889L/en
Priority to HK06101291A priority patent/HK1081196A1/en
Priority to NO20110773A priority patent/NO20110773L/en

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    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
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    • C07D417/02—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 two hetero rings
    • C07D417/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/08—Tripeptides
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    • C07K5/1027—Tetrapeptides containing heteroatoms different from O, S, or N

Definitions

  • the present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents.
  • the invention further relates to compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection.
  • the invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention.
  • HCV hepatitis C virus
  • the HCV genome encodes a polyprotein of 3010-3033 amino acids [Q.L. Choo, et. al . , "Genetic Organization and Diversity of the Hepatitis C Virus.” Proc . Natl .
  • HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication.
  • the NS proteins are derived by proteolytic cleavage of the polyprotein [R. Bartenschlager et. al., "Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions," J . Virol . , 67, pp. 3835-3844 (1993); A. Grakoui et . al . , "Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites," J. Virol . , 67, pp. 2832-2843 (1993); A. Grakoui et . al . , "Expression and Identification of Hepatitis C Virus
  • NS3 is a serine protease required for processing of hepatitis C virus polyprotein
  • J. Virol., 67, pp. 4017-4026 (1993) The HCV NS protein 3 (NS3) contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decreases viral infectivity [Chambers, T.J. et. al .
  • HCV NS3 serine protease and its associated cofactor, NS4A helps process all of the viral enzymes, and is thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing HIV protease inhibitors, which inhibit viral protein processing are potent antiviral agents in man, indicating that interrupting this stage of the viral life cycle results in therapeutically active agents . Consequently it is an attractive target for drug discovery.
  • HCV protease inhibitors have been described in the prior art [PCT publication Nos.
  • Such inhibitors would have therapeutic potential as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors.
  • such compounds may be useful as antiviral agents, particularly as anti-HCV agents .
  • the present invention provides a compound of formulae (IA) :
  • A together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, SO, or S0 2 ; wherein said ring is optionally fused to a (C6-
  • J is halogen, -OR', -N0 2 , -CF 3 , -OCF 3 , -R' , oxo, -OR', -O-benzyl, -O-phenyl, 1, 2-methylenedioxy, -N(R') 2 , -SR', -SOR', -S0 2 R', -C(0)R', -COOR' or
  • R' is independently selected from: hydrogen
  • Ri and R 3 are independently: (C1-C12) -aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl,
  • Ri and R 3 are independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and R 3 may be replaced by a heteroatom selected from O, NH, S, SO, or S0 2 in a chemically stable arrangement; R 2 and R 4 are independently hydrogen,
  • R 2 and R 4 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R and R may be replaced by a heteroatom selected from 0, NH, S, SO, or S0 2 ;
  • R 5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of R 5 is optionally substituted with sulfhydryl or hydroxy;
  • W is selected from:
  • each R 6 is independently: hydrogen
  • V is -C(0)N(R 8 )-, -S(0)N(R 8 )-, or -S (0) 2 N(R 8 ) -; wherein R 8 is hydrogen or (C1-C12) -aliphatic; T is selected from: (C6-C10)-aryl,
  • T is selected from:
  • Rio is : hydrogen, (C1-C12) -aliphatic,
  • K is a bond, (C1-C12) -aliphatic, -0-, -S-, -NRg-, -C(O)-, or -C(0)-NR 9 -, wherein R 9 is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
  • the invention also provides compounds of formula (IB) :
  • the invention also relates to compositions that comprise the above compounds and the use thereof. Such compositions may be used to pre-treat invasive devices to be inserted into a patient, to treat biological samples, such as blood, prior to administration to a patient, and for direct administration to a patient. In each case the composition will be used to inhibit HCV replication and to lessen the risk of or the severity of HCV infection.
  • the invention also relates to processes for preparing the compounds of formulae (IA) , (IB) , and (II) . DETAILED DESCRIPTION OF THE INVENTION
  • the present invention provides a compound of formula
  • A together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, SO, or S0 2 ; wherein said ring is optionally fused to a (C6-
  • J is halogen, -OR', -N0 2 , -CF 3 , -OCF 3 , -R' , oxo,
  • R' is independently selected from: hydrogen,
  • R 3 are independently:
  • Ri and R 3 are independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and
  • R 3 may be replaced by a heteroatom selected from
  • R 4 are independently hydrogen,
  • R 2 and R 4 are independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R 2 and R 4 may be replaced by a heteroatom selected from 0, NH, S, SO, or S0 2 ;
  • R 5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy;
  • W is selected from:
  • each R 6 is independently: hydrogen, (C1-C12) -aliphatic,
  • T is selected from:
  • K is a bond, (C1-C12) -aliphatic, -0-, -S-, -NR 9 -, -C(O)-, or -C(0)-NR 9 -, wherein R 9 is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
  • the invention provides a compound of formula (IB) :
  • A together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, S, SO, or S0 2 ; wherein said ring is optionally fused to a (C6-
  • J is halogen, -OR', -OC (O)N(R' ) 2 , -N0 2 , -CN, -CF 3 , -OCF 3 , -R 1 , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethylenedioxy, -N(R') 2 , -SR' , -SOR' , -S0 2 R' , -S0 2 N(R') 2 , -S0 3 R', -C(0)R', -C(0)C(0)R ⁇ -C (0) CH 2 C (0) R' , -C(S)R ⁇ -C(0)OR', -OC(0)R', -C(0)N(R') 2 , -OC (O)N(R' ) 2 , -C(S)N(R') 2 , -(CH 2 ) 0 - 2 NHC(O)R' , -N (R'
  • J 2 is halogen, -OR', -OC (O)N(R' ) 2 , -N0 2 , -CN, -CF 3 , -OCF 3 , -R' , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethylenedioxy, -N(R') 2 , -SR' , -SOR' , -S0 2 R' , -S0 2 N(R') 2 , -S0 3 R', -C(0)R', -C(0)C(0)R', -C (0) CH 2 C (0) R' , -C(S)R', -C(0)0R', -OC(0)R', -C(0)N(R') 2 , -OC (O)N(R' ) 2 .
  • Ri and R 3 are independently: (C1-C12 ) -aliphatic- , (C3-C10) -cycloalkyl- or -cycloalkenyl-,
  • Ri and R 3 are independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and R 3 may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S0 2 in a chemically stable arrangement;
  • R 2 and R 4 are independently: hydrogen- , (C1-C12) -aliphatic-,
  • each of R 2 and R 4 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R 2 and R 4 may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S0 2 ;
  • R 5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any terminal carbon atom of R 5 is optionally substituted with sulfhydryl or hydroxy;
  • R 5 is hydrogen or (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of R 5 is optionally substituted with sulfhydryl or hydroxy; W is :
  • each R 6 is independently: hydrogen- , (C1-C12) -aliphatic-, (C6-Cl0)-aryl-, (C6-C10 ) -aryl- (C1-C12 ) aliphatic- , (C3-CIO) -cycloalkyl or -cycloalkenyl-, [ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic- , (C3-C10) -heterocyclyl-,
  • V is -C(0)N(R 8 )-, -S(0)N(R 8 )-, -S(0) 2 N(R 8 )-, -0S(0)-, -OS(0) 2 -, -0C(0)-, or -0-; wherein R 8 is hydrogen or (C1-C12) -aliphatic; T is:
  • K is a bond, (C1-C12) -aliphatic, -0-, -S-, -NR 9 -, -C(O)-, or -C(0)-NR 9 -, wherein R 9 is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
  • the invention provides a compound of formula (II) :
  • Xi is -N(R 20 )-, -0-, -S-, or -C(R') 2 ⁇ ;
  • X 2 is -C(O)-, -C(S)-, -S(O)-, or -S(0) 2 ⁇ ;
  • W is:
  • each R 17 is independently: hydrogen- , (C1-C12 ) -aliphatic- ,
  • each R 18 is independently -OR' ,- or both OR' groups together with the boron atom, is a (C5-C20) -membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, 0, S, SO, and S0 2 ;
  • R 5 and R 5 are independently hydrogen or (C1-C12)- aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any terminal carbon atom is optionally substituted with sulfhydryl or hydroxy, and wherein up to two aliphatic carbon atoms may be replaced by a heteroatom selected from N, NH, 0, S, SO, or S0 2 ; or R 5 and R 5 > together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, 0, S, SO, or S0 2 ; wherein the ring has up to 2 substituents selected independently from J;
  • Ri, Ri., RH, Rii-, R ⁇ 3 , and R 13 - are independently: hydrogen- ,
  • R H and Rn- together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, O, S, SO, or S0 2 ; wherein the ring has up to 2 substituents selected independently from J; or
  • Ri 3 and R ⁇ 3 together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, O, S, SO, or S0 2 ; wherein the ring has up to 2 substituents selected independently from J; wherein each of Ri, Ri-, Rn, Rn>, R13, and R 1 3- is independently and optionally substituted with up to 3 substituents independently selected from J; and wherein any ring is optionally fused to a (C6-C10) aryl, (C5- C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10)heterocyclyl; and wherein up to 3 aliphatic carbon atoms in each of Ri, Ri-, Rn, Rn-, R ⁇ 3 , and R i3 .
  • R 2 , R 4 , R 1 2, and R 2 o are independently hydrogen- , (C1-C12 ) -aliphatic- , (C3-CIO) -cycloalkyl-, (C3-C10) -cycloalkyl- (C1-C12) -aliphatic-, or
  • Rn and R 1 2 together with the atoms to which they are bound form a 3- to a 20-membered mono-, a 4- to 20- membered bi-, or a 5- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S0 2 ; wherein each ring is optionally fused to a (C6-
  • each ring has up to 3 substituents selected independently from J; or R 12 and R ⁇ 3 together with the atoms to which they are bound form a 4- to a 20-membered mono-, a 5- to 20- membered bi-, or a 6- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S0 2 ; wherein each ring is optionally fused to a (C6- ClO)aryl, (C5-C10) heteroaryl, (C3-
  • Rn and R i3 together with the atoms to which they are bound form a 5- to a 20-membered mono-, a 6- to 20- membered bi-, or a 7- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic,- wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S0 2 ; wherein each ring is optionally fused to a (C6- CIO) aryl, (C5-CIO)heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or
  • Rn# R12, and R ⁇ 3 together with the atoms to which they are bound form a 5- to a 20-membered bi-, or a 6- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S0 2 ; wherein each ring is optionally fused to a (C6-
  • each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, and S0 2 ; wherein each ring is optionally fused to a (C6- C10)aryl, (C5-C10)heteroaryl, (C3-CIO) cycloalkyl, or (C3- Cl0) heterocyclyl ; and wherein said ring has up to 3 substituents selected independently from J;
  • R 5 and R i3 together with the atoms to which they are bound form a 18- to a 23-membered mono-, a 19- to 24- membered bi-, or a 20- to 25-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S0 2 ; wherein each ring is optionally fused to a (C6- ClO)aryl, (C5-C10)heteroaryl, (C3-C10) cycloalkyl, or (C3- CIO) heterocyclyl; and wherein said ring has up to 6 substituents selected independently from J; or Ri and R 12 together with the atoms to which they are
  • Ri4 is -H, -S(0)R', -S(0) 2 R', -C(0)R', -C(0)0R', -C(0)N(R') 2 , -N(R' )C(0)R' , -N (COR ' ) COR' , -S0 2 N(R') 2 , -S0 3 R ⁇ -C(0)C(0)R', -C(0)CH 2 C(0)R' , -C(S)R', -C(S)N(R') 2 , -(CH 2 ) o .- 2 NHC(0)R' , -N (R' )N (R' ) COR ' , -N (R' ) N (R' ) C (0) OR' , -N(R' )N(R' )CON(R' ) 2 , -N(R')S0 2 R ⁇ -N (R' ) S0 2 N (R'
  • R ⁇ 9 is -OR', -CF 3 , -OCF 3 , -R' , -N(R') 2 , -SR' , -C(0)R ⁇ -COOR' -CON(R') 2 , -N(R')COR', or -N(COR' ) COR' ;
  • J is halogen, -OR', -OC (O)N(R' ) 2 , -N0 2 , -CN, -CF 3 , -OCF 3 , -R' , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethyenedioxy, -N(R') 2 , -SR' , -SOR' , -S0 2 R' , -S0 2 N(R') 2 , - S0 3 R' , -C(0)R', -C(0)C(0)R', -C (O) CH 2 C (O) R' , ⁇ C(S)R', -C(0)OR', -OC(0)R', -C(0)N(R') 2 , -OC (O)N (R' ) 2 , -C(S)N(R') 2 , -(CH 2 ) 0 -2NHC(O)R' ,
  • J 2 is halogen, -OR', -OC (O)N(R' ) 2 , -N0 2 , -CN, -CF 3 , -0CF 3 , -R' , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethylenedioxy, -N(R') 2 , -SR' , -SOR' , -S0 2 R' , -S0 2 N(R') 2 , -S0 3 R', -C(0)R', -C(0)C(0)R', -C (0) CH 2 C (O) R' , -C(S)R', -C(0)OR', -OC(0)R', -C(0)N(R') 2 , -OC (O)N(R' ) 2 , -C(S)N(R') 2 , -(CH 2 )o-2NHC(0)R' , -N (R'
  • aryl as used herein means a monocyclic or bicyclic carbocyclic aromatic ring system. Phenyl is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems wherein both rings are aromatic, e.g., naphthyl, and systems wherein only one of the two rings is aromatic, e.g., tetralin.
  • heterocyclyl as used herein means a monocyclic or bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from 0, N, NH, S, SO, or SO2 in a chemically stable arrangement.
  • one or both rings may contain said heteroatom or heteroatom groups .
  • heteroaryl as used herein means a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from 0, N, NH or S in a chemically stable arrangement.
  • heteroaryl a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from 0, N, NH or S in a chemically stable arrangement.
  • - one or both rings may be aromatic; and - one or both rings may contain said heteroatom or heteroatom groups .
  • aliphatic as used herein means a straight chained or branched alkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynyl embodiments need at least two carbon atoms in the aliphatic chain.
  • cycloalkyl or cycloalkenyl refers to a monocyclic or fused or bridged bicyclic carbocyclic ring system that is not aromatic. Cycloalkenyl rings have one or more units of unsaturation. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, nornbornyl, adamantyl and decalin-yl.
  • chemically stable arrangement refers to a compound structure that renders the compound sufficiently stable to allow manufacture and administration to a mammal by methods known in the art.
  • such compounds are stable at a temperature of
  • the compounds of formulae (IA) and (IB) of the present invention represent a selection from the genus of WO 02/18369. Applicants have invented a subgenus within the genus of WO 02/18369 that contain one or both of the following two distinct structural elements: 1. a fused azaheterocyclic ring system containing ring A, wherein ring A in formula (I) is adjacent to the ring nitrogen atom (i.e., atom X in. formula (I) is adjacent to the ring nitrogen atom of the backbone) ; 2. a hydrogen bond donor in the P4 cap part of the compounds of formula (I) [radical T in formula (I) ] .
  • the first structural element namely, ring A
  • the second structural element a hydrogen bond donor in radical T in formula (I)
  • the second structural element comprises the following moiety:
  • this pyrrole moiety (as the second structural element) provides particularly favorable hydrogen bond interactions with the serine protease active site, thereby enhancing the binding affinity of compounds having this moiety.
  • This favorable interaction enhances the binding affinity of compounds having the first structural element (i.e., ring A) as well as those having other structural elements.
  • the hydrogen on the 1-position of the pyrrole could be substituted with an appropriate group (e.g., R i4 as defined herein) to enhance biological properties .
  • one embodiment of this invention provides a compound of formula (III), wherein Pl, P2 , P3 , and P4 designate the residues of a serine protease inhibitor as known to those skilled in the art and R 14 , R15, R ⁇ 6 , Rig, and Z 2 are as defined herein:
  • any compound of the above publications may be modified to have this pyrrole moiety, or a derivative thereof. Any such compound is part of this invention.
  • compound A in WO 02/18369 (p. 41) may be modified to provide the following compound of this invention:
  • R 1 9, and Z 2 are as defined herein.
  • a together with X and Y is a 3-6 membered carbocyclic non-aromatic or aromatic ring. More preferably, A together with X and Y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl. Even more preferably, A together with X and Y is cylcohexyl or cyclopentyl . Most preferably, A together with X and Y is cyclohexyl. According to another preferred embodiment, A together with X and Y is a 3-6 membered heterocyclic ring. More preferably, A together with X and Y is a 5-6 membered heterocyclic ring. According to another preferred embodiment, A together with X and Y is a 5-6 membered heteroaryl ring.
  • a together with X and Y is fused to a (C6-C10) aryl, (C5- C10) eteroaryl, (C3-C10) cycloalkyl or (C3-C10)- heterocyclyl.
  • a together with X and Y is fused to cyclohexyl, cyclopentyl, phenyl or pyridyl.
  • A together with X, Y and the ring containing the nitrogen atom, is:
  • A together with X, Y and the ring containing the nitrogen atom, is :
  • T is selected from: (C6-C10) -aryl, (C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [(C3-C10)- cycloalkyl or -cycloalkenyl] - (C1-C12) -aliphatic, (C3- C10 ) -heterocyclyl , (C3-CIO ) -heterocyclyl- (C1-C12) - aliphatic, (C5-C10) heteroaryl, or (C5-C10) heteroaryl- (Cl- C12) -aliphatic, wherein each T is optionally substituted with up to 3 J substituents .
  • T is:
  • K is a bond, -R 9 , -0-, -S-, -NRg-, -C(O)-, or -C(O)- NR 9 -, wherein Rg is hydrogen or C1-C12 aliphatic; and n is 1-3.
  • T may also be :
  • T is
  • T contains at least one hydrogen bond donor moiety selected from -NH 2 , -NH-, -OH or -SH.
  • T is selected from:
  • T is optionally substituted with up to 3 J substituents ;
  • Z is independently 0, S, Rio, C(R ⁇ 0 )2; n is independently 1 or 2 ; and rr ⁇ r is independently a single bond or a double bond.
  • T is selected from:
  • T is
  • W is -C(O)- C(0)-R 6 (or, in formula (II), -C (0) -C (0) -R i7 ) .
  • R 6 and/or R 3 .
  • Preferred embodiments are selected from:
  • Re (and/or R 17 ) are isopropyl.
  • W is -C(0)-H.
  • W is -C (O) -C(O) -OR 6 - More preferably, R 6 is H or methyl.
  • Rg is selected from hydrogen, (C1-C12) -aliphatic, (C6-C10)- aryl, (C3-C10) -cycloalkyl or -cycloalkenyl, (C3-C10)- heterocyclyl or (C5-C10 ) heteroaryl .
  • W is -C (O) -C (0) -N(R ⁇ ) 2 • More preferably, Rs is selected from hydrogen, (C3-C10) -cycloalkyl or -cycloalkenyl, or (C3- C10) -heterocyclyl .
  • one R& is hydrogen and the other R 6 is: (C6-C10) -aryl- (C1-C3) alkyl-, wherein the alkyl is optionally substituted with CO 2 H; (C3- C6) cycloalkyl-; (C5) -heterocylyl- (C1-C3 ) alkyl-; (C3- C6) alkenyl-; or each R 6 is (C1-C6) -alkyl- .
  • each R 6 is (C1-C3) -alkyl- .
  • -NHR 6 in W is selected from:
  • W is , wherein R ⁇ 7 is hydrogen or C5-heteroaryl, or C9-heteroaryl, wherein R ⁇ 7 has up to 3 substituents selected from J.
  • R ⁇ 7 is hydrogen, (C1-C6) -alkyl, (C6- Cl0)-aryl, or C3-C6-cycloalkyl- (C1-C3) -alkyl, wherein the cycloalkyl is preferably a cyclopropyl group .
  • the aryl group is optionally substituted with up to 3 J groups, wherein J is halogen, preferably chloro or fluoro.
  • W is :
  • R ⁇ 7 is hydrogen or (C1-C6) -alkyl
  • R i7 is hydrogen, (C1-C6)- alkyl, (C1-C6) -alkenyl, (C6-C10) -aryl- (C1-C6) -alkyl-, or (C6-C10) -heteroaryl- (C1-C6) -alkyl-, wherein R i7 is optionally substituted with up to 3 J groups .
  • Preferred J substituents on the alkyl and aryl groups are halogen, carboxy, and heteroaryl. More preferred substituents on the aryl groups are halogen (preferably chloro or fluoro) and more preferred J substituents on the alkyl groups are carboxy and heteroaryl .
  • W is :
  • each R ⁇ 8 together with the boron atom is a (C5-C7) -membered heterocyclic ring having no additional heteroatoms other than the boron and the two oxygen atoms .
  • Preferred groups are selected from:
  • R' is, preferably, (C1-C6) -alkyl) and is, most preferably, methyl .
  • Ri is selected from:
  • R 3 is selected from:
  • R 3 is
  • R5 is -r ⁇ xn.
  • R 5 is selected from:
  • R 5 . is hydrogen and R 5 is other than hydrogen.
  • R 2 and R 4 are each independently selected from H, methyl, ethyl or propyl .
  • V is -C(0)-NR 8 -, More preferably, V is -C(0)-NH-.
  • J is halogen -OR', -N0 2 , -CF 3 , -OCF 3 , -R' , oxo, 1,2-methylenedioxy, -N(R') 2 , -SR' , -SOR', -S0 2 R', -C(0)R', -COOR' -C0N(R') 2 , -N(R')C0R', -N(COR' )COR' , -CN, or -S0 2 N(R') 2 .
  • J 2 is halogen, -OR', -N0 2 , -CF 3 , -OCF 3 , -R' , oxo, 1,2-methylenedioxy, -N(R') 2 , -SR' , -SOR', -S0 2 R', -C(0)R', -COOR' -CON(R') 2 , -N(R')COR', -N(COR' )COR' , -CN, or -S0 2 N(R') 2 .
  • the halogen is preferably chloro or fluoro. More preferably, the halogen is fluoro.
  • Xi is -N(R 20 )-, -0-, or -C(R') 2 -. More preferably, i is -N(R 20 )-. According to a preferred embodiment of formula (II) , X 2 is -C(O)-. According to a preferred embodiment of formula (II) , R 2 , R 4 , and R 2o , are each independently selected from H or (C1-C3) -alkyl- . More preferably, each of R 2 , R 4 , and R 20 , are H.
  • R X4 is -H, -S(0)R ⁇ -S(0) 2 R', -C(0)R', -C(0)OR', -C(0)N(R') 2 , -N(R' )C(0)R' , -N (COR' ) COR' , or -S0 2 N(R' ) 2 . More preferably, R 14 is hydrogen.
  • R 15 and Ri ⁇ are independently halogen, -OR', -N0 2 , -CF 3 ,
  • R X5 and Ri 6 are independently (C1-C6) -alkyl- . Even more preferably, each R 15 and R ⁇ 6 is methyl.
  • Z is 0 and R i9 is: (C1-C6) -alkyl- (C3-CIO) -cycloalkyl-, [ (C3-C10) -cycloalkyl] -(C1-C12) -aliphatic-, (C6-C10)- aryl-, (C6-C10) -aryl- (C1-C6) alkyl, (C3-CIO) -heterocyclyl, (C6-C10) -heterocyclyl- (C1-C6) alkyl, (C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C6) -alkyl; wherein R ⁇ 9 has up to 3 substituents selected independently from J 2 ; and wherein up to 3 aliphatic carbon atoms in R 13 may be replaced by a heteroatom selected from 0, NH, S, SO, or SO
  • R 14 is H; Z 2 is CH 2 ; or Rig is:
  • each Rig is methyl; Z 2 is 0; or R 14 is:
  • each Rig is methyl; Z 2 is 0; and R ⁇ 4 is as depicted immediately above. Even more preferably Ri4 is :
  • R' is, preferably, (C1-C6) alkyl .
  • Z 2 is:
  • Z 2 is:
  • Ri. is H.
  • Ri 3 > is H.
  • Rn. is H.
