US 2009/0022688 A1 · INHIBITORS OF SERINE PROTEASE, PARTICULARLY HCV NS3-NS4A PROTEASE

Abstract

The present invention relates to compounds of formula I: or a pharmaceutically acceptable salt, or mixtures 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 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, or mixtures thereof, wherein:
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-, or
wherein up to 3 aliphatic carbon atoms in each R6 may be optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)— in a chemically stable arrangement;
wherein R6 may be optionally substituted with up to 3 J substituents;
or
two R6 groups, together with the nitrogen atom to which they are bound, may optionally form a 5- to 6-membered aromatic or a 3- to 7-membered saturated or partially unsaturated ring system wherein up to 3 ring atoms may be optionally replaced with N, NH, O, S, SO, and SO2, wherein said ring system may be 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, may optionally form a (C3-C10)-membered heterocyclic ring wherein each R8 is independently —OR′;
or the R8 groups together with the boron atom, may optionally form a (C3-C10)-membered heterocyclic ring having, in addition to the boron, up to 3 ring atoms optionally replaced with N, NH, O, S, SO, and SO2;
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)NR′, —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-, and
(C5-C10)-heteroaryl-(C1-C12)-aliphatic-;
wherein up to 5 atoms in R′ may be optionally and independently substituted with J;
wherein two R′ groups bound to the same atom may optionally form a 5- to 6-membered aromatic or a 3- to 7-membered saturated or partially unsaturated ring system wherein up to 3 ring atoms may be optionally replaced with a heteroatom independently selected from N, NH, O, S, SO, and SO2, wherein said ring system may be 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;
R5 and R5′ are each independently hydrogen or (C1-C12)-aliphatic, wherein any hydrogen may be optionally replaced with halogen;
wherein any terminal carbon atom of R5 may be optionally substituted with sulfhydryl or hydroxy;
or R5 is Ph or —CH2Ph and R5′ is H, wherein said Ph or —CH2Ph group may be optionally substituted with up to 3 substituents independently selected from J;
or
R5 and R5′ together with the atom to which they are bound may optionally form a 3- to 6-membered saturated or partially unsaturated ring system wherein up to 2 ring atoms may be optionally replaced with N, NH, O, SO, or SO2;
wherein said ring system has up to 2 substituents selected independently 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 optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)— in a chemically stable arrangement;
wherein each of R2, R4, and R7 may be independently and optionally substituted with up to 3 substituents independently selected from J;
R1 and R3 are each 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 optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)— in a chemically stable arrangement;
wherein each of R1 and R3 may be independently and optionally substituted with up to 3 substituents independently selected from J;
R9, R9′, R10, and R10′ are each independently —X—Y-Z;
X is a bond, —C(H)(R6)—, —O—, —S—, or —N(R11)—;
R11 is:
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 R11 may be optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)— in a chemically stable arrangement;
wherein R11 may be optionally substituted with up to 3 J substituents;
or
wherein R11 and Z together with the atoms to which they are bound, optionally form a nitrogen containing 5-7-membered mono- or 6-11-membered bicyclic ring system optionally substituted with up to 3 J substitutents, wherein up to 3 ring atoms in said ring system may be optionally replaced with O, NH, S, SO, or SO2 in a chemically stable arrangement;
Y is a bond, —CH2—, —C(O)—, —C(O)C(O)—, —S(O)—, S(O)2—, or —S(O)(NR12)—;
R12 is:
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 R12 may be optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)—, in a chemically stable arrangement;
wherein R12 may be optionally substituted with up to 3 J substituents;
Z 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 three aliphatic carbon atoms in Z may be optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)—, in a chemically stable arrangement;
wherein any ring may be optionally fused to a (C6-C10)aryl, (C5-C10)heteroaryl, (C3-C10)cycloalkyl, or (C3-C10)heterocyclyl;
wherein Z may be independently and optionally substituted with up to 3 substituents independently selected from J;
V is —C(O)—, —S(O)—, or —S(O)2—;
R is —C(O)—, —S(O)—, —S(O)2—, —N(R12)—, —O—, or a bond;
T 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 T may be replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)—, in a chemically stable arrangement;
wherein each T may be optionally substituted with up to 3 J substituents;
or
T is selected from —N(R6)(R6′);
and
R6′ is
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-, or
wherein up to 3 aliphatic carbon atoms in each R6′ may be optionally replaced with S, —S(O)—, —S(O)2—, —O—, —N—, or —N(H)— in a chemically stable arrangement;
wherein R6′ may be optionally substituted with up to 3 J substituents;
or
R6 and R6′, together with the nitrogen atom to which they are bound, may optionally form a (C3-C10)-heterocyclic ring system wherein said ring system may be optionally substituted with up to 3 substituents independently selected from J.

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Inhibitors of serine protease, particularly hcv ns3-ns4a protease

Life of this patent

Inhibitors of serine protease, particularly hcv ns3-ns4a protease

Life of this patent

Abstract

Claims48