U.S. patent application number 12/462302 was filed with the patent office on 2010-01-07 for 2-amino-7,8-dihydro-6h-pyrido[4,3-d]pyrimidin-5-ones.
Invention is credited to William Antonios-McCrea, Paul Barsanti, Nathan Brammeier, Kristin Brinner, Abran Costales, John Dolan, Brandon M. Doughan, Zhenhai Gao, Baoqing Gong, Dan Gu, Barry H. Levine, Xiaodong Lin, Timothy D. Machakewski, Christopher McBride, Maureen McKenna, Kris Mendenhall, Teresa Pick, Daniel Poon, Paul A. Renhowe, Alice Rico, Cynthia M. Shafer, John Tulinsky, X. Michael Wang, Yi Xia, Yasheen Zhou.
Application Number | 20100004237 12/462302 |
Document ID | / |
Family ID | 37661234 |
Filed Date | 2010-01-07 |
United States Patent
Application |
20100004237 |
Kind Code |
A1 |
Machakewski; Timothy D. ; et
al. |
January 7, 2010 |
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
nervous system diseases.
Inventors: |
Machakewski; Timothy D.;
(Emeryville, CA) ; Shafer; Cynthia M.;
(Emeryville, CA) ; McBride; Christopher;
(Emeryville, CA) ; Antonios-McCrea; William;
(Emeryville, CA) ; Doughan; Brandon M.;
(Emeryville, CA) ; Levine; Barry H.; (Emeryville,
CA) ; Xia; Yi; (Emeryville, CA) ; McKenna;
Maureen; (Emeryville, CA) ; Wang; X. Michael;
(Emeryville, CA) ; Mendenhall; Kris; (Emeryville,
CA) ; Zhou; Yasheen; (Emeryville, CA) ; Gong;
Baoqing; (Emeryville, CA) ; Gu; Dan;
(Emeryville, CA) ; Dolan; John; (Emeryville,
CA) ; Tulinsky; John; (Emeryville, CA) ;
Brinner; Kristin; (Emeryville, CA) ; Gao;
Zhenhai; (Emeryville, CA) ; Poon; Daniel;
(Emeryville, CA) ; Barsanti; Paul; (Emeryville,
CA) ; Lin; Xiaodong; (Emeryville, CA) ;
Costales; Abran; (Emeryville, CA) ; Rico; Alice;
(Emeryville, CA) ; Brammeier; Nathan; (Emeryville,
CA) ; Pick; Teresa; (Emeryville, CA) ;
Renhowe; Paul A.; (Emeryville, CA) |
Correspondence
Address: |
NOVARTIS INSTITUTES FOR BIOMEDICAL RESEARCH, INC.
220 MASSACHUSETTS AVENUE
CAMBRIDGE
MA
02139
US
|
Family ID: |
37661234 |
Appl. No.: |
12/462302 |
Filed: |
July 31, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
11541462 |
Sep 28, 2006 |
|
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12462302 |
|
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60722796 |
Sep 30, 2005 |
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60836886 |
Aug 9, 2006 |
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Current U.S.
Class: |
514/234.2 ;
514/255.05; 514/264.11; 544/117; 544/279; 546/243 |
Current CPC
Class: |
A61P 35/00 20180101;
C07D 211/86 20130101; C07D 471/04 20130101 |
Class at
Publication: |
514/234.2 ;
514/255.05; 514/264.11; 544/117; 544/279; 546/243 |
International
Class: |
C07D 471/04 20060101
C07D471/04; A61K 31/5377 20060101 A61K031/5377; A61K 31/497
20060101 A61K031/497; A61K 31/519 20060101 A61K031/519 |
Claims
1-22. (canceled)
23. 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 compound, a stereoisomer,
tautomer, oxide, or ester of Formula (I) or a pharmaceutically
acceptable salt thereof ##STR00327## effective to inhibit HSP90
activity in the human or animal subject, wherein R.sup.a is
selected from the group consisting of (1) hydrogen, (2) halogen,
(3) hydroxyl, (4) C.sub.1-C.sub.6 alkoxy, (5) thiol, (6)
C.sub.1-C.sub.6 alkylthiol, (7) substituted or unsubstituted
C.sub.1-C.sub.6 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 C.sub.1-C.sub.6 alkyl,
(3) substituted or unsubstituted C.sub.2-C.sub.6 alkenyl, (4)
substituted or unsubstituted C.sub.2-C.sub.6 alkynyl, (5)
substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, (6)
substituted or unsubstituted C.sub.5-C.sub.7 cycloalkenyl. (7)
substituted or unsubstituted aryl, (8) substituted or unsubstituted
heteroaryl, and (9) substituted or unsubstituted heterocyclyl;
R.sup.b is selected from the group consisting of (1) substituted or
unsubstituted C.sub.3-C.sub.7 cycloalkyl, (2) substituted or
unsubstituted C.sub.5-C.sub.7 cycloalkenyl, (3) substituted or
unsubstituted aryl, (4) substituted or unsubstituted heteroaryl,
and (5) substituted or unsubstituted heterocyclyl; and with the
proviso that when R.sup.a is amino, then R.sup.b is not phenyl,
4-alkyl-phenyl, 4-alkoxy-phenyl, or 4-halo-phenyl.
24. The method of claim 23, wherein the condition is cancer.
25. A method for preparing a compound 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 ##STR00328## wherein
R.sup.a, R, and R.sup.b are as defined for formula (I) and W is O
or NR'R'' where R' and R'' are independently H or alkyl to form a
compound of formula (I).
26. The intermediate compound of claim 25 having formula (VI).
27. The intermediate compound of claim 26 wherein R.sup.a is
methyl.
28. The intermediate compound of claim 26 having formula (VII)
##STR00329## wherein R is as defined for formula (VI); R.sup.5 is
hydrogen or halo; and R.sup.6a is selected from the group
consisting of halo, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. 119(e)
to provisional applications U.S. Ser. No. 60/722,796 filed on Sep.
30, 2005, and U.S. Ser. No. 60/836,886 filed on Aug. 9, 2006, each
of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
[0002] 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
[0003] 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.
[0004] The HSP90 family, comprised of HSP90.alpha. and .beta.,
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
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.
[0005] 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.
[0006] 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-1.alpha.) 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, Myt1), 3)
evasion of apoptosis (Akt, RIP), 4) acquisition of limitless
replicative potential (hTERT), 5) sustained angiogenesis
(HIF-1.alpha., 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.
[0007] 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
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.
[0008] Cancer cells are highly adaptive to hostile
microenvironments and are capable of acquiring drug 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..sup.20-23 The cancers
include, for example, breast cancer.sup.1, ovarian.sup.2,
prostate.sup.3, chronic myelogenous leukemia (CML).sup.4,
melanoma.sup.5, gastrointestinal stromal tumors (GISTs).sup.6,
master cell leukemia.sup.7, testicular tumor.sup.7, acute
myelogenous leukemia.sup.8,9, gastric tumor.sup.10, lung.sup.11,
head and neck.sup.12, glioblastoma.sup.13, colon.sup.14,
thyroid.sup.15, stomach, liver, multiple myeloma.sup.16,
renal.sup.17, and lymphoma.sup.18,19.
[0009] 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.
SUMMARY OF THE INVENTION
[0010] In one aspect of the present invention, new
2-amino-7,8-dihydro-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 are HSP90
inhibitors and are useful in treating cellular proliferative,
viral, autoimmune, cardiovascular and central nervous system
diseases.
[0011] In one embodiment, the
2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds have
the formula (I):
##STR00001##
[0012] or a stereoisomer, tautomer, pharmaceutically acceptable
salt, or prodrug thereof, wherein
[0013] R.sup.a is selected from the group consisting of [0014] (1)
hydrogen, [0015] (2) halogen, [0016] (3) hydroxyl, [0017] (4)
C.sub.1-C.sub.6 alkoxy, [0018] (5) thiol, [0019] (6)
C.sub.1-C.sub.6 alkylthiol, [0020] (7) substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, [0021] (8) amino or substituted amino,
[0022] (9) substituted or unsubstituted aryl, [0023] (10)
substituted or unsubstituted heteroaryl, and [0024] (11)
substituted or unsubstituted heterocyclyl;
[0025] R is selected from the group consisting of [0026] (1)
hydrogen, [0027] (2) substituted or unsubstituted C.sub.1-C.sub.6
alkyl, [0028] (3) substituted or unsubstituted C.sub.2-C.sub.6
alkenyl, [0029] (4) substituted or unsubstituted C.sub.2-C.sub.6
alkynyl, [0030] (5) substituted or unsubstituted C.sub.3-C.sub.7
cycloalkyl, [0031] (6) substituted or unsubstituted C.sub.5-C.sub.7
cycloalkenyl, [0032] (7) substituted or unsubstituted aryl, [0033]
(8) substituted or unsubstituted heteroaryl, and [0034] (9)
substituted or unsubstituted heterocyclyl;
[0035] R.sup.b is selected from the group consisting of [0036] (1)
substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, [0037] (2)
substituted or unsubstituted C.sub.5-C.sub.7 cycloalkenyl, [0038]
(3) substituted or unsubstituted aryl, [0039] (4) substituted or
unsubstituted heteroaryl, and [0040] (5) substituted or
unsubstituted heterocyclyl;
[0041] with the proviso that when R.sup.a is amino, then R.sup.b is
not phenyl, 4-alkyl-phenyl, 4-alkoxy-phenyl, or 4-halo-phenyl.
[0042] 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.
[0043] 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.
[0044] 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.
[0045] In one embodiment, provided are compounds, compositions, and
methods for treating a condition by modulating HSP90 activity. In
some aspects, the condition is a cellular proliferative, viral,
autoimmune, cardiovascular, or central nervous system disease.
[0046] 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.
[0047] 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).
[0048] 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.
[0049] In one embodiment, provided are compounds, compositions, and
methods for treating a cardiovascular or central nervous system
disease.
[0050] 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
[0051] 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.
[0052] 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):
##STR00002##
[0053] or a stereoisomer, tautomer, pharmaceutically acceptable
salt, or prodrug thereof, wherein
[0054] R.sup.a is selected from the group consisting of [0055] (1)
hydrogen, [0056] (2) halogen, [0057] (3) hydroxyl, [0058] (4)
C.sub.1-C.sub.6 alkoxy, [0059] (5) thiol, [0060] (6)
C.sub.1-C.sub.6 alkylthiol, [0061] (7) substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, [0062] (8) amino or substituted amino,
[0063] (9) substituted or unsubstituted aryl, [0064] (10)
substituted or unsubstituted heteroaryl, and [0065] (11)
substituted or unsubstituted heterocyclyl;
[0066] R is selected from the group consisting of [0067] (1)
hydrogen, [0068] (2) substituted or unsubstituted C.sub.1-C.sub.6
alkyl, [0069] (3) substituted or unsubstituted C.sub.2-C.sub.6
alkenyl, [0070] (4) substituted or unsubstituted C.sub.2-C.sub.6
alkynyl, [0071] (5) substituted or unsubstituted C.sub.3-C.sub.7
cycloalkyl, [0072] (6) substituted or unsubstituted C.sub.5-C.sub.7
cycloalkenyl, [0073] (7) substituted or unsubstituted aryl, [0074]
(8) substituted or unsubstituted heteroaryl, and [0075] (9)
substituted or unsubstituted heterocyclyl;
[0076] R.sup.b is selected from the group consisting of [0077] (1)
substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, [0078] (2)
substituted or unsubstituted C.sub.5-C.sub.7 cycloalkenyl, [0079]
(3) substituted or unsubstituted aryl, [0080] (4) substituted or
unsubstituted heteroaryl, and [0081] (5) substituted or
unsubstituted heterocyclyl; and
[0082] with the proviso that when R.sup.a is amino, then R.sup.b is
not phenyl, 4-alkyl-phenyl, 4-alkoxy-phenyl, or 4-halo-phenyl.
[0083] Other embodiments provide a compound having formula (Ia)
##STR00003##
[0084] or a tautomer, pharmaceutically acceptable salt, or prodrug
thereof, wherein R, R.sup.a, and R.sup.b are as previously defined
for formula (I) and with the proviso that when R.sup.a is amino,
then R.sup.b is not phenyl, 4-alkyl-phenyl, 4-alkoxy-phenyl, or
4-halo-phenyl.
[0085] In some embodiments of the compounds of formula (I) or (Ia),
R.sup.a is hydrogen.
[0086] In other embodiments, R.sup.a is substituted or
unsubstituted C.sub.1-C.sub.6 alkyl.
[0087] In some embodiments, R.sup.a is C.sub.1-C.sub.6 alkyl or
halo C.sub.1-C.sub.6 alkyl. In some such embodiments, R.sup.a is
methyl.
[0088] In some embodiments, R.sup.b is aryl or heteroaryl. In some
such embodiments, R.sup.b 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 R.sup.b groups are substituted with substituted or
unsubstituted aryl, or substituted or unsubstituted heteroaryl. In
other aspects the R.sup.b groups are substituted with halo. In
still other aspects the R.sup.b groups are substituted with fluoro.
In still other aspects, the R.sup.b groups are substituted with
alkyl, haloalkyl, alkoxy, and haloalkoxy. In some aspects, the
R.sup.b groups are substituted with methyl. In other aspects, the
R.sup.b groups are substituted with methoxy.
[0089] In other embodiments, R.sup.b is selected from the group
consisting of substituted aryl, substituted heterocyclyl,
substituted heteroaryl, substituted C.sub.3-C.sub.7 cycloalkyl, and
substituted C.sub.5-C.sub.7 cycloalkenyl, wherein said aryl,
heterocyclyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, and
C.sub.5-C.sub.7 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.
[0090] 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, 1-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and
2-methyl-2-morpholinopropyl. In still other embodiment, R is
hydrogen.
