Claims for Patent: 6,291,504

Summary for Patent: 6,291,504

Title:	Acylsemicarbazides and their uses
Abstract:	The present invention relates to the synthesis of a new lass of indeno[1,2-c]pyrazol-4-ones of formula (I): ##STR1## that are potent inhibitors of the class of enzymes known as cyclin dependent kinases, which relate to the catalytic subunits cdk1-9 and their regulatory subunits know as cyclins A-H. This invention also provides a novel method of treating cancer or other proliferative diseases by administering a therapeutically effective amount of one of these compounds or a pharmaceutically acceptable salt form thereof. Alternatively, one can treat cancer or other proliferative diseases by administering a therapeutically effective combination of one of the compounds of the present invention and one or more other known anti-cancer or anti-proliferative agents.
Inventor(s):	Nugiel; David A. (Cherry Hill, NJ), Carini; David J. (Wilmington, DE), Di Meo; Susan V. (Wilmington, DE), Vidwans; Anup P. (Wilmington, DE), Yue; Eddy W. (Landenberg, PA)
Assignee:	DuPont Pharmaceuticals Company (Wilmington, DE)
Application Number:	09/692,023
Patent Claims:	1. A compound of formula (I): ##STR14## X is O or S; R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C.sub.1-4 alkyl substituted with 1-3 R.sup.4, C.sub.5-10 alkyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.10 alkenyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.10 alkynyl substituted with 0-3 R.sup.4, C.sub.3 -C.sub.10 carbocycle substituted with 0-5 R.sup.6, or 5-10 membered heterocycle substituted with 0-3 R.sup.6 ; provided that if R.sup.1 is phenyl or benzyl, then R.sup.1 is substituted with 1-5 R.sup.6 ; R.sup.2 is H, C.sub.1-10 alkyl substituted with 0-3 R.sup.7, C.sub.2-10 alkenyl substituted with 0-3 R.sup.7, C.sub.2-10 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-10 carbocycle substituted with 0-5 R.sup.8, or 3-10 membered heterocycle substituted with 0-5 R.sup.8 ; R.sup.3 and R.sup.3a are independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.4 and R.sup.7 are, at each occurance, independently selected from the group: halo, --CN, NO.sub.2, --NR.sup.9 R.sup.9a, NR.sup.9 NR.sup.9a R.sup.9b, NR.sup.9 C(O)OR.sup.10, NR.sup.9 C(O)R.sup.10, .dbd.O, OR.sup.10, SR.sup.10, --CF3, COR.sup.10, CO.sub.2 R.sup.10, CONR.sup.9 R.sup.9a, NHC(O)NR.sup.9 R.sup.9a, NHC(S)NR.sup.9 R.sup.9a, SO.sub.2 NR.sup.9 R.sup.9a, SO.sub.2 R.sup.10, C.sub.3-10 carbocycle substituted with 0-5 R.sup.11, and 5-10 membered heterocycle substituted with 0-3 R.sup.11 ; R.sup.5 is selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.6 and R.sup.8 are, at each occurance, independently selected from the group: halo, --CN, N.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, SO.sub.2 R.sup.14, C.sub.3-10 carbocycle substituted with 0-5 R.sup.15, and 5-10 membered heterocycle substituted with 0-3 R.sup.15, or when two R.sup.6s or R.sup.8s are attached to two adjacent carbon atoms, the two R.sup.6s or R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.9 is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.9b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.9 and R.sup.9a, together with the nitrogen atom to which they are attached, form a heterocycle substituted with 0-3 R.sup.16 ; R.sup.9a is selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.10, R.sup.14, R.sup.17 are, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, benzyl; R.sup.11 is, at each occurance, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.18 R.sup.18a, NR.sup.18 NR.sup.18a R.sup.18b, NR.sup.18 C(O)OR.sup.17, NR.sup.18 C(O)R.sup.17, .dbd.O, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2 R.sup.17, CONR.sup.18 R.sup.18a, NHC(O)NR.sup.18 R.sup.18a, NHC(S)NR.sup.18 R.sup.18a, SO.sub.2 NR.sup.18 R.sup.18a, SO.sub.2 R.sup.17, C.sub.3-10 carbocycle substituted with 0-5 R.sup.19, and 5-10 membered heterocycle substituted with 0-3 R.sup.19 ; R.sup.13 is is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.13a is, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.13 and R.sup.13a, together