Title of Invention

2-AMINO-7,8-DIHYDRO-6H-PYRIDO[4,3-D] PYRIMIDIN-5-ONES

Abstract Disclosed are 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, their stereoisomers, tautomers, pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one or more of the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one additional therapeutic agent. Disclosed also are methods of using the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cellular proliferative, viral, autoimmune, cardiovascular, and central nevous system diseases.
Full Text WO 2007/041362 PCT/US2006/038181
2-AMINO-7,8-DIHYDRO-6H-PYRIDO[4,3-D]PYRIMIDIN-5-ONES
CROSS REFERENCE TO RELATED APPLICATIONS
This application claims the benefit under 35 U.S.C. 119(e) to provisional
applications U.S. Serial No. 60/722,796 filed on September 30, 2005, and U.S. Serial No.
60/836,886 filed on August 9,2006, each of which is incorporated herein by reference in its
entirety.
FIELD OF THE INVENTION
The present invention relates to new 2-amino-7,8-dihydro-6H-pyrido[4,3-.
d]pyrimidin-5-one compounds, their stereoisomers, tautomers, pharmaceutically acceptable
salts, and prodrugs thereof; compositions of the new compounds, either alone or in
combination with at least one additional therapeutic agent, with a pharmaceutically
acceptable carrier; and uses of the new compounds and compositions, either alone or in
combination with at least one additional therapeutic agent, in the prophylaxis or treatment
of cellular proliferative, viral, autoimmune, cardiovascular, and central nervous system
diseases.
BACKGROUND OF THE INVENTION
Heat shock or stress dramatically increases cellular production of several classes of
highly conserved chaperone proteins, commonly known as heat-shock proteins (HSPs).
These chaperones, including the members of the HSP60, HSP70, and HSP90 families, are
ATP-dependent molecules that facilitate/ensure proper client protein (e.g. protein that
requires interaction with the chaperones for its activity and stability) folding, prevent non-
specific aggregations, and maintain active protein conformations.
The HSP90 family, comprised of HSP90 α and β, Grp94 and TRAP-1, represents
one of the most abundant cellular proteins, accounting for 1-2% of total protein in a
mammalian cell under normal conditions. HSP90 is unique among cellular chaperones in
that it is not required for general co-translational protein folding but is instead dedicated to a
unique set of cellular proteins, many of which are key signaling molecules critically
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involved in cell growth, differentiation, and apoptosis. So far over 100 proteins have been
documented to associate with HSP90 and this list of client proteins is expanding rapidly.
Crystallographic studies have revealed the existence of an unconventional low
affinity ATP binding cleft at their N-terminal domain that is well conserved among the four
HSP90 family members. ATP binding and hydrolysis play an essential role in the
regulation of chaperone functions. The occupancy of the ATP binding site by the
ansamycin antibiotics geldanamycin (GM) and herbimycin A (HA), as well as the
structurally unrelated fungal metabolite radicicol, inhibits the intrinsic ATPase activity of
HSP90 and blocks the ATP/ADP-regulated association-dissociation cycles between HSP90
and client proteins. Consequently, ATP-competitive HSP90 inhibitors induce
destabilization and eventual ubiquitin-dependent degradation of client proteins.
HSP90 has generated tremendous interest as a novel anti-cancer target following the
realization that many of its clients are bona fide oncoproteins that are frequently
overexpressed, mutated, or constitutively active in tumor cells. These include well known
and established cancer drug targets such as receptor tyrosine kinases (HER-2/neu, epidermal
growth factor receptor EGFR, Met and insulin-like growth factor-1 receptor IGF-1R),
metastable serine/threonine kinases (Akt and Raf-1), mutated signaling proteins (Flt3, v-
Src), chimeric oncoproteins (Bcr-Abl, NPM-ALK), cell-cycle regulators (CDK4 and
CDK6), transcription factors (estrogen and androgen receptors ER and AR, hypoxia-
inducible factor HIF-icc) and apoptosis regulators (Survivin and Apaf-1). It is notable that
HSP90 client proteins functionally contribute to all of the six "hallmarks of cancer", which
include (with examples of relevant HSP90 client proteins in parenthesis) 1) self-sufficiency
in growth signals (ErbB2, Raf-1), 2) insensitivity to growth suppression signals (Plk, Mytl),
3) evasion of apoptosis (Akt, RIP), 4) acquisition of limitless replicative potential (hTERT),
5) sustained angiogenesis (HIF-lcc, FAK) and 6) invasion and metastasis (Met). The
association with HSP90 ensures that these otherwise unstable oncoproteins function
properly in multiple signaling pathways that are essential in maintaining the unregulated
growth and the malignant phenotypes of tumors.
Inactivation of HSP90 by an ATP-competitive inhibitor will induce simultaneous
depletion of multiple oncoproteins and cause concurrent inhibition of various oncogenic
signaling pathways. Therefore, by disrupting the function of a single molecular entity
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HSP90, an HSP90 inhibitor may uniquely provide a combinatorial attack on multistep
oncogenesis and block all of the six hallmarks of cancer. Depending on cellular contexts,
HSP90 inhibitors effectively cause growth arrest, differentiation, or apoptosis of tumor cells
both in vitro and in vivo. In addition, HSP90 itself is overexpressed (about 2-20 fold) in
multiple tumor types as a result of oncogenic transformation (e.g. accumulation of mutated
proteins) and cellular stress (e.g. low pH and lack of nutrients). Overexpression of Hsp90
has been shown to correlate with poor prognosis in breast cancer.
Cancer cells are highly adaptive to hostile microenvironments and are capable of
acquiring drag resistance, in part due to their inherent genetic instability and plasticity.
Moreover, most forms of cancer are polygenic and harbor multiple signaling aberrations.
HSP90 may be a key component of the very machinery that allows certain cancer cells to
escape apoptotic death and evoke alternative or overlapping signaling to efficiently develop
resistance to a specific drug treatment. Consequently, inhibition of Hsp90 by concurrently
disrupting a wide range of oncogenic pathways may prove to be a very effective approach to
combat a variety of hard-to-treat tumor.20'23 The cancers include, for example, breast
cancer1, ovarian2, prostate3, chronic myelogenous leukemia (CML)4, melanoma5,
gastrointestinal stromal tumors (GISTs) , master cell leukemia , testicular tumor , acute
myelogenous leukemia8'9, gastric tumor10, lung11, head and neck12, glioblastoma13, colon14,
thyroid15, stomach, liver, multiple myeloma16, renal17, and lymphoma18'19.
In addition to cancers, Hsp90 inhibitors may also have the potential to treat non-
oncological indications where diseased cells show increased expression and usage of
HSP90. These include, but are not limited to viral diseases mediated by hepatitis B virus
(HBV), hepatitis C virus (HCV) and herpes simplex virus type 1 (HSV-1) as well as
autoimmune diseases including those mediated by persistent lymphocyte activation. In all
these cases, elevated Hsp90 activity either facilitates virus assembly and replication or is
required for aberrant signaling transduction in inappropriately activated lymphocyte.
Furthermore, HSP90 inhibitors are also known to induce upregulation of other heat shock
proteins (e.g. HSP70), which may offer neuroprotection and cardioprotection against
ischemic injury as well as damages caused by protein-aggregation. Therefore, HSP90
inhibitors offer therapeutic potential in treatment of central nervous system (CNS) disorders
and cardiovascular diseases.
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SUMMARY OF THE INVENTION
In one aspect of the present invention, new 2-amino-7,8-dih.ydro-6H-pyrido[4,3-
d]pyrimidin-5-one compounds, tautomers, and stereoisomers, and the pharmaceutically
acceptable salts and prodrugs thereof are provided. The 2-amino-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one compounds, pharmaceutically acceptable salts, and prodrugs
axe HSP90 inhibitors and are useful in treating cellular proliferative, viral, autoimmune,
cardiovascular and central nervous system diseases.
In one embodiment, the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
compounds have the formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof,
wherein
Ra is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) Ci-C6 alkoxy,
(5) thiol,
(6) Ci-C6 alkylthiol,
(7) substituted or unsubstituted C^-Cg alkyl,
(8) amino or substituted amino,
(9) substituted or unsubstituted aryl,
(10) substituted or unsubstituted heteroaryl, and
(11) substituted or unsubstituted heterocyclyl;
R is selected from the group consisting of
(1) hydrogen,
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(2) substituted or unsubstituted Cj-Cg alkyl,
(3) substituted or unsubstituted C2-Cg alkenyl,
(4) substituted or unsubstituted C2-C6 alkynyl,
(5) substituted or unsubstituted C3-C7 cycloalkyl,
(6) substituted or unsubstituted C5-C7 cycloalkenyl,
(7) substituted or unsubstituted aryl,
(8) substituted or unsubstituted heteroaryl, and
(9) substituted or unsubstituted heterocyclyl;
RD is selected from the group consisting of

(1) substituted or unsubstituted C3-C7 cycloalkyl,
(2) substituted or unsubstituted C5-C7 cycloalkenyl,
(3) substituted or unsubstituted aryl,
(4) substituted or unsubstituted heteroaryl, and
(5) substituted or unsubstituted heterocyclyl;
with the proviso that when Ra is amino, then Rb is not phenyl, 4-alkyl-phenyl, 4-
alkoxy-phenyl, or 4-halo-phenyl.
In another aspect, the present invention provides methods for treating cellular
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 cellular
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 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) in combination with one or more
additional agents for the treatment of cancer, as are commonly employed in cancer therapy.
In one embodiment, provided are compounds, compositions, and methods for
treating a condition by modulating HSP90 activity. In some aspects, the condition is a
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cellular proliferative, viral, autoimmune, cardiovascular, or central nervous system disease.
In one embodiment, provided are compounds, compositions, and methods for
treating cancers such as, for example, lung and bronchus; prostate; testicular tumor; 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; lymphoma; myeloid leukemia; master cell leukemia, brain; oral cavity and
pharynx; larynx; head; neck; glioblastoma; small intestine; gastrointestinal stromal tumors
(GISTs); gastric tumor; non-hodgkin lymphoma: melanoma; and villous colon adenoma.
In one embodiment, provided are compounds, compositions, and methods for
treating a viral disease. Such diseases include, for example, viral diseases mediated by
hepatitis B virus (HBV), hepatitis C virus (HCV), or herpes simplex virus type 1 (HSV-1).
In one embodiment, provided are compounds, compositions, and methods for
treating an autoimmune disease. In some aspects, the autoimmune disease is mediated by
persistent lymphocyte activation.
In one embodiment, provided are compounds, compositions, and methods for
treating a cardiovascular or central nervous system disease.
The invention further provides compositions, kits, methods of use, and methods of
manufacture and related synthetic intermediates as described in the detailed description of
the invention.
DETAILED DESCRIPTION
In one aspect of the present invention, new 2-amino-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one compounds, stereoisomers, and tautomers, and the pharmaceutically
acceptable salts and prodrugs thereof are provided. The 2-amino-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one compounds, stereoisomers, and tautomers, and the
pharmaceutically acceptable salts and prodrugs thereof are HSP90 inhibitors and are useful
in the treating cellular proliferative, viral, autoimmune, cardiovascular and central nervous
system diseases.
In one embodiment, the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
compounds of the invention have the formula (I):
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WO 2007/041362 PCT/US2006/038181

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof,
wherein
Ra is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) Ci-C6 alkoxy,
(5) thiol,
(6) Ci-C6 alkylthiol,
(7) substituted or unsubstituted CpCg alkyl,
(8) amino or substituted amino,
(9) substituted or unsubstituted aryl,
(10) substituted or unsubstituted heteroaryl, and
(11) substituted or unsubstituted heterocyclyl;
R is selected from the group consisting of

(1) hydrogen,
(2) substituted or unsubstituted Cj-Cg alkyl,
(3) substituted or unsubstituted C2-Cg alkenyl,
(4) substituted or unsubstituted C2-C6 alkynyl,
(5) substituted or unsubstituted C3-C7 cycloalkyl,
(6) substituted or unsubstituted C5-C7 cycloalkenyl,
(7) substituted or unsubstituted aryl,.
(8) substituted or unsubstituted heteroaryl, and
(9) substituted or unsubstituted heterocyclyl;
Rb is selected from the group consisting of
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(1) substituted or unsubstituted C3-C7 cycloalkyl,
(2) substituted or unsubstituted C5-C7 cycloalkenyl,
(3) substituted or unsubstituted aryl,
(4) substituted or unsubstituted heteroaryl, and
(5) substituted or unsubstituted heterocyclyl; and
with the proviso that when Ra is amino, then Rb is not phenyl, 4-alkyl-phenyl, 4-
alkoxy-phenyl, or 4-halo-phenyl.
Other embodiments provide a compound having formula (la)

or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein R, Ra,
and Rb are as previously defined for formula (I) and with the proviso that when Ra is amino,
then Rb is not phenyl, 4-alkyl-phenyl, 4-alkoxy-phenyl, or 4-halo-phenyl.
In some embodiments of the compounds of formula (I) or (la), Ra is hydrogen.
In other embodiments, R3 is substituted or unsubstituted CpCg alkyl.
In some embodiments, Ra is CpCg alkyl or halo CpC6 alkyl. In some such
embodiments, Ra is methyl.
In some embodiments, Rb is aryl or heteroaryl. In some such embodiments, Rb is
selected from the'group consisting of phenyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl,
thiazolyl, and thienyl, each of which can be substituted or unsubstituted. In some aspects,
the invention provides compounds wherein the aforementioned Rb groups are substituted
with substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. In other
aspects the Rb groups are substituted with halo. In still other aspects the Rb groups are
substituted with fluoro. In still other aspects, the Rb groups are substituted with alkyl,
haloalkyl, alkoxy, and haloalkoxy. In some aspects, the Rb groups are substituted with
methyl. In other aspects, the Rb groups are substituted with methoxy.
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In other embodiments, Rb is selected from the group consisting of substituted aryl,
substituted heterocyclyl, substituted heteroaryl, substituted C3-C7 cycloalkyl, and
substituted C5-C7 cycloalkenyl, wherein said aryl, heterocyclyl, heteroaryl, C3-C7
cycloalkyl, and C5-C7 cycloalkenyl is selected from the group consisting of pyrrolyl,
phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl,
indolyl, oxadiazole, thiadiazole, furanyl, quinolinyl, isoquinolinyl, isoxazolyl, oxazolyl,
thiazolyl, morpholino, piperidinyl, pyrrolidinyl, thienyl, cyclohexyl, cyclopentyl,
cyclohexenyl, and cyclopentenyl. In some aspects, the aforementioned groups are
substituted with one to two substituents selected from the group consisting of halo, alkoxy,
alkyl, amino, alkylamino, haloalkyl, and haloalkoxy.
In some embodiments, R is selected from the group consisting of hydrogen,
unsubstituted alkyl, and substituted alkyl. In some such embodiments, R is selected from
the group consisting of methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl. In other
embodiments, R is selected from the group consisting of hydrogen, benzyl, l-(4-
methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-morpholinopropyl. In still
other embodiment, R is hydrogen.
In another embodiment, the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
compounds have the formula (II):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof,
wherein
n is 0 or 1,
wherein Ra is selected from the group consisting of
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(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) CrC6 alkoxy,
(5) thiol,
(6) Ci-C6 alkylthiol,
(7) substituted or unsubstituted C i -C(, alky 1,
(8) amino or substituted amino,
(9) substituted or unsubstituted aryl,
(10) substituted or unsubstituted heteroaryl, and
(11) substituted or unsubstituted heterocyclyl;
wherein R is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted (VC6 alkyl,
(3) substituted or unsubstituted C2-Cg alkenyl,
(4) substituted or unsubstituted C2-C$ alkynyl,
(5) substituted or unsubstituted C3-C7 cycloalkyl,
(6) substituted or unsubstituted C5-C7 cycloalkenyl,
(7) substituted or unsubstituted aryl,
(8) substituted or unsubstituted heteroaryl, and
(9) substituted or unsubstituted heterocyclyl,
wherein when n is 1, X is C, Y is at each position independently selected from CQ1
and N, and Z is selected from CR2 and N with the proviso that no more than 3 Y and Z
groups are N, and
wherein when n is 0, X is C or N, Y is at each position independently selected from
CQ1, N, NQ2, O, and S with the proviso that no more than 4 X and Y groups are N and NQ2
and no more than 1 Y group is S or O;
wherein Q1 is at each position independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) substituted or unsubstituted Cj-Cg alkyl,
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(4) substituted or unsubstituted C2-C6 alkenyl,
(5) substituted or unsubstituted C2-Cg alkynyl,
(6) substituted or unsubstituted C3-C7 cycloalkyl,
(7) substituted or unsubstituted C5-C7 cycloalkenyl,
(8) substituted or unsubstituted aryl,
(9) substituted or unsubstituted heteroaryl,
(10) substituted or unsubstituted heterocyclyl,
(11) substituted or unsubstituted amino,
(12) -OR3or-SR3,
(13) -C(O)R3, -CO2R3, -C(O)N(R3)2, -S(O)R3, -SO2R3, or -SO2N(R3)2,
(14) -OC(O)R3, -N(R3)C(O)R3} or -N(R3)SO2R3,
(15) -CN,and
(16) -NO2;
wherein Q2 is at each position independently selected from the group consisting of
(1) hydrogen,
(3) substituted or unsubstituted C^-Cg alkyl,
(4) substituted or unsubstituted Cj-C^ alkenyl,
(5) substituted or unsubstituted C2-CQ alkynyl,
(6) substituted or unsubstituted C3-C7 cycloalkyl,
(7) substituted or unsubstituted C5-C7 cycloalkenyl,
(8) substituted or unsubstituted aryl,
(9) substituted or unsubstituted heteroaryl, and
(10) substituted or unsub stituted heterocyclyl;
wherein R2 is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) substituted or unsubstituted C1-C3 alkyl, and
(4) -OR3,-SR3,or-NHR3;
wherein R3 is at each position independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted CpCg alkyl,
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(3) substituted or unsubstituted C2-Cg alkenyl,
(4) substituted or unsubstituted C2-C6 alkynyl,
(5) substituted or unsubstituted C3-C7 cycloalkyl,
(6) substituted or unsubstituted C5-C7 cycloalkenyl,
(7) substituted or unsubstituted aryl,
(8) substituted or unsubstituted heteroaryl, and
(9) substituted or unsubstituted heterocyclyl,
with the proviso that when Ra is amino, then X, Y, Z, and n together do not form a
phenyl, 4-alkyI-phenyi, 4-alkoxy-phenyi, or 4-haio-phenyl group.
In other embodiments, the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
compounds have the formula (Ha):