[0091] In another embodiment, the
2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds have
the formula (II):
##STR00004##
[0092] or a stereoisomer, tautomer, pharmaceutically acceptable
salt, or prodrug thereof, wherein
[0093] n is 0 or 1,
[0094] wherein R.sup.a is selected from the group consisting of
[0095] (1) hydrogen, [0096] (2) halogen, [0097] (3) hydroxyl,
[0098] (4) C.sub.1-C.sub.6 alkoxy, [0099] (5) thiol, [0100] (6)
C.sub.1-C.sub.6 alkylthiol, [0101] (7) substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, [0102] (8) amino or substituted amino,
[0103] (9) substituted or unsubstituted aryl, [0104] (10)
substituted or unsubstituted heteroaryl, and [0105] (11)
substituted or unsubstituted heterocyclyl;
[0106] wherein R is selected from the group consisting of [0107]
(1) hydrogen, [0108] (2) substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, [0109] (3) substituted or unsubstituted
C.sub.2-C.sub.6 alkenyl, [0110] (4) substituted or unsubstituted
C.sub.2-C.sub.6 alkynyl, [0111] (5) substituted or unsubstituted
C.sub.3-C.sub.7 cycloalkyl, [0112] (6) substituted or unsubstituted
C.sub.5-C.sub.7 cycloalkenyl, [0113] (7) substituted or
unsubstituted aryl, [0114] (8) substituted or unsubstituted
heteroaryl, and [0115] (9) substituted or unsubstituted
heterocyclyl,
[0116] wherein when n is 1, X is C, Y is at each position
independently selected from CQ.sup.1 and N, and Z is selected from
CR.sup.2 and N with the proviso that no more than 3 Y and Z groups
are N, and
[0117] wherein when n is 0, X is C or N, Y is at each position
independently selected from CQ.sup.1, N, NQ.sup.2, O, and S with
the proviso that no more than 4 X and Y groups are N and NQ.sup.2
and no more than 1 Y group is S or O;
[0118] wherein Q.sup.1 is at each position independently selected
from the group consisting of [0119] (1) hydrogen, [0120] (2)
halogen, [0121] (3) substituted or unsubstituted C.sub.1-C.sub.6
alkyl, [0122] (4) substituted or unsubstituted C.sub.2-C.sub.6
alkenyl, [0123] (5) substituted or unsubstituted C.sub.2-C.sub.6
alkynyl, [0124] (6) substituted or unsubstituted C.sub.3-C.sub.7
cycloalkyl, [0125] (7) substituted or unsubstituted C.sub.5-C.sub.7
cycloalkenyl, [0126] (8) substituted or unsubstituted aryl, [0127]
(9) substituted or unsubstituted heteroaryl, [0128] (10)
substituted or unsubstituted heterocyclyl, [0129] (11) substituted
or unsubstituted amino, [0130] (12) --OR.sup.3 or --SR.sup.3,
[0131] (13) --C(O)R.sup.3, --CO.sub.2R.sup.3,
--C(O)N(R.sup.3).sub.2, --S(O)R.sup.3, --SO.sub.2R.sup.3, or
--SO.sub.2N(R.sup.3).sub.2, [0132] (14) --OC(O)R.sup.3,
--N(R.sup.3)C(O)R.sup.3, or --N(R.sup.3)SO.sub.2R.sup.3, [0133]
(15) --CN, and [0134] (16) --NO.sub.2;
[0135] wherein Q.sup.2 is at each position independently selected
from the group consisting of [0136] (1) hydrogen, [0137] (3)
substituted or unsubstituted C.sub.1-C.sub.6 alkyl, [0138] (4)
substituted or unsubstituted C.sub.2-C.sub.6 alkenyl, [0139] (5)
substituted or unsubstituted C.sub.2-C.sub.6 alkynyl, [0140] (6)
substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, [0141] (7)
substituted or unsubstituted C.sub.5-C.sub.7 cycloalkenyl, [0142]
(8) substituted or unsubstituted aryl, [0143] (9) substituted or
unsubstituted heteroaryl, and [0144] (10) substituted or
unsubstituted heterocyclyl;
[0145] wherein R.sup.2 is selected from the group consisting of
[0146] (1) hydrogen, [0147] (2) halogen, [0148] (3) substituted or
unsubstituted C.sub.1-C.sub.3 alkyl, and [0149] (4) --OR.sup.3,
--SR.sup.3, or --NHR.sup.3;
[0150] wherein R.sup.3 is at each position independently selected
from the group consisting of [0151] (1) hydrogen, [0152] (2)
substituted or unsubstituted C.sub.1-C.sub.6 alkyl, [0153] (3)
substituted or unsubstituted C.sub.2-C.sub.6 alkenyl, [0154] (4)
substituted or unsubstituted C.sub.2-C.sub.6 alkynyl, [0155] (5)
substituted or unsubstituted C.sub.3-C.sub.7 cycloalkyl, [0156] (6)
substituted or unsubstituted C.sub.5-C.sub.7 cycloalkenyl, [0157]
(7) substituted or unsubstituted aryl, [0158] (8) substituted or
unsubstituted heteroaryl, and [0159] (9) substituted or
unsubstituted heterocyclyl,
[0160] with the proviso that when R.sup.a 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.
[0161] In other embodiments, the
2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compounds have
the formula (IIa):
##STR00005##
or a tautomer, pharmaceutically acceptable salt, or prodrug
thereof, wherein R.sup.a, R, X, Y, Z, and n are previously defined
for formula (II) and with the proviso that when R.sup.a 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.
[0162] In some embodiments when n is 0, X is C, and Y adjacent to X
is not O.
[0163] In some embodiments of the compounds of formula (II) or
(IIa), R.sup.a is hydrogen.
[0164] In other embodiments, R.sup.a is substituted or
unsubstituted C.sub.1-C.sub.6 alkyl.
[0165] In some embodiments, R.sup.a is C.sub.1-C.sub.6 alkyl or
halo C.sub.1-C.sub.6 alkyl. In some such embodiments, R.sup.a is
methyl.
[0166] For the compounds of formula (I), (Ia), (II), or (IIa),
representative substituted alkyl groups include arylalkyl,
heteroarylalkyl, cycloalkylalkyl, heterocyclylalkyl, aminoalkyl,
alkylaminoalkyl, dialkylaminoalkyl, and sulfonamidoalkyl
groups.
[0167] Representative aryl groups include phenyl groups.
[0168] Representative heteroaryl groups include pyridyl, pyrazinyl,
pyrimidinyl, pyridazinyl, pyrazolyl, indolyl, quinolinyl,
isoquinolinyl, furanyl, oxazolyl, thiazolyl, and thienyl
groups.
[0169] In one embodiment, one of Q.sup.1 or Q.sup.2 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.
[0170] In one embodiment, one of Q.sup.1 or Q.sup.2 is selected
from the group consisting of piperidinyl, morpholinyl,
pyrrolidinonyl, and benzyl amino.
[0171] In one embodiment, one of Q.sup.1 or Q.sup.2 is selected
from the group consisting of cyclohexyl and cyclopentyl.
[0172] In one embodiment, one of Q.sup.1 or Q.sup.2 is selected
from the group consisting of cyclohexenyl and cyclopentenyl.
[0173] In one embodiment, one of Q.sup.1 or Q.sup.2 is selected
from the group consisting of substituted aryl, substituted
heterocyclyl, substituted heteroaryl, substituted C.sub.3-C.sub.7
cycloalkyl, and substituted C.sub.5-C.sub.7 cycloalkenyl, wherein
said aryl, heterocyclyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl,
and C.sub.5-C.sub.7 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.
[0174] In one embodiment, one of Q.sup.1 or Q.sup.2 is selected
from substituted and unsubstituted pyridyl, substituted and
unsubstituted pyrazinyl, substituted and unsubstituted phenyl,
substituted and unsubstituted isoquinolinyl, substituted and
unsubstituted pyrimidinyl, 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.
[0175] In other embodiments one of Q.sup.1 or Q.sup.2 is selected
from the group consisting of (2-hydroxy-ethylamino)-pyrazin-2-yl,
1H-pyrazol-4-yl, 1-methyl-1H-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-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-1,2-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-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl,
4-ethoxy-pyrimidin-5-yl, 4-ethyl-1H-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-1-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, 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.
[0176] In one embodiment Q.sup.1 is halo.
[0177] In one embodiment Q.sup.1 is alkyl. In some aspects, Q.sup.1
is methyl.
[0178] In one embodiment, R.sup.2 is selected from hydrogen and
fluoro. In some aspects, R.sup.2 is fluoro.
[0179] In one embodiment, R.sup.2 is selected from alkyl. In some
aspects, R.sup.2 is methyl.
[0180] In one embodiment, R.sup.2 is selected from alkoxy. In some
aspects, R.sup.2 is methoxy.
[0181] In one embodiment Q.sup.1 is OR.sup.3.
[0182] In one embodiment, R.sup.3 is selected from the group
consisting of methyl, ethyl, isopropyl, cyclopentyl, and
cyclohexyl.
[0183] In one embodiment, R.sup.3 is selected from substituted and
unsubstituted phenyl, substituted and unsubstituted thiazolyl,
substituted and unsubstituted pyridyl, substituted and
unsubstituted pyrazinyl, and substituted and unsubstituted
pyrimidinyl.
[0184] In one embodiment, R.sup.3 is selected from the group
consisting of 2-aminoethyl, 2-piperidinylethyl, 2-piperazinylethyl,
2-morpholinylethyl, and 2-(N-methylpiperazinyl)ethyl.
[0185] 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, 1-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and
2-methyl-2-morpholinopropyl.
[0186] In another embodiment of the invention, compounds of formula
(III) are provided:
##STR00006##
[0187] or a stereoisomer, tautomer, pharmaceutically acceptable
salt, or prodrug thereof, wherein
[0188] wherein R.sup.a is selected from the group consisting of
[0189] (1) hydrogen, [0190] (2) halogen, [0191] (3) hydroxyl,
[0192] (4) C.sub.1-C.sub.6 alkoxy, [0193] (5) thiol, [0194] (6)
C.sub.1-C.sub.6 alkylthiol, [0195] (7) substituted or unsubstituted
C.sub.1-C.sub.6 alkyl, [0196] (8) amino or substituted amino,
[0197] (9) substituted or unsubstituted aryl, [0198] (10)
substituted or unsubstituted heteroaryl, and [0199] (11)
substituted or unsubstituted heterocyclyl;
[0200] R.sup.4 is hydrogen or substituted or unsubstituted
C.sub.1-C.sub.6 alkyl;
[0201] R.sup.5 is hydrogen, alkyl, alkoxy, or halo;
[0202] each of R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are
independently selected from the group consisting of hydrogen,
alkyl, alkoxy, halo, substituted or unsubstituted aryl, and
substituted or unsubstituted heteroaryl; or
[0203] a stereoisomer, tautomer, pharmaceutically acceptable salt,
or prodrug thereof, and with the proviso that when R.sup.a is amino
and R.sup.6, R.sup.7, R.sup.8, and R.sup.9 are hydrogen, then
R.sup.5 is not hydrogen, alkyl, alkoxy, or halo.
[0204] In some embodiments, provided are compounds of formula
(IIa):
##STR00007##
or a tautomer, pharmaceutically acceptable salt, or prodrug
thereof, wherein R.sup.a, R.sup.4, R.sup.5, R.sup.6, R.sup.7,
R.sup.8, and R.sup.9 are as previously defined for formula (III)
and with the proviso that when R.sup.a is amino and R.sup.6,
R.sup.7, R.sup.8, and R.sup.9 are hydrogen, then R.sup.5 is not
hydrogen, alkyl, alkoxy, or halo.
[0205] In some embodiments, R.sup.a is hydrogen.
[0206] In some embodiments, R.sup.a is substituted or unsubstituted
C.sub.1-C.sub.6 alkyl.
[0207] In some embodiments, R.sup.a is C.sub.1-C.sub.6 alkyl or
halo C.sub.1-C.sub.6 alkyl. In some such embodiments, R.sup.a is
methyl.
[0208] In some embodiments of the invention, R.sup.4 is selected
from the group consisting of hydrogen, benzyl,
1-(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.
[0209] In some embodiments, R.sup.5 is hydrogen or fluoro. In some
aspects, R.sup.5 is fluoro.
[0210] In some embodiments, R.sup.5 is methyl or methoxy.
[0211] In some embodiments, R.sup.7, R.sup.8, and R.sup.9 are each
hydrogen.
[0212] In some embodiments, R.sup.6 is aryl or heteroaryl
substituted with one to two substituents selected from the group
consisting of halo, alkoxy, alkyl, amino, alkylamino, haloalkyl,
and haloalkoxy.
[0213] In some embodiments R.sup.6 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.
[0214] In other embodiments R.sup.6 is selected from the group
consisting of (2-hydroxy-ethylamino)-pyrazin-2-yl, 1H-pyrazol-4-yl,
1-methyl-1H-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-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-1,2-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-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl,
4-ethoxy-pyrimidin-5-yl, 4-ethyl-1H-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-1-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, 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.
[0215] In another embodiment of the invention, compounds of formula
(IV) are provided:
##STR00008##
[0216] or a stereoisomer, tautomer, pharmaceutically acceptable
salt, or prodrug thereof, wherein
[0217] R.sup.4 is hydrogen or substituted or unsubstituted
C.sub.1-C.sub.6 alkyl,
[0218] R.sup.5 is hydrogen or halo,
[0219] R.sup.6a is selected from the group consisting of halo,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0220] In some embodiments provided are compounds of formula
(IVa):
##STR00009##
[0221] or a tautomer, pharmaceutically acceptable salt, or prodrug
thereof, wherein
[0222] R.sup.4, R.sup.5, and R.sup.6a are as previously defined for
formula (IV).
[0223] In some embodiments of the compounds of formula (IV) or
(IVa), R.sup.4 is selected from the group consisting of hydrogen,
benzyl, 1-(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.
[0224] In some embodiments, R.sup.5 is hydrogen or fluoro. In some
aspects R.sup.5 is fluoro.
[0225] In some aspects, R.sup.6a is aryl or heteroaryl substituted
with one to two substituents selected from the group consisting of
halo, alkoxy, alkyl, amino, alkylamino, haloalkyl, and
haloalkoxy.
[0226] In some embodiments R.sup.6a 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.
[0227] In some embodiments, R.sup.6a is selected from the group
consisting of (2-hydroxy-ethylamino)-pyrazin-2-yl, 1H-pyrazol-4-yl,
1-methyl-1H-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-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-1,2-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-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl,
4-ethoxy-pyrimidin-5-yl, 4-ethyl-1H-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-1-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, 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.
[0228] In another embodiment, provided are compounds having formula
(V)
##STR00010##
[0229] wherein R.sup.10 and R.sup.11 are independently Q.sup.1, and
R.sup.a, R, Q.sup.1, and Q.sup.2 are as previously defined for
formula (II).
[0230] In another embodiment, 2-amino-quinazolin-5-one compounds
have formula (Va)
##STR00011##
[0231] wherein R.sup.10 and R.sup.11 are independently Q.sup.1, and
R.sup.a, R, Q.sup.1, and Q.sup.2 are as previously defined for
formula (V).
[0232] In some aspects of the compounds of formula (V) and (Va),
R.sup.a is methyl.
[0233] In other aspects of the compounds of formula (V) and (Va),
R.sup.a is hydrogen.
[0234] In some aspects of the compounds of formula (V) and (Va), R
is selected from the group consisting of hydrogen, benzyl,
1-(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.
[0235] In some aspects of the compounds of formula (V) and (Va),
Q.sup.2 is selected from the group consisting of substituted or
unsubstituted aryl, substituted or unsubstituted heterocyclyl,
substituted or unsubstituted heteroaryl, substituted or
unsubstituted C.sub.3-C.sub.7 cycloalkyl, and substituted or
unsubstituted C.sub.5-C.sub.7 cycloalkenyl. In other aspects said
aryl, heterocyclyl, heteroaryl, C.sub.3-C.sub.7 cycloalkyl, and
C.sub.5-C.sub.7 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.
[0236] In other aspects of the compounds of formula (V) and (Va),
Q.sup.2 is selected from the group consisting of
(2-hydroxy-ethylamino)-pyrazin-2-yl, 1H-pyrazol-4-yl,
1-methyl-1H-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-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-1,2-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-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl,
4-ethoxy-pyrimidin-5-yl, 4-ethyl-1H-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-1-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, 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.
[0237] In one embodiment of the compounds of formula (V) and (Va),
R.sup.9 and R.sup.10 are hydrogen. In another aspect one of R.sup.9
or R.sup.10 is hydrogen and the other is halo or C.sub.1-C.sub.6
alkoxy. In some aspects, one of R.sup.9 or R.sup.10 is fluoro. In
other aspects one of R.sup.9 or R.sup.10 is methoxy.
[0238] 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.
