6 525 025

6,525,025 Title:

Gamma-ketoacid dipeptides as inhibitors of caspase-3

This invention encompasses the novel compounds of Formula I, which are useful in the treatment of caspase-3 mediated diseases. ##STR1##The invention also encompasses certain pharmaceutical compositions comprising compounds of Formula I as well as methods for treatment of caspase-3 mediated diseases.

What is claimed is:

1. A compound represented by Formula I: ##STR98##

or a pharmaceutically acceptable salt, ester or hydrate thereof, wherein: W is a bond, --CH.sub.2 --, --C(O)-- or --C(O)CH.sub.2 --; Z is selected from the group consisting of: (1) H, (2) C.sub.1-11 alkyl, (3) C.sub.3-11 cycloalkyl or abenzofused analog thereof, (4) phenyl or naphthyl, and (5) HET.sup.1, wherein HET.sup.1 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)C.sub.1-4 alkyl, (e) C.sub.1-4 alkoxy, (f) C.sub.1-4 alkylthio, (g) C.sub.3-6 cycloalkyl, (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 selectedfrom O, S and N, groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C.sub.1-4 alkoxy, groups (h)-(l) above are optionally substituted with 1-3 substituents independently selected from haloand C.sub.1-4 alkyl, and group (4) is further optionally substituted up to its maximum with halo groups; R.sup.1 and R.sup.2 are independently selected from the group consisting of: (1) H, (2) halo, (3) hydroxy, (4) nitro, (5) cyano, (6) C.sub.1-10alkyl, C.sub.3-10 cycloalkyl, C.sub.1-10 alkoxy, --S(O).sub.0-2 C.sub.1-10 alkyl or --NHC.sub.1-10 alkyl, each optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with 1-3 substituents independently selected from thegroup consisting of: (a) halo, (b) hydroxy (c) cyano, (d) C.sub.1-4 alkoxy, (e) --NHR.sup.7, wherein R.sup.7 is H or C.sub.1-5 alkyl, said C.sub.1-5 alkyl optionally substituted with --NHR.sup.8, wherein R.sup.8 is C.sub.1-5 alkyl optionally substitutedwith 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).sub.0-2 C.sub.1-4 alkyl, and (g) HET.sup.2, wherein HET.sup.2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR.sup.7, wherein R.sup.7 is H or C.sub.1-5 alkyl, said HET.sup.2 beingoptionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo and C.sub.1-4 alkyl, said C.sub.1-4 alkyl being optionally substituted with 1-3 halo groups, (7) phenoxy or --S(O).sub.0-2 phenyl,(8) benzyloxy or --S(O).sub.0-2 benzyl, (9) benzoyl, (10) phenyl or naphthyl, (11) --O-HET.sup.2 or --S-HET.sup.2, said HET.sup.2 being optionally substituted with oxo and further optionally substituted as defined below, and (12) HET.sup.3, whereinHET.sup.3 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 HET.sup.3 being optionally substituted with oxo and further optionally substituted as definedbelow, groups (7)-(12) above are each optionally substituted with 1-2 substituents independently selected from the group consisting of: halo, cyano, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, said C.sub.1-4 alkyl and C.sub.1-4 alkoxy being optionallysubstituted with 1-3 halo groups; or R.sup.1 and R.sup.2 may be taken in combination and represent a fused ring as shown below: ##STR99## wherein Y and X are independently selected from the group consisting of --C(R.sup.10).sub.2 --,--C(R.sup.10).sub.2 C(R.sup.10).sub.2 --, --NR.sup.11 --, --O-- and --S--, R.sup.3 is as defined below, each R.sup.9 is independently selected from H and C.sub.1-4 alkyl, each R.sup.10 is independently selected from H and C.sub.1-4 alkyl, and R.sup.11 isH or C.sub.1-4 alkyl, or one R.sup.9 may be joined with either one R.sup.10 or R.sup.11 on an adjacent atom to form a double bond; R.sup.3 is C.sub.1-10 alkyl, optionally substituted with 1-2 oxo or carboxy groups and further optionally substituted with1-3 substituents independently selected from the group consisting of: (a) halo, (b) hydroxy (c) cyano, (d) C.sub.1-4 alkoxy, (e) --NHR.sup.7, wherein R.sup.7 is H or C.sub.1-5 alkyl, said C.sub.1-5 alkyl optionally substituted with --NHR.sup.8, whereinR.sup.8 is C.sub.1-5 alkyl 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).sub.0-2 C.sub.1-4 alkyl, and (g) HET.sup.2, wherein HET.sup.2 represents a 5- to 7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR.sup.7, wherein R.sup.7 is H orC.sub.1-5 alkyl, said HET.sup.2 being optionally substituted with oxo and further optionally substituted with 1-2 substituents independently selected from halo or C.sub.1-4 alkyl, said C.sub.1-4 alkyl being optionally substituted with 1-3 halo groups,each R.sup.4 is independently selected from the group consisting of: H, halo, hydroxy, C.sub.1-6 alkyl and C.sub.1-4 alkoxy, said C.sub.1-6 alkyl and C.sub.1-4 alkoxy being optionally substituted with oxo and further optionally substituted with 1-3 halogroups; and R.sup.5 is selected from the group consisting of: H, phenyl, naphthyl, C.sub.1-6 alkyl optionally substituted with OR.sup.12 and 1-3 halo groups, and C.sub.5-7 cycloalkyl optionally containing one heteroatom selected from O, S and NR.sup.13,wherein R.sup.12 is selected from the group consisting of: H, C.sub.1-5 alkyl optionally substituted with 1-3 halo groups, and benzyl optionally substituted with 1-3 substituents independently selected from halo, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, andR.sup.13 is H or C.sub.1-4 alkyl optionally substituted with 1-3 halo groups; and R.sup.6 represents H; or in the alternative, R.sup.5 and R.sup.6 are taken in combination and represent a ring of 4-7 members, said ring optionally containing oneheteroatom selected from O, S and NR.sup.13.

