US2005119189A1PendingUtilityA1
Inhibitors of serine proteases, particularly HCV NS3-NS4A protease
Priority: Sep 18, 2003Filed: Sep 17, 2004Published: Jun 2, 2005
Est. expirySep 18, 2023(expired)· nominal 20-yr term from priority
A61P 31/14A61P 31/12A61P 43/00C07K 5/10A61P 1/16C07K 7/06
56
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Claims
Abstract
The present invention relates to compounds of formula I: or a pharmaceutically acceptable salts thereof 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 useful as antiviral agents. The invention further relates to pharmaceutically acceptable compositions comprising said compounds either for ex vivo use or for administration to a patient suffering from HCV infection and to processes for preparing the compounds. The invention also relates to methods of treating an HCV infection in a patient by administering a pharmaceutical composition comprising a compound of this invention.
Claims
exact text as granted — not AI-modified1 . A compound of formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
R 9 and R 9′ are independently:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to three aliphatic carbon atoms in each of R 9 and R 9′ may be replaced by O, N, NH, S, SO, or SO 2 ;
wherein each of R 9 and R 9′ is independently and optionally substituted with up to 3 substituents independently selected from J;
J is halogen, —OR′, —NO 2 , —CN, —CF 3 , —OCF 3 , —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′) 2 , —SR′, —SOR′, —SO 2 R′, —SO 2 N(R′) 2 , —SO 3 R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′) 2 , —C(O)CH 2 C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —C(S)N(R′) 2 , —(CH 2 ) 0-2 NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′) 2 , —N(R′)SO 2 R′, —N(R′)SO 2 N(R′) 2 , —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)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(O)(R′) 2 , —P(O)(OR′) 2 , or —P(O)(H)(OR′); wherein;
R′ is independently selected from:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 5 atoms in R′ are optionally and independently substituted with J;
wherein two R′ groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J;
R 10 , R 10′ , R 11 , and R 11′ are each independently:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
wherein up to 3 aliphatic carbon atoms in each of R 10 , R 10′ , R 11 , and R 11′ may be replaced by a heteroatom selected from O, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 10 , R 10′ , R 11 , and R 11′ is independently and optionally substituted with up to 3 substituents independently selected from J; or
R 10 is —OR′ and R 10′ is H; or
R 10 and R 10′ are both —OR′ or —SR′; or
R 10 and R 10′ are both fluorine; or
R 10 and R 10′ are taken together with the carbon atom to which they are bound to form a 5- to 7-membered saturated or partially unsaturated ring;
wherein the R 10 and R 10′ atoms bound to the carbon atom are independently C(H), N, NH, O, S, SO, or SO 2 ;
wherein said ring may contain up to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 ;
wherein any atom is optionally singly or multiply substituted with up to 2 substituents selected independently from J; and
wherein said ring is optionally fused to a second ring selected from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a (C3-C10)heterocyclyl, wherein said second ring has up to 3 substituents selected independently from J; or
R 9 and R 10 are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or
R 10 and R 11 are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or
R 9 and R 11 are taken together with the ring atoms to which they are bound to form a bridged bicyclic saturated or partially unsaturated carbocyclic or heterocyclic ring system containing up to 10 atoms; wherein said ring system is optionally substituted with up to 3 substituents selected independently from J; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, or SO 2 ;
R 1 and R 3 are independently:
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
[(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)aliphatic-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 3 aliphatic carbon atoms in each of R 1 and R 3 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 1 and R 3 is independently and optionally substituted with up to 3 substituents independently selected from J;
R 2 , R 4 , and R 7 are each independently:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or
(C6-C10)-aryl-(C1-C12)-aliphatic-;
wherein up to two aliphatic carbon atoms in each of R 2 , R 4 , and R 7 may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2 in a chemically stable arrangement;
wherein each of R 2 , R 4 , and R 7 is optionally substituted with up to 3 substituents independently selected from J;
R 5 and R 5′ are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R 5 is optionally substituted with sulfhydryl or hydroxy; or
R 5 is Ph or —CH 2 Ph and R 5′ is H, wherein said Ph or —CH 2 Ph group is optionally substituted with up to 3 substituents independently selected from J; or
R 5 and R 5′ together with the atom to which they are bound optionally form a 3- to 6-membered saturated or partially unsaturated ring having up to 2 heteroatoms selected from N, NH, O, SO, and SO 2 ; wherein said ring is optionally substituted with up to 2 substituents selected independently from J;
W is:
wherein each R 6 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]-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-,
wherein R 6 is optionally substituted with up to 3 J substituents; or
two R 6 groups, together with the nitrogen atom to which they are bound, optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; wherein each R 8 is independently —OR′; or the R 8 groups together with the boron atom, optionally form a (C3-C10)-membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NR′, O, SO, and SO 2 ;
X is —C(O)—, —S(O)—, or —S(O) 2 —,
V is —C(O)—, —S(O)—, —S(O) 2 —, or —N(R 13 )—;
wherein R 13 is:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to two aliphatic carbon atoms in R 13 may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2 in a chemically stable arrangement;
wherein R 13 is independently and optionally substituted with up to 3 substituents independently selected from J;
R 12 and R 12′ are independently:
hydrogen;
(C1-C12)-aliphatic-;
(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-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 3 aliphatic carbon atoms in each of R 12 or R 12′ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 12 or R 12′ is optionally substituted with up to 3 substituents independently selected from J; or
R 12 and R 12′ together with the nitrogen atom to which they are bound, form a (C3-C10)-heterocyclic ring;
wherein said (C3-C10)-heterocyclic ring is optionally substituted with up to 3 substituents independently selected from J.