[0239] 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
[0240]
(R)-2-amino-7-[2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H--
pyrido[4,3-d]pyrimidin-5-one; [0241]
(S)-2-amino-6-benzyl-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-meth-
yl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0242]
(R)-2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-di-
hydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0243]
(R)-2-amino-7-(2-bromo-4-fluoro-phenyl)-6-[(S)-1-(4-methoxy-phenyl)-ethyl-
]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0244]
(R)-2-amino-7-[2-(6-methoxy-pyridin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-
-pyrido[4,3-d]pyrimidin-5-one; [0245]
(R)-2-amino-7-[4-fluoro-2-(6-methoxy-pyridin-2-yl)-phenyl]-4-methyl-7,8-d-
ihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0246]
2-amino-7-[4-fluoro-2-(6-methoxy-pyridin-2-yl)-phenyl]-4,6-dimethyl-7,8-d-
ihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0247]
2-amino-7-[4-fluoro-2-(2-fluoro-pyridin-3-yl)-phenyl]-4,6-dimethyl-7,8-di-
hydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0248]
2-amino-7-[4-fluoro-2-(6-methoxypyridin-2-yl)phenyl]-4-methyl-7,8-dihydro-
pyrido[4,3-d]pyrimidin-5(6H)-one; [0249]
2-amino-7-[2-(6-methoxy-pyrazin-2-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyr-
ido[4,3-d]pyrimidin-5-one; [0250]
(R)-2-amino-7-[4-fluoro-2-(6-methoxy-pyrazin-2-yl)-phenyl]-4-methyl-7,8-d-
ihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0251]
2-amino-7-[4-fluoro-2-(6-methoxy-pyrazin-2-yl)-phenyl]-4,6-dimethyl-7,8-d-
ihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0252]
2-amino-7-[2-(2-methoxy-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydro-6H-pyr-
ido[4,3-d]pyrimidin-5-one; [0253]
2-amino-7-(5,2'-difluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[4,-
3-d]pyrimidin-5-one; [0254]
2-amino-7-(5-fluoro-2'-trifluoromethoxy-biphenyl-2-yl)-4-methyl-7,8-dihyd-
ro-6H-pyrido[4,3-d]pyrimidin-5-one; [0255]
2-amino-7-[2-(2-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydr-
o-6H-pyrido[4,3-d]pyrimidin-5-one; [0256]
2-amino-7-[4-fluoro-2-(6-fluoro-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihydr-
o-6H-pyrido[4,3-d]pyrimidin-5-one; [0257]
2-amino-7-(4-fluoro-2-isoquinolin-4-yl-phenyl)-4-methyl-7,8-dihydro-6H-py-
rido[4,3-d]pyrimidin-5-one; [0258]
2-amino-7-(5,3'-difluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyrido[4,-
3-d]pyrimidin-5-one; [0259]
2-amino-7-[2-(4-chloro-pyridin-3-yl)-4-fluoro-phenyl]-4-methyl-7,8-dihydr-
o-6H-pyrido[4,3-d]pyrimidin-5-one; [0260]
2-amino-7-(5,2'-difluoro-3'-methoxy-biphenyl-2-yl)-4-methyl-7,8-dihydro-6-
H-pyrido[4,3-d]pyrimidin-5-one; [0261]
2-amino-7-(5,4'-difluoro-2'-methyl-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
-pyrido[4,3-d]pyrimidin-5-one; [0262]
2-amino-7-(5-fluoro-2'-methoxy-biphenyl-2-yl-4-methyl-7,8-dihydro-6H-pyri-
do[4,3-d]pyrimidin-5-one; [0263]
2-amino-7-(4-fluoro-2-pyrimidin-5-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyri-
do[4,3-d]pyrimidin-5-one; [0264]
2-amino-7-[4-fluoro-2-(2-methoxy-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihyd-
ro-6H-pyrido[4,3-d]pyrimidin-5-one; [0265]
2-amino-7-(5-fluoro-3'-methoxy-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-pyr-
ido[4,3-d]pyrimidin-5-one; [0266]
(R)-2-amino-6-(3-amino-propyl)-7-[4-fluoro-2-(6-methoxy-pyridin-2-yl)-phe-
nyl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0267]
2-amino-7-(4-fluoro-2-pyridin-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido-
[4,3-d]pyrimidin-5-one; [0268]
2-amino-7-(5,2'-difluoro-4'-methyl-biphenyl-2-yl)-4-methyl-7,8-dihydro-6H-
-pyrido[4,3-d]pyrimidin-5-one; [0269]
2-amino-7-[4-fluoro-2-(1-methyl-1H-pyrazol-4-yl)-phenyl]-4-methyl-7,8-dih-
ydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0270]
2-amino-7-[4-fluoro-2-(1H-pyrazol-4-yl)-phenyl]-4-methyl-7,8-dihydro-6H-p-
yrido[4,3-d]pyrimidin-5-one; [0271]
2-amino-4-methyl-7-(5,2',3'-trifluoro-biphenyl-2-yl)-7,8-dihydro-6H-pyrid-
o[4,3-d]pyrimidin-5-one; [0272]
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; [0273]
2-amino-7-(3'-dimethylamino-5-fluoro-biphenyl-2-yl)-4-methyl-7,8-dihydro--
6H-pyrido[4,3-d]pyrimidin-5-one; [0274]
2-amino-7-[2-(2,4-dimethoxy-pyrimidin-5-yl)-4-fluoro-phenyl]-4-methyl-7,8-
-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; [0275]
2-amino-7-[4-fluoro-2-(5-methoxy-pyridin-3-yl)-phenyl]-4-methyl-7,8-dihyd-
ro-6H-pyrido[4,3-d]pyrimidin-5-one; [0276]
2-amino-7-(4-fluoro-2-pyrimidin-5-yl-phenyl)-4-methyl-6-(2-methyl-2-morph-
olin-4-yl-propyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
[0277]
2-amino-7-[4-fluoro-2-(2-methoxy-pyridin-3-yl)-phenyl]-4-methyl-6-(2-meth-
yl-2-morpholin-4-yl-propyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
[0278]
2-amino-7-(5-fluoro-3'-methoxy-biphenyl-2-yl)-4-methyl-6-(2-methyl-
-2-morpholin-4-yl-propyl)-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one;
[0279]
(R)-2-amino-7-[4-fluoro-2-(4-methoxy-5-methyl-pyrimidin-2-yl)-phen-
yl]-4-methyl-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one; and
[0280]
2-amino-7-(4-fluoro-2-furan-3-yl-phenyl)-4-methyl-7,8-dihydro-6H-pyrido[4-
,3-d]pyrimidin-5-one.
[0281] 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.
[0282] 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.
[0283] In other aspects, the present invention provides
compositions that include the HSP90 inhibitors described herein,
and methods that utilize the HSP90 inhibitors described herein.
[0284] 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), (Ia), (II), (IIa), (III), (IIIa), (IV),
(IVa), (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.
[0285] 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-pyrido[4,3-d]pyrimidin-5-one compounds of
the invention are known to those skilled in the art.
[0286] 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, 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.
[0287] 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.
[0288] 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), (Ia),
(II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va)), either
alone or in combination with other anticancer agents.
[0289] 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.
[0290] 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), (Ia), (II), (IIa), (III), (IIIa), (IV),
(IVa), (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.
[0291] The present invention provides compounds that are inhibitors
of HSP90. The inhibitors are useful in pharmaceutical compositions
for human or veterinary use where 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.
[0292] 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), (Ia), (II), (IIa), (III),
(IIIa), (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.
[0293] 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 a
2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one compound (e.g,
a compound of formula (I), (Ia), (II), (IIa), (III), (IIIa), (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.
[0294] 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 IC.sub.50 value for inhibiting HSP90 activity
less than or equal to 100 .mu.M. In more preferred embodiments, the
IC.sub.50 value is less than or equal to 50 .mu.M, even more
preferred with an IC.sub.50 value less than or equal to 25 .mu.M.
Still more preferred embodiment have IC.sub.50 values less than or
equal to 10 .mu.M, and even more preferred embodiments have
IC.sub.50 values less than or equal to 1 .mu.M.
[0295] The following definitions are provided to better understand
the invention.
[0296] "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(CH.sub.3).sub.2, --CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH(CH.sub.2CH.sub.3).sub.2, --C(CH.sub.3).sub.3,
--C(CH.sub.2CH.sub.3).sub.3, --CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH(CH.sub.2CH.sub.3).sub.2, --CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2C(CH.sub.2CH.sub.3).sub.3,
--CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH(CH.sub.3).sub.2,
--CH.sub.2CH.sub.2CH(CH.sub.3)(CH.sub.2CH.sub.3),
--CH.sub.2CH.sub.2CH(CH.sub.2CH.sub.3).sub.2,
--CH.sub.2CH.sub.2C(CH.sub.3).sub.3,
--CH.sub.2CH.sub.2C(CH.sub.2CH.sub.3).sub.3,
--CH(CH.sub.3)CH.sub.2CH(CH.sub.3).sub.2,
--CH(CH.sub.3)CH(CH.sub.3)CH(CH.sub.3).sub.2,
--CH(CH.sub.2CH.sub.3)CH(CH.sub.3)CH(CH.sub.3)(CH.sub.2CH.sub.3),
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.
[0297] "Alkylene" or "unsubstituted alkylene" refers to the same
residues as noted above for "alkyl," but having two points of
attachment. Exemplary alkylene groups include ethylene
(--CH.sub.2CH.sub.2--), propylene (--CH.sub.2CH.sub.2CH.sub.2--),
and dimethylpropylene (--CH.sub.2C(CH.sub.3).sub.2CH.sub.2--).
[0298] "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.
[0299] "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.
[0300] "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.
[0301] "Cycloalkenyl" or "unsubstituted cycloalkenyl" refers to a
mono- or polycyclic alkyl substituents having at least one ring
carbon-carbon double bond. Preferred cycloalkenyl groups have 5 to
7 carbon atoms and include cyclopentenyl and cyclohexenyl.
[0302] "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: --(CH.sub.2).sub.3NH.sub.2, --(CH.sub.2).sub.3NH(CH.sub.3),
--(CH.sub.2).sub.3NH(CH.sub.3).sub.2,
--CH.sub.2C(.dbd.CH.sub.2)CH.sub.2NH.sub.2,
--CH.sub.2C(.dbd.O)CH.sub.2NH.sub.2,
--CH.sub.2S(.dbd.O).sub.2CH.sub.3, --CH.sub.2OCH.sub.2NH.sub.2,
--CH.sub.2CO.sub.2H. Examples of substituents of substituted alkyl
are: --CH.sub.2OH, --OH, --OCH.sub.3, --OC.sub.2H.sub.5,
--OCF.sub.3, OC(.dbd.O)CH.sub.3, --OC(.dbd.O)NH.sub.2,
--OC(.dbd.O)N(CH.sub.3).sub.2, --CN, --NO.sub.2,
--C(.dbd.O)CH.sub.3, --CO.sub.2H, --CO.sub.2CH.sub.3, --CONH.sub.2,
--NH.sub.2, --N(CH.sub.3).sub.2, --NHSO.sub.2CH.sub.3,
--NHCOCH.sub.3, --NHC(.dbd.O)OCH.sub.3, --NHSO--.sub.2CH.sub.3,
--SO.sub.2CH.sub.3, --SO.sub.2NH.sub.2, and halo.
[0303] "Substituted alkenyl" has the same meaning with respect to
unsubstituted alkenyl groups that substituted alkyl 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.
[0304] "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.
[0305] "Substituted cycloalkyl" has the same meaning with respect
to unsubstituted cycloalkyl groups that substituted alkyl groups
has with respect to unsubstituted alkyl groups.
[0306] "Substituted cycloalkenyl" has the same meaning with respect
to unsubstituted cycloalkenyl groups that substituted alkyl groups
has with respect to unsubstituted alkyl groups.
[0307] "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 substituents in compounds of
the present invention include phenyl, naphthyl, and the like.
[0308] "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.
[0309] "Alkoxy" refers to R.sup.20O-- wherein R.sup.20 is
C.sub.1-C.sub.7 alkyl or substituted alkyl. In some embodiments,
R.sup.20 is C.sub.1-C.sub.6 alkyl. Representative examples of
alkoxy groups include methoxy, ethoxy, t-butoxy, trifluoromethoxy,
and the like.
[0310] "Amino" refers herein to the group --NH.sub.2.
[0311] "Substituted amino" refers to the group --NR.sup.60R.sup.61
where R.sup.60 and R.sup.61 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,
--SO.sub.2-alkyl, --SO.sub.2-substituted alkyl, and where R.sup.60
and R.sup.61 are joined, together with the nitrogen bound thereto
to form a heterocyclic or substituted heterocyclic group provided
that R.sup.60 and R.sup.61 are both not hydrogen. When R.sup.60 is
hydrogen and R.sup.61 is alkyl, the substituted amino group is
sometimes referred to herein as alkylamino. When R.sup.60 and
R.sup.61 are alkyl, the substituted amino group is sometimes
referred to herein as dialkylamino. When referring to a
monosubstituted amino, it is meant that either R.sup.60 and
R.sup.61 is hydrogen but not both. When referring to a
disubstituted amino, it is meant that neither R.sup.60 and R.sup.61
is hydrogen. The term "alkylamino" refers herein to the group
--NR.sup.60R.sup.61 where R.sup.60 is C.sub.1-C.sub.7 alkyl and
R.sup.60 is hydrogen or C.sub.1-C.sub.7 alkyl. The term
"dialkylamino" refers to the group --NR.sup.60R.sup.61 where
R.sup.60 and R.sup.61 are C.sub.1-C.sub.7 alkyl. The term
"arylamino" refers herein to the group --NR.sup.60R.sup.61 where
R.sup.60 is C.sub.5-C.sub.7 aryl and R.sup.61 is hydrogen,
C.sub.1-C.sub.7 alkyl, or C.sub.5-C.sub.7 aryl. The term
"aralkylamino" refers herein to the group --NR.sup.60R.sup.61 where
R.sup.60 is aralkyl and R.sup.61 is hydrogen, C.sub.1-C.sub.7
alkyl, C.sub.5-C.sub.7 aryl, or C.sub.5-C.sub.7 aralkyl.
[0312] "Amidino" refers to the moieties
R.sup.40--C(.dbd.N)--NR.sup.41-- (the radical being at the
"N.sup.1" nitrogen) and R.sup.40(NR.sup.41)C.dbd.N-- (the radical
being at the "N.sup.2" nitrogen), where R.sup.40 and R.sup.41 can
be hydrogen, C.sub.1-C.sub.7 alkyl, aryl, or C.sub.5-C.sub.7
aralkyl.
[0313] "Alkoxyalkyl" refers to the group -alk.sub.1-O-alk.sub.2
where alk.sub.1 is C.sub.1-C.sub.7 alkyl, and alk.sub.2 is
C.sub.1-C.sub.7 alkyl. The term "aryloxyalkyl" refers to the group
--C.sub.1-C.sub.7 alkyl)-O--(C.sub.5-C.sub.7 aryl).
[0314] "Alkoxyalkylamino" refers herein to the group
--NR.sup.27-(alkoxyalkyl), where R.sup.27 is typically hydrogen,
C.sub.5-C.sub.7 aralkyl, or C.sub.1-C.sub.7 alkyl.
[0315] "Aminocarbonyl" refers herein to the group --C(O)--NH.sub.2.
"Substituted aminocarbonyl" refers herein to the group
--C(O)--NR.sup.28R.sup.29 where R.sup.28 is C.sub.1-C.sub.7 alkyl
and R.sup.29 is hydrogen or C.sub.1-C.sub.7 alkyl. The term
"arylaminocarbonyl" refers herein to the group
--C(O)--NR.sup.30R.sup.31 where R.sup.30 is C.sub.5-C.sub.7 aryl
and R.sup.31 is hydrogen, C.sub.1-C.sub.7 alkyl or C.sub.5-C.sub.7
aryl. "Aralkylaminocarbonyl" refers herein to the group
--C(O)--NR.sup.32R.sup.33 where R.sup.32 is C.sub.5-C.sub.7 aralkyl
and R.sup.33 is hydrogen, C.sub.1-C.sub.7 alkyl, C.sub.5-C.sub.7
aryl, or C.sub.5-C.sub.7 aralkyl.