with the nitrogen atom to which they are attached, form a heterocycle substituted with 0-3 R.sup.16 ; R.sup.13b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.15, R.sup.16 and R.sup.19 are, at each occurance, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.20 R.sup.20a, NR.sup.20.sup..sub.b NR.sup.20 R.sup.20.sup..sub.a , NR.sup.20 C(O)OR.sup.21, NR.sup.20 C(O)R.sup.21, .dbd.O, OR.sup.21, SR.sup.21, COR.sup.21, CO.sub.2 R.sup.21, CONR.sup.20 R.sup.20.sup..sub.a , NHC(O)NR.sup.20 R.sup.20.sup..sub.a , NHC(S)NR.sup.20 R.sup.20.sup..sub.a , SO.sub.2 NR.sup.20 R.sup.20.sup..sub.a , SO.sub.2 R.sup.21, or when two R.sup.15 s, R.sup.16 s or R.sup.19 s are attached to two adjacent carbon atoms, the two R.sup.15 s R.sup.16 s or R.sup.19 s may combine to form --OCH2O-- or --OCH2CH2O--; R.sup.18 is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.18a is, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.18 and R.sup.18a, together with the nitrogen atom to which they are attached, form a heterocycle substituted with 0-3 R.sup.19 ; R.sup.18b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.20 is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.20a is, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.20b is, at each occurance, independently selected from the group: H, --C(O)R.sup.12, --C(O)OR.sup.12, C.sub.1-4 alkyl, phenyl and benzyl; and R.sup.12 and R.sup.21 are, at each occurance, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, benzyl; or a pharmaceutically acceptable salt form thereof, a pharmaceutically acceptable prodrug form thereof, an N-oxide form thereof, or a stereoisomer thereof. 2. A compound accoding to claim 1 wherein: X is O or S; R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4, C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.4 alkynyl substituted with 0-3 R.sup.4, C.sub.3 -C.sub.10 carbocycle substituted with 0-5 R.sup.6, or 5-10 membered heterocycle substituted with 0-3 R.sup.6. 3. A compound accoding to claim 1 wherein: X is O or S; R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4, C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.4 alkynyl substituted with 0-3 R.sup.4, C.sub.3 -C.sub.6 carbocycle substituted with 0-5 R.sup.6, or 5-7 membered heterocycle substituted with 0-3 R.sup.6. 4. A compound accoding to claim 1 wherein: R.sup.1 is C.sub.3 -C.sub.6 saturated carbocycle substituted with 0-5 R.sup.6, or 5-7 membered saturated heterocycle substituted with 0-3 R.sup.6. 5. A compound accoding to claim 1 wherein: R.sup.1 is C.sub.5 -C.sub.6 partially saturated carbocycle substituted with 0-5 R.sup.6, or 5-7 membered partially saturated heterocycle substituted with 0-3 R.sup.6. 6. A compound accoding to claim 1 wherein: R.sup.1 is phenyl substituted with 1-5 R.sup.6, naphthyl substituted with 0-5 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6. 7. A compound accoding to claim 1 wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6. 8. A compound accoding to claim 1 wherein: R.sup.1 is C.sub.3 -C.sub.10 carbocycle substituted with 0-5 R.sup.6, or 5-10 membered heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--. 9. A compound accoding to claim 1 wherein: R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; and R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl. 10. A compound accoding to claim 1 wherein: R.sup.6 is independently at each occurrence selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14 ; R.sup.13, R.sup.13a and R.sup.13b are each independently selected from the group: H or methyl; and R.sup.14 is independently selected from the group: H, methyl, phenyl, and benzyl. 