or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein Ra, R, X, Y, Z,
and n are previously defined for formula (II) and with the proviso that when Ra is amino,
then X, Y, Z, and n together do not form a phenyl, 4-alkyl-phenyl, 4-alkoxy-phenyl, or 4-
halo-phenyl group.
In some embodiments when n is 0, X is C, and Y adjacent to X is not 0.
In some embodiments of the compounds of formula (II) or (Ha), Ra is hydrogen.
In other embodiments, Ra is substituted or unsubstituted CpCg alkyl.
In some embodiments, Rs is Cj-Cg alkyl or halo Cj-Cg alkyl. In some such
embodiments, Ra is methyl.
For the compounds of formula (I), (la), (II), or (Ila), representative substituted alkyl
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groups include arylalkyl, heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, and sulfonamidoalkyl groups.
Representative aryl groups include phenyl groups.
. Representative heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, pyrazolyl, indolyl, quinolinyl, isoquinolinyl, furanyl, oxazolyl, thiazolyl, and
thienyl groups.
In one embodiment, one of Q1 or Q2 is selected from the group consisting of
substituted and unsubstituted phenyl, substituted and unsubstituted pyridyl, substituted and
unsubstituted pyrimidinyl, substituted and unsubstituted pyrazinyl, substituted and
unsubstituted indolyl, substituted and unsubstituted thiazolyl, and substituted and
unsubstituted thienyl.
In one embodiment, one of Q1 or Q2 is selected from the group consisting of
piperidinyl, morpholinyl, pyrrolidinonyl, and benzyl amino.
In one embodiment, one of Q1 or Q2 is selected from the group consisting of
cyclohexyl and cyclopentyl.
In one embodiment, one of Q1 or Q2 is selected from the group consisting of
cyclohexenyl and cyclopentenyl.
In one embodiment, one of Ql or Q2 is selected from the group consisting of
substituted aryl, substituted heterocyclyl, substituted heteroaryl, substituted C3-C7
cycloalkyl, and substituted C5-C7 cycloalkenyl, wherein said aryl, heterocyclyl, heteroaryl,
C3-C7 cycloalkyl, and C5-C7 cycloalkenyl is selected from the group consisting of pyrrolyl,
phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyi, imidazolyl, triazolyl,
indolyl, oxadiazole, thiadiazole, furanyl, quinolinyl, isoquinolinyl, isoxazolyl, oxazolyl,
thiazolyl, morpholino, piperidinyl, pyrrolidinyl, thienyl, cyclohexyl, cyclopentyl,
cyclohexenyl, and cyclopentenyl. In some aspects, the aforementioned groups are
substituted with one to two substituents selected from the group consisting of halo, alkoxy,
alkyl, amino, alkylamino, haloalkyl, and haloalkoxy.
In one embodiment, one of Q1 or Q2 is selected from substituted and unsubstituted
pyridyl, substituted and unsubstituted pyrazinyl, substituted and unsubstituted phenyl,
substituted and unsubstituted isoquinolinyl, substituted and unsubstituted pyrimidinyl,
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substituted and unsubstituted pyrazolyl, and substituted and unsubstituted furanyl. In some
aspects, the aforementioned groups are substituted with one to two substituents selected
from the group consisting of halo, alkoxy, alkyl, amino, alkylamino, haloalkyl, and
haloalkoxy.
In other embodiments one of Q1 or Q2 is selected from the group consisting of (2-
hydroxy-ethylamino)-pyrazin-2-yl, lH-pyrazol-4-yl, 1 -methyl- lH-pyrazol-4-yl, 1-methyl-
lH-pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-phenyl, 2,3-dimethoxy-
phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-yl, 2,5-
difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl3 2-acetamidophenyl, 2-
aminocarbonylphenyl, 2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-pyrimidin-5-yl, 2-
chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl,
2-difluoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-fluoro-3-methoxy-
phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxy-phenyl, 2-
fluoro-5-methyIphenyl, 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-hydroxymethyl-3-
methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-5-trifluoromethyl-
phenyl, 2-methoxy-phenyl, 2-methoxy-pyridin-3-yl, 2-methoxy-pyrimidin-4-yl, 2-methoxy-
thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-dih.ydro-pyridin-3-yl, 2-
phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-trifhiorornethoxyphenyl, 2-
trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, S.S-dimethyl-isoxazoM-yl, 3,6-dimethyl-
pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl, 3-bromo-phenyl, 3-chloro-
pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-methyl-
phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-fluorophenyl, 3-fluoro-
pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-methoxycarbonylphenyl, 3-methoxyphenyl,
3-methoxy-pyrazin-2-yI, 3-methyl-3H-irnidazo[4,5-b]pyrazin-5-yl, 3-metliylphenyl, 3-
methyl-pyridin-2-yl, 3-trifluoromethoxyphenyl, 3-trifluoromethyIphenyl, 4,5-dimethoxy-
pyrimidin-2-yl, 4-amino-5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-
2-fluoro-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difluoro-2-
methyl-phenyl, 4-ethoxy-5-fluoro-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-
pyrimidin-5-yl, 4-ethyl-lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fiuoro-2-methyl-
phenyl, 4-fluorophenyl, 4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-
methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-
yl, 4-methyl-pyridin-3-yl, 4-pyrrolidin-l-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-
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acetyl-thiophen-2-yl, 5-amino-6-ethoxy-pyrazin-2-yl, 5-arnino-6-methoxy-3-methyl-
pyrazin-2-yl, 5-amino-6-methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-
chloro-6-methoxy-pyrazin-2-yl, 5-dimemylaniino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-
methoxyphenyl, 5-fluoro-4-methoxy-pyriinidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-
fluoro-pyridin-2-yl, 5-methoxy-pyridin-3-yl, 5-methoxy-thiophen-2-yl, 5-trifluoromethyl-
pyrimidin-2-yl, 6-acetyl-pyridin-2-yl5 6-chloro-pyrazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-
ethoxy-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl, 6-
raethoxy-5-methylamino-pyrazin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yl, 6-methoxy-
pyrazin-2-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-
yl, 6-methyl-pyridin-2-yl, 5-amino-6-(2,2,2-trifluoroethoxy)pyrazin-2-yl, and 6-
trifluoromethyl-pyridin-2-yl.
In one embodiment Q1 is halo.
In one embodiment Q1 is alkyl. In some aspects, Q1 is methyl.
In one embodiment, R2 is selected from hydrogen and fluoro. In some aspects, R2 is
fluoro.
In one embodiment, R2 is selected from alkyl. In some aspects, R2 is methyl.
In one embodiment, R2 is selected from alkoxy. In some aspects, R2 is methoxy.
In one embodiment Q1 is OR3.
In one embodiment, R3 is selected from the group consisting of methyl, ethyl,
isopropyl, cyclopentyl, and cyclohexyl.
In one embodiment, R3 is selected from substituted and unsubstituted phenyl,
substituted and unsubstituted thiazolyi, substituted and unsubstituted pyridyl, substituted
and unsubstituted pyrazinyl, and substituted and unsubstituted pyrimidinyl.
In one embodiment, R3 is selected from the group consisting of 2-aminoethyl, 2-
piperidinylethyl, 2-piperazinylethyl, 2-morpholinylethyl, and 2-(N-methylpiperazinyl)ethyl.
In some embodiments, R is selected from the group consisting of hydrogen,
unsubstituted alkyl, and substituted alkyl. In some such embodiments, R is selected from
the group consisting of methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl. In other
embodiments, R is selected from the group consisting of hydrogen, benzyl, l-(4-
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methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-morpholinopropyl.
In another embodiment of the invention, compounds of formula (III) are provided:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof,
wherein
wherein Ra is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) Ci-C6 alkoxy,
(5) thiol,
(6) d-C6 alkylthiol,
(7) substituted or unsubstituted Cj-C^ alkyl,
(8) amino or substituted amino,
(9) substituted or unsubstituted aryl,
(10) substituted or unsubstituted heteroaryl, and
(11) substituted or unsubstituted heterocyclyl;
R4 is hydrogen or substituted or unsubstituted CpCg alkyl;
R5 is hydrogen, alkyl, alkoxy, or halo;
each of R6, R7, R8, and R9 are independently selected from the group consisting of
hydrogen, alkyl, alkoxy, halo, substituted or unsubstituted aryl, and substituted or
unsubstituted heteroaryl; or
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a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, and
with the proviso that when Ra is amino and R6, R7, R8, and R9 are hydrogen, then R5 is not
hydrogen, aikyl, alkoxy, or halo.
In some embodiments, provided are compounds of formula (Ilia):

or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein Ra, R4, R5, R6,
R7, R8, and R9 are as previously defined for formula (111) and with the proviso that when Ra
is amino and R6, R7, R8, and R9 are hydrogen, then R5 is not hydrogen, alkyl, alkoxy, or
halo.
In some embodiments, R8 is hydrogen.
In some embodiments, Ra is substituted or unsubstituted CpCg alkyl.
In some embodiments, Ra is CyC6 alkyl or halo Cj-Cg alkyl. In some such
embodiments, Ra is methyl.
In some embodiments of the invention, R4 is selected from the group consisting of
hydrogen, benzyl, l-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-
morpholinopropyl. In other embodiments, R is selected from the group consisting of
methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl.
In some embodiments, R5 is hydrogen or fluoro. In some aspects, R5 is fluoro.
In some embodiments, R5 is methyl or methoxy.
In some embodiments, R7, R8, and R9 are each hydrogen.
In some embodiments, R6 is aryl or heteroaryl substituted with one to two
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substituents selected from the group consisting of halo, alkoxy, alkyl, amino, alkylamino,
haloalkyl, and haloalkoxy.
In some embodiments R6 is selected from the group consisting of substituted aryl
and substituted heteroaryl, wherein said aryl and heteroaryl is selected from the group
consisting of furanyl, pyrrolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazole, thiadiazole, quinolinyl, isoquinolinyl,
isoxazolyl, oxazolyl, thiazolyl, and thienyl. In some aspects, the aforementioned groups are
substituted with one to two substituents selected from the group consisting of halo, alkoxy,
alkyl, amino, alkylamino, haloalkyl. and haloalkoxy.
In other embodiments R6 is selected from the group consisting of (2-hydroxy-
ethylamino)-pyrazin-2-yl, lH-pyrazol-4-yl, 1 -methyl-lH-pyrazol-4-yl, 1-methyl-lH-
pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-phenyl, 2,3-dimethoxy-phenyl,
2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-yl, 2,5-difluoro-
phenyl, 2,6-difiuoro-phenyl, 2)6-dimethyl-pyridin-3-yl, 2-acetamidophenyl, 2-
aminocarbonylphenyl, 2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-pyrimidin-5-yl, 2-
chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl,
2-difluoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-iTuoro-3-methoxy-
phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxy-phenyl, 2-
fluoro-5-methylphenyl, 2-fluorophenyl, 2-fiuoro-pyridin-3-yl, 2-hydroxymethyl-3-
methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-5-trifluoromethyl-
phenyl, 2-methoxy-phenyl, 2-methoxy-p>Tidin-3-yl, 2-methoxy-pyrimidin-4-yl, 2-methoxy-
thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-dihydro-pyridin-3-yl, 2-
phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-
trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazol-4-yl, 3,6-dimethyl-
pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl5 3-bromo-phenyl, 3-chloro-
pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-methyl-
phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-fluorophenyl, 3-fluoro-
pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-methoxycarbonylphenyl, 3-methoxyphenyl,
3-methoxy-pyrazin-2-yl, 3-methyl-3H-imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl, 3-
methyl-pyridin-2-yl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4,5-dimethoxy-
pyrimidin-2-yl, 4-amino-5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-
2-fluoro-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difluoro-2-
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methyl-phenyl, 4-ethoxy-5-fluoro-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-
pyrimidin-5-yl, 4-ethyl-lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl3 4-fluoro-2-methyl-
phenyl, 4-fluorophenyl, 4-methoxy-5-methyl-pyrirnidin-2-yl, 4-methoxy-pyridin-3-yl, 4-
methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-
yl, 4-methyl-pyridin-3-yl, 4-pyrrolidin-l-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-
acetyl-thiophen-2-yl, 5-amino-6-ethoxy-pyrazin-2-yl, 5-amino-6-methoxy-3-methyl-
pyrazdn-2-yl, 5-amino-6-methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-
chloro-6-methoxy-pyrazin-2-ylJ5-dimethylamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-
methoxyphenyl, 5-fluoro-4-methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-
fluoro-pyridin-2-yl, 5-methoxy-pyridin-3-yl, 5-methoxy-thiophen-2-yl, 5-trifluoromethyl-
pyrimidin-2-yl, 6-acetyl-pyridin-2-yl, 6-chloro-pyrazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-
ethoxy-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl, 6-
methoxy-5 -methylamino-pyrazin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yI, 6-methoxy-
pyraziii-2-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-
yl, 6-methyl-pyridin-2-yl, 5-amino-6-(2,2,2-trifluoroethoxy)pyrazin-2-yl, and 6-
trifluoromethyl-pyridin-2-yl.
In another embodiment of the invention, compounds of formula (FV) are provided:

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof,
wherein
R4 is hydrogen or substituted or unsubstituted CpCg alkyl,
R5 is hydrogen or halo,
R5a is selected from the group consisting of halo, substituted or unsubstituted aryl,
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and substituted or unsubstituted heteroaryl.
In some embodiments provided are compounds of formula (TVa):

or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein
R4, R5, and R6a are as previously defined for formula (IV).
In some embodiments of the compounds of formula (TV) or (TVa), R4 is selected
from the group consisting of hydrogen, benzyl, l-(4-methoxyphenyl)ethyl, methyl, 3-
aminopropyl, and 2-methyl-2-morpholinopropyl. In other embodiments, R is selected
from the group consisting of methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl.
In some embodiments, R5 is hydrogen or fluoro. In some aspects R5 is fluoro.
In some aspects, R6a is aryl or heteroaryl substituted with one to two substituents
selected from the group consisting of halo, alkoxy, alkyl, amino, alkylamino, haloalkyl, and
haloalkoxy.
In some embodiments R a is selected from the group consisting of substituted aryl
and substituted heteroaryl, wherein said aryl and heteroaryl is selected from the group
consisting of furanyl, pyrrolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazole, thiadiazole, quinolinyl, isoquinolinyl,
isoxazolyl, oxazolyl, thiazolyl, and thienyl. hi some aspects, the aforementioned groups are
substituted with one to two substituents selected from the group consisting of halo, alkoxy,
alkyl, amino, alkylamino, haloalkyl, and haloalkoxy.
In some embodiments, R6a is selected from the group consisting of (2-hydroxy-
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WO 2007/041362 PCT/US2006/038181
ethylamino)-pyrazin-2-yl, lH-pyrazol-4-yl, 1 -methyl-lH-pyrazol-4-yl, 1-methyl-lH-
pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-pb.enyl, 2,3-dimethoxy-phenyl,
2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-yl, 2,5-difluoro-
phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-acetamidophenyl, 2-
aminocarbonylphenyl, 2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-pyrimidin-5-yl, 2-
chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl,
2-difluoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-fluoro-3-methoxy-
phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxy-phenyl, 2-
fluoro-5-methylphenyl, 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-hydroxymethyl-3-
methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-5-trifluoromethyl-
phenyl, 2-methoxy-phenyl, 2-methoxy-pyridin-3-yl, 2-methoxy-pyrimidin-4-yl, 2-methoxy-
thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-dihydro-pyridin-3-yl, 2-
phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-
trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazol-4-yl5 3,6-dimethyl-
pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl, 3-bromo-phenyl, 3-chloro-
pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-methyl-
phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-fluorophenyl, 3-flupro-
pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-methoxycarbonylphenyl, 3-methoxyphenyl,
3-methoxy-pyrazin-2-yl, 3-methyl-3H-imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl, 3-
methyl-pyridin-2-yl, 3-trifluoromethoxj-phenyl, 3-trifluoromethylphenyl, 4,5-dimethoxy-
p>Timidin-2-yl, 4-amino-5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-
2-fluoro-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difluoro-2-
methyl-phenyl, 4-ethoxy-5-fluoro-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-
pyrimidin-5-yl, 4-ethyl-lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fluoro-2-methyl-
phenyl, 4-fluorophenyl, 4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-
methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-
yl, 4-methyl-pyridin-3-yl, 4-pyrrolidin-l-yl-pyriniidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-
acetyl-thiophen-2-yl, 5-amino-6-ethoxy-pyrazin-2-yl, 5-amino-6-methoxy-3 -methyl-
pyrazin-2-yl, 5-amino-6-methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-
chloro-6-methoxy-pyrazin-2-yl, 5-dimethylamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-
methoxyphenyl, 5-fluoro-4-methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-
fluoro-pyridin-2-yl, 5-methoxy-pyridin-3-yl, 5-methoxy-thiophen-2-yl, 5-trifluoromethyl-
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pyrimidin-2-yl, 6-acetyi-pyridin-2-yl, 6-chloro-pyrazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-
ethoxy-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl, 6-
methoxy-5-methylamino-pyrazin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yl, 6-methoxy-
pyrazin-2-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-
yl, 6-methyl-pyridin-2-yl, 5-amino-6-(2,2,2-trifluoroethoxy)pyrazin-2-yl, and 6-
trifluoromethyl-pyridin-2-yl.
In another embodiment, provided are compounds having formula (V)

wherein R10 and R11 are independently Q1, and Ra, R, Q1, and Q2 are as previously
defined for formula (II).
In another embodiment, 2-amino-quinazolin-5-one compounds have formula (Va)

wherein R10 and R11 are independently Q1, and R\ R, Q1, and Q2 are as previously
defined for formula (V).
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WO 2007/041J62 PCT/US2006/038181
In some aspects of the compounds of formula (V) and (Va), Ra is methyl.
In other aspects of the compounds of formula (V) and (Va), Ra is hydrogen.
In some aspects of the compounds of formula (V) and (Va), R is selected from the
group consisting of hydrogen, benzyl, l-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl,
and 2-methyl-2-morpholinopropyl. In other aspects, R is selected from the group
consisting of methyl, ethyl, allyl, 3-methyl-butyl, and isobutyl.
. In some aspects of the compounds of formula (V) and (Va), Q2 is selected from the
group consisting of substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted C3-C7
cycloalkyl, and substituted or unsubstituted C5-C7 cycloalkenyl. In other aspects said aryl,
heterocyclyl, heteroaryl, C3-C7 cycloalkyl, and C5-C7 cycloalkenyl is selected from the
group consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl,
imidazolyl, triazolyl, indolyl, oxadiazole, thiadiazole, furanyl, quinolinyl, isoquinolinyl,
isoxazolyl, oxazolyl, thiazolyl, morpholino, piperidinyl, pyrrolidinyl, thienyl, cyclohexyl,
cyclopentyl, cyclohexenyl, and cyclopentenyl. In some aspects, the aforementioned groups
are substituted with one to two substituents selected from the group consisting of halo,
alkoxy, alkyl, amino, alkylamino, haloalkyl, and haloalkoxy.
In other aspects of the compounds of formula (V) and (Va), Q2 is selected from the
group consisting of (2-hydroxy-ethylarnino)-p>Tazin-2-yl, lH-pyrazol-4-yl, 1-methyl-1H-
pyrazol-4-yl, 1 -methyl-lH-pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-
phenyl, 2,3-dimethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-
pyrimidin-5-yl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-
acetamidophenyl, 2-aminocarbonylphenyl, 2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-
pyrimidin-5-yl, 2-chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-
chloro-pyridin-4-yl, 2-difluoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-
fluoro-3-methoxy-phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-
methoxy-phenyl, 2-fluoro-5-methylphenyl, 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-
hydroxymethyl-3-methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-
5-trifluoromethyl-phenyl, 2-methoxy-phenyl, 2-methoxy-pyridin-3-yl, 2-methoxy-
pyrimidin-4-yl, 2-methoxy-thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-
dihydro-pyridin-3-yl, 2-phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-
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WO 2007/041362 PCT/US2006/038181
trifluoromethoxyphenyl, 2-trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-
isoxazol-4-yl, 3,6-dimethyl-pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl, 3-
bromo-phenyl, 3-chloro-pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-
phenyl, 3-ethyl-4-methyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-
fluorophenyl, 3-fluoro-pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-
methoxycarbonylphenyl, 3-methoxyphenyl, 3-methoxy-pyrazin-2-yl, 3-methyl-3H-
imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl, 3-methyl-pyridin-2-yl, 3-
trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4,5-dimethoxy-pyrimidin-2-yl, 4-amino-
5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 4-
chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difIuoro-2-methyl-phenyl, 4-
ethoxy-5-fluoro-p>Timidin-2-yl, 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-pyrimidin-5-yl, 4-ethyl-
lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fluoro-2-methyl-phenyl, 4-fluorophenyl, 4-
methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-methoxy-pyriraidin-2-yl, 4-
methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-yl, 4-methyl-pyridin-3-yl, 4-
pyrrolidin-l-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-acetyl-thiophen-2-yl, 5-
amino-6-ethoxy-pyrazin-2-yl, 5-amino-6-methoxy-3-methyl-pyrazin-2-yl, 5-amino-6-
methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-chloro-6-methoxy-pyrazin-2-
yl, 5-dimethylamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-methoxyphenyl, 5-fluoro-4-
methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-fluoro-pyridin-2-yl, 5-
methoxy-pyridin-3-yl, 5-methoxy-thiophen-2:yl, S-trifluoromethyl-pyrimidin^-yl, 6-acetyl-
p>Tidin-2-yl, 6-chloro-pyrazin-2-yl, 6-ethoxy-pyra2dn-2-yl, 6-ethoxy-pyridin-2-yl, 6-fluoro-
pyridin-2-yl, 6-fluoro-pyridin-3-yl? 6-hydroxy-pyridin-2-yl, 6-methoxy-5-methylamino-
pyrazin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl, 6-methoxy-
pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-yl, 6-methyl-pyridin-2-yl,
5-amino-6-(2,2,2-trifluoroethoxy)pyrazin-2-yl, and6-trifluoromethyl-pyridin-2-yl.
In one embodiment of the compounds of formula (V) and (Va), R9 and R10 are
hydrogen. In another aspect one of R9 or R10 is hydrogen and the other is halo or C1-C6
alkoxy. In some aspects, one of R9 or R10 is fluoro. In other aspects one of R9 or R10 is
methoxy.
In one embodiment, the present invention provides a compound or a stereoisomer,
tautomer, pharmaceutically acceptable salt, or prodrug thereof selected from the group
consisting of the compounds in Example 9, Tables 1-5.
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In another embodiment, the present invention provides a compound or a
stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof selected from
the group consisting of
(R)-2-amino-7-[2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido[4,3 -d]pyrimidin-5 -one;
(S)-2-amino-6-benzyl-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4s3-d]pyrimidin-5-one;
(R)-2-amino-7-[4-fluoro-2-(2-fiuoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one;
(R)-2-amino-7-(2-bromo-4-fluoro-phenyl)-6-[(S)-l-(4-methoxy-phenyl)-ethyl]-4-
methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
(R)-2-amino-7-[2-(6-methoxy-pyridin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin-5 -one;
(R)-2-amino-7-[4-fluoro-2-(6-methoxy-pyridin-2-yl)-phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(6-methoxy-pyridin-2-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-
6H-pyrido[433-d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4,6-dimethyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(6-methoxypyridin-2-yl)phenyl]-4-methyl-7,8-
dihydropyrido[4,3-c(]pyrimidin-5(6//)-OIle;
2-amino-7-[2-(6-methoxy-p>Tazin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one;
(R)-2-amino-7-[4-fluoro-2-(6-methoxy-pyrazin-2-yl)-phenyl]-4-methyl-7,8-dihydro-
6H-pyrido [4,3 -d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(6-methoxy-pyrazin-2-yl)-phenyl]-456-dimethyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-[2-(2-methoxy-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin-5 -one;
2-amino-7-(5,2'-difluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one;
2-amino-7-(5-fluoro-2'-tiifluoromethoxy-biphenyl-2-yl)-4-methyl-7,8-diriydro-6H-
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pyrido [4,3 -d]pyrimidin-5-one;
2-amino-7-[2-(2-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin- 5 -one;
2-amino-7-[4-fluoro-2-(6-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-(4-fluoro-2-isoquinolin-4-yl-phenyl)-4-methyl-7,8-diliydro-6H-
pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-(5,3'-difluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[453-
d]pyrimidin-5-one;
2-amino-7-[2-(4-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin-5 -one;
2-amino-7-(5,2'-difluoro-3'-methoxy-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-(5,4'-difluoro-2'-methyl-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin-5 -one;
2-amino-7-(5-fluoro-2'-methoxy-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin-5 -one;
2-amino-7-(4-fluoro-2-pyrimidin-5-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(2-methoxy-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-(5-fluoro-3'-methoxy-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin-5 -one;
(R)-2-aniino-6-(3-arnino-propyl)-7-[4-fluoro-2-(6-methoxy-pyridin-2-yl)-phenyl]-4-
methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5 -one;
2-amino-7-(5,2'-difluoro-4'-methyl-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
pyrido [4,3 -d]pyrimidin-5 -one;
2-amino-7-[4-fluoro-2-(l-methyl-lH-pyrazol-4-yl)-phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(lH-pyrazol-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
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pyrido [4,3 -d]pyrimidin-5 -one;
2-amino-4-methyl-7-(5,2'53'-trifluoro-biphenyl-2-yl)-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one;
2-amino-7-(2-bromo-4-fluoro-phenyl)-4-methyl-6-(2-methyl-2-morpholin-4-yl-
propyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-(3'-dimethylamino-5-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-[2-(2,4-dimethoxy-pyrimidin-5-yl)-4-fluoro-phenyl]-4-methyl-7J8-
dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(5-methoxy-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
pyrido[4,3 -d]pyrimidin-5-one;
2-amino-7-(4-fluoro-2-pyrimidin-5-yl-phenyl)-4-methyl-6-(2-methyl-2-morpholiii-
4-yl-propyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-[4-fluoro-2-(2-methoxy-pyridin-3-yl)-phenyl]-4-methyl-6-(2-methyl-2-
morpholin-4-yl-propyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
2-amino-7-(5-fluoro-3'-methoxy-biphenyl-2-yl)-4-methyl-6-(2-methyl-2-morph.olin-
4-yl-propyl)-7,8 -dihydro-6H-pyrido [4,3 -d]pyrimidin-5 -one;
(R)-2-amino-7-[4-fluoro-2-(4-methoxy-5-methyl-pyrimidin-2-yl)-phenyl]-4-methyl-
7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; and
2-amino-7-(4-fluoro-2-furan-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-p>-rido[4,3-
d]pyrimidin-5-one.
In another embodiment, the compounds of the present invention exhibit helical
asymmetry. More particularly, the compounds of the present invention may be
atropisomers, which is a subclass of conformers that can be isolated as separate chemical
species and which arise from restricted rotation about a single bond.
In other aspects, the present invention provides methods for manufacture of 2-
amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds. Methods of making
representative compounds of the invention are described in Examples 1-8. 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.
In other aspects, the present invention provides compositions that include the
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HSP90 inhibitors described herein, and methods that utilize the HSP90 inhibitors described
herein.
In one aspect, the present invention provides pharmaceutical compositions
comprising at least one 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compound
(e.g., a compound of formula (I), (la), (II), (Ila), (Til), (Ilia), (TV), (TVa), (V), or (Va)) or a
stereoisomer, tautomer, or pharmaceutical acceptable salt or prodrug thereof 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 2-amino-7,8-dihydro-6H-p>Tido[4,3-d]pyrimidin-5-
one compounds of the invention are known to those skilled in the art.
In certain embodiments, anticancer agents to be used in combination with 2-amino-
7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one 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 Endothelial Growth Factor Receptor [VEGFR] 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 or Glivec]); antisense molecules; antibodies [e.g., Herceptin and Rituxan]; anti-
estrogens [e.g., raloxifene and tamoxifen]; anti-androgens [e.g., flutamide, bicalutamide,
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finasteride, amino-glutethamide, ketoconazole, and corticosteroids]; cyclooxygenase
2 (COX-2) inhibitors [e.g., Celecoxib, meloxicam, NS-398, and non-steroidal
anti-inflammatory drugs (NSAIDs)]; and cancer chemotherapeutic drugs [e.g., irinotecan
(Camptosar), CPT-11, fludarabine (Fludara), dacarbazine (DTIC), dexamethasone,
mitoxantrone, Mylotarg, VP-16, cisplatinum, 5-FU, Doxrubicin, Taxotere or Taxol];
cellular signaling molecules; ceramides and cytokines; and staurosparine; and the like.
In other aspects, the invention provides methods for using the compounds and
compositions described herein. For example, the compounds and compositions described
herein can be used in the treatment of cancer. The compounds and compositions 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 an 2-amino-
7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compound or composition (e.g., a compound
or composition of formula (I), (la), (II), (Ha), (HI), (Ilia), (IV), (TVa), (V), or (Va)), 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, administering to said subject an amount of an 2-amino-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one compound or composition (e.g., a compound or composition
of formula (I)-(V)) 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 an 2-amino-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one compound (e.g., a compound of formula (I), (la), (II), (Ha),
(III), (Ilia), (IV), (FVa), (V), and (Va)) 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 HSP90. The
inhibitors are useful in pharmaceutical compositions for human or veterinary use where
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inhibition of HSP90 is indicated, e.g., in the treatment of cellular proliferative diseases such
as tumor and/or cancerous cell growth mediated by HSP90. 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 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
HSP90 mediated disorder. In one method, an effective amount of an 2-amino-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one compound (e.g, a compound of formula (I), (la), (II),
(Ha), (III), (Ilia), (IV), (IVa), (V), and (Va)) is administered to a patient (e.g., a human or
animal subject) in need thereof to mediate (or modulate) HSP90 activity. In some aspects,
the HSP90 mediated disorder is a cellular proliferative, viral, autoimmune, cardiovascular,
and central nervous system disorder.
In another embodiment, the invention provides methods of treating a cellular
proliferative, viral, autoimmune, cardiovascular, or central nervous system disorder. In one
method, an effective amount of a2-ammo-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
compound (e.g, a compound of formula (I), (la), (II), (Ha), (III), (ma), (IV), (IVa), (V), and
(Va)) is administered to a patient (e.g., a human or animal subject) in need thereof to treat a
cellular proliferative, viral, autoimmune, cardiovascular, and central nervous system
disorder.
A representative assay for determining HSP90 inhibitory activity is described in
Example 10. In a preferred embodiment, the 2-amino-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one compounds of the invention have an IC50 value for inhibiting HSP90
activity less than or equal to 100 uM. In more preferred embodiments, the IC50 value is less
than or equal to 50 uM, even more preferred with an IC50 value less than or equal to 25 uM.
Still more preferred embodiment have IC50 values less than or equal to 10 uM, and even
more preferred embodiments have IC50 values less than or equal to 1 uM.
The following definitions are provided to better understand the invention.
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"Alkyl" or "unsubstituted alkyl" refers to saturated hydrocarbyl 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)(CH2CH3),
-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. 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 having 1 to 12,1 to 6, or 1 to
3 carbon atoms.
"Alkylene" or "unsubstituted alkylene" refers to the same residues as noted above
for "alkyl," but having two points of attachment. Exemplary alkylene groups include
ethyiene (-CH2CH2-), propylene (-CH2CH2CH2-), and dimethylpropylene (-
CH2C(CH3)2CH2-).
"Alkenyl" or "unsubstituted alkenyl" refers to straight chain and branched, chain
hydrocarbyl radicals having one or more carbon-carbon double bonds and from 2 to about
20 carbon atoms. Preferred alkenyl groups include straight chain and branched alkenyl
groups having 2 to 12, or 2 to 6 carbon atoms.
"Alkynyl" or "unsubstituted alkynyl" refers to straight chain and branched chain
hydrocarbyl 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, or 2 to 6 carbon atoms.
"Cycloalkyl" or "unsubstituted cycloalkyl" refers to a mono- or polycyclic alkyl
substituent. Representative cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. Preferred cycloalkyl groups have 3 to 7 carbon
atoms.
"Cycloalkenyl" or "unsubstituted cycloalkenyl" refers to a mono- or polycyclic alkyl
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subsutuents navmg at least one ring carbon-carbon double bond. Preferred cycloalkenyl
groups have 5 to 7 carbon atoms and include cyclopentenyl and cyclohexenyl.
"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 or non-carbon
atoms such as, but not limited to, a halogen atom such as F, Cl, 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, sulfone, sulfonyl, and sulfoxide
groups; a nitrogen atom in groups such as amino, amido, alkylamino, arylamino,
alkylarylamino, diarylamino, N-oxides, imides, and enamines. 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; or 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, cycloalkyl, or cycloalkenyl 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
amino, or a substituted or unsubstituted alkylamino, arylamino, heterocyclylamino. 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: -(CH2)3NH2, -(CH2)3NH(CH3),
-(CH2)3NH(CH3)2, -CH2C(=CH2)CH2NH2> -CH2C(=O)CH2NH2, -CH2S(=O)2CH3i
-CH2OCH2NH2, -CH2CO2H. Examples of substituents of substituted alkyl are: -CH2OH,
-OH, -OCH3, -OC2H5, -OCF3, OC(=O)CH3, -OC(=O)NH2,-OC(=O)N(CH3)2,-CN, -NO2,
-C(=O)CH3, -CO2H, -CO2CH3, -CONH2, -NH2, -N(CH3)2, -NHSO2CH3, -NHCOCH3,
-NHC(=O)OCH3, -NHSO-2CH3, -SO2CH3, -SO2NH2, and halo.
"Substituted alkenyl" has the same meaning with respect to unsubstituted alkenyl
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groups that substituted alky! groups has 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 unsubstituted alkynyl
groups that substituted alkyl groups has 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.
"Substituted cycloalkyl" has the same meaning with respect to unsubstituted
cycloalkyl groups that substituted alkyl groups has with respect to unsubstituted alkyl
groups.
"Substituted cycloalkenyl" has the same meaning with respect to unsubstituted
cycloalkenyl groups that substituted alkyl groups has with respect to unsubstituted alkyl
groups.
"Aryl" or "unsubstituted aryl" refers to monocyclic and polycyclic aromatic groups
that do not contain ring heteroatoms. Such groups can contain from 6 to 14 carbon atoms
but preferably 6. Exemplary aryl moieties employed as substiruents in compounds of the
present invention include phenyl, naphthyl, and the like.
"Aralkyl" or "arylalkyl" refers to an alkyl group substituted with an aryl group as
defined above. 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 and the like. "Heteroarylalkyl" or "heteroaralkyl" refers to an alkyl group
substituted with a heteroaryl group as defined above. Typically, heteroarylalkyl 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 heteroarylalkyl groups
employed in compounds of the present invention include, for example, picolyl and the like.
"Alkoxy" refers to R20O- wherein R20 is C1-C7 alkyl or substituted alkyl. In some
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embodiments", K*u is U1-C6 alkyl. Representative examples of alkoxy groups include
methoxy, ethoxy, t-butoxy, trifluoromethoxy, and the like.
"Amino" refers herein to the group -NH2.
"Substituted amino" refers to the group -NR60R61 where R60 and R61 are
independently selected from the group consisting of hydrogen, alkyl, substituted alkyl,
alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,
substituted cycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted
heterocyclic, -SC^-alkyl, -S02-substituted alkyl, and where R60 and R61 are joined, together
with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group
provided that R60 and R61 are both not hydrogen. When R60 is hydrogen and R61 is alkyl,
the substituted amino group is sometimes referred to herein as alkylamino. When R60 and
R61 are alkyl, the substituted amino group is sometimes referred to herein as dialkylamino.
When referring to a monosubstituted amino, it is meant that either R60 and R61 is hydrogen
but not both. When referring to a disubstituted amino, it is meant that neither R60 and R61 is
hydrogen. The term "alkylamino" refers herein to the group -NR60R61 where R60 is C1-C7
alkyl and R60 is hydrogen or C1-C7 alkyl. The term "dialkylamino" refers to the group -
NR60R61 where R60 and R61 are C1-C7 alkyl. The term "arylamino" refers herein to the
group -NR60R61 where R60 is C5-C7 aryl and R61 is hydrogen, C1-C7 alkyl, or C5-C7 aryl.
The term "aralkylamino" refers herein to the group -NR60R61 where R60 is aralkyl and R61 is
hydrogen, CpCy alkyl, C5-C7 aryl, or C5-C7 aralkyl.
'Amidino" refers to the moieties R40-C(=N)-NR41- (the radical being at the
"N1" nitrogen) and R40(NR41)C=N- (the radical being at the "N2" nitrogen), where R40 and
R41 can be hydrogen, C1-C7 alkyl, aryl, or C5-C7 aralkyl.
"Alkoxyalkyl" refers to the group -alki-O-alk2 where alki is C1-C7 alkyl, and a&2 is
C1-C7 alkyl. The term "aryloxyalkyl" refers to the group -{C1-C7 alkyl)-O-(C5-C7 aryl).
"Alkoxyalkylamino" refers herein to the group -NR27-(alkoxyalkyl), where R27 is
typically hydrogen, C5-C7 aralkyl, or C1-C7 alkyl.
"Aminocarbonyl" refers herein to the group -C(0)-NH2. "Substituted
aminocarbonyl" refers herein to the group -C(O)-NR28R29 where R28 is C1-C7 alkyl and R29
is hydrogen or C1-C7 alkyl. The term "arylarninocarbonyr1 refers herein to the group -C(O)-
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NRJURJI~\vhefe K™ is C5-C7 aryl and R31 is hydrogen, d-C7 alkyl or C5-C7 aryl.
"Aralkylaminocarbonyl" refers herein to the group -C(O)-NR32R33 where R32 is C5-C7
aralkyl and R33 is hydrogen, C1-C7 alkyl, C5-C7 aryl, or C5-C7 aralkyl.
"Aminosulfonyl" refers herein to the group -S(O)2-NH2. "Substituted
aminosulfonyl" refers herein to the group -S(O)2-NR34R35 where R34 is C1-C7 alkyl and R35
is hydrogen or C1-C7 alkyl. The term "aralkylaminosulfonlyaryl" refers herein to the group
-(C5-C7 aryl)-S(O)2-NH-aralkyl.
"Aryloxy" refers to R50O- wherein R50 is aryl.
"Carbonyl" refers to the divalent group -C(O)-. "Alkylcarbonyl' refers to the group
-C(O)alkyl. "Arylcarbonyl" refers to the group -C(O)aryl. Similarly, the term
"heteroarylcarbonyl", "aralkylcarbonyl", and "heteroaralkylcarbonyl" refers to -C(O)-R
where R is respectively heteroaryl, aralkyl, and heteroaralkyl.
"Carbonyloxy" refers generally to the group -C(O)-O-. Such groups include esters,
-C(O)-O-R36, where R36 is CrC7 alkyl, C3-C7 cycloalkyl, aryl, or C5-C7 aralkyl. The term
"arylcarbonyloxy" refers herein to the group -C(O)-O-(aryl). The term "aralkylcarbonyloxy"
refers herein to the group -C(O)-O-(C5-C7 aralkyl).
"Cycloalkylalkyl" refers to an alkyl group substituted with a cyloalkyl group as
defined above. Typically, cycloalkylalkyl groups have from 1 to 6 carbon atoms
incorporated within the alkyl portion of the cycloalkylalkyl group.
"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 C1-C7 alkyl, aryl, or
C5-C7 aralkyl group. Carbonylamino groups include moieties such as carbamate esters
(-NH-C(O)-O-R28) and amido -NH-C(O)-R28, where R28 is a straight or branched chain
C1-C7 alkyl, C3-C7 cycloalkyl, or aryl or C5-C7 aralkyl. The term "alkylcarbonylamino"
refers to the group -NH-C(O)-R where R is alkyl having from 1 to about 7 carbon
atoms in its backbone structure. The term "arylcarbonylamino" refers to group
-NH-C(O)-R29 where R29 is C5-C7 aryl. Similarly, the term "aralkylcarbonylamino" refers
to carbonylamino where R29 is C5-C7 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
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tormal double bond "(the 1T2"-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 substiruent, such as
C1-C7 alkyl, aryl, or C5-C7 aralkyl.
"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.
"Haloalkyl" groups include -CF3. The term "haloalkoxy" refers to an alkoxy radical
substituted with one or more halogen atoms. "Haloalkoxy" groups include -OCF3 and
-OCH2CF3.
"Hydroxyl" or "hydroxy" refers to the group -OH.
"Heterocyclic" or "unsubstituted heterocyclic group," "heterocycle" or
"unsubstituted heterocycle," and "heterocyclyl" or "unsubstituted heterocyclyl,"
"heterocycloalkyl" or "unsubstituted heterocycloalkyl group," as used herein refers to any
non-aromatic monocyclic or polycyclic ring compounds containing a heteroatom selected
from nitrogen, oxygen, or sulfur. Examples include 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 0-1 double bonds and the 6-membered
ring has 0-2 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 provided that the
point of attachment is through the heterocyclic ring.
Heterocyclic moieties can be, for example monosubstituted or disubstituted with
various substituents independently selected from but not limited to hydroxy, alkoxy, halo,
oxo (C=O), alkylimino (R31N=, wherein R31 is alkyl or alkoxy group), amino, alkylamino,
acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, alkyl, cycloalkyl or haloalkyl.
The heterocyclic groups may be attached at various positions as shown below 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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"Heteroaryl" or "unsubstituted heteroaryl" refers herein to an aromatic group having
from 1 to 4 heteroatoms as ring atoms in an aromatic ring with the remainder of the ring
atoms being carbon atoms. The term "heteroaryl" includes rings in which nitrogen is the
heteroatom as well as partially and fully-saturated rings 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., provided that the point of attachment is
through the heteroaryl ring. 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. Representative
substituted and unsubstituted heteroaryl groups include, for example, those found in the
compounds disclosed in this application and in the examples shown below