  • R12 is H.
  • R 12 is: (C1-C6) -alkyl-, (C3-C10) -cycloalkyl , [(C3-C10)- cycloalkyl]-(Cl-Cl2) -alkyl-, (C6-C10) -aryl-, (C6-C10)- aryl-(Cl-C6) alkyl-, (C3-CIO) -heterocyclyl-, (C6-C10)- heterocyclyl- (C1-C6) alkyl-, (C5-C10) -heteroaryl-, or (C5- CIO) -heteroaryl- (C1-C6) -alkyl-. More preferably, R i is is isobutyl, cyclohexyl, cyclohexylmethyl, benzyl, or phenyleth
  • Rn is (C1-C6) -alkyl-, (C3-C10) -cycloalkyl-, [(C3-C10)- cycloalkyl] -(C1-C12) -alkyl-, (C6-C10) -aryl-, (C6-C10)- aryl-(Cl-C6) alkyl-; (C3-CIO) -heterocyclyl-, (C6-C10)- heterocyclyl- (C1-C6) alkyl-, (C5-C10) -heteroaryl-, or (C5- C10) -heteroaryl- (C1-C6) -alkyl- .More preferably, Rn is (C1-C6) -alkyl-, (C3-C10) -cycloalkyl-, [(C3-C10)- cycloalkyl] -(C1-C12)
  • the radical is:
  • each B independently forms a 3- to a 20- membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, 0, S, SO, or S0 2 ; wherein each ring is optionally fused to a (C6- Cl0)aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or (C3- Cl0)heterocyclyl ; and wherein each ring has up to 3 substituents selected independently from J.
  • a preferred ring systems is :
  • Z 3 is a carbon atom, -CHR'-N-, -HN-CR'- or -CHR'-CHR'-, -0-CHR'-, -S-CHR'-, -SO-CHR'-, -S0 2 -CHR'-, or -N-.
  • R' is, preferably, (C1-C12) -aliphatic, (C6-C10)- aryl, (C6-C10) aryl- (C1-C12 ) -aliphatic, or (C3-C10)- cycloalkyl.
  • the aliphatic is, more preferably, a (Ci- C ⁇ ) -alkyl and the cycloalkyl is more preferably, a (C3- C7) -cycloalkyl .
  • ring systems are described more fully below. Preferred embodiments of ring systems 1, 2, 3, and 4, are described below; ring systems 1, 2, 3, and 4, are respectively:
  • ring C is preferably selected from:
  • R is aliphatic, aryl, aralkyl or cycloalkyl. More preferably, ring C is selected from:
  • Ring D is preferably selected from:
  • R is aliphatic, aryl, aralkyl or cycloalkyl, More preferably, ring D is selected from:
  • ring system 1 is selected from the group:
  • Ring System 2 In ring system 2, ring F is preferably selected from:
  • Ring system 2 is preferably selected from:
  • ring G is as defined above for preferred embodiments of ring D.
  • Preferred embodiments of ring H are as defined above for preferred embodiments of ring F.
  • Ring System 4 is a bridged bicyclic ring system containing 6- 12 carbon atoms, wherein ring I is saturated or partially unsaturated, and ring I has up to 3 substituents selected independently from J.
  • the radical is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoeth
  • each B independently forms a 3- to a 20- membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, O, S, SO, or S0 2 ; wherein each ring is optionally fused to a (C ⁇ - Cl0)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) heterocyclyl; and wherein each ring has up to 3 substituents selected independently from J.
  • the radical is :
  • the ring is also selected from:
  • B forms a 3- to a 20-membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic ; wherein each heteroatom in the heterocyclic ring system is N, NH, O, S, SO, or S0 2 ; wherein each ring is optionally fused to a (C ⁇ - C10)aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or (C3- C10) eterocyclyl; and wherein each ring has up to 3 substituents selected independently from J.
  • Rn- variable is hydrogen
  • Rn and R ⁇ 2 together with the atoms to which they are bound form a 6- to 10-membered mono- or bicyclic carbocyclic or heterocyclic ring system; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S0 2 ; and wherein said ring has up to 3 substituents selected independently from J.
  • the ring formed from R 5 and R ⁇ 3 if present, is preferably an 18-membered ring.
  • the ring formed from Ri and R ⁇ if present, is preferably an 18-membered ring.
  • any of the ring systems may be substituted as set forth herein.
  • the ring substituents are selected from oxo, fluoro, difluoro (particularly vicinal difluoro) , and hydroxy. These substituents are the most preferred on the following ring systems:
  • B is a 5-membered carbocyclic ring, optionally having one unsaturated bond.
  • heteroatoms are selected from the group consisting of N, NH, O, SO, and S0 2 .
  • Preferred embodiments for any formula are also preferred embodiments for any other formula (I) .
  • the preferred embodiments of R 3 in formula (I) are also the preferred embodiments of R ⁇ 3 in formula (II) ;
  • the preferred embodiments of R 2 in formula (I) are also the preferred embodiments of R 2o in formula (II);
  • the preferred embodiments of R 6 in formula (I) are also the preferred embodiments of R ⁇ 7 in formula (II) .
  • any of the preferred embodiments recited above for T, V, Ri, R 2 , R 3 , A, X, Y, R 4 , R 5 , and R 5 -, and W may be combined to produce a preferred embodiment of a compound of formula (IB) .
  • Any of the preferred embodiments recited above for Ri, R-2/ R/ R-5/ and R 5 ., Rn, R 2 , R i3 , R ⁇ 3 >, R ⁇ 4/ Rs, Ri ⁇ , R ⁇ 9 , R 2 Q / Z 2 , W may be combined to produce a preferred embodiment of a compound of formula (II) .
  • the present invention provides compounds of formula (I'):
  • Ri and R 3 each is independently(C1-C6) aliphatic, cyclopentyl or cyclohexyl;
  • R 5 is ethyl, propyl or allyl;
  • Re is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, (S) -methylbenzyl;
  • T is (C3-C10) eterocyclyl or (C5-C10) eteroaryl ring wherein said ring contains at least one hydrogen donor moiety selected from -NH 2 , -NH-, -OH or -SH; or T is selected from:
  • the stereochemistry of a compound of this invention corresponds to that depicted in compounds l-62a and 63- 68.
  • Another embodiment of this invention provides a process for preparing a compound of this invention. These process are described in the schemes and examples
  • the compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • each stereogenic carbon may be of the R or S configuration.
  • the compounds of this invention have the structure and stereochemistry depicted in compounds la-
  • PPTS pyridinium p-toluenesulfonate
  • AIBN 2,2' -azobisisobutyronitrile rt : room temperature
  • Scheme 3 above depicts a general route for the preparation of compounds of formula I, specifically compounds represented by structure 62a.
  • Scheme 1 or 2 in combination with scheme 7 above provide another general method for the preparation of certain compounds of formula I .
  • Scheme 1 or 2 in combination with scheme 9 above provide another general method for the preparation of certain compounds of formula I .
  • Scheme 1 or 2 in combination with scheme 11 above provide a general method for the preparation of compounds of formula I, specifically compounds 39, 40, 39a, and 40a.
  • Scheme 1 or 2 in combination with scheme 13 above provide a general method for the preparation of compounds of formula I, specifically compounds 25, 25a, 41a, 45a, 55a, 58a, 59a, and 61a.
  • Scheme 14 above provides a synthetic scheme for the preparation of compound 25a.
  • Scheme 15 provides a synthetic scheme for the preparation of compound 25a.
  • Scheme 15 above provides a synthetic scheme for the preparation of compound 39a.
  • Scheme 16 provides a synthetic scheme for the preparation of compound 39a.
  • Scheme 17 above provides a general method for the preparation of compounds of formula II . Although certain exemplary embodiments are depicted and described below, it will be appreciated that compounds of this invention can be prepared according to the methods described generally above using appropriate starting materials generally available to one of ordinary skill in the art.
  • compositions comprising a compound of formula I or a pharmaceutically acceptable salt thereof.
  • the compound of formula I is present in an amount effective to decrease the viral load in a sample or in a patient, wherein said virus encodes a serine protease necessary for the viral life cycle, and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable salts of the compounds of this invention are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases .
  • acid salts include the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate,
  • Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
  • the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
  • lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides
  • dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates
  • long chain halides such
  • compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties .
  • modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
  • compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers , polyethylene glycol and wool fat.
  • ion exchangers alumina, aluminum stearate, lecithin
  • serum proteins such as human serum albumin
  • buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial
  • compositions of this invention are formulated for pharmaceutical administration to a mammal, preferably a human being.
  • compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.
  • the compositions are administered orally or intravenously.
  • Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol .
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides .
  • Fatty acids such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions .
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • a long-chain alcohol diluent or dispersant such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions.
  • Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
  • Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease.
  • the pharmaceutical compositions of this invention will be administered from 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 carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a typical preparation will contain from about 5% to about 95% active compound (w/w) .
  • such preparations contain from about 20% to about 80% active compound.
  • compositions of this invention comprise a combination of a compound of formula I, II, III or IV, and one or more additional therapeutic or prophylactic agents
  • 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 to 80% of the dosage normally administered in a monotherapy regimen.
  • compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions.
  • carriers that are commonly used include lactose and corn starch.
  • Lubricating agents such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried cornstarch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
  • the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols .
  • the pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs .
  • Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
  • the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers .
  • Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water.
  • the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride.
  • the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
  • compositions of this invention may also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents .
  • compositions of this invention additionally comprise another anti-viral agent, preferably an anti-HCV agent.
  • anti-viral agents include, but are not limited to, immunomodulatory agents, such as -, ⁇ -, and ⁇ -interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors) ; inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in United States Patent 5,807,876, mycophenolic acid and derivatives thereof) ; or combinations of
  • a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
  • a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated.
  • the amount of active ingredients will also depend upon the particular described compound and the presence or absence and the nature of the additional anti-viral agent in the composition.
  • the invention provides a method for treating a patient infected with a virus characterized by a virally encoded serine protease that is necessary for the life cycle of the virus by administering to said patient a pharmaceutically acceptable composition of this invention.
  • the methods of this invention are used to treat a patient suffering from a HCV infection. Such treatment may completely eradicate the viral infection or reduce the severity thereof. More preferably, the patient is a human being.
  • the methods of this invention additionally comprise the step of administering to said patient an anti-viral agent preferably an anti- HCV agent.
  • anti-viral agents include, but are not limited to, immunomodulatory agents, such as ⁇ -, ⁇ -, and ⁇ -interferons, pegylated derivatized interferon- ⁇ compounds, and thymosin; other anti-viral agents, such as ribavirin and amantadine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors) ; inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in United States Patent 5,807,876, mycophenolic acid and derivatives thereof); or combinations of any of the above.
  • immunomodulatory agents such as ⁇ -, ⁇
  • Such additional agent may be administered to said patient as part of a single dosage form comprising both a compound of this invention and an additional anti-viral agent.
  • the additional agent may be administered separately from the compound of this invention, as part of a multiple dosage form, wherein said additional agent is administered prior to, together with or following a composition comprising a compound of this invention.
  • the present invention provides a method of pre-treating a biological substance intended for administration to a patient comprising the step of contacting said biological substance with a pharmaceutically acceptable composition comprising a compound of this invention.
  • Such biological substances include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, etc; sperm and ova; bone marrow and components thereof, and other fluids to be infused into a patient such as saline, dextrose, etc.
  • the invention provides methods of treating materials that may potentially come into contact with a virus characterized by a virally encoded serine protease necessary for its life cycle.
  • This method comprises the step of contacting said material with a compound according to the invention.
  • materials include, but are not limited to, surgical instruments and garments; laboratory instruments and garments; blood collection apparatuses and materials; and invasive devices, such as shunts, stents, etc.
  • the compounds of this invention may be used as laboratory tools to aid in the isolation of a virally encoded serine protease.
  • This method comprises the steps of providing a compound of this invention attached to a solid support; contacting said solid support with a sample containing a viral serine protease under conditions that cause said protease to bind to said solid support; and eluting said serine protease from said solid support.
  • the viral serine protease isolated by this method is HCV NS3-NS4A protease.
  • ⁇ -M R spectra were recorded at 500 MHz using a Bruker AMX 500 instrument. Mass spec, samples were analyzed on a MicroMass ZQ or Quattro II mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using flow injection (FIA) or chromatography. Mobile phase for all mass spec, analysis consisted of acetonitrile-water mixtures with 0.2% formic acid as a modifier.
  • R t (min) refers to the HPLC retention time, in minutes, associated with the compound. The HPLC retention times listed were either obtained from the mass spec, data or using the following method: Instrument: Hewlett Packard HP-1050; Column: YMC C i8 (Cat. No. 326289C46);
  • Example 1 3 ⁇ Acetyl-lH-indole-2-carboxylic acid (4b) and 5-Acetyl -1H- indole-2-carboxylic acid (5b) .
  • Aluminum chloride (7.75 g, 0.058 mol) was suspended in 200ml of anhydrous dichloroethane at room temp, followed by a slow addition of acetic anhydride (2.74 mL, 0.03 mol) . The mixture was stirred at room temp for 10 minutes after which, liT-indole-2-carboxylic acid ethyl ester (lb, 5.0 g, 0.0264 mol) was added as a solution in
  • Example 2 3-Acetyl-4,5-dimethyl-2-pyrrole carboxylic acid (10b).
  • Example 3 l-(2- ⁇ 20 [ (3-Acetyl-4,5-dimethyl-lH-pyrrole-lH-2-carbonyl)- amino] -2-cyclohexyl-acetylamino ⁇ -3,3-di ethyl-butyryl) - octahydro-indole-2-carboxylic acidd- cyclopropylaminooxalyl-butyl) -amide (25a) .
  • Octahydro-indole-2-carboxylic acid lib (5.0g, 29.5mmol, purchased from Bachem) was suspended in 200mL of CHC1 3 then cooled in a dry ice/acetone bath. H 2 S0 4 (120uL/mmol) was added followed by bubbling in excess isobutylene. The mixture was sealed and the ice bath removed. The mixture was stirred at RT for 12 hours. The reaction mixture was carefully unsealed after cooling and concentrated.
  • Ester 13b (4.0g, 8.4mmol) was stirred in EtOH (40mL) charged with 400mg 10%Pd(OH) 2 /C. H 2 gas was bubbled into the suspension until the reaction was complete. Catalyst was removed by filtration and the filtrate concentrated in vacuo to give 1- (2-amino-3 , 3-dimethyl-butyryl) - octahydro-indole-2-carboxylic acid tert-butyl ester 14b (2.8g, 8.4mmol, 100%) which was used as is in the next step without further purification.
  • BOC ester 22b (4.35 g, 7.43 mmol) was dissolved in 25 ml of CH 2 C1 2 and cooled in an ice water bath. 25 mL of TFA was added dropwise, the bath was removed and the reaction was allowed to warm to RT. TLC showed the BOC group removed after 30 minutes. After 1 hour, 25 mL of toluene was added and the reaction was concentrated to dryness and used as is in the next step.
  • Keto alcohol 26b (166mg, 0.21 mmol) was dissolved in dry EtOAc (6 mL) , treated with EDC (605 mg, 3.15 mmol), dry DMSO (3mL) was added and the reaction was cooled to 7°C. A solution of dichloroacetic acid (175 uL, 2.1 mmol) in dry EtOAc (1 mL) was added over 1 minute with a slight exother . Additional EtOAc (2 mL) was added and the ice bath was removed. After 1 hour, the reaction was cooled to 10°C, quenched with 1. ON HCI (2 mL) , then extracted twice with EtOAc.
  • Example 5 5-Acetyl-l2T-indole-2-carboxylic acid (cyclohexyl- ⁇ 1- [2- (1-cyclopropylaminooxalyl-butylcarbamoyl) -octahydro- indole-1-carbonyl] -2,2-dimethyl-propylcarbamoyl ⁇ -methyl) - amide (40a) .
  • Keto-alcohol 28b (142mg, 0.18 mmol) was dissolved in dry EtOAC (10 mL) treated with EDC (520 mg, 2.7 mmol) and dry DMSO (5 mL) and then cooled to 7°C. A solution of dichloroacetic acid (150uL, 1.8 mmol) in dry EtOAc (1 mL) was added over 1 minute giving a slight exotherm. EtOAc (1 mL) was added and the ice bath was removed. After 1 hour, the reaction was cooled to 10 °C, quenched with
  • HCV hepatitis C virus
  • replicon cell monolayer was treated with a trypsin: EDTA mixture, removed, and then media A was diluted into a final concentration of 100,000 cells per ml wit. 10,000 cells in 100 ul were plated into each well of a 96-well tissue culture plate, and cultured overnight in a tissue culture incubator at 37°C.
  • RNA virus such as Bovine Viral Diarrhea Virus (BVDV)
  • BVDV Bovine Viral Diarrhea Virus
  • RNA extraction reagents such as reagents from RNeasy kits
  • Total RNA was extracted according the instruction of manufacturer with modification to improve extraction efficiency and consistency.
  • total cellular RNA including HCV replicon RNA, was eluted and stored at -80°C until further processing.
  • a Taqman real-time RT-PCR quantification assay was set up with two sets of specific primers and probe. One was for HCV and the other was for BVDV. Total RNA extractants from treated HCV replicon cells was added to the PCR reactions for quantification of both HCV and BVDV RNA in the same PCR well. Experimental failure was flagged and rejected based on the level of BVDV RNA in each well . The level of HCV RNA in each well was calculated according to a standard curve run in the same PCR plate. The percentage of inhibition or decrease of HCV RNA level due to compound treatment was calculated using the DMSO or no compound control as 0% of inhibition. The IC50 (concentration at which 50% inhibition of HCV RNA level is observed) was calculated from the titration curve of any given compound.
  • Total assay volume was 100 ⁇ L
  • the buffer, KK4A, DTT, and tNS3 were combined; distributed 78 ⁇ L each into wells of 96 well plate. This was incubated at 30 C for -5-10 min.
  • test compound 2.5 ⁇ L was dissolved in DMSO (DMSO only for control) and added to each well . This was incubated at room temperature for
  • 5AB substrate 25 ⁇ M concentration is equivalent or slightly lower than the Km for 5AB. Incubated for 20 min at 30 C.
  • Solvent B HPLC grade acetonitrile + 0.1% TFA
  • Table 5 depicts Mass Spec, HPLC, Ki and IC50 data for certain compounds of the invention.
  • Compounds with Ki's ranging from I ⁇ M to 5 ⁇ M are designated A.
  • Compounds with Ki's ranging from l ⁇ M to 0.5 ⁇ M are designated B.
  • Compounds with Ki's below 0.5 ⁇ M are designated C.
  • Compounds with IC50's ranging from l ⁇ M to 5 ⁇ M are designated A.
  • Compounds with IC50's ranging from l ⁇ M to 0.5 ⁇ M are designated B.
  • Compounds with IC50's below 0.5uM are designated C.

Abstract

The present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The invention further relates to compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention. The invention further relates to processes for preparing these compounds.

Description

INHIBITORS OF SERINE PROTEASES, PARTICULARLY HCV NS3-NS4A PROTEASE
TECHNICAL FIELD OF THE INVENTION The present invention relates to compounds that inhibit serine protease activity, particularly the activity of hepatitis C virus NS3-NS4A protease. As such, they act by interfering with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The invention further relates to compositions comprising these compounds either for ex vivo use or for administration to a patient suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a patient by administering a composition comprising a compound of this invention.
BACKGROUND OF THE INVENTION Infection by hepatitis C virus ("HCV") is a compelling human medical problem. HCV is recognized as the causative agent for most cases of non-A, non-B hepatitis, with an estimated human sero-prevalence of 3% globally [A. Alberti et al . , "Natural History of Hepatitis C," J. Hepatology, 31., (Suppl. 1), pp. 17-24 (1999)] . Nearly four million individuals may be infected in the United States alone [M.J. Alter et al . , "The Epidemiology of Viral Hepatitis in the United States,
Gastroenterol. Clin. North Am. , 23, pp. 437-455 (1994); M. J. Alter "Hepatitis C Virus Infection in the United States," J. Hepatology, 31., (Suppl. 1), pp. 88-91 (1999)] .
Upon first exposure to HCV only about 20% of infected individuals develop acute clinical hepatitis while others appear to resolve the infection spontaneously. In almost 70% of instances, however, the virus establishes a chronic infection that persists for decades [S. Iwarson, "The Natural Course of Chronic Hepatitis," FEMS Microbiology Reviews, 14, pp. 201-204 (1994) ; D. Lavanchy, "Global Surveillance and Control of Hepatitis C," J. Viral Hepatitis, 6, pp. 35-47 (1999)]. This usually results in recurrent and progressively worsening liver inflammation, which often leads to more severe disease states such as cirrhosis and hepatocellular carcinoma [M.C. Kew, "Hepatitis C and
Hepatocellular Carcinoma", FEMS Microbiology Reviews, 14, pp. 211-220 (1994); I. Saito et . al . , "Hepatitis C Virus Infection is Associated with the Development of Hepatocellular Carcinoma, " Proc. Natl. Acad. Sci. USA, 87, pp. 6547-6549 (1990)]. Unfortunately, there are no broadly effective treatments for the debilitating progression of chronic HCV.
The HCV genome encodes a polyprotein of 3010-3033 amino acids [Q.L. Choo, et. al . , "Genetic Organization and Diversity of the Hepatitis C Virus." Proc . Natl .
Acad. Sci. USA, 88, pp. 2451-2455 (1991); N. Kato et al . , "Molecular Cloning of the Human Hepatitis C Virus Genome From Japanese Patients with Non-A, Non-B Hepatitis," Proc. Natl. Acad. Sci. USA, 87, pp. 9524-9528 (1990); A. Takamizawa et. al . , "Structure and Organization of the Hepatitis C Virus Genome Isolated From Human Carriers," J. Virol., 65, pp. 1105-1113 (1991)]. The HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication. The NS proteins are derived by proteolytic cleavage of the polyprotein [R. Bartenschlager et. al., "Nonstructural Protein 3 of the Hepatitis C Virus Encodes a Serine-Type Proteinase Required for Cleavage at the NS3/4 and NS4/5 Junctions," J . Virol . , 67, pp. 3835-3844 (1993); A. Grakoui et . al . , "Characterization of the Hepatitis C Virus-Encoded Serine Proteinase: Determination of Proteinase-Dependent Polyprotein Cleavage Sites," J. Virol . , 67, pp. 2832-2843 (1993); A. Grakoui et . al . , "Expression and Identification of Hepatitis C Virus
Polyprotein Cleavage Products," J . Virol . , 67, pp. 1385- 1395 (1993); L. Tomei et. al . , "NS3 is a serine protease required for processing of hepatitis C virus polyprotein", J. Virol., 67, pp. 4017-4026 (1993)]. The HCV NS protein 3 (NS3) contains a serine protease activity that helps process the majority of the viral enzymes, and is thus considered essential for viral replication and infectivity. It is known that mutations in the yellow fever virus NS3 protease decreases viral infectivity [Chambers, T.J. et. al . , "Evidence that the N-terminal Domain of Nonstructural Protein NS3 From Yellow Fever Virus is a Serine Protease Responsible for Site-Specific Cleavages in the Viral Polyprotein", Proc. Natl. Acad. Sci. USA, 87, pp. 8898-8902 (1990)]. The first 181 amino acids of NS3 (residues 1027-1207 of the viral polyprotein) have been shown to contain the serine protease domain of NS3 that processes all four downstream sites of the HCV polyprotein [C. Lin et al . , "Hepatitis C Virus NS3 Serine Proteinase: Trans-Cleavage Requirements and Processing Kinetics", J. Virol . , 68, pp. 8147-8157 (1994)].