11. A compound accoding to claim 1 wherein: X is O or S; R.sup.1 is --NR.sup.3 R.sup.3a, CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4 ; R.sup.4 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, --NR.sup.9 R.sup.9a, NR.sup.9 NR.sup.9a R.sup.9b, NR.sup.9 C(O)OR.sup.10, NR.sup.9 C(O)R.sup.10, .dbd.O, OR.sup.10, SR.sup.10, --CF3, COR.sup.10, CO.sub.2 R.sup.10, CONR.sup.9 R.sup.9a, NHC(O)NR.sup.9 R.sup.9a, NHC(S)NR.sup.9 R.sup.9a, SO.sub.2 NR.sup.9 R.sup.9a, and SO.sub.2 R.sup.10 ; R.sup.9 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.9a is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.9b is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.9 and R.sup.9a, together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycle substituted with 0-3 R.sup.16 ; R.sup.16 is, at each occurrence, independently selected from the group consisting of: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.20 R.sup.20a, NR.sup.20.sup..sub.b NR.sup.20 R.sup.20.sup..sub.a , NR.sup.20 C(O)OR.sup.21, NR.sup.20 C(O)R.sup.21, .dbd.O, OR.sup.21, SR.sup.21, COR.sup.21, CO.sub.2 R.sup.21, CONR.sup.20 R.sup.20.sup..sub.a , NHC(O)NR.sup.20 R.sup.20.sup..sub.a , NHC(S)NR.sup.20 R.sup.20.sup..sub.a , SO.sub.2 NR.sup.20 R.sup.20.sup..sub.a , and SO.sub.2 R.sup.21 ; and R.sup.20, R.sup.20a, and R.sup.20b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl. 12. A compound accoding to claim 1 wherein: X is O or S; R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4 ; R.sup.3 and R.sup.3a are independently selected from the group: H, methyl, phenyl and benzyl; R.sup.4 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, --NR.sup.9 R.sup.9a, NR.sup.9 NR.sup.9a R.sup.9b, NR.sup.9 C(O)OR.sup.10, NR.sup.9 C(O)R.sup.10, .dbd.O, OR.sup.10, SR.sup.10, --CF3, COR.sup.10, CO.sub.2 R.sup.10, CONR.sup.9 R.sup.9a, NHC(O)NR.sup.9 R.sup.9a, NHC(S)NR.sup.9 R.sup.9a, SO.sub.2 NR.sup.9 R.sup.9a, SO.sub.2 R.sup.10, C.sub.3-10 carbocycle substituted with 0-5 R.sup.11, and 5-10 membered heterocycle substituted with 0-3 R.sup.11 ; R.sup.9 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.9a is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.9b is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.10 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, benzyl; and R.sup.11 is, at each occurrence, independently selected from the group consisting of: selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.18 R.sup.18a, NR.sup.18 NR.sup.18a R.sup.18b, NR.sup.18 C(O)OR.sup.17, NR.sup.18 C(O)R.sup.17, .dbd.O, OR.sup.17, SR.sup.17, COR.sup.17, CO.sub.2 R.sup.17, CONR.sup.18 R.sup.18a, NHC(O)NR.sup.18 R.sup.18a, NHC(S)NR.sup.18 R.sup.18a, SO.sub.2 NR.sup.18 R.sup.18a, SO.sub.2 R.sup.17, C.sub.3-10 carbocycle substituted with 0-5 R.sup.19, and 5-10 membered heterocycle substituted with 0-3 R.sup.19. 13. A compound accoding to claim 1 wherein: R.sup.2 is C.sub.1-4 alkyl substituted with 0-3 R.sup.7, C.sub.2-4 alkenyl substituted with 0-3 R.sup.7, C.sub.2-4 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 3-7 membered heterocycle substituted with 0-5 R.sup.8. 14. A compound accoding to claim 1 wherein: R.sup.2 is C.sub.1-4 alkyl substituted with 0-3 R.sup.7, C.sub.2-4 alkenyl substituted with 0-3 R.sup.7, C.sub.2-4 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8. 15. A compound accoding to claim 1 wherein: R.sup.2 is C.sub.3-6 saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered saturated heterocycle substituted with 0-5 R.sup.8. 16. A compound accoding to claim 1 wherein: R.sup.2 is C.sub.5-6 partially saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered partially saturated heterocycle substituted with 0-5 R.sup.8. 17. A compound accoding to claim 1 wherein: R.sup.2 is phenyl substituted with 0-5 R.sup.8, naphthyl substituted with 0-5 R.sup.8 or or 5-6 membered aromatic heterocycle substituted with 0-5 R.sup.8. 18. A compound accoding to claim 1 wherein: R.sup.2 is phenyl substituted with 0-3 R.sup.8, naphthyl substituted with 0-3 R.sup.8 or or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.8. 19. A compound accoding to claim 1 wherein: R.sup.2 is C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8 ; R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.8s are attached to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; and R.sup.13 R.sup.13a, and R.sup.13b are are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.13 and R.sup.13a, together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycle substituted with 0-3 R.sup.16. 