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Preferred heterocycles and heteroaryls have 3 to 14 ring atoms and include, for
example: diazapinyl, pyrroyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazoyl,
imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, azetidinyl, pyrimidinyl,
pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl,
thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl,
benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, triazolyl, quinoxalinyl,
phthalazinyL naphthpyridinyl, indazolyl, and benzothienyl.
"HeteroarylalkyI" or "heteroaralkyl" refers to an alkyl group substituted with a
heteroaryl group as defined above. Typically, heteroarylalkyl groups have from 1 to 6
carbon atoms incorporated within the alkyl portion of the heteroarylalkyl group.
"Imino" refers to the group =NH.
"Nitro" refers to the group NO2.
"Sulfonyl" refers herein to the group -SO2-. "Alkylsulfonyl" refers to a substituted
sulfonyl of the structure -SO2R52- in which R52 is C1-C7 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.,
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where"FL52'"is methyl), ethylsulfonyl (i.e., where R52 is ethyl), propylsulfonyl (i.e., where R52
is propyl), and the like. The term "arylsulfonyl" refers herein to the group -SO2-aryl. The
term "heterocyclylsulfonyl" refers herein to the group -SO2-heterocyclyl. The term
"aralkylsulfonyl" refers herein to the group -SO2-aralkyl. The term "sulfonamido" refers
herein to -SO2NH2. The term "sulfonamidoalkyl" refers to (alkyl)SO2NH2-.
"Thio" or "thiol" refers to the group -SH. "Alkylthio" or "alkylthiol" refers to a
thio group substituted with an alkyl group such as, for example, a Ci-C& alkyl group.
"Thioamido" refers to the group -C(=S)NH2.
"Optionally substituted1' refers to the optional replacement of hydrogen with a
monovalent or divalent radical. "Substituted" refers to the replacement of hydrogen with a
monovalent or divalent radical. Unless indicated otherwise, suitable substitution groups
include, for example, hydroxyl, alkoxy, nitro, amino, imino, cyano, halo, thio, sulfonyl,
thioamido, amidino, oxo, oxamidino, methoxamidino, guanidino, sulfonamido, carboxyl,
formyl, alkyl, haloalkyl, alkylamino, haloalkylamino, alkoxy, haloalkoxy, alkoxy-alkyl,
alkylcarbonyl, aminocarbonyl, arylcarbonyl, aralkylcarbonyl, heteroarylcarbonyi,
heteroaralkyl-carbonyl, alkylthio, aminoalkyl, cyanoalkyl, aryl and the like. Other suitable
substitution groups include those substituents indicated for substituted alkyl. Examples of
various suitable substitution groups are also found in reference to the compounds disclosed
throughout this application.
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, -SR42, thioamido, -SO3H, -SO2R42, or cycloalkyl, where R42 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.
Unless indicated otherwise, the nomenclature of substituents that are not explicitly
defined herein are arrived at by naming the terminal portion of the functionality followed by
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the adjacent functionality toward the point of attachment. For example, the substituent
"alkoxyheteroaryl" refers to the group (alkoxy)-(heteroaryl)-.
Preferred compounds of the invention have a total molecular weight less than 1000
Daltons, preferably less than 750 Daltons. Compounds of the invention typically have a
minimum molecular weight of at least 150 Daltons. Preferred embodiments of the invention
have a molecular weight between 150 and 750 Daltons, more preferred embodiments have a
molecular weight between 200 and 500 Daltons. Other embodiments of the invention are
compounds with a molecular weight between 300 and 450 Daltons. In another aspect of the
invention compounds of the invention have a molecular weight between 350 and 400
Daltons.
Similarly, it is understood that the above definitions are not intended to include
impermissible substitution patterns (e.g., methyl substituted with 5 fluoro groups). Such
impermissible substitution patterns are well known to the skilled artisan.
"Carboxy-protecting group" refers to a carbonyl group which has been esterified
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
enantiomers, as well as enantiomers 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, FUNDAMENTAL STEREOCHEMISTRY,"
Pure Appl Chem. 45:13-30,1976. The terms a and P are employed for ring positions of
cyclic compounds. The ct-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 p descriptor. It should be noted that this usage
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WO 2007/041362 PCT/US2006/038181
differs from that for cyclic stereoparents, in which "a" means "below the plane" and denotes
absolute configuration. The terms a and p 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 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-
one compounds of the invention. These salts can be prepared in situ during the final
isolation and purification of the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
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, cam'phorsulfonate, digluconate, cyclopentanepropionate,
dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemi-sulfate,
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, tlie 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 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
compounds, 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 organic primary, secondary or tertiary amine. Pharmaceutically
acceptable salts include, but are not limited to, cations based on the alkali and alkaline earth
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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, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other
representative organic amines useful for the formation of base addition salts include
diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, and the like.
The term "pharmaceutically 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 the parent compound of the above
formula, for example by hydrolysis in blood. A thorough discussion is provided in
Higuchi, T., and V. Stella, "Pro-drugs as Novel Delivery Systems," A.C.S. Symposium
Series 14, and in "Bioreversible 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 "HSP90 mediated disorder" refers to a disorder that can be beneficially
treated by the inhibition of HSP90.
The term "cellular proliferative diseases" refers to diseases including, for example,
cancer, tumor, hyperplasia, restenosis, cardiac hypertrophy, immune disorder and
inflammation.
The term "cancer" refers to cancer diseases that can be beneficially treated by the
inhibition of HSP90, 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 myelognous 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
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growth of cancer cells. The compounds may be used alone or in compositions together with
a pharmaceutically acceptable carrier or excipient. Suitable pharmaceutically 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, sodium
carboxymethyl cellulose, dextrose, hydroxypropyl-p-cyclodextrin, polyvinyl-pyrrolidinone,
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 detectably inhibit HSP90 activity by any of the assays described herein, by
other HSP90 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 1000 mg/kg body weight daily and more preferred from 1.0 to
30 mg/kg body weight daily. Dosage unit compositions may contain such amounts of
submultiples thereof to make up the daily dose.
rhe 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,
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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,
intrastemal 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
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
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Uposomes. 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 XTV, Academic Press, New York, 1976, p. 33 et seq.
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, gefitinib, vatalanib, sunitinib, sorafenib, erlotinib, dexrazoxane,
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
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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 refactory breast
cancer cell lines and in so doing restored hormone sensitivity. Accordingly, in one aspect,
the compounds of formula (I), (la), (II), (Ha), (III), (Ilia), (TV), (IVa), (V), or (Va) 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.
In hematological cancers, such as chronic myelogenous leukemia (CML),
chromosomal translocation is responsible for the constitutively activated BCR-ABL
tyrosine kinase. The afflicted patients are responsive to gleevec, a small molecule tyrosine
kinase inhibitor, as a result of inhibition of Abl 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), (la), (II), (Ila), (III), (Ilia), (IV), (IVa), (V), or
(Va) 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 2-amino-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one compound of the invention (e.g., a compound of formula (I), (la), (II),
(Ila), (III), (Ilia), (IV), (IVa), (V), or (Va)) and a package insert or other labeling including
directions for treating a cellular proliferative disease by administering an HSP90 inhibitory
amount of the compound.
The synthesis of representative 2-amino-7>8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-
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one compounds are described in Examples 1-8. Representative 2-amino-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one compounds that were prepared are shown in Tables 1-5 in
Example 9.
In one aspect, certain compounds of the invention having a substituted 7-phenyl
moiety can be prepared as shown in Scheme 1. Benzyl amine 1-C, prepared from cbiral
amine 1-A by reductive amination, and cinnamate 1-D, prepared from a Wadsworth
Emmons homologation of aldehyde 1-B, are coupled to give the conjugate addition product
1-E (Steven D. Bull, Stephen G. Davies, Santiago Delgado-Ballester, Peter M. Kelly, Luke
J. Kotchie, Massimo Gianotti, Mario Laderas and Andrew D. Smith, J. Chem. Soc, Perkin
Trans. 1,2001, (23), 3112). Removal of the benzyl group is accomplished using 1.1 eq. of
cerric ammonium nitrate in acetonitrile and water. Resulting amine 1-F is acylated with
methyl malonyl chloride 1-G to give compound 1-H. Cyclization is effected via a
Dieckmann condensation upon treatment with base such as sodium ethoxide. The resulting
lactam is then treated with acid such as HC1 to effect decarboxylation and afford compound
1-1. O-acylation with acetyl chloride and treatment with catalytic dunethylaminopyridine in
boiling solvent such as acetonitrile or toluene to effect migration of the acetate group gives
compound I-J. Pyrimidine I-K is formed by treating I-J with guanidine/EtOH and
dimethylamine. The para-methoxybenzyl group can be removed at this stage (or after the
Suzuki coupling) with cerric ammonium nitrate or trifluoroacetic acid. The phenyl ring of
I-K can optionally be functionalized via a Suzuki coupling with a suitable boronic acid to
give the biaryl compound I-L. Subsequent deprotection of thepara-methoxybenzyl group
gives amine I-M.
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In another aspect, certain compounds of the invention can be prepared as shown in
Scheme 2. Condensation of an appropriate amine such as methyl amine with oxalic acid
and a desired aldehyde such as 2-A in refluxing ethanol results in formation of acid 2-B,
that is next converted to the corresponding ester 2-C under esterification conditions such as
with thionyl chloride in an appropriate alcoholic solvent at 0 °C. Formation of acetoamide
2-E is accomplished by treatment of the 2-C ester with diketene 2-D. Subsequent
cyclization of 2-D in the presence of base such as sodium methoxide and with microwave
heating produces lactam 2-F. Aminopyridine formation is accomplished in two steps, the
first being formation of an intermediate enamine by heating the lactam in an ethanolic
solution of pyrrolidine under microwave conditions and secondly, addition of guanidine-
HC1 to this solution followed by additional microwave heating. Isolation of the
aminopyrimidine 2-G by reverse phase HPLC followed by coupling with an appropriate
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arylboromc acid under Suzuki conditions and microwave heating gives the biaryl compound
2-H.