The HCV NS3 serine protease and its associated cofactor, NS4A, helps process all of the viral enzymes, and is thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing HIV protease inhibitors, which inhibit viral protein processing are potent antiviral agents in man, indicating that interrupting this stage of the viral life cycle results in therapeutically active agents . Consequently it is an attractive target for drug discovery. Several potential HCV protease inhibitors have been described in the prior art [PCT publication Nos. WO 02/18369, WO 02/08244, WO 00/09558, WO 00/09543, WO 99/64442, WO 99/07733, WO 99/07734, WO 99/50230, WO 98/46630, WO 98/17679 and WO 97/43310, United States Patent 5,990,276, M. Llinas-Brunet et al . , Bioorg. Med. Chem. Lett., 8, pp. 1713-18 (1998); W. Han et al . , Bioorg. Med. Chem. Lett., 10, 711-13 (2000); R. Dunsdon et al., Bioorg. Med. Chem. Lett., 10, pp. 1571-79 (2000); M. Llinas-Brunet et al . , Bioorg. Med. Chem. Lett., 10, pp. 2267-70 (2000); and S. LaPlante et al . , Bioorg. Med. Chem. Lett., 10, pp. 2271-74 (2000)].
Furthermore, the current understanding of HCV has not led to any other satisfactory anti-HCV agents or treatments . The only established therapy for HCV disease is interferon treatment. However, interferons have significant side effects [M. A. Wlaker et al . , "Hepatitis C Virus : An Overview of Current Approaches and Progress , " DDT, 4, pp. 518-29 (1999); D. Moradpour et al . , "Current and Evolving Therapies for Hepatitis C," Eur. J . Gastroenterol . Hepatol . , 11, pp. 1199-1202 (1999); H. L. A. Janssen et al . "Suicide Associated with Alfa- Interferon Therapy for Chronic Viral Hepatitis," J. Hepatol . , 21, pp. 241-243 (1994); P.F. Renault et al . , "Side Effects of Alpha Interferon, " Seminars in Liver Disease, 9, pp. 273-277. (1989)] and induce long term remission in only a fraction (~ 25%) of cases [0. Weiland, "Interferon Therapy in Chronic Hepatitis C Virus Infection" , FEMS Microbiol. Rev., 14, pp. 279-288 (1994)]. Moreover, the prospects for effective anti-HCV vaccines remain uncertain.
Thus, there is a need for more effective anti-HCV therapies . Such inhibitors would have therapeutic potential as protease inhibitors, particularly as serine protease inhibitors, and more particularly as HCV NS3 protease inhibitors. Specifically, such compounds may be useful as antiviral agents, particularly as anti-HCV agents .
SUMMARY OF THE INVENTION
The present invention provides a compound of formulae (IA) :
Figure imgf000006_0001
(IA) wherein:
A, together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, SO, or S02; wherein said ring is optionally fused to a (C6-
ClO)aryl, (C5-C10)heteroaryl, (C3-
C10) cycloalkyl or (C3-CIO) eterocyclyl; wherein A has up to 3 substituents selected independently from J;
J is halogen, -OR', -N02, -CF3, -OCF3, -R' , oxo, -OR', -O-benzyl, -O-phenyl, 1, 2-methylenedioxy, -N(R')2, -SR', -SOR', -S02R', -C(0)R', -COOR' or
-CON(R')2, wherein R' is independently selected from: hydrogen,
(C1-C12) -aliphatic,
(C3-CIO) -cycloalkyl or -cycloalkenyl, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl-
C12) -aliphatic, (C6-Cl0)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-CI0) -heterocyclyl , (C6-C10) -heterocyclyl- (C1-C12) aliphatic,
(C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic; Ri and R3 are independently: (C1-C12) -aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl,
[ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic, (C6-Cl0)-aryl,
(C6-C10 ) -aryl- (C1-C12 ) aliphatic, (C3-CIO) -heterocyclyl,
(C6-C10) -heterocyclyl- (C1-C12 ) aliphatic, (C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic, wherein each of Ri and R3 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and R3 may be replaced by a heteroatom selected from O, NH, S, SO, or S02 in a chemically stable arrangement; R2 and R4 are independently hydrogen,
(C1-C12) -aliphatic,
(C3-C10) -cycloalkyl- (C1-C12) -aliphatic, or (C6-C10) aryl- (C1-C12) -aliphatic, wherein each of R2 and R4 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R and R may be replaced by a heteroatom selected from 0, NH, S, SO, or S02; R5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy;
W is selected from:
Figure imgf000008_0001
wherein each R6 is independently: hydrogen,
(C1-C12) -aliphatic, (Cδ-ClO)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic, (C3-C10) -heterocyclyl, (C3-C10) -heterocyclyl- (C1-C12) -aliphatic, (C5-CIO)heteroaryl, or
(C5-C10) heteroaryl- (C1-C12) -aliphatic, or two R6 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)- heterocyclic ring; wherein Re is optionally substituted with up to 3 J substituents ;
V is -C(0)N(R8)-, -S(0)N(R8)-, or -S (0) 2N(R8) -; wherein R8 is hydrogen or (C1-C12) -aliphatic; T is selected from: (C6-C10)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic,
(C3-CI0) -heterocyclyl ,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic, (C5-C10) heteroaryl, or
(C5-C10)heteroaryl-(C1-C12) -aliphatic; or T is selected from:
Figure imgf000009_0001
Figure imgf000010_0001
wherein:
Rio is : hydrogen, (C1-C12) -aliphatic,
(Cβ-ClO)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic,
(C3-C10) -heterocyclyl,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic, (C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic, wherein each T is optionally substituted with up to 3 J substituents;
K is a bond, (C1-C12) -aliphatic, -0-, -S-, -NRg-, -C(O)-, or -C(0)-NR9-, wherein R9 is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
The invention also provides compounds of formula (IB) :
Figure imgf000011_0001
and formula (II) :
Figure imgf000011_0002
wherein the variables are as defined herein.
The invention also relates to compositions that comprise the above compounds and the use thereof. Such compositions may be used to pre-treat invasive devices to be inserted into a patient, to treat biological samples, such as blood, prior to administration to a patient, and for direct administration to a patient. In each case the composition will be used to inhibit HCV replication and to lessen the risk of or the severity of HCV infection. The invention also relates to processes for preparing the compounds of formulae (IA) , (IB) , and (II) . DETAILED DESCRIPTION OF THE INVENTION The present invention provides a compound of formula
(I)
Figure imgf000012_0001
(IA) wherein:
A, together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, SO, or S02; wherein said ring is optionally fused to a (C6-
C10)aryl, (C5-C10) heteroaryl, (C3-
C10) cycloalkyl or (C3-C10) heterocyclyl; wherein A has up to 3 substituents selected independently from J;
J is halogen, -OR', -N02, -CF3, -OCF3, -R' , oxo,
-OR', -O-benzyl, -O-phenyl, 1, 2-methylenedioxy,
-N(R')2, -SR', -SOR', -S02R', -C(0)R', -COOR' or -CON(R')2, wherein R' is independently selected from: hydrogen,
(C1-C12) -aliphatic,
(C3-CIO) -cycloalkyl or -cycloalkenyl,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic,
(C6-C10)-aryl, (C6-C10) -aryl- (C1-C12) aliphatic,
(C3-C10) -heterocyclyl,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic,
(C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic; R3 are independently:
(C1-C12) -aliphatic,
(C3-C10) -cycloalkyl or -cycloalkenyl,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic,
(C6-Cl0)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic,
(C3 -CI0 ) -heterocyclyl ,
(C6-C10 ) -heterocyclyl- (C1-C12 ) aliphatic, (C5-C10) -heteroaryl, or
(C5-C10) -heteroaryl- (C1-C12 ) -aliphatic, wherein each of Ri and R3 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and
R3 may be replaced by a heteroatom selected from
0, NH, S, SO, or S02 in a chemically stable arrangement ; R4 are independently hydrogen,
(C1-C12 ) -aliphatic,
(C3-C10) -cycloalkyl- (C1-C12) -aliphatic, or
(C6-Cl0)aryl- (C1-C12 ) -aliphatic, wherein each of R2 and R4 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R2 and R4 may be replaced by a heteroatom selected from 0, NH, S, SO, or S02; R5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy;
W is selected from:
Figure imgf000014_0001
wherein each R6 is independently: hydrogen, (C1-C12) -aliphatic,
(C6-C10)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic,
(C3-CIO) -heterocyclyl,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic, (C5-C10) heteroaryl, or
(C5-C10) heteroaryl- (C1-C12 ) -aliphatic, or two R6 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)- heterocyclic ring; wherein Rβ is optionally substituted with up to 3 J substituents ; V is -C(0)N(R8)-, -S(0)N(R8)-, or -S (0) 2N(R8) -; wherein R8 is hydrogen or (C1-C12) -aliphatic; T is selected from: (C6-Cl0)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic, (C3-CIO) -heterocyclyl,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic, (C5-C10) heteroaryl, or
(C5-C10) heteroaryl- (C1-C12) -aliphatic; or T is selected from:
Figure imgf000015_0001
Figure imgf000015_0002
wherein:
Rio is: hydrogen,
(C1-C12) -aliphatic, (C6-C10)-aryl, (C6-C10) -aryl- (C1-C12) aliphatic,
(C3-C10) -cycloalkyl or -cycloalkenyl,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl-
C12) -aliphatic,
(C3-CI0) -heterocyclyl ,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic,
(C5-CIO) -heteroaryl, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic, wherein each T is optionally substituted with up to 3 J substituents;
K is a bond, (C1-C12) -aliphatic, -0-, -S-, -NR9-, -C(O)-, or -C(0)-NR9-, wherein R9 is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
In another embodiment, the invention provides a compound of formula (IB) :
Figure imgf000016_0001
(IB) wherein:
A, together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, S, SO, or S02; wherein said ring is optionally fused to a (C6-
C10)aryl, (C5-C10)heteroaryl, (C3-
C10) cycloalkyl, or (C3-CIO) heterocyclyl; wherein A has up to 3 substituents selected independently from J and wherein the 5-membered ring to which A is fused has up to 4 substituents selected independently from J; and wherein X and Y are independently C(H) or N;
J is halogen, -OR', -OC (O)N(R' )2, -N02, -CN, -CF3, -OCF3, -R1 , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethylenedioxy, -N(R')2, -SR' , -SOR' , -S02R' , -S02N(R')2, -S03R', -C(0)R', -C(0)C(0)R\ -C (0) CH2C (0) R' , -C(S)R\ -C(0)OR', -OC(0)R', -C(0)N(R')2, -OC (O)N(R' ) 2, -C(S)N(R')2, -(CH2)0-2NHC(O)R' , -N (R' )N (R' ) COR' , -N(R' )N(R' )C(0)0R' , -N(R' )N(R' )CON(R' )2, -N(R')S02R', -N(R' )S02N(R' )2, -N(R' )C(0)0R' , -N(R' ) C (0) R' , -N(R' )C(S)R' , -N(R' )C(0)N(R')2, -N(R' )C (S)N(R' ) 2, -N(COR' )COR' , -N(OR')R', -CN, -C (=NH)N (R' ) 2,
-C(0)N(OR' )R' , -C(=NOR')R', -OP (O) (OR' ) 2, -P(0)(R')2, -P(0)(0R')2, or -P(O) (H) (OR' ) ; wherein: two R' groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or non- aromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, S, SO, or S02, wherein the ring is optionally fused to a (C6-C10) aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or a (C3-C10) heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J2; or each R' is independently selected from: hydrogen- , (C1-C12 ) -aliphatic- ,
(C3-CIO) -cycloalkyl or -cycloalkenyl-, [ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl-
C12 ) -aliphatic- ,
(C6-C10)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-,
(C3-C10) -heterocyclyl-, (C6-C10) -heterocyclyl- (C1-C12) aliphatic-, (C5-C10) -heteroaryl-, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic-; wherein R' has up to 3 substituents selected independently from J2; and
J2 is halogen, -OR', -OC (O)N(R' ) 2, -N02, -CN, -CF3, -OCF3, -R' , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethylenedioxy, -N(R')2, -SR' , -SOR' , -S02R' , -S02N(R')2, -S03R', -C(0)R', -C(0)C(0)R', -C (0) CH2C (0) R' , -C(S)R', -C(0)0R', -OC(0)R', -C(0)N(R')2, -OC (O)N(R' ) 2. -C(S)N(R')2, -(CH2)o-2NHC(0)R' , -N(R' )N (R' ) COR ' , -N(R' )N(R' )C(0)0R' , -N(R' )N(R' )CON(R' )2, -N(R')S02R', -N(R' )S02N(R' )2, -N(R' )C(0)0R' , -N (R' ) C (0) R' , -N(R')C(S)R' , -N(R' )C(0)N(R' )2, -N (R' ) C (S)N(R' ) 2, -N(C0R' )C0R' , -N(0R')R', -CN, -C (=NH) (R' ) 2,
-C(0)N(OR' )R' , -C(=N0R')R', -OP (0) (OR' ) 2, -P(0)(R')2, -P(O) (OR' )2, or -P(O) (H) (OR' ) .
Ri and R3 are independently: (C1-C12 ) -aliphatic- , (C3-C10) -cycloalkyl- or -cycloalkenyl-,
[ (C3-C10) -cycloalkyl- or -cycloalkenyl] - (C1-C12 ) - aliphatic-,
(C6-C10)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic-, (C5-C10) -heteroaryl-, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic-, wherein each of Ri and R3 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and R3 may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S02 in a chemically stable arrangement; R2 and R4 are independently: hydrogen- , (C1-C12) -aliphatic-,
(C3-C10) -cycloalkyl- (C1-C12) -aliphatic-, or (C6-C10) aryl- (C1-C12) -aliphatic-, wherein each of R2 and R4 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R2 and R4 may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S02;
R5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy;
R5. is hydrogen or (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy; W is :
Figure imgf000019_0001
wherein each R6 is independently: hydrogen- , (C1-C12) -aliphatic-, (C6-Cl0)-aryl-, (C6-C10 ) -aryl- (C1-C12 ) aliphatic- , (C3-CIO) -cycloalkyl or -cycloalkenyl-, [ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic- , (C3-C10) -heterocyclyl-,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic-, (C5-C10) heteroaryl-, or
(C5-C10 ) heteroaryl- (C1-C12 ) -aliphatic- , or two Re groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)- heterocyclic ring; wherein R6 is optionally substituted with up to 3 J substituents; each Ris is independently -OR' ; or the Rι8 groups together with the boron atom, is a (C3-CIO) -membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, 0, S, SO, and S02;
V is -C(0)N(R8)-, -S(0)N(R8)-, -S(0)2N(R8)-, -0S(0)-, -OS(0)2-, -0C(0)-, or -0-; wherein R8 is hydrogen or (C1-C12) -aliphatic; T is:
(C1-C12 ) -aliphatic- ; (C6-Cl0)-aryl-, (C6-C10 ) -aryl- (C1-C12 ) aliphatic- ,
(C3-C10) -cycloalkyl or -cycloalkenyl-, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (C1-C12) - aliphatic-,
(C3-C10) -heterocyclyl-, (C3-C10 ) -heterocyclyl- (C1-C12 ) -aliphatic- ,
(C5-C10) heteroaryl-, or
(C5-C10 ) heteroaryl- (C1-C12 ) -aliphatic- ; or T is :
Figure imgf000021_0001
Figure imgf000021_0002
Figure imgf000022_0001
Figure imgf000022_0002
wherein:
Rio is : Hydrogen- ,
(C1-C12 ) -aliphatic- , (C6-Cl0)-aryl-,
(C6-C10 ) -aryl- (C1-C12 ) aliphatic- , (C3-C10) -cycloalkyl or -cycloalkenyl-, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl-
C12 ) -aliphatic- ,
(C3-C10) -heterocyclyl-,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic-, (C5-C10) -heteroaryl-, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic-, wherein each T is optionally substituted with up to 3 J substituents;
K is a bond, (C1-C12) -aliphatic, -0-, -S-, -NR9-, -C(O)-, or -C(0)-NR9-, wherein R9 is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
In yet another embodiment, the invention provides a compound of formula (II) :
Figure imgf000023_0001
(ID
wherein :
Xi is -N(R20)-, -0-, -S-, or -C(R')2~;
X2 is -C(O)-, -C(S)-, -S(O)-, or -S(0)2~;
W is:
Figure imgf000023_0002
Figure imgf000024_0001
Figure imgf000024_0002
m is 0 or 1 ; each R17 is independently: hydrogen- , (C1-C12 ) -aliphatic- ,
(C3-CIO) -cycloalkyl or -cycloalkenyl-, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (C1-C12 ) - aliphatic-,
(Cβ-ClO)-aryl-,
(C6-C10) -aryl- (C1-C12 ) aliphatic- , (C3-C10) -heterocyclyl-, (C3-C10) -heterocyclyl- (C1-C12) -aliphatic-,
(C5-C10) heteroaryl-, or (C5-C10) heteroaryl- (C1-C12) -aliphatic-, or two Rι7 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)- membered heterocyclic ring having in addition to the nitrogen up to 2 additional heteroatoms selected from N, NH, 0, S, SO, and S02; wherein Rι7 is optionally substituted with up to 3 J substituents ; each R18 is independently -OR' ,- or both OR' groups together with the boron atom, is a (C5-C20) -membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, 0, S, SO, and S02;
R5 and R5. are independently hydrogen or (C1-C12)- aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any terminal carbon atom is optionally substituted with sulfhydryl or hydroxy, and wherein up to two aliphatic carbon atoms may be replaced by a heteroatom selected from N, NH, 0, S, SO, or S02; or R5 and R5> together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, 0, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J;
Ri, Ri., RH, Rii-, Rι3, and R13- are independently: hydrogen- ,
(C1-C12 ) -aliphatic- ,
(C3-C10) -cycloalkyl or -cycloalkenyl-, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic- , (C6-Cl0)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic, (C5-C10) -heteroaryl-, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic-; or Ri and Ri- together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, 0, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J; or
RH and Rn- together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, O, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J; or
Ri3 and Rχ3. together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, O, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J; wherein each of Ri, Ri-, Rn, Rn>, R13, and R13- is independently and optionally substituted with up to 3 substituents independently selected from J; and wherein any ring is optionally fused to a (C6-C10) aryl, (C5- C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10)heterocyclyl; and wherein up to 3 aliphatic carbon atoms in each of Ri, Ri-, Rn, Rn-, Rχ3, and Ri3. may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S02 in a chemically stable arrangement; R2, R4, R12, and R2o are independently hydrogen- , (C1-C12 ) -aliphatic- , (C3-CIO) -cycloalkyl-, (C3-C10) -cycloalkyl- (C1-C12) -aliphatic-, or
(C6-C10) aryl- (C1-C12) -aliphatic-, wherein each R2, R4, R12, and R2o is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R2, R4, R12, and R2o may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S02; or
Rn and R12 together with the atoms to which they are bound form a 3- to a 20-membered mono-, a 4- to 20- membered bi-, or a 5- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6-
Cl0)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or R12 and Rι3 together with the atoms to which they are bound form a 4- to a 20-membered mono-, a 5- to 20- membered bi-, or a 6- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- ClO)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or
Rn and Ri3 together with the atoms to which they are bound form a 5- to a 20-membered mono-, a 6- to 20- membered bi-, or a 7- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic,- wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- CIO) aryl, (C5-CIO)heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or
Rn# R12, and Rι3 together with the atoms to which they are bound form a 5- to a 20-membered bi-, or a 6- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6-
C10)aryl, (C5-CIO)heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10)heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or Rι3. and R2 together with the atoms to which they are bound form a 3- to a 20-membered mono-, a 4- to 20- membered bi-, or a 5- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, and S02; wherein each ring is optionally fused to a (C6- C10)aryl, (C5-C10)heteroaryl, (C3-CIO) cycloalkyl, or (C3- Cl0) heterocyclyl ; and wherein said ring has up to 3 substituents selected independently from J;
R5 and Ri3 together with the atoms to which they are bound form a 18- to a 23-membered mono-, a 19- to 24- membered bi-, or a 20- to 25-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- ClO)aryl, (C5-C10)heteroaryl, (C3-C10) cycloalkyl, or (C3- CIO) heterocyclyl; and wherein said ring has up to 6 substituents selected independently from J; or Ri and R12 together with the atoms to which they are bound form a 18- to a 23-membered mono-, a 19- to 24- membered bi-, or a 20- to 25-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- ClO)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) heterocyclyl; and wherein said ring has up to 6 substituents selected independently from J; or
Ri4 is -H, -S(0)R', -S(0)2R', -C(0)R', -C(0)0R', -C(0)N(R')2, -N(R' )C(0)R' , -N (COR ' ) COR' , -S02N(R')2, -S03R\ -C(0)C(0)R', -C(0)CH2C(0)R' , -C(S)R', -C(S)N(R')2, -(CH2)o.-2NHC(0)R' , -N (R' )N (R' ) COR ' , -N (R' ) N (R' ) C (0) OR' , -N(R' )N(R' )CON(R' )2, -N(R')S02R\ -N (R' ) S02N (R' ) 2, -N(R' )C(0)OR' , -N(R' )C(0)R' , -N (R' ) C (S) R' , -N(R' )C(0)N(R' )2, -N(R' )C(S)N(R' )2, -N (COR ' ) COR' , -N(OR')R', -C(=NH)N(R' )2, -C (O)N(OR' ) R' , -C(=N0R')R', -0P(0) (OR')2, -P(0)(R')2, -P(0)(OR')2, or -P (0) (H) (OR' ) ; Ri5 and Ri6 are independently halogen, -OR' , -OC(0)N(R' )2, -N02, -CN, -CF3, -OCF3, -R', oxo, 1,2- methylenedioxy, 1, 2-ethylenedioxy, -N(R')2, -SR' , -SOR', -S02R', -S02N(R')2, -S03R', -C(0)R\ -C(0)C(0)R', -C(0)CH2C(0)R' , -C(S)R', -C(0)0R', -0C(0)R', -C(0)N(R')2, -0C(0)N(R')2, -C(S)N(R')2, -(CH2)0-2NHC(O)R' , -N(R' )N(R' )COR' , -N(R' )N(R' )C(0)OR' , -N (R' ) (R' ) C0N(R' ) 2, -N(R')S02R', -N(R' )S02N(R' )2, -N (R' ) C (0) OR' , -N (R' ) C (O) R' , -N(R' )C(S)R' , -N(R' )C(0)N(R' )2, -N(R' ) C (S)N(R' ) 2, -N(COR')COR' , -N(OR')R', -CN, -C (=NH)N (R' ) 2, -C(0)N(OR' )R' , -C(=NOR')R', -OP (0) (OR' ) 2, -P(0)(R')2, -P(O) (0R')2, or -P(O) (H) (OR') ;
Z2 is =0, =NR', =NOR', or =C(R')2; Rι9 is -OR', -CF3, -OCF3, -R' , -N(R')2, -SR' , -C(0)R\ -COOR' -CON(R')2, -N(R')COR', or -N(COR' ) COR' ;
J is halogen, -OR', -OC (O)N(R' ) 2, -N02, -CN, -CF3, -OCF3, -R' , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethyenedioxy, -N(R')2, -SR' , -SOR' , -S02R' , -S02N(R')2, - S03R' , -C(0)R', -C(0)C(0)R', -C (O) CH2C (O) R' , ~C(S)R', -C(0)OR', -OC(0)R', -C(0)N(R')2, -OC (O)N (R' ) 2, -C(S)N(R')2, -(CH2)0-2NHC(O)R' , -N (R' )N(R' ) COR' , -N(R' )N(R' )C(0)OR' , -N(R' )N(R' )CON(R' )2, -N(R')S02R\ -N(R' )S02N(R' )2, -N(R' )C(0)OR' , -N (R' ) C (O) R' , -N(R' )C(S)R' , -N(R' )C(0)N(R' )2, -N(R' ) C (S)N(R' ) 2. -N(COR' )C0R' , -N(OR')R', -CN, -C (=NH)N (R' ) 2, -C(0)N(OR' )R' , -C(=NOR')R', -OP (0) (OR' ) 2, -P(0)(R')2, -P(0)(0R')2, or -P(O) (H) (OR' ) ; wherein: two R' groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or nonaromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO2, wherein the ring is optionally fused to a (C6-C10) aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or a (C3-C10) heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J2; or each R' is independently selected from: hydrogen- , (C1-C12 ) -aliphatic- , (C3-C10) -cycloalkyl or -cycloalkenyl-,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic- ,
(C6-Cl0)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C3-C10) -heterocyclyl-,
(C6-C10 ) -heterocyclyl- (C1-C12 ) aliphatic- , (C5-C10) -heteroaryl-, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic-; wherein R' has up to 3 substituents selected independently from J2; and
J2 is halogen, -OR', -OC (O)N(R' ) 2, -N02, -CN, -CF3, -0CF3, -R' , oxo, thioxo, 1, 2-methylenedioxy, 1,2- ethylenedioxy, -N(R')2, -SR' , -SOR' , -S02R' , -S02N(R')2, -S03R', -C(0)R', -C(0)C(0)R', -C (0) CH2C (O) R' , -C(S)R', -C(0)OR', -OC(0)R', -C(0)N(R')2, -OC (O)N(R' ) 2, -C(S)N(R')2, -(CH2)o-2NHC(0)R' , -N (R' ) N(R' ) COR' , -N(R' )N(R' )C(0)OR' , -N(R' )N(R' )CON(R' )2, -N(R')S02R', -N(R' )S02N(R' )2, -N(R' )C(0)OR' , -N (R' ) C (0) R' , -N(R' )C(S)R' , -N(R' )C(0)N(R' )2, -N (R' ) C (S)N(R' ) 2, -N(COR' )COR' , -N(OR')R', -CN, -C (=NH)N (R' ) 2, -C(0)N(OR' )R' , -C(=NOR')R', -OP (0) (OR' ) 2, -P(0)(R')2, -P(0)(0R')2, or -P(0) (H) (OR' ) .