2 . A compound of formula I-1:
or a pharmaceutically acceptable salt thereof,
wherein:
z is 0 or 1;
R 9 and R 9′ are independently:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to three aliphatic carbon atoms in each of R 9 and R 9′ may be replaced by O, N, NH, S, SO, or SO 2 ;
wherein each of R 9 and R 9′ is independently and optionally substituted with up to 3 substituents independently selected from J;
J is halogen, —OR′, —NO 2 , —CN, —CF 3 , —OCF 3 , —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′) 2 , —SR′, —SOR′, —SO 2 R′, —SO 2 N(R′) 2 , —SO 3 R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′) 2 , —C(O)CH 2 C(O)R′, —C(S)R′, —C(S)OR′, —C(O)OR′, —OC(O)R′, —C(O)N(R′) 2 , —OC(O)N(R′) 2 , —C(S)N(R′) 2 , —(CH 2 ) 0-2 NHC(O)R′, —N(R′)N(R′)COR′, —N(R′)N(R′)C(O)OR′, —N(R′)N(R′)CON(R′) 2 , —N(R′)SO 2 R′, —N(R′)SO 2 N(R′) 2 , —N(R′)C(O)OR′, —N(R′)C(O)R′, —N(R′)C(S)R′, —N(R′)C(O)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(O)(R′) 2 , —P(O)(OR′) 2 , or —P(O)(H)(OR′); wherein;
R′ is independently selected from:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 5 atoms in R′ are optionally and independently substituted with J;
wherein two R′ groups bound to the same atom optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J;
R 10 , R 10′ , R 11 , and R 11′ are each independently:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
wherein up to 3 aliphatic carbon atoms in each of R 10 , R 10′ , R 11 , and R 11′ may be replaced by a heteroatom selected from O, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 10 , R 10′ , R 11 , and R 11′ is independently and optionally substituted with up to 3 substituents independently selected from J; or
R 10 is —OR′ and R 10′ is H; or
R 10 and R 10′ are both —OR′ or —SR′; or
R 10 and R 10′ are both fluorine; or
R 10 and R 10′ are taken together with the carbon atom to which they are bound to form a 5- to 7-membered saturated or partially unsaturated ring;
wherein the R 10 and R 10′ atoms bound to the carbon atom are independently C(H), N, NH, O, S, SO, or SO 2 ;
wherein said ring may contain up to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 ;
wherein any atom is optionally singly or multiply substituted with up to 2 substituents selected independently from J; and
wherein said ring is optionally fused to a second ring selected from (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, and a (C3-C10)heterocyclyl, wherein said second ring has up to 3 substituents selected independently from J; or
R 9 and R 10 are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or
R 10 and R 11 are taken together with the ring atoms to which they are bound to form a 3- to 6-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, or SO 2 ; wherein said ring is optionally substituted with up to 3 substituents selected independently from J; or
R 9 and R 11 are taken together with the ring atoms to which they are bound to form a bridged bicyclic saturated or partially unsaturated carbocyclic or heterocyclic ring system containing up to 10 atoms; wherein said ring system is optionally substituted with up to 3 substituents selected independently from J; wherein each heteroatom in the heterocyclic ring system is selected from the group consisting of N, NH, O, S, SO, or SO 2 ;
R 1 (if present) and R 3 are independently:
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
[(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)aliphatic-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 3 aliphatic carbon atoms in each of R 1 (if present) and R 3 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 1 (if present) and R 3 is independently and optionally substituted with up to 3 substituents independently selected from J;
R 2 , R 4 , and R 7 (if present) are each independently:
hydrogen-,
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl-(C1-C12)-aliphatic-, or
(C6-C10)-aryl-(C1-C12)-aliphatic-;
wherein up to two aliphatic carbon atoms in each of R 2 , R 4 , and R 7 (if present) may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2 in a chemically stable arrangement;
wherein each of R 2 , R 4 , and R 7 (if present) is optionally substituted with up to 3 substituents independently selected from J;