2. A compound according to claim 1 wherein R.sup.1 is selected from the group consisting of: (1) halo, (2) hydroxy, (3) nitro, (4) cyano, (5) C.sub.1-10 alkyl, C.sub.3-10 cycloalkyl, C.sub.1-10 alkoxy, --S(O).sub.0-2 C.sub.1-10 alkyl or--NHC.sub.1-10 alkyl, 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) C.sub.1-4 alkoxy, (e)--NHR.sup.7, wherein R.sup.7 is H or C.sub.1-5 alkyl, said C.sub.1-5 alkyl optionally substituted with --NHR.sup.8, wherein R.sup.8 is C.sub.1-5 alkyl optionally substituted with oxo and further optionally substituted with a 5- to 10-membered mono- orbicyclic, 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).sub.0-2 C.sub.1-4 alkyl, and (g) HET.sup.2, wherein HET.sup.2 represents a 5- to7-membered aromatic or non-aromatic ring containing 1-4 heteroatoms selected from O, S and NR.sup.7, wherein R.sup.7 is H or C.sub.1-5 alkyl, said HET.sup.2 being optionally substituted with oxo and further optionally substituted with 1-2 substituentsindependently selected from halo and C.sub.1-4 alkyl, said C.sub.1-4 alkyl being optionally substituted with 1-3 halo groups, (6) phenoxy or --S(O).sub.0-2 phenyl, (7) benzyloxy or --S(O).sub.0-2 benzyl, (8) benzoyl, (9) phenyl or naphthyl, (10)--O-HET.sup.2 or --S-HET.sup.2, said HET.sup.2 being optionally substituted with oxo and further optionally substituted as defined below, and (11) HET.sup.3, wherein HET.sup.3 is a 5- or 6-membered aromatic or non-aromatic ring, or a benzofused analogthereof, containing from 1 to 4 heteroatoms selected from O, S and N, said HET.sup.3 being optionally substituted with oxo and further optionally substituted as defined below, and groups (6)-(11) above are each optionally substituted with 1-2substituents independently selected from the group consisting of: halo, cyano, C.sub.1-4 alkyl and C.sub.1-4 alkoxy, said C.sub.1-4 alkyl and C.sub.1-4 alkoxy being optionally substituted with 1-3 halo groups.

