5-AMINOINDENO(1,2-)PYRAZOL-4-ONES AS ANTI-CANCER AND ANTI-PROLIFERATIVE AGENTS

• Main Authors: CARINI, DAVID, J, NUGIEL, DAVID, A, YUE, EDDY, W, DIMEO, SUSAN, V
• Format: Patent
• Language: English; Russian
• Published: 26.08.2004
• Edition: 7
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; HUMAN NECESSITIES; HYGIENE; MEDICAL OR VETERINARY SCIENCE; METALLURGY; ORGANIC CHEMISTRY; PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES; SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS ORMEDICINAL PREPARATIONS

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 R ; R is selected from the group: H, C1-10alkyl substituted with 0-3 R, C2-10alkenyl substituted with 0-3 R, C2-10alkynyl substituted with 0-3 R,-NHR , C3-10carbocycle substituted with 0-5 R, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R; R is independently at each occurrence selected from the group: halo, -CN, N3, NO2, C1-4alkyl, C1-4haloalkyl, NR R , =O, OR , COR , CO2R, CONR R , NHC(O)NR R , NHC(S)NR R , NR C(O)OR , NR C(O)R , SO2NR R , SO2R , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; alternatively, when two R's are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; R is independently at each occurrence selected from the group: halo, -CN, NO2, C1-4alkyl, C1-4haloalkyl, NR R , NR C(O)OR , NR C(O)R , OR , COR , CO2R , CONR R , NHC(O)NR R , NHC(S)NR R , SO2NR R , and SO2R ; R is independently at each occurrence selected from the group: halo, -CN, NO2, C1-4alkyl, C1-4haloalkyl, NR R , NR NR R , NR C(O)OR , NR C(O)R , =O, OR , COR , CO2R , CONR R , NHC(O)NR R , NHC(S)NR R , SO2N3R , SO2R , C3-10carbocycle substituted with 0-5 R, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R ; R is selected from the group: H, C1-10alkyl substituted with 0-3 R, C2-10alkenyl substituted with 0-3 R, C2-10alkynyl substituted with 0-3 R, -(CF2)mCF3, C3-10carbocycle substituted with 0-5 R, and 3-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R; R is selected from the group: H, halo, -CN, NO2, C1-4haloalkyl, NR R , NR NR R , NR C(O)OR , (O)OR , NR C(O)R , =O, OR , COR , CO2R , CONR R , NHC(O)NR R , NHC(S)NR R , SO2NR R , SO2R , C1-4alkyl, phenyl, and benzyl; R is selected from the group: H, C1-4alkyl, phenyl, and benzyl; alternatively, R and R , 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 ; R is selected from the group: H, C1-4alkyl, phenyl, and benzyl; R is independently at each occurrence selected from the group: halo, -CN, N3, NO2, C1-4alkyl, C1-4haloalkyl, NR R , =O, OR , COR , CO2R , CONR R , NHC(O)NR R , NHC(S)NR R , NR C(O)OR , NR C(O)R , SO2NR R , SO2R , and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; R is independently at each occurrence selected from the group: H, -CN, C1-4lkyl, C1-4haloalkyl, NR R , NR C(O)OR , NR C(O)R , OR , COR , CO2R , CONR R , NHC(O)NR R , NHC(S)NR R , SO2NR R , SO2R , C3-10carbocycle substituted with 0-5 R, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R ; R is independently selected from the group: H, C1-4alkyl, phenyl and benzyl; R a is independently selected from the group: H, C1-4alkyl, phenyl and benzyl; R 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 is an unsubstituted branched C1-4alkyl, then R is not CH3; or when R is NHR , and R is NR R , then R and R can not be both phenyl. 2. A compound according to claim 1, wherein X is O or S; R is H, C1-C10alkyl substituted with 0-3 R, NHR , C3-C10carbocycle substituted with 0-5 R or 3-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S and substituted with 0-5 R; R is independently selected from the group: halo, C3-C10carbocycle substituted with 0-5 R, and 5-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S substituted with 0-3 R , NR R ; R 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 ; R is selected from the group: H, C1-C4alkyl, NR R , C3-C10carbocycle substituted with 0-5 R, or 5-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S, substituted with 0-3 R ; R is selected from the group: C3-C10carbocycle substituted with 0-5 R and 3-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S and substituted with 0-5 R and C1-C10alkyl substituted with 0-3 R; 3. A compound according to claim 1, wherein X is selected from the group: O or S; R is selected from the group: C1-C4alkyl substituted with 0-3 R, wherein R is independently selected from the group consisting of C3-C6carbocycle substituted with 0-5 R, 5-6-membered heterocycle substituted with 0-3 R , NR R and OR ; C3-C6carbocycle substituted with 0-5 R, wherein R is independently selected from the