[0316] "Aminosulfonyl" refers herein to the group
--S(O).sub.2--NH.sub.2. "Substituted aminosulfonyl" refers herein
to the group --S(O).sub.2--NR.sup.34R.sup.35 where R.sup.34 is
C.sub.1-C.sub.7 alkyl and R.sup.35 is hydrogen or C.sub.1-C.sub.7
alkyl. The term "aralkylaminosulfonlyaryl" refers herein to the
group --(C.sub.5-C.sub.7 aryl)-S(O).sub.2--NH-aralkyl.
[0317] "Aryloxy" refers to R.sup.50O-- wherein R.sup.50 is
aryl.
[0318] "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.
[0319] "Carbonyloxy" refers generally to the group --C(O)--O--.
Such groups include esters, --C(O)--O--R.sup.36, where R.sup.36 is
C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.7 cycloalkyl, aryl, or
C.sub.5-C.sub.7 aralkyl. The term "arylcarbonyloxy" refers herein
to the group --C(O)--O-(aryl). The term "aralkylcarbonyloxy" refers
herein to the group --C(O)--O--(C.sub.5-C.sub.7 aralkyl).
[0320] "Cycloalkylalkyl" refers to an alkyl group substituted with
a cycloalkyl group as defined above. Typically, cycloalkylalkyl
groups have from 1 to 6 carbon atoms incorporated within the alkyl
portion of the cycloalkylalkyl group.
[0321] "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 C.sub.1-C.sub.7 alkyl, aryl, or
C.sub.5-C.sub.7 aralkyl group. Carbonylamino groups include
moieties such as carbamate esters (--NH--C(O)--O--R.sup.28) and
amido --NH--C(O)--R.sup.28, where R.sup.28 is a straight or
branched chain C.sub.1-C.sub.7 alkyl, C.sub.3-C.sub.7 cycloalkyl,
or aryl or C.sub.5-C.sub.7 aralkyl. The term "alkylcarbonylamino"
refers to the group --NH--C(O)--R.sup.28' where R.sup.28' is alkyl
having from 1 to about 7 carbon atoms in its backbone structure.
The term "arylcarbonylamino" refers to group --NH--C(O)--R.sup.29
where R.sup.29 is C.sub.5-C.sub.7 aryl. Similarly, the term
"aralkylcarbonylamino" refers to carbonylamino where R.sup.29 is
C.sub.5-C.sub.7 aralkyl.
[0322] "Guanidino" or "guanidyl" refers to moieties derived from
guanidine, H.sub.2N--C(.dbd.NH)--NH.sub.2. Such moieties include
those bonded at the nitrogen atom carrying the formal double bond
(the "2"-position of the guanidine, e.g., diaminomethyleneamino,
(H.sub.2N).sub.2C.dbd.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., H.sub.2N--C(.dbd.NH)--NH--).
The hydrogen atoms at any of the nitrogens can be replaced with a
suitable substituent, such as C.sub.1-C.sub.7 alkyl, aryl, or
C.sub.5-C.sub.7 aralkyl.
[0323] "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 --CF.sub.3. The term "haloalkoxy" refers to an alkoxy
radical substituted with one or more halogen atoms.
[0324] "Haloalkoxy" groups include --OCF.sub.3 and
--OCH.sub.2CF.sub.3.
[0325] "Hydroxyl" or "hydroxy" refers to the group --OH.
[0326] "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.
[0327] Heterocyclic moieties can be, for example monosubstituted or
disubstituted with various substituents independently selected from
but not limited to hydroxy, alkoxy, halo, oxo (C.dbd.O), alkylimino
(R.sup.31N.dbd., wherein R.sup.31 is alkyl or alkoxy group), amino,
alkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, alkyl,
cycloalkyl or haloalkyl.
[0328] 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.
##STR00012##
[0329] where R is H or a heterocyclic substituent, as described
herein.
[0330] "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.,
##STR00013##
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
##STR00014##
[0331] 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.
[0332] "Heteroarylalkyl" 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.
[0333] "Imino" refers to the group .dbd.NH.
[0334] "Nitro" refers to the group NO.sub.2.
[0335] "Sulfonyl" refers herein to the group --SO.sub.2--.
"Alkylsulfonyl" refers to a substituted sulfonyl of the structure
--SO.sub.2R.sup.52-- in which R.sup.52 is C.sub.1-C.sub.7 alkyl.
Alkylsulfonyl groups employed in compounds of the present invention
are typically alkylsulfonyl groups having from 1 to 6 carbon atoms
in its backbone structure. Thus, typical alkylsulfonyl groups
employed in compounds of the present invention include, for
example, methylsulfonyl (i.e., where R.sup.52 is methyl),
ethylsulfonyl (i.e., where R.sup.52 is ethyl), propylsulfonyl
(i.e., where R.sup.52 is propyl), and the like. The term
"arylsulfonyl" refers herein to the group --SO.sub.2-aryl. The term
"heterocyclylsulfonyl" refers herein to the group
--SO.sub.2-heterocyclyl. The term "aralkylsulfonyl" refers herein
to the group --SO.sub.2-aralkyl. The term "sulfonamido" refers
herein to --SO.sub.2NH.sub.2. The term "sulfonamidoalkyl" refers to
(alkyl)SO.sub.2NH.sub.2--.
[0336] "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 C.sub.1-C.sub.6 alkyl group.
[0337] "Thioamido" refers to the group --C(.dbd.S)NH.sub.2.
[0338] "Optionally substituted" 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, heteroarylcarbonyl, 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.
[0339] The substitution group can itself be substituted. The group
substituted onto the substitution group can be carboxyl, halo,
nitro, amino, cyano, hydroxyl, alkyl, alkoxy, aminocarbonyl,
--SR.sup.42, thioamido, --SO.sub.3H, --SO.sub.2R.sup.42, or
cycloalkyl, where R.sup.42 is typically hydrogen, hydroxyl or
alkyl.
[0340] 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.
[0341] 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 the adjacent
functionality toward the point of attachment. For example, the
substituent "alkoxyheteroaryl" refers to the group
(alkoxy)-(heteroaryl)-.
[0342] 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.
[0343] 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.
[0344] "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.
[0345] 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 .alpha. and .beta. are employed for ring positions
of cyclic compounds. The .alpha.-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 .beta. descriptor. It should be
noted that this usage differs from that for cyclic stereoparents,
in which ".alpha." means "below the plane" and denotes absolute
configuration. The terms .alpha. and .beta. configuration, as used
herein, are as defined by the "Chemical Abstracts Index Guide,"
Appendix IV, paragraph 203, 1987.
[0346] 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, camphorsulfonate, 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, the basic nitrogen-containing groups can be
quaternized with such agents as alkyl halides, such as methyl,
ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl
sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long
chain halides such as decyl, lauryl, myristyl, and stearyl
chlorides, bromides and iodides, aralkyl halides like benzyl and
phenethyl bromides, and others. Water or oil-soluble or dispersible
products are thereby obtained.
[0347] 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 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.
[0348] 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.
[0349] The term "HSP90 mediated disorder" refers to a disorder that
can be beneficially treated by the inhibition of HSP90.
[0350] The term "cellular proliferative diseases" refers to
diseases including, for example, cancer, tumor, hyperplasia,
restenosis, cardiac hypertrophy, immune disorder and
inflammation.
[0351] 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.
[0352] The compounds of the invention are useful in vitro or in
vivo in inhibiting the growth of cancer cells. The compounds may be
used alone or in compositions together with a 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-.beta.-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.
[0353] 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.
[0354] 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.
[0355] 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.
[0356] The compounds of the present invention may be administered
orally, parenterally, sublingually, by aerosolization or inhalation
spray, rectally, or topically in dosage unit formulations
containing conventional nontoxic pharmaceutically acceptable
carriers, adjuvants, and vehicles as desired. Topical
administration may also involve the use of transdermal
administration such as transdermal patches or ionophoresis devices.
The term parenteral as used herein includes subcutaneous
injections, intravenous, intramuscular, intrasternal injection, or
infusion techniques.
[0357] 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.
[0358] 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.
[0359] 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.
[0360] 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.
[0361] The compounds of the present invention can also be
administered in the form of liposomes. As is known in the art,
liposomes are generally derived from phospholipids or other lipid
substances. Liposomes are formed by mono- or multi-lamellar
hydrated liquid crystals that are dispersed in an aqueous medium.
Any non-toxic, physiologically acceptable and metabolizable lipid
capable of forming liposomes can be used. The present compositions
in liposome form can contain, in addition to a compound of the
present invention, stabilizers, preservatives, excipients, and the
like. The preferred lipids are the phospholipids and phosphatidyl
cholines (lecithins), both natural and synthetic. Methods to form
liposomes are known in the art. See, for example, Prescott (ed.),
"Methods in Cell Biology," Volume XIV, Academic Press, New York,
1976, p. 33 et seq.
[0362] 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.
[0363] 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.
[0364] 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.
[0365] Antiestrogens, such as tamoxifen, inhibit breast cancer
growth through induction of cell cycle arrest, that requires the
action of the cell cycle inhibitor p27Kip. Recently, it has been
shown that activation of the Ras-Raf-MAP Kinase pathway alters the
phosphorylation status of p27Kip such that its inhibitory activity
in arresting the cell cycle is attenuated, thereby contributing to
antiestrogen resistance (Donovan, et al, J. Biol. Chem. 276:40888,
2001). As reported by Donovan et al., inhibition of MAPK signaling
through treatment with MEK inhibitor changed the phosphorylation
status of p27 in hormone refactory breast cancer cell lines and in
so doing restored hormone sensitivity. Accordingly, in one aspect,
the compounds of formula (I), (Ia), (II), (IIa), (III), (IIIa),
(IV), (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.
[0366] 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-Av1 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), (Ia), (II),
(IIa), (III), (IIIa), (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.
[0367] 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), (Ia),
(II), (IIa), (III), (IIa), (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.
[0368] The synthesis of representative
2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-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.
[0369] 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 chiral 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 HCl to effect decarboxylation and afford compound 1-I.
O-acylation with acetyl chloride and treatment with catalytic
dimethylaminopyridine 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 1-K can
optionally be functionalized via a Suzuki coupling with a suitable
boronic acid to give the biaryl compound I-L. Subsequent
deprotection of the para-methoxybenzyl group gives amine I-M.
##STR00015## ##STR00016## ##STR00017##
[0370] 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.degree. 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-HCl to this solution
followed by additional microwave heating. Isolation of the
aminopyrimidine 2-G by reverse phase HPLC followed by coupling with
an appropriate arylboronic acid under Suzuki conditions and
microwave heating gives the biaryl compound 2-H.
##STR00018##
[0371] Scheme 3 shows another means for synthesizing certain
compounds of the invention. Reductive amination of p-anisole 3-A
with (S)-1-(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-I following the
steps shown in the Scheme 2 and described above.
##STR00019##
[0372] In one embodiment, provided is a method of preparing a
compound of formula (I), comprising
[0373] (a) reacting a compound of formula (I) with an acid to form
an acid addition salt; or
[0374] (b) reacting an acid addition salt of formula (I) to form a
free base compound of formula (I); or
[0375] (c) reacting an intermediate compound of formula (VI) with
guanidine or a guanidine derivative
##STR00020##
[0376] wherein R.sup.a, R, and R.sup.b are as defined for formula
(I) and W is O or NR'R'' where R' and R'' are independently H or
alkyl to form a compound of formula (I).
[0377] In one embodiment, provided is an intermediate compound of
formula (VI). In one aspect, R.sup.a is methyl. In another aspect,
the intermediate compound of formula (VI) is a compound of formula
(VII)
##STR00021##
[0378] wherein
[0379] R is as defined for formula (VI);
[0380] R.sup.5 is hydrogen or halo; and
[0381] R.sup.6a is selected from the group consisting of halo,
substituted or unsubstituted aryl, and substituted or unsubstituted
heteroaryl.
[0382] 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,
1-(4-methoxyphenyl)ethyl, methyl, 3-aminopropyl, and
2-methyl-2-morpholinopropyl. In still other embodiment, R is
hydrogen.
[0383] In some embodiments, R.sup.5 is halo. In some aspects
R.sup.5 is fluoro.
[0384] In other embodiments R.sup.5 is hydrogen.
[0385] In some embodiments, R.sup.6a is halo. In some aspects
R.sup.6a is bromo.
[0386] In some embodiments R.sup.5 and R.sup.6a are both halo. In
other embodiments R.sup.5 is fluoro and R.sup.6a is bromo.
[0387] In some embodiments R.sup.6a 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.
[0388] In some embodiments, R.sup.6a is selected from the group
consisting of (2-hydroxy-ethylamino)-pyrazin-2-yl, 1H-pyrazol-4-yl,
1-methyl-1H-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-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-1,2-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-pyrimidin-2-yl, 4-ethoxy-pyrimidin-2-yl,
4-ethoxy-pyrimidin-5-yl, 4-ethyl-1H-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-1-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, 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.
[0389] In another embodiment the guanidine derivative is acetyl
guanidine.
[0390] In another embodiment, provided is a use of compound of
formula (VI) or (VII) for the manufacture of a compound of formula
(I).
[0391] 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
[0392] 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.
[0393] 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, Mass.). The analytical columns were Alltima C-18 reversed
phase, 4.6.times.250 mm from Alltech (Deerfield, Ill.). 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 nm. HPLC solvents were from Burdick and Jackson (Muskegan,
Mich.), or Fisher Scientific (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.
[0394] 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.times.50 mm; solvent system: 5-95% (or 35-95%, or 65-95% or
95-95%) acetonitrile in water with 0.05% TFA; flow rate 0.8 mL/min;
molecular weight range 500-1500; cone Voltage 20 V; column
temperature 40.degree. C.) or a Hewlett Packard System (Series 1100
HPLC; Column: Eclipse XDB-C18, 2.1.times.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.degree. C.). All masses were reported as those of
the protonated parent ions.
[0395] GCMS analysis is performed on a Hewlett Packard instrument
(HP6890 Series gas chromatograph with a Mass Selective Detector
5973; injector volume: 1 .mu.L; initial column temperature:
50.degree. C.; final column temperature: 250.degree. 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.times.25
m.times.0.25 m).
[0396] Nuclear magnetic resonance (NMR) analysis was performed on
some of the compounds with a Varian 300 MHz NMR (Palo Alto,
Calif.). 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.degree. C.) to promote increased
sample solubility.
[0397] The purity of some of the invention compounds is assessed by
elemental analysis (Desert Analytics, Tucson, Ariz.)
[0398] Melting points are determined on a Laboratory Devices
MeI-Temp apparatus (Holliston, Mass.).
[0399] 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 chromatography were dichloromethane, methanol,
ethyl acetate, hexane, acetone, aqueous hydroxyamine, and triethyl
amine. Typical solvents employed for the reverse phase HPLC were
varying concentrations of acetonitrile and water with 0.1%
trifluoroacetic acid.
[0400] The following are abbreviations used in the examples: [0401]
aq.: Aqueous [0402] Boc: tert-Butoxycarbonyl [0403] BSA: bovine
serum albumin [0404] Celite Diatomaceous earth [0405] DCM:
Dichloromethane [0406] eq.: equivalent [0407] Et.sub.3N:
Triethylamine [0408] EtOAc: Ethyl acetate [0409] GC Gas
Chromatography [0410] h: hour [0411] HPLC: High performance liquid
chromatography [0412] IC.sub.50 value: The concentration of an
inhibitor that causes a 50% reduction in a measured activity.
