Indian Patents
Title of Invention

PYRAZOLE COMPOUNDS
Abstract This invention describes novel pyrazole compounds of formula (IIA): wherein R1 is T-Ring D, wherein Ring D is 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl; Rx and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 heteroatoms; and R2 and R2' are as described in the specification. The compounds are useful as protein kinase inhibitors, especially as inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer's disease.
Full Text PYRAZOLE COMPOUNDS
CROSS REFERENCE TO RELATED APPLICATION
This application claims priority to US
Provisional Patent Application 60/257,387 filed December
21, 200C and US Provisional Patent Application 60/286, 949
filed April 27, 2001, the contents of which are
incorporated herein by reference.
FIELD OF THE INVENTION
The. present invention is in the field Of
medicinal chemistry and relates to compounds that are
protein kinase inhibitors, compositions containing nuch
compounds and methods of use. More particularly, this
invention relates to compounds that are inhibitors of
Aurora-2 protein kinase. The invention also relates to
methods of treating diseases associated with protein
kinases, especially diseases associated with Aurora-2,
such as cancer.
BACKGROUND OF THE INVENTION
The search for new therapeutic agents has been
greatly aided in recent years by better understanding of
the structure of enzymes and other biomolecules
associated with target diseases. One important class of
enzymes that has been the subject cf extensive study is
the protein kinases.
Protein kinases mediate ir.trace bhulrr signal
transduction. They do this by effecting a phosphoryl
transfer from a nucleoside triphosphate to a protein
acceptor that is involved in a signaling pathway. There
are a number of kinases and pathways through which

extracellular and other stimuli cause a variety of
cellular responses to occur inside the cell. Examples of
such stimuli include environmental and chemical stress
signals(e.g. osmotic shock, heat shock, ultraviolet
radiation, bacterial endotoxin, K2O2), cytokines(e.g.
interleukin-1(IL-1) and tumor necrosis factor a(TNF-α)), and growth factors(e.g. granulocyte macrophage-colony-stimulating factor(GM-C3F), and fibroblast growth
factor(FGF). An extracellular stimulus may effect one
or more cellular responses related to ceil growth,
migration, differentiation, secretion of hormones,
activation of transcription factors, muscle contraction,
glucose metabolism, control of protein synthesis and
regulation of cell cycle.
Many diseases are associated with abnormal
cellular responses triggered by protein kinase-mediated
events. These diseases include autoimmune diseases,
inflammatory diseases, neurological and neurodegenerative
diseases, cancer, cardiovascular diseases, allergies and
asthma, Alzheimer's disease or hormone-related diseases.
Accordingly, there has been a substantial effort in
medicinal chemistry to find protein kinase inhibitors
that are effective as therapeutic agents.
Aurora-2 is a serine/threonine protein kinase
that has been implicated in human cancer, such as colon,
breast and other solid tumors. This kinase is believed
to be involved in protein phosphorylation events that
regulate the cell cycle. Specifically, Aurora-2 may play
a role in controlling the accurate segregation of
chromosomes during mitosis. Misregulation of the cell
cycle can lead to cellular proliferation and other
abnormalities. In human colon cancer tissue, the aurora-2 protein has been found to be overexpressed. See

Bischoff et al., EMBO J., 1398, 17, 3052-3065; Schumacher
et al . , J. Cell Biol., 1998, 143, 1635-1646; Kimura et
al., J. Biol. Chem., 1997, 272, 13766-13771.
Glycogen synthase kinase-3(GSK-3) is a
serine/threonine protein kinase comprised of α and β
isoforms that are each encoded by distinct genes [Coghlan
et al., Chemistry & Biology, 7, 793-303(2000); Kim and
Kimmel, Curr. Opinion Genetics Dev. , 10, 508-514(2000)] .
GSK-3 has been implicated in various diseases including
diabetes, Alzheimer's disease, CNS disorders such as
manic depressive disorder and neurodegenerative diseases,
and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675;
and Haq et al., J. Cell Biol.(2000) 151, 117]. These
diseases may be caused by, or result in, the abnormal
operation of certain cell signaling pathways in which
GSK-3 plays a role. GSK-3 has been found to
phosphorylate and modulate the activity of a number of
regulatory proteins. These proteins include glycogen
synthase which is the rate limiting enzyme necessary for
glycogen synthesis, the microtubule associated protein
Tau, the gene transcription factor β-catenin, the
translation initiation factor elF23, as well as ATP
citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc,
c-Myb, CREB, and CEPBOt. These diverse protein targets
implicate GSK-3 in many aspects of cellular metabolism,
proliferation, differentiation and development.
In a GSK-3 mediated pathway that is relevant
for the treatment of type II diabetes, insulin-induced
signaling leads to cellular glucose uptake and glycogen
synthesis. Along this pathway, GSK-3 is a negative
regulator of the insulin-induced signal. Normally, the
presence of insulin causes inhibition of GSK-3 mediated

phosphorylation and deactivation of glycogen synthase.
The inhibition of GSK-3 leads to increased glycogen
synthesis and glucose uptake [Klein et al., PNAS, 93,
8455-9(1996); Cross et al., Biochem. J., 303, 21-25(1994); Cohen, Biochem. Soc. Trans., 21, 555-567(1993);
Massillon et al., Biochem J. 299, 123-128(1994)].
However, in a diabetic patient where the insulin response
is impaired, glycogen synthesis and glucose uptake fail
to increase despite the presence of relatively high blood
levels of insulin. This leads to abnormally high blood
levels of glucose with acute and long term effects that
may ultimately result in cardiovascular disease, renal
failure and blindness. In such patients, the normal
insulin-induced inhibition of GSK-3 fails to occur. It
has also been reported that in patients with type II
diabetes, GSK-3 is overexpressed [WO 00/38675].
Therapeutic inhibitors of GSK-3 therefore are considered
to be useful for treating diabetic patients suffering
from an impaired response to insulin.
GSK-3 activity has also been associated with
Alzheimer's disease. This disease is characterized by
the well-known β-amyloid peptide and the formation of
intracellular neurofibrillary tangles. The
neurofibrillary tangles contain hyperphosphorylated Tau
protein where Tau is phosphorylated on abnormal sites.
GSK-3 has been shown to phosphorylate these abnormal
sites in cell and animal models. Furthermore, inhibition
of GSK-3 has been shown to prevent hyperphosphorylation
of Tau in cells [Lovestone et al. , Current Biology 4,
1077-86(1994); 3rownlees et al . , Neuroreport 8, 3251-55(1997)]. Therefore, it is believed that GSK-3 activity
may promote generation of the neurofibrillary tangles and
the progression of Alzheimer's disease.

