Gamma-ketoacid dipeptides as inhibitors of caspase-3

A compound represented by Formula I:

• 115
• or a pharmaceutically acceptable salt, ester or hydrate thereof, wherein:
• W is a bond, —CH2—, —C(O)— or —C(O)CH2—;
• Z is selected from the group consisting of:
• (1) H,
• (2) C1-11alkyl,
• (3) C3-11cycloalkyl or a benzofused analog thereof,
• (4) phenyl or naphthyl, and
• (5) HET1, wherein HET1 represents a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N,
• groups (2), (3) and (5) above are optionally substituted with 1-2 oxo groups, groups (2)-(5) above are further optionally substituted with 1-3 substituents independently selected from the group consisting of:
• (a) halo
• (b) nitro,
• (c) hydroxy,
• (d) C1-4alkyl,
• (e) C1-4alkoxy,
• (f) C1-4alkylthio,
• (g) C3-6cycloalkyl,
• (h) phenyl or naphthyl,
• (i) phenoxy,
• (j) benzyl,
• (k) benzyloxy, and
• (l) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N,
• groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C1-4alkoxy,
• groups (h)-(l) above are optionally substituted with 1-3 substituents independently selected from halo and C1-4alkyl, and
• group (4) is further optionally substituted up to its maximum with halo groups;
• R1 and R2 are independently selected from the group consisting of:
• (1) H,
• (2) halo,
• (3) hydroxy,
• (4) nitro,
• (5) cyano,
• (6) C1-10alkyl, C3-10cycloalkyl, C1-10alkoxy, —S(O)0-2C1-10alkyl or —NHC1-10alkyl, each optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
• (a) halo,
• (b) hydroxy
• (c) cyano,
• (d) C1-4alkoxy,
• (e) —NHR7, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with —NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N, and optionally substituted with oxo,
• (f) —S(O)0-2C1-4alkyl, and
• (g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR7, wherein R7 is H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo and C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
• (7) phenoxy or —S(O)0-2phenyl,
• (8) benzyloxy or —S(O)0-2benzyl,
• (9) benzoyl,
• (10) phenyl or naphthyl,
• (11) —O—HET2 or —S—HET2, said HET2 being optionally substituted with oxo and further optionally substituted as defined below, and
• (12) HET3, wherein HET3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, said HET3 being optionally substituted with oxo and further optionally substituted as defined below,
• groups (7)-(12) above are each optionally substituted with 1-2 substituents independently selected from the group consisting of:
• halo, cyano, C1-4alkyl and C1-4alkoxy, said C1-4alkyl and C1-4alkoxy being optionally substituted with 1-3 halo groups;
• or R1 and R2 may be taken in combination and represent a fused ring as shown below:
• 116
• wherein Y and X are independently selected from the group consisting of —C(R10)2—, —C(R10)2C(R10)2—, NR11—, —O— and —S—, R3 is as defined below, each R9 is independently selected from H and C1-4alkyl, each R10 is independently selected from H and C1-4alkyl, and R11 is H or C1-4alkyl, or one R9 may be joined with either one R10 or R11 on an adjacent atom to form a double bond;
• R3 is C1-10alkyl, optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of:
• (a) halo,
• (b) hydroxy
• (c) cyano,
• (d) C1-4alkoxy,
• (e) —NHR7, wherein R7 is H or C1-5alkyl, said C1-5alkyl optionally substituted with —NHR8, wherein R8 is C1-5alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- or bicyclic, aromatic or non-aromatic ring, or a benzofused analog thereof, containing 1-3 heteroatoms selected from O, S and N, and optionally substituted with oxo,
• (f) —S(O)0-2C1-4alkyl, and
• (g) HET2, wherein HET2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR7, wherein R7 is H or C1-5alkyl, said HET2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo or C1-4alkyl, said C1-4alkyl being optionally substituted with 1-3 halo groups,
• each R4 is independently selected from the group consisting of:
• H, halo, hydroxy, C1-6alkyl and C1-4alkoxy, said C1-6alkyl and C1-4alkoxy being optionally substituted with oxo and further optionally substituted with 1-3 halo groups;
• and
• R5 is selected from the group consisting of:
• H, phenyl, naphthyl, C1-6alkyl optionally substituted with OR12 and 1-3 halo groups, and C5-7 cycloalkyl optionally containing one heteroatom selected from O, S and NR13,
• wherein R12 is selected from the group consisting of:
• H, C1-5alkyl optionally substituted with 1-3 halo groups, and benzyl optionally substituted with 1-3 substituents independently selected from halo, C1-4alkyl and C1-4alkoxy, and
• R13 is H or C1-4alkyl optionally substituted with 1-3 halo groups;
• and
• R6 represents H;
• or in the alternative, R5 and R6 are taken in combination and represent a ring of 4-7 members, said ring optionally containing one heteroatom selected from O, S and NR13.