[0413] L: liter [0414] LC/MS: Liquid chromatography/mass
spectrometry [0415] LRMS: Low resolution mass spectrometry [0416]
MeOH: Methanol [0417] min: minute [0418] mL: milliliter [0419] mm:
millimeter [0420] mM: millimolar [0421] mmol: millimole [0422] nm:
Nanometer [0423] NMP: N-Methylpyrrolidone [0424] RP-HPLC:
Reversed-phase high-performance liquid chromatography [0425] rt
room temperature [0426] sat: Saturated [0427] THF: Tetrahydrofuran
[0428] TMS: Trimethylsilane [0429] TLC: Thin layer chromatography
[0430] TRF: Time resolved fluorescence.
[0431] Nomenclature for the compounds disclosed in this application
was provided using ACD Name version 5.07 software (Nov. 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.
[0432] 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.
[0433] 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.
[0434] The following examples illustrate methods for making
representative compounds of the invention.
Example 1
Representative Procedures for Compounds of the Invention
Step A: .alpha.,.beta.-Unsaturated Ester
##STR00022##
[0436] n-Butyllithium (84 mmol) was added dropwise to a stirred
solution of triethylphosphono acetate (88 mmol) in dry THF (176 mL)
at -78.degree. C. under N.sub.2. The solution was left to stir for
30 min. keeping inner temperature below -70.degree. C. The
phosphonate solution was transferred via cannula to a solution of
2-bromo-4-fluorobenzaldehyde 1-1 (80 mmol) in THF (160 mL) at
-78.degree. C. under N.sub.2. The resulting solution was warmed to
room temperature over 2 h. The reaction mixture was quenched by
adding aqueous NH.sub.4Cl and then extracted with EtOAc (.times.3).
The organics were combined, washed with H.sub.2O (.times.3), sat.
brine (.times.3), then dried (Na.sub.2SO.sub.4), 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 E-ethyl
3-(2-bromo-4-fluorophenyl)acrylate was collected as a white
crystals.
Step B: Conjugate Addition of Asymmetric Amine to
.alpha.,.beta.-Unsaturated Ester
##STR00023##
[0438] To a stirred solution of
(S)--N-benzyl-1-(4-methoxyphenyl)ethanamine 1-3 (58 mmol) in dry
THF (116 mL) was added compound 1-2. The reaction was cooled to
-78.degree. C., and n-butyl lithium (56.2 mmol) was added dropwise
at -78.degree. C. under N.sub.2. After addition, the reaction
mixture was stirred at -78.degree. C. for 40 min. Then the reaction
mixture was partitioned between aqueous NH.sub.4Cl, and EtOAc,
extracted with EtOAc (.times.3), the organics separated, then
washed with H.sub.2O (.times.3), sat. brine (.times.3), then dried
(Na.sub.2SO.sub.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.
Step C: CAN (Ceric Ammonium Nitrate) Deprotection
##STR00024##
[0440] The 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.times.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).
Step D: Acylation
##STR00025##
[0442] 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 NaHCO.sub.3, extracted with DCM (.times.3), the organic
layers were combined, then washed with H.sub.2O (.times.3), sat.
brine (.times.3), then dried (Na.sub.2SO.sub.4), filtered, and
evaporated under reduced pressure to give crude oil, which was then
purified on silica gel column (hexane/EtOAc) to provide compound
1-6.
Step E: Cyclization
##STR00026##
[0444] 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.degree. C. for 5 min.
After cooling to room temperature, the reaction mixture was diluted
with aqueous ammonium chloride, washed with DCM (.times.3), then
washed with H.sub.2O (.times.3), sat. brine (.times.3), then dried
(Na.sub.2SO.sub.4), filtered, and evaporated under reduced pressure
to give crude product, piperidine-dione 1-7, which was used
directly in the next step.
Step F: Amino-Pyrimidine-Lactam
##STR00027##
[0446] To the mixture of piperidindione 1-7 (0.915 mmol) and
guanidine HCl (4.573 mmol) in ethanol (9 mL) was added pyrrolidine
(18.3 mmol). The reaction mixture was treated in microwave
(PowerMAX setting) at 160.degree. C. for 10 min. After cooling to
room temperature, the reaction mixture was extracted with DCM
(.times.3), then washed with H.sub.2O (.times.3), sat. brine
(.times.3), then dried (Na.sub.2SO.sub.4), filtered, and evaporated
under reduced pressure to give crude product 1-8, which was then
purified on silica gel column (EtOAc).
Step G: Suzuki Coupling
##STR00028##
[0448] To the mixture of amino-pyrimidine-lactam 1-8 (1 eq.),
boronic acid or ester (4 eq.) in DMA was added
Pd(dppf).sub.2Cl.sub.2 (0.4 eq.) and 2 M K.sub.2CO.sub.3 (8 eq).
The reaction mixture was treated in microwave at 120.degree. C. for
15 min. After cooling down to room temperature the reaction mixture
was diluted with DCM (.times.3), washed with H.sub.2O (.times.3),
sat. brine (.times.3), then dried (Na.sub.2SO.sub.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 Amination
##STR00029##
[0450] 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 NaHCO.sub.3, extracted with DCM (.times.3)
and the organics combined, then washed with H.sub.2O (.times.3),
sat. brine (.times.3), then dried (Na.sub.2SO.sub.4), 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 Coupling
##STR00030##
[0452] Step B to Step E were the same as Step E to Step G in
Example 1.
Step F: Deprotection
##STR00031##
[0454] 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.
[0455] Other alkylated amine compounds of the invention were
prepared in a similar manner.
Example 3
##STR00032##
[0457] 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.degree. 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.degree. C. in an
ice/water bath. To this solution was then added 1N HCl until pH=1,
during which the internal temperature was maintained below
10.degree. C. The mixture was stirred until a smooth suspension
formed and then was filtered. The collected solids were washed with
water (100 mL.times.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).
Example 4
##STR00033##
[0458] Step 1:
[0459] A 500 mL round-bottom flask was charged with dry THF (50
mL), titanium ethoxide (41 mL), (S)-(-)-tert-butanesulfinamide
(Advanced Asymmetrics, 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 N.sub.2 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 separatory funnel, and the aqueous layer removed.
The organics were washed with brine (200 mL), then dried
(Na.sub.2SO.sub.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%). .sup.1H NMR (300 MHz, CD.sub.3Cl) .delta. 8.86 (s, 1H), 8.03
(m, 1H), 7.35 (m, 1H), 7.11 (m, 1H), 1.11 (s, 9H) LCMS m/z 307.9
(MH.sup.+), t.sub.R=3.22 min.
Step 2:
[0460] A three-necked 100 mL round-bottom flask, reflux condenser,
and addition funnel were oven-dried overnight. Upon removal from
the oven, they were assembled and put under positive N.sub.2
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.degree. 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 funnel 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.degree. C. for 30 min. The reaction mixture
was then cooled to 0.degree. 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.degree. 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 Et.sub.2O (2.times.100 mL). The filtrate was washed with 0.25
M citric acid (200 mL), sat. NaHCO.sub.3(aq) (2.times.200 mL),
dried (Na.sub.2SO.sub.4), and concentrated in vacuo to afford 4.3
(7.30 g, 18.4 mmol, 86%) as a clear oil. .sup.1H NMR (300 MHz,
CD.sub.3Cl) .delta. 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.sub.1=,
J.sub.2=, J.sub.3=, 2H), 1.22 (m, 3H, 9H). LCMS m/z 396.0
(MH.sup.+), t.sub.R=2.96 min. HPLC (frac.sub.--10 min.sub.--2070%
B), t.sub.R=4.108 (major diastereomer), t.sub.R=3.962 (Claisen
condensation byproduct) t.sub.R=3.888 (minor diastereomer),
95.5:2.1:2.1. de=96%.
Step 3:
[0461] A 500 mL round-bottom flask was charged with 4.3 (7.30 g,
18.4 mmol, 1.0 equiv), Et.sub.2O (37 mL), EtOH (1.2 mL, 1.1 equiv)
and 4M HCl in Et.sub.2O (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 Et.sub.2O
(3.times.40 mL) and hexanes (2.times.40 mL). The solid was dried
under vacuum to afford 4.4 as a white solid (5.23 g, 15.2 mmol,
83%). .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.61 (m, 2H), 7.33
(m, 1H), 5.18 (m, 1H), 4.85 (bs, 3H), 4.13 (q, J=7.2, 2H), 3.15
(ddd, 2H), 1.22 (t, J=7.5, 3H) LCMS m/z 292.0 (MH.sup.+),
t.sub.R=1.97 min. To free base the HCL salt, 4.4 (50 mg) was
dissolved in EtOAc (20 mL) and washed with 10% Na.sub.2CO.sub.3
(3.times.20 mL). The organics were dried (Na.sub.2SO.sub.4) and
concentrated in vacuo to afford the free base. A racemic mixture of
the final .beta.-amino ester product was prepared and analyzed by
chiral HPLC to confirm separation of the enantiomers (Chiralpak AD
column, 1 mL/min, S, t.sub.R=5.84; R, t.sub.R=7.47 min)
Example 5
##STR00034##
[0462] Step 1:
[0463] A 250 mL round-bottom flask was charged with dry THF (54
mL), titanium ethoxide (18.25 g, 3 equiv),
(S)-(-)-tert-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 N.sub.2 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 separatory funnel, and the
aqueous layer removed. The organics were washed with brine (200
mL), then dried (Na.sub.2SO.sub.4) and concentrated in vacuo to
afford 5.2 as a yellowish oil (7.9 g, 100%). .sup.1H NMR (300 MHz,
CD.sub.3Cl) .delta. 8.88 (s, 1H), 8.72 (s, 1H), 1.21 (s, 9H) LCMS
m/z 296.9 (MH.sup.+), t.sub.R=2.35 min.
Step 2:
[0464] A three-necked 100 mL round-bottom flask, reflux condenser,
and addition funnel were oven-dried overnight. Upon removal from
the oven, they were assembled and put under positive N.sub.2
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.degree. 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 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.degree. C. for 30 min. The reaction mixture
was then cooled to 0.degree. 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.degree. 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
Et.sub.2O (2.times.100 mL). The filtrate was washed with 0.25 M
citric acid (200 mL), sat. NaHCO.sub.3(aq) (2.times.200 mL), dried
(Na.sub.2SO.sub.4), and concentrated in vacuo to afford 5.3 (10 g)
as a clear oil.
Step 3:
[0465] A 500 mL round-bottom flask was charged with 5.3 (10 g,
26.67 mmol, 1.0 equiv), Et.sub.2O (27 mL), EtOH (1.7 mL) and 4M HCl
in Et.sub.2O (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 Et.sub.2O (3.times.40 mL)
and hexanes (2.times.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.sup.+), t.sub.R=1.63 min.
Example 6
Preparation of
(R)-2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-methyl-7,8-dihydropyr-
ido[4,3-d]pyrimidin-5(6H)-one
##STR00035##
[0467] A microwave vial was charged with
(R)-2-amino-7-(2-bromo-4-fluorophenyl)-4-methyl-7,8-dihydropyrido[4,3-d]p-
yrimidin-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.degree. C. for 20 min. After cooling to RT, the
reaction mixture was concentrated and purified by reverse phase
HPLC to afford
(R)-2-amino-7-(2-(cyclopentyloxy)-4-fluorophenyl)-4-methyl-7,8-dihydropyr-
ido[4,3-d]pyrimidin-5(6H)-one (m/z=357 (M+H)).
Example 7
##STR00036##
[0469] 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.degree. C. Triethylamine
(3 eq) was added followed by dropwise addition of methyl malonyl
chloride (1.3 eq). The reaction was stirred for 2 h 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.
[0470] 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.degree. 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.
[0471] Compound 7.3 was taken up in acetonitrile containing 1%
water. The reaction vessel was sealed and heated for 10 min at
120.degree. C. (microwave). Concentration in vacuo provided
compound 7.4 in a quantitative yield.
[0472] Compound 7.4 was taken up in dimethylacetamide dimethyl
acetal and heated at 140.degree. 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.degree. C. for 10 min. The
crude reaction mixture was concentrated in vacuo and the resulting
solid 7.6, used without purification.
[0473] 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)Cl.sub.2.CH.sub.2Cl.sub.2. The reaction mixture was heated
at 120.degree. 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-Amino-7-[5-(6-methoxy-pyrazin-2-yl)-thiazol-4-yl]-4-methyl-7,8-dihy-
dro-6H-pyrido[4,3-d]pyrimidin-5-one
##STR00037##
[0475] 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.
Example 9
Representative 2-amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one
compounds
[0476] 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-US-00001 TABLE 1 Representative
2-Amino-7,8-dihydro-6H-pyrido[4,3-d]pyrimidin-5-one Compounds. IC50
(.mu.M) LC/MS observed A .gtoreq. 10 Cmpd. Structure Name R.sub.t
(min) m/z B < 10 1 ##STR00038## (R)-2-Amino-7-[2-(2-fluoro-
pyridin-3-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5- one 1.65 350.3 B 2 ##STR00039##
(S)-2-Amino-6-benzyl-7-[4- fluoro-2-(2-fluoro-pyridin-3-
yl)-phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one
2.61 458.1 A 3 ##STR00040## (R)-2-Amino-7-[4-fluoro-2-
(2-fluoro-pyridin-3-yl)- phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 1.73 368.1 B 4
##STR00041## (R)-2-Amino-7-(2-bromo-4- fluoro-phenyl)-6-[(S)-1-(4-
methoxy-phenyl)-ethyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5- one 2.61 485 A 5 ##STR00042##
(R)-2-Amino-7-[2-(6- methoxy-pyridin-2-yl)- phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 1.86 362 B 6 ##STR00043##
(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 2.07
380 B 7 ##STR00044## 2-Amino-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)- phenyl]4,6-dimethyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 2.41 394.2 B 8
##STR00045## 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
1.88 382 B 9 ##STR00046## 2-amino-7-[4-fluoro-2-(6-
methoxypyridin-2- yl)phenyl]-4-methyl-7,8- dihydropyrido[4,3-
d]pyrimidin-5(6R)-one 1.97 380 B 10 ##STR00047##
2-Amino-7-[2-(6-methoxy- pyrazin-2-yl)-phenyl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 1.68 363 B 11
##STR00048## (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 1.85
381.1 B 12 ##STR00049## 2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)- phenyl]-4,6-dimethyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 2.19 395.1 B 13
##STR00050## 2-Amino-7-[2-(2-methoxy- pyridin-3-yl)-phenyl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 2.01 362.1 B
14 ##STR00051## 2-Amino-7-(5,2'-difluoro-
biphenyl-2-yl)-4-methyl-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one 2.02 367.1 B 15 ##STR00052##
2-Amino-7-(5-fluoro-2'- trifluoromethoxy-biphenyl-
2-yl)-4-methyl-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin- 5-one 2.27
433.1 B 16 ##STR00053## 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 1.75 384.1 B 17
##STR00054## 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 1.75
368.1 B 18 ##STR00055## 2-Amino-7-(4-fluoro-2-
isoquinolin-4-yl-phenyl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5- one 1.46 400.1 B 19 ##STR00056##
2-Amino-7-(5,3'-difluoro- biphenyl-2-yl)-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 2.31 367.1 B 20
##STR00057## 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 2.09
384.1 B 21 ##STR00058## 2-Amino-7-(5,2'-difluoro-3'-
methoxy-biphenyl-2-yl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5- one 2.3 397.1 A 22 ##STR00059##
2-Amino-7-(5,4'-difluoro-2'- methyl-biphenyl-2-yl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 2.44 381.1 B
23 ##STR00060## 2-Amino-7-(5-fluoro-2'- methoxy-biphenyl-2-yl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 2.29 379.1 B
24 ##STR00061## 2-Amino-7-(4-fluoro-2- pyrimidin-5-yl-phenyl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 1.66 351.1 A
25 ##STR00062## 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 1.84
380 A 26 ##STR00063## 2-Amino-7-(5-fluoro-3'-
methoxy-biphenyl-2-yl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5- one 2.11 379 B 27 ##STR00064##
(R)-2-Amino-6-(3-amino- propyl)-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)- phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one 1.97 437.1 B 28 ##STR00065##
2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 1.24 350 B 29
##STR00066## 2-Amino-7-(5,2'-difluoro-4'- methyl-biphenyl-2-yl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 2.43 381.1 B
30 ##STR00067## 2-Amino-7-[4-fluoro-2-(1- methyl-1H-pyrazol-4-yl)-
phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 1.87
353.1 B 31 ##STR00068## 2-Amino-7-[4-fluoro-2-(1H-
pyrazol-4-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5- one 2.68 339 A 32 ##STR00069##
2-Amino-4-methyl-7- (5,2',3'-trifluoro-biphenyl-2-
yl)-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5- one 2.08 385 B 33
##STR00070## 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 2.08 492.1 A 34 ##STR00071##
2-Amino-7-(3'- dimethylamino-5-fluoro- biphenyl-2-yl)-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 1.54 392.1 A 35
##STR00072## 2-Amino-7-[2-(2,4- dimethoxy-pyrimidin-5-yl)-
4-fluoro-phenyl]-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one 1.99 411.1 A 36 ##STR00073##
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 1.65
380.1 B 37 ##STR00074## 2-Amino-7-(4-fluoro-2-
pyrimidin-5-yl-phenyl)-4- methyl-6-(2-methyl-2-
morpholin-4-yl-propyl)-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one 1.8 492.2 A 38 ##STR00075##
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 2.08 521.2 A
39 ##STR00076## 2-Amino-7-(5-fluoro-3'- methoxy-biphenyl-2-yl)-4-
methyl-6-(2-methyl-2- morpholin-4-yl-propyl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one 2.25 520.2 A 40
##STR00077## (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 3.11 395.1 B 41 ##STR00078##
2-Amino-7-(4-fluoro-2- furan-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5- one 1.84 339.1 B
TABLE-US-00002 TABLE 2 IC50 (.mu.M) LC/MS (Rt A .gtoreq. 10 Cmpd.