Another substrate of GSK-3 is β-catenin which
is degradated after phosphorylation by GSK-3. Reduced
levels of β-catenin have beer: reported in schizophrenic
patients and have also been associated with other
diseases related to increase in neuronal cell death
[Zhong et al., Nature, 395, 598-702(1998); Takashima et
al. , PNAS, 90, 7789-93(1993); Pei et al., J.
Neuropathcl. Exp, 56, 7O-78(1997)].
As a result of the biological importance of
GSK-3, there is current interest in therapeutically
effective GSK-3 inhbitors. Small molecules that inhibit
GSK-3 have recently been reported [WO 99/65897(Chiron)
and WO 00/38675(SmithKline Beecham)].
For many of the aforementioned diseases
associated with abnormal GSK-3 activity, other protein
kinases have also been targeted for treating the same
diseases. However, the various protein kinases often act
through different biological pathways. For example,
certain quinazoline derivatives have been reported
recently as inhibitors of p38 kinase(WO 00/12497 to
Scios). The compounds are reported to be useful for
treating conditions characterized by enhanced p38-α
activity and/or enhanced TGF-β activity. While p38
activity has been implicated in a wide variety of
diseases, including diabetes, p38 kinase is not reported
to be a constituent of an insulin signaling pathway that
regulates glycogen synthesis or glucose uptake.
Therefore, unlike GSK-3, p38 inhibition would not be
expected to enhance glycogen synthesis and/or glucose
uptake.
There is a continued need to find new
therapeutic agents to treat human diseases. The protein

kinases Aurora-2 and GSK-3 are especially attractive
targets for the discovery of new therapeutics due to
their important roles in cancer and diabetes,
respectively.
DESCRIPTION OF THE INVENTION
It has now been found that compounds of this
invention and pharmaceutical compositions thereof are
effective as protein kinase inhibitors, particularly as
inhibitors of Aurora-2. These compounds have the general
formula I:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Z1 is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein
at least one of Z1 and Z2 is nitrogen;
Rx and Ry are independently selected from T-R3 or L-Z-R3,
or Rx and Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having O-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused
ring formed by Rx and Ry is independently substituted
by oxo, T-R3, or L-Z-R3, and each substitutable ring

nitrogen of said ring formed by Rx and Ry is
independently substituted by R4;
Q is selected from-N(R4)-,-O-,-S-,-C(R6')2-, 1,2-cyclopropanediyi, 1,2-cyclobutanediyi, or 1,3-cyclobutanediyl;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4 ;
T is a valence bond or a C1-4 alkylidene chain, wherein
when Q is-C(R6')2-, a methylene unit of said C1-4
aikylidene chain is optionally replaced by-O-,-S-,-N(R4)-,-CO-,-CONK-,-NKCO-,-S2-,-SO2NH-,-NHSO2-,-CO2-,-OC(O)-,-OC(O)NH-, or-NHCO2-;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6) C(O) O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6 ) N(R6)-,-C(0)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6) 2N(R6)-,-C(R6)2N(Rs)C(O)-,-C(RG)2N(R6)C(O)O-,-C(R6) =NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6) 2N(R6) SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having O-3 ring heteroatoms

selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCK2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2/-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C2-6 aliphatic) ,-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2 ,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6) N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2K(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,

-C(R6)=N-O-,-C(R6)2N(R6)N(RC)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)-SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R€)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6),N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen cr an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom may be taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R6' is independently selected from hydrogen or a C1-4
aliphatic group, or two R6' on the same carbon atom are
taken together to form a 3-6 membered carbocyclic ring;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring; and
R8 is selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)COz(optionally
substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4) CON(R4)-,-N(R4 ) SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2.
As used herein, the following definitions shall
apply unless otherwise indicated. The phrase "optionally
substituted" is used interchangeably with the phrase
"substituted or unsubstituted" or with the term
"(un)substituted." Unless otherwise indicated, an
optionally substituted group may have a substituent at

each substitutable position of the group, and each
substitution is independent of the other.
The term "aliphatic" as used herein means
straight-chain, branched or cyclic C1-C12 hydrocarbons
which are . completely saturated or which contain one or
more units of unsaturation but which are not aromatic.
For example, suitable, aliphatic groups include
substituted or unsubstituted linear, branched or cyclic
alkyl, alkenyl, alkynyl groups and hybrids thereof such
as(cycloalkyl)alkyl,(cycloalkenyl) alkyl or(cycloalkyl)alkenyl. The terms "alkyl", "alkoxy",
"hydroxyalkyl", "alkoxyalkyl", and "alkoxycarbonyl" , used
alone or as part of a larger moiety includes both
straight and branched chains containing one to twelve
carbon atoms. The terms "alkenyl" and "alkynyl" used
alone or as part of a larger moiety shall include both
straight and branched chains containing two to twelve
carbon atoms. The term "cycloalkyl" used alone or as
part of a larger moiety shall include cyclic C3-C12
hydrocarbons which are completely saturated or which
contain one or more units of unsaturation, but which are
not aromatic.
The terms "haloalkyl", "haloalkenyl" and
"haloalkoxy" means alkyl, alkenyl or alkoxy, as the case
may be, substituted with one or more halogen atoms. The
term "halogen" means F, Cl, Br, or I.
The term "heteroatom" means nitrogen, oxygen,
or sulfur and includes any oxidized form of nitrogen and
sulfur, and the quaternized form of any basic nitrogen.
Also the term "nitrogen" includes a substitutable
nitrogen of a heterocyclic ring. As an example, in a
saturated or partially unsaturated ring having O-3
heteroatoms selected from oxygen, sulfur or nitrogen, the

nitrogen may be N(as in 3,4-dihydro-2H-pyrrolyl) , NH(as
in pyrrolidinyl) or NR+(as in N-substituted
pyrrolidinyl).
The terms "carbocycle", "carbocyclyi",
"carbocyclo", or "carbocyclic" as used herein means an
aliphatic ring system having three to fourteen members.
The terms "carbocycle", "carbocyclyi", "carbocyclo", or
"carbocyclic" whether saturated or partially unsaturated,
also refers to rings that are optionally substituted.
The terms "carbocycle", "carbocyclyi", "carbocyclo", or
"carbocyclic" also include aliphatic rings that are fused
to one or more aromatic or nonaromatic rings, such as in
a decahydronaphthyl or tetrahydronaphthyl, where the
radical or point of attachment is on the aliphatic ring.
The term "aryl" used alone or as part of a
larger moiety as in "aralkyl", "aralkoxy", or
"aryloxyalkyl", refers to aromatic ring groups having
five to fourteen members, such as phenyl, benzyl,
phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. The term "aryl" also refers to rings that are
optionally substituted. The term "aryl" may be used
interchangeably with the term "aryl ring". "Aryl" also
includes fused polycyclic aromatic ring systems in which
an aromatic ring is fused to one or more rings. Examples
include l-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl. Also included within the scope of the term
"aryl", as it is used herein, is a group in which an
aromatic ring is fused to one or more non-aromatic rings,
such as in an indanyl, phenanthridinyl, or
tetrahydronaphthyl, where the radical or point of
attachment is on the aromatic ring.
The term "heterocycle", "heterocyclyl", or
"heterocyclic" as used herein includes non-aromatic ring

