Indian Patents
Title of Invention

PYRIDINO[1,2-A]PYRIMIDIN-4-ONE COMPOUNDS AS ANTICANCER AGENTS .
Abstract Pyridino[1,2.-a]pyrimidinyl compounds of formula (I), pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically.acceptable carrier and one or more of the pyridino[1,2-a]pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the pyridino[1,2-a]pyrirnidinyl compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.
Full Text WO 2004/113335 PCT/US2004/019158
PYRIDINO[l,-A]PYRIMIDIN-4-ONE COMPOUNDS AS ANTICANCER AGENTS
FIELD OF THE INVENTION
The present invention relates to new pyridmo[l,2-a]pyrimidinyl compounds, their
phannaceutically acceptable salts, and prodrugs thereof; compositions of the new
compounds, either alone or in combination with at least one additional therapeutic agent,
with a phannaceutically acceptable carrier; and uses of the new compounds, either alone
or in combination with at least one additional therapeutic agent, in the prophylaxis or
treatment of proliferative diseases.
BACKGROUND OF THE INVENTION
Kinesins are motor proteins that use adenosine triphosphate to bind to
microtubules and generate mechanical force. Kinesins are characterized by a motor
domain having about 350 amino acid residues. The crystal structures of several kinesin
motor domains have been resolved.
Currently, about one hundred kinesin-related proteins (KRP) have been identified.
Kinesins are involved in a variety of cell biological processes including transport of
organelles and vesicles, and maintenance of the endoplasmatic reticulum. Several KRPs
interact with the microtubules of the mitotic spindle or with the chromosomes directly,
and appear to play a pivotal role during the mitotic stages of the cell cycle. These mitotic
KRPs are of particular interest for the development of cancer therapeutics.
KSP (also known as Eg5, HsKSP kinesin, KNSL1,) is one of several kinesin-like
motor proteins that are localized to the mitotic spindle and known to be required for
formation and/or function of the bipolar mitotic spindle.
In 1995, the depletion of KSP kinesin using an antibody directed against the
C-terminus of KSP was shown to arrest HeLa cells in mitosis with monoastral
microtubule arrays (Blangy et al., Cell 53:1159-1169, 1995). Mutations in bimC and
cut7 genes, which are considered to be homologues of KSP kinesin, cause failure in
centrosome separation in Aspergillus nidulans (Enos, A.P., and N.R Morris,
Cell £0:1019-1027,1990) and Schizosaccharomyces pombe (Hagan, I., and M. Yanagida,
Nature 347:563-566, 1990). Treatment of cells with either ATRA (all trans-retinoic
acid), which reduces HsKSP kinesin expression on protein level, or depletion of HsKSP
kinesin using antisense oligonucleotides revealed a significant growth inhibition in
DAN-G pancreatic carcinoma cells indicating that HsKSP kinesin might be involved in
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the antiproliferative action of all trans-retinoic acid (Kaiser, A., et aL, J. Biol Chem. 274,
18925-18931, 1999). Interestingly, the Xenopus laevis Aurora-related protein kinase
pEg2 was shown to associate and phosphorylate X1KSP kinesin (Giet, R., et al., J. Biol
Chem. 274:15005-15013, 1999). Potential substrates of Aurora-related kinases are of
particular interest for cancer drug development For example, Aurora 1 and 2 kinases are
overexpressed on protein and RNA level and the genes are amplified in colon cancer
patients.
The first cell permeable small molecule inhibitor for HsKSP kinesin, "monastrol",
was shown to arrest cells with monopolar spindles without affecting microtubule
polymerization as do conventional chemotherapeutics such as taxanes and vinca alkaloids
(Mayer, T.U., et al., Science 286:911-974, 1999). Monastrol was identified as an
inhibitor in phenotype-based screens and it was suggested that this compound may serve
as a lead for the development of anticancer drugs. The inhibition was determined not to
be competitive in respect to adenosine triphosphate and to be rapidly reversible
(DeBonis, S., et al., Biochemistry 42:338-349, 2003; Kapoor, T.M., et al., J. Cell
Biol 750:975-988,2000).
Recently, other KSP kinesin inhibitors have been described WO 02/057244 and
WO 02/056880 describe phenothiazine compounds and triphenylmethane compounds,
respectively, for treating proliferative diseases. WO 02/078639 describes
cyano-substituted dmydropyrimidine compounds for treating proliferative diseases.
U.S. Patent No. 6,472,521 describes oligonucleotides and oligonucleotide derivatives for
inhibiting human KSP expression.
WO 01/98278, WO 01/30768, and WO 03/039460 describe quinazoiinone
compounds that are useful in treating cellular proliferative diseases associated with KSP
kinesin activity. The compounds described in these references are
2-(2-arninomethyl)quinazolinone derivatives. The quinazolinone compounds described
in WO 01/98278 and WO 01/30768 have 2-aminomethyl substituents that are either
amine, amide, or sulfonamide substituents. The quinazolinone compounds described in
WO 03/039460 have the amino group of the 2-aminomethyl substituent incorporated into
a 5-12 membered nitrogen-containing heterocycle.
WO 03/050064 describes thienopyrirnidinone compounds that are useful for
treating cellular proliferative disease, for treating disorders associated with KSP kinesin
activity, and for inhibiting KSP kinesin.
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WO 03/103575 describes heterocyclic-feed pyrimidinone derivatives that are
inhibitors of the mitotic kinesin KSP and that are useful in the treatment of cellular
proliferative diseases. These derivatives are N-heterocyclic-fused pyrimidinone
derivatives. Representative derivatives that are described include
pyrido[a,]pyrimidin-8-ones, pyrimido[a9p-y]pyriiiudin-5-ones,
pyrimido[]pyridazin--ones, and pteridin-4-ones.
SUMMARY OF THE INVENTION
In one aspect of the present invention, new pyridmo[l,2-a]pyrimidinyl
compounds, their pharmaceutically acceptable salts, and prodrugs thereof are provided.
The pyritoo[l,2-a]pyrimidinyl compounds, pharmaceutically acceptable salts, and
prodrugs are KSP inhibitors and are useful in the treating cellular proliferation diseases.
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In one embodiment, the pyridmo[l,2-a]pyrirmdinyl compounds have the formula

or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug
thereof, wherein
R1 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) substituted or unsubstituted alkylsulfonyl, and
(9) substituted or unsubstituted arylsulfonyl;
R2 and R3 are independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) substituted or unsubstituted alkylsulfonyl,
(9) substituted or unsubstituted arylsulfonyl,
(10) cyano,
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(11) COR10
(12) CO2R10
(13) CON11R12,
(14) S(O)mR10,and
(15) SO2NR11R12;or
R2 and R3 taken together with the carbon atom to which they are attached form a
3- to 7-membered carbocyclic or heterocyclic ring;
R4 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl, and
(8) L-R13, wherein L is a C1-C10 saturated or unsaturated branched or
unbranched carbon chain comprising one or more methylene groups, wherein one or
more methylene groups are optionally independently replaced by O, N, or S; and wherein
L is optionally substituted with one or two oxo groups and one or more C1-C10 branched
or unbranched alkyl optionally substituted by one or more halogen atoms;
R5 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) COR10,
(9) CO2RI0'
(10) CONR11R12,
(ll) S(O)mR10, and
(12) SO2NR11R12;
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WO 2004/113335 PCT/US2004/019158
R6, R7, R8 and R9 are independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) nitro,
(4) cyano,
(5) hydroxy,
(6) substituted or unsubstituted alkoxy,
(7) substituted or unsubstituted methylenedioxy,
(8) substituted or unsubstituted amino,
(9) substituted or unsubstituted alkyl,

(10) substituted or unsubstituted alkenyl,
(11) substituted or unsubstituted alkynyl,
(12) substituted or unsubstituted aryl,
(13) substituted or unsubstituted heteroaryl,
(14) substituted or unsubstituted alkylsulfonyl, and
(15) substituted or unsubstituted arylsulfonyl;
R10, R11, and R12 are independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl, and
(7) substituted or unsubstituted heterocyclyl; or
R11 and R12 taken together with the nitrogen atom to which they are
attached form a 3- to 7-membered heterocyclic ring;
R13 is selected from the group consisting of
(1) substituted or unsubstituted amino,
(2) substituted or unsubstituted aryl,
(3) substituted or unsubstituted heteroaryl, and
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(4) substituted or unsubstitutedheterocyclyl; and
m = 0, l,or2.
In another aspect, the present invention provides methods for treating proliferative
diseases in a human or animal subject in need of such treatment comprising administering
to said subject an amount of a compound of formula (I) effective to reduce or prevent
cellular proliferation in the subject
In another aspect, the present invention provides methods for treating proliferative
diseases in a human or animal subject in need of such treatment, comprising
adrninistering to said subject an amount of a compound of formula (I) effective to reduce
or prevent cellular proliferation in the subject in combination with at least one additional
agent for the treatment of cancer.
In other aspects, the present invention provides therapeutic compositions,
comprising at least one compound of formula (I) optionally in combination with one or
more additional agents for the treatment of cancer, as are commonly employed in cancer
therapy.
The compounds of the invention are useful in the treatment of cancers, including,
for example, lung and bronchus; prostate; breast; pancreas; colon and rectum; thyroid;
stomach; liver and intrahepatic bile duct; kidney and renal pelvis; urinary bladder; uterine
corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute myelogenous
leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid leukemia;
brain; oral cavity and pharynx; larynx; small intestine; non-hodgkin lymphoma;
melanoma; and villous colon adenoma.
The invention further provides compositions, kits, methods of use, and methods of
manufacture as described in the detailed description of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In one aspect of the present invention, new pyritoo[l,2-a]pyrirnidinyl
compounds, their pharmaceutically acceptable salts, and prodrugs thereof are provided.
The pyridino[l,2-a]pyrimidinyl compounds, pharmaceutically acceptable salts, and
prodrugs are KSP inhibitors and are useful in the treating cellular proliferation diseases.
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The pyridino[l,2-a]pyrimidinyl compounds have the formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug
thereof, wherein
R1 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) substituted or unsubstituted alkylsulfonyl, and
(9) substituted or unsubstituted arylsulfonyl;
R2 and R3 are independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) substituted or unsubstituted alkylsulfonyl,
(9) substituted or unsubstituted arylsulfonyl,
(10) cyano,
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WO 2004/113335 PCTYUS2004/019158
(11) COR10
(12) CO2R10,
(13) CONR11R12,
(14) S(O)mR10,and
(15) SO2NR11R12; or
R2 and R3 taken together with the carbon atom to which they are attached form a
3- to 7-membered carbocyclic or heterocyclic ring;
R4 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl, and
(8) L-R13, wherein L is a C1-C10 saturated or unsaturated branched or
unbranched carbon chain comprising one or more methylene groups, wherein one or
more methylene groups are optionally independently replaced by O, N, or S; and wherein
L is optionally substituted with one or two oxo groups and one or more C1-C10 branched
or unbranched alkyl optionally substituted by one or more halogen atoms;
R5 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) COR10,
(9) CO2R10,
(10) CONR11R12,
(11) S(O)mR10, and
(12) SO2NR11R12;
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R6, R7, R8, and R9 are independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) nitro,
(4) cyano,
(5) hydroxy,
(6) substituted or unsubstituted alkoxy,
(7) substituted or unsubstituted methylenedioxy,
(8) substituted or unsubstituted amino,
(9) substituted or unsubstituted alkyl,

(10) substituted or unsubstituted alkenyl,
(11) substituted or unsubstituted alkynyl,
(12) substituted or unsubstituted aryl,
(13) substituted or unsubstituted heteroaryl,
(14) substituted or unsubstituted alkylsulfonyl, and
(15) substituted or unsubstituted arylsulfonyl;
R10, R11, and R12 are independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl, and
(7) substituted or unsubstituted heterocyclyl; or
R11 and R12 taken together with the nitrogen atom to which they are
attached form a 3- to 7-membered heterocyclic ring;
R13 is selected from the group consisting of
(1) substituted or unsubstituted amino,
(2) substituted or unsubstituted aryl,
(3) substituted or unsubstituted heteroaryl, and
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(4) substituted or unsubstituted heterocyclyl; and
m = 0, l,or 2.
Suitable substituted alkyl groups include arylalkyl, heteroarylalkyl,
heterocyclyalkyl, aminoalkyl, alkylaminoalkyl, dialkyaminoalkyl, and sulfonamidoalkyl
groups.
In one embodiment, R1 is arylalkyl. In one embodiment, the arylalkyl is benzyl.
In one embodiment, R2 is hydrogen and R3 is selected from substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl. In one embodiment, R3 is alkyl, such as
ethyl, propyl, isopropyl, or cyclopropyl. In one embodiment, R3 is alkenyl, such as
2-propenyl. In one embodiment, R3 is aryl, such as phenyl, thienyl, or pyridyl.
In one embodiment, R4 is L-R13. In one embodiment, L is a C1-C10 saturated or
unsaturated branched or unbranched carbon chain. In one embodiment, R13 is amino,
cycloalkyl, aryl, and heterocyclyl. In one embodiment, R13 is substituted or unsubstituted
aminoalkyl, such as aminopropyl.
In one embodiment, R5 is COR10. In one embodiment, R10 is substituted or
unsubstituted aryl or substituted or unsubstituted heteroaryl. In one embodiment, R10 is
substituted phenyl or substituted pyridyl. In one embodiment, the substituted phenyl is an
alkyl- or halo-substituted phenyl.
In one embodiment, R6, R7, R8, and R9 are independently selected from hydrogen,
alkyl, and halo.
In other aspects, the present invention provides methods for manufacture of
compounds of formula (I). Methods of making representative compounds of the
invention are described in Examples 1 and 2. It is further contemplated that, in addition
to the compounds of formula (I), intermediates and their corresponding methods of
syntheses are included within the scope of the invention. Representative compounds of
the invention are illustrated in Table 1 in Example 3.
Compounds of formula (I) may be prepared as illustrated schematically in
Scheme 1 shown below.
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Scheme 1


