Claims
- 1. A compound according to formula (I):
- 2. A compound according to claim 1, 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, C1-5 alkyl substituted with 0-3 Rc, C2-5 alkenyl substituted with 0-3 Rc, C2-5 alkynyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; R2 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, C2-5 alkenyl substituted with 0-3 Rc, C2-5 alkynyl substituted with 0-3 Rc, —(CF2)mCF3, C3-6 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, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; and provided that if R3 is phenyl, it is substituted with 1-5 Ra; 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; provided that at least one R3 is present and that this R3 is selected from the group: C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; Ra is independently at each occurrence selected from the group: halo, —CN, N3, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, NHC(S)NR3R3a, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—; Rb is independently at each occurrence selected from the group: 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 at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, NR5NR5R5a, ═O, 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; R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl; alternatively, R3 and R3a, together with the nitrogen atom 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 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, NR3 R3b, ═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; 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; R5b is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl; R6 is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5; and m is selected from 0, 1, 2, and 3.
- 3. A compound according to claim 2, wherein:
X is selected from the group: O and S; R1 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, C2-5 alkenyl substituted with 0-3 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; R2 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, C2-5 alkenyl substituted with 0-3 Rc, —(CF2)mCF3, C3-6 carbocycle substituted with 0-5 Ra, and 3-6 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, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; and provided that if R3 is phenyl, it is substituted with 1-5 Ra; 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; provided that at least one R3 is present and that this R3 is selected from the group: C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; Ra is independently at each occurrence selected from the group: halo, —CN, N3, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, SO2R3b, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—; Rb is independently at each occurrence selected from the group: halo, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, and SO2R3b; Rc is independently at each occurrence selected from the group: halo, —CN, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, ═O, OR3, COR3, CO2R3, CONR3R3a, NHC(O)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; R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl; alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 5-6 atoms in the ring containing an additional 0-1 N, S, or O 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; 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; R5b is independently selected from the group: H, C1-4 alkyl, phenyl, and benzyl; R6 is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5; and m is selected from 0, 1, 2, and 3.
- 4. A compound according to claim 3, wherein:
X is selected from the group: O and S; R1 is selected from the group: H, C1-5 alkyl substituted with 0-2 Rc, —NHR4, C3-6 carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-5 Rb; R2 is selected from the group: H, C1-5 alkyl substituted with 0-3 Rc, —(CF2)mCF3, C3-6 carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S and substituted with 0-3 Rb; R3 is selected from the group: H, halo, —CN, NO2, C1-4 haloalkyl, NR5R5a, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C1-4 alkyl, phenyl, benzyl, C1-4 alkyl substituted with 1-3 Rc, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; and provided that if R3 is phenyl, it is substituted with 1-5 Ra; 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; provided that at least one R3 is present and that this R3 is selected from the group: C1-4 alkyl substituted with 1-3 R6, C5-10 alkyl substituted with C2-10 alkenyl optionally substituted with 0-3 R6, C2-10 alkynyl substituted with 0-3 R6, —(CF2)mCF3, C3-10 carbocycle substituted with 0-5 R6, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R6; Ra is independently at each occurrence selected from the group: halo, —CN, N3, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, SO2R3b, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S; alternatively, when two Ra's are present on adjacent carbon atoms they combine to form —OCH2O— or —OCH2CH2O—; Rb is independently at each occurrence selected from the group: halo, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, and SO2R3b; Rc is independently at each occurrence selected from the group: halo, C1-4 alkyl, C1-4 haloalkyl, NR3R3a, NR5NR5R5a, NR3C(O)OR3, NR3C(O)R3, OR3, COR3, CO2R3, CONR3R3a, NHC(O)NR3R3a, SO2NR3R3a, SO2R3b, C3-10 carbocycle substituted with 0-5 Ra, and 5-6 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R3; R3a is selected from the group: H, C1-4 alkyl, phenyl, and benzyl; alternatively, R3 and R3a, together with the nitrogen atom to which they are attached, form a heterocycle having 5-6 atoms in the ring containing an additional 0-1 N, S, or O 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; R5 is independently selected from the group: H and C1-4 alkyl; R5a is independently selected from the group: H, C1-4 alkyl, phenyl and benzyl; R5b is independently selected from the group: H and C1-4 alkyl; R6 is independently at each occurrence selected from the group: halo, —CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR5R5, NR5NR5R5a, NR5C(O)OR5, NR5C(O)R5, ═O, OR5, COR5, CO2R5, CONR5R5a, NHC(O)NR5R5a, NHC(S)NR5R5a, SO2NR5R5a, SO2R5b, C3-10 carbocycle substituted with 0-5 R5, and 5-10 membered heterocycle containing from 1-4 heteroatoms selected from O, N, and S, substituted with 0-3 R5; and m is selected from 0, 1, 2, and 3.