20. A compound accoding to claim 1 wherein: R.sup.2 is C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8 ; R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, SO.sub.2 R.sup.14, C.sub.3-10 carbocycle substituted with 0-5 R.sup.15, and 5-10 membered heterocycle substituted with 0-3 R.sup.15, or when two R.sup.8s are attached to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13 R.sup.13a, and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; and R.sup.15 is, at each occurrence, independently selected from the group consisting of: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.20 R.sup.20a, NR.sup.20.sup..sub.b NR.sup.20 R.sup.20.sup..sub.a , NR.sup.20 C(O)OR.sup.21, NR.sup.20 C(O)R.sup.21, .dbd.O, OR.sup.21, SR.sup.21, COR.sup.21, CO.sub.2 R.sup.21, CONR.sup.20 R.sup.20.sup..sub.a , NHC(O)NR.sup.20 R.sup.20.sup..sub.a , NHC(S)NR.sup.20 R.sup.20.sup..sub.a , SO.sub.2 NR.sup.20 R.sup.20.sup..sub.a , and SO.sub.2 R.sup.21, or when two R.sup.15 s, are attached to two adjacent carbon atoms, the two R.sup.15 s may combine to form --OCH2O-- or --OCH2CH2O--. 21. A compound accoding to claim 1 wherein: X is O or S; R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4, C.sub.2 -C.sub.4 alkenyl substituted with 0-3 R.sup.4, C.sub.2 -C.sub.4 alkynyl substituted with 0-3 R.sup.4, C.sub.3 -C.sub.6 carbocycle substituted with 0-5 R.sup.6, or 5-7 membered heterocycle substituted with 0-3 R.sup.6 ; and R.sup.2 is C.sub.1-4 alkyl substituted with 0-3 R.sup.7, C.sub.2-4 alkenyl substituted with 0-3 R.sup.7, C.sub.2-4 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8. 22. A compound accoding to claim 1 wherein: R.sup.1 is phenyl substituted with 1-5 R.sup.6, naphthyl substituted with 0-5 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.2 is C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8 ; R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.8s are attached to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; and R.sup.13 R.sup.13a, and R.sup.13b are are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.13 and R.sup.13a, together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycle substituted with 0-3 R.sup.16. 23. A compound accoding to claim 1 wherein: X is O or S; R.sup.1 is --NR.sup.3 R.sup.3a, --CF.sub.3, C1-C4 alkyl substituted with 1-3 R.sup.4 ; R.sup.2 is C.sub.1-4 alkyl substituted with 0-3 R.sup.7, C.sub.2-4 alkenyl substituted with 0-3 R.sup.7, C.sub.2-4 alkynyl substituted with 0-3 R.sup.7, --CF.sub.3, C.sub.3-6 carbocycle substituted with 0-5 R.sup.8, or 5-7 membered heterocycle substituted with 0-5 R.sup.8 ; R.sup.4 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, --NR.sup.9 R.sup.9a, NR.sup.9 NR.sup.9a R.sup.9b, NR.sup.9 C(O)OR.sup.10, NR.sup.9 C(O)R.sup.10, .dbd.O, OR.sup.10, SR.sup.10, --CF3, COR.sup.10, CO.sub.2 R.sup.10, CONR.sup.9 R.sup.9a, NHC(O)NR.sup.9 R.sup.9a, NHC(S)NR.sup.9 R.sup.9a, SO.sub.2 NR.sup.9 R.sup.9a, and SO.sub.2 R.sup.10 ; R.sup.9 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.9a is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.9b is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; or R.sup.9 and R.sup.9a, together with the nitrogen atom to which they are attached, form a 5-7 membered heterocycle substituted with 0-3 R.sup.16 ; R.sup.16 is, at each occurrence, independently selected from the group consisting of: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.20 R.sup.20a, NR.sup.20.sup..sub.b NR.sup.20 R.sup.20.sup..sub.a , NR.sup.20 C(O)OR.sup.21, NR.sup.20 C(O)R.sup.21, .dbd.O, OR.sup.21, SR.sup.21, COR.sup.21, CO.sub.2 R.sup.21, CONR.sup.20 R.sup.20.sup..sub.a , NHC(O)NR.sup.20 R.sup.20.sup..sub.a , NHC(S)NR.sup.20 R.sup.20.sup..sub.a , SO.sub.2 NR.sup.20 R.sup.20.sup..sub.a , and SO.sub.2 R.sup.21 ; and R.sup.20, R.sup.20a, and R.sup.20b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl. 24. A compound accoding to claim 1 selected from the group: 3-(4-methoxyphenyl)-5-(2-(3,5-dimethoxybenzoyl)hydrazinecarboxamido)indeno[ 1,2-c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-isonicotinoylhydrazinecarboxamido)indeno[1,2-c]pyr azol-4-one; 3-(4-methoxyphenyl)-5-(2-nictinoylhydrazinecarboxamido)indeno[1,2-c]pyrazol -4-one; 3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxybenzoyl)hydrazinecarboxamido)indeno[ 1,2-c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(4-hydroxybenzoyl)hydrazinecarboxamido)indeno[1,2- c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(3-aminobenzoyl)hydrazinecarboxamido)indeno[1,2-c] pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(4-aminobenzoyl)hydrazinecarboxamido)indeno[1,2-c] pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(2-aminobenzoyl)hydrazinecarboxamido)indeno[1,2-c] pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylaminobenzoyl)hydrazinecarboxamido)i ndeno[1,2-c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-methoxybenzoylhydrazinecarboxamido)indeno[1,2-c]py razol-4-one; 3-(4-methoxyphenyl)-5-(2-(2-hydroxybenzoyl)hydrazinecarboxamido)indeno[1,2- c]pyrazol-4-one; and 3-(4-methoxyphenyl)-5-(2-(3,5-diaminobenzoyl)hydrazinecarboxamido)indeno[1, 2-c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(1-naphthoyl)hydrazinecarboxamido)indeno[1,2-c]pyr azol-4-one; 3-(4-methoxyphenyl)-5-(2-amidohydrazinecarboxamido)indeno[1,2-c]pyrazol-4-o ne; 3-(4-methoxyphenyl)-5-(2-phenylamidohydrazinecarboxamido)indeno[1,2-c]pyraz ol-4-one; 3-(4-methoxyphenyl)-5-(2-(4-methylbenzoylhydrazinecarboxamido)indeno[1,2-c] pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(2-naphthoyl)hydrazinecarboxamido)indeno[1,2-c]pyr azol-4-one; 3-(4-methoxyphenyl)-5-(2-(3-(4-hydroxyphenyl)propionyl)hydrazinecarboxamido )indeno[1,2-c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(4-methoxybenzoyl)hydrazinecarboxamido)indeno[1,2- c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(3-nitrobenzoyl)hydrazinecarboxamido)indeno[1,2-c] pyrazol-4-one; 3-(4-methoxyphenyl)-5(2-(3-nitrobenzoyl)hydrazinecarboxamido)indeno[1,2-c]p yrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(2-thienoyl)hydrazinecarboxamido)indeno[1,2-c]pyra zol-4-one; 3-(4-methoxyphenyl)-5-(2-(3-methylbenzoyl)hydrazinecarboxamido)indeno[1,2-c ]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(3-amino-4-hydroxybenzoyl)hydrazinecarboxamido)ind eno[1,2-c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(2,5-dichlorobenzoyl)hydrazinecarboxamido)indeno[1 ,2-c]pyrazol-4-one; 3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxybenzoyl)hydrazinecarboxamido)indeno[ 1,2-c]pyrazol-4-one; 3-(4-piperazinylphenyl)-5-(2-(nicotinoyl)hydrazinecarboxamido)indeno[1,2-c] pyrazol-4-one; 3-(4-(4-methylpiperazinyl)phenyl)-5-(2-(nicotinoyl)hydrazinecarboxamido)ind eno[1,2-c]pyrazol-4-one; 3-(4-(4-methylpiperazinyl)phenyl)-5-(2-(isonicotinoyl)hydrazinecarboxamido) indeno[1,2-c]pyrazol-4-one; 3-(4-piperazinylphenyl)-5-(2-(isonicotinoyl)hydrazinecarboxamido)indeno[1,2 -c]pyrazol-4-one; and 3-(4-piperazinylphenyl)-5-(2-(3,5-dimethoxybenzoyl)hydrazinecarboxamido)ind eno[1,2-c]pyrazol-4-one; or a pharmaceutically acceptable salt form thereof, a pharmaceutically acceptable prodrug form thereof, an N-oxide form thereof, or a stereoisomer thereof. 25. A pharmaceutical composition, comprising: a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1. 26. A pharmaceutical composition, comprising a pharmaceutically acceptable carrier, a compound according to claim 1 or a pharmaceutically acceptable salt or prodrug form thereof, and a cytostatic or cytotoxic agent. 27. A method of treating a cell proliferative disease associated with CDK activity in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the proliferative diseases is selected from the group consisting of: Alzheimer's disease, viral infections, auto-immune diseases, fungal disease, cancer, psoriasis, vascular smooth cell proliferation associated with atherosclerosis, pulmonary fibrosis, arthritis glomerulonephritis, neurodegenerative disorders and post-surgical stenosis and restenosis. 28. A method of treating a disease associated with apoptosis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the disease associated with apoptosis is selected from the group consisting of: cancer, viral infections, autoimmune diseases and neurodegenerative disorder. 