Scheme 3 shows another means for synthesizing certain compounds of the
invention. Reductive amination of p-anisole 3-A with (S)-l-(4-methoxyphenyl)ethanamine
3-B and sodium borohydride over molecular sieves gives amine 3-C. Subsequent formation
of the amine anion such as by reacting 3-C with n-butyl lithium and treatment with the
appropriate cinnamate ester 3-D gives the conjugate addition product 3-E. Deprotection
with trifluoroacetic acid gives amine 3-F that can be converted to 3-1 following the steps
shown in the Scheme 2 and described above.
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In one embodiment, provided is a method of preparing a compound of formula (I),
comprising
(a) reacting a compound of formula (I) with an acid to form an acid addition
salt; or
(b) reacting an acid addition salt of formula (I) to form a free base compound of
formula (I); or
(c) reacting an intermediate compound of formula (VI) with guanidine or a
guanidine derivative

wherein Ra, R, and Rb are as defined for formula (I) and W is O or NR'R" where R1
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WO 2007/041362 PCT/US2006/038181
and R" are independently H or alkyl to form a compound of formula (I).
In one embodiment, provided is an intermediate compound of formula (VI). In one
aspect, Ra is methyl. In another aspect, the intermediate compound of formula (VI) is a
compound of formula (VII)

R is as defined for formula (VI);
R5 is hydrogen or halo; and
R6a is selected from the group consisting of halo, substituted or unsubstituted aryl,
and substituted or unsubstituted heteroaryl.
In some embodiments of the compounds of formula (VI) or (VII), R is selected from
the group consisting of hydrogen, unsubstituted alkyl, and substituted alkyl. In some such
embodiments, R is selected from the group consisting of methyl, ethyl, allyl, 3-methyl-
butyl, and isobutyl. In other embodiments, R is selected from the group consisting of
hydrogen, benzyl, l-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-
morpholinopropyl. In still other embodiment, R is hydrogen.
In some embodiments, R5 is halo. In some aspects R5 is fluoro.
In other embodiments R5 is hydrogen.
In some embodiments, R6a is halo. In some aspects R6a is bromo.
In some embodiments R5 and R6a are both halo. In other embodiments R5 is fluoro
and R6a is bromo.
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In some embodiments R6a is selected from the group consisting of substituted aryl
and substituted heteroaryl wherein said aryl and heteroaryl is selected from the group
consisting of furanyl, pyrrolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazole, thiadiazole, quinolinyl, isoquinolinyl,
isoxazolyl, oxazolyl, thiazolyl, and thienyl.
In some embodiments, R6a is selected from the group consisting of (2-hydroxy-
ethylamino)-pyrazin-2-yl, lH-pyrazol-4-yl, 1 -methyl- lH-pyrazol-4-yl, 1-methyl-1H-
pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-phenyl, 2,3-dimethoxy-phenyl,
2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-yl, 2,5-difluoro-
phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-acetamidophenyl, 2-
aminocarbonylphenyl, 2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-pyrimidin-5-yl, 2-
chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl,
2-difiuoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-fluoro-3-methoxy-
phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxy-phenyI, 2-
fluoro-5-methylphenyl, 2-fiuorophenyl, 2-fluoro-pyridin-3-yl, 2-hydroxymethyl-3-
methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-5-trifluoromethyl-
phenyl, 2-methoxy-phenyl, 2-methoxy-pyridin-3-yl, 2-methoxy-pyrimidin-4-yl, 2-methoxy-
thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-dihydro-pyridin-3-yl, 2-
phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-
trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazol-4-yl, 3,6-dimethyl-
pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl, 3-bromo-phenyl, 3-chloro-
pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-methyl-
phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-fluorophenyl, 3-fluoro-
pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-methoxycarbonylphenyl, 3-methoxyphenyl,
3-methoxy-pyrazin-2-yl, 3-methyl-3H-imidazo[4,5-b]pyrazin-5-yl5 3-methylphenyI, 3-
methyl-pyridin-2-yl, 3-trifluoromethoxyphenyI, 3-trifluoromethylphenyl, 4,5-dimethoxy-
pyrimidin-2-yl, 4-amino-5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-
2-fiuoro-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difluoro-2-
methyl-phenyl, 4-ethoxy-5-fluoro-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-
pyrimidin-5-yl, 4-ethyl-lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fiuoro-2-methyl-
phenyl, 4-fluorophenyl, 4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-
methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-
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yl, 4-methyl-pyridin-3-yl, 4-pyrrolidin-l-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-
acetyl-thiophen-2-yl, 5-amino-6-ethoxy-pyrazin-2-yls 5-amino-6-methoxy-3-methyl-
pyrazin-2-yl, 5-amino-6-methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-
chloro-6-methoxy-pyrazin-2-yl, 5-dimethylamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-
methoxyphenyl, 5-fluoro-4-methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-
fluoro-pyridin-2-yl, 5-methoxy-pyridin-3-yl, 5-methoxy-thiophen-2-yl, 5-trifiuoromethyl-
pyrimidin-2-yl, 6-acetyl-pyridin-2-yl, 6-chloro-pyrazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-
ethoxy-pyridin-2-yl, 6-fiuoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl, 6-
methoxy-5-methylamino-pyrazb-2-yls6-methoxy-5-methyl-pyrazin-2-yl, 6-methoxy-
pyrazin-2-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-
yl, 6-methyl-pyridin-2-yl, 5-anuno-6-(2,2,2-trifluoroethoxy)pyrazin-2-yl, and 6-
trifluoromethyl-pyridin-2-yl.
In another embodiment the guanidine derivative is acetyl guanidine.
In another embodiment, provided is a use of compound of formula (VI) or (VII) for
the manufacture of a compound of formula (I).
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 and/or intermediates were characterized by high performance liquid
chromatography (HPLC) using a Waters Millenium chromatography system with a
2690 Separation Module (Milford, MA). The analytical columns were Alltima C-18
reversed phase, 4.6 x 250 mm from Alltech (Deerfield, IL). A gradient elution was used,
typically starting with 5% acetonitrile/95% water and progressing to 100% acetonitrile over
a period of 40 minutes. All solvents contained 0.1% trifluoroacetic acid (TFA).
Compounds were detected by ultraviolet light (UV) absorption at either 220 or 254 run.
HPLC solvents were from Burdick and Jackson (Muskegan, MI), or Fisher Scientific
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WO 2007/041362 PCT/US2006/038181
(Pittsburgh, PA). In some instances, purity was assessed by thin layer chromatography
(TLC) using glass or plastic backed silica gel plates, such as, 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 LC/MS 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 rnL/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 were reported as those
of the protonated parent ions.
GCMS analysis is performed on a Hewlett Packard instrument (HP6890 Series gas
chromatograph with a Mass Selective Detector 5973; injector volume: 1 yL; initial column
temperature: 50 °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 on some of the
compounds with a Varian 300 MHz NMR (Palo Alto, CA). 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 is assessed by elemental analysis
(Desert Analytics, Tucson, AZ)
Melting points are determined on a Laboratory Devices Mel-Temp apparatus
(Holliston, MA).
Preparative separations were carried out using a Flash 40 chromatography system
and KP-Sil, 60A (Biotage, Charlottesville, VA), 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
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cnromatography 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.
The following are abbreviations used in the examples:
aq.: Aqueous
Boc: tert-Butoxycarbonyl
BSA: bovine serum albumin
Celite Diatomaceous earth
DCM: Dichloromethane
eq.: equivalent
Et3N: Triethylamine
EtOAc: Ethyl acetate
GC Gas Chromatography
h: hour
HPLC: High performance liquid chromatography
IC50 value: The concentration of an inhibitor that causes a 50% reduction
in a measured activity.
L: liter
LC/MS: Liquid chromatography/mass spectrometry
LRMS: Low resolution mass spectrometry
MeOH: Methanol
min: minute
mL: milliliter
mm: millimeter
mM: millimolar
mmol: millimole
run: Nanometer
NMP: N-Methylpyrrolidone
RP-HPLC: Reversed-phase high-performance liquid chromatography
rt room temperature
sat: Saturated
THF: Tetrahydrofuran
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TMS: Trimethylsilane
TLC: Thin layer chromatography
TRF: Time resolved fluorescence.
Nomenclature for the compounds disclosed in this application was provided using
ACD Name version 5.07 software (November 14, 2001) or ACD Name Batch version 5.04
(May 28,2002) available from Advanced Chemistry Development, Inc., or by using
AutoNom 2000 (Automatic Nomenclature) for ISIS/Base, implementing IUPAC
standardized nomenclature. Other compounds, intermediates, 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.
The following examples illustrate methods for making representative compounds of
the invention.

n-Butyllithium (84 mmol) was added dropwise to a stirred solution of
triethylphosphono acetate (88 mmol) in dry THF (176 mL) at -78 °C under N2. The
solution was left to stir for 30 min. keeping inner temperature below -70 CC. The
phosphonate solution was transferred via cannula to a solution of 2-bromo-4-
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fluorobenzaldehyde 1-1 (80 mmol) in THF (160 mL) at -78 °C under N2. The resulting
solution was warmed to room temperature over 2 h. The reaction mixture was quenched by
adding aqueous NH4CI and then extracted with EtOAc (x3). The organics were combined,
washed with H2O (x3), sat. brine (x3), then dried (Na.2SO4), filtered, and evaporated under
reduced pressure to give pale yellow oil. White crystals formed after cooling in refrigerator.
The crystals were filtered and washed with methanol to provide the pure compound 1-2.
The mother liquor was concentrated, cooled and filtered. This process was repeated until
most of the theoretical yield of is-ethyl 3-(2-bromo-4-fluorophenyl)acrylate was collected as
a white crystals.
Step B: Conjugate Addition of Asymmetric Amine to
To a stirred solution of (iS}-N-benzyl-l-(4-methoxyphenyl)ethanamine 1-3 (58mmol)
in dry THF (116 mL) was added compound 1-2. The reaction was cooled to -78 °C, and n-
butyl lithium (56.2 mmol) was added dropwise at -78 °C under N2. After addition, the
reaction mixture was stirred at -78 °C for 40 min. Then the reaction mixture was
partitioned between aqueous NRjCl, and EtOAc, extracted with EtOAc (x3), the organics
separated, then washed with H2O (x3), sat. brine (x3), then dried (Na2SC>4), filtered, and
evaporated under reduced pressure to give crude oil, which was then purified on silica gel
column (hexane/EtOAc) to provide compound 1-4.


WO 2007/041362 PCT/US2006/038181
lhe starting material 1-4 (81.78 mmol) was dissolved in acetonitrile:water (5:1,
1.6 L). While stirring CAN (490.68 mmol) compound 1-4 was added in three separate
portions stirring for 1 h between each addition. The reaction was then allowed to stir
overnight at room-temperature. Next, the acetonitrile was removed under vacuum, and the
remaining aqueous layer was extracted (4 x 400 mL) with EtOAc. The EtOAc layers were
combined, dried over sodium sulfate, filtered, and concentrated to yield the crude product
compound 1-5. The crude product was purified using a flash column (5% MeOH in DCM).

To a stirred solution of free amine 1-5 (5.27 mmol) in DCM (26 mL) was added
triethyl amine (21.08 mmol) and diketene (6.33 mmol) at room temperature. The reaction
was stirred until judged complete by LCMS. Then the mixture was partitioned between
DCM and aqueous NaHCO3, extracted with DCM (x3), the organic layers were combined,
then washed with H2O (x3), sat. brine (x3), then dried (Na2SO4), filtered, and evaporated
under reduced pressure to give crude oil, which was then purified on silica gel column
(hexane/EtOAc) to provide compound 1-6.

To the reaction vial containing compound 1-6(1.1 mmol) in methanol (5 mL) was
added 25% NaOMe in MeOH (0.5 mL). The reaction mixture was heated in the microwave
at 144 °C for 5 min. After cooling to room temperature, the reaction mixture was diluted
with aqueous ammoinium choride, washed with DCM (x3), then washed with H2O (x3), sat.
brine (x3), then dried (Na2SC>4), filtered, and evaporated under reduced pressure to give
crude product, piperidine-dione 1-7, which was used directly in the next step.
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To the mixture of piperidindione 1-7 (0.915 mmol) and guanidine HC1 (4.573 mmol)
in ethanol (9 mL) was added pyrrolidine (18.3 ramol). The reaction mixture was treated in
microwave (PowerMAX setting) at 160 °C for 10 min. After cooling to room temperature,
the reaction mixture was extracted with DCM (x3), then washed with H2O (x3), sat, brine
(x3), then dried (NazSCU), filtered, and evaporated under reduced pressure to give crude
product 1-8, which was then purified on silica gel column (EtOAc).

To the mixture of amino-pyrimidine-lactam 1-8 (1 eq.), boronic acid or ester (4 eq.)
in DMA was added Pd(dppfhCl2 (0.4 eq.) and 2 M K2CO3 (8 eq). The reaction mixture was
treated in microwave at 120 °C for 15 min. After cooling down to room temperature the
reaction mixture was diluted with DCM (x3), washed with H2O (x3), sat. brine (x3), then
dried (Na2SC>4), filtered, and evaporated under reduced pressure to give crude product,
which was then purified reverse-phase prep HPLC to give the pure HSP90 inhibitor.
Example 2
Synthesis of Representative N-Alkylated Compounds of the Invention
Step A: Reductive Animation
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To a stirred solution of free amine 1-5 (1 eq.), aldehyde 2-1 (1 eq.) in DCM was
added sodium triacetoxyborohydride (1.1 eq.) at room temperature. The reaction was
stirred at room temperature until judged complete by LCMS. Then the mixture was
partitioned between DCM and aqueous NaHCC>3, extracted with DCM (x3) and the organics
combined, then washed with HaO (x 3), sat. brine (x 3). then dried (NaiSCU), filtered, and
evaporated under reduced pressure to give crude product, compound 2-2, which was used
directly for the next reaction.
Steps B -E: Acylation, Cyclization, Amino-Pyrimidine-Lactam Formation, Suzuki

Step B to Step E were the same as Step E to Step G in Example 1.

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To the solution of Boc-protected N-alkylated lactam in DCM was treated with 50%
TFA. The reaction mixture was stirred at room temperature. After completion, the reaction
mixture was concentrated and purified on reverse phase prep HPLC to give the pure
compound.
Other alkylated amine compounds of the invention were prepared in a similar
manner.

