SEMI-CARBAZIDES ACYLE ET UTILISATIONS DE CELLES-CI COMME INHIBITEURS DE KINASE DEPENDANTE DES CYCLINES (CDK)

ACYLSEMICARBAZIDES AND THEIR USE AS CYCLIN DEPENDENT KINASE (CDK) INHIBITORS

Abrégé français

La présente invention concerne la synthèse d'une nouvelle classe de indéno [1,2-c]pyrazol-4-ones représentés par la formule (I), qui sont des inhibiteurs puissants de la classe des enzymes connues sous l'appellation de kinases dépendantes des cyclines, qui sont liés aux sous unités catalytiques cdk1-9 et à leurs sous unités régulatrices connues sous l'appellation de cyclines A-H. Cette invention concerne aussi une nouvelle technique de traitement du cancer ou d'autres maladies proliférantes, qui consiste à administrer une quantité thérapeutiquement efficace de l'un de ces composés ou d'un sel de ceux-ci répondant aux normes pharmaceutiques. Dans un autre mode de réalisation de cette invention, on peut traiter le cancer ou d'autres maladie proliférantes en administrant une combinaison thérapeutiquement efficace de l'un de ces composés et d'un ou de plusieurs autres agents anticancéreux ou inhibiteurs de la prolifération connus.

Abrégé anglais

The present invention realtes to the synthesis fo a new class of indeno [1,2-
c]pyrazol-4-ones of formula (I): 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. The
invention also provides a novel method of treating cancer or otehr
profiferative disease 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 disease by
administering a therapeutically effective combination of one of the compounds
of teh present invention and one or more other known anti-cancer or anti-
proliferative agents.

Revendications

CLAIMS
What is claimed is:
1. A compound of formula (I):
<IMG>
X is O or S;
R1 is -NR3R3a, -CF3, C1-4 alkyl substituted with 1-3 R4, C5-
alkyl substituted with 0-3 R4, C2-C10 alkenyl
substituted with 0-3 R4, C2-C10 alkynyl substituted
with 0-3 R4, C3-C10 carbocycle substituted with 0-5 R6,
or 5-10 membered heterocycle substituted with 0-3 R6;
provided that if R1 is phenyl or benzyl, then R1 is
substituted with 1-5 R6;
R2 is H, C1-10 alkyl substituted with 0-3 R7, C2-10 alkenyl
substituted with 0-3 R7, C2-10 alkynyl substituted with
0-3 R7, -CF3, C3-10 carbocycle substituted with 0-5 R8,
or 3-10 membered heterocycle substituted with 0-5 R8;
R3 and R3a are independently selected from the group: H,
C1-4 alkyl, phenyl and benzyl;
R4 and R7 are, at each occurance, independently selected
from the group: halo, -CN, NO2, -NR9R9a, NR9NR9a R9b,
NR9C(O)OR10, NR9C(O)R10, =O, OR10, SR10, -CF3, COR10,
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CO2R10, CONR9R9a, NHC(O)NR9R9a, NHC(S)NR9R9a,
SO2NR9R9a, SO2R10, C3-10 carbocycle substituted with
0-5 R11, and 5-10 membered heterocycle substituted with
0-3 R11;
R5 is selected from the group: H, -C(O)R12, -C(O)OR12, C1-4
alkyl, phenyl and benzyl;
R6 and R8 are, at each occurance, independently selected
from the group: halo, -CN, NO2, C1-4 alkyl, C1-4
haloalkyl, NR13R13a, NR13NR13a R13b, NR13C(O)OR14,
NR13C(O)R14, =O, OR14, SR14,-CF3, COR14, CO2R14,
CONR13R13a, NHC(O)NR13R13a, NHC(S)NR13R13a,
SO2NR13R13a, SO2R14, C3-10 carbocycle substituted with
0-5 R15, and 5-10 membered heterocycle substituted with
0-3 R15, or when two R6s or R8s are attachd to two
adjacent carbon atoms, the two R6s or R8s may combine
to form -OCH2O- or -OCH2CH2O-;
R9 is, at each occurance, independently selected from the
group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl and
benzyl;
R9b is, at each occurance, independently selected from the
group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl and
benzyl; or
R9 and R9a, together with the nitrogen atom to which they
are attached, form a heterocycle substituted with 0-3
R16;
R9a is selected from the group: H, C1-4 alkyl, phenyl and
benzyl;
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R10, R14, R17 are, at each occurance, independently selected
from the group: H, C1-4 alkyl, phenyl, benzyl;
R11 is, at each occurance, independently selected from the
group: halo, -CN, NO2, C1-4 alkyl, C1-4 haloalkyl,
NR18R18a, NR18NR18a R18b, NR18C(O)OR17, NR18C(O)R17, =O,
OR17, SR17, COR17, CO2R17, CONR18R18a, NHC(O)NR18R18a,
NHC(S)NR18R18a, SO2NR18R18a, SO2R17, C3-10 carbocycle
substituted with 0-5 R19, and 5-10 membered heterocycle
substituted with 0-3 R19;
R13 is is, at each occurance, independently selected from
the group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl
and benzyl;
R13a is, at each occurance, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl; or
R13 and R13a, together with the nitrogen atom to which they
are attached, form a heterocycle substituted with 0-3
R16;
R13b is, at each occurance, independently selected from the
group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl and
benzyl;
R15, R16 and R19 are, at each occurance, independently
selected from the group: halo, -CN, NO2, C1-4 alkyl,
C1-4 haloalkyl, NR20R20a, NR20b NR20R20a, NR20C(O)OR21,
NR20C(O)R21, =O, OR21, SR21, COR21, CO2R21, CONR20R20a,
NHC(O)NR20R20a, NHC(S)NR20R20a, SO2NR20R20a, SO2R21, or
when two R15s, R16s or R19s are attachd to two adjacent
75

carbon atoms, the two R15s R16s or R19s may combine to
form -OCH20- or -OCH2CH20-;
R18 is, at each occurance, independently selected from the
group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl and
benzyl;
R18a is, at each occurance, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;or
R18 and R18a, together with the nitrogen atom to which they
are attached, form a heterocycle substituted with 0-3
R19;
R18b is, at each occurance, independently selected from the
group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl and
benzyl; or
R20 is, at each occurance, independently selected from the
group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl and
benzyl;
R20a is, at each occurance, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R20b is, at each occurance, independently selected from the
group: H, -C(O)R12, -C(O)OR12, C1-4 alkyl, phenyl and
benzyl; and
R12 and R21 are, at each occurance, independently selected
from the group: H, C1-4 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;
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R1 is -NR3R3a, -CF3,C1-C4 alkyl substituted with 1-3 R4, C2-
C4 alkenyl substituted with 0-3 R4, C2-C4 alkynyl
substituted with 0-3 R4, C3-C10 carbocycle substituted
with 0-5 R6, or 5-10 membered heterocycle substituted
with 0-3 R6.
3. A compound accoding to claim 1 wherein:
X is O or S;
R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4,
C2-C4 alkenyl substituted with 0-3 R4, C2-C4 alkynyl
substituted with 0-3 R4, C3-C6 carbocycle substituted
with 0-5 R6, or 5-7 membered heterocycle substituted
with 0-3 R6.
4. A compound accoding to claim 1 wherein:
R1 is C3-C6 saturated carbocycle substituted with 0-5 R6, or
5-7 membered saturated heterocycle substituted with 0-3
R6.
5. A compound accoding to claim 1 wherein:
R1 is C5-C6 partially saturated carbocycle substituted with
0-5 R6, or 5-7 membered partially saturated heterocycle
substituted with 0-3 R6.
6. A compound accoding to claim 1 wherein:
R1 is phenyl substituted with 1-5 R6, naphthyl substituted
with 0-5 R6, or 5-6 membered aromatic heterocycle
substituted with 0-3 R6.
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7. A compound accoding to claim 1 wherein:
R1 is phenyl substituted with 1-3 R6, naphthyl substituted
with 0-3 R6, or 5-6 membered aromatic heterocycle
substituted with 0-3 R6.
8. A compound accoding to claim 1 wherein:
R1 is C3-C10 carbocycle substituted with 0-5 R6, or 5-10
membered heterocycle substituted with 0-3 R6;
R6 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a, NR13NR13a R13b, NR13C(O)OR14, NR13C(O)R14, =O,
OR14, SR14,-CF3, COR14, CO2R14, CONR13R13a,
NHC(O)NR13R13a, NHC(S)NR13R13a, SO2NR13R13a, and
SO2R14, or when two R6s are attached to two adjacent
carbon atoms, the two R6s may combine to form -OCH2O-
or -OCH2CH2O-.
9. A compound accoding to claim 1 wherein:
R6 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a, NR13NR13a R13b, NR13C(O)OR14, NR13C(O)R14, =O,
OR14, SR14,-CF3, COR14, CO2R14, CONR13R13a,
NHC(O)NR13R13a, NHC(S)NR13R13a, SO2NR13R13a, and
SO2R14, or when two R6s are attached to two adjacent
carbon atoms, the two R6s may combine to form -OCH2O-
or -OCH2CH2O-;
78

R13, R13a and R13b are, at each occurrence, independently
selected from the group: H, C1-4 alkyl, phenyl and
benzyl; and
R14 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl, and benzyl.
10. A compound accoding to claim 1 wherein:
R6 is independently at each occurrence selected from the
group: halo, -CN, NO2, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a, NR13C(O)OR14, NR13C(O)R14, OR14, SR14,-CF3,
COR14, CO2R14, CONR13R13a, NHC(S)NR13R13a, SO2NR13R13a,
and SO2R14;
R13, R13a and R13b are each independently selected from the
group: H or methyl; and
R14 is independently selected from the group: H, methyl,
phenyl, and benzyl.
11. A Compound accoding to claim 1 wherein:
X is O or S;
R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4;
R4 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, -NR9R9a, NR9NR9a R9b,
NR9C(O)OR10, NR9C(O)R10, =O, OR10, SR10, -CF3, COR10,
CO2R10, CONR9R9a, NHC(O)NR9R9a, NHC(S)NR9R9a,
SO2NR9R9a, and SO2R10;
R9 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
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R9a is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9b is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl; or
R9 and R9a, together with the nitrogen atom to which they
are attached, form a 5-7 membered heterocycle
substituted with 0-3 R16;
R16 is, at each occurrence, independently selected from the
group consisting of: halo, -CN, NO2, C1-4 alkyl, C1-4
haloalkyl, NR20R20a, NR20b NR20R20a, NR20C(O)OR21,
NR20C(O)R21, =O, OR21, SR21, COR21, CO2R21, CONR20R20a,
NHC(O)NR20R20a, NHC(S)NR20R20a, SO2NR20R20a, and
SO2R21; and
R20, R20a, and R20b are, at each occurrence, independently
selected from the group: H, C1-4 alkyl, phenyl and
benzyl.
12. A compound accoding to claim 1 wherein:
X is O or S;
R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4;
R3 and R3a are independently selected from the group: H,
methyl, phenyl and benzyl;
R4 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, -NR9R9a, NR9NR9a R9b,
NR9C(O)OR10, NR9C(O)R10, =O, OR10, SR10, -CF3, COR10,
CO2R10, CONR9R9a, NHC(O)NR9R9a, NHC(S)NR9R9a,
SO2NR9R9a, SO2R10, C3-10 carbocycle substituted with
80

0-5 R11, and 5-10 membered heterocycle substituted with
0-3 R11;
R9 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9a is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9b is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R10 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl, benzyl; and
R11 is, at each occurrence, independently selected from the
group consisting of: selected from the group: halo,
-CN, NO2, C1-4 alkyl, C1-4 haloalkyl, NR18R18a,
NR18NR18a R18b, NR18C(O)OR17, NR18C(O)R17, =O, OR17,
SR17, COR17, CO2R17, CONR18R18a, NHC(O)NR18R18a,
NHC(S)NR18R18a, SO2NR18R18a, SO2R17, C3-10 carbocycle
substituted with 0-5 R19, and 5-10 membered heterocycle
substituted with 0-3 R19.
13. A compound accoding to claim 1 wherein:
R2 is C1-4 alkyl substituted with 0-3 R7, C2-4 alkenyl
substituted with 0-3 R7, C2-4 alkynyl substituted with
0-3 R7, -CF3, C3-6 carbocycle substituted with 0-5 R8,
or 3-7 membered heterocycle substituted with 0-5 R8.
14. A compound accoding to claim 1 wherein:
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R2 is C1-4 alkyl substituted with 0-3 R7, C2-4 alkenyl
substituted with 0-3 R7, C2-4 alkynyl substituted with
0-3 R7, -CF3, C3-6 carbocycle substituted with 0-5 R8,
or 5-7 membered heterocycle substituted with 0-5 R8.
15. A compound accoding to claim 1 wherein:
R2 is C3-6 saturated carbocycle substituted with 0-5 R8, or
5-7 membered saturated heterocycle substituted with 0-5
R8.
16. A compound accoding to claim 1 wherein:
R2 is C5-6 partially saturated carbocycle substituted with
0-5 R8, or 5-7 membered partially saturated heterocycle
substituted with 0-5 R8.
17. A compound accoding to claim 1 wherein:
R2 is phenyl substituted with 0-5 R8, naphthyl substituted
with 0-5 R8 or or 5-6 membered aromatic heterocycle
heterocycle substituted with 0-5 R8.
18. A compound accoding to claim 1 wherein:
R2 is phenyl substituted with 0-3 R8, naphthyl substituted
with 0-3 R8 or or 5-6 membered aromatic heterocycle
heterocycle substituted with 0-3 R8.
19. A compound accoding to claim 1 wherein:
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R2 is C3-6 carbocycle substituted with 0-5 R8, or 5-7
membered heterocycle substituted with 0-5 R8;
R8 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a, NR13NR13a R13b, NR13C(O)OR14, NR13C(O)R14, =O,
OR14, SR14,-CF3, COR14, CO2R14, CONR13R13a,
NHC(O)NR13R13a, NHC(S)NR13R13a, SO2NR13R13a, and
SO2R14, or when two R8s are attachd to two adjacent
carbon atoms, the two R8s may combine to form -OCH2O-
or -OCH2CH2O-; and
R13 R13a, and R13b are are, at each occurrence,
independently selected from the group: H, C1-4 alkyl,
phenyl and benzyl; or
R13 and R13a, together with the nitrogen atom to which they
are attached, form a 5-7 membered heterocycle
substituted with 0-3 R16.
20. A compound accoding to claim 1 wherein:
R2 is C3-6 carbocycle substituted with 0-5 R8, or 5-7
membered heterocycle substituted with 0-5 R8;
R8 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a, NR13NR13a R13b, NR13C(O)OR14, NR13C(O)R14, =O,
OR14, SR14,-CF3, COR14, CO2R14, CONR13R13a,
NHC(O)NR13R13a, NHC(S)NR13R13a, SO2NR13R13a, SO2R14,
C3-10 carbocycle substituted with 0-5 R15, and 5-10
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membered heterocycle substituted with 0-3 R15,or when
two R8s are attachd to two adjacent carbon atoms, the
two R8s may combine to form -OCH2O- or -OCH2CH2O-;
R13 R13a, and R13b are, at each occurrence, independently
selected from the group: H, C1-4 alkyl, phenyl and
benzyl; and
R15 is, at each occurrence, independently selected from the
group consisting of: halo, -CN, NO2, C1-4 alkyl, C1-4
haloalkyl, NR20R20a, NR20bNR20R20a, NR20C(O)OR21,
NR20C(O)R21, =O, OR21, SR21, COR21, CO2R21, CONR20R20a,
NHC(O)NR20R20a, NHC(S)NR20R20a, SO2NR20R20a, and
SO2R21, or when two R15s, are attachd to two adjacent
carbon atoms, the two R15s may combine to form -OCH20-
or -OCH2CH20-.
21. A compound accoding to claim 1 wherein:
X is O or S;
R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4,
C2-C4 alkenyl substituted with 0-3 R4, C2-C4 alkynyl
substituted with 0-3 R4, C3-C6 carbocycle substituted
with 0-5 R6, or 5-7 membered heterocycle substituted
with 0-3 R6; and
R2 is C1-4 alkyl substituted with 0-3 R7, C2-4 alkenyl
substituted with 0-3 R7, C2-4 alkynyl substituted with
0-3 R7, -CF3, C3-6 carbocycle substituted with 0-5 R8,
or 5-7 membered heterocycle substituted with 0-5 R8.
84