Definitions
References herein to formula (I) are meant to include both formula (IA) and formula (IB) .
The term "aryl" as used herein means a monocyclic or bicyclic carbocyclic aromatic ring system. Phenyl is an example of a monocyclic aromatic ring system. Bicyclic aromatic ring systems include systems wherein both rings are aromatic, e.g., naphthyl, and systems wherein only one of the two rings is aromatic, e.g., tetralin.
The term "heterocyclyl" as used herein means a monocyclic or bicyclic non-aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from 0, N, NH, S, SO, or SO2 in a chemically stable arrangement. In a bicyclic non-aromatic ring system embodiment of "heterocyclyl" one or both rings may contain said heteroatom or heteroatom groups .
The term "heteroaryl" as used herein means a monocyclic or bicyclic aromatic ring system having 1 to 3 heteroatom or heteroatom groups in each ring selected from 0, N, NH or S in a chemically stable arrangement. In such a bicyclic aromatic ring system embodiment of "heteroaryl" :
- one or both rings may be aromatic; and - one or both rings may contain said heteroatom or heteroatom groups .
The term "aliphatic" as used herein means a straight chained or branched alkyl, alkenyl or alkynyl. It is understood that alkenyl or alkynyl embodiments need at least two carbon atoms in the aliphatic chain.
The term "cycloalkyl or cycloalkenyl" refers to a monocyclic or fused or bridged bicyclic carbocyclic ring system that is not aromatic. Cycloalkenyl rings have one or more units of unsaturation. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, nornbornyl, adamantyl and decalin-yl.
The phrase "chemically stable arrangement" as used herein refers to a compound structure that renders the compound sufficiently stable to allow manufacture and administration to a mammal by methods known in the art.
Typically, such compounds are stable at a temperature of
40°C or less, in the absence of moisture or other chemically reactive condition, for at least a week. The compounds of formulae (IA) and (IB) of the present invention represent a selection from the genus of WO 02/18369. Applicants have invented a subgenus within the genus of WO 02/18369 that contain one or both of the following two distinct structural elements: 1. a fused azaheterocyclic ring system containing ring A, wherein ring A in formula (I) is adjacent to the ring nitrogen atom (i.e., atom X in. formula (I) is adjacent to the ring nitrogen atom of the backbone) ; 2. a hydrogen bond donor in the P4 cap part of the compounds of formula (I) [radical T in formula (I) ] .
Without wishing to be bound by theory, applicants believe that the first structural element, namely, ring A, by being adjacent to the ring nitrogen atom on the backbone of compounds of formula (I) , provides a facile orientation such that compounds of the present invention have an enhanced interaction with the P2 region of the active site of the serine protease. Applicants believe that the second structural element, a hydrogen bond donor in radical T in formula (I) , provides an additional point of interaction between the compounds of the present invention and the serine protease active site, thereby enhancing the binding affinity.
In a preferred embodiment, the second structural element comprises the following moiety:
Figure imgf000034_0001
Without being bound by theory, applicants further believe that this pyrrole moiety (as the second structural element) provides particularly favorable hydrogen bond interactions with the serine protease active site, thereby enhancing the binding affinity of compounds having this moiety. This favorable interaction enhances the binding affinity of compounds having the first structural element (i.e., ring A) as well as those having other structural elements. As would be recognized by a skilled practitioner, the hydrogen on the 1-position of the pyrrole could be substituted with an appropriate group (e.g., Ri4 as defined herein) to enhance biological properties . Therefore, one embodiment of this invention provides a compound of formula (III), wherein Pl, P2 , P3 , and P4 designate the residues of a serine protease inhibitor as known to those skilled in the art and R14, R15, Rι6, Rig, and Z2 are as defined herein:
Figure imgf000035_0001
All compounds, therefore, having: 1) structural elements of a serine protease inhibitor; and 2) the pyrrole-moiety are considered part of this invention. Compounds having the structural elements of a serine protease inhibitor include, but are not limited to, the compounds of the following publications: WO 97/43310, US20020016294, WO 01/81325, WO 02/08198, WO 01/77113, WO 02/08187, WO 02/08256, WO 02/08244, WO 03/006490, WO 01/74768, WO 99/50230, WO 98/17679, WO 02/48157, US20020177725, WO 02/060926, US20030008828, WO 02/48116, WO 01/64678, WO 01/07407, WO 98/46630, WO 00/59929, WO 99/07733, WO 00/09588, US20020016442 , WO 00/09543, WO 99/07734, US6,018,020, WO 98/22496, US5,866,684,
WO 02/079234, WO 00/31129, WO 99/38888, WO 99/64442, and WO 02/18369, which are incorporated herein by reference. Thus, any compound of the above publications may be modified to have this pyrrole moiety, or a derivative thereof. Any such compound is part of this invention. For example, compound A in WO 02/18369 (p. 41) :
Figure imgf000036_0001
may be modified to provide the following compound of this invention:
Figure imgf000036_0002
wherein R14, R15, Rι6,
R19, and Z2 are as defined herein. Preferred Embodiments
According to a preferred embodiment of formula (I) , A together with X and Y is a 3-6 membered carbocyclic non-aromatic or aromatic ring. More preferably, A together with X and Y is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl. Even more preferably, A together with X and Y is cylcohexyl or cyclopentyl . Most preferably, A together with X and Y is cyclohexyl. According to another preferred embodiment, A together with X and Y is a 3-6 membered heterocyclic ring. More preferably, A together with X and Y is a 5-6 membered heterocyclic ring. According to another preferred embodiment, A together with X and Y is a 5-6 membered heteroaryl ring.
According to yet another preferred embodiment, A together with X and Y is fused to a (C6-C10) aryl, (C5- C10) eteroaryl, (C3-C10) cycloalkyl or (C3-C10)- heterocyclyl. Preferably, A together with X and Y is fused to cyclohexyl, cyclopentyl, phenyl or pyridyl. According to another preferred embodiment, the ring
Figure imgf000037_0001
in formula (I) is selected from Table 1 below:
Table 1
Figure imgf000037_0002
Figure imgf000037_0003
Figure imgf000038_0002
Figure imgf000038_0003
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000039_0002
According to a more preferred embodiment, the ring
system
Figure imgf000039_0003
in formula (I) is selected from:
Figure imgf000040_0001
According to another more preferred embodiment, A, together with X, Y and the ring containing the nitrogen atom, is:
Figure imgf000040_0002
More preferably, A, together with X, Y and the ring containing the nitrogen atom, is :
Figure imgf000040_0003
According to a preferred embodiment, T is selected from: (C6-C10) -aryl, (C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [(C3-C10)- cycloalkyl or -cycloalkenyl] - (C1-C12) -aliphatic, (C3- C10 ) -heterocyclyl , (C3-CIO ) -heterocyclyl- (C1-C12) - aliphatic, (C5-C10) heteroaryl, or (C5-C10) heteroaryl- (Cl- C12) -aliphatic, wherein each T is optionally substituted with up to 3 J substituents . According to another preferred embodiment, T is:
Figure imgf000041_0001
UV±l cv-i-TJ_'Ci 'i- l • •
Rio is : hydrogen,
(C1-C12) -aliphatic, (C6-C10) -aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl-
C12 ) -aliphatic, (C3-C10) -heterocyclyl,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic, (C5-C10) heteroaryl, or (C5-C10) heteroaryl- (C1-C12) -aliphatic, wherein each T is optionally substituted with up to 3 J substituents;
K is a bond, -R9, -0-, -S-, -NRg-, -C(O)-, or -C(O)- NR9-, wherein Rg is hydrogen or C1-C12 aliphatic; and n is 1-3. In the above embodiment, T may also be :
Figure imgf000042_0001
Figure imgf000042_0002
In a preferred embodiment , T is
Figure imgf000042_0003
According to a more preferred embodiment, T contains at least one hydrogen bond donor moiety selected from -NH2, -NH-, -OH or -SH.
According to another more preferred embodiment, T is selected from:
Figure imgf000043_0001
Figure imgf000043_0002
Figure imgf000043_0003
Figure imgf000044_0001
wherein:
T is optionally substituted with up to 3 J substituents ;
Z is independently 0, S, Rio, C(Rι0)2; n is independently 1 or 2 ; and rr^r is independently a single bond or a double bond.
According to yet another preferred embodiment, T is selected from:
Figure imgf000045_0001
Figure imgf000045_0002
Figure imgf000045_0003
Figure imgf000045_0004
wherein Z is as defined above.
In a more preferred embodiment, T is
Figure imgf000045_0005
According to a preferred embodiment, W is -C(O)- C(0)-R6 (or, in formula (II), -C (0) -C (0) -Ri7) . Preferably, R6 (and/or R3.7) are: phenyl, pyridyl, (C3- C6) -alkyl, (C3-C6) -cycloalkyl, -OH, -0- (C1-C6) -alkyl, - N(H)-(C3-C6) -cycloalkyl, -N(H) -C (H) (CH3) - (C6-C10) aryl, - N(H)-C(H) (CH3)- (C3 -CIO) -heterocylyl, or -N(H) -C (H) (CH3) - (C5-C10) -heteroaryl, wherein each aryl, heterocyclyl, and heteroaryl is optionally substituted with halogen. Preferred embodiments are selected from:
Figure imgf000046_0001
More preferably, Re (and/or R17) are isopropyl. According to another preferred embodiment of formula (II) , W is -C(0)-H.
According to another preferred embodiment, W is -C (O) -C(O) -OR6- More preferably, R6 is H or methyl. According to a more preferred embodiment, Rg is selected from hydrogen, (C1-C12) -aliphatic, (C6-C10)- aryl, (C3-C10) -cycloalkyl or -cycloalkenyl, (C3-C10)- heterocyclyl or (C5-C10 ) heteroaryl .
According to another preferred embodiment, W is -C (O) -C (0) -N(Rε) 2 • More preferably, Rs is selected from hydrogen, (C3-C10) -cycloalkyl or -cycloalkenyl, or (C3- C10) -heterocyclyl . Alternatively, one R& is hydrogen and the other R6 is: (C6-C10) -aryl- (C1-C3) alkyl-, wherein the alkyl is optionally substituted with CO2H; (C3- C6) cycloalkyl-; (C5) -heterocylyl- (C1-C3 ) alkyl-; (C3- C6) alkenyl-; or each R6 is (C1-C6) -alkyl- . Alternatively, each R6 is (C1-C3) -alkyl- .
Most preferably, -NHR6 in W is selected from:
Figure imgf000047_0001
According to a preferred embodiment of formula (II) ,
Figure imgf000047_0002
Figure imgf000047_0003
Figure imgf000047_0004
More preferred embodiments of W are as follows W is
Figure imgf000048_0001
, wherein Rι7 is hydrogen or C5-heteroaryl, or C9-heteroaryl, wherein Rι7 has up to 3 substituents selected from J.
W is :
Figure imgf000048_0002
wherein Rι7 is hydrogen, (C1-C6) -alkyl, (C6- Cl0)-aryl, or C3-C6-cycloalkyl- (C1-C3) -alkyl, wherein the cycloalkyl is preferably a cyclopropyl group . The aryl group is optionally substituted with up to 3 J groups, wherein J is halogen, preferably chloro or fluoro. W is :
Figure imgf000048_0003
Rι7 is hydrogen or (C1-C6) -alkyl ,
W is
Figure imgf000048_0004
wherein Ri7 is hydrogen, (C1-C6)- alkyl, (C1-C6) -alkenyl, (C6-C10) -aryl- (C1-C6) -alkyl-, or (C6-C10) -heteroaryl- (C1-C6) -alkyl-, wherein Ri7 is optionally substituted with up to 3 J groups . Preferred J substituents on the alkyl and aryl groups are halogen, carboxy, and heteroaryl. More preferred substituents on the aryl groups are halogen (preferably chloro or fluoro) and more preferred J substituents on the alkyl groups are carboxy and heteroaryl . According to yet other preferred embodiments of formula (II), W is :
Figure imgf000049_0001
Figure imgf000049_0003
.yγγJ
Figure imgf000049_0002
Figure imgf000049_0004
According to a preferred embodiment, each Rι8 together with the boron atom, is a (C5-C7) -membered heterocyclic ring having no additional heteroatoms other than the boron and the two oxygen atoms . Preferred groups are selected from:
Figure imgf000050_0001
; wherein R' is, preferably, (C1-C6) -alkyl) and is, most preferably, methyl .
According to a preferred embodiment, Ri is selected from:
Figure imgf000050_0002
According to a preferred embodiment, R3 is selected from:
Figure imgf000050_0003
According to a preferred embodiment, R3 is
Figure imgf000050_0004
According to a preferred embodiment , R5 is -rυxn.
Figure imgf000051_0001
Figure imgf000051_0002
According to a preferred embodiment, R5 is selected from:
Figure imgf000051_0003
According to a preferred embodiment, R5. is hydrogen and R5 is other than hydrogen.
According to a preferred embodiment, R2 and R4 are each independently selected from H, methyl, ethyl or propyl . According to a preferred embodiment, V is -C(0)-NR8-, More preferably, V is -C(0)-NH-.
According to a preferred embodiment, J is halogen -OR', -N02, -CF3, -OCF3, -R' , oxo, 1,2-methylenedioxy, -N(R')2, -SR' , -SOR', -S02R', -C(0)R', -COOR' -C0N(R')2, -N(R')C0R', -N(COR' )COR' , -CN, or -S02N(R')2.
According to a preferred embodiment, J2 is halogen, -OR', -N02, -CF3, -OCF3, -R' , oxo, 1,2-methylenedioxy, -N(R')2, -SR' , -SOR', -S02R', -C(0)R', -COOR' -CON(R')2, -N(R')COR', -N(COR' )COR' , -CN, or -S02N(R')2. In J and J2 the halogen is preferably chloro or fluoro. More preferably, the halogen is fluoro.
According to a preferred embodiment of formula (II) , Xi is -N(R20)-, -0-, or -C(R')2-. More preferably, i is -N(R20)-. According to a preferred embodiment of formula (II) , X2 is -C(O)-. According to a preferred embodiment of formula (II) , R2, R4, and R2o, are each independently selected from H or (C1-C3) -alkyl- . More preferably, each of R2, R4, and R20, are H. According to a preferred embodiment of formula (II) , RX4 is -H, -S(0)R\ -S(0)2R', -C(0)R', -C(0)OR', -C(0)N(R')2, -N(R' )C(0)R' , -N (COR' ) COR' , or -S02N(R' ) 2. More preferably, R14 is hydrogen.
According to a preferred embodiment of formula (II) , R15 and Riε are independently halogen, -OR', -N02, -CF3,
-OCF3, -R' , oxo, 1,2-methylenedioxy, -N(R')2, -SR' , -SOR', -S02R\ -C(0)R', -COOR' -CON(R')2, -N(R')COR', -N(COR' )COR' , -CN, or -S02N(R')2. More preferably, RX5 and Ri6 are independently (C1-C6) -alkyl- . Even more preferably, each R15 and Rι6 is methyl.
According to a preferred embodiment of formula (II) , Z is 0 and Ri9 is: (C1-C6) -alkyl- (C3-CIO) -cycloalkyl-, [ (C3-C10) -cycloalkyl] -(C1-C12) -aliphatic-, (C6-C10)- aryl-, (C6-C10) -aryl- (C1-C6) alkyl, (C3-CIO) -heterocyclyl, (C6-C10) -heterocyclyl- (C1-C6) alkyl, (C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C6) -alkyl; wherein Rι9 has up to 3 substituents selected independently from J2; and wherein up to 3 aliphatic carbon atoms in R13 may be replaced by a heteroatom selected from 0, NH, S, SO, or SO2 in a chemically stable arrangement. More preferably, Rι9 is (C1-C6) -alkyl- . Most preferably, Rig is methyl.
According to a preferred embodiment of formula (II) , R14 is H; Z2 is CH2; or Rig is:
Figure imgf000053_0001
More preferably, Rχ4 is H; Z2 is CH2; and Ri9 is as depicted immediately above.
According to another preferred embodiment of formula (II), each Rig is methyl; Z2 is 0; or R14 is:
Figure imgf000053_0002
Figure imgf000053_0003
More preferably, each Rig is methyl; Z2 is 0; and Rι4 is as depicted immediately above. Even more preferably Ri4 is :
Figure imgf000054_0001
. In this embodiment, R' is, preferably, (C1-C6) alkyl .
According to another preferred embodiment of formula (II) , Z2 is:
R'
,R' Aθ
N' π-rtnjfv or o-π-r-Jruv
More preferably, each Ri9 is methyl; Ri4 is H; and Z2 is as depicted immediately above.
According to another preferred embodiment of formula (II) , Z2 is:
Figure imgf000054_0002
According to a preferred embodiment of formula (II) , Ri. is H.
According to a preferred embodiment of formula (II) , Ri3> is H. According to a preferred embodiment of formula (II) , Rn. is H.
According to a preferred embodiment of formula (II) , R12 is H. According to a preferred embodiment of formula (II) , R12 is: (C1-C6) -alkyl-, (C3-C10) -cycloalkyl , [(C3-C10)- cycloalkyl]-(Cl-Cl2) -alkyl-, (C6-C10) -aryl-, (C6-C10)- aryl-(Cl-C6) alkyl-, (C3-CIO) -heterocyclyl-, (C6-C10)- heterocyclyl- (C1-C6) alkyl-, (C5-C10) -heteroaryl-, or (C5- CIO) -heteroaryl- (C1-C6) -alkyl-. More preferably, Ri is isobutyl, cyclohexyl, cyclohexylmethyl, benzyl, or phenylethyl. Even more preferably, Rn is H.
According to a preferred embodiment of formula (II) , Rn is (C1-C6) -alkyl-, (C3-C10) -cycloalkyl-, [(C3-C10)- cycloalkyl] -(C1-C12) -alkyl-, (C6-C10) -aryl-, (C6-C10)- aryl-(Cl-C6) alkyl-; (C3-CIO) -heterocyclyl-, (C6-C10)- heterocyclyl- (C1-C6) alkyl-, (C5-C10) -heteroaryl-, or (C5- C10) -heteroaryl- (C1-C6) -alkyl- .More preferably, Rn is (C1-C6) -alkyl-, (C3-C10) -cycloalkyl-, [(C3-C10)- cycloalkyl] -(C1-C12) -alkyl-, (C6-C10) -aryl- (C1-C6) alkyl- ; (C6-C10 ) -heterocyclyl- (C1-C6) alkyl-, or (C5-C10)- heteroaryl- (C1-C6) -alkyl- . Even more preferably, Rn. and R12 are H.
According to a preferred embodiment of formula (II) , the
Figure imgf000055_0001
radical is:
Figure imgf000056_0001
More preferably, the radical is:
Figure imgf000056_0002
According to a preferred embodiment of formula (II) , the
Figure imgf000056_0003
radical is
Figure imgf000057_0001
Alternatively, this radical is
Figure imgf000058_0001
According to a preferred embodiment of formula (II) , the
Figure imgf000058_0002
radical is :
Figure imgf000058_0003
or the radical is :
Figure imgf000059_0001
wherein each B independently forms a 3- to a 20- membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, 0, S, SO, or S02; wherein each ring is optionally fused to a (C6- Cl0)aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or (C3- Cl0)heterocyclyl ; and wherein each ring has up to 3 substituents selected independently from J.
In the embodiment immediately above, a preferred ring systems is :
Figure imgf000059_0002
wherein Z3 is a carbon atom, -CHR'-N-, -HN-CR'- or -CHR'-CHR'-, -0-CHR'-, -S-CHR'-, -SO-CHR'-, -S02-CHR'-, or -N-. R' is, preferably, (C1-C12) -aliphatic, (C6-C10)- aryl, (C6-C10) aryl- (C1-C12 ) -aliphatic, or (C3-C10)- cycloalkyl. The aliphatic is, more preferably, a (Ci- Cβ) -alkyl and the cycloalkyl is more preferably, a (C3- C7) -cycloalkyl . These ring systems are described more fully below. Preferred embodiments of ring systems 1, 2, 3, and 4, are described below; ring systems 1, 2, 3, and 4, are respectively:
Figure imgf000060_0001
Figure imgf000060_0002
System 1 In ring system 1, ring C is preferably selected from:
Figure imgf000060_0003
Figure imgf000061_0001
Figure imgf000062_0001
wherein R is aliphatic, aryl, aralkyl or cycloalkyl. More preferably, ring C is selected from:
Figure imgf000063_0001
Figure imgf000063_0002
Figure imgf000063_0003
Ring D is preferably selected from:
Figure imgf000064_0001
Figure imgf000065_0001
Figure imgf000066_0001
Figure imgf000066_0002
wherein R is aliphatic, aryl, aralkyl or cycloalkyl, More preferably, ring D is selected from:
Figure imgf000067_0001
According to another preferred embodiment, ring system 1 is selected from the group:
Figure imgf000068_0001
Figure imgf000068_0002
Figure imgf000068_0003
Figure imgf000068_0004
Figure imgf000069_0001
Ring System 2 In ring system 2, ring F is preferably selected from:
Figure imgf000069_0002
Ring system 2 is preferably selected from:
Figure imgf000069_0003
Figure imgf000070_0001
Ring System 3
In ring system 3, preferred embodiments of ring G are as defined above for preferred embodiments of ring D. Preferred embodiments of ring H are as defined above for preferred embodiments of ring F.
Figure imgf000070_0002
Ring System 4. According to a preferred embodiment of ring system 3, ring I is a bridged bicyclic ring system containing 6- 12 carbon atoms, wherein ring I is saturated or partially unsaturated, and ring I has up to 3 substituents selected independently from J.
Preferred embodiments of ring I are selected from:
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000072_0002
According to a preferred embodiment of formula (II) , the
Figure imgf000073_0001
radical is
Figure imgf000073_0002
According to a preferred embodiment of formula (II) , the
Figure imgf000073_0003
radical is :
Figure imgf000074_0001
According to a preferred embodiment of formula (II) , the
Figure imgf000074_0002
radical is :
Figure imgf000075_0001
Figure imgf000075_0002
According to a preferred embodiment of formula (II) the
Figure imgf000075_0003
radical is
Figure imgf000076_0001
According to a preferred embodiment of formula (II ) , the
Figure imgf000076_0002
radical is
Figure imgf000077_0001
According to a preferred embodiment of formula (II) , the
Figure imgf000077_0002
radical is : wherein each B independently forms a 3- to a 20- membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, O, S, SO, or S02; wherein each ring is optionally fused to a (Cβ- Cl0)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) heterocyclyl; and wherein each ring has up to 3 substituents selected independently from J.