Structure Name (min), m/z) B < 10 42 ##STR00079##
(R)-2-Amino-7-[2-(6- methoxy-pyrazin-2-yl)- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.87 m/z = 349.1 B 43
##STR00080## (R)-2-Amino-7-[2-(6- methoxy-pyridin-2-yl)-
phenyl]-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 1.83 m/z
= 348.1 B 44 ##STR00081## (R)-2-Amino-7-[2-(5-amino-
6-methoxy-pyridin-2-yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.07; m/z = 395.1 B
45 ##STR00082## (R)-2-Amino-7-[2-(5-amino- 6-methoxy-pyridin-2-yl)-
phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt =
1.85; m/z = 377.1 B 46 ##STR00083## (R)-2-Amino-7-[2-(5-amino-
6-methoxy-pyridin-2-yl)-4- fluorophenyl]-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 2.08; m/z = 381.1 B 47
##STR00084## (R)-2-Amino-7-[2-(4-ethoxy- pyrimidin-2-yl)-4-fluoro-
phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt =
2.13; m/z = 395 B 48 ##STR00085## (R)-2-Amino-7-[4-fluoro-2-
(4-methoxy-pyrimidin-2-yl)- phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.00; m/z = 381 B 49
##STR00086## (R)-2-Amino-7-[4-fluoro-2-
(4-pyrrolidin-1-yl-pyrimidin- 2-yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.72; m/z = 420 A 50
##STR00087## 2-((R)-2-Amino-4-methyl-5- oxo-5,6,7,8-tetrahydro-
pyrido[4,3-d]pyrimidin-7-yl)- 5-fluoro-benzonitrile Rt = 2.03; m/z
= 298 A 51 ##STR00088## (R)-2-Amino-7-[2-(4,5-
dimethoxy-pyrimidin-2.yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one m/z = 411 B 52
##STR00089## (R)-2-Amino-7-[2-(5-chloro-
4-methoxy-pyrimidin-2-yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.27; m/z = 415 B 53
##STR00090## (R)-2-Amino-7-[4-fluoro-2- (6-methoxy-pyrazin-2-yl)-
phenyl]-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 1.93; m/z
= 367 B 54 ##STR00091## (R)-2-Amino-7-(5-fluoro-2'-
methoxy-biphenyl-2-yl)-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.21; m/z = 365 B 55 ##STR00092##
(R)-2-Amino-7-(5,5'-difluoro- 2'-methoxy-biphenyl-2-yl)-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.27; m/z = 383 B
56 ##STR00093## (R)-2-Amino-7-(5,4'-difluoro-
2'-methoxy-biphenyl-2-yl)- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.28; m/z = 383 B 57 ##STR00094##
(R)-2-Amino-7-(5-fluoro-3',4'- dimethoxy-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.11; m/z = 395 A 58
##STR00095## (R)-2-Amino-7-(5-fluoro-3'- methyl-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.35; m/z = 349 B 60
##STR00096## (R)-2-Amino-7-(5-fluoro-4'- methyl-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.36; m/z = 349 B 61
##STR00097## (R)-2-Amino-7-(5,4'-difluoro-
2'-methyl-biphenyl-2-yl)-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.36; m/z = 367 B 62 ##STR00098##
(R)-2-Amino-7-(4-fluoro-2- pyridin-3-yl-phenyl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.4 m/z = 336 B 63
##STR00099## (R)-2-Amino-7-[2-(2,4- dimethoxy-pyrimidin-5-yl)-4-
fluoro-phenyl]-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin-5- one Rt =
1.95 m/z = 397 A 64 ##STR00100## (R)-2-Amino-7-[2-(5-fluoro-
4-methoxy-pyrimidin-2-yl)- phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.971 m/z = 381.2 B
65 ##STR00101## (R)-2-Amino-7-[4-fluoro-2-
(5-methoxy-thiophen-2-yl)- phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.064 m/z = 385.0 B
66 ##STR00102## (R)-2-Amino-7-(2-bromo- phenyl)-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.85 m/z =
332.9/334.9 A 67 ##STR00103## (R)-2-Amino-7-[2-(2-
methoxy-thiazol-4-yl)- phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.10 m/z = 368.0 B 68 ##STR00104##
(R)-2-Amino-7-[2-(5,6- dimethoxy-pyrazin-2-yl)-
phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt =
2.11 m/z = 393.1 B 69 ##STR00105## (R)-2-Amino-7-[2-(6-
methoxy-pyrazin-2-yl)- phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.94 m/z = 363.0 B 70 ##STR00106##
(R)-2-Amino-7-(2-bromo-4- fluoro-phenyl)-4-ethyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.05 m/z = 367.0 A 71
##STR00107## (R)-2-Amino-7-[2-(6-ethoxy- pyrazin-2-yl)-phenyl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.07 m/z =
377.1 B 72 ##STR00108## (R)-2-Amino-7-[2-(4-ethoxy-
5-fluoro-pyrimidin-2-yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.33; m/z = 413.1 B
73 ##STR00109## (R)-2-Amino-7-(5-fluoro-2',3'-
dimethoxy-biphenyl-2-yl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.067; m/z = 409.1 B 74
##STR00110## (R)-2-Amino-7-[2-(6-ethoxy- pyridin-2-yl)-4-fluoro-
phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt =
2.37; m/z = 394.0 B 75 ##STR00111## (R)-2-Amino-7-[2-(5-amino-
6-ethoxy-pyrazin-2-yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.84; m/z = 410.1 B
76 ##STR00112## (R)-2-Amino-7-[2-(5-amino- 6-ethoxy-pyrazin-2-yl)-
phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt =
1.76; m/z = 392.1 B 77 ##STR00113## (R)-2-Amino-4-ethyl-7-[2-(6-
methoxy-pyridin-2-yl)- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.24; m/z = 376.1 B 78
##STR00114## (R)-2-Amino-4-ethyl-7-[2-(6- methoxy-pyrazin-2-yl)-
phenyl]-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.03; m/z
= 377.1 B 79 ##STR00115## (R)-2-Amino-7-[2-(5-amino-
6-methoxy-pyrazin-2-yl)- phenyl]-4-ethyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.76; m/z = 392.2 B 80
##STR00116## (R)-2-Amino-4-ethyl-7-[2-(2- methoxy-thiazol-4-yl)-
phenyl]-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.24; m/z
= 382.0 A 81 ##STR00117## (R)-2-Amino-4-ethyl-7-[4-
fluoro-2-(6-methoxy-pyridin- 2-yl)-phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.33; m/z = 394.1 B 82
##STR00118## (R)-2-Amino-4-ethyl-7-[4- fluoro-2-(6-methoxy-pyrazin-
2-yl)-phenyl]-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt =
2.11; m/z = 395.1 B 83 ##STR00119## (R)-2-Amino-7-[2-(5-amino-
6-ethoxy-pyrazin-2-yl)-4- fluoro-phenyl]-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.84; m/z = 396.1 B 84
##STR00120## (R)-2-Amino-4-ethyl-7-[4- fluoro-2-(2-methoxy-thiazol-
4-yl)-phenyl]-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt =
2.07; m/z = 400.0 B 85 ##STR00121## (R)-2-Amino-7-[2-(6-ethoxy-
pyrazin-2-yl)-4-fluoro- phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.92; m/z = 395.1 B
86 ##STR00122## (R)-2-Amino-7-[2-(6-ethoxy- pyrazin-2-yl)-4-fluoro-
phenyl]-4-ethyl-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin-5- one Rt =
2.00; m/z = 409.1 B 87 ##STR00123## (R)-2-Amino-7-[2-(6-ethoxy-
pyrazin-2-yl)-4-fluoro- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.15; m/z = 381.0 B 88
##STR00124## (R)-2-Amino-7-[5-(6- methoxy-pyrazin-2-yl)-
thiazol-4-yl]-4-methyl-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.72; m/z = 370.0 B
TABLE-US-00003 TABLE 3 IC50 (.mu.M) LC/MS (Rt A .gtoreq. 10 Cmpd.
Structure Name (min), m/z) B < 10 89 ##STR00125##
2-Amino-7-(5-fluoro-2'- trifluoromethyl-biphenyl-2-yl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.2 m/z =
417.0 B 90 ##STR00126## 2-Amino-7-(4-fluoro-2-pyridin-
4-yl-phenyl)-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one
Rt = 2.63 m/z = 350.0 A 91 ##STR00127##
2-Amino-7-(5,3'-difluoro-4'- methoxy-biphenyl-2-yl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.07 m/z =
397.0 A 92 ##STR00128## 2-Amino-4-methyl-7-phenyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.39 m/z = 255.0 A 93
##STR00129## 2-Amino-6-(2-amino-ethyl)-7-[4-
fluoro-2-(6-methoxy-pyrazin-2- yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.87 m/z = 424.2 B 94
##STR00130## (R)-2-Amino-7-(2-bromo-4- fluoro-phenyl)-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.95 m/z =
350.9/353.0 95 ##STR00131## (R)-2-Amino-7-[4-fluoro-2-(2-
methoxy-thiazol-4-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.19 m/z = 386.3 B 96
##STR00132## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.09; m/z = 366 B 97 ##STR00133##
(R)-2-Amino-7-[2-(5-amino-6- methoxy-pyrazin-2-yl)-4-fluoro-
phenyl]-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 1.61; m/z
= 328 B 98 ##STR00134## (R)-2-Amino-7-(4-fluoro-
phenyl)-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one B 99
##STR00135## 2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.46 m/z = 396.0 B 100
##STR00136## (S)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.46 m/z = 396.0 A 101
##STR00137## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.46 m/z = 396.0 B 102
##STR00138## (R)-2-Amino-7-(4-fluoro- phenyl)-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.622 m/z = 273.1 B 103
##STR00139## (R)-2-Amino-4-methyl-7-phenyl-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.534 m/z = 255.2
B 104 ##STR00140## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.538 m/z = 378.2 B 105
##STR00141## (R)-6-Allyl-2-amino-7-[2-(5-
amino-6-methoxy-pyrazin-2-y yl)- 4-fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.917 m/z = 436.2 B
106 ##STR00142## (R)-2-Amino-6-ethyl-7-[4-
fluoro-2-(6-methoxy-pyridin-2- yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.51 m/z = 408.1 B
107 ##STR00143## (R)-2-Amino-6-ethyl-7-[4-
fluoro-2-(2-methoxy-pyridin-3- yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.32 m/z = 408.1 B
108 ##STR00144## (R)-2-Amino-6-ethyl-7-[4-
fluoro-2-(6-methoxy-pyrazin-2- yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.29 m/z = 409.1 B
109 ##STR00145## (R)-2-Amino-6-ethyl-7-(5-
fluoro-3'-methoxy-biphenyl-2- yl)-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.58 m/z = 407.1 B 110
##STR00146## (R)-2-Amino-6-ethyl-7-(4-
fluoro-2-pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.74 m/z = 378.1 B 111
##STR00147## (R)-2-Amino-7-[2-(2,4- dimethoxy-pyrimidin-5-yl)-4-
fluoro-phenyl]-6-ethyl-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.24 m/z = 439.1 A 112 ##STR00148##
(R)-2-Amino-6-benzyl-7-[2-(5- chloro-4-hydroxy-pyrimidin-2-
yl)-4-fluoro-phenyl]-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.29 m/z = 491.1 A 113 ##STR00149##
(R)-2-Amino-7-[4-fluoro-2-(6- methoxy-pyrazin-2-yl)-phenyl]-
6-(2-hydroxy-ethyl)-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.01 m/z = 425.1 B 114 ##STR00150##
(R)-2-Amino-7-(2-bromo-4- fluoro-phenyl)-6-(2,4-
dimethoxy-benzyl)-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.72 m/z = 501.0, 503.0 A 115 ##STR00151##
(R)-2-Amino-6-(3-chloro- benzyl)-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.79 m/z = 505.0 B 116
##STR00152## (R)-2-Amino-6-(3-chloro- benzyl)-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 3.05 m/z = 504.0 B 117
##STR00153## (R)-2-Amino-6-(3-chloro- benzyl)-7-[2-(5,6-dimethoxy-
pyrazin-2-yl)-4-fluoro-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.94 m/z = 535.0 B 118
##STR00154## (R)-2-Amino-6-(2,4-dimethoxy-
benzyl)-7-[4-fluoro-2-(6- methoxy-pyrazin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.58 m/z
= 531.1 B 119 ##STR00155## (R)-2-Amino-6-(2,4-dimethoxy-
benzyl)-7-[4-fluoro-2-(6- methoxy-pyridin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.82 m/z
= 530.1 B 120 ##STR00156## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 4-methyl-6-pyridin-4-ylmethyl-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.01 m/z = 471.1
B 121 ##STR00157## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-6-pyridin-4-ylmethyl-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.89 m/z = 472.1
B 122 ##STR00158## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-4-methyl-6-pyridin-4-
ylmethyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 1.72 m/z
= 487.1 B 123 ##STR00159## (R)-2-Amino-6-(2-fluoro-
benzyl)-7-[4-fluoro-2-(6- methoxy-pyridin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.90 m/z
= 488.0 B 124 ##STR00160## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-6-(2-fluoro-benzyl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.27 m/z =
504.0 B 125 ##STR00161## (R)-2-Amino-6-(2-chloro-
benzyl)-7-[4-fluoro-2-(6- methoxy-pyridin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 3.03 m/z
= 504.0 B 126 ##STR00162## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-6-(2-chloro-benzyl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.36 m/z =
520.1 B 127 ##STR00163## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-6-(3-trifluoromethyl-
benzyl)-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.87 m/z
= 539.1 B 128 ##STR00164## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 4-methyl-6-(3-trifluoromethyl-
benzyl)-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 3.11 m/z
= 538.1 B 129 ##STR00165## (R)-2-Amino-6-(2-fluoro-
benzyl)-7-[4-fluoro-2-(6- methoxy-pyrazin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.64 m/z
= 489.0 B 130 ##STR00166## (R)-2-Amino-6-(2-chloro-
benzyl)-7-[4-fluoro-2-(6- methoxy-pyrazin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.73 m/z
= 505.1 B 131 ##STR00167## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-6-(tetrahydra-pyran-4-
ylmethyl)-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.29
m/z = 479.1 B 132 ##STR00168## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 4-methyl-6-(tetrahydro-pyran-4-