3. A compound according to claim 1 wherein R.sup.3 is methyl, optionally substituted with 1-3 halo groups.

4. A compound according to claim 1 wherein one R.sup.4 is hydroxy and the other R.sup.4 is H.

5. A compound according to claim 1 wherein R.sup.5 is isopropyl and R.sup.6 is H.

6. A compound according to claim 1 wherein W is a bond.

7. A compound according to claim 1 wherein W is --CH.sub.2 --.

8. A compound according to claim 1 wherein W is --C(O)--.

9. A compound according to claim 1 wherein W is --C(O)CH.sub.2 --.

10. A compound according to claim 1 wherein Z is phenyl or naphthyl, wherein: said phenyl or naphthyl is optionally substituted with 1-3 substituents independently selected from the group consisting of: (a) nitro, (b) hydroxy, (c) C.sub.1-4alkyl, (d) C.sub.1-4 alkoxy, (e) C.sub.1-4 alkylthio, (f) C.sub.3-6 cycloalkyl, (g) phenyl or naphthyl, (h) phenoxy, (i) benzyl, (j) benzyloxy, and (k) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S andN, groups (c)-(f) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C.sub.1-4 alkoxy, groups (g)-(k) above are optionally substituted with 1-3 substituents independently selected from halo and C.sub.1-4alkyl, and said phenyl or naphthyl is further optionally substituted up to its maximum with halo groups.

11. A compound according to claim 1 wherein Z is C.sub.1-11 alkyl, optionally substituted with 1-2 oxo groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of: (a) halo (b) nitro, (c)hydroxy, (d) C.sub.1-4 alkyl, (e) C.sub.1-4 alkoxy, (f) C.sub.1-4 alkylthio, (g) C.sub.3-6 cycloalkyl, (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 heteroatomsselected from O, S and N, groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C.sub.1-4 alkoxy, and groups (h)-(l) above are optionally substituted with 1-3 substituents independentlyselected from halo and C.sub.1-4 alkyl.

12. A compound according to claim 1 wherein Z is C.sub.3-11 cycloalkyl or a benzofused analog thereof, optionally substituted with 1-2 oxo groups and further optionally substituted with 1-3 substituents independently selected from the groupconsisting of: (a) halo (b) nitro, (c) hydroxy, (d) C.sub.1-4 alkyl, (e) C.sub.1-4 alkoxy, (f) C.sub.1-4 alkylthio, (g) C.sub.3-6 cycloalkyl, (h) phenyl or naphthyl, (i) phenoxy, (j) benzyl, (k) benzyloxy, and (l) a 5 or 6-membered aromatic ornon-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 C.sub.1-4 alkoxy, and groups (h)-(l) above are optionallysubstituted with 1-3 substituents independently selected from halo and C.sub.1-4 alkyl.

13. A compound according to claim 1 wherein Z is HET.sup.1, optionally substituted with 1-2 oxo groups and further optionally substituted with 1-3 substituents independently selected from the group consisting of: (a) halo (b) nitro, (c) hydroxy,(d) C.sub.1-4 alkyl, (e) C.sub.1-4 alkoxy, (f) C.sub.1-4 alkylthio, (g) C.sub.3-6 cycloalkyl, (h) phenyl or naphthyl, (j) phenoxy, (i) benzyl, (j) benzyloxy, and (k) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selectedfrom O, S and N, groups (d)-(g) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C.sub.1-4 alkoxy, and groups (h)-(k) above are optionally substituted with 1-3 substituents independently selected fromhalo and C.sub.1-4 alkyl.

14. A compound according to claim 13 wherein HET.sup.1 represents a member selected from the group consisting of: pyridine, pyrimidine, pyridazine, pyrazine, furan, thiophene, thiazole and oxazole, or a benzofused analog thereof, each optionallysubstituted with 1-3 substituents independently selected from the group consisting of: (a) halo, (b) nitro, (c) C.sub.1-4 alkyl, (d) C.sub.1-4 alkoxy, (e) C.sub.1-4 alkylthio, (f) C.sub.3-6 cycloalkyl, (g) phenoxy, (h) benzyl, (i) benzyloxy, and (j) a 5or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N, groups (c)-(f) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C.sub.1-4 alkoxy, and groups (g)-(j)above are optionally substituted with 1-3 substituents independently selected from halo and C.sub.1-4 alkyl.

15. A compound according to claim 1 wherein HET.sup.2 is selected from the group consisting of: butyrolactone, tetrahydrofuran, tetrahydropyran, 2-pyrrolidinone, pyridine and pyrimidine, each optionally substituted with 1-2 substituentsindependently selected from halo or C.sub.1-4 alkyl, said C.sub.1-4 alkyl being optionally substituted with 1-3 halo groups.

16. A compound according to claim 1 wherein HET.sup.3 is selected from the group consisting of: 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,3,4-oxadiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, thiophene, pyrrole, pyridine,tetrazole, oxazole, thiazole, 1,2,3-triazole, 1,2,4-triazole and 1,3,4-triazole, each optionally substituted with 1-2 substituents independently selected from halo or C.sub.1-4 alkyl, said C.sub.1-4 alkyl being optionally substituted with 1-3 halogroups.