R 5 and R 5′ are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen; wherein any terminal carbon atom of R 5 is optionally substituted with sulfhydryl or hydroxy; or R 5 is Ph or —CH 2 Ph and R 5′ is H, wherein said Ph or —CH 2 Ph group is optionally substituted with up to 3 substituents independently selected from J; or
R 5 and R 5′ together with the atom to which they are bound optionally form a 3- to 6-membered saturated or partially unsaturated ring having up to 2 heteroatoms selected from N, NH, O, SO, and SO 2 ; wherein said ring is optionally substituted with up to 2 substituents selected independently from J;
W is:
wherein Y is —CO 2 H, a derivative of —CO 2 H, or a bioisostere of —CO 2 H; each R 6 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]-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-,
wherein R 6 is optionally substituted with up to 3 J substituents; or
two R 6 groups, together with the nitrogen atom to which they are bound, optionally form a 3- to 10-membered aromatic or non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, S, SO, and SO 2 , wherein said ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or a (C3-C10)heterocyclyl, wherein any ring has up to 3 substituents selected independently from J; wherein each R 8 is independently —OR′; or the R 8 groups together with the boron atom, optionally form a (C3-C10)-membered heterocyclic ring having in addition to the boron up to 3 additional heteroatoms selected from N, NR′, O, SO, and SO 2 ;
X is —C(O)—, —S(O)—, or —S(O) 2 —,
V is —C(O)-*, —S(O)—, —S(O) 2 —, or —N(R 13 )—;
wherein R 13 is:
hydrogen-,
(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-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to two aliphatic carbon atoms in R 13 may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO 2 in a chemically stable arrangement;
wherein R 13 is independently and optionally substituted with up to 3 substituents independently selected from J;
R 12 and R 12 , are independently:
hydrogen;
(C1-C12)-aliphatic-;
(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-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 3 aliphatic carbon atoms in each of R 12 or R 12′ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 12 or R 12′ is optionally substituted with up to 3 substituents independently selected from J; or
R 12 and R 12′ together with the nitrogen atom to which they are bound, form a (C3-C10)-heterocyclic ring;
wherein said (C3-C10)-heterocyclic ring is optionally substituted with up to 3 substituents independently selected from J; and
R 14 and R 15 are independently:
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
[(C3-C10)-cycloalkyl- or -cycloalkenyl]-(C1-C12)-aliphatic-,
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C5-C10)-heteroaryl-(C1-C12)aliphatic-,
wherein up to 3 aliphatic carbon atoms in R 14 and R 15 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement;
wherein each of R 14 and R 15 is independently and optionally substituted at each substitutable position with up to 3 substituents independently selected from J.
3 . The compound according to claim 1 or claim 2 , wherein the
radical is:
wherein:
R 12 , R 12′ , and R 13 are as defined in claim 1 or claim 2 .
4 . The compound according to claim 3 , wherein the in the
radical;
R 12′ is hydrogen;
R 12 is:
(C1-C12)-aliphatic-;
(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-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 3 aliphatic carbon atoms in R 12 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement; and
wherein R 12 is optionally substituted with up to 3 substituents independently selected from J; and
R 13 is as defined in claim 1 or claim 2 .
5 . The compound according to claim 4 , wherein;
R 12 is: (C1-C12)-aliphatic-; (C6-C10)-aryl-(C1-C12)aliphatic-, or (C3-C10)-cycloalkyl or -cycloalkenyl-;
wherein up to 3 aliphatic carbon atoms in R 12 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement; and
wherein R 12 is optionally substituted with up to 3 substituents independently selected from J; and
R 13 is as defined in claim 1 or claim 2 .
6 . The compound according to claim 5 , wherein the radical is:
7 . The compound according to claim 6 , wherein the
radical is:
8 . The compound according to claim 1 or claim 2 , wherein the
radical is:
wherein:
R 12 , R 12′ , and R 13 are as defined in claim 1 or claim 2 .