WO 2004/113335 PCT7US2004/019158
In other aspects, the present invention provides compositions that include at least
one of the KSP inhibitors described herein, and methods that utilize the KSP inhibitors
described herein.
In one aspect, the present invention provides pharmaceutical compositions
comprising at least one pyridmo[l,2-a]pyrimidinyl compound (e.g., a compound of
formula (I)) together with a pharmaceutically acceptable carrier suitable for
administration to a human or animal subject, either alone or together with other
anticancer agents.
A number of suitable anticancer agents to be used as combination therapeutics are
contemplated for use in the compositions and methods of the present invention. Suitable
anticancer agents to be used in combination with the compounds of the invention include
agents that induce apoptosis; polynucleotides (e.g., ribozymes); polypeptides
(e.g., enzymes); drugs; biological mimetics; alkaloids; alkylating agents; antitumor
antibiotics; antimetabolites; hormones; platinum compounds; monoclonal antibodies
conjugated with anticancer drugs, toxins, and/or radionuclides; biological response
modifiers (e.g. interferons [e.g., IFN-a] and interleukins [e.g., IL-2]); adoptive
immunotherapy agents; hematopoietic growth factors; agents that induce tumor cell
differentiation (e.g., all-trans-retinoic acid); gene therapy reagents; antisense therapy
reagents and nucleotides; tumor vaccines; inhibitors of angiogenesis, and the like.
Numerous other examples of chemotherapeutic compounds and anticancer therapies
suitable for co-administration with the compounds of formula (I) are known to those
skilled in the art.
In certain embodiments, anticancer agents to be used in combination with the
compounds of the invention comprise agents that induce or stimulate apoptosis. Agents
that induce apoptosis include, but are not limited to, radiation; kinase inhibitors
(e.g., Epidermal Growth Factor Receptor [EGFR] kinase inhibitor, Vascular Growth
Factor Receptor [VGFR] kinase inhibitor, Fibroblast Growth Factor Receptor [FGFR]
kinase inhibitor, Platelet-derived Growth Factor Receptor [PGFR] I kinase inhibitor, and
Bcr-Abl kinase inhibitors such as STI-571, gleevec, and Glivec]); antisense molecules;
antibodies (e.g., herceptin and rituxan); anti-estrogens (e.g., raloxifene and tamoxifen);
anti-androgens (e.g., flutamide, bicalutamide, finasteride, aniinoglutethamide,
ketoconazole, and corticosteroids); cyclooxygenase 2 (COX-2) inhibitors (e.g., celecoxib,
meloxicam, NS-398, and non-steroidal anti-inflammatory drugs (NSAIDs)); and cancer
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chemotherapeutic drugs (e.g., irinotecan [camptosar], CPT-11, fludarabine [fludara],
dacarbazine (DTTC), dexamethasone, mitoxantrone, mylotarg, VP-16, cisplatinum, 5-FU,
doxrubicin, taxotere and taxol); cellular signaling molecules; ceramides and cytokines;
and staurosprine; and the like.
In other aspects, the invention provides methods for using the compounds
described herein. For example, the compounds described herein can be used in the
treatment of cancer. The compounds described herein can also be used in the
manufacture of a medicament for the treatment of cancer.
In one embodiment, the present invention provides methods of treating human or
animal subjects suffering from a cellular proliferative disease, such as cancer. The
present invention provides methods of treating a human or animal subject in need of such
treatment, comprising administering to the subject a therapeutically effective amount of a
pyridmo[l,2-a]pyrimidinyl compound (e.g., a compound of formula (I)), either alone or
in combination with other anticancer agents.
In another embodiment, the present invention provides methods for treating a
cellular proliferative disease in a human or animal subject in need of such treatment
comprising, adrninistering to said subject an amount of a pyridmo[l,2-a]pyrimidinyl
compound (e.g., a compound of formula (I)) effective to reduce or prevent cellular
proliferation or tumor growth in the subject.
In another embodiment, the present invention provides methods for treating a
cellular proliferative disease in a human or animal subject in need of such treatment
comprising administering to said subject an amount of a pyridmo[l,2-a]pyrimidinyl
compound (e.g., a compound of formula (I)) effective to reduce or prevent cellular
proliferation in the subject in combination with at least one additional agent for the
treatment of cancer.
The present invention provides compounds that are inhibitors of KSP. The
inhibitors are useful in pharmaceutical compositions for human or veterinary use where
inhibition of KSP is indicated, for example, in the treatment of cellular proliferative
diseases such as tumor and/or cancerous cell growth mediated by KSP. In particular, the
compounds are useful in the treatment of human or animal (e.g., murine) cancers,
including, for example, lung and bronchus; prostate; breast; pancreas; colon and rectum;
thyroid; stomach; liver and intrahepatic bile duct; kidney and renal pelvis; urinary
bladder; uterine corpus; uterine cervix; ovary; multiple myeloma; esophagus; acute
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myelogenous leukemia; chronic myelogenous leukemia; lymphocytic leukemia; myeloid
leukemia; brain; oral cavity and pharynx; larynx; small intestine; non-hodgkin
lymphoma; melanoma; and villous colon adenoma.
In another embodiment, the invention provides methods of treating an KSP
mediated disorder. In one method, an effective amount of a pyridmo[l,2-a]pyrimidinyl
compound (e.g., a compound of formula (I)) compound is administered to a patient
(e.g., a human or animal subject) in need thereof to mediate (or modulate) KSP activity.
A representative assay for determining KSP inhibitory activity is described in
Example 4.
The following definitions are provided to better understand the invention.
"Alkyl" refers to alkyl groups that do not contain heteroatoms. Thus the phrase
includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl, pentyl, hexyl,
heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also includes
branched chain isomers of straight chain alkyl groups, including but not limited to, the
following which are provided by way of example: -CH(CH3)2, -CH(CH3)(CH2CH3),
-CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2, -CH2CH(CH3)(CH2CH3),
-CH2CH(CH2CH3)2, -CH2C(CH3)3) -CH2C(CH2CH3)3, -CH(CH3)CH(CH3)(CH2CH3),
-CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH), -CH2CH2CH(CH2CH3)2,
-CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3, -CH(CH3)CH2CH(CH3)2,
-CH(CH3)CH(CH3)CH(CH3)2, -CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3), and others.
The phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with straight and
branched chain alkyl groups as defined above. Thus the phrase "alkyl groups" includes
primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups. Preferred alkyl
groups include straight and branched chain alkyl groups and cyclic alkyl groups having
1 to 12 carbon atoms.
"Alkylene" refers to the same residues as noted above for "alkyl", but having two
points of attachment. Exemplary alkylene groups include ethylene (-CH2CH2-),
propylene (-CH2CH2CH2-), dimethylpropylene (-CH2C(CH3)2CH2-), and
cyclohexylpropylene (-CH2CH2CH(C6H13)-).
"Alkenyl" refers to straight chain, branched, or cyclic radicals having one or more
carbon-carbon double bonds and from 2 to about 20 carbon atoms. Preferred alkenyl
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groups include straight chain and branched alkenyl groups and cyclic alkenyl groups
having 2 to 12 carbon atoms.
"Alkynyl" refers to straight chain, branched, or cyclic radicals having one or more
carbon-carbon triple bonds and from 2 to about 20 carbon atoms. Preferred alkynyl
groups include straight chain and branched alkynyl groups having 2 to 12 carbon atoms.
Alkyl, alkenyl, and alkynyl groups may be substituted. "Substituted alkyl" refers
to an alkyl group as defined above in which one or more bonds to a carbon(s) or
hydrogen(s) are replaced by a bond to non-hydrogen and non-carbon atoms such as, but
not limited to, a halogen atom such as F, Cl2, Br, and I; an oxygen atom in groups such as
hydroxyl groups, alkoxy groups, aryloxy groups, and ester groups; a sulfur atom in
groups such as thiol groups, alkyl and aryl sulfide groups, sulfone groups, sulfonyl
groups, and sulfoxide groups; a nitrogen atom in groups such as amines, amides,
alkylamines, dialkylamines, arylamines, alkylarylamines, diarylamines, N-oxides, imides,
and enamines; a silicon atom in groups such as in trialkylsilyl groups, dialkylarylsilyl
groups, alkyldiarylsilyl groups, and triarylsilyl groups; and other heteroatoms in various
other groups. Substituted alkyl groups also include groups in which one or more bonds to
a carbon(s) or hydrogen(s) atom is replaced by a higher-order bond (e.g., a double- or
triple-bond) to a heteroatom such as oxygen in oxo, carbonyl, carboxyl, and ester groups;
nitrogen in groups such as imines, oximes, hydrazones, and nitriles. . Substituted alkyl
groups further include alkyl groups in which one or more bonds to a carbon(s) or
hydrogen(s) atoms is replaced by a bond to an aryl, heteroaryl, heterocyclyl, or cycloalkyl
group. Preferred substituted alkyl groups include, among others, alkyl groups in which
one or more bonds to a carbon or hydrogen atom is/are replaced by one or more bonds to
fluoro, chloro, or bromo group. Another preferred substituted alkyl group is the
trifluoromethyl group and other alkyl groups that contain the trifluoromethyl group.
Other preferred substituted alkyl groups include those in which one or more bonds to a
carbon or hydrogen atom is replaced by a bond to an oxygen atom such that the
substituted alkyl group contains a hydroxyl, alkoxy, or aryloxy group. Other preferred
substituted alkyl groups include alkyl groups that have an amine, or a substituted or
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unsubstituted alkylamine, dialkylamine, arylamine, (alkyl)(aryl)amine, diarylamine,
heterocyclylamine, diheterocyclylamine, (alkyl)(heterocyclyl)amine, or
(aryl)(heterocyclyl)amine group. Still other preferred substituted alkyl groups include
those in which one or more bonds to a carbon(s) or hydrogen(s) atoms is replaced by a
bond to an aryl, heteroaryl, heterocyclyl, or cycloalkyl group. Examples of substituted
alkyl are: - CH2C(=O)CH2NH25-CH2S(=O)2CH3,-CH2OCH2NH2, -CO2H Examples of substituents
of substituted alkyl are: -CH3, -C2H5, -CH2OH, -OH, -OCH3, -OC2H5, -OCF3, -
OC(=O)CH3, -OC(=O)NH2, -OC(=O)N(CH3)2, -CN5 -NO2 -C(=O)CH3; -CO2H3 -
CO2CH3, -CONH2, -NH2,-N(CH3)2, -NHSO2CH3, -NHCOCH3, -NHC(=O)OCH3, -
NHSO2CH3, -SO2CH3, -SO2NH2, Halo.
"Aralkyl" refers to an alkyl group substituted with an aryl group. Typically,
aralkyl groups employed in compounds of the present invention have from 1 to 6 carbon
atoms incorporated within the alkyl portion of the aralkyl group. Suitable aralkyl groups
employed in compounds of the present invention include, for example, benzyl, picolyl,
and the like.
"Substituted alkenyl" has the same meaning with respect to alkenyl groups that
substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted
alkenyl group includes alkenyl groups in which a non-carbon or non-hydrogen atom is
bonded to a carbon double bonded to another carbon and those in which one of the
non-carbon or non-hydrogen atoms is bonded to a carbon not involved in a double bond
to another carbon.
"Substituted alkynyl" has the same meaning with respect to alkynyl groups that
substituted alkyl groups had with respect to unsubstituted alkyl groups. A substituted
alkynyl group includes alkynyl groups in which a non-carbon or non-hydrogen atom is
bonded to a carbon triple bonded to another carbon and those in which a non-carbon or
non-hydrogen atom is bonded to a carbon not involved in a triple bond to another carbon.
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"Alkoxy" refers to RO- wherein R is alkyl. Representative examples of alkoxy
groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy, and the like.
"Halogen" or "halo" refers to chloro, bromo, fluoro, and iodo groups. The term
"haloalkyl" refers to an alkyl radical substituted with one or more halogen atoms. The
term "haloalkoxy" refers to an alkoxy radical substituted with one or more halogen atoms.
"Amino" refers herein to the group -NH2- The term "alkylamino" refers herein to
the group -NRR' where R is alkyl and R' is hydrogen or alkyl. The term "arylamino"
refers herein to the group -NRR' where R is aryl and R' is hydrogen, alkyl, or aryl. The
term "aralkylamino' refers herein to the group -NRR' where R is aralkyl and R' is
hydrogen, alkyl, aryl, or aralkyl.
"Alkoxyalkyl" refers to the group -alki-O-alk2 where alk1 is alkyl or alkenyl, and
alk2 is alkyl or alkenyl. The term "aryloxyalkyl" refers to the group -alkyl O-aryl. The
term "aralkoxyalkyl" refers to the group -alkylenyl-O-aralkyl.
"Alkoxyalkylamino" refers herein to the group -NR-( alkoxyalkyl), where R is
typically hydrogen, aralkyl, or alkyl.
"Aminocarbonyl" refers herein to the group -C(O)-NH2 "Substituted
arninocarbonyl" refers herein to the group -C(O)-NRR' where R is alkyl and R' is
hydrogen or alkyl. The term "arylaminocarbonyl" refers herein to the group -C(O)-NRR'
where R is aryl and R1 is hydrogen, alkyl or aryl. "Aralkylaminocarbonyl" refers herein
to the group -C(O)-NRR' where R is aralkyl and R' is hydrogen, alkyl, aryl, or aralkyl.
"Aminosulfonyl" refers herein to the group -S(O)2-NH2. "Substituted
aminosulfonyl" refers herein to the group -S(O)2-NRR' where R is alkyl and R' is
hydrogen or alkyl. The term "aralkylarninosulfonlyaryr1 refers herein to the group
-aryl-S(O)2-NH-aralkyl.
"Carbonyl" refers to the divalent group -C(O)-.
"Carbonyloxy" refers generally to the group -C(O)-O. Such groups include
esters, -C(O)-O-R, where R is alkyl, cycloalkyl, aryl, or aralkyl. The term
"carbonyloxycycloalkyl" refers generally herein to both a "carbonyloxycarbocycloalkyl"
and a "carbonyloxyheterocycloalkyl", i.e., where R is a carbocycloalkyl or
heterocycloalkyl, respectively. The term "arylcarbonyloxy" refers herein to the group
-C(O)-O-aryl9 where aryl is a mono- or polycyclic, carbocycloaryl or heterocycloaryl.
The term "aralkylcarbonyloxy" refers herein to the group -C(O)-O-aralkyl.
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"Sulfonyl" refers herein to the group -SO2-. "Alkylsulfonyl" refers to a
substituted sulfonyl of the structure -SO2R- in which R is alkyl. Alkylsulfonyl groups
employed in compounds of the present invention are typically alkylsulfonyl groups
having from 1 to 6 carbon atoms in its backbone structure. Thus, typical alkylsulfonyl
groups employed in compounds of the present invention include, for example,
methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e., where R is ethyl),
propylsulfonyl (i.e., where R is propyl), and the like. The term "arylsulfonyl" refers
herein to the group -SO,aryl. The term "aralkylsulfonyl" refers herein to the group
-SO2-aralkyl. The term "sulfonamido" refers herein to -SO2NH2.
"Carbonylamino" refers to the divalent group -NH-C(O)- in which the hydrogen
atom of the amide nitrogen of the carbonylamino group can be replaced alkyl, aryl, or
aralkyl group. Such groups include moieties such as carbamate esters (-NH-C(O)-O-R)
and amides -NH-C(O)-R, where R is a straight or branched chain alkyl, cycloalkyl, or
aryl or aralkyl. The term 'alkylcarbonylamino" refers to alkylcarbonylamino where R is
alkyl having from 1 to about 6 carbon atoms in its backbone structure. The term
"arylcarbonylamino" refers to group -NH-C(O)-R where R is an aryl. Similarly, the term
"aralkylcarbonylamino " refers to carbonylamino where R is aralkyl.
"Guanidino" or "guanidyl" refers to moieties derived from guanidine,
H2N-C(=NH)-NH2. Such moieties include those bonded at the nitrogen atom carrying the
formal double bond (the "2"-position of the guanidine, e.g., diaminomethyleneamino,
(H2N)2C=NH-)) and those bonded at either of the nitrogen atoms carrying a formal single
bond (the "1-" and/or "3 "-positions of the guandine, e.g., H2N-C(-NH)-NH-)). The
hydrogen atoms at any of the nitrogens can be replaced with a suitable substituent, such
as alkyl, aryl, or aralkyl.
"Amidino" refers to the moieties R-C(=N)-NR'- (the radical being at the
"N1" nitrogen) and R(NR')C=N- (the radical being at the "N2" nitrogen), where R and R'
can be hydrogen, alkyl, aryl, or aralkyl.
"Cycloalkyl" refers to a mono- or polycyclic, heterocyclic or carbocyclic alkyl
substituent. Typical cycloalkyl substituents have from 3 to 8 backbone (i.e., ring) atoms
in which each backbone atom is either carbon or a heteroatom. The term
"heterocycloalkyl" refers herein to cycloalkyl substituents that have from 1 to 5, and more
typically from 1 to 4 heteroatoms in the ring structure. Suitable heteroatoms employed in
compounds of the present invention are nitrogen, oxygen, and sulfur. Representative
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heterocycloalkyl moieties include, for example, morpholino, piperazinyl, piperadinyl and
the like. Carbocycloalkyl groups are cycloalkyl groups in which all ring atoms are
carbon. When used in connection with cycloalkyl substituents, the term "polycyclic"
refers herein to fused and non-fused alkyl cyclic structures.
"Substituted heterocycle," "heterocyclic group," "heterocycle," or "heterocyclyl,"
as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from
nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three
heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; wherein
the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double
bonds; wherein the nitrogen and sulfur atom maybe optionally oxidized; wherein the
nitrogen and sulfur heteroatoms maybe optionally quarternized; and including any
bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or
another 5- or 6-membered heterocyclic ring independently defined above. The term
"heterocycle" thus includes rings in which nitrogen is the heteroatom as well as partially
and fully-saturated rings. Preferred heterocycles include, for example: diazapinyl, pyrryl,
pyrrolinyi, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl,
imidazolidinyl, pyridyi, piperidinyl, pyrazinyl, piperazinyl, N-methyl piperazinyl,
azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.
Heterocyclic moieties can be unsubstituted or monosubstituted or disubstituted
with various substituents independently selected from hydroxy, halo, oxo (C=O),
alkylimino (RN=, wherein R is alkyl or alkoxy group), amino, alkylamino, dialkylamino,
acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, alkyl, cycloalkyl or haloalkyl.
The heterocyclic groups may be attached at various positions as will be apparent
to those having skill in the organic and medicinal chemistry arts in conjunction with the
disclosure herein.
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WO 2004/113335 PCT/US2004/019158

