US 2009/0291902 A1 · INHIBITORS OF SERINE PROTEASES, PARTICULARLY HCV NS3-NS4A PROTEASE

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.

A compound of formula I:

or a pharmaceutically acceptable salt thereof,
wherein:
R9 and R9′ 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 R9 and R9′ may be replaced by O, N, NH, S, SO, or SO2;
wherein each of R9 and R9′ is independently and optionally substituted with up to 3 substituents independently selected from J;
J is halogen, —OR′, —NO2, —CN, —CF3, —OCF3, —R′, oxo, thioxo, ═N(R′), ═N(OR′), 1,2-methylenedioxy, 1,2-ethylenedioxy, —N(R′)2, —SR′, —SOR′, —SO2R′, —SO2N(R′)2, —SO3R′, —C(O)R′, —C(O)C(O)R′, —C(O)C(O)OR′, —C(O)C(O)N(R′)2, —C(O)CH2C(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, —(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′)SO2R′, —N(R′)SO2N(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 SO2, 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;
R10, R10′, R11, and R11′ 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 R10, R10′, R11, and R11′ may be replaced by a heteroatom selected from O, NH, S, SO, or SO2 in a chemically stable arrangement;
wherein each of R10, R10′, R11, and R11′ is independently and optionally substituted with up to 3 substituents independently selected from J;
or
R10 is —OR′ and R10′ is H;
or
R10 and R10′ are both —OR′ or —SR′;
or
R10 and R10′ are both fluorine;
or
R10 and R10′ 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 R10 and R10′ atoms bound to the carbon atom are independently C(H), N, NH, O, S, SO, or SO2;
wherein said ring may contain up to 4 heteroatoms independently selected from N, NH, O, S, SO, and SO2;
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
R9 and R10 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 SO2;
wherein said ring is optionally substituted with up to 3 substituents selected independently from J;
or
R10 and R11 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 SO2;
wherein said ring is optionally substituted with up to 3 substituents selected independently from J;
or
R9 and R11 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 SO2;
R1 and R3 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 R1 and R3 may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO2 in a chemically stable arrangement;
wherein each of R1 and R3 is independently and optionally substituted with up to 3 substituents independently selected from J;
R2, R4, and R7 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 R2, R4, and R7 may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO2 in a chemically stable arrangement;
wherein each of R2, R4, and R7 is optionally substituted with up to 3 substituents independently selected from J;
R5 and R5′ are independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen is optionally replaced with halogen;
wherein any terminal carbon atom of R5 is optionally substituted with sulfhydryl or hydroxy;
or
R5 is Ph or —CH2Ph and R5′ is H, wherein said Ph or —CH2Ph group is optionally substituted with up to 3 substituents independently selected from J;
or
R5 and R5′ 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 SO2;
wherein said ring is optionally substituted with up to 2 substituents selected independently from J;
W is:
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]-(C1-C12)-aliphatic-,
(C3-C10)-heterocyclyl-,
(C3-C10)-heterocyclyl-(C1-C12)-aliphatic-,
(C5-C10)-heteroaryl-, or
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-,
wherein R6 is optionally substituted with up to 3 J substituents;
or
two R6 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 SO2, 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 R8 is independently —OR′;
or the R8 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 SO2;
X is —C(O)—, —S(O)—, or —S(O)2—,
V is C(O)—, —S(O)—, —S(O)2—, or —N(R13)—;
wherein R13 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 R13 may be replaced by a heteroatom selected from O, N, NH, S, SO, and SO2 in a chemically stable arrangement;
wherein R13 is independently and optionally substituted with up to 3 substituents independently selected from J;
R12 and R12′ 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 R12 or R12′ may be replaced by a heteroatom selected from O, N, NH, S, SO, or SO2 in a chemically stable arrangement;
wherein each of R12 or R12′ is optionally substituted with up to 3 substituents independently selected from J;
or
R12 and R12′ 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.

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Inhibitors of serine proteases, particularly hcv ns3-ns4a protease

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Inhibitors of serine proteases, particularly hcv ns3-ns4a protease

Life of this patent

Abstract

Claims55