9 . The compound according to claim 8 , wherein:
R 12′ is hydrogen; and R 12 is: (C1-C12)-aliphatic-; (C6-C10)-aryl-(C1-C12)aliphatic-, or (C3-C10)-cycloalkyl or -cycloalkenyl-;
wherein up to 3 aliphatic carbon atoms in R 12 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO 2 in a chemically stable arrangement; and
wherein R 12 is optionally substituted with up to 3 substituents independently selected from J.
10 . The compound according to any one of claims 1 - 9 , wherein the
radical is:
wherein:
n is 0, 1, or 2;
Z and Z′ are independently C(H), N, NH, O, or S;
R 9 , R 9′ , R 11 , and R 11′ are as defined in claim 1; and
the spirocyclic ring containing Z and Z′ is optionally substituted with up to 3 J substituents, wherein J is as defined in claim 1 .
11 . The compound according to claim 10 , wherein the radical is:
wherein:
R 9 , R 9′ , R 11 , and R 11′ are H; and
n is 0, 1, or 2.
12 . The compound according to claim 11 , wherein the
radical is:
wherein:
n is 0 or 1.
13 . The compound according to any one of claims 1 - 9 , wherein the
radical is:
wherein:
R′ is:
(C6-C10)-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-;
wherein up to 5 atoms in R′ are optionally and independently substituted with J; and
R 9 , R 9′ , R 10′ , R 11 , and R 11′ are as defined in claim 1 .
14 . The compound according to claim 13 , wherein the
radical is:
wherein the R′ ring is optionally substituted with up to 5 substituents independently selected from J.
15 . The compound according to claim 14 , wherein the radical is:
16 . The compound according to any one of claims 1 - 9 , wherein the
radical is:
wherein:
R′ is selected from:
(C6-C10)-aryl-(C1-C12) aliphatic-,
(C3-C10)-heterocyclyl-(C1-C12)aliphatic-, and
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 5 atoms in R′ are optionally and independently substituted with J; and
R 9 , R 9′ , R 10′ , R 11 , and R 11′ are as defined in claim 1 .
17 . The compound according to claim 16 , wherein the
radical is:
wherein up to 5 atoms in R′ are optionally and independently substituted with J.
18 . The compound according to anyone of claims 1 - 9 , wherein in the
radical;
R 9 , R 10 , R 10′ , R 11 , and R 11′ are as defined in claim 1; and
R 9′ is:
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
(C6-C10)-aryl-,
(C3-C10)-heterocyclyl-, or
(C5-C10)-heteroaryl-;
wherein up to three aliphatic carbon atoms in R 9′ may be replaced by O, N, NH, S, SO, or SO 2 ; and
wherein R 9′ is independently and optionally substituted with up to 3 substituents independently selected from J.
19 . The compound according to claim 18 , wherein the radical is:
wherein R 9′ is independently and optionally substituted with up to 3 substituents independently selected from J.
20 . The compound according to any one of claims 1 - 9 , wherein in the
radical;
R 9 , R 9′ , R 10 , R 11 , and R 11′ are H; and
R 10′ is:
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
(C6-C10)-aryl-,
wherein any ring is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
wherein up to 3 aliphatic carbon atoms in R 10′ may be replaced by a heteroatom selected from O, NH, S, SO, or SO 2 in a chemically stable arrangement; and
wherein R 10′ , is independently and optionally substituted with up to 3 substituents independently selected from J.
21 . The compound according to claim 20 , wherein the radical is:
wherein the R 10′ group, is independently and optionally substituted with up to 3 substituents independently selected from J.
22 . The compound according to any one of claims 1 - 9 , wherein in the
radical,
R 9 , R 10 , R 11 , and R 11′ are H; and
R 9′ and R 10′ are:
(C1-C12)-aliphatic-,
(C3-C10)-cycloalkyl- or -cycloalkenyl-,
wherein up to 3 aliphatic carbon atoms in R 9′ and R 10′ may be replaced by a heteroatom selected from O, NH, S, SO, or SO 2 in a chemically stable arrangement; and
wherein R 9′ and R 10′ are independently and optionally substituted with up to 3 substituents independently selected from J.
23 . The compound according to claim 22 , wherein the radical is:
24 . The compound according to any one of claims 1 - 9 , wherein the
radical is:
wherein;
ring A is a 5- to 6-membered aromatic or a 3- to 6-membered non-aromatic ring having up to 3 heteroatoms independently selected from N, NH, O, SO, or SO 2 ;
wherein said ring A is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
wherein any ring has up to 3 substituents selected independently from J; and
R 9 , R 9′ , R 10′ , and R 11′ are as defined in claim 1 .
25 . The compound according to claim 24 , wherein the radical is:
wherein any ring has up to 3 substituents selected independently from J.