systems having five to fourteen members, preferably five
to ten, in which one or more ring carbons, preferably one
to four, are each replaced by a heteroatom such as N, O,
or S. Examples of heterocyclic rings include 3-1K-benzimidazol-2-one,(1-substituced)-2-oxo-benzimidazol-3-yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahydropyranyl, 3-tetrahydropyranyl, 4-tetrahydropyranyl, [1,3]-dioxalanyl, [1,3]-dithiolanyl,
[1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3-tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4-thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,
4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidinyl, benzoxanyl, benzopyrrolidinyl,
benzopiperidinyl, benzoxolanyl, benzothiolanyl, and
benzothianyl. Also included within the scope of the term
"heterocyclyl" or "heterocyclic", as it is used herein,
is a group in which a non-aromatic heteroatom-containing
ring is fused to one or more aromatic or non-aromatic
rings, such as in an indolinyl, chromanyl,
phenanthridinyl, or tetrahydroquinolinyl, where the
radical or point of attachment is on the non-aromatic
heteroatom-containing ring. The term "heterocycle",
"heterocyclyl" , or "heterocyclic" whether saturated or
partially unsaturated, also refers to rings that are
optionally substituted.
The term "heteroaryl", used alone or as part of
a larger moiety as in "heteroaralkyl" or
"heteroarylalkoxy", refers to heteroaromatic ring groups
having five to fourteen members. Examples of heteroaryl
rings include 2-furanyl, 3-furanyl, 3-furazanyl, N-

imidazolyi, 2-imidazolyl, 4-itnidazolyl, 5-imidazolyl, 2-isoxazolyl, 4-isoxazolyl, 5-isoxazclyl, 2-oxadiazolyl, 5-oxadiazolyi, 2-oxazolyl, 4-oxazcIyl, 5-oxazolyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2-pyrazoiyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl,
2-pyrinidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazoiyl, 2-triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl,
benzimidazolyl, benzothienyl, benzofuranyl, indolyl,
quinoiinyl, benzotriazolyl, benzothiazolyl,
benzooxazolyl, benzimidazolyl, isoquinolinyl, indazolyl,
isoindolyl, acridinyl, or benzoisoxazolyl. Also included
within the scope of the term "heteroaryl", as it is used
herein, is a group in which a heteroatomic ring is fused
to one or more aromatic or nonaromatic rings where the
radical or point of attachment is on the heteroaromatic
ring. Examples include tetrahydroquinolinyl,
tetrahydroisoquinolinyl, and pyrido [3 , 4-d] pyrimidinyl.
The term "heteroaryl" also refers to rings that are
optionally substituted. The term "heteroaryl" may be
used interchangeably with the term "heteroaryl ring" or
the term "heteroaromatic" .
An aryl(including aralkyl, aralkoxy,
aryloxyalkyl and the like) or heteroaryl(including
heteroaralkyl and heteroarylalkoxy and the like) group
may contain one or more substituents. Examples of
suitable substituents on the unsaturated carbon atom of
an aryl, heteroaryl, aralkyl, or heteroaralkyl group
include a halogen,-R°,-OR°,-SR°, 1,2-methylene-dioxy,
1, 2-ethylenedioxy, protected OH(such as acyloxy), phenyl(Ph), substituted Ph,-O(Ph), substituted-O(Ph),-CH2(Ph), substituted-CH2(Ph),-CH2CH2(Ph), substituted-CH2CH2(Pb),-NO2,-CN,-N(R°)2,-NR°C(O)Rc,-NR°C(O)N(R°)2,

-NR°CO2R°,-NR°NR°C(O)R°,-NR°NR°C(O)N(R°) 2 ,-NR°NR°CO2R°,-C(O)C(O)R°,-C(O)CK2C(O)R°,-CO2R°,-C(O)R°,-C(O)N(R°)2,-OC(O)N(R°)2,-S(O)2R°,-SO2N(R°)2,-S(O)R°,-NR°SO2N(R°)2,-NR°SO2R°,-C(=S)N(R°)2,-C(=NK)-N(R°)2 ,-(CK2)yNKC(O)R°,-(CH2)yNHC(O)CH(V-Ro)(R°) ; wherein each R° is independently
selected from hydrogen, a substituted or unsubstituted
aliphatic group, an unsubstituted heteroaryl or
heterocyclic ring, phenyl(Ph) , substituted Ph,-O(Ph),
substituted-O(Ph),-CH2(Ph), or substituted-CH2(Ph); y
is O-6; and V is a linker group. Examples of
substituents on the aliphatic group or the phenyl ring of
R° include amino, alkylamino, dialkylamino, aminocarbonyl,
halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl,
alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy,
nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl,
hydroxy, haloalkoxy, or haloalkyl.
An aliphatic group or a non-aromatic
heterocyclic ring may contain one or more substituents.
Examples of suitable substituents on the saturated carbon
of an aliphatic group or of a non-aromatic heterocyclic
ring include those listed above for the unsaturated
carbon of an aryl or heteroaryl group and the following:
=O, =S, =NNHR*, =NN(R*)2, =N-, =NNHC(O)R* =NNHCO2(alkyl),
=NNHSO2(alkyl) , or =NR*, where each R* is independently
selected from hydrogen, an unsubstituted aliphatic group
or a substituted aliphatic group. Examples of
substituents on the aliphatic group include amino,
alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,
alkylaminocarbonyl, dialkylaminocarbonyl,
alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy,
nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl,
hydroxy, haloalkoxy, or haloalkyl.

Suitable substituents on the nitrogen of a non-aromatic heterocyclic ring include-R+,-N(R+)2,-C(O)R',-CO2R+-C(O)C(O)R+-C(O)CH2C(O)R+-SO2R+-SO2N(R+)2,-C(=S)N(R+)-,-C(=NK)-N(R+)2, and-NR+SO2R+; wherein each R+
is independently selected from hydrogen, an aliphatic
group, a substituted aliphatic group, phenyl(Ph) ,
substituted Ph,-O(Ph), substituted-O(Ph), CH2(Ph),
substituted CH2(Ph), or an unsubstituted heteroaryl or
heterocyclic ring. Examples of substituents on the
aliphatic group or the phenyl ring include amino,
alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl,
alkylaminocarbonyl, dialkylaminocarbonyl,
alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy,
nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl,
hydroxy, haloalkoxy, or haloalkyl.
The term "linker group" or "linker" means an
organic moiety that connects two parts of a compound.
Linkers are typically comprised of an atom such as oxygen
or sulfur, a unit such as-NH-,-CH2-,-C(O)-,-C(O)NH-,
or a chain of atoms, such as an alkylidene chain. The
molecular mass of a linker is typically in the range of
about 14 to 200, preferably in the range of 14 to 96 with
a length of up to about six atoms. Examples of linkers
include a saturated or unsaturated C1-6 alkylidene chain
which is optionally substituted, and wherein one or two
saturated carbons of the chain are optionally replaced by-C(O)-,-C(O)C(O)-,-CONH-,-CONHNH-,-CO2-,-OC(O)-,-NHCO2-,-O-,-NHCONH-,-OC(O)NH-,-NHNH-,-NHCO-,-S-,-SO-,-SO2-,-NH-,-SO2NH-, or-NHSO2-.
The term "alkylidene chain" refers to an
optionally substituted, straight or branched carbon chain
that may be fully saturated or have one or more units of