22. A compound accoding to claim 1 wherein:
R1 is phenyl substituted with 1-5 R6, naphthyl substituted
with 0-5 R6, or 5-6 membered aromatic heterocycle
substituted with 0-3 R6;
R2 is C3-6 carbocycle substituted with 0-5 R8, or 5-7
membered heterocycle substituted with 0-5 R8;
R8 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a, NR13NR13aR13b, NR13C(O)OR14, NR13C(O)R14, =O,
OR14, SR14,-CF3, COR14, CO2R14, CONR13R13a,
NHC(O)NR13R13a, NHC(S)NR13R13a, SO2NR13R13a, and
SO2R14, or when two R8s are attachd to two adjacent
carbon atoms, the two R8s may combine to form -OCH2O-
or -OCH2CH2O-; and
R13 R13a and Rl3b are are, at each occurrence,
independently selected from the group: H, C1-4 alkyl,
phenyl and benzyl; or
R13 and Rl3a, together with the nitrogen atom to which they
are attached, form a 5-7 membered heterocycle
substituted with 0-3 R16.
23. A compound accoding to claim 1 wherein:
X is O or S;
R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4;
R2 is C1-4 alkyl substituted with 0-3 R7, C2-4 alkenyl
substituted with 0-3 R7, C2-4 alkynyl substituted with
85

0-3 R7, -CF3, C3-6 carbocycle substituted with 0-5 R8,
or 5-7 membered heterocycle substituted with 0-5 R8;
R4 is, at each occurrence, independently selected from the
group: halo, -CN, NO2, -NR9R9a, NR9NR9aR9b,
NR9C(O)OR10, NR9C(O)R10, =O, OR10, SR10, -CF3, COR10,
CO2R10, CONR9R9a, NHC(O)NR9R9a, NHC(S)NR9R9a,
SO2NR9R9a, and SO2R10;
R9 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9a is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9b is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl; or
R9 and R9a, together with the nitrogen atom to which they
are attached, form a 5-7 membered heterocycle
substituted with 0-3 R16;
R16 is, at each occurrence, independently selected from the
group consisting of: halo, -CN, NO2, C1-4 alkyl, C1-4
haloalkyl, NR20R20a, NR20bNR20R20a, NR20C(O)OR21,
NR20C(O)R21, =O, OR21, SR21, COR21, CO2R21, CONR20R20a,
NHC(O)NR20R20a, NHC(S)NR20R20a, SO2NR20R20a, and
SO2R21; and
R20, R20a, and R20b are, at each occurrence, independently
selected from the group: H, C1-4 alkyl, phenyl and
benzyl.
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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-isonicotinoyl
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-nictinoylhydrazinecarbox
amido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxybenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(4-hydroxybenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(3-aminobenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(4-aminobenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(2-aminobenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylaminobenzoyl)
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-methoxybenzoylhydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
87

3-(4-methoxyphenyl)-5-(2-(2-hydroxybenzoyl)hydrazine
carboxamido)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]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-amido
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-phenylamido
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(4-methylbenzoyl
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(2-naphthoyl)
hydrazinecarboxamido)indeno[1,2-c]pyrazol-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]pyrazol-4-one;
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3-(4-methoxyphenyl)-5-(2-(2-thienoyl)
hydrazinecarboxamido)indeno[1,2-c]pyrazol-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)indeno[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)indeno[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)indeno[1,2-c]pyrazol-4-one; or
89

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 administrering 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 cancer associated with CDK
activity in a patient in need thereof, comprising
administrering 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 such as bladder, breast, colon, kidney, liver,
lung, including small cell lung cancer, esophagus, gall-
bladder, ovary, pancreas, stomach, cervix, thyroid,
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prostate, and skin, including squamous cell carcinoma;
hematopoietic tumors of lymphoid lineage, including
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,
including acute and chronic myelogenous leukemias,
myelodysplastic syndrome and promyelocytic leukemia; tumors
of mesenchymal origin, including fibrosarcoma and
rhabdomyosarcoma; tumors of the central and peripheral
nervous system, including astrocytoma, neuroblastoma, glioma
and schwannomas; other tumors, including melanoma, seminoma,
teratocarcinoma, osteosarcoma, xenoderoma pigmentosum,
keratoctanthoma, thyroid follicular cancer and Kaposi's
sarcoma.
29. A method of treating a disease associated with
apoptosis in a patient in need thereof, comprising
administrering 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.
30. A method of inhibiting tumor angiogenesis and
metastasis in a patient in need thereof, comprising
administrering to said patient a pharmaceutically effective
amount of a compound according to claim 1, or a
pharmaceutically acceptable salt or prodrug form thereof.
31. 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
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amount of a compound according to claim 1, or a
pharmaceutically acceptable salt or prodrug form thereof.
32. 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.
33. 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.
34. A method of inhibiting CDK activity comprising
combining an effective amount of a compound according to
claim 1, with a composition containing CDK.
35. A method of treating cancer associated with CDK
activity in a patient in need thereof, comprising
administrering 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-cancer treatments such as radiation therapy or
with cytostatic or cytotoxic agents, wherein such agents are
selected from the group consisting of: DNA interactive
agents, such as cisplatin or doxorubicin; topoisomerase II
inhibitors, such as etoposide; topoisomerase I inhibitors
such as CPT-11 or topotecan; tubulin interacting agents,
such as paclitaxel, docetaxel or the epothilones; hormonal
agents, such as tamoxifen; thymidilate synthase inhibitors,
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such as 5-fluorouracil; and anti-metabolites, such as
methoxtrexate.
36. A method treating cell proliferative diseases
associated with CDK activity in a patient in need thereof,
comprising administrering 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.
37. A method of inhibiting CDK1 activity, comprising
adminsitering 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.
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38. A method of inhibiting CDK2 activity, comprising
adminsitering 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.
39. A method of inhibiting CDK3 activity, comprising
adminsitering 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.
40. A method of inhibiting CDK4 activity, comprising
adminsitering 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.
41. A method of inhibiting CDK5 activity, comprising
adminsitering 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.
42. A method of inhibiting CDK6 activity, comprising
adminsitering 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.
43. A method of inhibiting CDK7 activity, comprising
adminsitering 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.
44. A method of inhibiting CDK8 activity, comprising
adminsitering 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.
94

45. A method of inhibiting CDK9 activity, comprising
adminsitering 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.
46. 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
or cytotoxic agents, such as for example, but not limited
to, DNA interactive agents, such as carboplatin, cisplatin
or doxorubicin; topoisomerase II inhibitors, such as
etoposide; topoisomerase I inhibitors such as CPT-11 or
topotecan; tubulin interacting agents, such as paclitaxel,
taxane, docetaxel or the epothilones; hormonal agents, such
as tamoxifen; thymidilate synthase inhibitors, such as 5-
fluorouracil; and anti-metabolites, such as methoxtrexate,
and said containers optionally contain a pharmaceutical
carrier, which kit may be effectively utilized for carrying
out combination therapies according to the invention.
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Description

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TITLE
ACYLSEMICARBAZIDES AND THEIR USE AS CYCLIN DEPENDENT KINASE (CDK) INHIBITORS
FIELD OF THE INVENTION
This invention relates generally to novel 5-
substituted-indeno[1,2-c]pyrazol-4-ones which are useful as
cyclin dependent kinase (cdk) inhibitors, pharmaceutical
compositions comprising the same, kits and methods for using
the same for treating proliferative diseases, and
intermediates and processes for making the same.
BACKGROUND OF THE INVENTION
One of the most important and fundamental processes in
biology is the division of cells mediated by the cell cycle.
This process ensures the controlled production of subsequent
generations of cells with defined biological function. It is
a highly regulated phenomenon and responds to a diverse set
of cellular signals both within the cell and from external
sources. A complex network of tumor promoting and
suppressing gene products are key components of this
cellular signaling process. Over expression of the tumor
promoting components or the subsequent loss of the tumor
suppressing products will lead to unregulated cellular
proliferation and the generation of tumors (Pardse, Science
246:603-608, 1989).
Cyclin dependent kinases (cdks) play a key role in
regulating the cell cycle machinery. These complexes consist
of two components: a catalytic subunit (the kinase) and a
regulatory subunit (the cyclin). To date, nine kinase
subunits (cdk 1-9) have been identified along with several
regulatory subunits (cyclins A-H)(A.M. Senderowicz and E.A.
Sausville Journal of the National Cancer Institute (2000),
92 (5), 376-387; S. Mani; C. Wang; K. Wu; R. Francis; R.
1

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Pestell Exp. Opin. Invest. Drugs (2000) 9(8), 1849-1870;
Brizuela, Leonardo; Gyuris, Jeno; Mansuri, Muzammil, Princ.
Mol. Oncol. (2000), 197-236; Fry, David W.; Garrett,
Michelle Curr. Opin. Oncol., Endocr. Metab. Invest. Drugs
(2000), 2(1), 40-59).
Each kinase associates with a specific regulatory
partner and together make up the active catalytic moiety.
Each transition of the cell cycle is regulated by a
particular cdk complex: G1/S by cdk2/cyclin E, cdk4/cyclin
D1 and cdk6/cyclinD2; S/G2 by cdk2/cyclin A and cdkl/cyclin
A; G2/M by cdkl/B. The coordinated activity of these kinases
guides the individual cells through the replication process
and ensures the vitality of each subsequent generation
(Sherr, Cell 73:1059-1065, 1993; Draetta, Trends Biochem.
Sci. 15:378-382, 1990)
An increasing body of evidence has shown a link between
tumor development and cdk related malfunctions. Over
expression of the cyclin regulatory proteins and subsequent
kinase hyperactivity have been linked to several types of
cancers (Jiang, Proc. Natl. Acad. Sci. USA 90:9026-9030,
1993; Wang, Nature 343:555-557, 1990). More recently,
endogenous, highly specific protein inhibitors of cdks were
found to have a major affect on cellular proliferation (Kamb
et al, Science 264:436-440, 1994; Beach, Nature 336:701-704,
1993). These inhibitors include pl6INK4 (an inhibitor of
cdk4/D1), p21CIP1 (a general cdk inhibitor), and p27KIP1 (a
specific cdk2/E inhibitor). A recent crystal structure of
p27 bound to cdk2/A revealed how these proteins effectively
inhibit the kinase activity through multiple interactions
with the cdk complex (Pavletich, Nature 382:325-331, 1996).
These proteins help to regulate the cell cycle through
specific interactions with their corresponding cdk
complexes. Cells deficient in these inhibitors are prone to
unregulated growth and tumor formation.
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Protein kinases, in particular, CDK, play a role in
the regulation of cellular proliferation. Therefore, CDK
inhibitors could be useful in the treatment of cell
proliferative disorders such as cancer, familial
adenomatosis polyposis, neuro-fibromatosis, psoriasis,
fungal infections, endotoxic shock, trasplantaion rejection,
vascular smooth cell proliferation associated with
atherosclerosis, pulmonary fibrosis, arthritis
glomerulonephritis and post-surgical stenosis and restenosis
(U. S. Patent No. 6,114,365).
CDKs are also known to play a role in apoptosis.
Therefore CDK inhibitors, could be useful in the treatment
of useful of cancer; viral infections, for example,
herpevirus, poxvirus, Epstein-Barr virus, Sindbis virus and
adenovirus; prevention of AIDS development in HIV-infected
individuals; autoimmune diseases, for example, systemic
lupus, erythematosus, autoimmune mediated
glomerulonephritis, rheumatoid arthritis, psoriasis,
inflammatory bowel disease, and autoimmune diabetes
mellitus; neurodegenerative disorders, for example,
Alzheimer's disease, AIDS-relateddementia, Parkinson's
disease, amyotrophic lateral sclerosis, retinitis
pigmentosa, spinal muscular atrophy and cerebellar
degeneration; myelodysplastic syndromes, aplastic anemia,
ischemic injury associated with myocardial infarctions,
stroke and reperfusion injury, arrhythmia, atherosclerosis,
toxin-induced or alcohol related liver diseases,
hematological diseases, for example, chronic anemia and
aplastic anemia; degenerative diseases of the
musculoskeletal system, for example, osteoporosis and
arthritis, aspirin-sensitive rhinosinusitis, cystic
fibrosis, multiple sclerosis, kidney diseases and cancer
pain (U. S. Patent No. 6,107,305).
It has also been discovered that some cyclin-dependent
kinase inhibitors can be used in combination therapy with
other anticancer agents. For example, the cytotoxic
activity of the cyclin-dependent kinase inhibitor,
flavopiridol, has been used with other anticancer agents in
3

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cancer combination therapy. Cancer Research, 57, 3375
(1997).
Also, it has recenly been disclosed that CDK
inhibitors may be useful in the chemoprevention of cancer.
Chemoprevention is defined as inhibiting the development of
invasive cancer by either blocking the initiating mutagenic
event or by blocking the progression of pre-malignant cells
that have already suffered an insult or inhibiting tumor
relapse (U. S. Patent No. 6,107,305).
Furthermore, it has recently been discovered that cdk5
is involved in the phosphorylation of tau protein, and
therefore CDK inhibitors may be useful in the treatment of
Alzheimer's disease (J. Biochem., 117, 741-749, 1995).
This body of evidence has led to an intense search for
small molecule inhibitors of the cdk family as an approach
to cancer chemotherapy. There are no known examples of
molecules related to the current invention which describe 5-
substituted-indeno[1,2-c]pyrazoles as cdk inhibitors. There
is one case describing indeno(1,2-c]pyrazoles haring
anticancer activity. There are two other examples which
describe indeno[1,2-c]pyrazoles having unrelated utilities
and structures.
A series of indeno[1,2-c]pyrazoles having anticancer
activity are described in JP 60130521 and JP 62099361 with
the following generic structure:
R2
N~N
R1
No substitution is claimed on the indenophenyl portion of
the molecule and the molecules are not indicated to be cdk
4

