Patent EA-004805-B1 (EA)
Title: 5-aminoindeno(1,2-)pyrazol-4-ones as anti-cancer and anti-proliferative agents
Inventor: NUGIEL DAVID A
IPC: C07D413/14
Filed: 1999-04-20
Abstract: 1. A compound according to 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, C1-4alkyl, and NR<5>R<5A>; R<1> is selected from the group: H, C1-10alkyl substituted with 0-3 R<C>, C2-10alkenyl substituted with 0-3 R<C>, C2-10alkynyl substituted with 0-3 R<C>,-NHR<4>, C3-10carbocycle substituted with 0-5 R<A>, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R<B>; R<A> is independently at each occurrence selected from the group: halo, -CN, N3, NO2, C1-4alkyl, C1-4haloalkyl, NR<3>R<3A>, =O, OR<3>, COR<3>, CO2R, CONR<3>R<3A>, NHC(O)NR<3>R<3A>, NHC(S)NR<3>R<3A>, NR<3>C(O)OR<3>, NR<3>C(O)R<3>, SO2NR<3>R<3A>, SO2R<3B>, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; alternatively, when two R<A>'s are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; R<B> is independently at each occurrence selected from the group: halo, -CN, NO2, C1-4alkyl, C1-4haloalkyl, NR<3>R<3A>, NR<3>C(O)OR<3>, NR<3>C(O)R<3>, OR<3>, COR<3>, CO2R<3>, CONR<3>R<3A>, NHC(O)NR<3>R<3A>, NHC(S)NR<3>R<3A>, SO2NR<3>R<3A>, and SO2R<3B>; R<C> is independently at each occurrence selected from the group: halo, -CN, NO2, C1-4alkyl, C1-4haloalkyl, NR<3>R<3A>, NR<5>NR<5>R<5A>, NR<3>C(O)OR<3>, NR<3>C(O)R<3>, =O, OR<3>, COR<3>, CO2R<3>, CONR<3>R<3A>, NHC(O)NR<3>R<3>, NHC(S)NR<3>R<3A>, SO2N3R<3A>, SO2R<3B>, C3-10carbocycle substituted with 0-5 R<A>, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R<3>; R<2> is selected from the group: H, C1-10alkyl substituted with 0-3 R<C>, C2-10alkenyl substituted with 0-3 R<C>, C2-10alkynyl substituted with 0-3 R<C>, -(CF2)mCF3, C3-10carbocycle substituted with 0-5 R<A>, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R<B>; R<3> is selected from the group: H, halo, -CN, NO2, C1-4haloalkyl, NR<5>R<5A>, NR<5>NR<5>R<5A>, NR<5>C(O)OR<5>, (O)OR<5>, NR<5>C(O)R<5>, =O, OR<5>, COR<5>, CO2R<5>, CONR<5>R<5A>, NHC(O)NR<5>R<5A>, NHC(S)NR<5>R<5A>, SO2NR<5>R<5A>, SO2R<5B>, C1-4alkyl, phenyl, and benzyl; R<3A> is selected from the group: H, C1-4alkyl, phenyl, and benzyl; alternatively, R<3> and R<3A>, 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 O atom and substituted with 0-3 R<3C>; R<3B> is selected from the group: H, C1-4alkyl, phenyl, and benzyl; R<3C> is independently at each occurrence selected from the group: halo, -CN, N3, NO2, C1-4alkyl, C1-4haloalkyl, NR<3>R<3B>, =O, OR<3>, COR<3>, CO2R<3>, CONR<3>R<3B>, NHC(O)NR<3>R<3B>, NHC(S)NR<3>R<3B>, NR<3>C(O)OR<3>, NR<3>C(O)R<3>, SO2NR<3>R<3B>, SO2R<3B>, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; R<4> is independently at each occurrence selected from the group: H, -CN, C1-4lkyl, C1-4haloalkyl, NR<3>R<3A>, NR<3>C(O)OR<3>, NR<3>C(O)R<3>, OR<3>, COR<3>, CO2R<3>, CONR<3>R<3A>, NHC(O)NR<3>R<3A>, NHC(S)NR<3>R<3A>, SO2NR<3>R<3A>, SO2R<3B>, C3-10carbocycle substituted with 0-5 R<A>, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R<3>; R<5> is independently selected from the group: H, C1-4alkyl, phenyl and benzyl; R<5>a is independently selected from the group: H, C1-4alkyl, phenyl and benzyl; R<5B> is independently selected from the group: H, C1-4alkyl, phenyl and benzyl; and m is selected from 0, 1, 2, and 3; provided that when R<2> is an unsubstituted branched C1-4alkyl, then R<1> is not CH3; or when R<1> is NHR<4>, and R<4> is NR<3>R<3A>, then R<3> and R<3A> can not be both phenyl. 