Patent NZ-507567-A (NZ)
Title: 5-aminoindeno(1,2-c)pyrazol-4-ones as anti-cancer and anti-proliferative agents
Inventor: CARINI DAVID J
IPC: A61K31/416
Filed: 1999-04-20
Abstract: A compound of formula (I) or a stereoisomer or pharmaceutically acceptable salt form thereof, wherein:  X is selected from the group: O, S, and NR;  R is selected from the group: H, C1-4 alkyl, and NR5R5a;  R1 is selected from the group: H, C1-10 alkyl substituted with 0-3 RC, C2-10 alkenyl substituted with 0-3 Rc, C2-10  alkynyl substituted with 0-3 Rc,-NHR4, C3-10 membered carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;  Ra is independently selected from the groups: halo,-CN, N3, N02, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, =O, OR3, COR3, CO2R3,CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, NR3C(O)OR3, NR3C(O)R3, S02NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; or, when two Ra's are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; Rb is independently selected from the groups: halo,-CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, and SO2R3b ;  Rc is independently selected from the groups: halo,-CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a,  NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, =O, OR3, COR3 , CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2N3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3;  R2 is selected from the groups: H, C1-10 alkyl substituted with 0-3 Rc, C2-l0 alkenyl substituted with 0-3 RC, C2-10 alkynyl substituted with 0-3 Rc, -(CF2)mCF3, C3-10 carbocycle substituted with 0-5 Ra, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb;  R3 is selected from the group: H, halo,-CN, NO2, C1-4 haloalkyl, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, =O, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, and benzyl;  R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;  or R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S, or 0 atom and substituted with 0-3 R3c;  R3b is selected from the group: H, C1-4 alkyl, phenyl, and benzyl;  R3c is independently at each occurrence selected from the group: halo,-CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3b, =O, OR3, COR3, CO2R3, CONR3R3b, NHC(O)NR3R3b, NHC(S)NR3R3b, NR3C(O)OR3, NR3C(O)R3, SO2NR3R3b, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S;  R4 is independently at each occurrence selected from the group: H, -CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3 ;  R5 is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl; R5a is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl; or, R5 and R5a together with the atoms to which they are attached, form a heterocycle having 4-8 atoms in the ring containing an additional 0-1 N, S, or O atom; R5b is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl;  and m is selected from 0,1,2, and 3. Provided that: when R2 is a C1-4 unsubstituted, branched alkyl then R1 is not CH3; or when R1 is NHR4 and R4 is NR3R3a then R3 and R3a cannot both be phenyl. Also described is a pharmaceutical compound comprising the compound of formula (I) which is useful for treating cell proliferative disease associated with CDK activity i.e. cancer, inhibiting tumor angiogenesis and metastasis, modulating levels of cellular RNA and DNA synthesis and to inhibit CDK1-9 activity.