26 . The compound according to claim 25 , wherein the radical is:
wherein any ring has up to 3 substituents selected independently from J.
27 . The compound according to claim 26 , wherein the radical is:
28 . The compound according to any one of claims 1 - 9 , wherein the
radical is:
wherein:
ring 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, SO, or SO 2 ;
wherein ring B is optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
wherein each ring has up to 3 substituents selected independently from J; and
R 9′ and R 11′ are as defined in claim 1 .
29 . The compound according to claim 28 , wherein the
radical is:
30 . The compound according to any one of claims 1 - 29 , wherein W is:
wherein in the W, the NR 6 R 6 is selected from —NH—(C1-C6 aliphatic), —NH—(C3-C6 cycloalkyl), —NH—CH(CH 3 )-aryl, or —NH—CH(CH 3 )-heteroaryl, wherein said aryl or said heteroaryl is optionally substituted with up to 3 halogens.
31 . The compound according to claim 30 , wherein in the W, the NR 6 R 6 is:
32 . The compound according to claim 31 , wherein in the W, the NR 6 R 6 is:
33 . The compound according to claim 32 , wherein in the W, the NR 6 R 6 is:
34 . The compound according to claim 33 , wherein in the W, the NR 6 R 6 is:
35 . The compound according to any one of claims 1 - 34 , wherein R 5′ is hydrogen and R 5 is:
36 . The compound according to claim 35 , wherein R 5′ is hydrogen and R 5 is:
37 . The compound according to any one of claims 1 - 36 , wherein R 2 , R 4 , R 7 , and R 12′ , if present, are each independently H, methyl, ethyl, or propyl.
38 . The compound according to claim 37 , wherein R 2 , R 4 , R 7 , and R 12′ , if present, are each H.
39 . The compound according to any one of claims 1 - 38 , wherein R 3 is:
40 . The compound according to claim 39 , wherein R 3 is:
41 . The compound according to claim 40 , wherein R 3 is:
42 . The compound according to any one of claims 1 - 41 , wherein R 1 , if present, is:
43 . The compound according to claim 42 , wherein R 1 , if present, is:
44 . The compound according to claim 43 , wherein R 1 , if present, is cyclohexyl.
45 . The compound according to claim 1 , wherein the compound is:
46 . A pharmaceutical composition comprising a compound according to any one of claims 1 - 45 , or a pharmaceutically acceptable salt thereof in an amount effective to inhibit a serine protease; and a acceptable carrier, adjuvant or vehicle.
47 . The composition according to claim 46 , wherein said composition is formulated for administration to a patient.
48 . The composition according to claim 47 , 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; and a cytochrome P-450 inhibitor; or combinations thereof.
49 . The composition according to claim 48 , wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; said antiviral agent is ribavirin, amantadine, or telbivudine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
50 . The composition according to claim 48 , wherein said cytochrome P-450 inhibitor is ritonavir.
51 . 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 - 45 .
52 . The method according to claim 51 , wherein said protease is an HCV NS3 protease.
53 . A method of treating an HCV infection in a patient comprising the step of administering to said patient a composition according to claim 47 .
54 . The method according to claim 53 , comprising 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 47 or as a separate dosage form.
55 . The method according to claim 54 , wherein said immunomodulatory agent is α-, β-, or γ-interferon or thymosin; said antiviral agent is ribavarin or amantadine; or said inhibitor of another target in the HCV life cycle is an inhibitor of HCV helicase, polymerase, or metalloprotease.
56 . 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 46 .
57 . The method according to claim 56 , wherein said sample or equipment is selected from blood, other body fluids, biological tissue, a surgical instrument, a surgical garment, a laboratory instrument, a laboratory garment, a blood or other body fluid collection apparatus; a blood or other body fluid storage material.
58 . The method according to claim 57 , wherein said body fluid is blood.
59 . A process for preparing a compound of formula I, as defined in claim 1 , or a compound of formula I-1 as defined in claim 2 , comprising the step of: reacting a compound of formula VII in the presence of a compound of formula VIII to provide a compound of formula IX:
wherein:
R 17 is an amine protecting group, a P3-residue of an HCV protease inhibitor described herein, or a P4-P3-residue of an HCV protease inhibitor as described herein, and wherein the P3 and the P4-P3 residues are optionally substituted with an amino-terminal capping group;
R 17 is a carboxy protecting group or a P1 residue of an HCV protease inhibitor described herein, wherein the P1 residue is optionally substituted with a carboxy terminal protecting group or with W; R′ is as defined in claim 1;
and X is an appropriate leaving group.Join the waitlist — get patent alerts
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