According to a preferred embodiment of formula (II) , the
Figure imgf000077_0003
radical is :
Figure imgf000078_0001
According to a preferred embodiment of formula (II) , the
Figure imgf000079_0001
radical is :
Figure imgf000079_0002
In the embodiment immediately above, the ring is also selected from:
Figure imgf000080_0001
Figure imgf000080_0002
Figure imgf000080_0003
According to a preferred embodiment of formula (II) , the
Figure imgf000080_0004
radical is :
Figure imgf000081_0001
According to a preferred embodiment of formula (II) , the
radical is:
Figure imgf000081_0002
wherein B forms a 3- to a 20-membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic ; wherein each heteroatom in the heterocyclic ring system is N, NH, O, S, SO, or S02; wherein each ring is optionally fused to a (Cβ- C10)aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or (C3- C10) eterocyclyl; and wherein each ring has up to 3 substituents selected independently from J.
According to a preferred embodiment of formula (II) , the
Figure imgf000082_0001
radical is
Figure imgf000082_0002
In the above radicals, it is understood that that Rn- variable is hydrogen.
According to a preferred embodiment of formula (II) , Rn and Rχ2 together with the atoms to which they are bound form a 6- to 10-membered mono- or bicyclic carbocyclic or heterocyclic ring system; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; and wherein said ring has up to 3 substituents selected independently from J. According to a preferred embodiment, the ring formed from R5 and Rι3, if present, is preferably an 18-membered ring.
According to a preferred embodiment, the ring formed from Ri and Rι , if present, is preferably an 18-membered ring.
Any of the ring systems may be substituted as set forth herein. Preferably, the ring substituents are selected from oxo, fluoro, difluoro (particularly vicinal difluoro) , and hydroxy. These substituents are the most preferred on the following ring systems:
Figure imgf000083_0001
wherein B is a 5-membered carbocyclic ring, optionally having one unsaturated bond. In preferred embodiments, heteroatoms are selected from the group consisting of N, NH, O, SO, and S02. Preferred embodiments for any formula are also preferred embodiments for any other formula (I) . For example, the preferred embodiments of R3 in formula (I) are also the preferred embodiments of Rι3 in formula (II) ; the preferred embodiments of R2 in formula (I) are also the preferred embodiments of R2o in formula (II); and the preferred embodiments of R6 in formula (I) are also the preferred embodiments of Rι7 in formula (II) .
Any of the preferred embodiments recited above for T, V, Ri, R2, R3, A, X, Y, R4, R5 and W may be combined to produce a preferred embodiment of a compound of formula (IA) .
Any of the preferred embodiments recited above for T, V, Ri, R2, R3, A, X, Y, R4, R5, and R5-, and W may be combined to produce a preferred embodiment of a compound of formula (IB) . Any of the preferred embodiments recited above for Ri, R-2/ R/ R-5/ and R5., Rn, R2, Ri3, Rι3>, Rι4/ Rs, Riε, Rι9, R2Q/ Z2, W may be combined to produce a preferred embodiment of a compound of formula (II) .
According to another embodiment, the present invention provides compounds of formula (I'):
Figure imgf000084_0001
(I')
wherein:
Ri and R3 each is independently(C1-C6) aliphatic, cyclopentyl or cyclohexyl;
R5 is ethyl, propyl or allyl; Re is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, benzyl, (S) -methylbenzyl; and
T is (C3-C10) eterocyclyl or (C5-C10) eteroaryl ring wherein said ring contains at least one hydrogen donor moiety selected from -NH2, -NH-, -OH or -SH; or T is selected from:
Figure imgf000085_0001
wherein Rio and K are as defined above. According to another embodiment, the present invention provides compounds of formulae (II' and II'
Figure imgf000085_0002
(II1); and
Figure imgf000086_0001
(II11); wherein the variables are as defined herein.
According to a preferred embodiment, the stereochemistry of a compound of this invention corresponds to that depicted in compounds l-62a and 63- 68.
Another embodiment of this invention provides a process for preparing a compound of this invention. These process are described in the schemes and examples
Examples of specific compounds of formula (I) are set forth below in Table 2. Table 2
Figure imgf000087_0001
1 2
Figure imgf000087_0002
4
Figure imgf000087_0003
Figure imgf000087_0004
Figure imgf000087_0005
10
Figure imgf000088_0001
11 12
Figure imgf000088_0002
13 14
Figure imgf000088_0003
15 16
Figure imgf000088_0004
17 18
Figure imgf000088_0005
19 20
Figure imgf000089_0001
21 22
Figure imgf000089_0002
23 24
Figure imgf000089_0003
25 26
Figure imgf000089_0004
27 28
Figure imgf000089_0005
29 30 .9 -
Figure imgf000090_0001
31 32
Examples of specific compounds of formula (I) are set forth below in Table 3. Table 3
Figure imgf000090_0002
la 2a
Figure imgf000090_0003
3a 4a
Figure imgf000090_0004
5a 6a
Figure imgf000091_0001
7a 8a
Figure imgf000091_0002
9a 10a
Figure imgf000091_0003
lla 12a
Figure imgf000091_0004
13a 14a
15a 16a
Figure imgf000092_0001
17a 18a
Figure imgf000092_0002
19a 20a
Figure imgf000092_0003
21a 22a
Figure imgf000092_0004
23a 24a
Figure imgf000092_0005
25a 26a
Figure imgf000093_0001
27a 28a
Figure imgf000093_0002
29a 30a
Figure imgf000093_0003
31a 32a
Figure imgf000093_0004
33a 34a
Figure imgf000093_0005
35a 36a
Figure imgf000094_0001
37a 38a
Figure imgf000094_0002
39a 40a
Figure imgf000094_0003
41a 42a
Figure imgf000094_0004
43a 44a
Figure imgf000094_0005
45a 46a
Figure imgf000095_0001
47a 48a
Figure imgf000095_0002
49a 50a
Figure imgf000095_0003
51a 52a
Figure imgf000095_0004
53a 54a
Figure imgf000095_0005
15 55a 56a
Figure imgf000096_0001
57a 58a
Figure imgf000096_0002
59a 60a
Figure imgf000096_0003
61a 62a
Examples of other specific compounds of formula (II) of the present invention are set forth below in Table 4. Table 4
Figure imgf000096_0004
63 64
Figure imgf000097_0001
65 66
Figure imgf000097_0002
67 68
The compounds of this invention may contain one or more asymmetric carbon atoms and thus may occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
All such isomeric forms of these compounds are expressly included in the present invention. Each stereogenic carbon may be of the R or S configuration. Preferably, the compounds of this invention have the structure and stereochemistry depicted in compounds la-
62a and 63-68.
Any of the preferred embodiments recited above, including those embodiments in the above species, may be combined to produce a preferred embodiment of this invention.
Abbreviations which are used in the schemes, preparations and the examples that follow are:
THF : tetrahydrofuran DMF: N,N, -dimethylformamide
EtOAc : ethyl acetate AcOH: acetic acid
HOBt: 1-hydroxybenzotriazole hydrate
EDC : 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride NMM: N-methylmorpholine
NMP: N-methylpyyrolidinone
EtOH: ethanol t-BuOH: tert-butanol
Et2θ: diethyl ether BOC : tert-butyloxycarbonyl
BOC20: di-tert-butyldicarbonate
Cbz : benzyloxycarbonyl
Chg: cyclohexylglycine tBG: tert-butylglycine Fmoc: 9-fluorenyl methyloxycarbonyl
DMSO: diemthyl sulfoxide
TFA: trifluoroacetic acid
DCM: dichloromethane
DCE: dichloroethane DIEA: diisopropylethylamine
MeCN: acetonitrile
PyBrOP: tris (pyrrolidino)bromophosphonium hexafluorophosphate
TBTU or HATU: 2- (lH-benzotriazole-1-yl) -1 , 1 , 3 , 3- tetramethyluronium tetrafluoroborate
DMAP: 4-dimethylaminopyridine
PPTS: pyridinium p-toluenesulfonate
IBX: periodobenzoic acid
AIBN: 2,2' -azobisisobutyronitrile rt : room temperature
ON: overnight
ND: not determined
MS: mass spectrometry
LC : liquid chromatography General Synthetic Methodology:
The compounds of this invention may be prepared in general by methods known to those skilled in the art. Schemes 1-17 below illustrate synthetic routes to the compounds of the present invention. Other equivalent schemes, which will be readily apparent to the ordinary skilled organic chemist, may alternatively be used to synthesize various portions of the molecule as illustrated by the general scheme below, and the preparative examples that follow.
Scheme 1 :
Figure imgf000099_0001
or R COCI, DIEA, DMF
Dess-Martin periodinane tBuOH, CH2CI2'
Figure imgf000099_0002
Scheme 1 above provides a general route for the preparation of compounds of formula I . Scheme 2
PyBOP, DIEA, DMF
Figure imgf000100_0001
Figure imgf000100_0002
Figure imgf000100_0003
Schemes 2 above provides another general route for the preparation of compounds of formula I.
Scheme 3
Figure imgf000101_0001
Scheme 3 above depicts a general route for the preparation of compounds of formula I, specifically compounds represented by structure 62a.
Scheme 4 :
Figure imgf000102_0001
Figure imgf000102_0002
Scheme 4 above provides another method for the preparation of compounds of formula I .
Scheme 5
Figure imgf000103_0001
imidazole
Figure imgf000103_0002
Figure imgf000103_0003
Figure imgf000103_0004
Scheme 1 or 2 in combination with scheme 5 above provide another general method for the preparation of compounds of formula I.
Scheme 6
Figure imgf000103_0005
Scheme 1 or 2 in combination with scheme 6 above provide another general method for the preparation of compounds of formula I . Scheme 7
Figure imgf000104_0001
Figure imgf000104_0002
Figure imgf000104_0003
Scheme 1 or 2 in combination with scheme 7 above provide another general method for the preparation of certain compounds of formula I .
Scheme 8 :
Ba(OH)2.8 H20 H20, Reflux
Figure imgf000104_0005
Figure imgf000104_0004
Scheme 1 or 2 in combination with scheme 8 above provide another general route for the preparation of compounds of formula I . Scheme 9
reflυx
Figure imgf000105_0002
Figure imgf000105_0001
Scheme 1 or 2 in combination with scheme 9 above provide another general method for the preparation of certain compounds of formula I .
Scheme 10
Figure imgf000105_0003
Scheme 1 or 2 in combination with scheme 10 above provide yet another general method for the preparation of compounds of formula I . Scheme 11
Figure imgf000106_0001
R3= fully grown petidomimetic with cap installed
Figure imgf000106_0002
or CI2HCCOOH, DMSO CH CI2
Scheme 11 above shows a general route for the preparation of compounds of formula I using a solid phase synthetic route based on the procedure of Ξllman, J. et al., J". Med. Chem. 1995, 38, 1427.
Scheme 12
Figure imgf000107_0001
1)10%KOH/EtOH 1)10%KOH/EtOH
1h/60°C 1h/60°C 2)HCI1M 2)HCI1M
Figure imgf000107_0002
4b 5b
Scheme 1 or 2 in combination with scheme 11 above provide a general method for the preparation of compounds of formula I, specifically compounds 39, 40, 39a, and 40a.
Scheme 13 o
Ethyl formate
Sodium / ether 0°C to rt / 16h
Figure imgf000108_0001
8b
Figure imgf000108_0002
8b 9b 10b
Scheme 1 or 2 in combination with scheme 13 above provide a general method for the preparation of compounds of formula I, specifically compounds 25, 25a, 41a, 45a, 55a, 58a, 59a, and 61a.
Scheme 14 :
Figure imgf000109_0001
25a
Scheme 14 above provides a synthetic scheme for the preparation of compound 25a. Scheme 15 :
Figure imgf000110_0001
Scheme 15 above provides a synthetic scheme for the preparation of compound 39a. Scheme 16 :
Figure imgf000111_0001
Figure imgf000111_0002
Scheme 16 above provides a synthetic scheme for the preparation of compound 40a.
- Ill
Scheme 17
Figure imgf000112_0001
EDC, HOBt, DIEA, DCM
TFA, DCM
Figure imgf000112_0002
Moffatt-Pfitzner oxidation
Figure imgf000112_0003
Scheme 17 above provides a general method for the preparation of compounds of formula II . Although certain exemplary embodiments are depicted and described below, it will be appreciated that compounds of this invention can be prepared according to the methods described generally above using appropriate starting materials generally available to one of ordinary skill in the art.
Another embodiment of this invention provides a composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof. According to a preferred embodiment, the compound of formula I is present in an amount effective to decrease the viral load in a sample or in a patient, wherein said virus encodes a serine protease necessary for the viral life cycle, and a pharmaceutically acceptable carrier. If pharmaceutically acceptable salts of the compounds of this invention are utilized in these compositions, those salts are preferably derived from inorganic or organic acids and bases . Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzene sulfonate, bisulfate, butyrate, citrate, camphorate, camphor sulfonate, cyclopentane-propionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenyl-propionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate. Base salts include ammonium salts, alkali metal salts, such as sodium and potassium salts, alkaline earth metal salts, such as calcium and magnesium salts, salts with organic bases, such as dicyclohexylamine salts, N-methyl-D-glucamine, and salts with amino acids such as arginine, lysine, and so forth.
Also, the basic nitrogen-containing groups may be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides and iodides; dialkyl sulfates, such as dimethyl, diethyl, dibutyl and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides, such as benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained.
The compounds utilized in the compositions and methods of this invention may also be modified by appending appropriate functionalities to enhance selective biological properties . Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.
Pharmaceutically acceptable carriers that may be used in these compositions include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers , polyethylene glycol and wool fat.
According to a preferred embodiment, the compositions of this invention are formulated for pharmaceutical administration to a mammal, preferably a human being.
Such pharmaceutical compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally or intravenously.
Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1, 3-butanediol . Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or di-glycerides . Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions . These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.
Dosage levels of between about 0.01 and about 100 mg/kg body weight per day, preferably between about 0.5 and about 75 mg/kg body weight per day of the protease inhibitor compounds described herein are useful in a monotherapy for the prevention and treatment of antiviral, particularly anti-HCV mediated disease. Typically, the pharmaceutical compositions of this invention will be administered from 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 carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. A typical preparation will contain from about 5% to about 95% active compound (w/w) . Preferably, such preparations contain from about 20% to about 80% active compound.
When the compositions of this invention comprise a combination of a compound of formula I, II, III or IV, and one or more additional therapeutic or prophylactic agents, 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 to 80% of the dosage normally administered in a monotherapy regimen.
The pharmaceutical compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers that are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These may be prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols . The pharmaceutical compositions of this invention may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs .
Topical application for the lower intestinal tract may be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers . Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with our without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.
The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other conventional solubilizing or dispersing agents .
Most preferred are pharmaceutical compositions formulated for oral administration. In another embodiment, the compositions of this invention additionally comprise another anti-viral agent, preferably an anti-HCV agent. Such anti-viral agents include, but are not limited to, immunomodulatory agents, such as -, β-, and γ-interferons, pegylated derivatized interferon-α compounds, and thymosin; other anti-viral agents, such as ribavirin, amantadine, and telbivudine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors) ; inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in United States Patent 5,807,876, mycophenolic acid and derivatives thereof) ; or combinations of any of the above.
Upon improvement of a patient's condition, a maintenance dose of a compound, composition or combination of this invention may be administered, if necessary. Subsequently, the dosage or frequency of administration, or both, may be reduced, as a function of the symptoms, to a level at which the improved condition is retained when the symptoms have been alleviated to the desired level, treatment should cease. Patients may, however, require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.
It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of active ingredients will also depend upon the particular described compound and the presence or absence and the nature of the additional anti-viral agent in the composition.
According to another embodiment, the invention provides a method for treating a patient infected with a virus characterized by a virally encoded serine protease that is necessary for the life cycle of the virus by administering to said patient a pharmaceutically acceptable composition of this invention. Preferably, the methods of this invention are used to treat a patient suffering from a HCV infection. Such treatment may completely eradicate the viral infection or reduce the severity thereof. More preferably, the patient is a human being.
In an alternate embodiment, the methods of this invention additionally comprise the step of administering to said patient an anti-viral agent preferably an anti- HCV agent. Such anti-viral agents include, but are not limited to, immunomodulatory agents, such as α-, β-, and γ-interferons, pegylated derivatized interferon-α compounds, and thymosin; other anti-viral agents, such as ribavirin and amantadine; other inhibitors of hepatitis C proteases (NS2-NS3 inhibitors and NS3-NS4A inhibitors) ; inhibitors of other targets in the HCV life cycle, including helicase and polymerase inhibitors; inhibitors of internal ribosome entry; broad-spectrum viral inhibitors, such as IMPDH inhibitors (e.g., VX-497 and other IMPDH inhibitors disclosed in United States Patent 5,807,876, mycophenolic acid and derivatives thereof); or combinations of any of the above. Such additional agent may be administered to said patient as part of a single dosage form comprising both a compound of this invention and an additional anti-viral agent. Alternatively the additional agent may be administered separately from the compound of this invention, as part of a multiple dosage form, wherein said additional agent is administered prior to, together with or following a composition comprising a compound of this invention. In yet another embodiment the present invention provides a method of pre-treating a biological substance intended for administration to a patient comprising the step of contacting said biological substance with a pharmaceutically acceptable composition comprising a compound of this invention. Such biological substances include, but are not limited to, blood and components thereof such as plasma, platelets, subpopulations of blood cells and the like; organs such as kidney, liver, heart, lung, etc; sperm and ova; bone marrow and components thereof, and other fluids to be infused into a patient such as saline, dextrose, etc.
According to another embodiment the invention provides methods of treating materials that may potentially come into contact with a virus characterized by a virally encoded serine protease necessary for its life cycle. This method comprises the step of contacting said material with a compound according to the invention. Such materials include, but are not limited to, surgical instruments and garments; laboratory instruments and garments; blood collection apparatuses and materials; and invasive devices, such as shunts, stents, etc.
In another embodiment, the compounds of this invention may be used as laboratory tools to aid in the isolation of a virally encoded serine protease. This method comprises the steps of providing a compound of this invention attached to a solid support; contacting said solid support with a sample containing a viral serine protease under conditions that cause said protease to bind to said solid support; and eluting said serine protease from said solid support. Preferably, the viral serine protease isolated by this method is HCV NS3-NS4A protease.
In order that this invention be more fully understood, the following examples are set forth. These examples are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.
EXAMPLES
^-M R spectra were recorded at 500 MHz using a Bruker AMX 500 instrument. Mass spec, samples were analyzed on a MicroMass ZQ or Quattro II mass spectrometer operated in single MS mode with electrospray ionization. Samples were introduced into the mass spectrometer using flow injection (FIA) or chromatography. Mobile phase for all mass spec, analysis consisted of acetonitrile-water mixtures with 0.2% formic acid as a modifier. As used herein, the term "Rt(min)" refers to the HPLC retention time, in minutes, associated with the compound. The HPLC retention times listed were either obtained from the mass spec, data or using the following method: Instrument: Hewlett Packard HP-1050; Column: YMC Ci8 (Cat. No. 326289C46);
Gradient/Gradient Time: 10-90% CH3CN/H20 over 9 minutes, then 100% CH3CN for 2 minutes; Flow Rate: 0.8ml/min; Detector Wavelength: 215nM and 245nM; Chemical naming for selected compounds herein was accomplished using the naming program provided by CambridgeSoft Corporations ChemDraw Ultra®, version 7.0.1.
Example 1 : 3~Acetyl-lH-indole-2-carboxylic acid (4b) and 5-Acetyl -1H- indole-2-carboxylic acid (5b) . Aluminum chloride (7.75 g, 0.058 mol) was suspended in 200ml of anhydrous dichloroethane at room temp, followed by a slow addition of acetic anhydride (2.74 mL, 0.03 mol) . The mixture was stirred at room temp for 10 minutes after which, liT-indole-2-carboxylic acid ethyl ester (lb, 5.0 g, 0.0264 mol) was added as a solution in
15 mL of dichloroethane. The reaction mixture was stirred under nitrogen at 40°C for 10 h. The reaction was quenched with an ice-water mixture and the organic layer was washed with water (3X) . The organic phase was dried over anh. Na2S0 , filtered and concentrated in vacuo .
Chromatography on Si02 (4% Ethyl acetate / 96% CH2C12) provided 3.2 g of 3 -acetyl-lH-indole-2-carboxylic acid ethyl ester 2b (52%) and 770 mg of 5-acetyl-lH-indole-2- carboxylic acid ethyl ester 3b (13%) . 2b: XH NMR (CDC13) d 9.1 (bs,lH), 8.1 (d,lH), 7.5 (m,2H), 7.3 (s,lH), 4.4 (q,2H), 2.7 (s,3H), 1.5 (t,3H) ppm. 3b: ^Η NMR (CDC13) d 9.3 (bs,lH), 8.25 (s,lH), 8.1 (d, IH), 7.6 (d,lH), 7.2 (S,1H), 4.3 (q, 2H) , 2.7 (s,3H), 1.7 (t, 3H) ppm. Saponification of 2b and 3b with 10% KOH in ethanol at 60°C for lh followed by acidification with IM HCI provided 3 -acetyl-lH-indole-2-carboxylic acid 4b and 5- acetyl-liT-indole-2-carboxylic acid 5b in 95% and 93% yield respectively. The crude acids were used directly without purification in the next step.
Example 2 : 3-Acetyl-4,5-dimethyl-2-pyrrole carboxylic acid (10b).
A solution- of sodium nitrite (36.9 g, 0.534 mol) in 70 mL of water was added dropwise to a stirred solution of ethylacetoacetate (70 g, 0.538 mol) in 1401 mL of glacial acetic acid at 0°C. After the addition was complete, the light yellow reaction mixture was allowed to warm to room temperature. After 30 minutes, all the starting material had been consumed, the reaction was quenched with 350 mL of water and extracted with ethyl acetate (2 X 125 mL) . The organic extracts were combined and washed with water (2 X 125 mL) and saturated sodium hydrogen carbonate aqueous solution (2 X 105 L) . The organic layer was dried with sodium sulfate and concentrated in vacuo to give 84.2 g (98%) of Ethyl-2- Hydroxyimino-3-oxobutanoate 6b as a pale yellow oil. XH NMR (CDC13) d 10.3 (s,lH), 4.2 (q,2H), 2.3 (s,3H), 1.3 (t, 3H) ppm.
Crushed sodium (12.4 g, 0.540 mol) was added to a solution of 2-butanone (48.2 mL, 0.538 mol) and ethyl formate (43.47 mL, 0.538 mol) in dry ether (540 mL) with vigorous mechanical stirring over a period of 1 h, during which time the mixture was chilled in an ice-salt bath. The mixture was then stirred at room temp, for 14 h. After cooling the reaction mixture to 4°C for a few hours, the precipitated sodium salt was obtained by filtration and washed thoroughly with cold, dry ether to afford 49.3 g (75%) of the desired sodium salt of 2-Methy-3- oxobutyraldehyde 7b. XH NMR (DMSO-dg) d 9.1 (s,lH), 1.9 (s,3H), 1.3 (s,3H) ppm. Sodium salt 7b (49.3 g, 0.404 mol) and oxime 6b (64.23, 0.404 mol) were stirred in 300 mL of 70% acetic acid/ 30% water and warmed to 50°C. Zinc powder (42.21 g, 0.646 mol) was added portion-wise over 30 minutes maintaining the temperature below 100°C. When the addition was complete, the suspension was refluxed for 15 minutes, then poured into 4 L of ice-water. After a short time, the product precipitated out to give, after filtration, 30.1 g (45%) of the desired ethyl-4, 5- dimethyl-2-pyrrole carboxylate 8b. XH NMR (CDC13) d 9.0 (bs,lH), 6.7 (s,lH), 4.3 (q,2H), 2.3 (s, 3H) , 2.0 (s,3H), 1.3 (t,3H) ppm.