- 5. A compound according to claim 1, wherein the compound is selected from:
(a) 3-(4-methoxyphenyl)-5-(2-benzoylhydrazinecarboxamido)indeno [1,2-c]pyrazol-4-one; (b) 3-(4-methoxyphenyl)-5-(2-isonicotinoylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; (c) 3-(4-methoxyphenyl)-5-(2-nictinoylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; (d) 3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxybenzoyl) hydrazine carboxamido) indeno[1,2-c]pyrazol-4-one; (e) 3-(4-methoxyphenyl)-5-(2-(4-hydroxybenzoyl)hydrazine carboxamido) indeno[1,2-c]pyrazol-4-one; (f) 3-(4-methoxyphenyl)-5-(2-(3-aminobenzoyl)hydrazine carboxamido) indeno[1,2-c]pyrazol-4-one; (g) 3-(4-methoxyphenyl)-5-(2-(4-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; (h) 3-(4-methoxyphenyl)-5-(2-(2-aminobenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; (i) 3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylaminobenzoyl) hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one; (j) 3-(4-methoxyphenyl)-5-(2-phenethylacetylhydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; (k) 3-(4-methoxyphenyl)-5-(2-(2-hydroxybenzoyl)hydrazine carboxamido)indeno[1,2-c]pyrazol-4-one; and (l) 3-(4-methoxyphenyl)-5-(2-methoxycarbonyl hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one; (m) 1-[3-(4-methoxy-phenyl)-4-oxo-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-3-morpholin-4-yl-urea; (n) [3-(4-methoxy-phenyl)-4-oxo-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-urea; (o) 1-(2-amino-cyclohexyl)-3-[3-(4-methoxy-phenyl)-4-oxo-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-urea; (p) 2-(4-aminomethyl-piperidin-1-yl)-N-[3-(4-methoxy-phenyl)-4-oxo-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-acetamide; (q) 1-[3-(4-methoxy-phenyl)-4-oxo-2,4-dihydro-indeno[1,2-c]pyrazol-5-yl]-3-morpholin-4-yl-urea. or a pharmaceutically acceptable salt thereof.
- 6. A pharmaceutical composition, comprising:
a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1.
- 7. A method of treating cancer and proliferative diseases comprising:
administering to a host in need of such treatment a therapeutically effective amount of a compound of claim 1, or a pharmaceutically acceptable salt or prodrug form thereof.
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part application of U.S. Ser. No. 09/692,023, Filed Oct. 19, 2000, entitled “ACYLSEMICARBAZIDES AND THEIR USES”, which is a non-provisional filing of provisional application 60/160,713, filed Oct. 20, 1999, entitled “ACYLSEMICARBAZIDES AS CYCLIN DEPENDENT KINASE INHIBITORS USEFUL AS ANTI-CANCER AND ANTI-PROLIFERATIVE AGENTS” which applications are herein incorporated by reference in their entirity as though set forth in full.
Provisional Applications (1)
|
Number |
Date |
Country |
|
60160713 |
Oct 1999 |
US |
Continuation in Parts (1)
|
Number |
Date |
Country |
Parent |
09692023 |
Oct 2000 |
US |
Child |
09906963 |
Jul 2001 |
US |