A mixture of sodium methoxide (25% by wt in methanol, 0.193 mol), methyl acetate
(0.0644 mole) and 100 mL anhydrous methanol was stirred at room temperature under
nitrogen for one hour. Then, neat amide 1-6 (24.1 g, 0.0644 mol) was added. The reaction
was refluxed under nitrogen for one hour and then solvent were distilled out gradually until
the internal temperature reached 85 °C. The reaction was monitored with HPLC until 1-6
was completely consumed. Reaction was cooled to room temperature and remaining
solvent was removed under reduced pressure. The residue was dissolved in 100 mL water
and then cooled to 5 °C in an ice/water bath. To this solution was then added IN HC1 until
pH=l, during which the internal temperature was maintained below 10 °C. The mixture was
stirred until a smooth suspension formed and then was filtered. The collected solids were
washed with water (lOOmL x 3) and air-dried overnight to give 20.7 g of lactam 1-7 as a
slightly yellowish solid with a yield of 98.1% and purity of 98.3% (HPLC area ratio).
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A 500 mL round-bottom flask was charged with dry THF (50 mL), titanium
ethoxide (41 mL), (S)-(-)-tert-butanesulfinamide (Advanced Asymmetries, 12.0 g, 99.1
mmol, 1.1 equiv), and 2-bromo-4-fluorobenzaldehyde 4.1 (Matrix Scientific, cat. # 011279,
18.2 g, 90.1 mmol, 1.0 equiv). The resulting reaction mixture was stirred under N2 at rt for
4 h. Upon reaction completion as monitored by LCMS, the reaction mixture was diluted
with EtOAc (360 mL), and a mixture of brine (200 mL) with celite was added with vigorous
stirring. The resulting emulsion was filtered through a pad of celite and washed with
EtOAc (200 mL). The filtrate was transferred to a seperatory runnel, and the aqueous layer
removed. The organics were washed with brine (200 mL), then dried (Na2SC>4) and
concentrated in vacuo to afford 4.2 as a yellowish oil that may solidify upon standing (26.5
g, 86.3 mmol, 96%). lU NMR (300 MHz, CD3CI) 5 8.86 (s, 1H), 8.03 (m, 1H), 7.35 (m,
1H), 7.11 (m, 1H), 1.11 (s, 9H) LCMS mlz 307.9 (MH4), tK = 3.22 min.
Step 2:
A three-necked 100 mL round-bottom flask, reflux condensor, and addition funnel •
were oven-dried overnight. Upon removal from the oven, they were assembled and put
under positive N2 pressure and cooled to room temperature. The flask was charged with Zn
dust (21.3 g, 326.0 mmol, 15.0 equiv), CuCl (32.6 g, 32.6.mmol, 1.5 equiv), and dry THF
(60 mL). The resulting reaction mixture was heated to reflux temperature (bath temperature
approximately 90 °C) and stirred vigorously with an overhead stirrer for 30 min. The
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reaction was removed from the oil bath (maintaining vigorous stirring) and the addition
runnel was then charged with ethylbromoacetate (3.6 mL, 32.6 mmol, 1.5 equiv) and dry
THF (30 mL). Addition of the ethylbromoacetate should be done at a rate to maintain
gentle refluxing of the reaction mixture. Once addition is complete, the reaction mixture
was stirred for an additional 20 min, then heated to 50 °C for 30 min. The reaction mixture
was then cooled to 0 °C, and the addition funnel charged with 4.2 (6.60 g, 21.5 mmol, 1.0
equiv) and dry THF (20 mL). This solution was then added dropwise to the reaction
mixture, which was stirred an additional 4 hours at 0 °C. Once the reaction has gone to
completion as judged by LCMS, the reaction mixture was filtered through a pad of celite,
washing the Zn and the filter pad with Et2O (2x100 mL). The filtrate was washed with 0.25
M citric acid (200 mL), sat. NaHCO3(aq) (2x200 mL), dried (Na2SO4), and concentrated in
vacuo to afford 4.3 (7.30 g, 18.4 mmol, 86%) as a clear oil. : *H NMR (300 MHz, CD3C1)
5 7.39 (m, 1H), 7.28 (m, 1H), 7.01 (m, 1H), 5.14 (m, 1H), 4.92 (d, J = 5.4, 2H), 4.1 (m,
2H), 2.90 (ddd, J, =, J2 =, J3 = , 2H), 1.22 (m, 3H, 9H). LCMS m/z 396.0 (MH*), tR =
2.96 min. HPLC (frac_10min_2070%B), tR = 4.108 (major diastereomer), tR = 3.962
(Claisen condensation byproduct) tR = 3.888 (minor diastereomer), 95.5:2.1:2.1. de = 96%.
Step 3:
A 500 mL round-bottom flask was charged with 4.3 (7.30 g, 18.4 mmol, 1.0 equiv),
Et2O (37 mL), EtOH (1.2 mL, 1.1 equiv) and 4M HC1 in Et2O (37 mL, 2.0 equiv). The
reaction mixture was stirred at room temperature for 30 minutes. The resulting suspension
was filtered and the solids triturated with Et2O (3x 40 mL) and hexanes (2x 40 mL). The
solid was dried under vacuum to afford 4.4 as a white solid (5.23 g, 15.2 mmol, 83%). ;H
NMR (300 MHz, CD3OD) 5 7.61 (m, 2H), 7.33 (m, 1H), 5.18 (m, 1H), 4.85 (bs, 3H), 4.13
(q,/= 7.2,2H), 3.15 (ddd, 2H), 1.22 (t,/= 7.5, 3H) LCMS m/z292.0 (MH+), fc= 1.97
min. To free base the HCL salt, 4.4 (50 mg) was dissolved in EtOAc (20 mL) and washed
with 10% Na2CO3 (3x 20 mL). The organics were dried (Na2SO4) and concentrated in
vacuo to afford the free base. A racemic mixture of the final [3-amino ester product was
prepared and analyzed by chiral HPLC to confirm separation of the enantiomers (Chiralpak
AD column, lmL/min, S, tR = 5.84; R, tR = 7.47 min)
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A 250 mL round-bottom flask was charged with dry THF (54 mL), titanium
ethoxide (18.25 g, 3equiv), (S)-(-)-te^butanesulfinamide (4.85 g, 1.5 equiv), and 5-
bromothiazole-4-carbaldehyde 5.1 (5.12 g, 1.0 equiv). The resulting reaction mixture was
stirred under N2 at rt. Upon reaction completion as monitored by LCMS, the reaction
mixture was diluted with EtOAc (360 mL), and a mixture of brine (200 mL) with celite was
added with vigorous stirring. The resulting emulsion was filtered through a pad of celite
and washed with EtOAc (200 mL). The filtrate was transferred to a seperatory funnel, and
the aqueous layer removed. The organics were washed with brine (200 mL), then dried
(Na2SO4) and concentrated in vacno to afford 5.2 as a yellowish oil (7.9 g, 100%). :H NMR
(300 MHz, CD3CI) 5 8.88 (s, 1H), 8.72 (s, 1H), 1.21 (s, 9H) LCMS m/z 296.9 (MH+), fo. =
2.35 min.
Step 2:
A three-necked 100 mL round-bottom flask, reflux condensor, and addition funnel
were oven-dried overnight. Upon removal from the oven, they were assembled and put
under positive N2 pressure and cooled to room temperature. The flask was charged with Zn
dust (25.4 g, 400.0 mmol, 15.0 equiv), CuCl (3.96 g, 40.mmol, 1.5 equiv), and dry THF (80
mL). The resulting reaction mixture was heated to reflux temperature (bath temperature
approximately 90 °C) and stirred vigorously with an overhead stirrer for 30 min. The
reaction was removed from the oil bath (maintaining vigorous stirring) and the addition
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funnel was then charged with ethylbromoacetate (6.68 g, 40 mmol, 1.5 equiv) and dry THF
(40 mL). Addition of the ethylbromoacetate should be done at a rate to maintain gentle
refluxing of the reaction mixture. Once addition is complete, the reaction mixture was
stirred for an additional 30 min, then heated to 50 °C for 30 min. The reaction mixture was
then cooled to 0 °C, and the addition funnel charged with 5.2 (26.67 mmol, 1.0 equiv) and
dry THF (27 mL). This solution was then added dropwise to the reaction mixture, which
was stirred an additional 4 hours at 0 °C. Once the reaction has gone to completion as
judged by LCMS, the reaction mixture was filtered through a pad of celite, washing the Zn
and the filter pad with Et2O (2x100 mL). The filtrate was washed with 0.25 M citric acid
(200 mL), sat. NaHCO3(aq) (2x200 mL), dried (Na2SO4), and concentrated in vacuo to afford
5.3 (10 g) as a clear oil.
Step 3:
A 500 mL round-bottom flask was charged with 5.3 (10 g, 26.67 mmol, 1.0 equiv),
Et2O (27 mL), EtOH (1.7 mL) and 4M HC1 in Et2O (53 mL, 2.0 equiv). The reaction
mixture was stirred at room temperature for 30 minutes. The resulting suspension was
filtered and the solids triturated with Et2O (3x 40 mL) and hexanes (2x 40 mL). The solid
was dried under vacuum to afford 5.4 as a white solid (6.6 g, 88.7%). LCMS m/z 280.9
(MH+),rR= 1.63 min.
EXAMPLE 6
Preparation of (R)-2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-methyl-7,8-
dihydropyrido[4,3 -d]pyrimidin-5(6H)-one

A microwave vial was charged with (R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-
methyl-7,8-dihydropyrido[4,3-d]pyrimidin-5(6H)-one, cesium carbonate (2 eq), copper (I)
iodide (10 mol%), 1,10-phenanthroline (20 mol%), and cyclopentanol. The reaction mixture
was heated with microwave irradiation to a temperature of 180 °C for 20 min. After cooling
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to RT, the reactionmixture was concentrated and purified by reverse phase HPLC to afford
(R)-2-arnino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-rnethyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one (m/z = 357 (M+H)).

Aminoester hydrochloride 7.1 (prepared according to the general procedure of
Example 1) was taken up in methylene chloride and the resulting solution was cooled to 0
°C. Triethylamine (3 eq) was added followed by dropwise addition of methyl malonyl
chloride (1.3 eq). The reaction was stirred for 2h the partitioned between water and
methylene chloride. The layers were separated and the organic layer was dried over
anhydrous sodium sulfate and concentrated in vacuo to afford compound 7.2 in 71% yield.
Compound 7.2 was dissolved in methanol to which freshly prepared 4.2M sodium
methoxide in methanol was added. The reaction vessel was sealed and heated for 10 min at
140 °C (microwave). The reaction mixture was cooled to room temperature and partitioned
between 1M aqueous hydrochloric acid and methylene chloride. The organic and aqueous
layers were separated and the organic layer was dried over anhydrous sodium sulfate and
concentration in vacuo afforded compound 7.3 in 93% yield.
Compound 7.3 was taken up in acetonitrile containing 1% water. The reaction vessel
was sealed and heated for 10 min at 120 °C (microwave). Concentration in vacuo provided
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compound 7.4 in a quantitative yield.
Compound 7.4 was taken up in dimethylacetamide dimethyl acetal and heated at 140
°C for 5 min. Cooling to room temperature and concentration in vacuo provided 7.5 as an
orange solid, which was immediately taken up in a 5.0 M solution of dimethyl amine in
ethanol. Acetyl guanidine (1.5 eq) was added and the resulting mixture was heated at 140 °C
for 10 min. The crude reaction mixture was concentrated in vacuo and the resulting solid
7.6, used without purification.
Bromide 7.6 was taken up in a 1:1 mixture of dimethoxyethane and 2M aqueous
sodium carbonate. Boronic acid 6-methoxy-pyrazin-2-yl boronic acid was added followed
by Pd(dppf)Cl2.CH2Cl2. The reaction mixture was heated at 120 °C for 10 min (microwave).
After cooling to room temperature, the layers were separated and the organic layer was
concentrated under a stream of nitrogen. Purification by reverse-phase HPLC afforded
compound 7.7.
EXAMPLE 8
Preparation of (R)-2-Arnino-7-[5-(6-methoxy-pyrazin-2-yl)-thiazol-4-yl]-4-methyl-
7,8-dmydro-6H-pyrido[4,3-d]pyrimidin-5-one

Compound 88 was prepared as shown above from 5.4, the synthesis of which is
given in Example 5. Compound 5.4 is converted to 88 following the general procedure of
Example 1 using the indicated reagents.
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EXAMPLE 9
Representative 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds
Representative 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds
are shown in Tables 1-5. In the tables, m/z refers to the molecular ion observed by mass
spectrometry.
Table 1. Representative 2-Amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
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Table 3


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Using the procedure described in Example 10, certain compounds in Tables 1-5
were shown to have HSP90 inhibitory activity at an IC50 of less than 25 ^M. Some of the
compounds have an IC50 of less than about 10 uM.
EXAMPLE 10
HSP90 INHIBITOR BINDING POTENCY: TRF BINDING ASSAY
In this example, the binding potency of HSP90 inhibitors as measured by a TRF
binding assay is described.
TRF competition binding assays were performed to determine the binding potency
(IC50 values) of HSP90 inhibitors. Purified His-tagged N-terminal ATP binding domain
(amino acid residues 9-236) of HSP90a (HSP90a GenelD: 3320; mRNA Sequence
NM_005348) was incubated for two hours at room temperature in binding buffer (50 mM
HEPES, 6 mM MgCl2, 20 mM KC1 and 0.1% BSA) with biotinylated radicicol and
progressively higher concentrations of the competing compounds. A fraction of the mixture
was transferred to capture plates (coated with streptavidin) and incubated for one hour at
room temperature. After washing with DELFIA wash buffer, europium-labeled anti-his
antibody was added and incubated for two hours at room temperature, followed by washing
with DELFIA buffer. DELFIA enhancement solution was then added. After gentle shaking
for 10 minutes, the plates were read in VICTOR for europium counts.
Note: IC50 values can also be determined using published methods in the following
references:
1. Carreras, C. W., A. Schirmer, et al. (2003). "Filter binding assay for the
geldanamycin-heat shock protein 90 interaction." Anal Biochem 317(1): 40-6;
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WO 2007/041362 PCT/US2006/038I81
2. Kim, J., S. Felts, et al. (2004). "Development of a fluorescence polarization
assay for the molecular chaperone HSP90." J Biomol Screen 9(5): 375-81; and
3. Zhou, V., S. Han, et al. (2004). "A time-resolved fluorescence resonance
energy transfer-based HTS assay and a surface plasmon resonance-based binding assay for
heat shock protein 90 inhibitors." Anal Biochem 331(2): 349-57.
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.
Documents Cited
The following publications were referred to in the specification:
1. Beliakoff J, Bagatell R, Paine-Murrieta G, et al (2003) Hormone-refractory breast
cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.
Clin Cancer Res, 9,4961-71.
2. Smith V, Hobbs S, Court W, et al (2002) ErbB2 overexpression in an ovarian cancer
cell line confers sensitivity to the HSP90 .inhibitor geldanamycin. Anticancer Res,
22,1993-9.
3. Solit D B, Zheng F F, Drobnjak M, et al (2002) 17-Allylamino-17-
demethoxygeldanamycin induces the degradation of androgen receptor and HER-
2/neu and inhibits the growth of prostate cancer xenografts. Clin Cancer Res, 8, 986-
93.
4. Blagosklonny M V, Fojo T, Bhalla K N, et al (2001) The Hsp90 inhibitor
geldanamycin selectively sensitizes Bcr-Abl-expressing leukemia cells to cytotoxic
chemotherapy. Leukemia, 15,1537-43
5. Burger A M, Fiebig H H, Stinson S F, et al (2004) 17-(Allylamino)-17-
demethoxygeldanamycin activity in human melanoma models. Anticancer Drugs,
15,377-87.
6. Nakatani H, Kobayashi M, Jin T, et al (2005) STI571 (Glivec) inhibits the
interaction between c-KIT and heat shock protein 90 of the gastrointestinal stromal
tumor cell line, GIST-T1. Cancer Sci, 96,116-9.
7. Fumo G, Akin C, Metcalfe D D, et al (2004) 17-Allylamino-17-
demethoxygeldanamycin (17-AAG) is effective in down-regulating mutated,
constitutively activated KIT protein in human mast cells. Blood, 103,1078-84.
8. George P, Bali P, Annavarapu S, et al (2005) Combination of the histone
deacetylase inhibitor LBH589 and the hsp90 inhibitor 17-AAG is highly active
against human CML-BC cells and AML cells with activating mutation of FLT-3.
Blood, 105,1768-76.
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WO 2007/041362 PCT/US2006/038181
9. George P, Bali P, Cohen P, et al (2004) Cotreatment with 17-aHylamino-
demethoxygeldanamycin and FLT-3 kinase inhibitor PKC412 is highly effective
against human acute myelogenous leukemia cells with mutant FLT-3. Cancer Res,
64, 3645-52.
10. Heideman DA, Snijders PJ, Bloemena E, Meijer CJ, Offerhaus GJ, Meuwissen SG,
Gerritsen WR, Craanen ME (2001) Absence of tpr-met and expression of c-met in
human gastric mucosa and carcinoma. J Pathol. 194(4):428-35
11. Nguyen D M, Lorang D, Chen G A, et al (2001) Enhancement of paclitaxel-
mediated cytotoxicity in lung cancer cells by 17-allylamino geldanamycin: in vitro
and in vivo analysis. Ann Thorac Surg, 72,371-8; discussion 378-9.
12. Yin X, Zhang H, Burrows F, et al (2005) Potent activity of a novel dimeric heat
shock protein 90 inhibitor against head and neck squamous cell carcinoma in vitro
and in vivo. Clin Cancer Res, 11,3889-96.
13. Yang J, Yang J M, Iannone M, et al (2001) Disruption of the EF-2 kinase/Hsp90
protein complex; a possible mechanism to inhibit glioblastoma by geldanamycin.
Cancer Res, 61,4010-6.
14. Chung YL, Troy H, Banerji U, Jackson LE, Walton MI, Stubbs M, Griffiths JR,
Judson IR, Leach MO, Workman P, Ronen SM. Magnetic resonance spectroscopic
pharmacodynamic markers of the heat shock protein 90 inhibitor 17-allylamino, 17-
demethoxygeldanamycin (17AAG) in human colon cancer models. J Natl Cancer
Inst. 2003 Nov 5;95(21):1624-33.
15. Park JW, Yeh MW, Wong MG, Lobo M, Hyun WC, Duh QY, Clark OH. The heat
shock protein 90-binding geldanamycin inhibits cancer cell proliferation, down-
regulates oncoproteins, and inhibits epidermal growth.factor-induced invasion in
thyroid cancer cell lines. J Clin Endocrinol Metab. 2003 Jul;88(7):3346-53.
16.Mitsiades CS, Mitsiades NS, McMullan CJ, Poulaki V, Kung AL, Davies FE,
Morgan G, Akiyama M, Shringarpure R, Munshi NC, Richardson PG, Hideshima T,
Chauhan D, Gu X, Bailey C, Joseph M, Libermann TA, Rosen NS, Anderson KC.
Antimyeloma activity of heat shock protein-90 inhibition. Blood 2006 Feb
l;107(3):1092-100.
17. Isaacs JS, Jung YJ, Mimnaugh EG, Martinez A, Cuttitta F, Neckers LMHsp90
regulates a von Hippel Lindau-independent hypoxia-inducible factor-1 alpha-
degradative pathway. J Bioi Chem. 2002 Aug 16;277(33):29936-44
18. Bonvini P, Gastaldi T, Falini B, Rosolen A. Nucleophosmin-anaplastic lymphoma
kinase (NPM-ALK), a novel Hsp90-client tyrosine kinase: down-regulation of
NPM-ALK expression and tyrosine phosphorylation in ALK(+) CD30(+) lymphoma
cells by the Hsp90 antagonist 17-allylamino, 17-demethoxygeldanamycin. Cancer
Res. 2002 Mar 1;62(5): 1559-66
19. Georgakis GV, Li Y, Rassidakis GZ, Martinez-Valdez H, Medeiros LJ, Younes A.
Inhibition of heat shock protein 90 function by 17-allylamino-17-demethoxy-
geldanamycin in Hodgkin's lymphoma cells down-regulates Akt kinase,
dephosphorylates extracellular signal-regulated kinase, and induces cell cycle arrest
and cell death. Clin. Cancer Res. 2006 Jan 15;12(2):584-90
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20. Neckers L, Ivy, b. P. Heat shock protein 90. Current Opinion in Onclology 2003 Jan
15:419-424.
21. Bagatell R., Whitesell L. Altered Hsp90 function in cancer: A unique therapeutic
opportunity. Molecular Cancer Therapeutics 2004 3(8):1021-1030.
22. Machajewski T., Lin X.D., Jefferson A.B., Gao, Z. AKT kinase and Hsp90
inhibitors as novel anti-cancer therapeutics. Annual Reports in Medicinal Chemistry
2005 40: 263-276.
23. Gao Z., Harrison S., and Duhl D. Beyond kinases for anticancer discovery: purine-
binding enzymes and ATPases. Annual Reports in Medicinal Chemistry 2003 38:
194-202.
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What is claimed is:
1. A compound of the formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof,
wherein
Ra is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) Ci-Ce alkoxy,
(5) thiol,
(6) Ci-C6 alkylthiol,
(7) substituted or unsubstituted Cj-Cg alkyl,
(8) amino or substituted amino,
(9) substituted or unsubstituted aryl,
(10) substituted or unsubstituted heteroaryl, and
(11) substituted or unsubstituted heterocyclyl;
R is selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted Cj-Cg alkyl,
(3) substituted or unsubstituted C2-C6 alkenyl,
(4) substituted or unsubstituted C2-Cg alkynyl,
(5) substituted or unsubstituted C3-C7 cycloalkyl,
(6) substituted or unsubstituted C5-C7 cycloalkenyl,
(7) substituted or unsubstituted aryl,
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WO 2007/041362 PCT/US2006/038181
(8) substituted or unsubstituted heteroaryl, and
(9) substituted or unsubstituted heterocyclyl;
Rb is selected from the group consisting of