unsaturation. The optional substituents are as described
above for an aliphatic group.
A combination of substituents or variables is
permissible only if such a combination results in a
stable or chemically feasible compound. A stable
compound or chemically feasible compound is one in which
the chemical structure is not substantially altered when
kept at a temperature of 40 °C or less, in the absence of
moisture or other chemically reactive conditions, for at
least a week.
Unless otherwise stated, structures depicted
herein are also meant to include all stereochemical forms
of the structure; i.e., the R and S configurations for
each asymmetric center. Therefore, single stereochemical
isomers as well as enantiomeric and diastereomeric
mixtures of the present compounds are within the scope of
the invention. Unless otherwise stated, structures
depicted herein are also meant to include compounds which
differ only in the presence cf one or more isotopically
enriched atoms. For example, compounds having the
present structures except for the replacement of a
hydrogen by a deuterium or tritium, or the replacement of
a carbon by a l3C-or 14C-enriched carbon are within the
scope of this invention.
Compounds of formula I or salts thereof may be
formulated into compositions. In a preferred embodiment,
the composition is a pharmaceutical composition. In one
embodiment, the composition comprises an amount of the
protein kinase inhibitor effective to inhibit a protein
kinase, particularly Aurora-2, in a biological sample or
in a patient. Compounds of this invention and
pharmaceutical compositions thereof, which comprise an
amount of the protein kinase inhibitor effective to treat

or prevent ar. Aurora-2-mediated condition and a
pharmaceutically acceptable carrier, adjuvant, or
vehicle, may be formulated for administration to a
patient.
Another aspect of this invention relates to a
method of treating cr preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula I or a pharmaceutical composition
thereof.
The term "Aurora-2-mediated disease" or
"Aurora-2-mediated condition", as used herein, means any
disease or other deleterious condition in which Aurora is
known to play a role. The terms "Aurora-2-mediated
disease" or "Aurora-2-mediated condition" also mean those
diseases or conditions that are alleviated by treatment
with an Aurora-2 inhibitor. Such conditions include,
without limitation, colon, breast, stomach, and ovarian
cancer.
Another aspect of the invention relates to
inhibiting Aurora-2 activity in a biological sample,
which method comprises contacting the biological sample
with the Aurora-2 inhibitor of formula I, or a
composition thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula I or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises

administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof.
The terms "GSK-3-mediated disease" or "GSK-3-mediated condition", as used herein, mean any disease or
other deleterious condition or state in which GSK-3 is
known to play a role. Such diseases or conditions
include, without limitation, diabetes, Alzheimer's
disease, Huntington's Disease, Parkinson's Disease, AIDS-associated dementia, amyotrophic lateral sclerosis(AML),
multiple sclerosis(MS), schizophrenia, cardiomycete
hypertrophy, reperfusion/ischemia, and baldness.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of P-catenin, which is useful for
treating schizophrenia.
Another aspect of the invention relates to
inhibiting GSK-3 activity in a biological sample, which
method comprises contacting the biological sample with a
GSK-3 inhibitor of formula I.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula I or a composition comprising said compound.

Another aspect of this invention relates to a
method of treating or preventing a CDK-2-mediated disease
with a CDK-2 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof.
The terms "CDK-2-mediated disease" or "CDK-2-mediated condition", as used herein, mean any disease or
other deleterious condition in which CDK-2 is known to
play a role. The terms "CDK-2-mediated disease" or "CDK-2-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with a CDK-2
inhibitor. Such conditions include, without limitation,
cancer, Alzheimer's disease, restenosis, angiogenesis,
glomerulonephritis, cytomegalovirus, HIV, herpes,
psoriasis, atherosclerosis, alopecia, and autoimmune
diseases such as rheumatoid arthritis. See Fischer, P.M.
and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245(2000); Mani, S., Wang, C, Wu, K. , Francis, R. and
Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849(2000);
Fry, D.W. and Garrett, M.D., Cur-rent Opinion in
Oncologic, Endocrine & Metabolic Investigational Drugs,
2, 4O-59(2C00).
Another aspect of the invention relates to
inhibiting CDK-2 activity in a biological sample or a
patient, which method comprises administering to the
patient a compound of formula I or a composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing an ERK-2-mediated
diseases with an ERK-2 inhibitor, which method comprises
administering to a patient in need of such a treatment a

therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof.
The terms "ERK-mediated disease" or "ERK-mediated condition", as used herein mean any disease or
ether deleterious condition in which ERK is known to play
a role. The terms "ERK-2-mediated disease" or "ERK-2-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with a ERK-2
inhibitor. Such conditions include, without limitation.,
cancer, stroke, diabetes, hepatomegaly, cardiovascular
disease including cardiomegaly, Alzheimer's disease,
cystic fibrosis, viral disease, autoimmune diseases,
atherosclerosis, restenosis, psoriasis, allergic
disorders including asthma, inflammation, neurological
disorders and hormone-related diseases. The term
"cancer" includes, but is not limited to the following
cancers: breast, ovary, cervix, prostate, testis,
genitourinary tract, esophagus, larynx, glioblastoma,
neuroblastoma, stomach, skin, keratoacanthoma, lung,
epidermoid carcinoma, large cell carcinoma, small cell
carcinoma, lung adenocarcinoma, bone, colon, adenoma,
pancreas, adenocarcinoma, thyroid, follicular carcinoma,
undifferentiated carcinoma, papillary carcinoma,
seminoma, melanoma, sarcoma, bladder carcinoma, liver
carcinoma and biliary passages, kidney carcinoma, myeloid
disorders, lymphoid disorders, Hodgkin's, hairy cells,
buccal cavity and pharynx(oral), lip, tongue, mouth,
pharynx, small intestine, colon-rectum, large intestine,
rectum, brain and central nervous system, and leukemia.
ERK-2 protein kinase and its implication in various
diseases has been described [Bokemeyer et al. 1996,
Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343,
£51; Crews et al. , 1992, Science 258, 476; Bjorbaek et

al., 1995, J. Biol. Chem. 270, 18848; Rouse et al. , 1994,
Cell 78, 1027; Raingeaud et al. , 1996, Mol. Cell Biol.
16, 1247; Raingeaud et al. 1996; Chen et al. , 1993 Proc.
Natl. Acad. Sci. USA 90, 10352; Oliver et al., 1995,
Proc. Soc. Exp. Biol. Med. 210, 162; Moodie et al., 1953,
Science 2 60, 1658; Frey and Mulder, 1997, Cancer Res. 57,
628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478;
Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16,
589) .
Another aspect of the invention relates to
inhibiting ERK-2 activity in a biological sample or a
patient, which method comprises administering to the
patient a compound of formula I or a composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing an AKT-mediated diseases
with an AKT inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof.
The terms "AKT-mediated disease" or "AKT-mediated condition", as used herein, near, any disease or
other deleterious condition in which AKT is known to play
a role. The terms "AKT-mediated disease" or "AKT-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with a AKT
inhibitor. AKT-mediated diseases or conditions include,
but are not limited to, proliferative disorders, cancer,
and neurodegenerative disorders. The association of AKT,
also known as protein kinase B, with various diseases has
been described [Khwaja, A., Mature, pp. 33-34, 1990;
Zang, Q. Y., et al, Oncogene, 19 2000; Kazuhiko, N., et
al, The Journal of Neuroscience, 20 2000].