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inhibitors. In addition, we discovered that substitution at
the 5-position was critical for cdk inhibitory activity.
A series of indeno[1,2-c]pyrazoles having herbicidal
activity are described in GB 2223946 with the following
generic structure:
O
R2
N, N
R1
wherein Xn is defined as halo, alkyl, haloalkyl, and
haloalkoxy; n = 0-2. In addition, R1 is defined as acyl and
R2 is defined as alkyl or cycloalkyl.
A series of 1-(6'-substituted-4'-methylquinol-2'-yl)-3-
methylindeno[1,2-c]pyrazoles having CNS activity are
described by Quraishi, Farmaco 44:753-8, 1989 with the
following generic structure:
x
Me
N~N
Me
~ ~N
2O
Compounds of this series are not considered to be part of
the presently claimed invention.
SUMMARY OF THE INVENTION
The present invention describes a novel class of
indeno[1,2-c]pyrazol-4-ones or pharmaceutically acceptable
5

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salt forms thereof that are potent inhibitors of the class
of enzymes known as cyclin dependent kinases, which relate
to the catalytic subunits cdk 1-9 and their regulatory
subunits known as cyclins A-H.
It is another object of this invention to provide a
novel method of treating proliferative diseases associated
with CDK activity by administering a therapeutically
effective amount of one of the compounds of the invention or
a pharmaceutically acceptable salt form thereof.
It is another object of this invention to provide a
novel method of treating cancer associated with CDK activity
by administering a therapeutically effective amount of one
of the compounds of the invention or a pharmaceutically
acceptable salt form thereof.
It is another object of this invention to provide a
novel method of treating a proliferative disease, which
comprises administering a therapeutically effective
combination of one of the compounds of the present invention
and one or more other known anti-cancer treatments such as
radiation therapy, chemotoxic or chemostatic agents.
These and other objectives have been achieved by the
inventors' discovery that compounds of formula (I):
R5 X
1
R NwN~NH O
H
/ ~ R2
~ ,NH
N
(I)
6

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wherein R1, R2, R5 and X are defined below or
pharmaceutically acceptable salts thereof are cyclin
dependent kinase inhibitors.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The invention pertains to novel cyclin dependent kinase
inhibitors (cdks) and specifically, but not exclusively, as
inhibitors of cdk/cyclin complexes. The inhibitors of this
invention are indeno[1,2-c]pyrazol-4-one analogs. Certain
analogs were selective for their activity against cdks and
their cyclin bound complexes and were less active against
other known serine/threonine kinases such as Protein Kinase
A (PKA) and Protein Kinase C (PKC).
As described herein, the inhibitors of this invention
are capable of inhibiting the cell-cycle machinery and
consequently would be useful in modulating cell-cycle
progression, which would ultimately control cell growth and
differentiation. Such compounds would be useful for treating
subjects having disorders associated with excessive cell
proliferation, such as the treatment of cancer, psoriasis,
immunological disorders involving unwanted leukocyte
proliferation, in the treatment of restinosis and other
smooth muscle cell disorders, and the like.
(1) The present invention, in a first embodiment, describes
a novel compound of formula (I):
R5 X
R1 N~ ~
N_ 'NH
H O
/ R2
~ ,NH
N
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X is 0 or S;
R1 is -NR3R3a, -CF3, C1-4 alkyl substituted with 1-3 R4, C5_
alkyl substituted with 0-3 R4, C2-C10 alkenyl
substituted with 0-3 R4, C2-C10 alkynyl substituted
with 0-3 R4, C3-C10 carbocycle substituted with 0-5 R6,
10 or 5-10 membered heterocycle substituted with 0-3 R6;
provided that if R1 is phenyl or benzyl, then R1 is
substituted with 1-5 R6;
R2 is H, C1-10 alkyl substituted with 0-3 R~, C2-10 alkenyl
substituted with 0-3 R~, C2-10 alkynyl substituted with
0-3 R~, -CF3, C3-10 carbocycle substituted with 0-5 R8,
or 3-10 membered heterocycle substituted with 0-5 R8;
R3 and R3a are independently selected from the group: H,
C1-4 alkyl, phenyl and benzyl;
R4 and R~ are, at each occurance, independently selected
from the group: halo, -CN, N02, -NR9R9a, NR9NR9aR9b~
NR9C(0)OR10, NR9C(O)R10, =0, OR10, SR10, -CF3, COR10,
C02R10, CONR9R9a, NHC(0)NR9R9a, NHC(S)NR9R9a,
S02NR9R9a, S02R10, C3-10 carbocycle substituted with
0-5 R11, and 5-10 membered heterocycle substituted with
11
0-3 R ;
R5 is selected from the group: H, -C(0)R12, -C(0)OR12, C1-4
alkyl, phenyl and benzyl;
R6 and R8 are, at each occurance, independently selected
from the group: halo, -CN, N02, C1-4 alkyl, C1-4
haloalkyl, NR13R13a~ NR13NR13aR13b~ NR13C(O)OR14,
NR13C(0)R14~ =0~ OR14~ SR14,-CF3, COR14, C02R14,
CONR13R13a~ NHC(0)NR13R13a~ NHC(S)NR13R13a~
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S02NR13R13a~ Sp2R14~ C3-10 carbocycle substituted with
0-5 R15, and 5-10 membered heterocycle substituted with
0-3 R , or when two R6s or R8s are attachd to two
adjacent carbon atoms, the two R6s or R8s may combine
to form -OCH20- or -OCH2CH20-;
10 R9 is, at each occurance, independently selected from the
group: H, -C(0)R12, -C(0)OR12, C1-4 alkyl, phenyl and
benzyl;
R9b is, at~each occurance, independently selected from the
group: H, -C(0)R1~, -C(0)OR12, C1-4 alkyl, phenyl and
15 benzyl; or
R9 and R9a, together with the nitrogen atom to which they
are attached, form a heterocycle substituted with 0-3
R16
R9a is selected from the group: H, C1-4 alkyl, phenyl and
benzyl;
R10~ R14~ R17 are, at each occurance, independently selected
from the group: H, C1-4 alkyl, phenyl, benzyl;
R11 is, at each occurance, independently selected from the
group: halo, -CN, N02, C1-4 alkyl, C1-4 haloalkyl,
NR18R.18a~ NR18NR18aR18b~ NR18C(0)OR17, NR18C(0)R17~ -0,
OR17, SR17, COR17, CO~R17, CONR18R18a, NHC(O)NR18R18a,
NHC(S)NR18R18a, SO~NR18R18a, S02R17, C3-10 carbocycle
substituted with 0-5 R19, and 5-10 membered heterocycle
19
substituted with 0-3 R ;
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R13 is is, at each occurance, independently selected from
the group: H, -C(0)R12, -C(0)OR12, C1_4 alkyl, phenyl
and benzyl;
Rl3a is, at each occurance, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl; or
R13 and Rl3a, together with the nitrogen atom to which they
are attached, form a heterocycle substituted,with 0-3
R16
Rl3b is, at each occurance, independently selected from the
group: H, -C(0)R12, -C(0)OR12, C1-4 alkyl, phenyl and
benzyl;
R15~ R16 and R19 are, at each occurance, independently
selected from the group: halo, -CN, N02, C1-g alkyl,
C1-g haloalkyl, NR20R20a, NR20bNR20R20a, NR20C(0)OR21,
NR20C(0)R21, --0, OR21, SR21, COR21, C02R21, CONR20R20a~
NHC(0)NR20R20a, NHC(S)NR20R20a, S02NR20R20a, S02R21, or
when two RlSs, Rl6s or Rl9s are attachd to two adjacent
carbon atoms, the two RlSs Rl6s or Rl9s may combine to
form -OCH20- or -OCH2CH20-;
R18 is, at each occurance, independently selected from the
group: H, -C(0)R12, -C(0)OR12, C1-4 alkyl, phenyl and
benzyl;
Rl8a is, at each occurance, independently selected from the
group: H, C1-g alkyl, phenyl and benzyl;or
R1g and Rl8a, together with the nitrogen atom to which they
are attached, form a heterocycle substituted with 0-3
R19;

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Rl8b is, at each occurance, independently selected from the
group: H, -C(0)R12, -C(0)OR12, C1-g alkyl, phenyl and
benzyl; or
R20 is, at each occurance, independently selected from the
group: H, -C(0)R12, -C(0)OR12, C1-4 alkyl, phenyl and
benzyl;
R20a is, at each occurance, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R20b is, at each occurance, independently selected from the
group: H, -C(0)R12, -C(0)OR12, C1-g alkyl, phenyl and
benzyl; and
R12 and R21 are, at each occurance, independently selected
from the group: H, C1-g 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) Another embodiment of the invention is a compound of
embodiment (1) wherein:
X is 0 or S;
R1 is -NR3R3a, -CF3,C1-C4 alkyl substituted with 1-3 R4, C2-
Cg alkenyl substituted with 0-3 R4, C2-Cg alkynyl
substituted with 0-3 R4, C3-C10 carbocycle substituted
with 0-5 R6, or 5-10 membered heterocycle substituted
with 0-3 R6.
(3) Another embodiment of the invention is a compound of
embodiment (1) wherein:
X is 0 or S;
11

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R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4,
C2-C4 alkenyl substituted with 0-3 R4, C2-Cg alkynyl
substituted with 0-3 R4, C3-C6 carbocycle substituted
with 0-5 R6, or 5-7 membered heterocycle substituted
with 0-3 R6.
(4) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R1 is C3-C6 saturated carbocycle substituted with 0-5 R6, or
5-7 membered saturated heterocycle substituted with 0-3
R6.
(5) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R1 is C5-C6 partially saturated carbocycle substituted with
0-5 R6, or 5-7 membered partially saturated heterocycle
substituted with 0-3 R6
(6) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R1 is phenyl substituted with 1-5 R6, naphthyl substituted
with 0-5 R6, or 5-6 membered aromatic heterocycle
substituted with 0-3 R6.
(7) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R1 is phenyl substituted with 1-3 R6, naphthyl substituted
with 0-3 R6, or 5-6 membered aromatic heterocycle
substituted with 0-3 R6.
12

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(8) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R1 is C3-C10 carbocycle substituted with 0-5 R6, or 5-10
membered heterocycle substituted with 0-3 R6;
R6 is, at each occurrence, independently selected from the
group: halo, -CN, N02, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a~ NR13NR13aR13b~ NR13C(0)OR14, NR13C(0)R14~ -O,
OR14, SR14,-CF3, COR14, C02R14, CONR13R13a~
NHC(O)NR13R13a~ NHC(S)NR13R13a~ S02NR13R13a~ and
S02R14, or when two R6s are attached to two adjacent
carbon atoms, the two R6s may combine to form -OCH20-
or -OCH2CH20-.
(9) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R6 is, at each occurrence, independently selected from the
group: halo, -CN, N02, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a~ NR13NR13aR13b~ NR13C(0)OR14, NR13C(0)R14, =0,
OR14, SR14,-CF3, COR14, C02R14, CONR13R13a~
NHC(0)NR13R13a~ NHC(S)NR13R13a~ S02NR13R13a~ and
S02R14, or when two R6s are attached to two adjacent
carbon atoms, the two R6s may combine to form -OCH20-
or -OCH2CH20-;
R13~ Rl3a and Rl3b are, at each occurrence, independently
selected from the group: H, C1-4 alkyl, phenyl and
benzyl; and
13

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R14 is, at each occurrence, independently selected from the
group: H, C1_4 alkyl, phenyl, and benzyl.
(10) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R6 is independently at each occurrence selected from the
group: halo, -CN, N02, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a~ NR13C(0)OR14, NR13C(0)R14, OR14, SR14,-CF3,
COR14, C02R14, CONR13R13a~ NHC(S)NR13R13a~ S02NR13R13a~
and S02R14;
R13, Rl3a and Rl3b are each independently selected from the
group: H or methyl; and
R14 is independently selected from the group: H, methyl,
phenyl, and benzyl.
(11) Another embodiment of the invention is a compound of
embodiment (1) wherein:
X is 0 or S;
R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4;
R4 is, at each occurrence, independently selected from the
group: halo, -CN, N02, -NR9R9a, NR9NR9aR9b,
NR9C(0)OR10, NR9C(0)R10, =O, OR10, SR10, -CF3, COR10,
C02R10, CONR9R9a, NHC(O)NR9R9a, NHC(S)NR9R9a,
S02NR9R9a, and S02R10;
R9 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9a is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
14

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R9b is, at each occurrence, independently selected from the
group: H, C1-g alkyl, phenyl and benzyl; or
R9 and R9a, together with the nitrogen atom to which they
are attached, form a 5-7 membered heterocycle
substituted with 0-3 R16;
R16 is, at each occurrence, independently selected from the
group consisting of: halo, -CN, N02, C1-4 alkyl, C1-4
haloalkyl, NR20R.20a~ NR20bNR20R20a, NR20C(0)OR21,
NR20C(0)R21~ =0~ OR21~ SR21, COR21, C02R21, CONR20R20a~
NHC(0)NR20R20a, NHC(S)NR20R20a, S02NR20R20a, and
S02R21; and
R20, R20a, and R20b are, at each occurrence, independently
selected from the group: H, C1-4 alkyl, phenyl and
benzyl.
(12) Another embodiment of the invention is a compound of
embodiment (1) wherein:
X is 0 or S;
R1 is -NR3R3a, -CF3, C1-C4 alkyl substituted with 1-3 R4;
R3 and R3a are independently selected from the group: H,
methyl, phenyl and benzyl;
R4 is, at each occurrence, independently selected from the
group: halo, -CN, N02, -NR9R9a, NR9NR9aR9b~
NR9C(0)OR10, NR9C(0)R10, =0, OR10, SR10, -CF3, COR10,
C02R10, CONR9R9a, NHC(0)NR9R9a, NHC(S)NR9R9a,
S02NR9R9a, S02R10, C3-10 carbocycle substituted with
0-5 R11, and 5-10 membered heterocycle substituted with
11
0-3 R ;

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R9 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9a is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R9b is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl and benzyl;
R10 is, at each occurrence, independently selected from the
group: H, C1-4 alkyl, phenyl, benzyl; and
R11 is, at each occurrence, independently selected from the
group consisting of: selected from the group: halo,
18 18a
CN, N02, C1-4 alkyl, C1-4 haloalkyl, NR R ,
NR18NR18aR18b~ NR18C(0)OR17, NR18C(0)R17~ =O~ OR17
SR17, COR17, C02R17, CONR18R18a, NHC(O)NR18R18a,
NHC(S)NR18R18a, SO~NR18R18a, SO~R17, C3-10 carbocycle
substituted with 0-5 R19, and 5-10 membered heterocycle
19
substituted with 0-3 R
(13) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R2 is C1-4 alkyl substituted with 0-3 R7, C~-4 alkenyl
substituted with 0-3 R7, C2-4 alkynyl substituted with
0-3 R7, -CF3, C3-6 carbocycle substituted with 0-5 R8,
or 3-7 membered heterocycle substituted with 0-5 R8.
(14) Another embodiment of the invention is a compound of
embodiment (1) wherein:
16