29. A method of inhibiting tumor angiogenesis and metastasis in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 30. A method of modulating the level of cellular RNA and DNA synthesis in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 31. A method of treating viral infections in a patient in need thereof, comprising administering to said patient a CDK inhibitory effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the viral infections is selected from the group consiting of HIV, human papilloma virus, herpesvirus, poxvirus, Epstein-Barr virus, Sindbis virus and adenovirus. 32. A method of chemopreventing cancer in a patient, comprising administering to said patient in need thereof, a CDK inhibitory effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 33. A method of inhibiting CDK activity comprising combining an effective amount of a compound according to claim 1, with a composition containing CDK. 34. A method treating cell proliferative diseases associated with CDK activity in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with known anti-proliferating agents selected from the group consisting of: altretamine, busulfan, chlorambucil, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, thiotepa, cladribine, fluorouracil, floxuridine, gemcitabine, thioguanine, pentostatin, methotrexate, 6-mercaptopurine, cytarabine, carmustine, lomustine, streptozotocin, carboplatin, cisplatin, oxaliplatin, iproplatin, tetraplatin, lobaplatin, JM216, JM335, fludarabine, aminoglutethimide, flutamide, goserelin, leuprolide, megestrol acetate, cyproterone acetate, tamoxifen, anastrozole, bicalutamide, dexamethasone, diethylstilbestrol, prednisone, bleomycin, dactinomycin, daunorubicin, doxirubicin, idarubicin, mitoxantrone, losoxantrone, mitomycin-c, plicamycin, paclitaxel, docetaxel, CPT-11, epothilones , topotecan, irinotecan, 9-amino camptothecan, 9-nitro camptothecan, GS-211, etoposide, teniposide, vinblastine, vincristine, vinorelbine, procarbazine, asparaginase, pegaspargase, methoxtrexate, octreotide, estramustine, and hydroxyurea. 35. A method of inhibiting CDK1 activity, comprising administering to a patient in need thereof an efective CDK1 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 36. A method of inhibiting CDK2 activity, comprising administering to a patient in need thereof an efective CDK2 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 37. A method of inhibiting CDK3 activity, comprising administering to a patient in need thereof an efective CDK3 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 38. A method of inhibiting CDK4 activity, comprising administering to a patient in need thereof an efective CDK4 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 39. A method of inhibiting CDK5 activity, comprising administering to a patient in need thereof an efective CDK5 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 40. A method of inhibiting CDK6 activity, comprising administering to a patient in need thereof an efective CDK6 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 41. A method of inhibiting CDK7 activity, comprising administering to a patient in need thereof an efective CDK7 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 42. A method of inhibiting CDK8 activity, comprising administering to a patient in need thereof, an efective CDK8 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 43. A method of inhibiting CDK9 activity, comprising administering to a patient in need thereof an efective CDK9 inhibitory amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof. 44. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; and R.sup.14 is, at eacb occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and bonzyl. 45. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is incdependcenLly at each occurrence selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14 ; R.sup.13, R.sup.13a and R.sup.13b are each independently selected from the group: H or methyl; and R.sup.14 is independlently selected from the group: H, methyl, phenyl, and benzyl. 