Another aspect of the invention relates to
inhibiting AKT activity in a biological sample or a
patient, which method comprises administering to the
patient a compound of formula I or a composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a Src-mediated disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof.
The terms "Src-mediated disease" or "Src-mediated condition", as used herein mean any disease or
other deleterious condition in which Src is known to play
a role. The terms "Src-mediated disease" or "Src-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with a Src
inhibitor. Such conditions include, without limitation,
hypercalcemia, osteoporosis, osteoarthritis, cancer,
symptomatic treatment of bone metastasis, and Paget's
disease. Src protein kinase and its implication in
various diseases has been described [Soriano, Cell, 69,
551(1992); Soriano et al., Cell, 64, 693(1991);
Takayanagi, J. Clin. Invest., 104, 137(1999); Boschelli,
Drugs of the Future 2000, 25(7), 717,(2000); Talamonti,
J. Clin. Invest., 91, 53(1993); Lutz, Biochem. Biophys.
Res. 243, 503(1998); Rosen, J. Biol. Chem., 261, 13754(1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251(1987); Masaki, Hepatology, 27, 1257(1993) ; Biscardi,
Adv. Cancer Res., 76, 61(1999); Lynch, Leukemia, 7, 1416(1993); Wiener, Clin. Cancer Res., 5, 2164(1999);
Staley, Ceil Growth Diff., 8, 269(1997)].

Another aspect of the invention relates to
inhibiting Src activity in a biological sample or a
patient, which method comprises administering to the
patient a compound of formula I or a composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing an Lck-mediated diseases
with an Lck inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
I or a pharmaceutical composition thereof.
The terms "Lck-mediated disease" or "Lck-mediated condition", as used herein, mean any disease
state or other deleterious condition in which Lck is
known to play a role. The terms "Lck-mediated disease"
or "Lck-mediated condition" also mean those diseases or
conditions that are alleviated by treatment with an Lck
inhibitor. Lck-mediated diseases or conditions include,
but are not limited to, autoimmune diseases such as
transplant rejection, allergies, rheumatoid arthritis,
and leukemia. The association of Lck with various
diseases has been described [Molina et al., Mature, 357,
161(1992)].
Another aspect of the invention relates to
inhibiting Lck activity in a biological sample or a
patient, which method comprises administering to the
patient a compound of formula I or a composition
comprising said compound.
The term "pharmaceutically acceptable carrier,
adjuvant, or vehicle" refers to a non-toxic carrier,
adjuvant, or vehicle that may be administered to a
patient, together with a compound of this invention, and

which does not destroy the pharmacological activity
thereof.
The term "patient" includes human and
veterinary subjects.
The term "biological sample", as used herein,
includes, without limitation, cell cultures or extracts
thereof; preparations of an enzyme suitable for in vitro
assay; biopsied material obtained from a mammal or
extracts thereof; and blood, saliva, urine, feces, semen,
tears, or other body fluids or extracts thereof.
An amount effective to inhibit protein kinase,
for example, Aurora-2 and GSK-3, is an amount that causes
measurable inhibition of the kinase activity when
compared to the activity of the enzyme in the absence of
an inhibitor. Any method may be used to determine
inhibition, such as, for example, the Biological Testing
Examples described below.
Pharmaceutically acceptable carriers that may
be used in these pharmaceutical compositions are
generally known in the art. They include, but are not
limited to, ion exchangers, alumina, aluminum stearate,
lecithin, serum proteins, such as human serum albumin,
buffer substances such as phosphates, glycine, sorbic
acid, potassium sorbate, partial glyceride mixtures of
saturated vegetable fatty acids, water, salts or
electrolytes, such as protamine sulfate, disodium
hydrogen phosphate, potassium hydrogen phosphate, sodium
chloride, zinc salts, colloidal silica, magnesium
trisilicate, polyvinyl pyrrolidone, cellulose-based
substances, polyethylene glycol, sodium
carboxymethylcellulose, polyacrylates, waxes,
polyethylene-polyoxypropylene-block polymers,
polyethylene glycol and wool fat.

The compositions cf the present invention may
be administered orally, parenterally, by inhalation
spray, topically, rectally, nasally, buccally, vaginally
or via an implanted reservoir. The term "parenteral" as
used herein includes subcutaneous, intravenous,
intramuscular, intra-articular, intra-synovial,
intrasternal, intrathecal, intrahepatic, intralesional
and intracranial injection or infusion techniques.
Preferably, the compositions are administered orally,
intraperitoneally or intravenously.
Sterile injectable forms of the compositions of
this invention may be aqueous or oleaginous suspension.
These suspensions may be formulated according to
techniques known in the 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 non-toxic parenterally-acceptable diluent or solvent, for example as a solution
in 1, 3-butanediol. 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. Fatty acids, such as oleic acid and
its glyceride derivatives are useful in the preparation
of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil,
especially in their polyoxyethylated versions. These oil
solutions or suspensions may also contain a long-chain
alcohol diluent or dispersant, such as carboxymethyl
cellulose or similar dispersing agents which are commonly
used in the formulation of pharmaceutically acceptable

dosage forms including emulsions and suspensions. Other
commonly used surfactants, such as Tweens, Spans and
other emulsifying agents or bioavailability enhancers
which are commonly used in the manufacture of
pharmaceutically acceptable solid, liquid, or other
dosage forms may also be used for the purposes of
formulation.
The pharmaceutical compositions of this
invention may be orally administered in any orally
acceptable dosage form including, but not limited to,
capsules, tablets, aqueous suspensions or solutions. In
the case of tablets for oral use, carriers commonly used
include lactose and corn starch. Lubricating agents,
such as magnesium stearate, are also typically added.
For oral administration in a capsule form, useful
diluents include lactose and dried cornstarch. When
aqueous suspensions are required for oral use, the active
ingredient is combined with emulsifying and suspending
agents. If desired, certain sweetening, flavoring or
coloring agents may also be added.
Alternatively, the pharmaceutical compositions
of this invention may be administered in the form of
suppositories for rectal administration. These can be
prepared by mixing the agent with a suitable non-irritating excipient which is solid at room temperature
but liquid at rectal temperature and therefore will melt
in the rectum to release the drug. Such materials
include cocoa butter, beeswax and polyethylene glycols.
The pharmaceutical compositions of this
invention may also be administered topically, especially
when the target of treatment includes areas or organs
readily accessible by topical application, including
diseases of the eye, the skin, or the lower intestinal