where R is H or a heterocyclic substituent, as described herein.
Representative heterocyclics include, for example, imidazolyl, pyridyl,
piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl, benzothiazolyl,
benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolyl,
naphthpyridinyl, indazolyl, and quinolizinyl.
"Aryl" refers to optionally substituted monocyclic and polycyclic aromatic groups
having from 3 to 14 backbone carbon or hetero atoms, and includes both carbocyclic aryl
groups and heterocyclic aryl groups. Carbocyclic aryl groups are aryl groups in which all
ring atoms in the aromatic ring are carbon. The term "heteroaryl" refers herein to aryl
groups having from 1 to 4 heteroatoms as ring atoms in an aromatic ring with the
remainder of the ring atoms being carbon atoms. When used in connection with aryl
substituents, the term "polycyclic aryl" refers herein to fused and non-fused cyclic
structures in which at least one cyclic structure is aromatic, such as, for example,
benzodioxozolo (which has a heterocyclic structure fused to a phenyl group,
i.e., , naphthyl, and the like. Exemplary aryl moieties employed as substituents
in compounds of the present invention include phenyl, pyridyl, pyrimidinyl, thiazolyl,
indolyl, irnidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl,
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WO 2004/113335 PCT/US2004/019158
quinolinyl, purinyl, naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and the
like.
"Aralkyl" or "arylalkyl" refers to an alkyl group substituted with an aryl group.
Typically, aralkyl groups employed in compounds of the present invention have from 1 to
'6 carbon atoms incorporated within the alkyl portion of the aralkyl group. Suitable
aralkyl groups employed in compounds of the present invention include, for example,
benzyl, picolyl, and the like.
Representative heteroaryl groups include, for example, those shown below. These
heteroaryl groups can be further substituted and may be attached at various positions as
will be apparent to those having skill in the organic and medicinal chemistry arts in
conjunction with the disclosure herein.