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R2 is C1-g alkyl substituted with 0-3 R7, C2-g alkenyl
substituted with 0-3 R7, C2-4 alkynyl substituted with
0-3 R7, -CF3, C3-6 carbocycle substituted with 0-5 R8,
or 5-7 membered heterocycle substituted with 0-5 R8.
(15) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R2 is C3-6 saturated carbocycle substituted with 0-5 R8, or
5-7 membered saturated heterocycle substituted with 0-5
R8.
(16) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R2 is C5-6 partially saturated carbocycle substituted with
0-5 R8, or 5-7 membered partially saturated heterocycle
substituted with 0-5 R8.
(17) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R2 is phenyl substituted with 0-5 R8, naphthyl substituted
with 0-5 R8 or or 5-6 membered aromatic heterocycle
heterocycle substituted with 0-5 R8.
(18) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R2 is phenyl substituted with 0-3 R8, naphthyl substituted
with 0-3 R8 or or 5-6 membered aromatic heterocycle
heterocycle substituted with 0-3 R8.
17

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(19) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R2 is C3-6 carbocycle substituted with 0-5 R8, or 5-7
membered heterocycle substituted with 0-5 R8;
R8 is, at each occurrence, independently selected from the
group: halo, -CN, N02, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a~ NR13NR13aR13b~ NR13C(0)OR14, NR13C(0)R14~ -O,
OR14, SR14,-CF3, COR14, CO~R14, CONR13R13a~
NHC(0)NR13R13a~ NHC(S)NR13R13a~.S02NR13R13a~ and
S02R14, or when two R8s are attachd to two adjacent
carbon atoms, the two R8s may combine to form -OCH20-
or -OCH2CH20-; and
R13 Rl3a~ and Rl3b are are, at each occurrence,
independently selected from the group: H, C1-4 alkyl,
phenyl and benzyl; or
R13 and Rl3a, together with the nitrogen atom to which they
are attached, form a 5-7 membered heterocycle
substituted with 0-3 R16.
(20) Another embodiment of the invention is a compound of
embodiment (1) wherein:
R2 is C3-6 carbocycle substituted with 0-5 R8, or 5-7
membered heterocycle substituted with 0-5 R8;
R8 is, at each occurrence, independently selected from the
group: halo, -CN, N02, C1-4 alkyl, C1-4 haloalkyl,
NR13R13a~ NR13NR13aR13b~ NR13C(0)OR14, NR13C(0)R14~ -O.
18

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OR14, SR14,-CF3, COR14, C02R14, CONR13R13a~
NHC(O)NR13R13a~ ~C(S)NR13R13a~ S02NR13R13a~ S02R14~
C3-10 carbocycle substituted with 0-5 R15, and 5-10
membered heterocycle substituted with 0-3 R ,or when
two R8s are attachd to two adjacent carbon atoms, the
10 two Rgs may combine to form -OCH20- or -OCH2CH20-;
R13 Rl3a~ and Rl3b are, at each occurrence, independently
selected from the group: H, C1-4 alkyl, phenyl and
benzyl; and
R15 is, at each occurrence, independently selected from the
15 group consisting of: halo, -CN, N02, C1-4 alkyl, C1-4
haloalkyl, NR20R20a~ NR20bNR20R20a~ NR20C(0)OR21,
NR20C(0)R21, =0, OR21, SR21, COR21, C02R21, CONR20R20a,
NHC(O)NR20R20a, NHC(S)NR20R20a, S02NR20R20a, and
S02R21, or when two RlSs, are attachd to two adjacent
carbon atoms, the two RlSs may combine to form -OCH20-
or -OCH2CH20-.
A more preferred embodiment, is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(13) .
A more preferred embodiment, is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(14).
A more preferred embodiment, is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(15) .
19

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A more preferred embodiment, is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(16) .
A more preferred embodiment, is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(17) .
A more preferred embodiment, is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(18) .
A more preferred embodiment; is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(19) .
A more preferred embodiment, is a compound according to
any of embodiments (2) to (12) further comprising embodiment
(20) .
In a most preferred embodiment, the compounds of
formula (I) are selected from:
3-(4-methoxyphenyl)-5-(2-(3,5-dimethoxybenzoyl)
hydrazinecar]aoxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-isonicotinoyl
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-nictinoylhydrazinecarbox
amido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(3,4-dihydroxybenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(4-hydroxybenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;

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3-(4-methoxyphenyl)-5-(2-(3-aminobenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(4-aminobenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(2-aminobenzoyl)hydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylaminobenzoyl)
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-methoxybenzoylhydrazine
carboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(2-hydroxybenzoyl)hydrazine
carboxamido)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]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-amido
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-phenylamido
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
21

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3-(4-methoxyphenyl)-5-(2-(4-methylbenzoyl
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(2-naphthoyl)
hydrazinecarboxamido)indeno[1,2-c]pyrazol-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]pyrazol-4-one;
3-(4-methoxyphenyl)-5-(2-(2-thienoyl)
hydrazinecarboxamido)indeno[1,2-c]pyrazol-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)indeno[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;
22

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3-(4-piperazinylphenyl)-5-(2-(nicotinoyl)
hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one;
3-(4-(4-methylpiperazinyl)phenyl)-5-(2-(nicotinoyl)
hydrazinecarboxamido)indeno[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)indeno[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.
Another embodiment of the present invention is a
pharmaceutical composition comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of
a compound of formula (I).
Another embodiment of the present invention is a method
of treating a proliferative disease associated with CDK
activity comprising: administering to a host in need of
such treatment a therapeutically effective amount of a
compound of formula (I), or a pharmaceutically effective
salt form thereof.
Another embodiment of the present invention is a method
of treating a cell proliferative disease associated with CDK
activity in a patient, comprising administrering to said
patient a pharmaceutically effective amount of a compound of
23

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formula (I), 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.
Another embodiment of the present invention is a method
of treating cancer associated with CDK activity in a
patient,comprising administrering to said patient a
pharmaceutically effective amount of a compound of formula
(I), wherein the cancer is selected from the group
consisting of: carcinoma such as bladder, breast, colon,
kidney, liver, lung, including small cell lung cancer,
esophagus, gall-bladder, ovary, pancreas, stomach, cervix,
thyroid, prostate, and skin, including squamous cell
carcinoma; hematopoietic tumors of lymphoid lineage,
including 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, including acute and chronic myelogenous
leukemias, myelodysplastic syndrome and promyelocytic
leukemia; tumors of mesenchymal origin, including
fibrosarcoma and rhabdomyosarcoma; tumors of the central and
peripheral nervous system, including astrocytoma,
neuroblastoma, glioma and schwannomas; other tumors,
including melanoma, seminoma, teratocarcinoma, osteosarcoma,
xenoderoma pigmentosum, keratoctanthoma, thyroid follicular
cancer and Kaposi's sarcoma.
Another embodiment of the present invention is a method
of treating a disease associated with apoptosis in a
patient,comprising administrering to said patient a
pharmaceutically effective amount of a compound of formula
(I), wherein the disease associated with apoptosis is
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selected from the group consisting of: cancer, viral
infections, autoimmune diseases and neurodegenerative
disorder.
Another embodiment of the present invention is a method
of inhibiting tumor angiogenesis and metastasis in a
patient,comprising administrering to said patient a
pharmaceutically effective amount of a compound of formula
(I) .
Another embodiment of the present invention is a method
of treating a disease associated with protein kinase
activity in a patient, comprising administrering to said
patient a pharmaceutically effective amount of a compound of
formula (I), wherein the protein kinase is selected from the
group consisting of: e.g. protein kinase C, her2, rafl,
MEK1, MAP kinase, EGF receptor, PDGF receptor, IGF receptor,
PI3 kinase, weel kinase, Src, and Abl.
Another embodiment of the present invention is a method
of modulating the level of cellular RNA and DNA synthesis in
a patient, comprising administering to said patient a CDK
inhibitory effective amount of a compound of formula (I).
Another embodiment of the present invention is a method
of treating viral infections in a patient, comprising
administering to said patient a CDK inhibitory effective
amount of a compound of formula (I), wherein the viral
infections is selected from the group consiting of HIV,
human papilloma virus, herpesvirus, poxvirus, Epstein-Barr
virus, Sindbis virus and adenovirus.
Another embodiment of the present invention is a method
of chemopreventing cancer in a patient, comprising
administering to said patient a CDK inhibitory effective
amount of a compound of formula (I).
Another embodiment of the present invention is a method
of inhibiting CDK activity comprising combining an effective
amount of the compound of formula (I) with a composition
containing CDK.

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Another embodiment of the present invention is a method
of treating cancer associated with CDK activity in a
patient,comprising administrering to said patient a
pharmaceutically effective amount of a compound of formula
(I) in combination (administered together or sequentially)
.10 with known anti-cancer treatments such as radiation therapy
or with cytostatic or cytotoxic agents, such as for example,
DNA interactive agents, such as cisplatin or doxorubicin;
topoisomerase II inhibitors, such as etoposide;
topoisomerase I inhibitors such as CPT-11 or topotecan;
tubulin interacting agents, such as paclitaxel, docetaxel or
the epothilones; hormonal agents, such as tamoxifen;
thymidilate synthase inhibitors, such as 5-fluorouracil; and
anti-metabolites, such as methoxtrexate.
Another embodiment of the present invention is a method
treating proliferative diseases associated with CDK
activity, in a patient, comprising administrering to said
patient a pharmaceutically effective amount of a compound of
formula (I), 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, JNl335,
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,
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teniposide, vinblastine, vincristine, vinorelbine,
procarbazine, asparaginase, pegaspargase, methoxtrexate,
octreotide, and estramustine, hydroxyurea.
Another embodiment of the present invention is a method
of inhibiting CDK1 activity, adminsitering to
comprising a
patient in need thereof an efective CDK1 inhibitory amount
of a compound according to claim 1, or pharmaceutically
a
acceptable salt or prodrug form thereof.
Another embodiment of the present
invention
is a method
of inhibiting CDK2 activity, adminsitering to
comprising a
patient in need thereof an efective CDK2 inhibitory amount
of a compound according to claim 1, or pharmaceutically
a
acceptable salt or prodrug form thereof.
Another embodiment of the present nvention is a method
i
of inhibiting CDK3 activity, adminsitering to
comprising a
patient in need thereof an efective CDK3 inhibitory amount
of a compound according to claim 1, or pharmaceutically
a
acceptable salt or prodrug form thereof.
Another embodiment of the present nvention is a method
i
of inhibiting CDK4 activity, adminsitering to
comprising a
patient in need thereof an efective CDK4 inhibitory amount
of a compound according to claim 1, or pharmaceutically
a
acceptable salt or prodrug form thereof.
Another embodiment of the present nvention is a method
i
of inhibiting CDK5 activity, adminsitering to
comprising a
patient in need thereof an efective CDK5 inhibitory amount
of a compound according to claim 1, or pharmaceutically
a
acceptable salt or prodrug form thereof.
Another embodiment of the present nvention is a method
i
of inhibiting CDK6 activity, adminsitering to
comprising a
patient in need thereof an efective CDK6 inhibitory amount
of a compound according to claim 1, or pharmaceutically
a
acceptable salt or prodrug form thereof.
Another embodiment of the present nvention is a method
i
of inhibiting CDK7 activity, adminsitering to
comprising a
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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.
Another embodiment of the present invention is a method
of inhibiting CDK8 activity, comprising adminsitering 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.
Another embodiment of the present invention is a method
of inhibiting CDK9 activity, comprising adminsitering 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.
It is a further object of the invention to provide a
pharmaceutical kit for combination treatment of
proliferative diseases associated with CDK activity, said
kit comprising a plurality of separate containers, wherein
at least one of said containers contains a compound of
formula (I), and at least another of said containers
contains one or more compounds 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,
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teniposide, vinblastine, vincristine, vinorelbine,
procarbazine, asparaginase, pegaspargase, methoxtrexate,
octreotide, and estramustine, hydroxyurea, and said
containers optionally contain a pharmaceutical carrier.
It is a further object of the invention to provide a
method of treating a patient having a disorder associated
with excessive cell proliferation, comprising administering
to the patient a therapeutically effective amount of a
compound of formula (I), such that the excessive cell
proliferation in the patient is reduced.
It is appreciated that certain feactures of the
invention, which are, for clarity, described in the context
of separate embodiments, may also be provided in combination
in a single embodiment. Conversely, various feactures of
the invention which are, for brevity, described in the
context of a single embodiment, may also be provided
seperately or in any suitable subcombination.
DETAILED DESCRIPTION OF THE INVENTION
As used above, and throughout the description of the
invention, the following terms, unless otherwise indicated,
shall be understood to have the following meanings:
Definitions
As used herein, the following terms and expressions
have the indicated meanings.
The term "compounds of the invention", and equivalent
expressions, are meant to embrace compounds of the invention
as hereinbefore described i.e. compounds of formula (I),
which expression includes the prodrugs thereof, N-oxides
thereof, the pharmaceutically acceptable salts thereof, and
the solvates thereof, e.g. hydrates, where the context so
permits. Similarly, reference to intermediates, whether or
not they themselves are claimed, is meant to embrace their
salts, and solvates, where the context so permits.
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The term "derivative" means a chemically modified
compound wherein the modification is considered routine by
the ordinary skilled chemist, such as an ester or an amide
of an acid, protecting groups, such as a benzyl group for an
alcohol or thiol, and tert-butoxycarbonyl group for an
amine.
The term "effective amount" means an amount of a
compound/composition according to the present invention
effective in producing the desired therapeutic effect.
The term "amine protecting group" means an easily
removable group which is known in the art to protect an
amino group against undesirable reaction during synthetic
procedures and to be selectively removable. The use of
amine protecting groups is well known in the art for
protecting groups against undesirable reactions during a
synthetic procedure and many such protecting groups are
known, for example, T.H. Greene and P.G.M. Wuts, Protective
Groups in Organic Synthesis, 2nd edition, John Wiley & Sons,
New York (1991), incorporated herein by reference.
Preferred amine protecting groups are aryl, including
formyl, acetyl, chloroacetyl, trichloroacetyl, o-
nitrophenylacetyl, o-nitrophenoxyacetyl, trifluoroacetyl,
acetoacetyl, 4-chlorobutyryl, isobutyryl, o-nitrocinnamoyl,
picolinoyl, acylisothiocyanate, aminocaproyl, benzoyl and
the like, and acyloxy including methoxycarbonyl, 9-
fluorenylmethoxycarbonyl, 2,2,2-trifluoroethoxycarbonyl, 2-
trimethylsilylethxoycarbonyl, vinyloxycarbonyl,
allyloxycarbonyl, t-butyloxycarbonyl (BOC), 1,1-
dimethylpropynyloxycarbonyl, benzyloxycarbonyl (CBZ), p-
nitrobenzyloxycarbony, 2,4-dichlorobenzyloxycarbonyl, and
the like.
The term "acid labile amine protecting group" means an
amine protecting group as defined above which is readily
removed by treatment with acid while remaining relatively

