Bridged bicyclic serine protease inhibitors

A compound of the formula (I):

• 52
• wherein:
• A, together with X and the atoms to which X is bound, is a 4- to 7-membered aromatic or non-aromatic ring having up to 4 heteroatoms independently selected from N, NH, O, SO, or SO2;
• 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;
• X is —[CH2]o—, —[CJ′J′]o—, —[CH2]m—O—, —[CH2]m—S(O)2—, —[CH2]m—SO—, —[CH2]m—S—, —[CR20R20]m—NR21—, or —[CR20R20]m—NJ″-, wherein:
• R21 is hydrogen or —C(O)—O—R22;
• o is 1 or 2;
• R22 is —(C1-C6)alkyl, —(C2-C6)alkenyl, or —(C2-C6)alkynyl;
• m is 0 or 1;
• J is halogen, —OR′, —NO2, —CF3, —OCF3, —R′, oxo, —OR′, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, —N(R′)2, —SR′, —SOR′, —SO2R′, —C(O)R′, —COOR′, or —CON(R′)2;
• J′ is halogen, —OR′, —NO2, —CF3, —OCF3, —R′, —OR′, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, —N(R′)2, —SR′, —SOR′, —SO2R′, —C(O)R′, —COOR′, or —CON(R′)2;
• J″ is —OR′, —CF3, —OCF3, —R′, oxo, —OR′, —O-benzyl, —O-phenyl, 1,2-methylenedioxy, —N(R′)2, —SR′, —SOR′, —SO2R′, —C(O)R′, —COOR′, or —CON(R′)2, wherein each R′ is independently:
• hydrogen,
• —(C1-C12) aliphatic,
• —(C3-C10)cycloalkyl or -cycloalkenyl,
• —(C1-C12)aliphatic-[(C3-C10)cycloalkyl or -cycloalkenyl],
• —(C6-C10)aryl,
• —(C1-C12)aliphatic-(C6-C10)aryl,
• —(C3-C10)heterocyclyl,
• —(C1-C12)aliphatic-(C6-C10)heterocyclyl,
• —(C5-C10)-heteroaryl, or
• —(C1-C12)-aliphatic-(C5-C10)heteroaryl;
• R1 and R3 are independently:
• —(C1-C12)aliphatic,
• —(C3-C10)-cycloalkyl or -cycloalkenyl,
• —(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
• —(C6-C10) -aryl,
• (C1-C12)aliphatic-(C6-C10)aryl,
• —(C3-C10)-heterocyclyl,
• —(C1-C12)aliphatic-(C6-C10)heterocyclyl,
• —(C5-C10)heteroaryl, or
• —(C1-C12)aliphatic-(C5-C10)heteroaryl,
• wherein each of R1 and R3 is independently and optionally substituted with up to 3 substituents independently selected from J;
• wherein up to 3 aliphatic carbon atoms in R1 and R3 may be replaced by a heteroatom selected from O, NH, S, SO, and SO2 in a chemically stable arrangement;
• R2 and R4 are independently
• hydrogen,
• —(C1-C12)aliphatic,
• —(C1-C12)aliphatic-(C3-C10)cycloalkyl, or
• —(C1-C12)aliphatic-(C6-C10)aryl,
• 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, and SO2;
• 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:
• —C(O)OH;
• 53
• wherein each R6 is independently:
• hydrogen,
• —(C1-C12)aliphatic,
• (C6-C10)aryl,
• —(C6-C10)aryl-(C1-C12)aliphatic,
• —(C3-C10)-cycloalkyl or -cycloalkenyl,
• —(C1-C12)-aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
• —(C3-C10)heterocyclyl,
• —(C3-C10)heterocyclyl-(C1-C12)aliphatic,
• —(C5-C10)heteroaryl, or
• —(C1-C12)aliphatic-(C5-C10)heteroaryl, 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 or with a suitable electron withdrawing group;
• V is —C(O)N(R8)—, —S(O)N(R8)—, —S(O)2N(R8)—, a bond, —CH(R8)—, —N(R8)—, —O—, —O—CH(R8)—, —S—, —S—CH(R8), —C(O)—, —C(O)—O—, —C(O)—S—, —C(O)—CHR8—, —S(O)—, —S(O)—CH(R8), —S(O)—N(R8)—CHR8, —S(O)2—, —S— (O)2—CH(R8)—, or —S(O)2—N(R8)—CHR8;
• wherein R8 is hydrogen or —(C1-C12)aliphatic;
• T is:
• —(C6-C10)aryl,
• —(C1-C12)aliphatic-(C6-C10)aryl,
• —(C3-C10)-cycloalkyl or -cycloalkenyl,
• —(C1-C12)aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
• —(C3-C10)heterocyclyl,
• —(C1-C12)aliphatic-(C3-C10)heterocyclyl,
• —(C5-C10)heteroaryl, or
• —(C1-C12)aliphatic-(C5-C10)heteroaryl;
• or
• T is:
• 54
• wherein:
• R10 is:
• hydrogen,
• —(C1-C12)aliphatic,
• —(C6-C10)aryl,
• —(C1-C12)aliphatic-(C6-C10)aryl,
• —(C3-C10)-cycloalkyl or -cycloalkenyl,
• —(C1-C12)aliphatic-[(C3-C10)-cycloalkyl or -cycloalkenyl],
• —(C3-C10)heterocyclyl,
• —(C1-C12)aliphatic-(C3-C10)heterocyclyl,
• —(C5-C10)heteroaryl, or
• —(C1-C12)aliphatic-(C5-C10)heteroaryl,
• wherein each T is optionally substituted with up to 3 J substituents;
• K is a bond, —(C1-C12)aliphatic, —O—, —S—, —NR9—, —C(O)—, or —C(O)—NR9—, wherein R9 is hydrogen or —(C1-C12)aliphatic;
• n is 1-3;
• and
• each R20 is independently hydrogen, —(C1-C6)aliphatic or —O—((C1-C6)aliphatic);
• or each R20 is taken together with the carbon atoms to which they are bound to form a (C3-C6)cycloalkyl.