WO 2004/113335 PCT/US2004/019158

Representative heteroaryl's include, for example, imidazolyl, pyridyl, thiazolyl,
triazolyl benzirnidazolyl, benzothiazolyl, and benzoxazolyl.
"Biaryl" refers to a group or substituent to which two aryl groups, which are not
condensed to each other, are bound. Exemplary biaryl compounds include, for example,
phenylbenzene, diphenyldiazene, 4-methylthio-l-phenylbenzene, phenoxybenzene,
(2-phenylethynyl)benzene, diphenyl ketone, (4-phenylbuta-l,3-diynyl)benzene,
phenylbenzylamine, (phenylmethoxy)benzene, and the like. Preferred optionally
substituted biaryl groups include: 2-(phenylamino)-N-[4-(2-phenylethynyl)-
phenyl]acetamide, 1,4-diphenylbenzene, N-[4-(2-phenylethynyl)phenyl]-2-[benzyl-
amino]acetamide, 2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide, 2-amino-N-[4-
(2-phenylethynyl)phenyl]acetamide, 2-(cyclopropylammo)-N-[4-(2-phenylethynyl)-
phenyl]acetamide, 2-(ethylarnmo)-N-[4-(2-phenylethynyl)phenyl]acetamide,
2-[(2-methylpropyl)armino]-N-[4-(2-phenylethynyl)phenyl]acetamide, 5-phenyl-2H-
benzo[d]l,3-dioxolene, 2-chloro-l-methoxy-4-phenylbenzene, 2-[(imidazolylmethyl)-
amino]-N-[4-(2-phenylethynyl)phenyl]acetamide, 4-phenyl-l-phenoxybenzene,
N-(2-aminoemyl)[4-(2-phenylethynyl)phenyl]carboxamide, 2-{[(4-fiuorophenyl)methyl]-
arrmio}-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-{[(4-methylphenyl)methyl]amino}-
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WO 2004/113335 PCT/US2004/019158
N-[4-(2-phenylemynyl)phenyl]acetamide, 4-phenyl-l-(trifluoromethyl)benzene,
1 -butyl-4-phenylbenzene, 2-(cyclohexylanaino)-N-[4-(2-
phenylethynyl)phenyl]acetamide, 2-(ethylmethylamino)-N-[4-(2-
phenyle%nyl)phenyl]acetamide, 2-(butylamino)-N-[4-(2-phenylethynyl)-
phenyl]acetamide, N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide, N-[4-
(2-phenylethynyl)phenyl]-2-(quinuclidin-3-ylamino)acetamide, N-[4-(2-phenyl-
ethynyl)phenyl]pyrrolidin-2-ylcarboxamide, 2-amino-3-methyl-N-[4-(2-phenylethynyl)-
phenyl]butanamide, 4-(4-phenylbuta-l,3-diynyl)phenylamine, 2-(dimethylamino)-N-[4-
(4-phenylbuta-l,3-diynyl)phenyl]acetainide, 2-(ethylamino)-N-[4-(4-phenylbuta-l,3-
diynyl)phenyl]acetamide, 4-ethyl-l -phenylbenzene, 1 -[4-(2-phenylethynyl)phenyl]ethan-
1-one, N-(l-carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta-l,3-diynyl)phenyl]carbox-
amide, N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxyphenyl phenyl ketone,
phenyl-N-benzamide, (tert-butoxy)-N-[(4-phenylphenyl)methyl]carboxamides
2-(3-phenylphenoxy)ethanehydroxamic acid, 3-phenylphenyl propanoate,
1 -(4-ethoxyphenyl)-4-methoxybenzene, and [4-(2-phenylethynyl)phenyl]pyrrole.
"Heteroarylaryl" refers to a biaryl group where one of the aryl groups is a
heteroaryl group. Exemplary heteroarylaryl groups include, for example,
2-phenylpyridine, phenylpyrrole, 3-(2-phenylethynyl)pyridine, phenylpyrazole,
5-(2-phenylethynyl)-1,3-dihydropyrirnidine-2,4-dione, 4-phenyl-l ,2,3 -thiadiazole,
2-(2phenylethynyl)pyrazine, 2-phenylthiophene, phenylimidazole, 3 -(2-piperazinyl-
phenyl)furan, 3-(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferred optionally
substituted heteroarylaryl groups include: 5-(2-phenylemynyl)pyrimidine-2-ylamine,
l-methoxy-4-(2-thienyl)benzene, l-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenyl-
pyridine, 5-methyl-3-phenylisoxazole, 2-[3-(trifluoromethyl)phenyl]furan) 3-fluoro-5-
(2-furyl)-2-methoxy-l-prop-2-enylbenzene, (hydroxyirnino)(5-phenyl(2-thienyl))-
methane, 5-[(4-methylpiperazinyl)methyl]-2-phenylthiophene, 2-(4-ethylphenyl)thio-
phene, 4-methylthio-l-(2-thienyl)benzene, 2-(3-nitrophenyl)thiophene, (tert-butoxy)-N-
[(5-phenyl(3-pyridyl))methyl]carboxamide, hydroxy-N-[(5-phenyl(3-pyridyl))methyl]-
amide, 2-(phenylmethylthio)pyridine, and benzylimidazole.
"Heteroarylheteroaryl" refers to a biaryl group where both of the aryl groups is a
heteroaryl group. Exemplary heteroarylheteroaryl groups include, for example,
3-pyridylimidazole, 2-imidazolylpyrazine, and the like. Preferred optionally substituted
heteroarylheteroaryl groups include: 2-(4-piperazinyl-3-pyridyl)furan, diethyl(3-pyrazin-
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WO 2004/113335 PCT/US2004/019158
2-yl(4-pyridyl))amine, and dimethyl{2-[2-(5-methylpyrazin-2-yl)ethynyl](4-
pyridyl)} amine.
"Optionally substituted" or "substituted" refers to the replacement of hydrogen
with a monovalent or divalent radical. Suitable substitution groups include, for example,
hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino,
oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl,
alkyl, haloalkyl, alkyamino, haloalkylamino, alkoxy, haloalkoxy, alkoxyalkyl,
alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl,
heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like.
The substitution group can itself be substituted. The group substituted onto the
substitution group can be carboxyl, halo; nitro, amino, cyano, hydroxyl, alkyl, alkoxy,
aminocarbonyl, -SR, thioamido, -SO3H, -SO2R or cycloalkyl, where R is typically
hydrogen, hydroxyl or alkyl.
When the substituted substituent includes a straight chain group, the substitution
can occur either within the chain (e.g., 2-hydroxypropyl, 2-aminobutyl, and the like) or at
the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted
substituents can be straight chain, branched or cyclic arrangements of covalently bonded
carbon or heteroatoms.
"Carboxy-protecting group" refers to a carbonyl group which has been esterifled
with one of the commonly used carboxylic acid protecting ester groups employed to
block or protect the carboxylic acid function while reactions involving other functional
sites of the compound are carried out. In addition, a carboxy protecting group can be
attached to a solid support whereby the compound remains connected to the solid support
as the carboxylate until cleaved by hydrolytic methods to release,the corresponding free
acid. Representative carboxy-protecting groups include, for example, alkyl esters,
secondary amides and the like.
Certain of the compounds of the invention comprise asymmetrically substituted
carbon atoms. Such asymmetrically substituted carbon atoms can result in the
compounds of the invention comprising mixtures of stereoisomers at a particular
asymmetrically substituted carbon atom or a single stereoisomer. As a result, racemic
mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of
the invention are included in the present invention. The terms "S" and "R" configuration,
as used herein, are as defined by the IUPAC 1974 "RECOMMENDATIONS FOR SECTION E,
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WO 2004/113335 PCT/US2004/019158
FUNDAMENTAL STEREOCHEMISTRY," Pure Appl. Chem. 45:13-30,1976. The terms a and
 are employed for ring positions of cyclic compounds. The -side of the reference plane
is that side on which the preferred substituent lies at the lower numbered position. Those
substituents lying on the opposite side of the reference plane are assigned  descriptor. It
should be noted that this usage differs from that for cyclic stereoparents, in which ""
means "below the plane" and denotes absolute configuration. The terms  and 
configuration, as used herein, are as defined by the "Chemical Abstracts Index Guide,"
Appendix IV, paragraph 203,1987.
As used herein, the term "pharmaceutically acceptable salts" refers to the nontoxic
acid or alkaline earth metal salts of the compounds of formula (I). These salts can be
prepared in situ during the final isolation and purification of the compounds, or by
separately reacting the base or acid functions with a suitable organic or inorganic acid or
base, respectively. Representative salts include, but are not limited to, the following:
acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate,
butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,
dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphates hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate,
2-napthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate,
pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such
agents as alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and
iodides; dialkyl sulfates like- dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain
halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl
halides like benzyl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
Examples of acids that may be employed to form pharmaceutically acceptable
acid addition salts include such inorganic acids as hydrochloric acid, sulfuric acid and
phosphoric acid and such organic acids as oxalic acid, maleic acid, methanesulfonic acid,
succinic acid and citric acid. Basic addition salts can be prepared in situ during the final
isolation and purification of the compounds of formula (I), or separately by reacting
carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an
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WO 2004/113335 PCT/US2004/019158
organic primary, secondary or tertiary amine. Pharmaceuticaliy acceptable salts include,
but are not limited to, cations based on the alkali and alkaline earth metals, such as
sodium, lithium, potassium, calcium, magnesium, aluminum salts and the like, as well as
nontoxic ammonium, quaternary ammonium, and amine cations, including, but not
limited to ammonium, tetramethylammonium, tetraethylammonium, memylamine,
dimemylamine, trhnethylamine, triemylamine, elhylamine, and the like. Other
representative organic amines useful for the formation of base addition salts include
diethylamine, etnylenediamine, ethanolamine, diethanolamine, piperazine and the like,
The term "pharmaceuticaliy acceptable prodrugs" as used herein refers to those
prodrugs of the compounds of 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 without 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. The term
"prodrug" refers to compounds that are rapidly transformed in vivo to yield a parent
compound of one of formula (I), for example, by hydrolysis in blood. A thorough
discussion of prodrugs is provided in Higuchi, T., and V. Stella, "Pro-drugs as Novel
Delivery Systems," ACS. Symposium Series 14, and in "Bibreversible Carriers in Drug
Design," in Edward B. Roche (ed.), American Pharmaceutical Association, Pergamon
Press, 1987, both of which are incorporated herein by reference.
The term "cancer" refers to cancer diseases that can be beneficially treated by the
inhibition of KSP, including, for example, lung and bronchus; prostate; breast; pancreas;
colon and rectum; thyroid; stomach; liver and intrahepatic bile duct; kidney and renal
pelvis; urinary bladder; uterine corpus; uterine cervix; ovary; multiple myeloma;
esophagus; acute myelogenous leukemia; chronic myelogenous leukemia; lymphocytic
leukemia; myeloid leukemia; brain; oral cavity and pharynx; larynx; small intestine;
non-hodgkin lymphoma; melanoma; and villous colon adenoma.
The compounds of the invention are useful in vitro or in vivo in inhibiting the
growth of cancer cells. The compounds may be used alone or in compositions together
with a pharmaceuticaliy acceptable carrier or excipient Suitable pharmaceuticaliy
acceptable carriers or excipients include, for example, processing agents and drug
delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium
stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose,
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sodium carboxymethyl cellulose, dextrose, hydroxypropyl--cyclodextrin,
polyvmylpyrrolidinone, low melting waxes, ion exchange resins, and the like, as well as
combinations of any two or more thereof. Other suitable pharmaceutically acceptable
excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co.,
New Jersey, 1991, incorporated herein by reference.
Effective amounts of the compounds of the invention generally include any
amount sufficient to detectahly inhibit KSP activity by any of the assays described herein,
by other KSP activity assays known to those having ordinary skill in the art, or by
detecting an inhibition or alleviation of symptoms of cancer.
The amount of active ingredient that may be combined with the carrier materials
to produce a single dosage form will vary depending upon the host treated and the
particular mode of administration. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of factors including the activity
of the specific compound employed, the age, body weight, general health, sex, diet, time
of administration, route of administration, rate of excretion, drug combination, and the
severity of the particular disease undergoing therapy. The therapeutically effective
amount for a given situation can be readily determined by routine experimentation and is
within the skill and judgment of the ordinary clinician.
For purposes of the present invention, a therapeutically effective dose will
generally be a total daily dose administered to a host in single or divided doses may be in
amounts, for example, of from 0.001 to l000 mg/kg body weight daily and more
preferred from 1.0 to 30mg/kg body weight daily. Dosage unit compositions may
contain such amounts of submultiples thereof to make up the daily dose.
The compounds of the present invention may be administered orally, parenterally,
sublingually, by aerosolization or inhalation spray, rectally, or topically in dosage unit
formulations containing conventional nontoxic pharmaceutically acceptable carriers,
adjuvants, and vehicles as desired. Topical administration may also involve the use of
transdermal administration such as transdermal patches or ionophoresis devices. The
term parenteral as used herein includes subcutaneous injections, intravenous,
intramuscular, intrasternal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or
wetting agents and suspending agents. The sterile injectable preparation may also be a
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sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or
solvent, for example, as a solution in 1,3-propanediol. Among the acceptable vehicles
and solvents that may be employed are water, Ringer's solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent
or suspending medium. For this purpose any bland fixed oil may be employed including
synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the
preparation of injectables.
Suppositories for rectal administration of the drug can be prepared by mixing the
drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols,
which are solid at ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
Solid dosage forms for oral administration may include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound may be
admixed with at least one inert diluent such as sucrose lactose or starch. Such dosage
forms may also comprise, as is normal practice, additional substances other than inert
diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules,
tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills
can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents
commonly used in the art, such as water. Such compositions may also comprise
adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and
sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of
liposomes. As is known in the art, liposomes are generally derived from phospholipids or
other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes can be used. The
present compositions in liposome form can contain, in addition to a compound of the
present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids
are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott (ed.),
"Methods in Cell Biology," Volume XIV, Academic Press, New York, 1976, p. 33 et seq.
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WO 2004/113335 PCT/US2004/019158
While the compounds of the invention can be administered as the sole active
pharmaceutical agent, they can also be used in combination with one or more other agents
used in the treatment of cancer. Representative agents useful in combination with the
compounds of the invention for the treatment of cancer include, for example, irinotecan,
topotecan, gemcitabine, gleevec, herceptin, 5-fluorouracil, leucovorin, carboplatin,
cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca alkaloids, imatinib,
anthracyclines, rituximab, trastuzumab, topoisomerase I inhibitors, as well as other cancer
chemotherapeutic agents.
The above compounds to be employed in combination with the compounds of the
invention will be used in therapeutic amounts as indicated in the Physicians' Desk
Reference (PDR) 47th Edition (1993), which is incorporated herein by reference, or such
therapeutically useful amounts as would be known to one of ordinary skill in the art.
The compounds of the invention and the other anticancer agents can be
administered at the recommended maximum clinical dosage or at lower doses. Dosage
levels of the active compounds in the compositions of the invention may be varied so as
to obtain a desired therapeutic response depending on the route of administration, severity
of the disease and the response of the patient. The combination can be administered as
separate compositions or as a single dosage form containing both agents. When
administered as a combination, the therapeutic agents can be formulated as separate
compositions, which are given at the same time or different times, or the therapeutic
agents, can be given as a single composition.
Antiestrogens, such as tamoxifen, inhibit breast cancer growth through induction
of cell cycle arrest, that requires the action of the cell cycle inhibitor p27Kip. Recently, it
has been shown that activation of the Ras-Raf-MAP Kinase pathway alters the
phosphorylation status of p27Kip such that its inhibitory activity in arresting the cell
cycle is attenuated, thereby contributing to antiestrogen resistance (Donovan, et al,
J. Biol Chem. 276:40888, 2001). As reported by Donovan et al., inhibition of MAPK
signaling through treatment with MEK inhibitor changed the phosphorylation status of
p27 in hormone refectory breast cancer cell lines and in so doing restored hormone
sensitivity. Accordingly, in one aspect, the compounds of formula (I) may be used in the
treatment of hormone dependent cancers, such as breast and prostate cancers, to reverse
hormone resistance commonly seen in these cancers with conventional anticancer agents.
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WO 2004/113335 PCT/US2004/019158
In hematological cancers, such as chronic myelogenous leukemia (CML),
chromosomal translocation is responsible for the constitutively activated BCR-AB1
tyrosine kinase. The afflicted patients are responsive to gleevec, a small molecule
tyrosine kinase inhibitor, as a result of inhibition of Ab 1 kinase activity. However, many
patients with advanced stage disease respond to gleevec initially, but then relapse later
due to resistance-conferring mutations in the Abl kinase domain. In vitro studies have
demonstrated that BCR-Avl employs the Raf kinase pathway to elicit its effects. In
addition, inhibiting more than one kinase in the same pathway provides additional
protection against resistance-conferring mutations. Accordingly, in another aspect of the
invention, the compounds of formula (I) are used in combination with at least one
additional agent, such as gleevec, in the treatment of hematological cancers, such as
chronic myelogenous leukemia (CML), to reverse or prevent resistance to the at least one
additional agent
In another aspect of the invention, kits that include one or more compounds of the
invention are provided. Representative kits include a compound of formula (I) and a
package insert or other labeling including directions for treating a cellular proliferative
disease by administering an KSP inhibitory amount of the compound.
The present invention will be understood more readily by reference to the
following examples, which are provided by way of illustration and are not intended to be
limiting of the present invention.
EXAMPLES
Referring to the examples that follow, compounds of the present invention were
synthesized using the methods described herein, or other methods, which are well known
in the art The compounds were characterized by high performance liquid
chromatography (HPLC) using a Waters Millenium chromatography system with a
2690 Separation Module (Milford, Massachusetts). The analytical columns were Alltima
C-18 reversed phase, 4.6 x 250 mm from Alltech (Deerfield, Illinois). A gradient elution
was used, typically starting with 5% acetonitrile/95% water and progressing to 100%
acetonitrile over a period of 40 rninutes. All solvents contained 0.1 % trifluoroacetic acid
(TFA). Compounds were detected by ultraviolet light (UV) absorption at either 220 or
254 nm. HPLC solvents were from Burdick and Jackson (Muskegan, Michigan), or
Fisher Scientific (Pittsburgh, Pennsylvania). In some instances, purity was assessed by
thin layer chromatography (TLC) using glass or plastic backed silica gel plates, such as,
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for example, Baker-Flex Silica Gel 1B2-F flexible sheets. TLC results were readily
detected visually under ultraviolet light, or by employing well known iodine vapor and
other various staining techniques.
Mass spectrometric analysis was performed on one of two LCMS instruments: a
Waters System (Alliance HT HPLC and a Micromass ZQ mass spectrometer; Column:
Eclipse XDB-C18, 2.1 x 50 mm; solvent system: 5-95% (or 35-95% or 65-95% or
95-95%) acetonitrile in water with 0.05%TFA; flow rate 0.8 mL/min; molecular weight
range 500-1500; cone Voltage 20 V; column temperature 40°C) or a Hewlett Packard
System (Series 1100 HPLC; Column: Eclipse XDB-C18, 2.1 x 50 mm; solvent system:
1-95% acetonitrile in water with 0.05%TFA; flow rate 0.4 mL/min; molecular weight
range 150-850; cone Voltage 50 V; column temperature 30°C). All masses are reported
as those of the protonated parent ions.
GCMS analysis was performed on a Hewlett Packard instrument (HP6890 Series
gas chromatograph with a Mass Selective Detector 5973; injector volume: 1 L; initial
column temperature: 5.0°C; final column temperature: 250.°C; ramp time: 20 minutes;
gas flow rate: 1 mL/min; column: 5% phenyl methyl siloxane, Model
No. HP 190915-443, dimensions: 30.0 m x 25 m x 0.25 m).
Nuclear magnetic resonance (NMR) analysis was performed with a
Varian 300 MHz NMR (Palo Alto, California). The spectral reference was either TMS or
the known chemical shift of the solvent. Some compound samples were run at elevated
temperatures (e.g., 75°C) to promote increased sample solubility.
The purity of some of the invention compounds was assessed by elemental
analysis (Desert Analytics, Tucson, Arizona)
Melting points were determined on a Laboratory Devices Mel-Temp apparatus
(Holliston, Massachusetts).
Preparative separations were carried out using a Flash 40 chromatography system
and KP-Sil, 60A (Biotage, Charlottesville, Virginia), or by flash column chromatography
using silica gel (230-400 mesh) packing material, or by HPLC using a C-18 reversed
phase column. Typical solvents employed for the Flash 40 Biotage system and flash
column chromatography were dichloromethane, methanol, ethyl acetate, hexane, acetone,
aqueous hydroxyamine and triethyl amine. Typical solvents employed for the reverse
phase HPLC were varying concentrations of acetonitrile and water with
0.1% trifluoroacetic acid.
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The following are abbreviations used in the examples:
AcOH: Acetic acid
aq: Aqueous
ATP: Adenosine triphosphate
9-BBN 9-Borabicyclo[3.3.1]nonane
Boc: tert-butoxycarbonyl
Celite Filter agent
DAP or Dap: Diaminopropionate
DCM: Dichloromethane
DEAD: Diethyl azodicarboxylate
DIEA: Diisopropylemylamine
DMAP 4-Dimethylaminopyridine
DME: 1,2-Dimethoxyethane
DMF: N,N-Dimethylfonnamide
DMSO: Dimethyl sulfoxide
DPPA: Diphenyl phosphoryl azide
Et3N: Triethylamine
EDC: N-(3-Dimemylaniinopropyl)-N-ethylcarbodiimide
EDCI: l-(3-Dimemylaniinopropyl)3-emylcarbodiimide
EtOAc: Ethyl acetate
EtOH: Ethanol
Fmoc: 9-Fluorenylmethoxycarbonyl
Gly-OH: Glycine
HATU: 0-(7-Azabenzotriaazol-1 -yl)-N,N,N'N,-tetramethyluronium
hexafluorophosphate
HBTU: 2-(lH-Benzotriazol-l-yl)-l,l,3,3-tetramethyluronium
hexafluorophosphate
Hex: Hexane
HOBt: Butyl alcohol
HOBT: 1-Hydroxybenzotriazole
HPLC: High pressure liquid chromatography
NIS N-Iodosuccinimide
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IC50 value: The concentration of an inhibitor that causes a 50% reduction
in a measured activity.
iPrOH: Isopropanol
LC/MS: Liquid chromatography/mass spectrometry
LRMS: Low resolution mass spectrometry
MeOH: Methanol
NaOMe: Sodium methoxide
nm: Nanometer
NMP: N-Methylpyrrolidone
PPA Polyphosphoric acid
PPh3: Triphenyl phosphine
PTFE Polytetrafluoroethylene
RP-HPLC: Reversed-phase high-pressure liquid chromatography
RT: Room temperature
sat: Saturated
TEA: Triethylamine
TFA: Trifluoroacetic acid
THF: Tetrahydrofuran
Thr: Threonine
TLC: Thin layer chromatography
Trt-Br: Tert-butyl bromide
Nomenclature for the Example compounds was provided using ACD Name
version 5.07 software (November 14, 2001) available from Advanced Chemistry
Development, Inc. Some of the compounds and starting materials were named using
standard IUPAC nomenclature.
It should be understood that the organic compounds according to the invention
may. exhibit the phenomenon of tautomerism. As the chemical structures within this
specification can only represent one of the possible tautomeric forms, it should be
understood that the invention encompasses any tautomeric form of the drawn structure.
It is understood that the invention is not limited to the embodiments set forth
herein for illustration, but embraces all such forms thereof as come within the scope of
the above disclosure.
Example 1
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Synthesis of a Representative Pyridinor[2-a1pyrimidin-4-one:
N-(3-aminnprnpy1(4-bromophenyl)-N-{[4-OXO-3-benzy1(5-hydropyridino[1,2-
a]pyrimidin-2-yl)]propyl} carboxamide
In this example, the synthesis of a representative pyridmo[l,2-a]pyrirnidin-4-one
of the invention is described. The representative pyridino[l,2-a]pyriraidin-4-one is
synthesized in twelve steps as described below.
Step 1: 2-(choromethyI)-5-hydropyridmo[l,2-a]pyrimidin-4-one.