46. A compound according to claim 1, wherein: R.sup.1 is, phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic hetcrocycle substituted with 0-3 R.sup.6 ; and R.sup.6 is NH.sub.2. 47. A coompound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected trom the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, pheniyl, and benzyl; and R.sup.2 is phenyl substituted with 0-3 R.sup.8, naphthyl substituted with 0-3 R.sup.8 or or 5-6 membered aromatic heterocycle hecterocycle substituted with 0-3 R.sup.8. 48. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attachod to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sub.13a and R.sup.13b are, at each occurrence, independently selcected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl; and R.sup.2 is C.sub.3-6 saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered saturated heterocycle substituted with 0-5 R.sup.8. 49. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6 ; or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14,--CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl; and R.sup.2 is C.sub.5-6 partially saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered partially saturated heterocycle substituted with 0-5 R.sup.8. 50. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sub.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl; R.sup.2 is phenyl substituted with 0-3 R.sup.8, naphthyl substituted with 0-3 R.sup.8 or or 5-6 membered aromatic heterocycle heterocycle substituted with 0-3 R.sup.8 ; and R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.8s are attached to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--. 51. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached Lo two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl; R.sup.2 is C.sub.3-6 saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered saturated heterocycle substituted with 0-5 R.sup.8 ; and R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.8s are attached to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--. 52. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; p1 R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14,--CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s nay combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl; R.sup.2 is C.sub.5-6 partially saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered partially saturated heterocycle substituted with 0-5 R.sup.8 ; and R.sup.8 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O , OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.8s are attached to two adjacent carbon atoms, the two R.sup.8s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--. 53. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic hotcrocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.2 is phenyl substituted with R.sup.8, naphthyl substituted with R.sup.8 or or 5-6 membered aromatic heterocycle heterocycle substituted with R.sup.8 ; R.sup.8 is OR.sup.14 or piperazinyl; and R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl. 54. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to form --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.2 is C.sub.3-6 saturated carbocycle substituted with R.sup.8, or 5-7 membered saturated heterocycle substituted with R.sup.8 ; R.sup.8 is OR.sup.14 or piperazinyl; and R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl. 55. A compound according to claim 1, wherein: R.sup.1 is phenyl substituted with 1-3 R.sup.6, naphthyl substituted with 0-3 R.sup.6, or 5-6 membered aromatic heterocycle substituted with 0-3 R.sup.6 ; R.sup.6 is, at each occurrence, independently selected from the group: halo, --CN, NO.sub.2, C.sub.1-4 alkyl, C.sub.1-4 haloalkyl, NR.sup.13 R.sup.13a, NR.sup.13 NR.sup.13a R.sup.13b, NR.sup.13 C(O)OR.sup.14, NR.sup.13 C(O)R.sup.14, .dbd.O, OR.sup.14, SR.sup.14, --CF3, COR.sup.14, CO.sub.2 R.sup.14, CONR.sup.13 R.sup.13a, NHC(O)NR.sup.13 R.sup.13a, NHC(S)NR.sup.13 R.sup.13a, SO.sub.2 NR.sup.13 R.sup.13a, and SO.sub.2 R.sup.14, or when two R.sup.6s are attached to two adjacent carbon atoms, the two R.sup.6s may combine to fonn --OCH.sub.2 O-- or --OCH.sub.2 CH.sub.2 O--; R.sup.13, R.sup.13a and R.sup.13b are, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl and benzyl; R.sup.2 is C.sub.5-6 partially saturated carbocycle substituted with 0-5 R.sup.8, or 5-7 membered partially saturated heterocycle substituted with 0-5 R.sup.8 ; R.sup.8 is OR.sup.14 or piperazinyl; and R.sup.14 is, at each occurrence, independently selected from the group: H, C.sub.1-4 alkyl, phenyl, and benzyl. 