To a solution of aluminum chloride (50.19 g, 0.376 mol) in dry dichloroethane (580 mL) at 25°C was added slowly acetic anhydride (17.75 mL, 0.188 mol). The resulting mixture was stirred at room temp, for 10 minutes, then a solution of pyrrole 8b (10.49 g, 0.0627 mol) in dichloroethane (30 mL) was added and the reaction mixture was stirred at room temp, for 2h. After an additional 3h at 80°C, the mixture was poured into ice water and extracted with dichloromethane. The organic layer was dried with anhy. sodium sulfate and concentrated in vacuo to an orange residue. Short plug filtration over silica gel (30% ethyl acetate / 70% hexanes) gave 7.5 g (60%) of ethyl-3-acetyl-4, 5-dimethyl-2-pyrrole carboxylate 9b.
XH NMR (CDC13) d 9.0 (bs,lH), 4.3 (q,2H), 2.7 (s,3H), 2.1 (s, 3H) , 1.9 (s,3H), 1.3 (t,3H) ppm.
A mixture of pyrrole ester 9b (8.2 g, 0.0392 mol), in ethanol and 100 mL of 10% potassium hydroxide were refluxed for 1 h. The mixture was cooled and concentrated in vacuo to an oil. Water was added to the oil, the mixture acidified with dilute HCI and extracted with ether. The organic phase was dried with anhy. sodium sulfate and concentrated in vacuo to a solid residue. The compound was recrystallized in 80 mL of ethanol to give 5.8 g of pure 3-acetyl-4, 5-dimethyl-2-pyrrole carboxylic acid 10b as a solid. Hϊ NMR (DMSO-de) d 2.5 (s,3H), 2.2 (s,3H), 2.0 (s,3H) ppm.
Example 3 : l-(2-{20 [ (3-Acetyl-4,5-dimethyl-lH-pyrrole-lH-2-carbonyl)- amino] -2-cyclohexyl-acetylamino}-3,3-di ethyl-butyryl) - octahydro-indole-2-carboxylic acidd- cyclopropylaminooxalyl-butyl) -amide (25a) .
Octahydro-indole-2-carboxylic acid lib (5.0g, 29.5mmol, purchased from Bachem) was suspended in 200mL of CHC13 then cooled in a dry ice/acetone bath. H2S04 (120uL/mmol) was added followed by bubbling in excess isobutylene. The mixture was sealed and the ice bath removed. The mixture was stirred at RT for 12 hours. The reaction mixture was carefully unsealed after cooling and concentrated. EtOAc was added and washed with saturated sodium bicarbonate soln, brine, dried over sodium sulfate, then filtered and concentrated to give octahydro-indole-2-carboxylic acid tert-butyl ester 12b (6.65g, 29.5mmol, 100%).
^-NMR (CDC13) d 1.22 (2H,m), 1.38 (2H,m), 1.48 (9H,s), 1.50 (2H,m), 1.66 (2H,m) , 1.71 (lH,m) , 2.02, (IH m) , 2.18 (IH, m) , 2.85 (lH,bs), 3.10 (IH m) , 3.70 (lH,dd) ppm.
L-CBz- ert-butyl glycine (5.0g, 11.2mmol)was stirred in CH2C12 (40mL) . EDC (2.25g, 11.7mmol) and HOBt(1.58g, 11.7 mmol) were added and the mixture stirred 15 minutes. This solution was cannulated into a solution of 12b (2.4g, 10.6mmol) in CH2C12 (20mL) and stirred overnight. The reaction was monitored by HPLC observing the consumption of the amine. The mixture was concentrated, EtOAc added, followed by a 1. ON aqueous glycine sodium salt solution and the mixture stirred until all Cbz- ert-butyl glycine-OBt was consumed. The layers were separated and the organic phase washed with IN HC1(3X), brine, 10% potassium carbonate (3X) , and brine then dried over sodium sulfate, filtered and concentrated in vacuo . Chromatography through a silica gel plug (10%EA/Hex) gave 1- (2-benzyloxycarbonylamino-3 , 3- dimethyl-butyryl) -octahydro-indole-2-carboxylic acid tert-butyl ester 13b (4.4g, 9.3mmol, 88%). ^Η-NMR (CDC13) d 1.05 (9H,s), 1.30 (2H,m) , 1.46 (9H,s), 1.50-1.72 (5H,m), 1.94-2.10 (3H,m) , 2.30 (IH m) , 4.18 (IH, m) , 4.22, (lH,d), 4.28 (lH,dd), 5.05-5.17 (2H,dd), 5.30 (lH,d), 7.33 (5H,m) ppm.
Ester 13b (4.0g, 8.4mmol) was stirred in EtOH (40mL) charged with 400mg 10%Pd(OH)2/C. H2 gas was bubbled into the suspension until the reaction was complete. Catalyst was removed by filtration and the filtrate concentrated in vacuo to give 1- (2-amino-3 , 3-dimethyl-butyryl) - octahydro-indole-2-carboxylic acid tert-butyl ester 14b (2.8g, 8.4mmol, 100%) which was used as is in the next step without further purification.
1H-NMR (CDCI3) 3:2 ratio of rotamers, d 0.98 and 1.02 (9H, pair of singlets), 1.20-1.34 (2H,m) , 1.47 and 1.50 (9H, pair of singlets), 1.58-1.78 (6H,m), 1.99 (lH,m) , 2.1 (IH, ) , 2.3 (lH,m) , 2.4 (lH,m), 3.86 and 4.13 (lH,m), 4.32 (IH, m) ppm.
L-CBz-cyclohexyl glycine (3.0g, 10.3mmol) in CH2CI2 (30mL) was treated with EDC (2.07g, 10.8mmol) and HOBt (1.65g, 10.8mmol) and stirred for 15 minutes. The resulting mixture was added to a solution of 14b (3.32g, 9.8mmol in CH2C12 (20mL) and stirred at RT, monitoring consumption of amine by HPLC. 1. ON glycine sodium salt solution was added until all L-CBz-cyclohexyl glycine- OBt was consumed (several hours) with monitoring by HPLC. The reaction mixture was washed with 1. ON HCI (3X) , brine, 10% potassium carbonate (3X) , and brine, then dried over sodium sulfate, filtered and concentrated in vacuo . The solid product obtained was recrystallized from hot IPA/H20 (-3.3:1) by dissolving the compound in hot IPA and adding water slowly until product started to precipitate out. Cold filtration afforded 4.79g (80%) of l-[2-(2- benzyloxycarbonylamino-2-cyclohexyl-acetylamino) -3,3- di ethyl-butyryl] -octahydroindole-2-carboxylic acid tert- butyl ester 15b as a solid.
1H-NMR (CDCI3) d 0.98 (lH,m), 1.03 (9H,s), 1.12-1.32 (5H, m) , 1.43 (9H,s), 1.59-1.79 (12H,m) , 1.93-2.10 (3H,m) , 2.20 (lH,m), 3.98 (lH,m) , 4.12 (lH,m), 4.22 (IH m) 4.55 (lH,d), 5.10 (2H,m), 5.27 (lH,d), 6.25 (lH,d), 7.35 (5H,m) ppm.
CBz ester 15b (3.0g, 4.9mmol) was stirred in EtOH (25mL) and charged with 300mg 10%Pd(OH) 2/C. H2 gas was bubbled into the suspension until the reaction was complete. Catalyst was removed by filtration and the filtrate concentrated in vacuo to give 1- [2- (2-amino-2- cyclohexyl-acetylamino) - 3 , 3-dimethyl-butyryl] -octahydro- indole-2-carboxylic acid tert-butyl ester 16b (2.34g, 4.9 mmol, 100%) which was used as is in the next step without further purification. 1H-NMR (CDCI3) d 1.08 (9H,s), 1.10-1.25 (7H,m) , 1.44 (9H, s), 1.50-1.78 (10H,m) , 1.94 (2H,m), 2.07 (2H,m) , 2.30 (IH, m) , 3.21 (lH,m), 4.22 (lH,m) . 4.34 (lH,m) , 4.52 (lH,d) , 8.04 (lH,d) ppm.
3-acetyl-4, 5-dimethyl-2-pyrrole carboxylic acid 10b (2.5g, 13.7 mmol) in DMF (56 mL) was treated with EDC (2.75g, 14.4 mmol) and HOBt (2.20g, 14.4 mmol) and stirred at RT for 15 minutes. Amine 16b (6.23g, 13.0 mmol) in DMF (lOmL) was added, the reaction mixture stirred at RT and monitored by HPLC. The mixture was concentrated in vacuo, then dissolved in EtOAc. 1.0N glycine sodium salt aqueous solution was added until all excess amino ester 16b was consumed (several hours) . The mixture was washed with IN HCI (3X) , brine, bicarb (3X) , and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo . Purification through a short plug of silica gel (25%EA/Hex) afforded 7.08g, (85%) of l-(2- {2- [ (3-acetyl-4, 5-dimethyl-lH-pyrrole-2-carbonyl) -amino] - 2-cyclohexyl-acetylamino}-3 , 3-dimethyl-butyryl) - octahydro-indole-2-carboxylic acid tert-butyl ester 17b. ^-NMR (CDC13) d 0.94 (9H,s), 0.99-1.33 (6H,m), 1.42 (9H, s), 1.45-2.22 (16H,m) , 2.24 (3H,s), 2.28 (3H,s), 2.55 (3H, s), 4.30 (lH,m), 4.39 (lH,m) , 4.73 (lH,d), 5.00 (lH,m), 11.30 (lH,d) ppm. tert-Butyl ester 17b (3.0g, 4.68 mmol) was stirred in CH2C12 (20mL) in an ice bath and TFA (20mL) was added slowly. The mixture was warmed to RT and stirred until ester was no longer observed by HPLC. Added toluene and concentrated in vacuo several times (3X) . Most of the residual TFA was removed in vacuo to give l-(2-{2-[(3- acetyl-4, 5-dimethyl-lH-pyrrole-2-carbonyl) -amino] -2- cyclohexyl-acetylamino}-3 , 3-dimethyl-butyryl) -octahydro- indole-2-carboxylic acid tert-butyl ester 18b as a pink solid which was used in the next step without further purification.
Crude acid 18b from above in CH2C12 (20 mL) was treated with DIEA dropwise and stirred at RT until fuming ceased (from quenching excess TFA). EDC (0.99g, 5.1 mmol) and HOBt (0.78g, 5.1 mmol) were added and the mixture stirred for 15 minutes. 3-Amino-2-hydroxy- hexanoic acid cyclopropylamine 19b (950mg, 5.1 mmol, prepared according to the methods described by U. Schoellkopf et al . , Justus Liebigs Ann . Chem. GE, 1976, 183-202, and J. Stemple et al . , Organic Letters 2000, 2 (18) , 2769-2772) in CH2C12 (10 mL) was added and the mixture stirred at RT overnight. The mixture was poured onto IN HCI/EtOAc, the organic layer washed with IN HCI
(3X) , brine, sat'd NaHC03 (3X) , and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo. Purification through a plug of silica gel eluting with 100% CH2C12 —»l%MeOH/ CH2C12—>»2%MeOH/ CH2C12 afforded 3.0 g (85% for two steps) of 1- (2-{2- [ (3-acetyl-4, 5- dimethyl-lH-pyrrole-2-carbonyl) -amino] -2-cyclohexyl- acetylamino}-3 , 3-dimethyl-butyryl) -octahydro-indole-2- carboxylic acid[l- (cyclopropylcarbamoyl-hydroxy-methyl) - butyl] -amide 20b.
NMR XH-NMR (CDCI3) d 0.50 (2H,m), 0.67 (lH,m), 0.75
(lH,m), 0.85 (4H,m), 0.93 (8H,m) , 1.03 (3H,m) , 1.22 (2H,m), 1.30 (3H,m) , 1.50-2.03 (18H,m), 2.25 (3H,s), 2,26
(3H,s), 2.60 (3H,s), 2.71 (lH,m) , 3.89 and 3.91 (lH,bm) , 4.10 and 4.21 (IH, pair of singlets), 4.38 (lH,m), 4.52
(lH,m), 4.67 and 4.71 (IH, pair of doublets), 4.80
(lH,m) , 6.95 and 7.00 (IH, pair of doublets) ppm. To a solution of EDC (38.2g. 199.2 mmol) in dry
EtOAc (98 mL) was added keto-alcohol 20b (lO.Og, 13.3mmol) in dry EtOAc (52 mL) . Dry DMSO (75 mL) was added, the mixture cooled to 7°C and dichloroacetic acid (10.97 mL, 133 mmol) in dry EtOAc (31mL) was added as quickly as possible allowing the temperature to go no higher than 25°C. The ice bath was removed and the mixture stirred for 15 minutes. TLC showed complete disappearance of 20b. The mixture was cooled to 15°C before adding 1. ON HCI (200 mL) to quench as quickly as possible without allowing the temp, to go above 25°C.
The organic layer was washed with water (3X) , dried over sodium sulfate, filtered and concentrated in vacuo. Purification through a silica gel plug (100% CH2C12 — >50%EtOAc/CH2Cl2) afforded a white solid which was stirred in Et20, filtered and dried in vacuo to remove residual dimethyl sulfide and dichloroacetic acid. Obtained 7.49 g (75%) of desired 1- (2-{2- [ (3-acetyl-4, 5- dimethyl-lH-pyrrole-2-carbonyl) -amino] -2-cyclohexyl- acetylamino}-3 , 3-dimethyl-butyryl) -octahydro-indole-2- carboxylic acid (1-cyclopropylaminooxalyl-butyl) -butyl) - amide 25a.
1H-NMR (CDC13) d 0.61 (2H,m), 0.82 (2H,d), 0.91 (3H,t), 0.97 (7H,s), 1.05 (3H,m), 1.20 (2H,m) , 1.32 (4H,m) , 1.50 (5H,m), 1.68 (5H,m) , 1.79 (3H,m) , 1.89 (3H,m) , 2.01 (IH, m) , 2.18 (lH,m), 2.23 (3H,s), 2.24 (3H,s), 2.37 (lH,m) , 2.59 (3H,s), 2.78 (lH,m) , 4.41 (lH,m), 4.56 (lH,t), 4.85 (lH,d), 4.91 (lH,m), 5.31 (lH,m) , 6.90 (lH, broad), 7.03 (IH, broad) ppm.
Example 4 :
3-Acetyl-lH-indole-2-carboxylic acid (cyclohexyl-{1- [2-(l- cyclopropylaminooxalyl-butylcarbamoyl) -octahydro-indole-1- carbonyl] -2, 2-dimethyl-propylcarbamoyl}-methyl) -amide (39a).
BOC-L-Octahydro-indole-2-carboxylic acid 21b (3.4g, 12.6mmol, purchased from Bachem) , was suspended in 30 mL CH2C12 and cooled in a water/ice bath. N-methylmorpholine (3.0 eq. , 4.2 mL, 38 mmol) was added followed by addition of solid PyBOP (1.1 eq. , 7.2g, 13.8 mmole). The ice bath was removed and the reaction stirred at RT for 1 hour under N2. In a separate flask, 5.8 g of 3-amino-2- hydroxy-hexanoic acid cyclopropylamine 19b was dissolved in 30 mL of DMF and 10 mL of CH2C12. at RT. The acid (21b) /PyBOP/NMM solution was cannulated into the solution of amine 19b along with 20 mL of CH2C12. The reaction was stirred at RT for 16 hours, then quenched with aqueous sodium bicarbonate solution and concentrated in vacuo . The residue was extracted twice with EtOAc. The combined organic layers were washed with 10% citric acid solution, saturated sodium bicarbonate solution, water (5 X) , then brine, dried over sodium sulfate, filtered, and concentrated in vacuo . Flash chromatography on silica gel eluting with 30 % EtOAc/hexanes to 100% EtOAc gave 4.35 g of 2- [1- (Cyclopropylcarbamoyl-hydroxy-methyl) - butylcarbamoyl] -octahydro-indole-1-carboxylic acid tert- butyl ester 22b. LC/MS M+H = 438.2, M-H = 436.3. ^■H-NMR (CDC13) d 0.50 (2H,m), 0.70 (2H,m) , 0.91 (3H,t), 1.14 (lH,m) , 1.2-1.37 (4H,m) , 1.42 (9H,s), 1.59-1.71 (5H,m), 1.93 (2H,m) , 2.10 (lH,bs) , 2.22 (lH,m) , 2.7 (lH,m) , 3.8 (lH,bs) , 3.98 (lH,bs) 4.02-4.2 (3H,m) , 5.80 (lH,s), 7.1 (2H,bs) ppm.
BOC ester 22b (4.35 g, 7.43 mmol) was dissolved in 25 ml of CH2C12 and cooled in an ice water bath. 25 mL of TFA was added dropwise, the bath was removed and the reaction was allowed to warm to RT. TLC showed the BOC group removed after 30 minutes. After 1 hour, 25 mL of toluene was added and the reaction was concentrated to dryness and used as is in the next step.
L-CBz- ert-butyl glycine (3.16g, 11.9 mmol) in CH2C12 (25 mL) was treated with solid PyBOP(6.7g, 12.9 mmol) and DIEA (1.7 mL, 9.8 mmol) in 5 L of CH2C12. The bath was removed and the reaction was allowed to warm to RT and stirred for 50 minutes. The crude free amine was dissolved in CH2C12 (25 mL) , treated with DIEA (3.5 mL, 20 mmol) and then the mixture was cannulated into the Cbz-L- Tbg-OH/ PyBOP solution with additional CH2C12 (40 mL) added and the mixture stirred overnight. After 21 hours, the reaction was quenched with saturated sodium bicarbonate solution and concentrated. The residue was partitioned between EtOAc and water and extracted twice with EtOAc, the combined organic layers were washed with 0.5N HCI, saturated sodium bicarbonate, water, and brine then dried over sodium sulfate, filtered, and concentrated in vacuo . Flash chromatography on silica gel eluting with 2 % MeOH/EtOAc to 5 % MeOH/EtOAc gave 4.2 g (72%) of (l-{2- [1- (Cyclopropylcarbamoyl-hydroxy-methyl) - 5 butylcarbamoyl] -octahydro-indole-l-carbonyl}-2 , 2- dimethy1-propyl) -carbamic acid benzyl ester 23b. LC/MS M+H = 585.4, M-H = 583.3.
^-NMR (CDC13) d 0.55 (2H,m) , 0.75 (2H,m) , 0.88 (3H,t), 0.98 (9H,s), 1.22-1.41(5H,m) , 1.71 (5H,m) , 1.96 (2H,m) ,
10 2.21-2.44 (2H,m), 2.72(lH,m), 3.98 (lH,m) , 4.07 (lH,s)
4.2-4.29 (2H,m) , 4.39-4.49 (lH,m), 5.02-5.15 (2H,m) , 5.4 (lH,m), 6.75(lH,m) 6.85(lH,m), 7.33 (5H,m) ppm.
Cbz ester 23b (4.2g, 7.2mmol) was stirred in EtOH (50 mL) and flushed with N2. 800mg of 10%Pd/C was added
15 with EtOH (100 mL) . The reaction was flushed with H2 and left under an H2 atmosphere overnight. After 18 hours, the reaction was filtered and concentrated, azeotroped first with CH3CN then with CHC12 and concentrated in vacuo to provide intermediate free amine (3.26g 7.2mmol, 100%)
■20 which was used as is in the next step.
2- (lH-benzotriazole-1-yl) -1,1,3, 3-tetramethyluronium tetrafluoroborate (TBTU, 2.45g, 7.6 mmol) was combined with DMF (20 mL) and CH2C12 (10 L) and warmed slightly (45°C) to dissolve all solids, then cooled in an ice water
25 bath. A solution of L-CBz-cyclohexyl glycine (2.2g, 7.6 mmol) in CHC12 (30 mL) was added and the ice bath was removed. The reaction was warmed to 35°C for 5 minutes. N-methylmorpholine (1.5eq., 1.05 mL, 9.5 mmol) was added and the reaction stirred at RT for 30 minutes. A
30 solution of the crude amine (2.85g 6.32 mmol) obtained above in CH2C12 (20 mL) was cannulated into the reaction with additional CH2C12 (20mL) and the reaction was stirred at RT overnight. After 19 hours, the reaction was quenched with saturated sodium bicarbonate solution and concentrated. The residue was partitioned between EtOAc and water and extracted twice with EtOAc . The combined organic layers were washed with 0.5N HCI, saturated sodium bicarbonate, water (4 x) . The water washes were back extracted with EtOAc and the combined organics were washed with brine, dried over sodium sulfate, filtered, and concentrated. Flash chromatography on silica gel eluting with 1 % MeOH/ CH2C12 to 4 % MeOH/CH2Cl2 gave 2.8g (61%) of [Cyclohexyl- (1- {2- [1- (cyclopropylcarbamoyl- hydroxy-methyl) -butylcarbamoyl] -octahydro-indole-1- carbonyl}-2 , 2-dimethyl-propylcarbamoyl) -methyl] -carbamic acid benzyl ester 24b. LC/MS M+H = 724.2, M-H = 722.3. XH-NMR (CDC13) d 0.55 (2H,m), 0.74 (2H,m), 0.88 (3H,t), 1.02 (9H,s), 1.1-1.65 (22H,mm) , 1.94 (2H,m) , 2.12 (2H,m) , 2.68-2.79(lH,m) , 3.98-4.27 (4H,m) , 4.46-4.6 (lH,m) , 4.68 (lH,d) 4.55 (lH,d), 5.10 (2H,s), 5.40 (lH,s), 5.62 (lH,m), 6.96-7.1(2H,m) , 7.3 (5H,m) ppm.
Cbz amine 24b (2.8g, 3.9 mmol) was stirred in EtOH (60mL) and treated with 520mg of 10%Pd/C in EtOH(100 mL) . The reaction was flushed with H2 and left under H2 atmosphere overnight. After 19 hours, the reaction was filtered and concentrated, azeotroped with CH2C12 and concentrated to obtain the intermediate free amine (2.33g 3.9mmol, 100%) which was used as is. 3-Acetyl-lH-indole-2-carboxylic acid 25b(67mg, 0.33 mmol) in CH2C12 (2 mL) and DMF (2 mL) was treated with EDC (69mg, 0.36 mmol) and HOAT (123mg, 0.39 mmol) dissoleved in CH2C12(1 mL) and DIEA (160 ul, 0.9 mmol) and stirred at RT for 5 minutes. Crude amine obtained above (175 mg, 0.30 mmol) in CH2CI2 ( 5 mL) was added via cannula and the mixture stirred at RT. After 46 hours, the reaction was quenched with 0.5N HCI and concentrated. The residue was partitioned between EtOAc and water, extracted twice with EtOAc, the combined organic layers washed with 0.5N HCI, water (4 x) , brine then dried over sodium sulfate, filtered, and concentrated. Flash chromatography on silica gel eluting with EtOAc to 5 % MeOH/EtOAc gave 166mg (71%) of 3-acetyl-lH-indole-2-carboxylic acid [cyclohexyl- (l-{2- [1- (cyclopropylcarbamoyl-hydroxy- methyl) -butylcarbamoyl] -octahydro-indole-l-carbonyl}-2 , 2- dimethyl-propylcarbamoyl) -methyl] -amide 26b. FIA MS M+H = 775.4, M-H = 773.4, HPLC RT 8.75 + 8.85 (2 diastereomers) . 1H-NMR was consistent for the desired product.