15 g (159.4 mmol) of 2-aminopyridine was combined with approximately 80 g of
polyphosphoric acid and heated to 120 °C to allow stirring. To the resulting solution was
added slowly 30.5 mL (223.2 mmol) of ethyl-4-chloroacetoacetate and stirred at 120°C
under nitrogen for two hours. The hot reaction mixture was then poured over 1500 mL of
ice water and stirred vigorously. The aqueous layer was separated and extracted with
methylene chloride (6X, approximately 6 L). The combined organic layers were washed
with saturated NaHCO3 and brine and dried over MgSO4 and activated carbon. The
solvent was removed in vacuo yielding 30.7 g (157.7 mmol, 99%) of 2-(chloromethyl)-5-
hydropyridmo[l,2-a]pyrimidin-4-one as a white solid.
Step 2: 2-(chloromemyl)-3-iodo-5-hydropyridmo[l,2-a]pyrimidin-4-one.

A mixture of 21.9 g (112.5 mmol) of 2-(chloromethyl)-5-hydropyridino[l,2-
a]pyrimidin-4-one and 38.9 g (168.8 mmol) of N-iodosuccinimide in 660 mL of
acetonitrile was stirred at 80°C under nitrogen for 16 hours. The reaction mixture was
then allowed to cool to ambient temperature and the acetonitrile was removed in vacuo.
The resulting solid was washed with water, saturated Na2O3S2, saturated NaHCO3 brine,
and filtered. Drying under reduced pressure at 40°C overnight yielded 29.8 g
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WO 2004/113335 PCT/US2004/019158
(92.9 mmol, 83%) of 2-(chlromethyl)-3-iodo-5-hydropyridino [1,2-a] pyrimidin-4-one as
a light brown solid.
Step 3: (3-iodo-4-oxo-5-hydropyridino[l,2-a]pyrimidin-2-yl)methyl acetate.

A mixture of 20.0 g (62.4 mmol) of 2-(chloromethyl)-3-iodo-5-
hydropyridino[1,2-a]pyrimidin-4-one and 9.2 g (93.6 mmol) of potassium acetate in
200 mL DMF was stirred at 40°C under nitrogen for three hours. The reaction mixture
was allowed to cool to ambient temperature and the addition of excess water to the
reaction solution caused the product to precipitate out of solution. The product was
filtered, washed with water (3X), and drying under reduced pressure at 40°C overnight
yielded 19.4 g (56.4 mmol, 90%) of (3-iodo-4-oxo-5-hytopyridmo[l,2-a]pyrimidin-2-
yl)methyl acetate as a white solid.

WO 2004/113335 PCT7US2004/019158
Step 4: 2-(hydroxymethyl)-3-iodo-5-hydropyridino[1,2-a]pyrimidin-4-one.

A mixture of 16.5 g (48.0 mmol) of (3-iodo-4-oxo-5-hydropyridino[l,2-.
a]pyrimidin-2-yl)methyl acetate and 13.3 g (96.0 mmol) of potassium carbonate in
300 mL methanol was stirred at ambient temperature for 3 hours. Excess water was
added to the reaction mixture and the mixture was extracted using ethyl acetate (3X).
The organic layers were combined, dried over MgSO4 and activated carbon, and the
solvent was removed in vacuo yielding 12 g (39.7 mmol, 83%) of 2-(hydroxymethyl)-3-
iodo-5-hydropyridino[l ,2-a]pyrimidin-4-one as a white solid.
Step 5: 2-(hydroxymemyl)-3-benzyl-5-hydropyri

A mixture of 4.0 g (13.24 mmol) of 2-(hydroxymethyl)-3-iodo-5-
hydropyridmo[l,2-a]pyrimidin-4-one, 1.0 g (1.32 mmol) of dichloro[1,1'-
bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane adduct, and 8.4 g
(39.72 mmol) of K3PO4 in 30 mL of DMF was heated to 80°C. To the resulting solution
was added dropwise 40 mL (19.9 mmol) of B-Benzyl-9-BBN and stirred at 80°C under
nitrogen for 12 hours. The reaction was then cooled to 0°C and excess IN NaOH was
added to the reaction mixture. Excess 30% H2O2 was then added to the mixture at 0°C
resulting in significant gas evolution. Stirring continued for at least one additional hour
or until gas ceased to evolve. The mixture was extracted with ethyl acetate (3X) and
washed with saturated Na2O3S2 and brine. The organic layers were combined, dried over
MgSO4 and activated carbon, and the solvent was removed in vacuo. The resulting
material was subjected to flash chromatography on a 10 cm column. Elution with a
gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in hexanes,
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43% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, 57% ethyl acetate in
hexanes, 67% ethyl acetate in hexanes, and 100% ethyl acetate yielded 3.2 g (12.0 mmol,
91%) of 2-(hydroxymethyl)-3-benzyl-5-hydropyridino[l,2-a]pyrimidin-4-one as a pale
yellow solid.
Step 6: 2-carbonyl-3-ben2yl-5-hydropyriddno[l,2-a]pyrimidin-4-one.

A solution of 26.5 mL (53.0 mmol) of oxalyl chloride in 40 mL dichloromethane
was cooled to -78°C. To the resulting solution was added a solution of 7.52 mL
(105.9 mmol) of DMSO in 24 mL dichloromethane and stirred at -78°C for one hour.
Then was added a solution of 4.7 g (17.65 mmol) of 2-(hydroxymethyl)-3-benzyl-5-
hydropyridmo[l,2-a]pyrimidin--4-one in 60 mL dichloromethane and the resulting
mixture was stirred at -78°C for one hour. Then was added 24.6 mL (176.5 mmol) of
triethylarnine and stirred at -78°C for one hour. The mixture was then allowed to warm
to 0°C and stirred for another hour. Finally, the rnixture was allowed to warm to ambient
temperature over the course of one hour. Excess water was added to the reaction mixture
and the mixture was extracted (3X) using dichloromethane. The combined organic layers
were dried over MgSO4 and activated carbon and the solvent was removed in vacuo. The
resulting material was subjected to flash chromatography on a 10 cm column. Elution
with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in
hexanes, 43% ethyl acetate in hexanes, and 50% ethyl acetate in hexanes yielded 3.1 g
(11.7 mmol, 67%) of 2-carbonyl-3-benzyl-5-hydropyridino[l,2-a]pyrinridin-4-one as a
yellow solid.
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WO 2004/113335 PCT/US2004/019158
Step 7: 2-(l-hydroxyprop-2-enyl)-3-benzyl-5-hydropyridino[l,2-a]pyrinidin-4-
one.

A mixture of 2.5 g (9.5 mmol) of 2-carbonyl-3-benzyl-5-hydropyridino[l,2-
a]pyrimidin-4-one in 35 mL THF was cooled to -78°C. To the resulting solution was
added dropwise 11.4 mL (11.4 mmol) of vinylmagnesium bromide and stirred at -78°C
for 3 hours. The reaction was quenched with saturated NH4CI and extracted with ethyl
acetate (4X). The combined organic layers were dried over MgSO4 and the solvent was
removed in vacuo yielding 2.95 g (10.1 mmol, 106%) of 2-(l-hydroxyprop-2-enyl)-3-
benzyl-5-hydropyridino[l,2-a]pyrirnidin-4-one as a yellow oil.
Step 8: 2-(hydroxypropyl)-3-benzyl-5-hydropyridino[l,2-a]pyrirmidin-4-one.