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stable to other reagents. A preferred acid labile amine
protecting group is tert-butoxycarbonyl (BOC).
The term "hydrogenation labile amine protecting group"
means an amine protecting group as defined above which is
readily removed by hydrogenation while remaining relatively
stable to other reagents. A preferred hydrogenation labile
amine protecting group is benzyloxycarbonyl (CBZ).
The term "hydrogenation labile acid protecting group"
means an acid protecting group as defined above which is
readily removed by hydrogenation while remaining relatively
stable to other reagents. A preferred hydrogenation labile
acid protecting group is benzyl.
The term "analogue" means a compound which comprises a
chemically modified form of a specific compound or class
thereof, and which maintains the pharmaceutical and/or
pharmacological activities characteristic of said compound
or class.
The term "patient" includes both human and other
mammals.
The term "pharmaceutical composition" means a
composition comprising a compound of formula (I) and at
least one component selected from the group comprising
pharmaceutically acceptable carriers, diluents, adjuvants,
excipients, or vehicles, such as preserving agents, fillers,
disintegrating agents, wetting agents, emulsifying agents,
suspending agents, sweetening agents, flavoring agents, per-
fuming agents, antibacterial agents, antifungal agents,
lubricating agents and dispensing agents, depending on the
nature of the mode of administration and dosage forms.
Examples of suspending agents include ethoxylated isostearyl
alcohols, polyoxyethylene sorbitol and sorbitan esters,
microcrystalline cellulose, aluminum metahydroxide,
bentonite, agar-agar and tragacanth, or mixtures of these
substances. Prevention of the action of microorganisms can
be ensured by various antibacterial and antifungal agents,
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for example, parabens, chlorobutanol, phenol, sorbic acid,
and the like. It may also be desirable to include isotonic
agents, for example sugars, sodium chloride and the like.
Prolonged absorption of the injectable pharmaceutical form
can be brought about by the use of agents delaying
absorption, for example, aluminum monosterate and gelatin.
Examples of suitable carriers, diluents, solvents or
vehicles include water, ethanol, polyols, suitable mixtures
thereof, vegetable oils (such as olive oil) and injectable
organic esters such as ethyl oleate. Examples of excipients
include lactose, milk sugar, sodium citrate, calcium
carbonate, dicalcium phosphate phosphate. Examples of
disintegrating agents include starch, alginic acids and
certain complex silicates. Examples of lubricants include
magnesium stearate, sodium lauryl sulphate, talc, as well as
high molecular weight polyethylene glycols.
The term "solvate" means a physical association of a
compound of this invention with one or more solvent
molecules. This physical association includes hydrogen
bonding. In certain instances the solvate will be capable
of isolation, for example when one or more solvent molecules
are incorporated in the crystal lattice of the crystalline
solid. "Solvate" encompasses both solution-phase and
isolable solvates. Exemplary solvates include hydrates,
ethanolates, methanolates, and the like.
The term "alkyl" is intended to include both branched
and straight-chain saturated aliphatic hydrocarbon groups
having the specified number of carbon atoms. Examples of
alkyl include, but are not limited to, methyl, ethyl, n-
propyl, i-propyl, n-butyl, s-butyl, t-butyl, n-pentyl, and
s-pentyl. In addition, the term is intended to include both
unsubstituted and substituted alkyl groups, the latter
referring to alkyl moieties having one or more hydrogen
substituents replaced by, but not limited to halogen,
hydroxyl, carbonyl, alkoxy, ester, ether, cyano, phosphoryl,
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amino, imino, amido, sulfhydryl, alkythio, thioester,
sulfonyl, nitro, heterocyclo, aryl or heteroaryl. It will
also be understood by those skilled in the art that the
substituted moieties themselves can be substituted as well
when appropriate.
The term "alkenyl" means an aliphatic hydrocarbon group
containing a carbon-carbon double bond and which may be
straight or branched having about 2 to about 10 carbon atoms
in the chain. Preferred alkenyl groups have 2 to about 8
carbon atoms in the chain; and more preferably about 2 to
about 4 carbon atoms in the chain. Branched means that one
or more lower alkyl groups such as methyl, ethyl or propyl
are attached to a linear alkenyl chain. Exemplary alkenyl
groups include ethenyl, propenyl, n-butenyl, i-butenyl, 3-
methylbut-2-enyl, n-pentenyl, heptenyl, octenyl, and
decenyl.
The term "alkynyl" means an aliphatic hydrocarbon group
containing a carbon-carbon triple bond and which may be
straight or branched having about 2 to about 10 carbon atoms
in the chain. Preferred alkynyl groups have 2 to about 8
carbon atoms in the chain; and more preferably about 2 to
about 4 carbon atoms in the chain. Branched means that one
or more lower alkyl groups such as methyl, ethyl or propyl
are attached to a linear alkynyl chain. Exemplary alkynyl
groups include ethynyl, propynyl, n-butynyl, 2-butynyl, 3-
methylbutynyl, n-pentynyl, heptynyl, octynyl and decynyl.
The terms "halo" or "halogen" as used herein refer to
fluoro, chloro, bromo and iodo. The term "aryl" is intended
to mean an aromatic moiety containing the specified number
of carbon atoms, such as, but not limited to phenyl, indanyl
or naphthyl. The terms "cycloalkyl" and "bicycloalkyl" are
intended to mean any stable ring system, which may be
saturated or partially unsaturated. Examples of such
include, but are not limited to, cyclopropyl, cyclopentyl,
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cyclohexyl, norbornyl, bicyclo[2.2.2]nonane, adamantly, or
tetrahydronaphthyl (tetralin).
As used herein, "carbocycle" or "carbocyclic residue"
is intended to mean any stable 3- to 7-membered monocyclic
or bicyclic or 7- to 13-membered bicyclic or tricyclic, any
of which may be saturated, partially unsaturated, or
aromatic. Examples of such carbocycles include, but are not
limited to, cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,;
[3.3.0]bicyclooctane, [4.3.0]bicyclononane,
[4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane,
fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or
tetrahydronaphthyl (tetralin).
As used herein, the term "heterocycle" or "heterocyclic
system" is intended to mean a stable 5- to 7- membered
monocyclic or bicyclic or 7- to 10-membered bicyclic
heterocyclic ring which is saturated partially unsaturated
or unsaturated (aromatic), and which consists of carbon
atoms and from 1 to 4 heteroatoms independently selected
from the group consisting of N, 0 and S and including any
bicyclic group in which any of the above-defined
heterocyclic rings is fused to a benzene ring. The nitrogen
and sulfur heteroatoms may optionally be oxidized. The
heterocyclic ring may be attached to its pendant group at
any heteroatom or carbon atom which results in a stable
structure. The heterocyclic rings described herein may be
substituted on carbon or on a nitrogen atom if the resulting
compound is stable. If specifically noted, a nitrogen in
the heterocycle may optionally be quaternized. It is
preferred that when the total number of S and 0 atoms in the
heterocycle exceeds 1, then these heteroatoms are not
adjacent to one another. It is preferred that the total
number of S and 0 atoms in the heterocycle is not more than
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1. As used herein, the term "aromatic heterocyclic system"
is intended to mean a stable 5- to 7- membered monocyclic or
bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic
ring which consists of carbon atoms and from 1 to 4
heterotams independently selected from the group consisting
of N, 0 and S. It is preferred that the total number of S
and O atoms in the aromatic heterocycle is not more than 1.
Examples of heterocycles include, but are not limited
to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl,
2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-
quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl,
benzimidazolyl, benzofuranyl, benzothiofuranyl,
benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,
benztetrazolyl, benzisoxazolyl, benzisothiazolyl,
benzimidazalonyl, carbazolyl, 4aH-carbazolyl, b-carbolinyl,
chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,
2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran,
furanyl, furazanyl, imidazolidinyl, imidazolinyl,
imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl,
indolyl, isobenzofuranyl, isochromanyl, isoindazolyl,
isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,
isoxazolyl, morpholinyl, naphthyridinyl,
octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl,
oxazolidinyl., oxazolyl, oxazolidinylperimidinyl,
phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,
phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,
piperazinyl, piperidinyl, pteridinyl, piperidonyl, '
4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl,
pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl,
pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl,
pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl,

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quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,
quinuclidinyl, carbolinyl, tetrahydrofuranyl,
tetrahydroisoquinolinyl, tetrahydroquinolinyl, 6H-1,2,5-
thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-
thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,
thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl,
thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl,
1,2,5-triazolyl, 1,3,4-triazolyl, xanthenyl. Preferred
heterocycles include, but are not limited to, pyridinyl,
furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl,
benzimidazolyl, 1H-indazolyl, oxazolidinyl, benzotriazolyl,
benzisoxazolyl, oxindolyl, benzoxazolinyl, or isatinoyl.
Also included are fused ring and spiro compounds containing,
for example, the above heterocycles.
As used herein, "pharmaceutically acceptable salts"
refer to derivatives of the disclosed compounds wherein the
parent compound is modified by making acid or base salts
thereof. Examples of pharmaceutically acceptable salts
include, but are not limited to, mineral or organic acid
salts of basic residues such as amines; alkali or organic
salts of acidic residues such as carboxylic acids; and the
like. The pharmaceutically acceptable salts include the
conventional non-toxic salts or the quaternary ammonium
salts of the parent compound formed, for example, from non-
toxic inorganic or organic acids. For example, such
conventional non-toxic salts include those derived from
inorganic acids such as hydrochloric, hydrobromic, sulfuric,
sulfamic, phosphoric, nitric and the like; and the salts
prepared from organic acids such as acetic, propionic,
succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic, malefic, hydroxymaleic,
phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-
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acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic,
ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent compound which
contains a basic or acidic moiety by conventional chemical
methods. Generally, such salts can be prepared by reacting
the free acid or base forms of these compounds with a
stoichiometric amount of the appropriate base or acid in
water or in an organic solvent, or in a mixture of the two;
generally, nonaqueous media like ether, ethyl acetate,
ethanol, isopropanol, or acetonitrile are preferred. Lists
of suitable salts are found in Remington's Pharmaceutical
Sciences, 18th ed., Mack Publishing Company, Easton, PA,
1990, p. 1445, the disclosure of which is hereby
incorporated by reference.
The phrase "pharmaceutically acceptable" is employed
herein to refer to those compounds, materials, compositions,
and/or dosage forms which are, within the scope of sound
medical judgment, suitable for use in contact with the
tissues of human beings and animals without excessive
toxicity, irritation, allergic response, or other problem or
complication commensurate with a reasonable benefit/risk
ratio.
The term "Pharmaceutically acceptable prodrugs" as used
herein means those prodrugs of the compounds useful
according to the present invention which are, within the
scope of sound medical judgment, suitable for use in contact
with the tissues of humans and lower animals with undue
toxicity, irritation, allergic response, and the like,
commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the
zwitterionic forms, where possible, of the compounds of the
invention.
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The term "Prodrugs", as the term is used herein, are
intended to include any covalently bonded carriers which
release an active parent drug of the present invention in
vitro when such prodrug is administered to a mammalian
subject. Since prodrugs are known to enhance numerous
desirable qualities of pharmaceuticals (i.e., solubility,
bioavailability, manufacturing, etc.) the compounds of the
present invention may be delivered in prodrug form. Thus,
the present invention is intended to cover prodrugs of the
presently claimed compounds, methods of delivering the same,
and compositions containing the same. Prodrugs of the
present invention are prepared by modifying functional
groups present in the compound in such a way that the
modifications are cleaved, either in routine manipulation or
in vivo, to the parent compound. The transformation in vivo
may be, for example, as the result of some metabolic
process, such as chemical or enzymatic hydrolysis of a
carboxylic, phosphoric or sulphate ester, or reduction or
oxidation of a susceptible functionality. Prodrugs include
compounds of the present invention wherein a hydroxy, amino,
or sulfhydryl group is bonded to any group that, when the
prodrug of the present invention is administered to a
mammalian subject, it cleaves to form a free hydroxyl, free
amino, or free sulfydryl group, respectively. Functional
groups which may be rapidly transformed, by metabolic
cleavage, in vivo form a class of groups reactive with the
carboxyl group of the compounds of this invention. They
include, but are not limited to such groups as alkanoyl
(such as acetyl, propionyl, butyryl, and the like),
unsubstituted and substituted aroyl (such as benzoyl and
substituted benzoyl), alkoxycarbonyl (such as
ethoxycarbonyl), trialkylsilyl (such as trimethyl- and
triethysilyl), monoesters formed with dicarboxylic acids
(such as succinyl), and the like. Because of the ease with
which the metabolically cleavable groups of the compounds
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useful according to this invention are cleaved in vivo, the
compounds bearing such groups act as pro-drugs. The
compounds bearing the metabolically cleavable groups have
the advantage that they may exhibit improved bioavailability
as a result of enhanced solubility and/or rate of absorption
conferred upon the parent compound by virtue of the presence
of the metabolically cleavable group. A thorough discussion
of prodrugs is provided in the following: Design of
Prodrugs, H. Bundgaard, ed., Elsevier, 1985; Methods in
Enzymology, K. Widder et al, Ed., Academic Press, 42, p.309-
396, 1985; A Textbook of Drug Design and Development,
Krogsgaard-Larsen and H. Bundgaard, ed., Chapter 5; "Design
and Applications of Prodrugs" p.113-191, 1991; Advanced Drug
Delivery Reviews, H. Bundgard, 8, p.1-38, 1992; Journal of
Pharmaceutical Sciences, 77, p. 285, 1988; Chem. Pharm.
Bull., N. Nakeya et al, 32, p. 692, 1984; Pro-drugs as
Novel Delivery Systems, T. Higuchi and V. Stella, Vol. 14 of
the A.C.S. Symposium Series, and Bioreversible Carriers in
Drug Design, Edward B. Roche, ed., American Pharmaceutical
Association and Pergamon Press, 1987, which are incorporated
herein by reference.
"Substituted" is intended to indicate that one or more
hydrogens on the atom indicated in the expression using
"substituted" is replaced with a selection from the
indicated group(s), provided that the indicated atom's
normal valency is not exceeded, and that the substitution
results in a stable compound. When a substituent is keto
(i.e., =0) group, then 2 hydrogens on the atom are replaced.
The term "Treating" refers to:
(i) preventing a disease, disorder or condition from
occurring in an animal which may be predisposed to the
disease, disorder and/or condition but has not yet
been diagnosed as having it;
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(ii) inhibiting the disease, disorder or condition, i.e.,
arresting its development; and
(iii) relieving the disease, disorder or condition, i.e.,
causing regression of the disease, disorder and/or
condition.
Preparation of Compounds of the Invention
It will be apparent to those skilled in the art that
certain compounds of formula (I) can exhibit isomerism, for
example geometrical isomerism, e.g., E or Z isomerism, and
optical isomerism, e.g., R or S configurations. Geometrical
isomers include the cis and trans forms of compounds of the
invention having alkenyl moieties. It is well known in the
art how to prepare optically active forms, such as by
resolution of racemic forms or by synthesis from optically
active starting materials. All chiral, diastereomeric,
racemic forms and all geometric isomeric forms of a
structure are intended, unless the specific stereochemistry
or isomer form is specifically indicated.
Such isomers can be separated from their mixtures, by
the application or adaptation of known methods, for example
chromatographic techniques and recrystallization techniques,
or they are separately prepared from the appropriate isomers
of their intermediates, for example by the application or
adaptation of methods described herein.
The compounds of the present invention are useful in
the form of the free base or acid or in the form of a
pharmaceutically acceptable salt thereof. All forms are
within the scope of the invention.
Where the compound of the present invention is
substituted with a basic moiety, acid addition salts are
formed and are simply a more convenient form for use; and in
practice, use of the salt form inherently amounts to use of
the free base form. The acids which can be used to prepare
the acid addition salts include preferably those which
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acceptable salts, that is, salts whose anions are non-toxic
to the patient in pharmaceutical doses of the salts, so that
the beneficial inhibitory effects on CDK inherent in the
free base are not vitiated by side effects ascribable to the
anions. Although pharmaceutically acceptable salts of said
basic compounds are preferred, all acid addition salts are
useful as sources of the free base form even if the
particular salt, per se, is desired only as an intermediate
product as, for example, when the salt is formed only for
purposes of purification, and identification, or when it is
used as intermediate in preparing a pharmaceutically
acceptable salt by ion exchange procedures.
According to a further feature of the invention, acid
addition salts of the compounds of this invention are
prepared by reaction of the free base with the appropriate
acid, by the application or adaptation of known methods.
For example, the acid addition salts of the compounds of
this invention are prepared either by dissolving the free
base in aqueous or aqueous-alcohol solution or other
suitable solvents containing the appropriate acid and
isolating the salt by evaporating the solution, or by
reacting the free base and acid in an organic solvent, in
which case the salt separates directly or can be obtained by
concentration of the solution.
The compounds of this invention can be regenerated from
their corresponding acid addition salts by the application
or adaptation of known methods. For example, parent
compounds of the invention can be regenerated from their
acid addition salts by treatment with an alkali, e.g.
aqueous sodium bicarbonate solution or aqueous ammonia
solution.
Where the compound of the invention is substituted with
an acidic moiety, base addition salts may be formed and are
simply a more convenient form for use; and in practice, use
of the salt form inherently amounts to use of the free acid
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form. The bases which can be used to prepare the base
addition salts include preferably those which produce, when
combined with the free acid, pharmaceutically acceptable
salts, that is, salts whose rations are non-toxic to the
animal organism in pharmaceutical doses of the salts, so
that the beneficial inhibitory effects on CDK inherent in
the free acid are not vitiated by side effects ascribable to
the rations. Pharmaceutically acceptable salts, including
for example alkali and alkaline earth metal salts, within
the scope of the invention are those derived from the
following bases: sodium hydride, sodium hydroxide,
potassium hydroxide, calcium hydroxide, aluminum hydroxide,
lithium hydroxide, magnesium hydroxide, zinc hydroxide,
ammonia, ethylenediamine, N-methyl-glucamine, lysine,
arginine, ornithine, eholine, N,N'-dibenzylethylenediamine,
chloroprocaine, diethanolamine, procaine,
N-benzylphenethylamine, diethylamine, piperazine,
tris(hydroxymethyl)-aminomethane, tetramethylammonium
hydroxide, and the like.
Metal salts of compounds of the present invention may
be obtained by contacting a hydride, hydroxide, carbonate or
similar reactive compound of the chosen metal in an aqueous
or organic solvent with the free acid form of the compound.
The aqueous solvent employed may be water or it may be a
mixture of water with an organic solvent, preferably an
alcohol such as methanol or ethanol, a ketone such as
acetone, an aliphatic ether such as tetrahydrofuran, or an
ester such as ethyl acetate. Such reactions are normally
conducted at ambient temperature but they may, if desired,
be conducted with heating.
Amine salts of compounds of the present invention may
be obtained by contacting an amine in an aqueous or organic
solvent with the free acid form of the compound. Suitable
aqueous solvents include water and mixtures of water with
alcohols such as methanol or ethanol, ethers such as
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tetrahydrofuran, nitriles such as acetonitrile, or ketones
such as acetone. Amino acid salts may be similarly
prepared.
The compounds of this invention can be regenerated from
their corresponding base addition salts by the application
or adaptation of known methods. For example, parent
compounds of the invention can be regenerated from their
base addition salts by treatment with an acid, e.g.
hydrochloric acid.
Pharmaceutically acceptable salts also include
quaternary lower alkyl. ammonium salts. The quaternary salts
are prepared by the exhaustive alkylation of basic nitrogen
atoms in compounds, including nonaromatic and aromatic basic
nitrogen atoms, according to the invention, i.e., alkylating
the non-bonded pair of electrons of the nitrogen moieties
with an alkylating agent such as methylhalide, particularly
methyl iodide, or dimethyl sulfate. Quaternarization
results in the nitrogen moiety becoming positively charged
and having a negative counter ion associated therewith.
As will be self-evident to those skilled in the art,
some of the compounds of this invention do not form stable
salts. However, acid addition salts are more likely to be
formed by compounds o~ this invention having a nitrogen-
containing heteroaryl group and/or wherein the compounds
contain an amino group as a substituent. Preferable acid
addition salts of the compounds of the invention are those
wherein there is not an acid labile group.
As well as being useful in themselves as active
compounds, salts of compounds of the invention are useful
for the purposes of purification of the compounds, for
example by exploitation of the solubility differences
between the salts and the parent compounds, side products
and/or starting materials by techniques well known to those
skilled in the art.
43