2. A compound according to claim 1, wherein X is O or S; R<1> is H, C1-C10alkyl substituted with 0-3 R<C>, NHR<4>, C3-C10carbocycle substituted with 0-5 R<A> or 3-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S and substituted with 0-5 R<B>; R<C> is independently selected from the group: halo, C3-C10carbocycle substituted with 0-5 R<A>, and 5-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S substituted with 0-3 R<3>, NR<3>R<3A>; R<3> is selected from the group: H, C1-C4alkyl, phenyl and benzyl, or together with the atoms to which they are attached, form heterocycle having 4-8 atoms in the ring and containing an additional 0-1 N, S or O atom substituted with 0-3 R<3C>; R<4> is selected from the group: H, C1-C4alkyl, NR<3>R<3A>, C3-C10carbocycle substituted with 0-5 R<A>, or 5-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S, substituted with 0-3 R<3>; R<2> is selected from the group: C3-C10carbocycle substituted with 0-5 R<A> and 3-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S and substituted with 0-5 R<B> and C1-C10alkyl substituted with 0-3 R<C>; 3. A compound according to claim 1, wherein X is selected from the group: O or S; R<1> is selected from the group: C1-C4alkyl substituted with 0-3 R<C>, wherein R<C> is independently selected from the group consisting of C3-C6carbocycle substituted with 0-5 R<A>, 5-6-membered heterocycle substituted with 0-3 R<3>, NR<3>R<3A> and OR<3>; C3-C6carbocycle substituted with 0-5 R<A>, wherein R<A> is independently selected from the group consisting of OR<3>, halo, C1-C4-alkyl, NR<3>C(O)R<3>, COR<3>, CO2R<3>, N3, NR<3>C(O)OR<3>, NR<3>R<3A>, CONR<3>R<3A>, and 5-6-membered heterocycle; or when two R<A>'s are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; or 5-6-membered heterocycle substituted with 0-5 R<B>, wherein R<B> is independently selected from the group: OR<3>, halo, COR<3>, C1-C4-alkyl, CO2R<3>, NR<3>C(O)R<3>, NR<3>C(O)OR<3>, NR<3>R<3A> and CONR<3>R<3A>; R<2> is selected from the group: C3-C6-carbocycle substituted with 0-5 R<A>, wherein R<A> is independently selected from the group consisting of OR<3>, halo, C1-C4-alkyl, NR<3>C(O)R<3>, COR<3>, CO2R<3>, N3, NR<3>C(O)OR<3>, NR<3>R<3A>, CONR<3>R<3A>, and 5-6-membered heterocycle; or when two R<A>'s are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; 3-6-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S, and substituted with 0-5 R<B>, wherein R<B> is independently selected from the group: OR<3>, halo, COR<3>, C1-C4-alkyl, CO2R<3>, NR<3>C(O)R<3>, NR<3>C(O)OR<3>, NR<3>R<3A> and CONR<3>R<3A>; or C1-C10alkyl substituted with 0-3 R<C>, wherein R<C> is independently selected from the group consisting of C3-C6carbocycle substituted with 0-5 R<A>, 5-6-membered heterocycle substituted with 0-3 R<3>, NR<3>R<3A> and OR<3>. 