A mixture of 2.77 g (9.5 mmol) of 2-(l-hydroxyprop-2-enyl)-3-benzyl-5-
hydropyridino[l,2-a]pyrimidin-4-one and 1.4 g (50% by weight) of palladium on
activated carbon in 35 mL of ethanol was heated to 65°C. To the resulting solution was
added 8.88 mL (90 mmol) 1,4-cyclohexadiene and stirred at 65°C for four days. Upon
completion, the reaction mixture was filtered through celite and the solvent was removed
in vacuo yielding 2.56 g (8.7 mmol, 92%) of 2-(hydroxypropyl)-3-benzyl-5-
hydropyrino[l,2-a]pyrimidin-4-one as a brown/yellow oil.
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WO 2004/113335 PCT/US2004/019158
Step 9: [4-oxo-3-benzyl-5-hydropyridino[l,2-a]pyrimidin-2-yl]propyl
methyl-sulfonate.

A mixture of 2.56 g (8.7 rnmol) of 2-(hydroxypropyl)-3-benzyl-5-
hydropyridino[l,2-a]pyrimidin-4-one and 2.42 mL (17.4 mmol) of triethylamine in
20 mL of dichloromethane was cooled to 0°C. To this solution was added dropwise
0.81 mL (10.44 mmol) of methane sulfonyl chloride and the resulting solution was
allowed to warm to ambient temperature. Upon completion, excess dichloromethane was
added to the reaction mixture and the solution was washed with water, saturated
NaHC03, and brine. The organic layer was dried over MgSO4 and the solvent was
removed in vacuo yielding 1.55 g (4.2 mmol, 48%) of [4-oxo-3-benzyl-5-
hydropyridino[l,2-a]pyrirnidin-2-yl]propyl methylsulfonate as a yellow oil.
Step 10: (t-butoxy)-N-[3-({[4-oxo-3-ben2yl(5-hydropyridmo[l,2-a]pyrimidin-2-
yl)]propyl}amino)propyl]carboxamide.

A mixture of 1.55 g (4.2 mmol) of [4-oxo-3-benzyl-5-hydropyridino[l,2-
a]pyrimidin-2-yl]propyl methylsulfonate, 4.4 g (25.2 mmol) of (3-aminopropyl)carbamic
acid tert-butyl ester, and 1.68 g (0.4 mmol) of potassium iodide in 20 mL of DMF was
heated to 60°C for 30 hours. The reaction mixture was quenched with water and
extracted with ethyl acetate (4X). The combined organic layers were washed with
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WO 2004/113335 PCT/US2004/019158
saturated NaHCO3 and brine, dried over MgSO4, and the solvent was removed in vacuo.
The resulting material was subjected to flash chromatography on a 10 cm column.
Elution with 97% dichloromethane: 3% methanol: 0.1% ammonia yielded 2.82 g
(6.3 mmol, 150%) of (t-butoxy)-N-[3-({[4-oxo-3-benzyl(5-hydropyridino[l,2-
a]pyrimidin-2-yl)]propyl}annno)propyl]carboxamide as a yellow oil.
. Step 11: (t-butoxy)-N-[3-((4-bromophenyl)-N-{[4-oxo-3-benzyl(5-
hydropyridino-[l,2-a]pyrimidin-2-yI)]propyl} carbonymino)propyl]caboxamide.

A mixture of 1.41 g (3.14 mmol) of (t-butoxy)-N-[3-({[4-oxo-3-benzyl(5-
hydropyridino[l,2-a]pyrimidin-2-yl)]propyl}ammo)propyl]carboxamide, 0.04 g
(0.314 mmol) of 4-(dimethylammo)pyridine, and 1.31 mL (9.42 mmol) of triethylamine
in 50 mL dichloromethane was cooled to 0°C. Then was added a solution of 2.76 g
(12.56 mmol) of 4-bromobenzoyl chloride in 40 mL of dichloromethane and slowly
allowed to warm to ambient temperature. Upon completion, excess dichloromethane was
added to the reaction mixture and the resulting solution was washed with saturated
NaHCO3 and brine, dried over MgSO4, and the solvent was removed in vacuo. The
resulting material was subjected to flash chromatography on a 10 cm column. Elution
with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in
hexanes, 43% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, 57% ethyl acetate
in hexanes, 67% ethyl acetate in hexanes, and 100% ethyl acetate yielded 0.53 g
(0.84 mmol, 27%) of (tert-butoxy)-N-[3-((4-bromophenyl)-N-{[4-oxo-3-benzyl(5-
hydropyridmo[l,2-a]pyrimidin-2yl)]propyl}carbonylamino)propyl]-carboxarnide as a
clear oil.
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WO 2004/113335 PCT/US2004/019158
Step 12: N-(3-aminopropyl)(4-bromophenyl)-N-{[4-oxo-3-ben2yl(5-
hydropyridino-[l,2-a]pyrimidin-2-yl)]propyl}carboxamide.

A mixture of 0.81 g (1.3 mmol) of (t-butoxy)-N-[3-((4-bromophenyl)-N-{[4-oxo-
3-benzyI(5-hydropyridino[l,2-a]pyrimidin-2-
yl)]propyl}carbonylamino)propyl]carboxarnide in 28 mL of dichloromethane was cooled
to 0°C. To the resulting solution was added slowly 6.5 mL (26.0 mmol) of hydrogen
chloride in 1,4-dioxane and the mixture was allowed to warm to ambient temperature.
Upon completion of the reaction the solvent was removed in vacuo yielding 0.79 g
(1.5 mmol, 100%) of N-(3-aminopropyl)(4-bromophenyl)-N-{[4-oxo-3-benzyl(5-
hydropyridmo[l,2-a]pyrimidin-2-yl)]propyl}carboxamide as a white solid.
Example 2
Synthesis of a Representative Pyridinon.2-a]pyrimidin-4-one:
N-(3-aminopropyl)-4-bromo-N-{1-[7-chloro-4-oxo-3-(phenvlmemvI)-4H-pvrido[1,2-
a1pvrimidin-2-yl]propvl}benzamide
In this example, the synthesis of a representative pyridino[l,2-a]pyrimidin-4-one
of the invention is described. The representative pyridino[l,2-a]pyrimidin-4-one is
synthesized in eleven steps as described below.
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WO 2004/113335 PCT/US2004/019158
Step 1: 7-chloro-2-(chloromethyl)-5-hydropyridino[l,2-a]pyrimidin-4-one.

15 g (116.7 mmol) of 2-amino-5-chloropyridine was combined with
approximately 80 g of polyphosphoric acid and heated to 120 °C to allow stirring. To the
resulting solution was added slowly 23.7 mL (175.1 mmol) of ethyl-4-chloroacetoacetate
and stirred at 120 °C under nitrogen for two hours. The hot reaction mixture was then
poured over 1500 mL of ice water and stirred vigorously. The aqueous layer was
separated and extracted with methylene chloride (6X, approximately 6 L). The combined
organic layers were washed with saturated NaHCO3 and brine and dried over MgS04 and
activated carbon. The solvent was removed in vacuo yielding 21.4 g (93.4 mmol, 80%)
of 7-chloro-2-(chloromemyl)-5-hydropyridmo[l,2-a]pyrimidm-4-one as a tan solid.
Step 2: 7chloro-2-(chloromemyl)-3iodo-5-hydropyridmo[l,2-a]pyrimidin-4-
one.

A mixture of 10.0 g (43.7 mmol) of 7-chloro-2-(chloromethyl)-5-
hydropyridino[l,2-a]pyrimidin-4-one and 14.8 g (65.6 mmol) of N-iodosuccinimide in
250 mL of acetonitrile was stirred at 80 °C under nitrogen for 16 hours. The reaction
mixture was then allowed to cool to ambient temperature and the acetonitrile was
removed in vacuo. The resulting solid was washed with water, saturated Na2O3S2,
saturated NaHCO3 brine, and filtered. Drying under reduced pressure at 40 °C overnight
yielded 14.8 g (41.7 mmol, 95%) of 7-chloro-2-(chloromethyl)-3-iodo-5-
hydropyridino[l,2-a]pyrirnidin-4-one as a yellow solid.
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WO 2004/113335 PCT/US2004/019158
Step 3: 7-chloro-2-(hydroxymethyl)-3-iodo-5-hydropyridino[1,2-a]pyrimidin-4-
one.

A mixture of 10 g (28.2 mmol) of 7-chloro-2-(chloromethyl)-3-iodo-5-
hydropyridino[1,2-a]pyrimidin-4-one and 100 mL of DMSO was heated to 85 °C. To the
resulting solution was added 7.1 g (84.6 mmol) of solid NaHC03 and 100 mL of H2O and
the mixture was stirred at 85 °C for 48 hours. The reaction was allowed to cool and
excess H2O was added to the reaction mixture. The aqueous layer was separated and
extracted with ethyl acetate (4X) and the combined organic layers were washed with
saturated NaHCO3 and brine, dried over MgSO4, and the solvent was removed in vacuo
yielding 8.6 g (25.6 mmol, 91%) of 7-chloro-2-(hydroxymethyl)3-iodo-5-
hydropyridino[l,2-a]pyrirnidin-4-one as a yellow solid.
Step 4: 7-chloro-2-(hydroxymemyl)-3-benzyl-5-hydropyrino [1,2-a] pyrimidin
4-one.

A mixture of 5.0 g (14.9 mmol) of 7-chloro-2-(hydroxymethyl)-3-iodo-5-
hydropyridmo[l,2-a]pyrirnidin-4-one, 1.09 g (1.49 mmol) of
dichloro[l,1'-bis(diphenylphosphino)ferrocene] palladium(II) dichloromethane adduct,
and 9.5 g (44.7 mmol) of K3PO4 in 50 mL of DMF was heated to 80 °C. To the resulting
solution was added dropwise 44.8 mL (22.4 mmol) of B-Benzyl-9-BBN and stirred at
80 °C under nitrogen for 6 hours. The reaction was then cooled to 0 °C and excess
IN NaOH was added to the reaction mixture. Excess 30% H2O2 was then added to the
mixture at 0 °C resulting in significant gas evolution. Stirring continued for at least one
additional hour or until gas ceased to evolve. The mixture was extracted with ethyl
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acetate (4X) and washed with saturated Na2O3S2 and brine. The organic layers were
combined, dried over MgSO4 and activated carbon, and the solvent was removed in
vacuo. The resulting material was subjected to flash chromatography on a 10 cm column.
Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate
in hexanes, 43% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, 57% ethyl
acetate in hexanes, 67% ethyl acetate in hexanes, and 100% ethyl acetate yielded 1.38 g
(4.6 mmol, 31%) of 7-chloro-2-(hydroxymethyl)-3-benzyl-5-
hydropyridmo[l,2-a]pyrimidin-4-one as a pale yellow solid.
Step 5: 2-carbonyl-7-chloro-3-benzyl-5-hydropyridino[l,2-a]pyrimidin-4-one.

6.9 mL (13.8 mmol) of oxalyl chloride in 13.8 mL dichloromethane was cooled to
-78 °C. To the resulting solution was added a solution of 1.95 mL (27.54 mmol) of
DMSO in 6.12 mL dichloromethane and stirred at -78 °C for one hour. Then was added
a solution of 1.38 g (4.59 mmol) of 7-chloro-2-(hydroxymethyl)-3-ben2yl-5-
hydropyridino[l,2-a]pyrimidin-4-one in 20 mL dichloromethane and the resulting
mixture was stirred at -78 °C for one hour. Then was added 6.41 mL (45.9 mmol) of
triethylamine and stirred at -78 °C for one hour. The mixture was then allowed to warm
to 0 °C and stirred for another hour. Finally, the mixture was allowed to warm to ambient
temperature over the course of one hour. Excess water was added to the reaction mixture
and the mixture was extracted (3X) using dichloromethane. The combined organic layers
were dried over MgSO4 and activated carbon and the solvent was removed in vacuo. The
resulting material was subjected to flash chromatography on a 10 cm column. Elution
with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 33% ethyl acetate in
hexanes, 43% ethyl acetate in hexanes, 50% ethyl acetate in hexanes, and 100% ethyl
acetate yielded 1.06 g (3.6 mmol, 78%) of 2-carbonyl-7-chloro-3-benzyl-5-
hydropyridmo[l,2-a]pyrimidin-4-one as a yellow solid.
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Step 6: 7-chloro-2-(l-hydroxyprop-2-enyl)-3-benzyl-5-hydropyridino[l,2-
a]pyrimidin-4-one.

A mixture of 0.1 g (0.34 mmol) of 2-carbonyl-7-chloro-3-benzyl-5-
hydropyridino[l,2-a]pyrimidin-4-one in 2 mL THF was cooled to -78 °C. To the
resulting solution was added dropwise 0.41 mL (0.41 mmol) of vinylmagnesium bromide
and stirred at -78 °C for 3 hours. The reaction was quenched with saturated NH4Cl and
extracted with ethyl acetate (3X). The combined organic layers were dried over MgSO4
and the solvent was removed in vacuo yielding 0.11 g (0.34 mmol, 100%) of 7-chloro-2-
(l-hydroxyprop-2-enyl)-3-benzyl-5-hyodropyridmo[l,2-a]pyrmidin-4-one as a yellow oil.
Step 7: 7-chloro-2-(hydroxypropyl)-3-benzyl-5-hydropyridmo[1,2-a]pyrirnidin-4-
one.