(1) substituted or unsubstituted C3-C7 cycloalkyl,
(2) substituted or unsubstituted C5-C7 cycloalkenyl,
(3) substituted or unsubstituted aryl,
(4) substituted or unsubstituted heteroaryl, and
(5) substituted or unsubstituted heterocyclyl; and
with the proviso that when Ra is amino, then Rb is not phenyl, 4-alkyl-phenyl, 4-
alkoxy-phenyl, or 4-halo-phenyl.
2. A compound of Claim 1, wherein Ra is hydrogen.
3. A compound of Claim 1, wherein Ra is Cj-Cg alkyl or halo C^-Cg alkyl.
4. A compound of Claim 3, wherein Ra is methyl.
5. A compound of Claim 1, wherein Rb is aryl or heteroaryl.
6. A compound of Claim 5, wherein Rb is selected from the group consisting of
phenyl, pyridyl, pyrimidinyl, pyrazinyl, indolyl, thiazolyl, and thienyl.
7. A compound of Claim 1, wherein Rb is selected from the group consisting of
substituted phenyl, substituted pyridyl, substituted pyrimidinyl, substituted pyrazinyl,
substituted indolyl, substituted thiazolyl, and substituted thienyl.
8. A compound of Claim 7, wherein said phenyl, pyridyl, pyrimidinyl,
pyrazinyl, indolyl, thiazolyl, and thienyl is substituted with substituted or unsubstituted aryl.
or substituted or unsubstituted heteroaryl.
9. A compound of Claim 7, wherein said phenyl, pyridyl, pyrimidinyl,
pyrazinyl, indolyl, thiazolyl, and thienyl is substituted with halo.
10. A compound of Claim 9, wherein said halo is fiuoro.
11. A compound of Claim 1, wherein R is selected from the group consisting of
hydrogen, unsubstituted alkyl, and substituted alkyl.
12. A compound of Claim 11, wherein R is selected from the group consisting of
hydrogen, benzyl, l-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-
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WO 2007/041362 PCT/US2006/038181
morpholinopropyl.
13. A compound of Claim 1 having formula (la)

wherein R, Ra, and Rb are previously defined for formula (I).
14. A compound of Claim 1 having formula (II):

or a stereoisomer, tautomer, phannaceutically acceptable salt, or prodrug thereof,
wherein
n is 0 or 1,
wherein Ra is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) Ci-C6 alkoxy,
(5) thiol,
(6) Ci-C6 alkylthiol,
(7) substituted or unsubstituted C^Cg alkyl,
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WO 2007/041362 PCT/US2006/038181
(8) amino or substituted amino,
(9) substituted or unsubstituted aryl,
(10) substituted or unsubstituted heteroaryl, and
(11) substituted or unsubstituted heterocyclyl;
wherein R is selected from the group consisting of

(1) hydrogen, •
(2) substituted or unsubstituted Cj-Cg alkyl,
(3) substituted or unsubstituted C2-Q alkenyl,
(4) substituted or unsubstituted C2-Cg alkynyl,
(5) substituted or unsubstituted C3-C7 cycloalkyl,
(6) substituted or unsubstituted C5-C7 cycloalkenyl,
(7) substituted or unsubstituted aryl,
(8) substituted or unsubstituted heteroaryl, and
(9) substituted or unsubstituted heterocyclyl,
wherein when n is 1, X is C, Y is at each position independently selected from CQl
and N, and Z is selected from CR2 and N with the proviso that no more than 3 Y and Z
groups are N, and
wherein when n is 0, X is C or N, Y is at each position independently selected from
CQ1, N, NQ2, O, and S with the proviso that no more than 4 X and Y groups are N and NQ2
and no more than 1 Y group is S or O;
wherein Q1 is at each position independently selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) substituted or unsubstituted C]-Cg alkyl,
(4) substituted or unsubstituted Cj-C^ alkenyl,
(5) substituted or unsubstituted C2-C$ alkynyl,
(6) substituted or unsubstituted C3-C7 cycloalkyl,
(7) substituted or unsubstituted C5-C7 cycloalkenyl,
(8) substituted or unsubstituted aryl,
(9) substituted or unsubstituted heteroaryl,
(10) substituted or unsubstituted heterocyclyl,
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(11) substituted or unsubstituted amino,
(12) -OR3or-SR3
(13) -C(O)R3, -CO2R3, -C(O)N(R3)2, -S(O)R3, -SO2R3, or -SO2N(R3)2,
(14) -OC(O)R3, -N(R3)C(O)R3, or -N(R3)SO2R3,
(15) -CN,and
(16) -NO2;
wherein Q2 is at each position independently selected from the group consisting of
(1) hydrogen,
(3) substituted or unsubstituted CpCg alkyl,
(4) substituted or unsubstituted C2-Cg alkenyl,
(5) substituted or unsubstituted C2-C6 alkynyl,
(6) substituted or unsubstituted C3-C7 cycloalkyl,
(7) substituted or unsubstituted C5-C7 cycloalkenyl,
(8) substituted or unsubstituted aryl,
(9) substituted or unsubstituted heteroaryl, and
(10) substituted or unsubstituted heterocyclyl;
wherein R2 is selected from the group consisting of

(1) hydrogen,
(2) halogen,
(3) substituted or unsubstituted C j -C3 alkyl, and
(4) -OR3,-SR3,or-NHR3;
wherein R3 is at each position independently selected from the group consisting of
(1) hydrogen,
(2) substituted or unsubstituted Cj-Cg alkyl,
(3) substituted or unsubstituted C2-C§ alkenyl,
(4) substituted or unsubstituted C2-Cg alkynyl,
(5) substituted or unsubstituted C3-C7 cycloalkyl,
(6) substituted or unsubstituted C5-C7 cycloalkenyl,
(7) substituted or unsubstituted aryl,
(8) substituted or unsubstituted heteroaryl, and
(9) substituted or unsubstituted heterocyclyl,
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WO 2007/041362 PCT/US2006/038181
with the proviso that when Ra is amino, then X, Y, Z, and n together do not form a
phenyl, 4-alkyl-phenyl, 4-alkoxy-phenyl, or 4-halo-phenyl group.
15. A compound of Claim 14 wherein Ra is hydrogen.
16. A compound of Claim 14 wherein Ra is substituted or unsubstituted C j -C6
alkyl.
17. A compound of Claim 16 wherein Ra is methyl.
18. A compound of Claim 14, wherein one of Q1 or Q2 is selected from the
group consisting of substituted or unsubstituted aryl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted heteroaryl, substituted or unsubstitued C3-C7
cycloalkyl, and substituted or unsubstitued C5-C7 cycloalkenyl.
19. A compound of Claim 18, wherein said aryl, heterocyclyl, heteroaryl, C3-C7
cycloalkyl, and C5-C7 cycloalkenyl is selected from the group consisting of phenyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazole,
thiadiazole, furanyl, quinolinyl, isoquinolinyl, isoxazolyl, oxazolyl, thiazolyl, morpholino,
piperidinyl, pyrrolidinyl, thienyl, cyclohexyl, cyclopentyl, cyclohexenyl, and cyclopentenyl.
20. A compound of Claim 19, wherein one of Q1 or Q2 is selected from the
group consisting of (2-hydroxy-ethylamino)-pyrazin-2-yl, lH-pyrazol-4-yl, 1-methyl-1H-
pyrazol-4-yl, 1 -methyl- lH-pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difiuoro-
phenyl, 2,3-dimethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-
pyrimidin-5-yl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-
acetamidophenyl, 2-aminocarbonylphenyl, 2-amino-pyrirnidin-5-yl, 2-chloro-4-methoxy-
pyrimidin-5-yl, 2-chloro-5-fiuoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-
chloro-pyridin-4-yl, 2-difiuoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-
fluoro-3-methoxy-phenyl, 2-fiuoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-
rnethoxy-phenyl, 2-fiuoro-5-methylphenyl, 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-
hydroxymethyl-3-methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-
5-trifluoromethyl-phenyl, 2-methoxy-phenyl, 2-methoxy-pyridin-3-yl, 2-methoxy-
pyrimidin-4-yl, 2-methoxy-thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-
dihydro-pyridin-3-yl, 2-phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-
trifluoromethoxyphenyl, 2-trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-
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isoxazol-4-yl, 3,6-dimethyl-pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonyIphenyl, 3-
bromo-phenyl, 3-chloro-pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-
phenyl, 3-ethyl-4-methyl-phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-
fluorophenyl, 3-fluoro-pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-
methoxycarbonylphenyl, 3-methoxyphenyl, 3-methoxy-pyrazin-2-yl, 3-methyl-3H-
imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl, 3-methyl-pyridin-2-yl, 3-
trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4,5-dimethoxy-pyrimidin-2-yl, 4-amino-
5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-2-fluoro-phenyl, 4-
chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difluoro-2-methyl-phenyl, 4-
ethoxy-5-fluoro-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-pyrimidin-5-yl, 4-ethyl-
lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fluoro-2-methyl-phenyl, 4-fluorophenyl, 4-
methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-raethoxy-pyrimidin-2-yl, 4-
methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-yl, 4-methyl-pyridin-3-yl, 4-
pyrrolidin-l-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-acetyl-thiophen-2-yl, 5-
amino-6-ethoxy-pyrazin-2-yl, 5-amino-6-methoxy-3-methyl-pyrazin-2-yl, 5-amino-6-
methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-chloro-6-methoxy-pyrazin-2-
yl, 5-dimethyIamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-methoxyphenyl, 5-fluoro-4-
methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-fluoro-pyridin-2-yl, 5-
methoxy-pyridin-3-yl, 5-methoxy-tbiophen-2-yl, 5-trifluoromethyl-pyrimidin-2-yl, 6-acetyl-
pyridin-2-yl, 6-chloro-p>Tazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-ethoxy-pyridin-2-yl, 6-fluoro-
pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl, 6-methoxy-5-methylamino-
pyrazin-2-yi, 6-metb.oxy-5-methyl-pyrazin-2-yl, 6-methoxy-pyrazin-2-yl) 6-methoxy-
pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-yl, 6-methyl-pyridin-2-ylJ
5-amino-6-(2.2,2-trifluoroethoxy)pyrazin-2-yl, and6-trifluoromethyl-pyridin-2-yl.
21. A compound of Claim 14 having formula (Ha):
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WO 2007/041362 PCT/US2006/038181

or a tautomer, pharmaceutically acceptable sait, or prodrug thereof, wherein Ra, R,
X, Y, Z, and n are previously defined for formula (II).
22. A compound of Claim 1 having formula (III):