4. A compound according to claim 1, wherein X is selected from the group: O or S; R<1> is selected from the group: H, NHR<4>, C1-C4alkyl substituted with 0-3 R<C>, C3-C6carbocycle substituted with 0-5 R<A> or 5-6-membered heterocycle substituted with 0-5 R<B>; R<2> is selected from the group: C3-C6carbocycle substituted with 0-5 R<A>, 3-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S, and substituted with 0-5 R<B> and C1-C10alkyl substituted with 0-3 R<C>, C2-C10alkenyl substituted with 0-3 R<C>; R<4> is independently selected from the group: H, C1-C4-alkyl, NR<3>R<3A>, C3-C6carbocycle substituted with 0-5 R<A>, and 5-6-membered heterocycle substituted with 0-3 R<3>; R<3> is selected from the group: H, halo, COR<5>, CO2R<5>, CONR<5>R<5A>, NR<5>C(O)OR<5>, NR<5>C(O)R<5>, C1-C4alkyl, phenyl and benzyl; R<3A> is independently selected from the group: H, C1-C4alkyl, phenyl and benzyl; or, R<3> and R<3A> together with the atoms to which they are attached, form 5-6-membered heterocycle containing an additional 0-1 N, S or O atoms substituted with 0-3 R<3C>; R<C> is independently selected from the group: C3-C6carbocycle substituted with 0-5 R<A>, and 5-6-membered heterocycle substituted with 0-3 R<3>, NR<3>R<3A> and OR<3>; R<A> is independently selected from the group: OR<3>, halo, C1-C4-alkyl, NR<3>C(O)R<3>, COR<3>, CO2R<3>, N3, NR<3>C(O)OR<3>, NR<3>R<3A>, CONR<3>R<3A>, 5-6-membered heterocycle; or when two R<A>'s are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; R<B> is independently selected from the group: OR<3>, halo, COR<3>, C1-C4-alkyl NR<3>C(O)R<3>, NR<3>C(O)OR<3>, NR<3>R<3A>, CO2R<3>, CONR<3>R<3A>; R<3C> is independently selected from the group: OR<3>, halo, COR<3>, CO2R<3>, N3, NR<3>R<3B>, C1-C4-alkyl, NR<3>C(O)R<3>, NR<3>C(O)OR<3>, CONR<3>R<3B> and 5-6-membered heterocycle; m is 1, 2, 3 and 4. 5. A compound according to claim 1, wherein R<1> is selected from the group: -NHR<4> and C1-C2alkyl, substituted with 1 R<C>. 6. A compound according to claim 1, wherein X is O or S; and R<1> is selected from the group: H, C1-C4alkyl substituted with 0-3 R<C>, C2-C4alkenyl substituted with 0-3 R<C>, C2-C4 alkynyl substituted with 0-3 R<C>, -NHR<4>, C3-C6carbocycle substituted with 0-5 R<C>, and 3-6-membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and substituted with 0-5 R<B>. 7. A compound according to claim 1, wherein X is O or S; and R<1> selected from the group: H, C1-C4alkyl substituted with 0-3 R<C>, C2-C4alkenyl substituted with 0-3 R<C>, C2-C4alkynyl substituted with 0-3 R<C>, -NHR<4>, C3-C6carbocycle substituted with 0-5 R<A>, and 3-6-membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R<B>; R<A> is independently at each occurrence selected from the group: -CH2N(CH3)2, -CH2NH2, -SH, -SCH3, -NR3C(O)R3, -N3, halo, C1-C4 alkyl, NR<3>R<3A>, and OR<3>; or, when two R<A>'s are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; R<B> independently at each occurrence selected from the group: halo, C1-C4alkyl, NR<3>R<3A>, OR<3>, COR<3>, and CO2R<3>; R<C> independently