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Compounds according to the invention, for example,
starting materials, intermediates or products, are prepared
as described herein or by the application or adaptation of
known methods, by which is meant methods used heretofore or
described in the literature, for example those described by
l0 R. C. Larock in Comprehensive Organic Transformations, VCH
publishers, 1989.
In the reactions described hereinafter it may be
necessary to protect reactive functional groups, for example
hydroxy, amino, imino, thio or carboxy groups, where these
are desired in the final product, to avoid their unwanted
participation in the reactions. Conventional protecting
groups may be used in accordance with standard practice, for
examples see T.W. Green and P.G.M.Wuts in "Protective Groups
in Organic Chemistry" John Wiley and Sons, 1991; J. F. W.
McOmie in "Protective Groups in Organic Chemistry" Plenum
Press, 1973.
Preferred methods of synthesizing the compounds of the
invention include, but are not limited to, those methods
described below. Each of the references cited below are
hereby incorporated herein by reference.
Scheme 1
44

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O O O
NO~ ' -NH / i R2 ~NH O ~ ~R2
/ C02Me 1.. H~, Pd/C CO~Me
/ /
Ac20, pyr. ~ ~ base
CO2Me C02Me ~ O
2 3 O
NH2 p ~ /R2
1. H2NNH2 / ~ ~ 1. SEMCI, Et3N, dioxane, reflux.
W
2. acid ~ ~ \ 2. PhOC(X)Cl, KzC03, dioxane, rt.
N~NH
4
x R2 R2
NH O ~ ~ ~ O H ~ O
PhO~ ~ 1. DMSO, 80 C N~N NH
R _
-I- Rp NHNH2 2, 4N HCI, dioxane
N~N~SEM O ~ ~ N~N~H
s x=o, s x=o, s s
An approach to preparing indeno[1,2-c]pyrazol-4-ones is
presented in Scheme 1 and can be used to prepare compounds
of the present invention. The nitro group of dimethyl 3-
nitrophthalate was reduced to the amine using catalytic
hydrogenation. The aniline was acylated using acetic
anhydride and pyridine as a base. A mixture of the resulting
acetamide 2 and an acetophenone were treated with a strong
base in an appropriate solvent at elevated temperature to
give the desired triketone 3. Additional means of preparing
triketones are known to one skilled in the art as described
in Kilgore et al, Industrial and Engineering Chemistry
34:494-497, 1946, the contents of which are hereby
incorporated herein by reference. The triketone was treated
with hydrazine at elevated temperature in an appropriate
solvent to give the indeno[1,2-c]pyrazol-4-one ring system.
Additional means of preparing indeno[1,2-c]pyrazol-4-ones
are known to one skilled in the art as described in Lemke et
al., J. Heterocyclic Chem. 19:1335-1340, 1982; Mosher and

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Soeder, J. Heterocyclic Chem. 8:855-59, 1971; Hrnciar and
Svanygova Collect. Czech. Chem. Commun. 59:2734-40, 1994 the
contents of which are hereby incorporated herein by
reference. The amide was deacylated by heating with a strong
acid in an appropriate solvent to give aniline 4. Treating
the intermediate 5-aminoindeno[1,2-c]pyrazol-4-one (4) with
2-(trimethylsilyl) ethoxymethylmethyl chloride (SEMC1) and a
suitable base in an inert solvent under reflux gives the SEM
protected intermediate. The aniline is converted to the
carbamate 5 using methods known to those skilled in the art.
This intermediate is reacted with carbazates in DMSO at
elevated temperatures and then the SEM group is removed by
treating with acid in a polar protic solvent to give the
desired acylsemicarbazide-containing indenopyrazole analogs
6.
Scheme 2
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O O O N02 O
RCO2Et,NaOEt/EtOH ~ + /
R CH3 R R2 ~ O
(R = CH3 or CF3) \
7 O
1 H
NH2 O R ~NwH NH O
O 1 ) PhOCOCI
or PhOCSCI / O
1 ) Ac20, Et3N
2) reduction \ R2 2) R1CONHNH2 \ ~ R2
O O
8 9
)
R1 N~
NH O
H2NNH2 O / 2
R
~ ~NH
N
10
Another method for preparing the triketones 3 of Scheme
1 employs the condensation of a 1,3-diketone 7 with 3-
nitrophthalic anhydride as described in Rotberg and Oshkaya,
Zh. Organ. Khim. 8:84-87, 1972; Zh. Organ. Khim. 9:2548-
2550, 1973, the contents of which are hereby incorporated
herein by reference. The 1,3-diketones~ when not
commercially available can be readily prepared by one
skilled in the art by the acetylation or
trifluoroacetylation of the requisite methyl ketone, R1COCH3.
Reduction of the nitro derivative to the aniline 8 can be
accomplished in a variety of ways including catalyic
hydrogenation, treatment with zinc or iron under acidic
conditions, or treatment with other reducing agents such as
sodium dithionite or stannous chloride. Acetylation of the
aniline 8 provides the triones 3.
47

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Alternatively, the indeno[1,2-c]pyrazol-4-ones of this
invention can be prepared as shown in Scheme2. Exposure of
aniline 8 to phenyl chloroformate or phenyl
chlorothionoformate in the presence of base, followed by
treatment of the intermediate with the appropriate
carbazate, provides either trione 9, a hydrazone of 9, or
mixtures of 9 and its hydrazone. When 9 or its hydrazone is
allowed to react with hydrazine as described above the
pyrazoles 10 are obtained.
Other features of the invention will become apparent
during the following descriptions of exemplary embodiments
which are given for illustration of the invention and are
not intended to be limiting thereof.
Examples
Abbreviations used in the Examples are defined as
follows: "°C" for degrees Celsius, "CIMS" for chemical
ionization mass spectroscopy, "eq" for equivalent or
equivalents, "g" for gram or grams, "h" for hour or hours,
"mg" for milligram or milligrams, "mL" for milliliter or
milliliters, "mmol" for millimolar, "M" for molar, "min" for
minute or minutes, "p-TsOH" for para-toluenesulphonic acid,
"DMF" for dimethylformamide, and "TFA" for trifluoroacetic
acid.
Example I
Preparation of 3-(4-methoxyt~henyl)-5-(2-(3,5-
dimethoxybenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-
4-one
48

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OMe Me
NH O / ~ O
H2N O Ph~O Me0
1. SEMCI, Et3N, dioxane, reflux. ~.. ~ ~NHNHg
~ ~NH 2. PhOCOCI, KZCOg, dioxane, rt. S ~NiN~SEM
N Me0
ii
7
OMe
Me0 O
~ O
1. DMSO, 80 C ~ ~ N~N~NH
2. 4N HCI, dioxane w
MeO~ O ~ ~ ~N~N~H
Step 1. Synthesis of 11 from 7.
The synthesis for the starting aniline is this example
is described in WO 9954308 and is incorporated herein by
reference. A suspension of aniline 7 (0.5 g, 1.7 mmol) in
dioxane (10 mL) was treated with triethylamine (0.48 mL, 3.4
mmol) in one portion at room temperature. Then 2-
(trimethylsilyl) ethyloxy chloride (SEMCl) (0.48 mL, 2.6
mmol) was added in one portion and the mixture heated to
reflux for 2 h. The reaction was cooled, diluted with EtOAc
(20 mL) washed with water (10 mL), dried (MgS04) and the
solvent removed at reduced pressure. The residue was taken
up in benzene (3 mL), applied to a plug of silica gel (10 g)
and eluted with EtOAc/Hexane (1:3) until all the yellow
color was washed from the silica gel plug. The solvent was
evaporated and the residue taken on to the next step. This
material was dissolved in dioxane (10 mL) and treated with
K2C03 (0.36 g, 2.6 mmol) in one portion. Then
phenylchloroformate (0.27 mL, 2.23 mmol) was added in one
portion and the reaction heated to 50 C for 2 h. The
reaction was cooled and the solvent removed at reduced
pressure. The residue was recrystalized from EtOH to give a
49

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yellow solid (0.4 g, 43%). mp °C; CIMS m/e calculated for
C3pH32N305Si: 542.2111, found: 542.2101.
Step 2. Synthesis of Ex. I from 11.
Compound 11 (0.015 g, 0.03 mmol) in DMSO (0.2 mL) was
treated with 3,5-dimethoxyphenylcarbazte (0.008 g, 0.06
mmol) in one portion and heated to 80 C for 30 minutes. The
solvent was removed at reduced pressure heating to 65 C. The
residue was disolved in EtOH (0.5 mL) and treated with 4N
HC1/dioxane (0.4 mL). The mixture was heated to 80 C for 20
minutes and then cooled. The desired product was filtered
and air dried (0.0088, 620). mp >300 °C; CIMS m/e calculated
for C27H24N50~(M+H+): 514.1727, found: 514.1777.
Example II
Preparation of 3-(4-methoxyt~henyl)-5-(2-
isonicotinoylhydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 4-pyridylcarbazate as the starting material. mp 248
°C; CIMS m/e calculated for C24H1gN604(M+H+): 455.1468,
found: 455.1400.
Example III
Preparation of 3-(4-methoxy~henyl)-5-(2-
nictinoylhydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 3-pyridylcarbazate as the starting material. mp 227
°C; CIMS m/e calc'd for C24H19N604(M+H+): 455.1468, found:
455.1487.
Example IV