Keto alcohol 26b (166mg, 0.21 mmol) was dissolved in dry EtOAc (6 mL) , treated with EDC (605 mg, 3.15 mmol), dry DMSO (3mL) was added and the reaction was cooled to 7°C. A solution of dichloroacetic acid (175 uL, 2.1 mmol) in dry EtOAc (1 mL) was added over 1 minute with a slight exother . Additional EtOAc (2 mL) was added and the ice bath was removed. After 1 hour, the reaction was cooled to 10°C, quenched with 1. ON HCI (2 mL) , then extracted twice with EtOAc. The combined organics were washed with water (4 x) and brine, then dried over sodium sulfate, filtered, and concentrated. Flash chromatography on silica gel eluting with 25% EtOAc/CH2Cl2 to 100% EtOAc followed by dissolving in CH3CN/water and lyophilizing gave 139 mg (86%) of 3-acetyl-lH-indole-2-carboxylic acid (cyclohexyl- {1- [2- (1-cyclopropylaminooxalyl- butylcarbamoyl) -octahydro-indole-1-carbonyl] -2 , 2- dimethyl-propylcarbamoyl}-methyl) -amide 39a. LC/MS M+H = 773.41, M-H = 771.49, LC/MS RT = 5.01 min, HPLC RT = 9.53 min. ^- MR (CDC13) d 0.50 (2H,m) , 0.72 (5H,m) , 0.92 (9H,s), 1.0-1.32 (10H,m), 1.47-1.75 (10H,m), 1.79-1.93 (3H,m) , 2.03 (lH,m) , 2.16 (lH,m) , 2.32 (lH,dd), 2.68 (lH,m) , 2.83 (3H, s), 4.4 (lH,m) 4.6 (lH,t), 4.8 (lH,d), 5.05 ( lH, m) , 5 . 3 (lH, m) , 6 . 77 (lH, d) , 7 . 02 ( lH, m) , 7 .27 (2H, m) , 7 . 61 ( IH, d) , 7 . 9 ( lH, d) 8 . 86 ( lH, bs ) ppm.
Example 5 : 5-Acetyl-l2T-indole-2-carboxylic acid (cyclohexyl-{1- [2- (1-cyclopropylaminooxalyl-butylcarbamoyl) -octahydro- indole-1-carbonyl] -2,2-dimethyl-propylcarbamoyl}-methyl) - amide (40a) .
5-Acetyl -lH-indole-2-carboxylic acid 27b (67 mg, 0.33 mmol) stirred in CH2C12(2 mL) and DMF (2 mL) was treated with EDC (69mg, 0.36 mmol) and HOAT (123mg, 0.39 mmol) dissolved in CHC12(1 mL) and DIEA (160ul, 0.9 mmol) and the mixture stirred at RT for 5 minutes. Added crude intermediate amine (175mg, 0.30mmol, identically prepared above in example 4) in CH2C12(5 mL) via cannula and stirred at RT. After 45 hours, the reaction was quenched with 0.5N HCI solution and concentrated. The residue was partitioned between EtOAc and water, extracted twice with EtOAc, the combined organic layers washed with 0.5N HCI, water (4 x) , and brine, then dried over sodium sulfate, filtered, and concentrated in vacuo . Flash chromatography on silica gel eluting with neat EtOAc to 5 % MeOH/EtOAc gave 142mg (61%) of 5-acetyl-lH-indole-2-carboxylic acid [cyclohexyl- (l-{2- [1- (cyclopropylcarbamoyl-hydroxy- methyl) -butylcarbamoyl] -octahydro-indole-l-carbonyl}-2, 2- dimethy1-propylcarbamoyl) -methyl] -amide 28b. LC/MS M+H = 775.44, M-H = 773.52, LC/MS RT = 3.78 min., HPLC RT = 7.70 min. """H-NMR was consistent for the desired product.
Keto-alcohol 28b (142mg, 0.18 mmol) was dissolved in dry EtOAC (10 mL) treated with EDC (520 mg, 2.7 mmol) and dry DMSO (5 mL) and then cooled to 7°C. A solution of dichloroacetic acid (150uL, 1.8 mmol) in dry EtOAc (1 mL) was added over 1 minute giving a slight exotherm. EtOAc (1 mL) was added and the ice bath was removed. After 1 hour, the reaction was cooled to 10 °C, quenched with
1.0N HCI (2 mL) and extracted twice with EtOAc. The combined organics were washed with water (4 x) and brine, then dried over sodium sulfate, filtered and concentrated in vacuo . Flash chromatography on silica gel eluting with 10% EtOAc/CH2Cl2 to 75% EtOAc/CH2Cl2 followed by dissolving in CHCN/water and lyophilizing afforded 129 mg
(93%) of 5-acetyl-lIT-indole-2-carboxylic acid
(cyclohexyl- {1- [2- (1-cyclopropylaminooxalyl- butylcarbamoyl) -octahydro-indole-1-carbonyl] -2,2- dimethyl-propylcarbamoyl}-methyl) -amide 40a. LC/MS M+H =
773.44, M-H = 771.48, LC/MS RT = 4.99 min, HPLC RT = 9.30 min.
^Η-NMR (CDC13) d 0.56 (2H,m), 0.8 (5H,m) , 0.98 (9H,s), 1.0-2.2 (25H,m), 2.45(lH,m), 2.68(3H,s), 2.86(lH,m), 4.27
(IH, m) 4.72 (lH,t), 4.8 (lH,d), 5.18 (lH,m) , 5.42
(lH,m), 6.92 (lH,d), 7.09 (2H,m) , 7.21 (lH,m) , 7.6
(lH,d), 7.91 (lH,d), 8.36 (lH,s), 9.1 (lH,bs), 11.32
(lH,bs) ppm. Example 6 :
HCV Replicon Cell Assay Protocol
Cells containing hepatitis C virus (HCV) replicon were maintained in DMEM containing 10% fetal bovine serum (FBS), 0.25 mg per ml of G418, with appropriate supplements (media A) .
On day 1, replicon cell monolayer was treated with a trypsin: EDTA mixture, removed, and then media A was diluted into a final concentration of 100,000 cells per ml wit. 10,000 cells in 100 ul were plated into each well of a 96-well tissue culture plate, and cultured overnight in a tissue culture incubator at 37°C.
On day 2, compounds (in 100% DMSO) were serially diluted into DMEM containing 2% FBS, 0.5% DMSO, with appropriate supplements (media B) . The final concentration of DMSO was maintained at 0.5% throughout the dilution series .
Media on the replicon cell monolayer was removed, and then media B containing various concentrations of compounds was added. Media B without any compound was added to other wells as no compound controls .
Cells were incubated with compound or 0.5% DMSO in media B for 48 hours in a tissue culture incubator at 37°C. At the end of the 48-hour incubation, the media was removed, and the replicon cell monolayer was washed once with PBS and stored at -80°C prior to RNA extraction.
Culture plates with treated replicon cell onolayers were thawed, and a fixed amount of another RNA virus, such as Bovine Viral Diarrhea Virus (BVDV) was added to cells in each well. RNA extraction reagents (such as reagents from RNeasy kits) were added to the cells immediately to avoid degradation of RNA. Total RNA was extracted according the instruction of manufacturer with modification to improve extraction efficiency and consistency. Finally, total cellular RNA, including HCV replicon RNA, was eluted and stored at -80°C until further processing.
A Taqman real-time RT-PCR quantification assay was set up with two sets of specific primers and probe. One was for HCV and the other was for BVDV. Total RNA extractants from treated HCV replicon cells was added to the PCR reactions for quantification of both HCV and BVDV RNA in the same PCR well. Experimental failure was flagged and rejected based on the level of BVDV RNA in each well . The level of HCV RNA in each well was calculated according to a standard curve run in the same PCR plate. The percentage of inhibition or decrease of HCV RNA level due to compound treatment was calculated using the DMSO or no compound control as 0% of inhibition. The IC50 (concentration at which 50% inhibition of HCV RNA level is observed) was calculated from the titration curve of any given compound.
Example 7 :
HCV Ki Assay Protocol
HPLC Microbore method for separation of 5AB substrate and products Substrate:
NH2-Glu-Asp-Val-Val- (alpha)Abu-Cys-Ser-Met-Ser-Tyr-COOH A stock solution of 20 mM 5AB (or concentration of your choice) was made in DMSO w/ 0.2M DTT. This was stored in aliquots at -20 C. Buffer: 50 mM HEPES, pH 7.8; 20% glycerol; 100 mM NaCl
Total assay volume was 100 μL
Figure imgf000139_0001
The buffer, KK4A, DTT, and tNS3 were combined; distributed 78 μL each into wells of 96 well plate. This was incubated at 30 C for -5-10 min.
2.5 μL of appropriate concentration of test compound was dissolved in DMSO (DMSO only for control) and added to each well . This was incubated at room temperature for
15 min.
Initiated reaction by addition of 20 μL of 250 μM
5AB substrate (25 μM concentration is equivalent or slightly lower than the Km for 5AB) . Incubated for 20 min at 30 C.
Terminated reaction by addition of 25 μL of 10% TFA Transferred 120 μL aliquots to HPLC vials Separated SMSY product from substrate and KK4A by the following method:
Microbore separation method:
Instrumentation: Agilent 1100
Degasser G1322A
Binary pump G1312A
Autosampler G1313A
Column thermostated chamber G1316A
Diode array detector G1315A
Column: Phenomenex Jupiter; 5 micron C18; 300 angstroms; 150x2 mm; P/O 00F-4053-B0
Column thermostat: 40 C
Injection volume: 100 μL
Solvent A = HPLC grade water + 0.1% TFA
Solvent B = HPLC grade acetonitrile + 0.1% TFA
Figure imgf000140_0001
Stop time: 17 min Post-run time: 10 min.
Table 5 below depicts Mass Spec, HPLC, Ki and IC50 data for certain compounds of the invention.
Compounds with Ki's ranging from IμM to 5μM are designated A. Compounds with Ki's ranging from lμM to 0.5μM are designated B. Compounds with Ki's below 0.5μM are designated C. Compounds with IC50's ranging from lμM to 5μM are designated A. Compounds with IC50's ranging from lμM to 0.5μM are designated B. Compounds with IC50's below 0.5uM are designated C.
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001

Claims

144-
What is claimed is
1. A compound of formula (IA)
Figure imgf000145_0001
(IA) wherein:
A, together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, SO, or S02; wherein said ring is optionally fused to a (C6-
Cl0)aryl, (C5-C10) heteroaryl, (C3-
C10) cycloalkyl, or (C3-CIO) heterocyclyl; wherein A has up to 3 substituents selected independently from J;
J is halogen, -OR', -N02, -CF3, ~OCF3, -R' , oxo,
-OR', -O-benzyl, -0-phenyl, 1,2-methylenedioxy,
-N(R')2, -SR', -SOR', -S02R', -C(0)R', -COOR' or ~C0N(R') , wherein R' is independently selected from: hydrogen,
(C1-C12) -aliphatic,
(C3-CIO) -cycloalkyl or -cycloalkenyl, 145-
[ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl-
C12) -aliphatic,
(C6-Cl0)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-CIO) -heterocyclyl,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic,
(C5-C10) -heteroaryl, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic; Rx and R3 are independently: (C1-C12) -aliphatic,
(C3-C10) -cycloalkyl or -cycloalkenyl,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl-
C12) -aliphatic,
(C6-Cl0)-aryl, (C6-Cl0)-aryl- (C1-C12) aliphatic,
(C3-CIO) -heterocyclyl,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic,
(C5-C10) -heteroaryl, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic, wherein each of R__ and R3 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and
R3 may be replaced by a heteroatom selected from 0, NH, S, SO, or S02 in a chemically stable arrangement; R2 and R4 are independently hydrogen,
(C1-C12 ) -aliphatic, (C3-C10) -cycloalkyl- (C1-C12) -aliphatic, or
(C6-C10) aryl- (C1-C12) -aliphatic, 146-
wherein each of R2 and R4 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R2 and R4 may be replaced by a heteroatom selected from O, NH, S, SO, or S02; R5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy;
W is selected from:
Figure imgf000147_0001
wherein each Rβ is independently: hydrogen,
(C1-C12) -aliphatic,
(C6-C10)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic,
(C3-C10) -cycloalkyl or -cycloalkenyl,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl-
C12) -aliphatic,
(C3-C10) -heterocyclyl,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic,
(C5-C10) heteroaryl, or
(C5-C10) heteroaryl- (C1-C12) -aliphatic, or two Rβ groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)- heterocyclic ring; ii- '-.. a ..■
Figure imgf000148_0001
j?„ „.IL "" -ft -si-
- 147-
wherein R6 is optionally substituted with up to 3 J substituents;
V is -C(0)N(R8)-, -S(0)N(R8)-, or -S (O) 2N(R8) -; wherein R8 is hydrogen or (C1-C12) -aliphatic; T is selected from:
(Cδ-ClO)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic,
(C3-CIO) -cycloalkyl or -cycloalkenyl,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl-
C12 ) -aliphatic,
(C3-CI0) -heterocyclyl ,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic,
(C5-C10)heteroaryl, or
(C5-C10) heteroaryl- (C1-C12) -aliphatic; or T is selected from:
Figure imgf000148_0002
- 148-
Figure imgf000149_0001
wherein:
Rio is: hydrogen, (C1-C12) -aliphatic,
(C6-Cl0)-aryl,
(C6-C10) -aryl- (C1-C12) aliphatic, (C3-C10) -cycloalkyl or -cycloalkenyl, [ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic,
(C3-C10) -heterocyclyl,
(C3-C10 ) -heterocyclyl- (C1-C12 ) -aliphatic, (C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic, wherein each T is optionally substituted with up to 3 J substituents;
K is a bond, (C1-C12) -aliphatic, -0-, -S-, -NR9-, -C(O)-, or -C(0)-NR9-, wherein Rg is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
A compound of formula (IB) -
Figure imgf000150_0001
149 -
Figure imgf000150_0002
wherein :
A, together with X and Y, is: a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, S, SO, or S02; wherein said ring is optionally fused to a (C6- Cl0)aryl, (C5-C10) heteroaryl, (C3- C10) cycloalkyl, or (C3-CIO) heterocyclyl; wherein A has up to 3 substituents selected independently from J and wherein the 5-membered ring to which A is fused has up to 4 substituents selected independently from J; and wherein X and Y are independently C(H) or N;
J is halogen, -OR', -OC (O)N(R' ) 2, -N02, -CN, -CF3, -OCF3, -R' , oxo, thioxo, 1,2-methylenedioxy, 1,2- ethylenedioxy, -N(R')2, -SR' , -SOR', -S02R' , -S02N(R')2, -SO3R', -C(0)R', -C(0)C(0)R', -C(O)CHC(0)R' , -C(S)R', -C(0)OR', -0C(0)R\ -C(0)N(R')2, -OC (O)N(R' ) 2. -C(S)N(R')2, - (CH2)0-2NHC(O)R' , -N (R' )N (R' ) COR' , -N(R' )N(R' )C(O)0R' , -N(R' )N(R' )CON(R' )2, -N(R')S0R', -N(R' )S02N(R' )2, -N(R' )C(O)0R' , -N (R' ) C (0) R' , -N(R' )C(S)R' , -N(R' )C(0)N(R' )2, -N(R' ) C (S)N(R' ) 2. -N(COR' )COR' , -N(0R')R', -CN, -C (=NH)N (R' ) 2, 150-
-C(0)N(OR' )R' , -C(=NOR')R', -OP (0) (OR' ) 2, -P(0) (R')2, -P(0) (OR')2, or -P(O) (H) (OR' ) ; wherein:
two R' groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or nonaromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, S, SO, or S02, wherein the ring is optionally fused to a (C6-Cl0)aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or a (C3-C10) heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J2; or
each R' is independently selected from: hydrogen- , (C1-C12) -aliphatic-,
(C3 -CIO) -cycloalkyl or -cycloalkenyl-, [ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl- C12) -aliphatic-,
(C6-Cl0)-aryl-, (C6-C10) -aryl- (C1-C12) aliphatic-,
(C3-CIO) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic-, (C5-C10) -heteroaryl-, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic-, wherein R' has up to 3 substituents selected independently from J2;
J2 is halogen, -OR', -OC (O)N(R' ) 2, -N02, -CN, -CF3, -OCF3, -R' , oxo, thioxo, 1,2-methylenedioxy, -N(R')2, -SR', -SOR', -S02R', -S02N(R')2, -SO3R' , -C(0)R',
-C(0)C(0)R', -C(0)CH2C(0)R' , -C(S)R', -C(0)0R', -OC(0)R', -C(0)N(R')2. -0C(0)N(R')2, -C(S)N(R')2, - (CH2) 0-2NHC (0) R' , - 151-
-N(R' )N(R' )COR' , -N(R' )N(R' )C(0)OR' , -N (R' )N (R' ) CON (R' ) 2 , -N(R')S02R' , -N(R' )S02N(R' )2, -N(R' ) C (O)OR' , -N(R' ) C (0) R' , -N(R' )C(S)R' , -N(R' )C(0)N(R' )2, -N(R' ) C (S)N(R' ) 2, -N(COR' )COR' , -N(OR')R' , -CN, -C (=NH) N (R* ) 2, -C(0)N(OR' )R' , -C(=NOR')R' , -OP (0) (OR ' ) 2, -P(0) (R' )2, -P(0) (OR')2, or -P(O) (H) (OR') ;
Ri and R3 are independently:
(C1-C12 ) -aliphatic- , (C3-C10) -cycloalkyl- or -cycloalkenyl-,
[ (C3-C10) -cycloalkyl- or -cycloalkenyl] - (Cl- C12) -aliphatic- ,
(C6-C10)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic- ,
(C5-C10) -heteroaryl-, or
(C5-C10) -heteroaryl- (C1-C12) -aliphatic-, wherein each of Ri and R3 is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to 3 aliphatic carbon atoms in Ri and R3 may be replaced by a heteroatom selected from 0, N, NH, S, SO, or SO2 in a chemically stable arrangement; R2 and R4 are independently: hydrogen- ,
(C1-C12) -aliphatic-,
(C3-C10 ) -cycloalkyl- (C1-C12 ) -aliphatic- , or
(C6-C10) aryl- (C1-C12) -aliphatic-, wherein each of R2 and R4 is independently and optionally substituted with up to 3 substituents independently selected from J; - ,
152-
wherein up to two aliphatic carbon atoms in R2 and R4 may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S02;
R5 is (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy;
R5. is hydrogen or (C1-C12) -aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any hydrogen or halogen atom bound to any terminal carbon atom of Rs< is optionally substituted with sulfhydryl or hydroxy;
W is:
Figure imgf000153_0001
wherein each Re is independently: hydrogen- , (C1-C12) -aliphatic-, (C6-C10)-aryl-,
(C6-C10) -aryl- (C1-C12 ) aliphatic-, (C3-C10) -cycloalkyl- or cycloalkenyl-, [ (C3-C10) -cycloalkyl- or cycloalkenyl] - (Cl- C12 ) -aliphatic- ,
(C3-C10) -heterocyclyl-,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic-, 153 -
(C5-C10) heteroaryl-, or
(C5-C10)heteroaryl- (C1-C12) -aliphatic-, or two R6 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)- heterocyclic ring; wherein R6 is optionally substituted with up to 3 J substituents; each Rι7 is independently -OR' ,- or the Rι7 groups together with the boron atom, is a (C3-CIO) -membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, O, S, SO, and S02;
V is -C(0)N(R8)-, -S(0)N(R8)-, -S(0)2N(R8)-, -OS(O)-, -OS (0)2-, -0C(0)-, or -0-; wherein R8 is hydrogen or (C1-C12) -aliphatic; T is:
(C1-C12 ) -aliphatic- ; (C6-C10)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C3-C10) -cycloalkyl or -cycloalkenyl-,
[ (C3-CIO) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic- ,
(C3 -CIO) -heterocyclyl-,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic-, (C5-C10) heteroaryl-, or
(C5-C10) heteroaryl- (C1-C12) -aliphatic-; or T is : ,
154-
Figure imgf000155_0001
Figure imgf000155_0002
155-
Figure imgf000156_0001
Figure imgf000156_0002
wherein :
Rio is : hydroge ,
(C1-C12 ) -aliphatic- , (C6-Cl0)-aryl-,
(C6-C10 ) -aryl- (C1-C12 ) aliphatic- , (C3-C10) -cycloalkyl or -cycloalkenyl-, [ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl-
C12 ) -aliphatic- , (C3-C10) -heterocyclyl-,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic-, (C5-C10) -heteroaryl-, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic-, wherein each T is optionally substituted with up to 3 J substituents; 156-
K is a bond, (C1-C12) -aliphatic, -0- , -S-, -NR9-, -C(O)-, or -C(0)-NR9-, wherein R9 is hydrogen or (C1-C12)- aliphatic; and n is 1-3.
3. The compound according to claim 1 or claim 2 , wherein A, together with X, Y and the ring containing the nitrogen atom, is :
Figure imgf000158_0001
157-
Figure imgf000158_0002
Figure imgf000159_0001
158-
Figure imgf000159_0002
Figure imgf000159_0003
- 159 -
Figure imgf000160_0001
Figure imgf000160_0002
4. The compound according to claim 1 or claim 2 , wherein A, together with X, Y and the ring containing the nitrogen atom, is:
. -
- 160-
Figure imgf000161_0001
5. The compound according to claim 4, wherein A, together with X, Y and the ring containing the nitrogen atom, is :
Figure imgf000161_0002
6. The compound according to claim 5 , wherein A, together with X, Y and the ring containing the nitrogen atom, is:
Figure imgf000161_0003
7. The compound according to any one of claims 1-6, wherein T contains at least one hydrogen bond donor moiety selected from -NH2, -NH-, -OH, and -SH. -
161-
The compound according to claim 7, wherein T is:
Figure imgf000162_0001
Figure imgf000162_0002
Figure imgf000162_0003
Figure imgf000162_0004
,-
162-
Figure imgf000163_0001
Figure imgf000163_0002
Figure imgf000163_0003
Figure imgf000163_0004
-
Figure imgf000164_0001
163-
Figure imgf000164_0002
or wherein:
T is optionally substituted with up to 3 J substituents, wherein J is as defined in claim 1;
Z is independently 0, S, NRι0, C(Rι0)2; n is independently 1 or 2 ; and
'zr z^~- is independently a single bond or a double bond.
9. The compound according to claim 8, wherein T is:
Figure imgf000164_0003
Figure imgf000164_0004
- 164-
Figure imgf000165_0001
165-
Figure imgf000166_0001
or wherein:
T is optionally substituted with up to 4 J substituents, wherein J is as defined in claim 1;
Z is independently O, S, NRχ0, C(Rι0)2, SO, S02; n is independently 1 or 2; and
=^ is independently a single bond or a double bond.
10. The compound according to claim 9, wherein T is:
166-
Figure imgf000167_0001
Figure imgf000167_0002
Figure imgf000167_0003
Figure imgf000167_0004
wherein :
T is optionally substituted with up to 4 J substituents, wherein J is as defined in claim 1; and
Z is independently O, S, NR10, C(Rι0)2, SO, S02.
11. The compound according to claim 10, wherein T - 167 -
Figure imgf000168_0001
12. The compound according to claim 11, wherein T
Figure imgf000168_0002
13. The compound according to any one of claims 1- , wherein T is :
168 -
Figure imgf000169_0001
Figure imgf000169_0002
Figure imgf000169_0003
14. The compound according to claim 13, wherein T 169-
14. The compound according to claim 13 , wherein T
Figure imgf000170_0001
15. The compound according to any one of claims 1- , wherein Ri is:
Figure imgf000170_0002
16. The compound according to any one of claims 1- , wherein R3 :
Figure imgf000170_0003
Figure imgf000171_0001
170-
17 . The compound according to any one of claims 1- 16 , wherein R5 is : nsu Ixn.
Figure imgf000171_0002
Figure imgf000171_0003
18. The compound according to claim 17, wherein R5:
Figure imgf000171_0004
19. The compound according to any one of claims 1-
18, wherein R2 and R4 are each independently H, methyl, ethyl or propyl .