A mixture of 0.11 g (0.34 mmol) of 7-chloro-2-(l-hydroxyprop-2-enyl)-3-benzyl-
5-hydropyridmo[l,2-a]pyrimidin-4-one and 0.05 g (50% by weight) of palladium on
activated carbon in 5 .mL of ethanol was heated to 65 °C. To the resulting solution was
added 0.64 mL (6.8 mmol) 1,4-cyclohexadiene and stirred at 65 °C for 4 hours. Upon
completion, the reaction mixture was filtered through celite and the solvent was removed
in vacuo. The resulting material was subjected to flash chromatography on a 5 cm
column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 50%
ethyl acetate in hexanes, and 100% ethyl acetate yielded 0.024 g (0.07mmol, 21%) of
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7-chloro-2-(hydroxypropyl)-3-benzyl-5-hydrophridino[1,2-a]pyrimidin-4- one as a brown
solid.
Step 8: [7-chloro -4-oxo-3-benzyl-5-hydropyridino[l,2-a]pyrimidin-2-yl]propyl
methylsulfonate.

A mixture of 0.024 g (0.07 mmol) of 7-chloro-2-(hydroxypropyl)-3-benzyl-5-
hydropyridino[l,2-a]pyrimidin-4-one and 0.02 mL (0.14 mmol) of triethylamine in 2 mL
of dichloromethane was cooled to 0 °C. To this solution was added dropwise 0.007 mL
(0.084 mmol) of methane sulfonyl chloride and the resulting solution was allowed to
warm to ambient temperature. Upon completion, excess dichloromethane was added to
the reaction mixture and the solution was washed with H2O, saturated NaHCO3, and
brine. The organic layer was dried over MgSO4 and the solvent was removed in vacuo
yielding 0.043 g (0.11 mmol, 151%) of [7-chloro-4-oxo-3-benzyl-5-hydropyridino[l,2-
a]pyrimidin-2-yl]propyl methylsulfonate as a brown oil.
Step 9: (t-butoxy)-N-[3-({[7-chloro-4-oxo-3-benzyl(5-hydropyridino[l,2-
a]pyrmiidm-2-yl)]propyl}arnino)propyl]carboxamide.

A mixture of 0.043 g (0.11 mmol) of [7-chloro-4-oxo-3-benzyl-5-
hydropyridmo[l,2-a]pyrimidin-2-yl]propyl methylsulfonate, 0.17 g (1.0 mmol) of
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(3-Amino-propyl)-carbamic acid ter/-butyl ester, and 0.01 g (0.06 mmol) of potassium
iodide in 2 mL of DMF was heated to 60 °C for 30 hours. The reaction mixture was
quenched with H2O and extracted with ethyl acetate (4X). The combined organic layers
were washed with saturated NaHCO3 and brine, dried over MgSO4, and the solvent was
removed in vacuo. The resulting material was subjected to flash chromatography on a
5 cm column. Elution with 97% dichloromethane: 3% methanol: 0.1% ammonia yielded
0.223 g (0.46 mmol, 418%) of (t-butoxy)-N-[3-({[7-chloro-4-oxo-3-
berizyl(5-hydropyridmo[l,2-a]pyrirmidin-2-yl)]propyl}-mnmo) propyl]carboxamide as a
crude brown oil.
Step 10; (t-butoxy)-N-[3-((4-bromophenyl)-N-{ [7-chloro-4-oxo-3-benzyl(5-
hydropyridmo[l,2-a]pyrimidm-2-yl)]propyl}carto

A mixture of 0.112 g (0.23 mmol) of (t-butoxy)-N-[3-({[7-chloro-4-
oxo-3-benzyl(5-hydropyridinoo[l,2-a]pyrimidin-2-yl)]propyl}amino)propyl]carboxamide,
0.003 g (0.023 mmol) of 4-(dimemylammo)pyridine, and 0.1 mL (0.69 mmol) of
triethylamine in 5.5 mL dichloromethane was cooled to 0 °C. Then was added a solution
of 0.26 g (1.2 mmol) of 4-bromobenzoyl chloride in 3.0 mL of dichloromethane and
slowly allowed to warm to ambient temperature. Upon completion, excess
dichloromethane was added to the reaction mixture and the resulting solution was washed
with saturated NaHCO3 and brine, dried over MgSO4 and the solvent was removed
in vacuo. The resulting material was subjected to flash chromatography on a 5 cm
column. Elution with a gradient of 100% hexanes, 20% ethyl acetate in hexanes, 50%
ethyl acetate in hexanes, and 100% ethyl acetate yielded 0.0063 g (0.009 mmol, 4%) of
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(t-butoxy)-N-[3-((4-bromophenyl)-N-{[7-chloro-4-oxo-3-benzyl(5-hydropyridino[l,2-
a]pyrimidin-2-yl)]propyl}carbonylamino)propyl]carboxamide as a clear oil.
Step 11: N-(3-aminopropyl)-4-bromo-N-{l-[7-chloro-4-oxo-3-(phenylmethyl)-
4H-pyrido[l,2-a]pyrirnidin-2-yl]propyl}benzamide.

A mixture of 0.0063 g (0.009 mmol) of (t-butoxy)-N-[3-((4-bromophenyl)-N-{[7-
chloro-4-oxo-3-benzyl(5-hydropyridino[l,2-a]pyrimidin-2-yl)]propy}carbonylamino)-
propyl]carboxamide 10 in 0.5 mL of dichloromethane and 0.05 mL of TFA was shaken at
ambient temperature for 2 hours. Upon completion, the solvent was removed in vacuo
yielding 0.0075 g (0.01 mmol, 110%) of N-(3-aminopropyl)-4-bromo-N-{l-[7-chloro-4-
oxo-3-(phenyhriemyl)-4H-pyrido[l,2-a]pyrmndm-2-yl]propyl}benzamide as a solid
white TFA salt.
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Example 3
Representative Pyidino[12-a1pyrimidin-4-one Compounds
Table 1. Representative Pyridino[1,2-a]pyrimidin-4-one Compounds.

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WO 2004/113335 PCT/US2004/019158

Using the procedure described in Example 4, certain of compounds in Table 1
were shown to have a KSP inhibitory activity at an IC50 of less than about 25 M. Some
of the compounds have an IC50 less than about 1 M, and certain others of the compounds
have an IC50 less than 100 nM.
Example 4
Assay for Determining KSP Activity
In this example, a representative in vitro assay for deterrnining KSP activity is
described.
Purified microtubules from bovine brain were purchased from Cytoskeleton Inc.
The motor domain of human KSP (KSP, KNSL1) was cloned and purified to a purity of
greater than 95%. Biomol Green was purchased from Affinity Research Products Ltd.
Microtubules and the KSP motor protein were diluted in assay buffer (20 mM
Tris-HCl, pH 7.5, 1 mM MgCl2, 10 mM DTT and 0.25 mg/mL BSA) to a concentration
of 35 ug/mL for microtubules and 45 nM for KSP. The microtubule/KSP mixture was
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WO 2004/113335 PCT/US2004/019158
then pre-incubated at 37°C for 10 min to promote the binding of KSP to microtubules.
ATP was also diluted to a concentration of 300 uM in the same assay buffer. To each
well of the testing plate (384 well plate) containing 1.25 uL of compounds in DMSO or
DMSO only, 25 uL of ATP solution. To start the reaction, 25 uL of microtubule/KSP
solution was added to the ATP/compound mixture. The plates were incubated at room
temperature for 1 hr. At the end of incubation period, 65 uL of Biomol Green was added
to each well. The plates were incubated for 5-10 min and then the absorbance at 630 nm
was determined. Biomol Green reagent is a malachite green based dye that detects the
release of inorganic phosphate. Developed color signal was read using a Victor II
reader. The concentration of each compound for 50% inhibition (IC50) was calculated by
nonlinear regression using either XLFit for Excel or Prism data analysis software by
GraphPad Software Inc.
While the preferred embodiment of the invention has been illustrated and
described, it will be appreciated that various changes can be made therein without
departing from the spirit and scope of the invention.

WO 2004/113335 PCT/US2004/019158
The embodiments of the invention in which an exclusive property or privilege is
claimed are defined as follows:
1. A compound having the formula:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, ester, or prodrug
thereof, wherein
R1 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) substituted or unsubstituted alkylsulfonyl, and
(9) substituted or unsubstituted arylsulfonyl;
R2 and R3 are independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) substituted or unsubstituted alkylsulfonyl,
(9) substituted or unsubstituted arylsulfonyl,
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WO 2004/113335 PCT/US2004/019158
(10) cyano,
(11) COR10
(12) C02R10,
(13) CONR11R12,
(14) S(0)mR10, and
(15) SO2NR11R12; or
R2 and R3 taken together with the carbon atom to which they are attached form a
3- to 7-membered carbocyclic or heterocyclic ring;
R4 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
. (7) substituted or unsubstituted heterocyclyl, and
(8) L-R13, wherein L is a C1-C10 saturated or unsaturated branched or
unbranched carbon chain comprising one or more methylene groups, wherein one or
more methylene groups are optionally independently replaced by O, N, or S; and wherein
L is optionally substituted with one or two oxo groups and one or more C1-C10 branched
or unbranched alkyl optionally substituted by one or more halogen atoms;
R5 is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl,
(7) substituted or unsubstituted heterocyclyl,
(8) COR10,
(9) CO2R10,

(10) CONR11R12,
(11) S(O)mR10, and

WO 2004/113335 PCT/US2004/019158
(12) SO2NR11R12;
R6 R7, R8, and R9 are independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) nitro,
(4) cyano,
(5) hydroxy,
(6) substituted or unsubstituted alkoxy,
(7) substituted or unsubstituted methylenedioxy,
(8) substituted or unsubstituted amino,
(9) substituted or unsubstituted alkyl,