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Preparation of 3-(4-methoxyt~henyl)-5 (2-(3,4-dihydroxy
benzoyl)hydrazinecarboxamido)indeno[1,2-c]pyrazol-4-one
Prepared in a similar fashion as described for example
I using 3,4-dihydroxyphenyl carbazate as the starting
material. mp >300 °C; CIMS m/e calc'd for C25H20N5~6(M+H+):
486.1414, found: 486.1497.
Example V
Preparation of 3-(4-methoxyphenyl)-5-(2-(4-hydroxy
benzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 4-hydroxyphenyl carbazate as the starting material.
mp 283 °C; CIMS m/e calc'd for C25H2pN505(M+H+): 470.1464,
found: 470.1544.
Example VI
Preparation of 3-(4-methoxyphenvl)-5-(2-(3
aminobenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 3-aminophenyl carbazate as the starting material, mp
250 °C; CIMS m/e calc'd for C25H21N604(M+H+): 469.1624,
found: 469.1513.
Example VII
Preparation of 3-(4-methoxyt~henvl)-5-(2-(4-
aminobenzovl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 4-aminophenyl carbazate as the starting material. mp
247 °C; CIMS m/e calc'd for C25H21N6~4(I''1+H+): 469.1624,
found: 469.1528.
Example VIII
51

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Preparation of 3-(4-methoxyphenyl)-5-(2-(2-
aminobenzoyl)hydrazinecarboxamido)indeno[1,2-cl~yrazol-4-one
Prepared in a similar fashion as described for example
I using 2-aminophenyl carbazate as the starting material. mp
257 °C; CIMS m/e calc'd for C25H21N6~4(M+H+): 469.1624,
found: 469.1548;
Example IX
Preparation of 3-(4-methoxyphenyl)-5-(2-(4-N,N-dimethylamino
benzoyl)hydrazinecarboxamido)indeno[1,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 4-N,N-dimethylaminophenyl carbazate as the starting
material. mp 259 °C; CIMS m/e calc'd for C27H25N604(M+H+):
497.1937, found: 497.1876.
' Example X
Preparation of 3-(4-methoxyphenyl)-5-(2-methoxybenzoyl
hydrazinecarboxamido)indeno[1,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 2-methoxyphenyl carbazate as the starting material.
mp 269 °C; CIMS m/e calc'd for C26H22N505(M+H+): 484.1621,
found: 484.1613.
Example XI
Preparation of 3-(4-methoxyt~henyl)-5-(2-(2-hydroxy
benzoyl)hydrazinecarboxamido)indeno[1,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 2-hydroxyphenyl carbazate as the starting material.
mp 280 °C; CIMS m/e calc'd for C25H20N5~5(M+H+): 470.1464,
found: 470.1419.
Example XII
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Preparation of 3-(4-methoxyt~henvl)-5-(2-(3,5-diaminobenzoyl)
hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 3,5-diaminophenyl carbazate as the starting
material. mp >300 °C; CIMS m/e calc'd for C25H22N704(M+H+):
484.1733, found: 484.1776.
Example XIII
Preparation of 3-(4-methoxyahenyl)-5-(2-(1-naphthoyl)
hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 1-naphthhydrazide as the starting material. CIMS m/e
calc'd for~C2gH22N504(M+H+): 504.1672, found: 504.1706.
Example XIV
Preparation of 3-(4-methoxvphenvl)-5-(2-amido
hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using semicarbazide as the starting material. CIMS m/e
calc'd for C1gH17N604(M+H+): 393.1311, found: 393.1333.
Example XV
Preparation of 3-(4-methoxyphenyl)-5-(2 phenylamido
hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 4-phenylsemicarbazide as the starting material. CIMS
m/e calc'd for C25H21Ng04(M+H+): 469.1624, found: 469.1681.
Example XVI
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Preparation of 3-(4-methox~mhenyl)-5-(2-(4-
methylbenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-
one
Prepared in a similar fashion as described for example
I using 4-methylphenyl carbazate as the starting material.
CIMS m/e calc'd for C26H22N504(M+H+): 468.1672, found:
468.1688.
Example XVII
Preparation of 3-(4-methoxyt~henyl)-5-(2-(2-
naphthovl)hydrazinecarboxamido)indenofl,2-clpvrazol-4-one
Prepared in a similar fashion as described for example
I using 2-naphthhadrazide as the starting material. CIMS m/e
calc'd for C2gH22N504(M+H+): 504.1672, found: 504.1710.
Example XVIII
Pret~aration of 3- (4-methoxyt~henyl) -5- (2- (3- (4-
hydroxyt~henyl)propionyl)hydrazinecarboxamido)indenofl,2-
clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 4-hydroxyhydrocinamic acid hydrazide as the starting
material. CIMS m/e calc'd for C27H24N505(M+H+): 498.1777,
found: 498.1711.
Example XIX
Preparation of 3-(4-methoxy~henyl)-5-(2-(4-
methoxybenzoyl)hydrazinecarboxamido)indenofl,2-c]pyrazol-4-
one
Prepared in a similar fashion as described for example
I using 4-methoxybenzhydrazide as the starting material.
CIMS m/e calc'd for C26H22N505(M+H+): 484.1621, found:
484.1600.
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Example XX
Preparation of 3- (4-methoxyt~hen.yl) -5- (2- (3-
nitrobenzoyl)hydrazinecarboxamido)indeno[1,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 3-nitrobenzhydrazide as the starting material. CIMS
m/e calc'd for C25H19N606(M+H+): 499.1366, found: 499.1304.
Example XXI
Preparation of 3-(4-methoxyphenyl)-5-(2-(3-
nitrobenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 3,4,5-trimethoxybenzhydrazide as the starting
material. CIMS mle calc'd for C28H26N507(M+H+): 544.1832,
found: 544.1812.
Example XXII
Preparation of 3-(4-methoxyt~henyl)-5-(2-(2-
thienoyl)hydrazinecarboxamido)indeno[1,2-clpyrazol-4-one
Prepared in a similar fashion as described for example
I using 2-thenoic hydrazide as the starting material. CIMS
m/e calc'd for C23H18N504S(M+H+): 460.1080, found: 460.1012.
Example XXIII
Preparation of 3-(4-methoxyt~henyl)-5-(2-(3-
methylbenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-
one
Prepared in a similar fashion as described for example
I using 3-methylbenzoic acid hydrazide as the starting
material. CIMS m/e calc'd for C26H22N504(M+H+): 468.1672,
found: 468.1640.

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Exams 1 a XXV
Preparation of 3-(4-methoxyt~henyl)-5-(2-(2,5-
dichlorobenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-
one
Prepared in a similar fashion as described for example
I using 2,5-dichlorobenzoic acid hydrazide as the starting
material. CIMS m/e calc'd for C25H1gN504C12(M+H+): 522.0736,
found: 522.0777.
Example XXVI
Preparation of 3-(4-methoxyt~henyl)-5-(2-(3,4-
dihydroxybenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-
4-one
Prepared in a similar fashion as described for example
I using 3,4-dihydroxybenzoic acid hydrazide as the starting
material. CIMS m/e calc'd for C25H2pN506(M+H+): 486.1414,
found: 486.1445.
Example XXVII
Preparation of 3-(4-pi~erazinylphen~rl)-5-(2-
~nicotinoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-one
56

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O CH3 O CHs O CFs N02 O
O
O I/
CNJ ~N~ CNJ N
N N
Boc 12 Boc 13 14 NBoc
O / I H OII
PhO~NH O N w N~H~NH O
O O ~ O
_ ~ / ~ ~ /
\O ~-~ \O
16 ~~ oc 17 ~~ oc
Boc / I H O ~~H
Nw Nw N~N~NH ~N
O a.
O ~ O H I ~
/ W _
N NH
1 g XXVII
Step 1. Preparation of 12
To a suspension of 1398 (680 mmol) of 4-
piperazinoacetophenone in 700mL of tetrahydrofuran at 25°C
was added slowly over 20 min. a solution of 1578 (720 mmol)
of di-tert-butyl Bicarbonate in 300mL of tetrahydrofuran.
The resulting mixture was refluxed for 15h. After cooling
the mixture was filtered, and the filtrate was concentrated
under vacuum to provide an off-white solid. This crude
product was recrystallized from diethyl ether/hexane to
57

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afford 1928 of the 12 as a white solid. NMR (CDC13) 8 7.89
(d, 2 H, J = 9 Hz) , 6.87 (d, 2 H, J = 9 Hz) , 3.59 (m, 4 H) ,
3.33 (m, 4 H) , 2.53 (s, 3 H) , 1.49 (s, 9 H) .
Step 2. Preparation of 13 from 12
To a solution of 1928 (630 mmol) of 12 and 90mL (750
mmol) of ethyl trifluoroacetate in 1000 mL of
tetrahydrofuran at 25 °C was added slowly over 15 min. 280
mL (750 mmol) of 21% sodium ethoxide in ethanol, and the
resulting solution then was stirred at 25°C for 16 h. The
reaction mixture was diluted with 500mL of water, and to
this mixture was added 45mL of acetic acid. The resulting
precipitate was recovered by filtration. The solids were
washed with diethyl ether/hexane and dried to furnish 236g
of 13 as an orange solid. NMR (CDC13) 8 7.87 (d, 2 H, J = 9
Hz), 6.87 (d, 2 H, J = 9 Hz), 6.45 (s, 1 H), 3.60 (m, 4 H),
3.41 (m, 4 H) , 1.48 (s, 9 H) .
Step 3. Preparation of 14 from 13
A suspension of 1178 (610 mmol) of 3-nitrophthalic
anhydride in 560mL of acetic anhydride was heated until the
mixture became homogeneous, and the solution then was
allowed to cool to room temperature. To this solution was
added 2368 (590 mmol) of 13. The resulting mixture was
cooled to 0°C, and 165mL (1200 mmol) of triethylamine was
added slowly over 10 min. The mixture was allowed to warm to
25°C, was stirred at 25°C for 1h, and then was heated to
65°C for 0.5h. After cooling to room temperature, the
reaction mixture was poured into a well-stirred solution of
1200mL of 1.0 N hydrochloric acid and 2000mL of ethanol. The
resulting precipitate was recovered by filtration, washed
with ethanol, and dried to provide 1408 of 14 as an orange
solid. NMR (acetone-ds) 8 8.34 (d, 2H, J = 9 Hz), 8.05 (m,
3H), 7.07 (d, 2H, J = 9 Hz), 3.59 (br s, 8H), 1.48 (s, 9H).
58

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Step 4. Preparation of 15 from 14
To a solution of 12.00g (25 mmol) of 14 in 500mL of
ethanol and 50mL of cons. ammonium hydroxide at 25°C was
added 500mL of water, followed by 15.38 (88 mmol) of sodium
dithionite. The resulting mixture was stirred at 25°C for
16h. The reaction mixture was filtered, and the filtrate was
reduced to ~1/2 the original volume under vacuum. This
solution was adjusted to pH 3 employing hydrochloric acid
and then extracted with ethyl acetate. The combined extracts
were washed with water and brine, dried over anhyd. sodium
sulfate, filtered, and concentrated. The resulting solids
were recrystallized from ethanol/water to provide 8.408 of
15 as a green solid. NMR (DMSO-ds) 8 8.20 (d, 2H, J = 9 Hz),
7.44 (t, 1H, J = 8 Hz), 7.02 (d, 2H, J = 9 Hz), 6.96 (d, 1H,
J = 8 Hz), 6.91 (d, 1H, J = 8 Hz), 6.70 (br s, 2H), 3.46 (br
s, 8H), 1.43 (s, 9H).
Step 5. Preparation of 16 from 15
To a mixture of 7.058 (15.6 mmol) of 15, 8.678 (63
mmol) of potassium carbonate, 250mL of acetone at 25°C was
added 2.40mL of phenyl chloroformate, and the resulting
mixture was stirred at 25°C for 20h. The mixture was diluted
with 500mL of water, adjusted to pH 3 employing hydrochloric
acid, and extracted with ethyl acetate. The combined
extracts were washed with water and brine, dried over anhyd,
sodium sulfate, filtered, and dried. The crude product was
recrystallized from ethanol/water to afford 6.328 of 16 as a
dark yellow solid. Mass Spec: m/e = 582 (M-H)-.
Step 6. Preparation of 18 from 16
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A solution of 0.578 (1.0 mmol) of 16 and 0.418 (3.0
mmol) of nicotinic acid hydrazide in 20mL of DMSO was
stirred at 90°C for 2h. After cooling the solvent was
removed under high vacuum to afford crude 17.
A solution of the crude 17, 0.10mL (2.0 mmol) of
hydrazine hydrate, and 0.0148 (0.2 mmol) of hydrazine
hydrochloride in 20mL of ethanol was refluxed for 20h. While
still at reflux the reaction mixture was diluted by dropwise
addition of lOmL of water at a rate such that the refluxing
of the solution was continuous. The mixture was allowed to
cool to room temperature, and the resulting precipitate was
recovered by filtration, washed with 95% ethanol, and dried
to provide 0.258 of 18 as a yellow solid.
Step 7. Preparation of XXVII from 18
A solution of 0.258 (0.4 mmol) of 18 in lOmL of
trifluoroacetic acid was stirred at 25°C for 2h. The excess
trifluoroacetic acid was removed under vacuum, and the
residue was dissolved in 20mL of hot ethanol. After cooling,
the resulting precipitate was recovered by filtration under
nitrogen and then dried under vacuum to afford 0.168 of the
desired product as its trifluoroacetate salt. mp 232 °C;
CIMS m/e calc'd for C27H25N803(M+H+): 509.2050, found:
509.2060.
Example XXVIII
Preparation of 3-(4-(4-methylpiperazinyl)phenyl)-5-(2
(nicotinoyl)hydrazinecarboxamido)indenofl,2-c~pyrazol-4-one