tract. Suitable topical formulations are readily
prepared for each of these areas or organs.
Topical application for the lower intestinal
tract can be effected in a rectal suppository formulation
(see above) or in a suitable enema formulation.
Topically-transdermal patches may also be used.
For topical applications, the pharmaceutical
compositions may be formulated in a suitable ointment
containing the active component suspended or dissolved in
one or more carriers. Carriers for topical
administration of the compounds of this invention
include, but are not limited to, mineral oil, liquid
petrolatum, white petrolatum, propylene glycol,
polyoxyethylene, polyoxypropylene compound, emulsifying
wax and water. Alternatively, the pharmaceutical
compositions can be formulated in a suitable lotion or
cream containing the active components suspended or
dissolved in one or more pharmaceutically acceptable
carriers. Suitable carriers include, but are not limited
to, mineral oil, sorbitan monostearate, polysorbate 60,
cetyl esters wax, cetearyl alcohol, 2-octyldodecanol,
benzyl alcohol and water.
For ophthalmic use, the pharmaceutical
compositions nay be formulated as micronized suspensions
in isotonic, pH adjusted sterile saline, or, preferably,
as solutions in isotonic, pH adjusted sterile saline,
either with or without a preservative such as
benzylalkoniurn chloride. Alternatively, for ophthalmic
uses, the pharmaceutical compositions may be formulated
in an ointment such as petrolatum.
The pharmaceutical compositions of this
invention may also be administered by nasal aerosol or
inhalation. Such compositions are prepared according co

techniques well-known in the art of pharmaceutical
formulation and may be prepared as solutions in saline,
employing benzyl alcohol or other suitable preservatives,
absorption promoters to enhance bioavailability,
fluorocarbons, and/or other conventional solubilizing or
dispersing agents.
In addition to the compounds of this invention,
pharmaceutically acceptable derivatives or prodrugs of
the compounds of this invention may also be employed in
compositions to treat or prevent the above-identified
diseases or disorders.
A "pharmaceutically acceptable derivative or
prodrug" means any pharmaceutically acceptable salt,
ester, salt of an ester or other derivative of a compound
of this invention which, upon administration to a
recipient, is capable of providing, either directly or
indirectly, a compound of this invention or an
inhibitorily active metabolite or residue thereof.
Particularly favored derivatives or prodrugs are those
that increase the bioavailability of the compounds of
this invention when such compounds are administered to a
patient(e.g., by allowing an orally administered
compound to be more readily absorbed into the blood) or
which enhance delivery of the parent compound to a
biological compartment(e.g., the brain or lymphatic
system) relative to the parent species.
Pharmaceutically acceptable prodrugs of the
compounds of this invention include, without limitation,
the following derivatives of the present compounds:
esters, amino acid esters, phosphate esters, metal salts
sulfonate esters, carbamates, and amides.
Pharmaceutically acceptable salts of the
compounds of this invention include those derived from

pharmaceutically acceptable inorganic and organic acids
and bases. Examples of suitable acid salts include
acetate, adipate, alginate, aspartate, benzoate,
benzenesulforate, bisulfate, butyrate, citrate,
camphorate, camphorsulfonate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate,
fumarate, giucoheptanoate, glycerophosphate, glycolate,
hemisuifate, heptanoate, hexanoate, hydrochloride,
hydrobromide, hydroiodide, 2-hydroxyethanesulfonate,
lactate, maleate, malcnate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oxalate,
palmoate, pectinate, persulfate, 3-phenylpropionate,
phosphate, picrate, pivalate, propionate, salicylate,
succinate, sulfate, tartrate, thiocyanate, tosylate and
undecanoate. Other acids, such as oxalic, while not in
themselves pharmaceutically acceptable, may be employed
in the preparation of salts useful as intermediates in
obtaining the compounds of the invention and their
pharmaceutically acceptable acid addition salts.
Salts derived from appropriate bases include
alkali metal(e.g., sodium and potassium), alkaline earth
metal(e.g., magnesium), ammonium and N+(C1-4 alkyl)4
salts. This invention also envisions the quaternization
of any basic nitrogen-containing groups of the compounds
disclosed herein. Water or oil-soluble or dispersible
products may be obtained by such quaternization.
The amount of the protein kinase inhibitor that
may be combined with the carrier materials to produce a
single dosage form will vary depending upon the patient
treated and the particular mode of administration.
Preferably, the compositions should be formulated so that
a dosage of between 0.01-100 mg/kg body weight/day of

the inhibitor can be administered to a patient receiving
these compositions.
It should also be understood that a specific
dosage and treatment regimen for any particular patient
will depend upon a variety of factors, including the
activity cf the specific compound employed, the age, body
weight, general health, sex, diet, time of
administration, rate of excretion, drug combination, and
the judgment of the treating physician and the severity
of the particular disease being treated. The amount of
the inhibitor will also depend upon the particular
compound in the composition.
Depending upon the particular protein kinase-mediated condition to be treated or prevented, additional
therapeutic agents, which are normally administered to
treat or prevent that condition, may be administered
together with the inhibitors of this invention. For
example, in the treatment of cancer other
chemotherapeutic agents or other anti-proliferative
agents may be combined with the present compounds to
treat cancer. These agents include, without limitation,
adriamycin, dexamethasone, vincristine, cyclophosphamide,
fluorouracil, topotecan, taxol, interferons, and platinum
derivatives.
Other examples of agents the inhibitors of this
invention may also be combined with include, without
limitation, agents for treating diabetes such as insulin
or insulin analogues, in injectable or inhalation form,
glitazones, alpha glucosidase inhibitors, biguanides,
insulin sensitizers, and sulfonyl ureas; anti-inflammatory agents such as corticosteroids, TNF
blockers, IL-1 RA, azathioprine, cyclophosphamide, and
sulfasalazine; immunomodulatory and immunosuppressive

agents such as cyclosporin, tacrolimus, rapamycin,
mycophenolate mofetil, interferons, corticosteroids,
cyciophophamide, azathioprine, and sulfasalazine;
neurotrophic factors such as acetylcholinesterase
inhibitors, MAO inhibitors, interferons, anti-convulsants, ion channel blockers, riluzole, and anti-parkinsonian agents; agents for treating cardiovascular
disease such as beta-blockers, ACE inhibitors, diuretics,
nitrates, calcium channel blockers, and statins; agents
for treating liver disease such as corticosteroids,
cholestyramine, interferons, and anti-viral agents;
agents for treating blood disorders such as
corticosteroids, anti-leukemic agents, and growth
factors; and agents for treating immunodeficiency
disorders such as gamma globulin.
Those additional agents may be administered
separately from the protein kinase inhibitor-containing
composition, as part of a multiple dosage regimen.
Alternatively, those agents may be part of a single
dosage form, mixed together with the protein kinase
inhibitor of this invention in a single composition.
Compounds of this invention may exist in
alternative tautomeric forms, as in tautomers i and ii
shown below. Unless otherwise indicated, the
representation of either tautomer is meant to include the
other.