(10) substituted or unsubstituted alkenyl,
(11) substituted or unsubstituted alkynyl,
(12) substituted or unsubstituted aryl,
(13) substituted or unsubstituted heteroaryl,
(14) substituted or unsubstituted alkylsulfonyl, and
(15) substituted or unsubstituted arylsulfonyl;
R10, Rll, and R12 are independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted alkyl,
(3) substituted or unsubstituted alkenyl,
(4) substituted or unsubstituted alkynyl,
(5) substituted or unsubstituted aryl,
(6) substituted or unsubstituted heteroaryl, and
(7) substituted or unsubstituted heterocyclyl; or
R11 and R12 taken together with the nitrogen atom to which they are
attached form a 3- to 7-membered heterocyclic ring;
R13 is selected from the group consisting of
(1) substituted or unsubstituted amino,
(2) substituted or unsubstituted aryl,
(3) substituted or unsubstituted heteroaryl, and
(4) substituted or unsubstituted heterocyclyl; and
m = 0, 1,or 2.
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2. A compound of Claim 1, wherein substituted alkyl comprises arylalkyl,
heteroarylalkyl, heterocyclylalkyl, aminoalkyl, alkylaminoalkyl, dialkyaminoalkyl, or
sulfonamidoalkyl.
3. A compound of Claim 1, wherein R1 is arylalkyl.
4. A compound of Claim 1, wherein R1 is benzyl.
5. A compound of Claim 1, wherein R2 is hydrogen and R3 is selected from
the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
6. A compound of Claim 5, wherein alkyl is selected from the group
consisting of ethyl, propyl, isopropyl, and cyclopropyl.
7. A compound of Claim 5, wherein alkenyl is 2-propenyl.
8. A compound of Claim 5, wherein aryl is selected from the group
consisting of phenyl, thienyl, and'pyridyl.
9. A compound of Claim 1, wherein R4 is L-R13.
10. A compound of Claim 9, wherein L is a C1-C10 saturated or unsaturated
branched or unbranched carbon chain.
11. A compound of Claim 9, wherein R13 is selected from the group consisting
of amino, cycloalkyl, aryl, and heterocyclyl.
12. A compound of Claim 9, wherein L-R13 is substituted or unsubstituted
aminoalkyl.
13. A compound of Claim 9, wherein L-R13 is aminopropyl.
14. A compound of Claim 1, wherein R5 is COR10.
15. A compound of Claim 14, wherein R10 is selected from the group
consisting of substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.
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16. A compound of.Claim 14, wherein R10 is substituted phenyl or substituted
pyridyl.
17. A compound of Claim 16, wherein the substituted phenyl is an alkyl- or
halo-substituted phenyl.
18. A compound of Claim 1, wherein R6, R7, R8, and R9 are independently
selected from the group consisting of hydrogen, alkyl, and halo.
19. A compound of Claim 1 selected from the group consisting of:
N-[l-(3-benzyl-8-methyl-4-oxo-4H-pyrido[l,2-a]pyrinndin-2-yl)propyl]-4-
bromo-N-[3-(dimethylamino)propyl]benzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)ethyl]-
4-bromobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl]-
4-methylbenzamide;
N-(3-aminopropyl)-N-[(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)(cyclopropyl)methyl]-4-bromobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-4-tert-butylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-4-(trifluoromethoxy)benzamide;
4-(acetylamino)-N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-
a]pyrimidin-2-yl)propyl]benzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-4-ethoxybenzamide;
N-(3-aminopropyl)-N-[l-(3-benzy1-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-2,6-dichlorobenzamide;
N-(3 -aminopropyl)-N-[l -(3 -benzyl-4-oxo-4H-pyrido [ 1,2-a]pyrimidin-2-
yl)propyl]benzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin
yl)propyl]-4-methylbenzenesulfonamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yI)propyl]-2,4-difluorobenzamide;
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N-(3-aminopropyl)-N[1-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2
yl)propyl]isonicotinamide;
N-(3 -aminopropyl)-N-[l-(3 -benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-3 -chloroisonicotinamide;
N-(3-aminopropyl)-N-[l -(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-5-methylpyrazine-2-carboxamide;
N-(3-aminopropyI)-N-[1-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]pyrazine-2-carboxamide;
N-[l-(3-benzyl-4-oxo4H-pyrido[l,2-a]pyrimidin-2-yl)propyl]-4-methyl-N-[4-
(methylamino)butyl]benzamide;
2-(2-aminoethoxy)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-N:,4-dimethylbenzamide;
2-(3-aminopropoxy)-N-[l -(3-benzyI-4-oxo-4H-pyrido[l ,2-a]pyrimidin-2-
yl)propyI]-N,4-dimethylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyI]thiophene-2-carboxamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-2-furamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyI]-5-chlorothiophene-2-carboxamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]pyridine-2-carboxamide; and
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]quinoxaline-6-carboxamide.
20. A compound of Claim 1 selected from the group consisting of:
N-(3-aminopropyl])-N-[l-(3-benzyl-8-methyl-4-oxo-4H-pyrido[l,2-a]pyrmidin-2-
yl)propyl]-4-bromobenzamide;
N-(3-aminopropyl)-N-[1-(3-benzyl-8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-4-chlorobenzamide;
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WO 2004/113335 PCT/US2004/019158
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-4-fluorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-4-cyanobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yI)propyl]-4-methoxybenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-2-chlorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-3-chIorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-3,5-dichlorobenzamide;
2-{ 1 -[(3-aminopropyl)(4-methylbenzyl)amino]propyl}-3-benzyl-4H-pyrido[l ,2-
a]pyrimidin-4-one;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-3,4-difluorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-3-fluorobenzamide;
N-[2-(aminomethyl)prop-2-enyl]-N-[l-(3-benzyl-4-oxo-4H-pyrido[l:,2-
a]pyrimidin-2-yl)butyl]-4-methylbenzamide;
N-[2-(aminomethyl)prop-2-enyl]-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-
a]pyrimidin-2-yl)but-3-enyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[ 1 -(3 -benzyl-4-oxo-4H-pyrido [1,2-a]pyrimidin-2-
yl)propyl]-2,4-dimethoxybenzamide;
N-[1-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)propyl]-4-methyl-N-
(piperidin-3-ylmethyl)benzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-2-methoxybenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-3,4-dimethoxybenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-2-chloro-4-fluorobenzamide;
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N-(3-aminopropyl)-N-[ 1 -(3 -benzyl-4-oxo-4H-pyrido[ 1 ,2-a]pyrimidin-2-
yI)propyI]-6-methoxynicotnamide;
N-(azetidin-3-ylmethyl)-N-[l -(3-benzyl-4-oxo-4H-pyrido[l ,2-a]pyrimidin-2-
yl)propyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-2-naphthamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-.
yl)propyl]-3-(trifluoromethyl)benzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-3-choro-l-benzothiophene-2-carboxamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)-2-
methylpropyl]-2,3 -dichlorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido
methylpropyl]-3,5-dichlorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]nicotinamide; and
N-(3-aminopropyl)-N-[l -(3-benzyl-4-oxo-4H-pyrido[l ,2-a]pyrimidin-2-
yl)propyl]-4-(dimethylamino)benzamide.
21.A compound of Claim 1 selected from the group consisting of:
N-(3 -aminopropyI)-N-[l -(3 -benzyl-4-oxo-4H-pyrido[l ,2-a]pyrimidin-2-
yl)propyl]-4-bromobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]4-methylbenzamide;
N-(3-ammopropyI)-N-[l-(3-benzyl-7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-4-bromobenzamide;
N-(3-ammopropyl)-N-[l-(3-benzyl-7-chloro-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-
yl)propyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[l-(3 -benzyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-2-
yl)propyl]-4-(trifIuoromethyI)benzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[ 1,2-a]pyrimidin-2-
yI)propyl]-4-ethylbenzamide;
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N-(3-aminopropyl)-N-[l-(3-benzyl -4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-3,4-dichlorobenzamide;
N-(3-amkopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yI)propyl]-2,4-dichlorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)propyl]-2,3-dicblorobenzamide;
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
4-methylbenzamide;
N-(4-anjinobutyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
4-methylbenzamide;
N-(3-aniino-2,2-dimethylpropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-
a]pyrimidin-2-yl)propyl]-4-methylbenzamide;
N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)propyl]-4-methyl-N-(2-
piperidin-2~ylethyl)benzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)but-3-
enyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)-2-
methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l;2-a]pyrimidin-2-yl)-2-
methylpropyl]-4-chlorobenzamide;
N-(3-aminopropyl)-N-[(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)(cyclopropyl)methyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)(cyclopropyl)methyl]-4-chlorobenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yI)propyI]-6-chloronicotinamide;
N-[1-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)propyl]-4-methyl-N-
(pyrrolidin-3-ylmethyl)benzamide;
N-(3-ammopropyl)-N-[(3-ben2yl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)(phenyI)methyl]-4-chlorobenzamide;
N-(3-amkopropyl)-N-[(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)(thien-2-
yl)methyl]-4-methylbenzamide;
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WO 2004/U3335 PCT/US2004/019158
N-(3-aminopropyl)-N[(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)(thien-2-
yl)methyl]-4-chlorobenzamide;
N-(3-ammopropyl)-N-[(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)(pyridin-
2-yl)methyl]-4-methyIbenzamide;
N-(3-aminopropyl)-N-[(3-benzyl-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)(thien-2-
2-yl)methyl]-4-cMorobenzamide;
N-(3-amkopropyl)-N-[(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)(phenyl)methyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[ls2-a]pyrimidin-2-yl)-2-
methylpropyl]-6-chloronicotinamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)-2-
methyIpropyI]-3,4-dichlorobenzamide;
N-(3-aminopropyl)-N-[l -(3-benzyl-4-oxo-4H-pyrido[l ,2-a]pyrimidin-2-
yl)propyl]-2,2-drfluoro-1,3-benzodioxole-5-carboxamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l ,2-a]pyrimidin-2-yl)-2-
methylpropyl]-3-fluoro-4-metbylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)-2-
methylpropyl]-2-chloro-4-methylbenzamide;
N-(3-aminopropyl)-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)-2-
methylpropyl]-3 -chloro-4-methylbenzamide;
N-(3-aminopropyl)-N-{1[3-(3-chlorobenzyl)-4-oxo-4H-pyrido[l,2-a]pyrimidin-
2-yl]-2-methylpropyl}-4-methylbenzamide;
N-(3-ann^opropyI)-N-[l-(3-benzyl-8-methyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)-2-methylpropyl]-4-methylbenzamide;
N-(3-aminopropyl)-N-[1-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-yl)-2-
methylpropyl]-3,4-dimethylbenzamide;
N-(3-aminopropyl)-4-metliyl-N-{2-methyl-l-[3-(3-methylben2yl)-4-oxo-4H-
pyrido[l,2-a]pyrimidin-2-yl]propyl}benzamide;
N-(3-anoiiiopropyl)-3-fluoro-4-methyl-N-{2-methyl-l-[3-(3-methylbenzyl)-4-oxo-
4H-pyrido[l,2-a]pyrimidin-2-yl]propyl}ben2amide;
N-[3-(ben2ylambo)propyl]-N-[l-(3-benzyl-4-oxo-4H-pyrido[l,2-a]pyrimidin-2-
yl)-2-metnylpropyl]-4-methylbenzamide; and
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WO 2004/113335 PCT/US2004/019158
N-[l-(3-beri2yl-4-oxo-4H-pyrido[l,2-a]pyrirmidin-2-yl)-2-methylpropyl]-N-{3-
[(cycIohexylmethyl)amino]propyl}-4-methylbenzamide.
22. A composition, comprising a pharmaceutically acceptable carrier and an
amount of a compound of Claim 1 effective to inhibit KSP activity in a human or animal
subject when administered thereto.
23. The composition of Claim 22 further comprising at least one additional
agent for the treatment of cancer.
24. The composition of Claim 23, wherein the at least one additional agent for
the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, imatinib,
trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, docetaxel, paclitaxel,
tezacitabine, cyclophosphamide, vinca alkaloids, anthracyclines, rituximab, and
trastuzumab.
25. A method for treating a condition by modulation of KSP protein activity
comprising administering to a human or animal subject in need of such treatment an
effective amount of a compound of Claim 1.
26. The method of Claim 25, wherein the compound has an IC50 value of less
than about 25 M in a cell proliferation assay.
27. The method of Claim 25, wherein the condition is cancer.
28. A method for inhibiting KSP activity in a human or animal subject,
comprising administering to the human or animal subject a composition comprising an
amount of a compound of Claim 1 effective to inhibit KSP activity the human or animal
subject
29. A method for treating a cancer disorder in a human or animal subject,
comprising administering to the human or animal subject a composition comprising an
amount of a compound of Claim 1 effective to inhibit KSP activity the human or animal
subject
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WO 2004/113335 PCT/US2004/019158
30. The method of Claim 29 further comprismgadmimstering to the human or
animal subject at least one additional agent for the treatment of cancer.
31. The method of Claim 30, wherein the at least one additional agent for the
treatment of cancer is selected from irinotecan, topotecan, gemcitabine, gleevec,
herceptin, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine,
cyclophosphamide, vinca alkaloids, imatinib, anthracyclines, rituximab, or trastuzumab.
32. A compound of Claim 1 for use in the treatment of cancer.
33. Use of a compound of Claim 1 in the manufacture of a medicament for the
treatment of cancer.
34. A kit, comprising a compound of Claim 1 and a package insert or other
labeling including directions for treating a cellular proliferative disease by administering
an KSP inhibitory amount of the compound.
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Pyridino[1,2.-a]pyrimidinyl compounds of formula (I), pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically.acceptable carrier and one or more of the pyridino[1,2-a]pyrimidinyl compounds, either alone or in combination with at least one additional therapeutic agent. Methods of using the pyridino[1,2-a]pyrirnidinyl compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of proliferative diseases.

Documents:

02472-kolnp-2005-abstract.pdf

02472-kolnp-2005-claims.pdf

02472-kolnp-2005-description complete.pdf

02472-kolnp-2005-form 1.pdf

02472-kolnp-2005-form 3.pdf

02472-kolnp-2005-form 5.pdf

02472-kolnp-2005-international publication.pdf

2472-kolnp-2005-granted-abstract.pdf

2472-kolnp-2005-granted-assignment.pdf

2472-kolnp-2005-granted-claims.pdf

2472-kolnp-2005-granted-correspondence.pdf

2472-kolnp-2005-granted-description (complete).pdf

2472-kolnp-2005-granted-examination report.pdf

2472-kolnp-2005-granted-form 1.pdf

2472-kolnp-2005-granted-form 13.pdf

2472-kolnp-2005-granted-form 18.pdf

2472-kolnp-2005-granted-form 3.pdf

2472-kolnp-2005-granted-form 5.pdf

2472-kolnp-2005-granted-gpa.pdf

2472-kolnp-2005-granted-reply to examination report.pdf

2472-kolnp-2005-granted-specification.pdf


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Patent Number 235681
Indian Patent Application Number 2472/KOLNP/2005
PG Journal Number 31/2009
Publication Date 31-Jul-2009
Grant Date 29-Jul-2009
Date of Filing 02-Dec-2005
Name of Patentee CHIRON CORPORATION
Applicant Address P.O. BOX 8097, EMERYVILLE CA
Inventors:
# Inventor's Name Inventor's Address
1 CONSTANTINE RYAN N CHIRON CORPORATION, P.O. BOX 8097, EMERYVILLE CA 94662-8097
2 LAGNITON LIANA M CHIRON CORPORATION, P.O. BOX 8097, EMERYVILLE CA 94662-8097
3 PECCHI SABINA CHIRON CORPORATION, P.O. BOX 8097, EMERYVILLE CA 94662-8097
4 BURGER MATTHEW T CHIRON CORPORATION, P.O. BOX 8097, EMERYVILLE CA 94662-8097
5 DESAI MANOJ C CHIRON CORPORATION, P.O. BOX 8097, EMERYVILLE CA 94662-8097
6 WANG WEIBO CHIRON CORPORATION, P.O. BOX 8097, EMERYVILLE CA 94662-8097
PCT International Classification Number C07D 471/00
PCT International Application Number PCT/US2004/019158
PCT International Filing date 2004-06-17
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/480,180 2003-06-20 U.S.A.