or a stereoisomer, tautomer. pharmaceutically acceptable salt, or prodrug thereof,
wherein
Ra is selected from the group consisting of
(1) hydrogen,
(2) halogen,
(3) hydroxyl,
(4) Ci-C6 alkoxy,
(5) tfaiol,
(6) Ci-Ce alkylthiol,
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(7) substituted or unsubstituted CpCg alkyl,
(8) amino or substituted arnino
(9) substituted or unsubstituted aryl,
(10) substituted or unsubstituted heteroaryl, and
(11) substituted or unsubstituted heterocyclyl;
R4 is hydrogen or substituted or unsubstituted Cj-Cg alkyl;
R5 is hydrogen, alkyl, alkoxy, or halo;
each of R6, R7, R8, and R9 are independently selected from the group consisting of
hydrogen, alkyl, alkoxy, halo, substituted or unsubstituted aryl, and substituted or
unsubstituted heteroaryl; or
a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, and
with the proviso that when Ra is amino and R6, R7, R8, and R9 are hydrogen, then R5 is not
hydrogen, alkyl, alkoxy, or halo.
23. A compound of Claim 22 wherein Ra is hydrogen.
24. A compound of Claim 22 wherein Ra is substituted or unsubstituted CpCs
alkyl.
25. A compound of Claim 24 wherein Ra is methyl.
26. A compound of Claim 25, wherein R4 is selected from the group consisting
of hydrogen, benzyl, l-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-
morpholinopropyl.
27. A compound of Claim 26, wherein R4 is hydrogen.
28. A compound of Claim 22, wherein R5 is hydrogen or fluoro.
29. A compound of Claim 22, wherein R7, R8, and R9 are each hydrogen.
30. A compound of Claim 22, wherein R6 is selected from the group consisting
of substituted aryl and substituted heteroaryl.
31. A compound of Claim 30, wherein said aryl and heteroaryl is selected from
the group consisting of furanyl, pyrrolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazole, thiadiazole, quinolinyl,
isoquinolinyl, isoxazolyl, oxazolyl, thiazolyl, and thienyl.
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WO 2007/041362 PCT/US2006/038181
32. A compound of Claim 31, wherein R6 is selected from the group consisting
of (2-hydroxy-ethylamino)-pyrazin-2-yl, lH-pyrazol-4-yl, 1 -methyl-lH-pyrazol-4-yl, 1-
methyl-lH-pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-phenyl, 2,3-
dimethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-
yl, 2,5-difiuoro-phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-acetamidophenyl,
2-aminocarbonylphenyl, 2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-pyrimidin-5-yl, 2-
chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl,
2-difluoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-fluoro-3-methoxy-
phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxy-phenyl, 2-
fluoro-5-methylphenyl, 2-fluorophenyl, 2-fluoro-pyridin-3-yl, 2-hydroxymethyl-3-
methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-5-trifluoromethyl-
phenyl, 2-methoxy-phenyl, 2-methoxy-pyridin-3-yl, 2-methoxy-pyrimidin-4-yl, 2-methoxy-
thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-dihydro-pyridin-3-yl, 2-
phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-
trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazol-4-yl, 3,6-dimethyl-
pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl, 3-bromo-phenyl, 3-chloro-
pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-methyl-
phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-fluorophenyl, 3-fluoro-
pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-methoxycarbonylphenyl, 3-methoxyphenyl,
3-methoxy-pyrazin-2-yl, 3-methyl-3H-imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl, 3-
methyl-pyridin-2-yl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4,5-dimethoxy-
pyrimidin-2-yl, 4-amino-5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-
2-fluoro-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difluoro-2-
methyl-phenyl, 4-ethoxy-5-fluoro-pyriniidin-2-yl. 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-
pyrimidin-5-yl, 4-ethyl-lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fluoro-2-methyl-:
phenyl, 4-fluorophenyl, 4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-
methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-
yl, 4-methyl-pyridin-3-yl, 4-pyrrolidin-l-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-
acetyl-thiophen-2-yl, 5-amino-6-ethoxy-pyrazin-2-yl, 5-amino-6-methoxy-3 -methyl-
pyrazin-2-yl, 5-amino-6-methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-
chloro-6-methoxy-pyrazin-2-yl, 5-dimethylamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-
methoxyphenyl, 5-fluoro-4-methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-
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fluoro-pyridin-2-yl, 5-methoxy-pyridin-3-yl, 5-methoxy-thiophen-2-yl, 5-trifluoromethyl-
pyrimidin-2-yl, 6-acetyl-pyridin-2-yl, 6-chloro-pyrazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-
ethoxy-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl, 6-
methoxy-5-methylamino-pyrazin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yl, 6-methoxy-
pyrazin-2-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-
yl, 6-methyl-pyridin-2-yl, 5-amino-6-(2,2,2-trifluoroethoxy)pyrazin-2-yl, and 6-
trifluoromethyl-pyridin-2-yl.
33. A compound of Claim 22 having formula (Ilia):

or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein Ra, R4,
X, Y, Z, and n are as previously defined for formula (III) and with the proviso that when Ra
is amino and R6, R7, R8, and R9 are hydrogen, then R5 is not hydrogen, alkyl, alkoxy, or
halo.
34. A compound of Claim 1 having formula (TV):

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WO 2007/041362 PCT/US2006/038181
or a stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof,
wherein
R4 is hydrogen or substituted or unsubstituted CpCg alkyl,
R5 is hydrogen or halo,
R6a is selected from the group consisting of hydrogen, halo, substituted or
unsubstituted aryl, and substituted or unsubstituted heteroaryl.
35. A compound of Claim 34, wherein R4 is selected from the group consisting
of hydrogen, benzyl, l-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and 2-methyl-2-
morphoiinopropyi.
36. A compound of Claim 35, wherein R5 is hydrogen or fluoro.
37. A compound of Claim 34, wherein R6a is selected from the group consisting
of substituted aryl and substituted heteroaryl.
38. A compound of Claim 37, wherein said aryl and heteroaryl is selected from
the group consisting of furanyl, pyrrolyl, phenyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, pyrazolyl, imidazolyl, triazolyl, indolyl, oxadiazole, thiadiazole, quinolinyl,
isoquinolinyl, isoxazolyl, oxazolyl, thiazolyl, and thienyl.
39. A compound of Claim 3 8, wherein R6a is selected from the group consisting
of (2-hydroxy-ethylamino)-pyrazin-2-yl, lH-pyrazol-4-yl, 1 -methyl- lH-pyrazol-4-yl, 1-
methyl-lH-pyrazol-4-yl, 2-(5-methyl-pyridin-2-yl)-phenyl, 2,3-difluoro-phenyl, 2,3-
dimethoxy-phenyl, 2,4-difluoro-phenyl, 2,4-dimethoxy-phenyl, 2,4-dimethoxy-pyrimidin-5-
yl, 2,5-difluoro-phenyl, 2,6-difluoro-phenyl, 2,6-dimethyl-pyridin-3-yl, 2-acetamidophenyl,
2-aminocarbonylphenyl, 2-amino-pyrimidin-5-yl, 2-chloro-4-methoxy-pyrimidin-5-yl, 2-
chloro-5-fluoro-pyridin-3-yl, 2-chloro-phenyl, 2-chloro-pyridin-3-yl, 2-chloro-pyridin-4-yl,
2-difluoro-3-methoxyphenyl, 2-ethyl-phenyl, 2-ethoxy-thiazol-4-yl, 2-fiuoro-3-methoxy-
phenyl, 2-fluoro-3-methylphenyl, 2-fluoro-4-methyl-phenyl, 2-fluoro-5-methoxy-phenyl, 2-
fluoro-5-methylphenyl, 2-fiuorophenyl, 2-fluoro-pyridin-3-yl, 2-hydroxymethyl-3-
methoxyphenyl, 2-hydroxymethylphenyl, 2-isoquinolin-4-yl, 2-methoxy-5-trifluoromethyl-
phenyl, 2-methoxy-phenyl, 2-methoxy-pyridin-3-yl, 2-methoxy-pyrimidin-4-yl, 2-methoxy-
thiazol-4-yl, 2-methyl-phenyl, 2-methyl-pyridin-3-yl, 2-oxo-l,2-dihydro-pyridin-3-yl, 2-
phenoxyphenyl, 2-pyridin-3-yl, 2-pyrimidin-5-yl, 2-trifluoromethoxyphenyl, 2-
trifluoromethoxy-phenyl, 3,4-dimethoxy-phenyl, 3,5-dimethyl-isoxazol-4-yl, 3,6-dimethyl-
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WO 2007/041362 PCT/US2006/0J8181
pyrazin-2-yl, 3-acetamidophenyl, 3-aminocarbonylphenyl, 3-bromo-phenyl, 3-chloro-
pyrazin-2-yl, 3-cyanophenyl, 3-dimethylaminophenyl, 3-ethoxy-phenyl, 3-ethyl-4-methyl-
phenyl, 3-ethynyl-phenyl, 3-fluoro-6-methoxy-pyridin-2-yl, 3-fluorophenyl, 3-fluoro-
pyrazin-2-yl, 3-methanesulfonamidophenyl, 3-methoxycarbonylphenyl, 3-methoxyphenyl,
3-methoxy-pyrazin-2-yl, 3-methyi-3H-imidazo[4,5-b]pyrazin-5-yl, 3-methylphenyl, 3-
methyl-pyridin-2-yl, 3-trifluoromethoxyphenyl, 3-trifluoromethylphenyl, 4,5-dimethoxy-
pyrimidin-2-yl, 4-amino-5-fluoro-pyrimidin-2-yl, 4-chloro-2,5-dimethoxy-phenyl, 4-chloro-
2-fiuoro-phenyl, 4-chloro-2-methoxy-5-methyl-phenyl, 4-chloro-pyridin-3-yl, 4-difluoro-2-
methyl-phenyl, 4-ethoxy-5-fl-uoro-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl, 4-ethoxy-
pyrimidin-5-yl, 4-ethyl-lH-pyrazol-3-yl, 4-fluoro-2-methoxy-phenyl, 4-fluoro-2-methyl-
phenyl, 4-fluorophenyl, 4-methoxy-5-methyl-pyrimidin-2-yl, 4-methoxy-pyridin-3-yl, 4-
methoxy-pyrimidin-2-yl, 4-methoxy-pyrimidin-5-yl, 4-methyl-phenyl, 4-methyl-pyridin-2-
yl, 4-methyl-pyridin-3-yl, 4-pyrrolidin-l-yl-pyrimidin-2-yl, 5,6-dimethoxy-pyrazin-2-yl, 5-
acetyl-tbiophen-2-yl, 5~amino-6-ethoxy-pyrazin-2-yl, 5-amino-6-methoxy-3-methyl-
pyrazin-2-yl, 5-amino-6-methoxy-pyridin-2-yl, 5-chloro-4-methoxy-pyrimidin-2-yl, 5-
chloro-6-methoxy-pyrazin-2-yl, 5-dimethylamino-6-methoxy-pyrazin-2-yl, 5-fluoro-2-
methoxyphenyl, 5-fluoro-4-methoxy-pyrimidin-2-yl, 5-fluoro-6-methoxy-pyrazin-2-yl, 5-
fluoro-pyridin-2-yl, 5-methoxy-pyridin-3-yl, 5-methoxy-thiophen-2-yl, 5-trifluoromethyl-
pyrimidin-2-yl, 6-acetyl-pyridin-2-yl, 6-chloro-pyrazin-2-yl, 6-ethoxy-pyrazin-2-yl, 6-
ethoxy-pyridin-2-yl, 6-fluoro-pyridin-2-yl, 6-fluoro-pyridin-3-yl, 6-hydroxy-pyridin-2-yl, 6-
methoxy-5-methylamino-pyrazin-2-yl, 6-methoxy-5-methyl-pyrazin-2-yl, 6-medioxy-
pyrazin-2-yl, 6-methoxy-pyridin-2-yl, 6-methoxy-pyridin-3-yl, 6-methylamino-pyrazin-2-
yl, 6-methyl-pyridin-2-yl, 5-amino-6-(2^,2-trifluoroethoxy)pyrazin-2-yl, and 6-
trifluoromethyl-p>Tidin-2-yl.
40. A compound of Claim 34 having formula (FVa):
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WO 2007/041362 PCT/US2006/038181

or a tautomer, pharmaceutically acceptable salt, or prodrug thereof, wherein
R4, R5, and R6a are as previously defined for formula (TV).
41. A compound of Claim 14 having formula (V):

wherein R10 and Ri! are independently Ql, and Ra, R, Q1, and Q2 are as previously
defined for formula (II).
42. A compound of Claim 41 having formula (Va):
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WO 2007/041362 PCT/US2006/038181

wherein R10 and R11 are independently Q1, and Ra, R, Q1, and Q2 are as previously
defined for formula (V).
43. A compound or a stereoisomer, tautomer, or pharmaceutically acceptable salt
thereof of Claim 1 selected from Tables 1-5.
44. A composition comprising a pharmaceutically acceptable carrier and a
compound of any one of Claims 1 to 43.
45. The composition of Claim 44, further comprising at least one additional
agent selected from the group consisting of irinotecan, topotecan, gemcitabine, imatinib,
trastuzumab, 5-fluorouracil, leucovorin, carboplatin, cisplatin, taxanes, tezacitabine,
cyclophosphamide, vinca alkaloids, geftinib, vatalanib, sunitinib, sorafenib, erlotinib,
dexrazoxane, anthracyclines, and rituximab.
46. A method for treating a condition by modulating HSP90 activity comprising
administering to a human or animal subject in need of such treatment an effective amount of
a composition of Claim 44.
47. The method of Claim 46, wherein the condition is cancer.
48. Use of a compound of any one of Claims 1 to 43 in the manufacture of a
medicament for treating a condition in a human or animal subject by modulating HSP90
activity.
49. The use of Claim 48 wherein the condition is cancer.
50. A compound of Claim 1 for use in the treatment of cancer.
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WO 2007/041362 PCT/US2006/038181
51. A method for preparing a compound of Claim 1 of formula (I) or a
stereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, comprising
(a) reacting a compound of formula (I) with an acid to form an acid addition
salt; or
(b) reacting an acid addition salt of formula (I) to form a free base compound of
formula (I); or
(c) reacting an intermediate compound of formula (VI) with guanidine or a
guanidine derivative

wherein Ra, R, and Rb are as defined for formula (I) and W is O or NR'R" where R1
and R" are independently H or alkyl to form a compound of formula (I).
52. The intermediate compound of Claim 51 having formula (VI).
53. The intermediate compound of Claim 52 wherein Ra is methyl.
54. The intermediate compound of Claim 52 having formula (VII) •

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WO 2007/041362 PCT/US2006/038181
R is as defined for formula (VI);
R5 is hydrogen or halo; and R6a is selected from the group consisting of halo,
substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.
-131-

Disclosed are 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, their stereoisomers, tautomers,
pharmaceutically acceptable salts, and prodrugs thereof; compositions that include a pharmaceutically acceptable carrier and one
or more of the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one
additional therapeutic agent. Disclosed also are methods of using the 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds, either alone or in combination with at least one additional therapeutic agent, in the prophylaxis or treatment of cellular
proliferative, viral, autoimmune, cardiovascular, and central nevous system diseases.

Documents:

01243-kolnp-2008-abstract.pdf

01243-kolnp-2008-claims.pdf

01243-kolnp-2008-correspondence others.pdf

01243-kolnp-2008-description complete.pdf

01243-kolnp-2008-form 1.pdf

01243-kolnp-2008-form 3.pdf

01243-kolnp-2008-form 5.pdf

01243-kolnp-2008-gpa.pdf

01243-kolnp-2008-international publication.pdf

01243-kolnp-2008-international search report.pdf

01243-kolnp-2008-others.pdf

01243-kolnp-2008-pct priority document notification.pdf

01243-kolnp-2008-pct request form.pdf

1243-KOLNP-2008-(03-12-2013)-CLAIMS.pdf

1243-KOLNP-2008-(03-12-2013)-CORRESPONDENCE.pdf

1243-KOLNP-2008-(03-12-2013)-DESCRIPTION PAGES.pdf

1243-KOLNP-2008-(03-12-2013)-FORM-13.pdf

1243-KOLNP-2008-(03-12-2013)-OTHERS.pdf

1243-KOLNP-2008-(11-11-2013)-ANNEXURE TO FORM 3.pdf

1243-KOLNP-2008-(11-11-2013)-CORRESPONDENCE.pdf

1243-KOLNP-2008-(14-06-2013)-ABSTRACT.pdf

1243-KOLNP-2008-(14-06-2013)-AMANDED PAGES OF SPECIFICATION.pdf

1243-KOLNP-2008-(14-06-2013)-ANNEXURE TO FORM-3.pdf

1243-KOLNP-2008-(14-06-2013)-CLAIMS.pdf

1243-KOLNP-2008-(14-06-2013)-CORRESPONDENCE.pdf

1243-KOLNP-2008-(14-06-2013)-FORM-2.pdf

1243-KOLNP-2008-(14-06-2013)-PETITION UNDER RULE 137.pdf

1243-KOLNP-2008-CORRESPONDENCE 1.1.pdf

1243-kolnp-2008-form 18.pdf

1243-KOLNP-2008-FORM 3 1.1.pdf


Patent Number 260029
Indian Patent Application Number 1243/KOLNP/2008
PG Journal Number 14/2014
Publication Date 04-Apr-2014
Grant Date 31-Mar-2014
Date of Filing 27-Mar-2008
Name of Patentee NOVARTIS AG
Applicant Address LICHTSTRASSE, 35, CH-4056 BASEL
Inventors:
# Inventor's Name Inventor's Address
1 MCBRIDE, CHRISTOPHER C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
2 ANTONIOS-MCCREA, WILLIAM C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
3 DOUGHAN, BRANDON M C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
4 LEVINE, BARRY H C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
5 XIA, YI C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
6 MCKENNA, MAUREEN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
7 WANG, X, MICHAEL C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
8 MENDENHALL, KRIS C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
9 ZHOU, YASHEEN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
10 TULINSKY, JOHN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
11 GONG, BAOQING C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
12 GU, DAN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
13 DOLAN, JOHN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
14 POON, DANIEL C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
15 MACHAJEWSKI, TIMOTHY D C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
16 BRINNER, KRISTIN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
17 GAO, ZHENHAI C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
18 BARSANTI, PAUL A C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
19 LIN, XIAODONG C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
20 COSTALES, ABRAN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
21 RICO, ALICE C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
22 BRAMMEIER, NATHAN C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
23 PICK, TERESA C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
24 RENHOWE, PAUL A C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
25 SHAFER, CYNTHIA C/O NOVARTIS VACCINES AND DIAGNOSTICS, INC., P.O. BOX 8097, EMERYVILLE, CA 94662-8097
PCT International Classification Number C07D 471/04
PCT International Application Number PCT/US2006/038181
PCT International Filing date 2006-09-28
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/722796 2005-09-30 U.S.A.
2 60/836886 2006-08-09 U.S.A.