Rx and Ry may be taken together to form a fused
ring, providing a bicyclic ring system containing Ring A.
Preferred Rx/Ry rings include a 5-, 6-, or 7-membered
unsaturated or partially unsaturated ring having O-2
heteroatoms, wherein said Rx/Ry ring is optionally
substituted. Examples of bicyclic systems containing
Ring A are shown below by compounds I-A through I-BB,
wherein Z1 is nitrogen or C(R8) and Z2 is nitrogen or
C(H).





Preferred bicyclic Ring A systems include I-A,
I-B, I-C, I-D, I-E, I-F, I-I, I-J, I-K, I-P, I-Q, I-V,
and I-U, more preferably I-A, I-B, I-D, I-E, I-J, I-P,
and I-V, and most preferably I-A, I-B, I-D, I-E and I-J.
In the monocyclic Ring A system, preferred Rx
groups, when present, include hydrogen, alkyl-or
dialkylamino, acetamido, or a Ci_4 aliphatic group such as
methyl, ethyl, cyclopropyl, or isopropyl. Preferred Ry
groups, when present, include T-R3 or L-Z-R3 wherein T is
a valence bond or a methylene, L is-O-,-S-,-C(R6)2O-,-CO-or-N(R4)-, and R3 is-R,-N(R"i)2, or-OR. Preferred
Ry groups include 5-6 membered heteroaryl or heterocyclyl
rings, such as 2-pyridyi, 4-pyridyl, pyrrolidinyl,
piperidinyl, morphoiinyi, or piperazinyl; C:.6 aliphatic,
such as methyl, ethyl, cyclopropyl, isoprcpyl, or

t-buryl; alkoxyalkylamino such as methoxyethyl amino;,
alkoxyalkyl such as methoxymethyl or methoxyethyl; alkyl-or dialkylamino such as erhylamino or dimethylamino;
alkyl-or dialkylaminoalkoxy such as
dimerhylaminopropyloxy; acetamido; and oprionally
substituted phenyl such as phenyl or halo-substituted
phenyl.
In the bicyclic Ring A system, the ring formed
when Rx and Ry are taken together may be substituted or
unsubstituted. Suitable substituents include-R, halo,-O(CK2)2-4,-N(R4)2,-O(CK2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6
aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, wherein R and R4 are as defined above.
Preferred Rx/Ry ring substituents include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2 ,-O(CH2)2-4-R,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is
hydrogen or an optionally substituted C1-6 aliphatic group.
R2 and R2' may be taken together to form a fused
ring, thus providing a bicyclic ring system containing a
pyrazole ring. Preferred fused rings include benzo,
pyrido, pyrimido, and a partially unsaturated 6-membered
carbocyclo ring, wherein said fused ring is optionally
substituted. These are exemplified in the following
formula I compounds having a pyrazole-containing bicyclic
ring system:


Preferred substituents on the R2/R2' fused ring
include one or more of the following:-halo,-N(R4)2,-C1-3
alkyl,-C1-3 haloalkyl,-NO2,-O(C1-3 alkyl) ,-CO2(C1-3
alkyl),-CN,-SO2(C1-3 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-3 alkyl),-NHC(O)(C1-3 alkyl),-C(O)NH2, and-CO(C1-3 alkyl), wherein the(C1-3 alkyl) is most preferably
methyl.
When the pyrazole ring system is monocyclic,
preferred R2 groups include hydrogen, C1-4 aliphatic,
alkoxycarbonyl,(un)substituted phenyl, hydroxyalkyl,
alkoxyalkyl, aminocarbonyl, mono-or
dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl,
dialkylaminoalkyl, phenylaminocarbonyl, and(N-heterocyclyl)carbonyl. Examples of such preferred R2
substituents include methyl, cyclopropyl, ethyl,
isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO2K,
CO2CH3, CH2OH, CH2OCH3, CH2CH2CH2OK, CH2CH2CH2OCH3,
CH2CH2CH2OCH2Ph, CH2CH2CH2NH2 , CH2CH2CH2NHCOOC(CH3)3,
CONHCH(CH3)2, CCNHCH2CK=CH2 , CONHCH2CK2OCH3, CONHCH2Ph,
CONH(cyclohexyl) , CON(Et)2, CON(CH3)CH2Ph, CONH(n-C3H7),
CON(Et)CH2CH2CH3, CONHCH2CH(CH3)2, CON(n-C3H7)2 , CO(3-methoxymethylpyrrolidin-1-yl) , CONH(3-tolyl), CONH(4-tolyl), CONHCH3, CO(morpholin-1-yl), CO(4-methylpiperazin-1-yl), CONHCH2CH2OH, CONH2, and CO(piperidin-1-yl). A
preferred R2' group is hydrogen.

An embodiment that is particularly useful for
treating Aurora-2-mediated diseases relates to compounds
of formula IIa:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;
Rx and Ry are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 metnbered ring having O-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each
substitutable ring carbon of said fused ring formed by
Rx and Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of said
ring formed by Rx and Ry is independently substituted
by R4;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C2-4 alkylidene chain;

Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6) 2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6) =NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6) 2N(R6) SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R1 and R2' are independently selected from-R,-T-W-R6, or
R2 and R: are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having O-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R', or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(C)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-S2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SOzN(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;

each R5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CM,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2 ,-OC(=O)R,-N(R4)COR,-N(R4)CO;(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6) 2N(R6) CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6) =N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)C0N(R6)-, or-C0N(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred rings formed by Rx and Ry include a
5-, 6-, or 7-membered unsaturated or partially
unsaturated ring having O-2 heteroatoms, wherein said

Rx/Ry ring is optionally substituted. This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula
IIa are shown below.



More preferred pyrimidine ring systems of
formula IIa include IIa-A, IIa-B, IIa-D, IIa-E, IIa-J,
IIa-P, and IIa-V, most preferably IIa-A, IIa-B, IIa-D,
IIa-E, and IIa-J.
The ring formed when Rx and Ry are taken
together may be substituted or unsubstituted. Suitable
substituents include-R, halo,-O(CH2)2-4-N(R4)2 ,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2.-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4) C02(optionally substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=H-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, wherein R and
R4 are as defined above. Preferred Rx/Ry ring
substituents include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen
or an optionally substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IIa may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula Ila
compounds having a pyrazole-containing bicyclic ring
system:


Preferred substituents on the R2/R2' fused ring
of formula IIa include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl) , wherein the(C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl) group is methyl or ethyl.
When the pyrazole ring system of formula Ila is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2 group
is hydrogen.
When Ring D of formula IIa is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyi, and pyrazinyl.
When Ring D of formula IIa is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoinaolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,

cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIa, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6) COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl) ,-NHSO2(isopropyl) ,-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3) 2,-NHCOCH2CH2CH2N(CH3) 2 ,
-NHCO(cyclopropyl),-NHCO(isobutyl),-NHCOCH2(morpholin-4-yl) ,-NHCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2(morpholin-4-yl) ,-NHCO2(t-butyl),-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic)2 such as"-NMe2, OH,-O(C1-4 aliphatic)
such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred formula IIa compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx and Ry are taken together with their
intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having O-2 heterbatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by Rx and
Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of

said ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(d) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring; and
(e) R3 is selected from-R,-halo,-OR, or-N(R4)2.
More preferred compounds of formula IIa have
one or more, and mere preferably all, of the features
selected from the group consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
Even more preferred compounds of formula IIa
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) Rx and Ry are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;
(b) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;
(c) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.
Representative compounds of formula IIa are
shown below in Table 1.
Table 1.