ylmethyl)-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.51
m/z = 478.2 B 133 ##STR00169## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-6-(2-methyl-2-
morpholin-4-yl-propyl)-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.00 m/z = 522.2 B 134 ##STR00170##
(R)-2-Amino-6-benzyl-7-[4- fluoro-2-(6-methoxy-pyridin-2-
yl)-phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one
Rt = 2.90 m/z = 470.2 B 135 ##STR00171## (R)-2-Amino-6-benzyl-7-[4-
fluoro-2-(2-methoxy-pyridin-3- yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.70 m/z = 470.1 B
136 ##STR00172## (R)-2-Amino-6-benzyl-7-[4-
fluoro-2-(6-methoxy-pyrazin-2- yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.64 m/z = 471.1 B
137 ##STR00173## (R)-2-Amino-6-benzyl-7-(5-
fluoro-3'-methoxy-biphenyl-2- yl)-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.94 m/z = 469.1 A 138
##STR00174## (R)-2-Amino-6-benzyl-4-methyl-
7-(5,2',3'-trifluoro-biphenyl-2- yl)-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.94 m/z = 475.1 B 139 ##STR00175##
(R)-2-Amino-6-benzyl-7-(5,3'- difluoro-4'4-methoxy-biphenyl-2-
yl)-4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.91
m/z = 487.1 A 140 ##STR00176## (R)-2-Amino-6-benzyl-7-(4-
fluoro-2-pyridin-3-yl-phenyl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.07 m/z = 440.1 B 141
##STR00177## (R)-2-Amino-6-benzyl-7-[2-(2,4-
dimethoxy-pyrimidin-5-yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.59 m/z = 501.1 A
142 ##STR00178## (R)-2-Amino-6-benzyl-7-(5,2'-
difluoro-4'4-methyl-biphenyl-2- yl)-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 3.08 m/z = 471.2 A 143
##STR00179## (R)-2-Amino-6-benzyl-7-[4-
fluoro-2-(2-fluoro-pyridin-3-yl)- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 2.61 m/z = 458.1 B 144
##STR00180## (R)-2-Amino-6-benzyl-7-(5,2'-
difluoro-3'4-methoxy-biphenyl-2- yl)-4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.92 m/z = 487.2 A 145
##STR00181## 2-Amino-7-[2-(5,6-dimethoxy-
pyrazin-2-yl)-4-fluoro-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.18 m/z = 411.1 B 146
##STR00182## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-6-(3-methyl-butyl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.72 m/z = 451.2 B
147 ##STR00183## (R)-2-Amino-7-[2-(5,6- dimethoxy-pyrazin-2-yl)-4-
fluoro-phenyl]-4-methyl-6-(3- methyl-butyl)-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.68 m/z = 481.1 B 148
##STR00184## (R)-2-Amino-7-(2-bromo-4-
fluoro-phenyl)-4-methyl-6-(3- methyl-butyl)-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.83 m/z = 421.1 A
149 ##STR00185## (R)-2-Amino-7-(2-bromo-4-
fluoro-phenyl)-6-isobutyl-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.67 m/z = 407.0 A 150
##STR00186## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 4-methyl-6-(3-methyl-butyl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.98 m/z = 450.2 B
151 ##STR00187## (R)-2-Amino-7-[4-fluoro-2-(2-
fluoro-pyridin-3-yl)-phenyl]-4- methyl-6-(3-methyl-butyl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.68 m/z = 438.1 B
152 ##STR00188## (R)-2-Amino-7-[4-fluoro-2-(2-
methoxy-pyridin-3-yl)-phenyl]- 4-methyl-6-(3-methyl-butyl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.79 m/z = 450.2 B
153 ##STR00189## (R)-2-Amino-7-[4-fluoro-2-(4-
methoxy-pyridin-3-yl)-phenyl]- 4-methyl-6-(3-methyl-butyl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.11 m/z = 450.2 B
154 ##STR00190## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 6-isobutyl-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 2.55 m/z = 437.1 B 155
##STR00191## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 6-isobutyl-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 2.79 m/z = 436.2 B 156
##STR00192## (R)-2-Amino-7-[2-(5,6- dimethoxy-pyrazin-2-yl)-4-
fluoro-phenyl]-6-isobutyl-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.74 m/z = 467.1 B 157
##STR00193## (R)-2-Amino-7-[4-fluoro-2-(2-
fluoro-pyridin-3-yl)-phenyl]-6- isobutyl-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 2.57 m/z = 424.1 B 158
##STR00194## (R)-2-Amino-7-[4-fluoro-2-(2-
methoxy-pyridin-3-yl)-phenyl]- 6-isobutyl-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 2.61 m/z = 436.2 B 159
##STR00195## (R)-2-Amino-7-[4-fluoro-2-(4-
methoxy-pyridin-3-yl)-phenyl]- 6-isobutyl-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.98 m/z = 436.1 A 160
##STR00196## (R)-2-Amino-6-(4-fluoro- benzyl)-7-[4-fluoro-2-(6-
methoxy-pyridin-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.92 m/z = 488.0 B 161
##STR00197## (R)-2-Amino-6-(4-fluoro- benzyl)-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.968 m/z = 489.1 B 162
##STR00198## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-6-(4-fluoro-benzyl)-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.30 m/z =
504.1 B 163 ##STR00199## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-fluoro- phenyl]-6-isobutyl-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.21 m/z = 452.1 B
164 ##STR00200## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-6-pyridin-3-ylmethyl-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.03 m/z = 471.1
B 165 ##STR00201## {3-[(R)-2-Amino-7-(2-bromo-4-
fluoro-phenyl)-4-methyl-5-oxo- 7,8-dihydro-5H-pyrido[4,3-
d]pyrimidin-6-yl]-propyl}- carbamic acid tert-butyl ester Rt = 2.61
m/z = 510.1 A 166 ##STR00202## (R)-2-Amino-6-(3-amino-
propyl)-7-(2-bromo-4-fluoro- phenyl)-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 1.76 m/z = 410.0 A 167
##STR00203## {3-[(R)-2-Amino-7-(4-fluoro-2-
pyridin-3-yl-phenyl)-4-methyl-5- oxo-7,8-dihydro-5H-pyrido[4,3-
d]pyrimidin-6-yl]-propyl}- carbamic acid tert-butyl ester Rt =
2.107 m/z = 507.2 B 168 ##STR00204## (R)-2-Amino-6-(3-amino-
propyl)-7-(4-fluoro-2-pyridin-3- yl-phenyl)-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.48 m/z = 407.1 B
169 ##STR00205## (3-{(R)-2-Amino-7-[4-fluoro-2-
(2-fluoro-pyridin-3-yl)-phenyl]- 4-methyl-5-oxo-7,8-dihydro-5H-
pyrido[4,3-d]pyrimidin-6-yl}- propyl)-carbamic acid tert-butyl
ester Rt = 2.55 m/z = 525.2 B 170 ##STR00206##
(R)-2-Amino-6-(3-amino- propyl)-7-[4-fluoro-2-(2-fluoro-
pyridin-3-yl)-phenyl]-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.87 m/z = 425.2 A 171 ##STR00207##
(R)-2-Amino-6-(3-amino- propyl)-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.89 m/z = 438.1 B 172
##STR00208## (R)-2-Amino-7-[5-(6-methoxy-
pyridin-2-yl)-thiazol-4-yl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.96 m/z 369.0 B 173 ##STR00209##
(R)-2-Amino-7-(5-bromo- thiazol-4-yl)-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.28 m/z = 341.9
TABLE-US-00004 TABLE 4 IC50 (.mu.M) LC/MS A .gtoreq. 10 Cmpd.
Structure Name (Rt, m/z) B < 10 174 ##STR00210##
(R)-2-Amino-7-[2-(4-ethoxy-5- fluoro-pyrimidin-2-yl)-4-fluoro-
phenyl]-4-methyl-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin-5-one Rt =
2.33; m/z = 413.1 B 175 ##STR00211## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-pyrazin-2-yl)-phenyl]- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.93; m/z = 367 B 176 ##STR00212##
(R)-2-Amino-7-(5-fluoro-2'- methoxy-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.21; m/z = 365 B 177
##STR00213## (R)-2-Amino-7-(5,5'-difluoro-2'-
methoxy-biphenyl-2-yl)-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.27; m/z = 383 B 178 ##STR00214##
(R)-2-Amino-7-(5,4'-difluoro-2'- methoxy-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.28; m/z = 383 B 179
##STR00215## (R)-2-Amino-7-(5-fluoro-3',4'-
dimethoxy-biphenyl-2-yl)-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.11; m/z = 395 A 180 ##STR00216##
(R)-2-Amino-7-(5-fluoro-3'- methyl-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.35; m/z = 349 B 181
##STR00217## (R)-2-Amino-7-(5-fluoro-2'- methyl-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.31; m/z = 349 B 182
##STR00218## (R)-2-Amino-7-(5-fluoro-4'- methyl-biphenyl-2-yl)-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.36; m/z = 349 B 183
##STR00219## (R)-2-Amino-7-(5,4'-difluoro-2'-
methyl-biphenyl-2-yl)-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one
Rt = 2.36; m/z = 367 B 184 ##STR00220## (R)-2-Amino-7-(2-bromo-
phenyl)-4-methyl-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin-5-one Rt =
1.85 m/z = 332.9/334.9 A 185 ##STR00221## (R)-2-Amino-7-[2-(4,5-
dimethoxy-pyrimidin-2-yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one B 186 ##STR00222##
(R)-2-Amino-7-[5-(6-methoxy- pyrazin-2-yl)-thiazol-4-yl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 1.72; m/z
= 370.0 B 187 ##STR00223## (R)-2-Amino-7-[2-(6-ethoxy-
pyridin-2-yl)-4-fluoro-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.37; m/z = 394.0 B 188
##STR00224## (R)-2-Amino-7-[2-(2-methoxy-
thiazol-4-yl)-phenyl]-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.10 m/z = 368.0 B 189 ##STR00225##
(R)-2-Amino-7-[2-(5,6- dimethoxy-pyrazin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.11 m/z
= 393.1 B 190 ##STR00226## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyridin-2-yl)-4-fluoro- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5- one Rt = 2.07; m/z = 395.1 (M + H) B
191 ##STR00227## (R)-2-Amino-7-(4-fluoro-2-
pyridin-3-yl-phenyl)-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin-5-one
Rt = 1.4 m/z = 336 B 192 ##STR00228## (R)-2-Amino-7-[2-(2,4-
dimethoxy-pyrimidin-5-yl)-4- fluoro-phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.95 m/z = 397 A 193 ##STR00229##
(R)-2-Amino-7-[2-(4-ethoxy- pyrimidin-2-yl)-4-fluoro-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.13;
m/z = 395 B 194 ##STR00230## (R)-2-Amino-7-[2-(6-methoxy-
pyrazin-2-yl)-phenyl]-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.94 m/z = 363.0 B 195 ##STR00231##
(R)-2-Amino-7-[4-fluoro-2-(4- methoxy-pyrimidin-2-yl)-phenyl]-
4-methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.00;
m/z = 381 B 196 ##STR00232## (R)-2-Amino-7-[2-(5-amino-6-
ethoxy-pyrazin-2-yl)-4-fluoro- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one Rt = 1.84; m/z = 410.1 B 197
##STR00233## (R)-2-Amino-7-[2-(5-amino-6-
ethoxy-pyrazin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.76; m/z = 392.1 B 198
##STR00234## (R)-2-Amino-4-ethyl-7-[2-(6-
methoxy-pyridin-2-yl)-phenyl]- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.24; m/z = 376.1 B 199 ##STR00235##
(R)-2-Amino-4-ethyl-7-[2-(6- methoxy-pyrazin-2-yl)-phenyl]-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.03; m/z = 377.1
B 200 ##STR00236## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-phenyl]-4- ethyl-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.76; m/z = 392.2 B 201 ##STR00237##
(R)-2-Amino-4-ethyl-7-[2-(2- methoxy-thiazol-4-yl)-phenyl]-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.24; m/z = 382.0
A 202 ##STR00238## (R)-2-Amino-7-[2-(5-chloro-4-
methoxy-pyrimidin-2-yl)-4- fluoro-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one B 203 ##STR00239##
(R)-2-Amino-7-[2-(6-methoxy- pyrazin-2-yl)-phenyl]-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one rt = 1.87 m/z = 349.1 B
204 ##STR00240## (R)-2-Amino-7-[2-(5-fluoro-4-
methoxy-pyrimidin-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.971 m/z = 381.2 B 205
##STR00241## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyridin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.85; m/z = 377.1 (M + H) B 206
##STR00242## (R)-2-Amino-7-[2-(6-methoxy-
pyridin-2-yl)-phenyl]-7,8- dihydro-6H-pyrido[4,3- d]pyrimidin-5-one
Rt = 1.83 m/z = 348.1 B 207 ##STR00243##
(R)-2-Amino-7-[4-fluoro-2-(4- pyrrolidin-1-yl-pyrimidin-2-yl)-
phenyl]-4-methyl-7,8-dihydro- 6H-pyrido[4,3-d]pyrimidin-5-one Rt =
1.72 min; m/z = 420 A 208 ##STR00244## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyridin-2-yl)-4-fluoro- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.08 min; m/z = 381.1 (M + H) B
209 ##STR00245## (R)-2-Amino-7-[4-fluoro-2-(5-
methoxy-thiophen-2-yl)-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.064; m/z = 385.0 B 210
##STR00246## (R)-2-Amino-7-(2-bromo-4- fluoro-phenyl)-4-ethyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.05 m/z = 367.0 A
211 ##STR00247## (R)-2-Amino-4-ethyl-7-[4-fluoro-
2-(6-methoxy-pyridin-2-yl)- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.33; m/z = 394.1 B 212
##STR00248## (R)-2-Amino-4-ethyl-7-[4-fluoro-
2-(6-methoxy-pyrazin-2-yl)- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.11; m/z = 395.1 B 213
##STR00249## (R)-2-Amino-7-(5-fluoro-2',3'-
dimethoxy-biphenyl-2-yl)-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.067; m/z = 409.1 B 214
##STR00250## (R)-2-Amino-7-[2-(5-amino-6-
ethoxy-pyrazin-2-yl)-4-fluoro- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.84; m/z = 396.1 B 215
##STR00251## (R)-2-Amino-4-ethyl-7-[4-fluoro-
2-(2-methoxy-thiazol-4-yl)- phenyl]-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.07; m/z = 400.0 B 216
##STR00252## (R)-2-Amino-7-[2-(6-ethoxy-