17. A compound according to claim 1 wherein: W is a bond, --CH.sub.2 --, --C(O)-- or --C(O)CH.sub.2 --; Z is selected from the group consisting of: (1) C.sub.5-6 cycloalkyl or a benzofused analog thereof, (2) phenyl or naphthyl, and (3)HET.sup.1, wherein HET.sup.1 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, wherein: groups (1) and (3) above are optionallysubstituted with 1-2 oxo groups; groups (1), (2) and (3) above are further optionally substituted with 1-3 substituents independently selected from the group consisting of: (a) halo, (b) nitro, (c) C.sub.1-4 alkyl, (d) C.sub.1-4 alkoxy, (e) C.sub.1-4alkylthio, (f) C.sub.3-6 cycloalkyl, (g) phenoxy, (h) benzyl, (i) benzyloxy, and (j) a 5 or 6-membered aromatic or non-aromatic ring containing from 1-3 heteroatoms selected from O, S and N, groups (c)-(f) above are optionally substituted with oxo and1-3 substituents independently selected from halo and C.sub.1-4 alkoxy, groups (g)-(j) above are optionally substituted with 1-3 substituents independently selected from halo and C.sub.1-4 alkyl, and group (2) is further optionally substituted up to itsmaximum with halo groups; R.sup.1 is selected from the group consisting of: (1) halo, (2) C.sub.1-4 alkyl or C.sub.1-4 alkoxy, each optionally substituted with oxo and 1-3 halo groups, and (3) HET.sup.3, wherein HET.sup.3 is a 5- or 6-membered aromaticor non-aromatic ring, or a benzofused analog thereof, containing from 1 to 4 heteroatoms selected from O, S and N, and optionally substituted with 1-2 substituents independently selected from halo and C.sub.1-4 alkyl, said C.sub.1-4 alkyl beingoptionally substituted with 1-3 halo groups, R.sup.2 is H, R.sup.3 is C.sub.1-4 alkyl, optionally substituted with 1-3 halo groups and further optionally substituted with oxo or --NHR.sup.7 or both, wherein R.sup.7 is H or C.sub.1-5 alkyl, said C.sub.1-5alkyl optionally substituted with --NHR.sup.8, wherein R.sup.8 is C.sub.1-5 alkyl optionally substituted with oxo and further optionally substituted with ##STR100## and each R.sup.4 is independently selected from the group consisting of: H and hydroxy.

18. A compound according to claim 17 wherein R.sup.5 is isopropyl and R.sup.6 is H.

19. A compound according to claim 18 wherein: HET.sup.1 is selected from the group consisting of: (1) pyridine, pyridazine, pyrimidine or pyrazine, or a benzofused analog thereof, each optionally substituted with 1-3 substituents independentlyselected from the group consisting of: (a) halo, (b) nitro, (c) C.sub.1-4 alkyl, (d) C.sub.1-4 alkoxy, (e) C.sub.1-4 alkylthio, (f) C.sub.3-6 cycloalkyl, (g) phenoxy, (h) benzyl, (i) benzyloxy, and (j) a 5 or 6-membered aromatic or non-aromatic ringcontaining from 1-3 heteroatoms selected from O, S and N, groups (c)-(f) above are optionally substituted with oxo and 1-3 substituents independently selected from halo and C.sub.1-4 alkoxy, groups (g)-(j) above are optionally substituted with 1-3substituents independently selected from halo and C.sub.1-4 alkyl, ##STR101## HET.sup.3 is 1,2,4-oxadiazole, optionally substituted with C.sub.1-4 alkyl.

20. A compound selected from the group consisting of: ##STR102## ##STR103## ##STR104## ##STR105## ##STR106## ##STR107## ##STR108## ##STR109## ##STR110## ##STR111## ##STR112## ##STR113##

or a salt, hydrate, ester, enantiomer or mixture thereof.

21. A pharmaceutical composition comprising a compound in accordance with claim 1 in combination with a pharmaceutically acceptable carrier.

22. A method of treating or preventing a caspase-3 mediated disease or condition in a mammalian patient in need of such treatment, comprising administering to said patient a compound in accordance with claim 1 in an amount that is effective totreat or prevent said caspase-3 mediated disease.