20. The compound according to any one of claims 1-
19, wherein V is -C(0)N(R8)- and R8 is hydrogen.
21. The compound according to any one of claims 1- 20, wherein W is:
Figure imgf000171_0005
22. The compound according to claim 21, wherein one R6 is hydrogen and the other R6 is : (C6-Cl0)-aryl- (C1-C3 ) alkyl-, wherein the alkyl is optionally substituted with C02H, (C3-C6 ) cycloalkyl- , t - „ι- • [ .,„ ι « - .--Ji » Jr, ,„!!« ii „„ ι- ,
- 171-
(C5) -heterocylyl- (C1-C3 ) alkyl- ,
(C3-C6) alkenyl-; or each R6 is (C1-C6) -alkyl- .
22. The compound according to claim 1, wherein said compound is selected from:
Figure imgf000172_0001
Figure imgf000172_0002
3 4
Figure imgf000172_0003
o o
Figure imgf000172_0004
172-
Figure imgf000173_0001
10
Figure imgf000173_0002
11 12
Figure imgf000173_0003
13 14
Figure imgf000173_0004
15 16
Figure imgf000173_0005
17 18 173-
Figure imgf000174_0001
19 20
Figure imgf000174_0002
21 22
Figure imgf000174_0003
23 24
Figure imgf000174_0004
25 26
Figure imgf000174_0005
27 28 174-
Figure imgf000175_0001
29 30
Figure imgf000175_0002
31 32
24. The compound according to claim 1, wherein the compound is selected from compound numbers la-62a.
25. The compound according to claim 1, wherein the compound is 25a.
26. A compound of formula (II) :
Figure imgf000175_0003
(II) wherein :
Xi is -N(R2o)-. -0-, -S-, or -C(R')2-;
.
175-
X2 is -C(O)-, -C(S)-, -S(O)-, or -S(0):
Figure imgf000176_0001
Figure imgf000176_0002
Figure imgf000176_0003
- .
176-
Figure imgf000177_0001
m is 0 or 1;
each Rι7 is independently: hydrogen- ,
(C1-C12 ) -aliphatic- ,
(C3-C10) -cycloalkyl- or cycloalkenyl-,
[ (C3-C10) -cycloalkyl- or cycloalkenyl] - (Cl- C12) -aliphatic-,
(C6-Cl0)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-,
(C3-C10) -heterocyclyl-,
(C3-C10) -heterocyclyl- (C1-C12) -aliphatic-,
(C5-C10) heteroaryl-, or
(C5-C10) heteroaryl- (C1-C12) -aliphatic-, or two Rχ7 groups, which are bound to the same nitrogen atom, form together with that nitrogen atom, a (C3-C10)- membered heterocyclic ring having in addition to the nitrogen up to 2 additional heteroatoms selected from N, NH, 0, S, SO, and S02; wherein Ri7 is optionally substituted with up to 3 J substituents ;
each Ris is independently -OR' ; or the OR' groups together with the boron atom, is a (C5-C20) -membered _t
177-
heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NH, O, S, SO, and S02;
R5 and R5. are independently hydrogen or (C1-C12)- aliphatic, wherein any hydrogen is optionally replaced with halogen, and wherein any terminal carbon atom is optionally substituted with sulfhydryl or hydroxy, and wherein up to two aliphatic carbon atoms may be replaced by a heteroatom selected from N, NH, 0, S, SO, or S02; or R5 and R5. together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, 0, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J;
Ri, Ri-, Rn, Rn>, Rι3, and Ri3. are independently: hydrogen- , (C1-C12 ) -aliphatic- , (C3-CIO) -cycloalkyl or -cycloalkenyl-,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic- ,
(C6-C10)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-, (C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic, (C5-C10) -heteroaryl-, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic-, wherein each of Ri, Rι>, Rn, Rn>, Rι3, and Rι3- is independently and optionally substituted with up to 3 substituents independently selected from J; - 17 !
wherein any ring is optionally fused to a (C6- C10)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- Cl0)heterocyclyl; wherein up to 3 aliphatic carbon atoms in each of Rl Ri-, Ru, Rn-, Rχ3, and R13. may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S02 in a chemically stable arrangement; or
Ri and Ri- together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, O, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J; or
Rn and R - together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, 0, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J; or
Rι3 and Rι3. together with the atom to which they are bound is a 3- to 6-membered ring having up to 2 heteroatoms selected from N, NH, O, S, SO, or S02; wherein the ring has up to 2 substituents selected independently from J;
R2, R, R12, and R20 are independently hydrogen- ,
(C1-C12 ) -aliphatic- ,
(C3-C10) -cycloalkyl or -cycloalkenyl-,
[ (C3-C10) -cycloalkyl or -cycloalkenyl]- (Cl- C12) -aliphatic-,
(C6-Cl0)-aryl-,
(C6-C10) -aryl- (C1-C12) aliphatic-, - 179-
(C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic, (C5-C10) -heteroaryl-, or (C5-C10) -heteroaryl- (C1-C12) -aliphatic-, wherein each R2, R4, Rι2, and R2o is independently and optionally substituted with up to 3 substituents independently selected from J; wherein up to two aliphatic carbon atoms in R2, R4/ i2/ and R2o may be replaced by a heteroatom selected from 0, N, NH, S, SO, or S02; or
Rn and Rι2 together with the atoms to which they are bound form a 3- to a 20-membered mono-, a 4- to 20- membered bi-, or a 5- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- C10)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- CIO) heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or
R12 and Ri3 together with the atoms to which they are bound form a 4- to a 20-membered mono-, a 5- to 20- membered bi-, or a 6- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; - 180-
wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, and S02; wherein each ring is optionally fused to a (C6- Cl0)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- CIO)heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or
Rn and Rι3 together with the atoms to which they are bound form a 5- to a 20-membered mono-, a 6- to 20- membered bi-, or a 7- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, and S02; wherein each ring is optionally fused to a (C6-
Cl0)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10)heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or
Rii Ri2 / and Ri3 together with the atoms to which they are bound form a 5- to a 20-membered bi- , or a 6- to 181-
20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6-
Cl0)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- Cl0)heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or
Rι3> and R2 together with the atoms to which they are bound form a 3- to a 20-membered mono-, a 4- to 20- membered bi-, or a 5- to 20-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- ClO)aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or (C3- C10) heterocyclyl; and wherein said ring has up to 3 substituents selected independently from J; or ^ ,
182 -
R5 and Rχ3 together with the atoms to which they are bound form a 18- to a 23-membered mono-, a 19- to 24- membered bi-, or a 20- to 25-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- Cl0)aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or (C3- Cl0) heterocyclyl ; and wherein said ring has up to 6 substituents selected independently from J; or
Ri and R12 together with the atoms to which they are bound form a 18- to a 23-membered mono-, a 19- to 24- membered bi-, or a 20- to 25-membered tri-cyclic carbocyclic or heterocyclic ring system; wherein, in the bi- and tri-cyclic ring system, each ring is linearly fused, bridged, or spirocyclic; wherein each ring is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, 0, S, SO, and S02; wherein each ring is optionally fused to a (C6- CIO) aryl, (C5-C10)heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10)heterocyclyl; and 183-
wherein said ring has up to 6 substituents selected independently from J; or
Ri is -H, -S(0)R', -S(0)2R', -C(0)R', -C(0)OR', -C(0)N(R')2, -N(R' )C(0)R' , -N (COR' ) COR' , -S02N(R')2,
-S03R', -C(0)C(0)R', -C(0)CH2C(0)R' , -C(S)R', -C(S)N(R')2, -(CH2)o-2NHC(0)R' , -N(R' )N(R' )COR' , -N (R* )N (R' ) C (0) OR' , -N(R' )N(R' )CON(R" )2, -N(R')S02R', -N (R' ) S02N (R' ) 2, -N(R' )C(0)OR' , -N(R' )C(0)R' , -N(R' ) C (S) R' , -N(R' )C(0)N(R' )2, -N(R' )C(S)N(R' )2, -N (COR' ) COR' ,
-N(OR')R', -C(=NH)N(R' )2, -C (O)N(OR' ) R' , -C(=NOR')R', -OP(O) (OR')2, -P(0)(R')2, -P(0)(OR')2, or -P (O) (H) (OR' ) ;
R15 and Ri6 are independently halogen, -OR' , -OC(0)N(R' )2, -N02, -CN, -CF3 , -OCF3, -R' , oxo, 1,2- methylenedioxy, 1, 2 -ethylenedioxy, -N(R')2, -SR', -SOR', -S02R\ -S02N(R')2, -S03R' , -C(0)R', -C(0)C(0)R', -C(0)CH2C(0)R' , -C(S)R', -C(0)OR', -OC(0)R', -C(0)N(R') . -0C(O)N(R')2, -C(S)N(R')2, -(CH2)0-2NHC(O)R', -N(R' )N(R' )COR' , -N(R ' )N (R' ) C (O) OR ' , -N(R ' )N (R ' ) CON(R ' ) 2, -N(R')S02R', -N(R' )S02N(R" )2, -N(R* ) C (O)OR' , -N (R' ) C (O) R' , -N(R' )C(S)R' , -N(R')C(0)N(R' )2, -N(R' )C (S)N(R' ) , -N(COR' )COR' , -N(OR')R', -CN, -C (=NH) N(R' ) 2, -C(0)N(OR' )R' , -C(=NOR')R', -OP (O) (OR' ) 2, -P(0) (R')2, -P(0) (OR')2, or -P(0) (H) (OR') ;
Z2 is =0, =NR', =NOR' , or =C(R')2;
Rι9 is -OR', -CF3, -OCF3, -R', -N(R')2, -SR' , -C(0)R', -COOR' -CON(R')2, -N(R')COR' , or -N (COR' ) COR' ; - 184-
J is halogen, -OR', -OC (O)N(R' )2, -N02, -CN, -CF3, -OCF3, -R' , oxo, thioxo, 1,2-methylenedioxy, 1,2- ethylenedioxy, -N(R')2, -SR' , -SOR', -S02R', -S02N(R')2, -S03R', -C(0)R', -C(0)C(0)R', -C (0) CH2C (0) R ' , -C(S)R', -C(0)OR', -OC(0)R', -C(0)N(R')2, -OC (O)N(R' ) 2, -C(S)N(R')2, -(CH2)0-2NHC(O)R' , -N (R' )N(R ' ) COR' , -N(R' )N(R' )C(0)OR' , -N(R' )N(R' )CON(R' )2, -N(R')S02R', -N(R' )S02N(R' )2, -N(R' )C(0)OR' , -N(R ' ) C (O) R' , -N(R' )C(S)R' , -N(R' )C(0)N(R' )2, -N(R' )C (S)N(R' ) 2. -N(COR' )COR* , -N(OR')R', -CN, -C (=NH)N(R ' ) 2,
-C(0)N(OR' )R' , -C(=NOR')R', -OP (O) (OR' ) 2, -P(0)(R')2, -P(0)(OR')2, or -P(O) (H) (OR' ) ; wherein:
two R' groups together with the atoms to which they are bound form a 3- to 10-membered aromatic or nonaromatic ring having up to 3 heteroatoms independently selected from N, NH, 0, S, SO, or S02, wherein the ring is optionally fused to a (C6-C10) aryl, (C5-C10) heteroaryl, (C3-C10) cycloalkyl, or a (C3-C10) heterocyclyl, and wherein any ring has up to 3 substituents selected independently from J2; or
each R' is independently selected from: hydrogen- , (C1-C12 ) -aliphatic- ,
(C3-C10) -cycloalkyl or -cycloalkenyl-,
[ (C3-C10) -cycloalkyl or -cycloalkenyl] - (Cl- C12 ) -aliphatic- ,
(C6-Cl0)-aryl-, (C6-C10) -aryl- (C1-C12) aliphatic-,
(C3-C10) -heterocyclyl-,
(C6-C10) -heterocyclyl- (C1-C12) aliphatic-, -
- 185-
(C5-C10) -heteroaryl-, or (C5-C10) -heteroaryl- (C1-C12 ) -aliphatic- , wherein R' has up to 3 substituents selected independently from J ; and
J2 is halogen, -OR', -OC (O)N(R' ) 2, -N02, -CN, -CF3, -OCF3, -R', oxo, thioxo, 1,2-methylenedioxy, -N(R')2, -SR', -SOR', -S02R', -S02N(R')2, -S03R', -C(0)R', -C(0)C(0)R', -C(0)CH2C(0)R' , -C(S)R', -C(0)OR', -OC(0)R', -C(0)N(R')2, -0C(0)N(R')2, -C(S)N(R')2, - (CH2) 0-2NHC (O) R ' , -N(R' )N(R' )COR' , -N(R' )N(R' )C(0)OR' , -N(R' )N(R' ) CON(R' ) 2, -N(R')S02R\ -N(R' )S02N(R' )2, -N(R' ) C (O) OR ' , -N(R' )C (O)R' , -N(R' )C(S)R' , -N(R' )C(0)N(R' )2, -N (R ' ) C (S) N (R' ) 2, -N(COR' )COR' , -N(OR')R', -CN, -C (=NH) N (R' ) 2, -C(0)N(OR' )R' , -C(=NOR')R", -OP (0) (OR' ) 2, -P(0)(R')2, -P(O) (OR' )2, or -P(O) (H) (OR' ) .
27. The compound according to claim 26, wherein:
Rn is H; and R12 is
(C1-C6) -alkyl,
(C3 -CIO ) -cycloalkyl ,
[ (C3-C10) -cycloalkyl] -(C1-C12) -alkyl,
(C6-Cl0)-aryl, (C6-C10) -aryl- (C1-C6) alkyl,
(C3 -CI0 ) -heterocyclyl ,
(C6-C10 ) -heterocyclyl- (C1-C6 ) alkyl ,
(C5-C10) -heteroaryl, or
(C5-C10) -heteroaryl- (C1-C6) -alkyl. - 186-
28. The compound according to claim 27, wherein R12 is isobutyl, cyclohexyl, cyclohexylmethyl, benzyl, or phenylethyl .
29. The compound according to claim 26, wherein: Rn is :
(C1-C6) -alkyl,
(C3-CIO) -cycloalkyl,
[ (C3-C10) -cycloalkyl]- (C1-C12) -alkyl,
(C6-C10)-aryl,
(C6-C10) -aryl- (C1-C6) alkyl ;
(C3-CI0) -heterocyclyl,
(C6-C10) -heterocyclyl- (C1-C6) alkyl ,
(C5-CI0) -heteroaryl , or
(C5-C10) -heteroaryl- (C1-C6) -alkyl; and R12 is H.
30. The compound according to claim 26, wherein the
Figure imgf000187_0001
radical is :
Figure imgf000187_0002
■ - --■• ∞--- ■ --_, _■■-, -t
- 187-
31. The compound according to claim 30, wherein the
Figure imgf000188_0001
radical is :
Figure imgf000188_0002
32. The compound according to claim 26, wherein the
Figure imgf000188_0003
radical is :
Figure imgf000189_0001
_, .
- Ii
Figure imgf000189_0002
Figure imgf000189_0003
wherein each B independently forms a 3- to a 20- membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, 0, S, SO, or S02; wherein each ring is optionally fused to a (C6- Cl0)aryl, (C5-C10) heteroaryl, (C3-CIO) cycloalkyl, or (C3- C10) eterocyclyl; and wherein each ring has up to 3 substituents selected independently from J.
33. The compound according to claim 32, wherein the
Figure imgf000189_0004
radical is: - ..
- 189-
Figure imgf000190_0001
34. The compound according to claim 32, wherein the
Figure imgf000190_0002
radical is:
- 190-
Figure imgf000191_0001
35. The compound according to claim 32, wherein the
Figure imgf000191_0002
radical is :
Figure imgf000192_0001
- 191-
Figure imgf000192_0002
36. The compound according to claim 32, wherein the
Figure imgf000192_0003
radical is _
192-
Figure imgf000193_0001
37. The compound according to claim 32, wherein the
Figure imgf000193_0002
radical is
- 193-
Figure imgf000194_0001
38. The compound according to claim 26, wherein the
Figure imgf000194_0002
radical is: wherein each B independently forms a 3- to a 20- membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, 0, S, SO, or S02; wherein each ring is optionally fused to a (C6- Cl0)aryl, (C5-C10)heteroaryl, (C3-C10) cycloalkyl, or (C3- Cl0 ) heterocyclyl ; and wherein each ring has up to 3 substituents selected independently from J. 194-
39. The compound according to claim 38, wherein the
Figure imgf000195_0001
s :
Figure imgf000195_0002
,
- 195-
Figure imgf000196_0001
196-
40. The compound according to claim 38, wherein the
Figure imgf000197_0001
radical is :
Figure imgf000197_0002
,
- 197 -
Figure imgf000198_0001
Figure imgf000198_0002
41. The compound according to claim 26, wherein the
Figure imgf000198_0003
radical is :
- 198-
Figure imgf000199_0001
42. The compound according to claim 26, wherein the
dical is :
Figure imgf000199_0002
wherein B forms a 3- to a 20-membered carbocyclic or heterocyclic ring system; wherein each ring B is either aromatic or nonaromatic; wherein each heteroatom in the heterocyclic ring system is N, NH, 0, S, SO, or S02;
Figure imgf000200_0001
_
- 199-
wherein each ring is optionally fused to a (C6- C10)aryl, (C5-CIO) eteroaryl, (C3-CIO) cycloalkyl, or (C3- Cl0) heterocyclyl ; and wherein each ring has up to 3 substituents selected independently from J.
43. The compound according to claim 42 , wherein the
Figure imgf000200_0002
radical is
■
Figure imgf000200_0003
44. The compound according to claim 26, wherein Rn and R12 together with the atoms to which they are bound form a 6- to 10-membered mono- or bicyclic carbocyclic or heterocyclic ring system; - 200-
wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, and S02; and wherein said ring has up to 3 substituents selected independently from J.
45. The compound according to any one of claims 1- 44, wherein R5. is H and R5 is (C1-C6) -alkyl, wherein the alkyl is optionally substituted with fluoro or -SH.
46. The compound according to claim 45, wherein the (C1-C6) -alkyl is substituted with 1 to 3 fluoro groups.
47. The compound according to claim 46, wherein R5 and R5. are independently:
Figure imgf000201_0001
48 . The compound according to any one of claims 26- 47 , wherein R13 is :
(C1-C6 ) -alkyl ,
(C3-C10) -cycloalkyl,
[ (C3-CIO) -cycloalkyl] - (C1-C12 ) -alkyl,
(Cδ-ClO)-aryl, (C6-C10) -aryl- (C1-C6) alkyl,
(C3-CIO) -heterocyclyl,
(C6-C10) -heterocyclyl- (C1-C6) alkyl,
(C5-C10) -heteroaryl, or ,
- 201-
(C5-CIO) -heteroaryl-(Cl-C6) -alkyl; wherein Ri3 is optionally substituted with up to 3 substituents independently selected from J; and wherein up to 3 aliphatic carbon atoms in Rχ3 may be replaced by a heteroatom selected from O, NH, S, SO, or S02 in a chemically stable arrangement.
49. The compound according to claim 48, wherein Ri3
Figure imgf000202_0001
50. The compound according to any one of claims 26- 49, wherein Ri is (C1-C6) -alkyl,
(C3-CIO) -cycloalkyl,
[ (C3-C10) -cycloalkyl]- (C1-C12) -alkyl, (C6-Cl0)-aryl, (C6-C10)-aryl- (C1-C6) alkyl, (C3-CIO) -heterocyclyl,
(C6-C10) -heterocyclyl- (C1-C6) alkyl, (C5-CIO) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C6) -alkyl; wherein Ri is optionally substituted with up to 3 substituents independently selected from J; and - 202-
wherein up to 3 aliphatic carbon atoms in Ri may be replaced by a heteroatom selected from 0, NH, S, SO, or S02 in a chemically stable arrangement.
51. The compound according to claim 36, wherein Ri is :
Figure imgf000203_0001
52. The compound according to any one of claims 26- 51, wherein W is:
Figure imgf000203_0002
Figure imgf000203_0003
- 203-
Figure imgf000204_0001
53 The compound according to claim 52, wherein W s
Figure imgf000204_0002
54. The compound according to any one of claims 26- 3, wherein R2, R4, and R20 are each independently H or (C1-C3) -alkyl.
Figure imgf000205_0001
- 204-
55. The compound according to claim 54, wherein R2, R4, and R2o are each H.
56. The compound according to any one of claims 26-
55, wherein Rι4 is hydrogen.
57. The compound according to any one of claims 26-
56, wherein each R15 and Ri6 is independently (C1-C6)- alkyl-.
58. The compound according to claim 57, wherein each R15 and Ri6 are each methyl .
59. The compound according to any one of claims 26- 58, wherein Z2 is 0 and Rι9 is:
(Cl-C6)-alkyl- (C3-C10) -cycloalkyl-,
[ (C3-C10) -cycloalkyl]- (C1-C12) -aliphatic-, (C6-C10)-aryl-, (C6-C10) -aryl- (C1-C6) alkyl,
(C3-C10) -heterocyclyl, (C6-C10) -heterocyclyl- (C1-C6) alkyl, (C5-C10) -heteroaryl, or (C5-C10) -heteroaryl- (C1-C6) -alkyl; wherein Rι9 has up to 3 substituents selected independently from J2; and wherein up to 3 aliphatic carbon atoms in Rι9 may be replaced by a heteroatom selected from O, NH, S, SO, or S02 in a chemically stable arrangement.
60. The compound according to claim 59, wherein each R19 is methyl . 205-
61. The compound according to any one of claims 26- , wherein Rχ4 is H; Z2 is CH2; and Ri9 is:
Figure imgf000206_0001
62. The compound according to any one of claims 26- , wherein each R19 is methyl; Z2 is 0; Rι4 is:
Figure imgf000206_0002
Figure imgf000207_0001
63. The compound according to any one of claims 26- 58, wherein each Ri9 is methyl; R14 is H; and Z2 is:
Figure imgf000207_0002
64. The compound according to claim 63 , wherein Z2
Figure imgf000207_0003
- 207-
65. The compound according to claim 26, wherein the compound is 63-67 or 68.
66. A composition comprising a compound according to any one of claims 1-65 or a pharmaceutically acceptable salt, derivative or prodrug thereof in an amount effective to inhibit a serine protease; and a acceptable carrier, adjuvant or vehicle.
67. The composition according to claim 66, wherein said composition is formulated for administration to a patient.
68. The composition according to claim 67, wherein said composition comprises an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target in the HCV life cycle; or combinations thereof.
69. The composition according to claim 68, wherein said immunomodulatory agent is oc—, β—, or γ-interferon or thymosin; the antiviral agent is ribavirin, amantadine, or telbivudine; or the inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
70. A method of inhibiting the activity of a serine protease comprising the step of contacting said serine protease with a compound according to any one of claims 1-65.
71. The method according to claim 70, wherein said protease is an HCV NS3 protease.
72. A method of treating an HCV infection in a patient comprising the step of administering to said patient a composition according to claim 67.
73. The method according to claim 72, comprising the additional step of administering to said patient an additional agent selected from an immunomodulatory agent; an antiviral agent; a second inhibitor of HCV protease; an inhibitor of another target' in the HCV life cycle; or combinations thereof; wherein said additional agent is administered to said patient as part of said composition according to claim 30 or as a separate dosage form.
74. The method according to claim 73, wherein said immunomodulatory agent is oc—, β~, or γ-interferon or thymosin; said antiviral agent is ribavarin, amantadine or telbivudine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
75. A method of eliminating or reducing HCV contamination of a biological sample or medical or laboratory equipment, comprising the step of contacting said biological sample or medical or laboratory equipment with a composition according to claim 66.
76. The method according to claim 75, wherein said sample or equipment is selected from blood, other body fluids, biological tissue, a surgical instrument, a - 209-
surgical garment, a laboratory instrument, a laboratory garment, a blood or other body fluid collection apparatus; a blood or other bodily fluid storage material .
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