group consisting of OR , halo, C1-C4-alkyl, NR C(O)R , COR , CO2R , N3, NR C(O)OR , NR R , CONR R , and 5-6-membered heterocycle; or when two R's are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; or 5-6-membered heterocycle substituted with 0-5 R, wherein R is independently selected from the group: OR , halo, COR , C1-C4-alkyl, CO2R , NR C(O)R , NR C(O)OR , NR R and CONR R ; R is selected from the group: C3-C6-carbocycle substituted with 0-5 R, wherein R is independently selected from the group consisting of OR , halo, C1-C4-alkyl, NR C(O)R , COR , CO2R , N3, NR C(O)OR , NR R , CONR R , and 5-6-membered heterocycle; or when two R'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, wherein R is independently selected from the group: OR , halo, COR , C1-C4-alkyl, CO2R , NR C(O)R , NR C(O)OR , NR R and CONR R ; or C1-C10alkyl substituted with 0-3 R, wherein R is independently selected from the group consisting of C3-C6carbocycle substituted with 0-5 R, 5-6-membered heterocycle substituted with 0-3 R , NR R and OR . 4. A compound according to claim 1, wherein X is selected from the group: O or S; R is selected from the group: H, NHR , C1-C4alkyl substituted with 0-3 R, C3-C6carbocycle substituted with 0-5 R or 5-6-membered heterocycle substituted with 0-5 R; R is selected from the group: C3-C6carbocycle substituted with 0-5 R, 3-10-membered heterocycle containing from 1-4 heteroatoms selected from O, N and S, and substituted with 0-5 R and C1-C10alkyl substituted with 0-3 R, C2-C10alkenyl substituted with 0-3 R; R is independently selected from the group: H, C1-C4-alkyl, NR R , C3-C6carbocycle substituted with 0-5 R, and 5-6-membered heterocycle substituted with 0-3 R ; R is selected from the group: H, halo, COR , CO2R , CONR R , NR C(O)OR , NR C(O)R , C1-C4alkyl, phenyl and benzyl; R is independently selected from the group: H, C1-C4alkyl, phenyl and benzyl; or, R and R 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 ; R is independently selected from the group: C3-C6carbocycle substituted with 0-5 R, and 5-6-membered heterocycle substituted with 0-3 R , NR R and OR ; R is independently selected from the group: OR , halo, C1-C4-alkyl, NR C(O)R , COR , CO2R , N3, NR C(O)OR , NR R , CONR R , 5-6-membered heterocycle; or when two R's are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; R is independently selected from the group: OR , halo, COR , C1-C4-alkyl NR C(O)R , NR C(O)OR , NR R , CO2R , CONR R ; R is independently selected from the group: OR , halo, COR , CO2R , N3, NR R , C1-C4-alkyl, NR C(O)R , NR C(O)OR , CONR R and 5-6-membered heterocycle; m is 1, 2, 3 and 4. 5. A compound according to claim 1, wherein R is selected from the group: -NHR and C1-C2alkyl, substituted with 1 R. 6. A compound according to claim 1, wherein X is O or S; and R is selected from the group: H, C1-C4alkyl substituted with 0-3 R, C2-C4alkenyl substituted with 0-3 R, C2-C4 alkynyl substituted with 0-3 R, -NHR , C3-C6carbocycle substituted with 0-5 R, and 3-6-membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, and substituted with 0-5 R. 7. A compound according to claim 1, wherein X is O or S; and R selected from the group: H, C1-C4alkyl substituted with 0-3 R, C2-C4alkenyl substituted with 0-3 R, C2-C4alkynyl substituted with 0-3 R, -NHR , C3-C6carbocycle substituted with 0-5 R, and 3-6-membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 R; R is independently at each occurrence selected from the group: -CH2N(CH3)2, -CH2NH2, -SH, -SCH3, -NR3C(O)R3, -N3, halo, C1-C4 alkyl, NR R , and OR ; or, when two R's are present on adjacent carbon atoms they combine to form -OCH2O- or -OCH2CH2O-; R independently at each occurrence selected from the group: halo, C1-C4alkyl, NR R , OR , COR , and CO2R ; R independently Настоящее изобретение относится к новому классу индено[1,2-с]пиразол-4-онов формулы (I)которые являются сильными ингибиторами класса ферментов, известных как циклинзависимые киназы, которые относятся к каталитическим субъединицам cdk1-7 и их регуляторным субъединицам, известным как циклины A-G. Изобретение также относится к новому способу лечения рака и других пролиферативных заболеваний путем введения терапевтически эффективного количества одного из этих соединений или его фармацевтически приемлемой соли. Возможно также лечение рака или других пролиферативных заболеваний путем введения терапевтически эффективной комбинации одного из соединений настоящего изобретения и одного или более других хорошо известных противораковых или антипролиферативных агентов.