56. A method of treating cancer associated with CDK activity in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof, wherein the cancer is selected from the group consisting of; carcinoma of the bladder, breast, colon, kidney, liver, lung, esophagus, gall-bladder, ovary, pancreas, stomach, cervix, thyroid, prostate, and skin; small cell lung cancer, squamous cell carcinoma, henatopoietic tumors of lymphoid lineage selected from the group consisting of leukemia, acute lymphocytic leukemia, acute lymphoblastic leukemia, B-cell lymphoma, T-cell-lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy cell lymphoma and Burkett's lymphoma; hematopoietic tumors of myeloid lineage selected from the group consisting of acute and chronic myelogenous leukemias, myelodysplastic syndrome and promyelocytic leukemia; tumors of mesenchymal origin selected from the group consisting of fibrosarcoma and rhabdomyosarcoma; turors of the central and peripheral nervous system selected from the group consisting of astrocytoma, neuroblastoma, glioma and schwannomas; other tumors selected from the group consisting of melanoma, seminoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, keratoctanthoma, thyroid follicular cancer and Kaposi's sarcoma. 57. A method of treating cancer associated with CDK activity in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound according to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof, in combination (administered together or sequentially) with radiation therapy cytostatic or cytotoxic agents, wherein such agents are selected from the group consisting of: DNA interactive agents selected from the group consisting of cisplatin and doxorubicin; topoisomerase II inhibitors selected from the group consisting of etoposide; topoisomerase I inhibitors selected fromn the group consisting of CPT-11 and topotecan; thymidilate synthase inhibitors selected from the group consisting of 5-fluorouracil; and anti-metabolites selected from the group consisting of methoxtrexate, tubulin interacting agents selected from the group consisting of paclitaxel, docetaxel and the epothilones; hormonal agents selected from the group consisting of tamoxifen. 58. A pharmaceutical kit for treating a cell proliferative disease associated with CDK activity, said kit comprising a plurality of separate containers, wherein at least one of said containers contains a compound accordig to claim 1, or a pharmaceutically acceptable salt or prodrug form thereof, and at least another of said containers contains one or more compounds selected from the group consisting of cytostatic and cytotoxic agents. 59. A pharmaceutical kit according to claim 58 wherein the cytostatic and cytotoxic agents are selected from the group consisting of DNA interactive agents selected from the group consisting of: carboplatin, cisplatin and doxorubicin; topoisomerase II inhibitors selected from the group consisting of: etoposide; topoisomerase I inhibitors selected from the group consisting of: CPT-11 and topotecan; tubulin interacting agents selected from the group consisting of: paclitaxel, taxane, docetaxel and epothilone; hormonal agents selected from the group consisting of: tamoxifen; thymidilate synthase inhibitors selected from the group consisting of: 5-fluorouracil; and anti-metabolites selected from the group consisting of: methoxtrexate, and said containers optionally contain a pharmaceutical carrier.

Details for Patent 6,291,504

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Recordati Rare Diseases, Inc.	ELSPAR	asparaginase	For Injection	101063	01/10/1978		2039-02-26
Servier Pharmaceuticals Llc	ONCASPAR	pegaspargase	Injection	103411	02/01/1994		2039-02-26