pyrazin-2-yl)-4-fluoro-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.92; m/z = 395.1 B 217
##STR00253## (R)-2-Amino-7-[2-(6-ethoxy-
pyrazin-2-yl)-4-fluoro-phenyl]-4- ethyl-7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.00; m/z = 409.1 B 218 ##STR00254##
(R)-2-Amino-7-[2-(6-ethoxy- pyrazin-2-yl)-4-fluoro-phenyl]-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.15; m/z = 381.0
B 219 ##STR00255## 2-((R)-2-Amino-4-methyl-5-oxo-
5,6,7,8-tetrahydro-pyrido[4,3- d]pyrimidin-7-yl)-5-fluoro-
benzonitrile Rt = 2.03; m/z = 298 A 220 ##STR00256##
(R)-2-Amino-7-[2-(6-ethoxy- pyrazin-2-yl)-phenyl]-4-methyl-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 2.07 m/z = 377.1
B 221 ##STR00257## (R)-2-Amino-7-[2-(4-methoxy-5-
methyl-pyrimidin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.553 m/z = 377.1 B 222
##STR00258## (R)-2-Amino-7-[4-fluoro-2-(5-
oxo-4,5-dihydro-[1,3,4]oxadiazol- 2-yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.72; m/z = 357 A 223
##STR00259## (R)-2-Amino-7-[4-fluoro-2-(5-
methoxy-[1,3,4]oxadiazol-2-yl)- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one Rt = 2.22; m/z = 371 B 224
##STR00260## (S)-2-Amino-7-[5-(6-methoxy-
pyrazin-2-yl)-thiazol-4-yl]-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.72 m/z = 356.1 B 225 ##STR00261##
(R)-2-Amino-7-[4-fluoro-2-(2- methoxy-thiazol-5-yl)-phenyl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 1.834 m/z
= 386.0 B 226 ##STR00262## (R)-2-Amino-7-[2-(5-amino-6-
ethoxy-pyrazin-2-yl)-4-fluoro- phenyl]-4-ethyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.91 m/z = 424.1 B 227
##STR00263## (R)-2-Amino-7-[4-methoxy-2-(6-
methoxy-pyrazin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.98; m/z = 393.1 B 228
##STR00264## (R)-2-Amino-7-(2-bromo- phenyl)-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.74, 322.9 229 ##STR00265##
(R)-2-Amino-7-[2-(5-amino-6- methoxy-pyrazin-2-yl)-phenyl]-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.65, m/z = 364.0
B 230 ##STR00266## (R)-2-Amino-7-[2-(2-ethoxy-
thiazol-4-yl)-phenyl]-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 2.63, m/z = 383 B 231 ##STR00267##
(R)-2-Amino-7-[2-(2-ethoxy- thiazol-4-yl)-4-fluoro-phenyl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.87, m/z
= 400 B 232 ##STR00268## (S)-2-Amino-7-[5-(6-methoxy-
pyridin-2-yl)-thiazol-4-yl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.96, m/z = 369.0 B 233
##STR00269## (S)-2-Amino-7-[5-(6-methoxy-
pyrazin-2-yl)-thiazol-4-yl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.72, m/z = 370.0 B 234
##STR00270## (R)-2-Amino-7-[2-(5-amino-6-
ethoxy-pyrazin-2-yl)-phenyl]-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.72, m/z = 378.1 B 235 ##STR00271##
(R)-2-Amino-7-[2-(5-amino-6- ethyl-pyrazin-2-yl)-phenyl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 1.68; m/z
= 376 B 236 ##STR00272## (R)-2-Amino-7-(2-bromo-4-
methoxy-phenyl)-4-methyl-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.95 min; m/z = 365.0 A 237 ##STR00273##
(R)-2-Amino-7-[4-methoxy-2-(6- methoxy-pyridin-2-yl)-phenyl]-4-
methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.15 min; m/z = 392.1 B 238
##STR00274## (R)-2-Amino-7-[2-(5-amino-6-
ethoxy-pyrazin-2-yl)-4-methoxy- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one Rt = 1.79 min; m/z = 422.1 B 239
##STR00275## (R)-2-Amino-7-[2-(6-ethoxy-
pyrazin-2-yl)-4-methoxy-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.11 min; m/z = 407.1 B
TABLE-US-00005 TABLE 5 IC50 (mM) LC/MS A .gtoreq. 10 Cmpd Structure
Name (Rt, m/z) B < 10 240 ##STR00276##
(R)-2-Amino-7-[2-(5-amino-6- methoxy-pyrazin-2-yl)-4-
methoxy-phenyl]-4-methyl-7,8- dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.69 m/z = 408.1 B 241 ##STR00277##
(R)-2-Amino-7-[4-methoxy-2-(2- methoxy-thiazol-4-yl)-phenyl]-4-
methyl-7,8-dihydro-6H- pyrido[4,3-d]pyrimidin-5-one Rt = 2.14 m/z =
398.1 242 ##STR00278## (R)-2-Amino-7-[2-(2-ethoxy-
thiazol-4-yl)-4-methoxy-phenyl]- 4-methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.31 m/z = 412.0 A 243
##STR00279## (R)-2-Amino-7-[2-(6-methoxy-5-
methylamino-pyrazin-2-yl)- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one Rt = 1.40 m/z = 392.1 B 244
##STR00280## (R)-2-Amino-7-[4-fluoro-2-(6-
methoxy-5-methylamino-pyrazin- 2-yl)-phenyl]-4-methyl-7,8-
dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.49 m/z = 410.1 B
245 ##STR00281## (R)-2-Amino-7-[5-methoxy-2-(6-
methoxy-pyrazin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.78 m/z = 393 B 246 ##STR00282##
(R)-2-Amino-7-[5-methoxy-2-(6- methoxy-pyrazin-2-yl)-phenyl]-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.75 m/z = 379 B
247 ##STR00283## (R)-2-Amino-7-[2-(5- dimethylamino-6-methoxy-
pyrazin-2-yl)-phenyl]-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.63 m/z = 406.1 B 248 ##STR00284##
(R)-2-Amino-7-[2-(5- dimethylamino-6-methoxy-
pyrazin-2-yl)-4-fluoro-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.77 m/z = 424.1 B 249
##STR00285## (R)-2-Amino-7-(5-bromo-2-
methoxy-pyridin-4-yl)-4-methyl- 7,8-dihydro-6H-pyrido[4,3-
d]pyrimidin-5-one Rt = 1.76 m/z = 364 B 250 ##STR00286##
(R)-2-Amino-7-(6,6'-dimethoxy- [2,3']bipyridinyl-4'-yl)-4-methyl-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.98 m/z = 393 B
251 ##STR00287## (R)-2-Amino-7-[5-methoxy-2-(6-
methoxy-pyridin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 1.95 m/z = 392 A 252 ##STR00288##
(R)-2-Amino-7-[5-methoxy-2-(6- methoxy-pyridin-2-yl)-phenyl]-
7,8-dihydro-6H-pyrido[4,3- d]pyrimidin-5-one Rt = 1.94 m/z = 378 B
253 ##STR00289## (R)-2-Amino-7-[2-(5-amino-6-
ethoxy-pyrazin-2-yl)-4-ethoxy- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one Rt = 1.91 m/z = 436.1 B 254
##STR00290## (R)-2-Amino-7-[2-(5-amino-6-
methoxy-pyrazin-2-yl)-4-ethoxy- phenyl]-4-methyl-7,8-dihydro-
6H-pyrido[4,3-d]pyrimidin-5-one Rt = 1.79 m/z = 422.1 B 255
##STR00291## (R)-2-Amino-7-[4-ethoxy-2-(6-
methoxy-pyridin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.29 m/z = 406.1 B 256
##STR00292## (R)-2-Amino-7-[4-ethoxy-2-(6-
methoxy-pyrazin-2-yl)-phenyl]-4- methyl-7,8-dihydro-6H-
pyrido[4,3-d]pyrimidin-5-one Rt = 2.13 m/z = 407.1 B 257
##STR00293## (R)-2-amino-7-(2- (cyclopentyloxy)-4-
fluorophenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin-
5(6H)-one Rt = 2.1 m/z = 357 B 258 ##STR00294## (R)-2-amino-7-(2-
(cyclopentyloxy)phenyl)-4- methyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 2.03 m/z = 339 B 259 ##STR00295##
(R)-2-amino-7-(4-fluoro-2- isopropoxyphenyl)-4-methyl-
7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one Rt = 1.87 m/z = 331 B
260 ##STR00296## (R)-2-amino-7-((R)-5-fluoro-2-
(6-methoxypyridin-2- yl)phenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 2.51 min, MH+ = 380.1
B 261 ##STR00297## (R)-2-amino-7-((R)-2-(6- methoxypyridin-2-yl)-4-
methylphenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin-
5(6H)-one Rt = 2.31 m/z = 376.2 B 262 ##STR00298##
(R)-2-amino-7-((R)-5-fluoro-2- (6-methoxypyrazin-2-
yl)phenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin- 5(6H)-one
Rt = 2.20 min, MH+ = 381.1 B 263 ##STR00299##
(R)-2-amino-7-((R)-2-(6- methoxypyrazin-2-yl)-4-
methylphenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin-
5(6H)-one Rt = 2.11 m/z = 377.2 B 264 ##STR00300##
(R)-2-amino-7-(2-((R)-5- amino-6-(2,2,2-
trifluoroethoxy)pyrazin-2-yl)-4- fluorophenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.79 m/z = 463.9 B
265 ##STR00301## (R)-2-amino-7-((R)-5-fluoro-2-
(2-methoxythiazol-4- yl)phenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 2.18 m/z = 386.1 B
266 ##STR00302## (R)-2-amino-7-((R)-2-(5-
amino-6-methoxypyrazin-2-yl)- 5-fluorophenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.73 m/z = 396.1 B
267 ##STR00303## (R)-2-amino-7-((R)-2-(2- methoxythiazol-4-yl)-4-
methylphenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin-
5(6H)-one Rt = 2.29 m/z = 382.1 B 268 ##STR00304##
(R)-2-amino-7-((R)-2-(5- amino-6-methoxypyrazin-2-yl)-
4-methylphenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin-
5(6H)-one Rt = 1.80 m/z = 392.2 B 269 ##STR00305##
(R)-2-amino-7-(2- (cyclopentyloxy)-4- fluorophenyl)-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 2.4 min m/z = 343 B
270 ##STR00306## (R)-2-amino-7-(2-((R)-5- amino-6-(2,2,2-
trifluoroethoxy)pyrazin-2- yl)phenyl)-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.68 m/z = 431.9 A
271 ##STR00307## (R)-2-amino-7-(2-((R)-5- amino-6-(2,2,2-
trifluoroethoxy)pyrazin-2- yl)phenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.67 m/z = 445.9 B
272 ##STR00308## (R)-2-amino-7-(2-((R)-5- amino-6-(2,2,2-
trifluoroethoxy)pyrazin-2-yl)-4- fluorophenyl)-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.79 m/z = 449.9 A
273 ##STR00309## (R)-2-amino-7-((S)-2-(5-amino-
6-methoxypyrazin-2-yl)-4- fluoro-5-methoxyphenyl)-4-
methyl-7,8-dihydropyrido[4,3- d]pyrimidin-5(6H)-one Rt = 1.75 m/z =
426.1 B 274 ##STR00310## (R)-2-amino-7-((S)-4-fluoro-5-
methoxy-2-(6-methoxypyrazin- 2-yl)phenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 2.06 m/z = 411.1 B
275 ##STR00311## (R)-2-amino-7-(4-fluoro-5- methoxy-2-((S)-6-
methoxypyridin-2-yl)phenyl)-4- methyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 2.30 m/z = 410.1 B 276 ##STR00312##
(R)-2-amino-7-((R)-4-fluoro-5- methoxy-2-(2-methoxythiazol-
4-yl)phenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin- 5(6H)-one
Rt = 2.25 m/z = 416.1 B 277 ##STR00313##
(R)-2-amino-7-((S)-2-(5-amino- 6-methoxypyrazin-2-yl)-4-
isopropoxy-5-methoxyphenyl)- 4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.87, m/z = 466.2 B
278 ##STR00314## (R)-2-amino-7-((S)-4- isopropoxy-5-methoxy-2-(6-
methoxypyrazin-2-yl)phenyl)- 4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 2.19 m/z = 451.1 B
279 ##STR00315## (R)-2-amino-7-(4-isopropoxy- 5-methoxy-2-((S)-6-
methoxypyridin-2-yl)phenyl)-4- methyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 2.37 m/z = 450.1 B 280 ##STR00316##
(R)-2-amino-7-((R)-4- isopropoxy-5-methoxy-2-(2-
methoxythiazol-4-yl)phenyl)-4- methyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 2.36, m/z = 456.1 A 281 ##STR00317##
(R)-2-amino-7-((S)-4,5- dimethoxy-2-(6-
methoxypyridin-2-yl)phenyl)-4- methyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 2.12 m/z = 422.1 B 282 ##STR00318##
(R)-2-amino-7-((S)-4,5- dimethoxy-2-(6-
methoxypyrazin-2-yl)phenyl)- 4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.94 m/z = 423.1 B
283 ##STR00319## (R)-2-amino-7-(2-bromo-4,5-
dimethoxyphenyl)-4-methyl- 7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 1.90 m/z = 395.1 A 284 ##STR00320##
(R)-2-amino-7-((R)-4,5- dimethoxy-2-(2-
methoxythiazol-4-yl)phenyl)-4- methyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 1.969 m/z = 428.1 B 285 ##STR00321##
(R)-2-amino-7-((R)-2-(5- amino-6-ethoxypyrazin-2-yl)-
4,5-dimethoxyphenyl)-4- methyl-7,8-dihydropyrido[4,3-
d]pyrimidin-5(6H)-one Rt = 1.45 m/z = 452.1 A 286 ##STR00322##
(R)-2-amino-7-(2-bromo-4- ethoxyphenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 2.13 m/z = 377.0 A
287 ##STR00323## (R)-2-amino-7-((S)-4-fluoro-2-
(6-hydroxypyridin-2-yl)phenyl)- 4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.382 m/z = 366.1 B
288 ##STR00324## (R)-2-amino-7-((R)-4-fluoro-2-
(6-hydroxypyrazin-2- yl)phenyl)-4-methyl-7,8-
dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.35 m/z = 367.1 B
289 ##STR00325## (R)-2-amino-7-(2-bromo-4,5-
diethoxyphenyl)-4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin-
5(6H)-one Rt = 2.20 m/z = 423.0 A 290 ##STR00326##
(R)-2-amino-7-((R)-4-fluoro-2- (2-hydroxythiazol-4-yl)phenyl)-
4-methyl-7,8- dihydropyrido[4,3-d]pyrimidin- 5(6H)-one Rt = 1.89
m/z = 377.2 A
[0477] Using the procedure described in Example 10, certain
compounds in Tables 1-5 were shown to have HSP90 inhibitory
activity at an IC.sub.50 of less than 25 .mu.M. Some of the
compounds have an IC.sub.50 of less than about 10 .mu.M.
Example 10
HSP90 Inhibitor Binding Potency
TRF Binding Assay
[0478] In this example, the binding potency of HSP90 inhibitors as
measured by a TRF binding assay is described.
[0479] TRF competition binding assays were performed to determine
the binding potency (IC.sub.50 values) of HSP90 inhibitors.
Purified His-tagged N-terminal ATP binding domain (amino acid
residues 9-236) of HSP90.alpha. (HSP90.alpha. GeneID: 3320; mRNA
Sequence NM.sub.--005348) was incubated for two hours at room
temperature in binding buffer (50 mM HEPES, 6 mM MgCl.sub.2, 20 mM
KCl 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:
[0480] Note: IC.sub.50 values can also be determined using
published methods in the following references:
[0481] 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;
[0482] 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
[0483] 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.
[0484] 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.
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