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N~CH3
N I N.N~NH ~~H N w I N.
11 H ~ i II
O ~\ \~ O
XXVII N-NH XXVI11
To a solution of 0.168 (0.26 mmol) of XXVII in l5mL of
methanol and 5mL of water at 25°C was added sequentially
0.778 (9.5 mmol) of 37% aqueous formaldehyde, 0.328 (5.1
mmol) of sodium cyanoborohydride, and 3 drop of acetic acid.
The resulting solution was stirred for 16h at 25°C. The
solution was made acidic (pH<1) with cons. hydrochloric acid
and was stirred for 20 min. until gas evolution ceased. The
solution then was made basic (pH.l3) with 50% aqueous sodium
hydroxide solution. The mixture was stirred for 20 min, and
then was adjusted to pH 9 with hydrochloric acid. The
resulting precipitate was recovered by filtration, washed
with 95% ethanol, and dried under vacuum. The yellow solid
thus obtained was dissolved in 2mL of trifluoroacetic acid,
and the solution was diluted with lOmL of hot anhydrous
ethanol. Upon cooling a precipitate formed. This solid was
recovered by filtration and dried under vacuum to afford
0.088 of the desired product as its trifluoroacetate salt.
mp 238 °C; CIMS m/e calc'd for C28H27Ng03(M+H+): 523.2206,
found: 523.2210.
Example XXIX
Preparation of 3-(4-(4-methylpiperazinvl)~henvl)-5-(2-
(isonicotinoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-
one
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Prepared from example XXX in a similar fashion as
described for example XXVIII. mp 240 °C; CIMS m/e calc'd for
C28H2~Ng03(M+H+): 523.2206, found: 523.2208.
Example XXX
Preparation of 3-(4-piperazinylphenyl)-5-(2-
(isonicotinoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-4-
one
Prepared in a similar fashion as described for example
XXVII using isonicotinic acid hydrazide as the starting
material. mp 232 °C; CIMS m/e calc'd for C2~H25Ng03(M+H+):
509.2050, found: 509.2065
Example XXXI
Preparation of 3-(4-piperazinylphenyl)-5-(2-(3,5-
dimethoxybenzoyl)hydrazinecarboxamido)indenofl,2-clpyrazol-
4-one
Prepared in a similar fashion as described for example
XXVII using 3,5-dimethoxybenzoic hydrazide as the starting
material. mp >300 °C; CIMS m/e calc'd for C3pH30N7~5(M+H+):
568.2309; found: 568.2316.
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Table 1
O
2
Example R1-C(O)N(R5)NH- R2 mass mp
# (M+H) (C)
I 3,5-diinethoxy 4-Me0C6H4- 514 >300
C(H3C(0)NHNH-
II 4-pyridylC(0)NHNH- 4-Me0CgH4- 455 248
III 3-pyridylC(0)NHNH- 4-Me0COH4- 455 227
IV 3,4-dihydroxy- 4-Me0C6H4- 486 >300
CgH3C(0)NHNH-
V 4-hydroxy- 4-Me0C6H4- 470 283
C6H4C(0)NHNH-
VI 3-amino-C6H4C(0)NHNH- 4-MeOC(H4- 469 250
VII 4-amino-C6H4C(O)NHNH- 4-Me0C6H4- 469 247
VIII 2-amino-CgH4C(O)NHNH- 4-Me0C6H4- 469 257
IX 4-N,N-dimethylamino- 4-Me0C6H4- 497 259
C6H4C(0)NHNH-
X 2-Me0-C6H4C(0)NHNH- 4-Me0CgH4- 484 269
XI 2-OH-C6H4C(0)NHNH- 4-Me0C6H4- 470 280
XII 3,5-di-NH2-C6H3C 4-Me0C6H4- 484 >300
( O ) NHNH-
XIII 1-naphthylC(0)NHNH- 4-MeOC6H4- 504
XIV HZNC(0)NHNH- 4-Me0C6H4- 393
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XV C6H4HNC(0)NHNH- 4-Me0C6H4- 469
XVI 4-Me-C(H4C(0)NHNH- 4-MeOC(H4- 468
XVII 2-naphthylC(0)NHNH- 4-MeOC(H4- 504
XVIII 4-OH- 4-MeOC6H4- 498
C 6H4CHZCHzC ( 0 ) NHNH-
XIX 4-Me0-C6H4C(0)NHNH- 4-Me0C6H4- 484
XX ~ 2-NO2-C6H4C(0)NHNH- 4-Me0C6H4- 499
XXI 3,4,5-tri-Me0- 4-MeOC6H4- 544
C6H2C(0)NHNH-
XXII 2-thienylC(0)NHNH- 4-Me0CgH4- 460
XXIII 3-Me-C(H4C(0)NHNH- 4-Me0C6H4- 468
XXIV 3-NH2-4-OH- 4-Me0C6H4- 485
C6H3C(0)NHNH-
XXV 2,5-di-Cl- 4-Me0C6H4- 522
C(H3C(0)NHNH-
XXVI 3,4-di-OH- 4-MeOC(H4- 486
C6H3C(0)NHNH-
XXVII 3-pyridylC(0)NHNH- 4-piperazinyl 509 232
C6H4-
XXVIII 3-pyridylC(0)NHNH- 4-(4-Me- 523 238
piperazinyl)
C6H4_
XXIX 4-pyridylC(0)NHNH- 4-(4-Me- 523 240
piperazinyl)
C6H4_
XXX 4-pyridylC(0)NHNH- 4-piperazinyl 509 232
C6H4_
XXXI 3,5-di-Me0- 4-piperazinyl 568 >300
C6H3C(0)NHNH- C6H4-
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The compounds useful according to the invention
optionally are supplied as salts. Those salts which are
pharmaceutically acceptable are of particular interest since
they are useful in administering the foregoing compounds for
medical purposes. Salts which are not pharmaceutically
acceptable are useful in manufacturing processes, for
isolation and purification purposes, and in some instances,
for use in separating stereoisomeric forms of the compounds
of this invention. The latter is particularly true of amine
salts prepared from optically active amines.
Where-the compound useful according to the invention
contains a carboxy group, or a sufficiently acidic
bioisostere, base addition salts may be formed and are
simply a more convenient form for use; and in practice, use
of the salt form inherently amounts to use of the free acid
form.
Also, where the compound useful according to the
invention contains a basic group, or a sufficiently basic
bioisostere, acid addition salts may be formed and are
simply a more convenient form for use; and in practice, use
of the salt form inherently amounts to use of the free base
form.
The foregoing compounds useful according to the
invention may also be mixed another therapeutic compound to
form pharmaceutical compositions (with or without diluent or
carrier) which, when administered, provide simultaneous
administration of a combination of active ingredients
resulting in the combination therapy of the invention.
While it is possible for the compounds useful according
to the invention to be administered alone it is preferably
to present them as pharmaceutical compositions. The
pharmaceutical compositions, both for veterinary and for
human use, useful according to the present invention
comprise at lease one compound of the invention, as above

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defined, together with one or more acceptable carriers
therefor and optionally other therapeutic ingredients.
In certain preferred embodiments, active ingredients
necessary in combination therapy may be combined in a single
pharmaceutical composition for simultaneous administration.
The choice of vehicle and the content of active
substance in the vehicle are generally determined in
accordance with the solubility and chemical properties of
the active compound, the particular mode of administration
and the provisions to be observed in pharmaceutical
practice. For example, excipients such as lactose, sodium
citrate, calcium carbonate, dicalcium phosphate and
disintegrating agents such as starch, alginic acids and
certain complex silicates combined with lubricants such as
magnesium stearate, sodium lauryl sulphate and talc may be
used for preparing tablets. To prepare a capsule, it is
advantageous to use lactose and high molecular weight
polyethylene glycols. When aqueous suspensions are used
they can contain emulsifying agents or agents which
facilitate suspension. Diluents such as sucrose, ethanol,
polyethylene glycol, propylene glycol, glycerol and
chloroform or mixtures thereof may also be used.
The oily phase of the emulsions of this invention may
be constituted from known ingredients in a known manner.
While the oily phase may comprise merely an emulsifier
(otherwise known as an emulgent), it desirably comprises a
mixture of at least one emulsifier with a fat or an oil or
with both a fat and an oil. Preferably, a hydrophilic
emulsifier is included together with a lipophilic emulsifier
which acts as a stabilizer. It is also preferred to include
both an oil and a fat. Together, the emulsifiers) with or
without stabilizers) make up the emulsifying wax, and the
way together with the oil and fat make up the emulsifying
ointment base which forms the oily dispersed phase of a
cream formulation. Emulgents and emulsion stabilizers
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suitable for use in the formulation of the present invention
include Tween~ 60, Span~ 80, cetostearyl alcohol, benzyl
alcohol, myristyl alcohol, glyceryl mono-stearate and sodium
lauryl sulfate.
If desired, the aqueous phase of the cream base may
include, for example, a least 30% w/w of a polyhydric
alcohol, i.e. an alcohol having two or more hydroxyl groups
such as propylene glycol, butane 1,3-diol, mannitol,
sorbitol, glycerol and polyethylene glycol (including PEG
400) and mixtures thereof. The topical formulations may
desirably include a compound which enhances absorption or
penetration of the active ingredient through the skin or
other affected areas. Examples of such dermal penetration
enhancers include dimethyl sulphoxide and related analogue.
The choice of suitable oils or fats for the formulation
is based on achieving the desired cosmetic properties. Thus
the cream should preferably be a non-greasy, non-staining
and washable product with suitable consistency to avoid
leakage from tubes or other containers. Straight or
branched chain, mono- or dibasic alkyl esters such as di-
isopropyl myristate, decyl oleate, isopropyl palmitate,
butyl stearate, 2-ethylhexyl palmitate or a blend of
branched chain esters known as Crodamol CAP may be used, the
last three being preferred esters. These may be used alone
or in combination depending on the properties required.
Alternatively, high melting point lipids such as white soft
paraffin and/or liquid paraffin or other mineral oils can be
used. Solid compositions of may also be employed as fillers
in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high
molecular weight polyethylene glycols, and the like.
The pharmaceutical compositions can be administered in
a suitable formulation to humans and animals by topical or
systemic administration, including oral, inhalational,
rectal, nasal, buccal, sublingual, vaginal, parenteral
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(including subcutaneous, intramuscular, intravenous,
intradermal, intrathecal and epidural), intracisternal and
intraperitoneal. It will be appreciated that the preferred
route may vary with for example the condition of the
recipient.
The formulations can be prepared in unit dosage form by
any of the methods well known. in the art of pharmacy. Such
methods include the step of bringing into association the
active ingredient with the carrier which constitutes one or
more accessory ingredients. In general the formulations are
prepared by uniformly and intimately bringing into
association the active ingredient with liquid carriers or
finely divided solid carriers or both, and then, if
necessary, shaping the product.
A tablet may be made by compression or moulding,
optionally with one or more accessory ingredients.
Compressed tables may be prepared by compressing in a
suitable machine the active ingredient in a free-flowing
form such as a powder or granules, optionally mixed with a
binder, lubricant, inert diluent, preservative, surface
active or dispersing agent. Moulded tablets may be made by
moulding in a suitable machine a mixture of the powdered
compounds moistened with an inert liquid diluent. The
tablets may optionally be coated or scored and may be
formulated so as to provide slow or controlled release of
the active ingredient therein.
Solid compositions for rectal administration include
suppositories formulated in accordance with known methods
and containing at least one compound of the invention.
If desired, and for more effective distribution, the
compounds can be microencapsulated in, or attached to, a
slow release or targeted delivery systems such as a
biocompatible, biodegradable polymer matrices (e. g.
poly(d,l-lactide co-glycolide)), liposomes, and microspheres
and subcutaneously or intramuscularly injected by a
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technique called subcutaneous or intramuscular depot to
provide continuous slow release of the compounds) for a
period of 2 weeks or longer. The compounds may be
sterilized, for example, by filtration through a bacteria
retaining filter, or by incorporating sterilizing agents in
the form of sterile solid compositions which can be
dissolved in sterile water, or some other sterile injectable
medium immediately before use.
Actual dosage levels of active ingredient in the
compositions of the invention may be varied so as to obtain
an amount of active ingredient that is effective to obtain a
desired therapeutic response for a particular composition
and method of administration. The selected dosage level
therefore depends upon the desired therapeutic effect, on
the route of administration, on the desired duration of
treatment and other factors.
Total daily dose of the compounds useful according to
this invention administered to a host in single or divided
doses may be in amounts, for example, of from about 0.001 to
about 100 mg/kg body weight daily and preferably 0.01 to 10
mg/kg/day. Dosage unit compositions may contain such
amounts of such submultiples thereof as may be used to make
up the daily dose. It will be understood, however, that the
specific dose level for any particular patient will depend
upon a variety of factors including the body weight, general
health, sex, diet, time and route of administration, rates
of absorption and excretion, combination with other drugs
and the severity of the particular disease being treated.
The amount of each component administered is determined
by the attending clinicians taking into consideration the
etiology and severity of the disease, the patient's
condition and age, the potency of each component and other
factors .
The formulations may be presented in unit-dose or
mufti-dose containers, for example sealed ampoules and vials
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with elastomeric stoppers, and may be stored in a freeze-
dried (lyophilized) condition requiring only the addition of
the sterile liquid carrier, for example water for
injections, immediately prior to use. Extemporaneous
injection solutions and suspensions may be prepared from
sterile powders, granules and tablets of the kind previously
described.
Administration of a compound of the present invention
in combination with additional therapeutic agents, may
afford an efficacy advantage over the compounds and agents
alone, and may do so while permitting the use of lower doses
of each. A lower dosage minimizes the potential of side
effects, thereby providing an increased margin of safety.
The combination of a compound of the present invention with
such additional therapeutic agents is preferably a
synergistic combination. Synergy, as described for example
by Chou and Talalay, Adv. Enzyme Regul. 22:27-55 (1984),
occurs when the therapeutic effect of the compound and agent
when administered in combination is greater than the
additive effect of the either the compound or agent when
administered alone. In general, a synergistic effect is most
clearly demonstrated at levels that are (therapeutically)
sub-optimal for either the compound of the present invention
or a known anti-proliferative agent alone, but which are
highly efficacious in combination. Synergy can be in terms
of improved inhibitory response without substantial
increases in toxicity over individual treatments alone, or
some other beneficial effect of the combination compared
with the individual components.
The compounds of the invention, their methods or
preparation and their biological activity will appear more
clearly from the examination of the following examples which
are presented as an illustration only and are not to be
considered as limiting the invention in its scope.

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Procedures for evaluating the biological activity of
compounds or compositions according to the invention are
carried out as described herein or by the application or
adaptation of known procedures, by which is meant procedures
used heretofore or as described in the literature.
UTILITY
Inhibition of Kinase/Cyclin Complex Enzymatic Activity
Several of the compounds disclosed in this invention
were assayed for their inhibitory activity against cdk4/D1
and cdk2/E kinase complexes. Briefly, the in vitro assays
employ cell lysates from insect cells expressing either of
the kinases and subsequently their corresponding regulatory
units. The cdk2/cyclinE is purified from insect cells
expressing His-tagged cdk2 and cyclin E. The cdk/cyclin
lysate is combined in a microtitre-type plate along with a
kinase compatible buffer, 32P-labeled ATP at a concentration
of 50 mM, a GST-Rb fusion protein and the test compound at
varying concentrations. The kinase reaction is allowed to
proceeded with the radiolabled ATP, then effectively stopped
by the addition of a large excess of EDTA and unlabeled ATP.
The GST-Rb labeled protein is sequestered on a GSH-Sepharose
bead suspension, washed, resuspended in scintillant, and the
32p activity detected in a scintillation counter. The
compound concentration which inhibits 50% of the kinase
activity was calculated for each compound. A compound was
considered active if its IC50 was found to be less than 1
~1M .
Inhibition of HCT 116 Cancer Cell Proliferation
To test the cellular activity of several compounds
disclosed in this invention, we examined the effect of these
compounds on cultured HCT116 cells and determined their
effect on cell-cycle progression by the colorimetric
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cytotoxcity test using sulforhodamine B (Skehan et al. J.
Natl. Cancer Inst. 82:1107-12, 1990). Briefly, HCT116 cells
are cultured in the presence of test compounds at increasing
concentrations. At selected time points, groups of cells are
fixed with trichloroacetic acid and stained with
sulforhodamine B (SRB). Unbound dye was removed by washing
and protein-bound dye was extracted for determination of
optical density. A compound was considered active if its
ICSp was found to be less than 10 ~.M.
72