In another embodiment, this invention provides
a composition comprising a compound of formula IIa and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IIa or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IIa or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a

therapeutically effective amount of a compound of formula
IIa or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IIa or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of P-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IIa or a composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a CDK-2-mediated disease
with a CDK-2 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIa or a pharmaceutical composition thereof.
Another aspect of the invention relates to
inhibiting CDK-2 activity in a patient, which method
comprises administering to the patient a compound of
formula IIa or a composition comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a Src-mediated disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a

therapeutically effective amount of a compound of formula
IIa or a pharmaceutical composition thereof.
Another aspect of the invention relates to
inhibiting Src activity in a patient, which method
comprises administering to the patient a compound of
formula IIa or a composition comprising said compound.
Another method relates to inhibiting Aurora-2,
GSK-3, CDK2, or Src activity in a biological sample,
which method comprises contacting the biological sample
with the Aurora-2, GSK-3, CDK2, or Src inhibitor of
formula IIa, or a pharmaceutical composition thereof, in
an amount effective to inhibit Aurora-2, GSK-3, CDK2, or
Src.
Each of the aforementioned methods directed to
the inhibition of Aurora-2, GSK-3, CDK2, or Src, or the
treatment of a disease alleviated thereby, is preferably
carried out with a preferred compound of formula IIa, as
described above.
Another embodiment of this invention relates to
compounds of formula IIb:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein,-
Rx and Ry are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having O-3 ring heteroatoms selected

from oxygen, sulfur, or nitrogen, wherein each
substitutable ring carbon of said fused ring formed by
Rx and Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of said
ring formed by Rx and Ry is independently substituted
by R4;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 9-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;
2 is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO,-,-N(R6)CO-,-N(R6) C(O) O-,-N(R6)CN(R6)-,-N(R6)SO2N(R6)-,-N(R6 ) N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having O-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2 is independently substituted by halo, oxo,

-CN,-NO2,-R7, or-V-R6, and each substitutabie ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4 ;
R3 is selected from-R,-halo,-OR,-C(=C)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)C02(C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each Rs is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4) CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6) 2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6) =NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6) SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,

-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(Re)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(Rc)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred rings formed by Rx and Ry include a
5-, 6-, or 7-membered unsaturated or partially
unsaturated ring having O-2 heteroatoms, wherein said
Rx/Ry ring is optionally substituted. This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula
IIb are shown below.



More preferred pyrimidine ring systems of
formula IIb include IIb-A, IIb-B, IIb-D, IIb-E, IIb-J,
IIb-P, and IIb-V, most preferably IIb-A, IIb-B, IIb-D,
IIb-E, and IIb-J.
The ring formed when Rx and Ry are taken
together may be substituted or unsubstituted. Suitable
substituents include-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO;,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4),-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-ON-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, R and R4 are

as defined above. Preferred Rx/Ry ring substituents
include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CK2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen or an optionally
substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IIb may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIb
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IIb include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl) ,-CN,-SO2(C2-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl) ,-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl) group is methyl or ethyl.
When the pyrazole ring system of formula IIb is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such

preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIb is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIb is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIb, preferred T-R5 or V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6) COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl) ,-NHSO2(isopropyl),-NHCOEt,-NHCOCH2NHCH3 ,-NHCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CH2N(CH3)2,
-NHCO(cyclopropyl) ,-NHCO(isobutyl) ,-NHCOCH2(morpholin-4-yl) ,-NHCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(d1-4 aliphatic)
such as-OMe, C1-4 aliphatic such as methyl, ethyl,

cyciopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred formula IIb compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
fa) Rx and Ry are taken together with their
intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having O-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by Rx and
Ry is independently substituted by oxo, T-R2, or
L-Z-R3, and each substitutable ring nitrogen of
said ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(d) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring; and
(e) R3 is selected from-R,-halo,-OR, or-N(R4)2.
More preferred compounds of formula IIb have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an

8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(c) R is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
Even more preferred compounds of formula IIb
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;
(b) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;
(c) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NK-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6

membered heteroaryl ring, cr a 5-6 membered
heterocyclic ring.
Representative compounds of formula IIb are
shown below in Table 2.
Table 2.

In another embodiment, this invention provides
a composition comprising a compound of formula IIb and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurcra-2 inhibitor, which method
comprises administering to a patient in need of such a

treatment a therapeutically effective amount of a
compound of formula IIb or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IIb or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIb or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IIb or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of β-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IIb or a composition comprising said compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method

comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IIb, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IIb, as described
above.
Another embodiment of this invention relates to
compounds of formula IIc:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;
Rx and Ry are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having O-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each
substitutable ring carbon of said fused ring formed by
Rx and Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of said
ring formed by Rx and Ry is independently substituted
by R4;
R1 is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyciic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkyiidene chain;
Z is a C1-4 alkyiidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-S membered, unsaturated or
partially unsaturated, ring having O-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO,,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic) ,-N(R4) N(R4)2 ,-C=NK(R4)2,

-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4) CON(R4) 2,-N(R4)SO2N(R4)2/-N(R4)SO2R, or-OC(=O)N(R4)2 ;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R')2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6) 2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6) =NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6) 2N(R6) CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N-(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together

with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred rings formed by Rx and Ry include a
5-, 6-, or 7-membered unsaturated or partially
unsaturated ring having O-2 heteroatoms, wherein said
Rx/Ry ring is optionally substituted. This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula
IIc are shown below.



More preferred pyrimidine ring systems of
formula IIc include IIc-A, IIc-B, IIc-D, IIc-E, IIc-J,
IIc-P, and IIc-V, most preferably IIc-A, IIc-B, IIc-D,
IIc-E, and IIc-J.
The ring formed when Rx and Ry of formula IIc
are taken together may be substituted or unsubstituted.
Suitable substituents include-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2 ,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, R and R4 are
as defined above. Preferred Rx/Ry ring substituents

include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR43O2R,-SC2N(R4)2 wherein R is hydrogen or an optionally
substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IIc may be
taken together to form a fused ring, thus providing a
bicyciic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIc
compounds having a pyrazole-containing bicyciic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IIc include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl) ,-CN,-SO2(C1-4 alkyl) ,-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl) ,-NKC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula IIc is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl,

cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIc is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazir.yl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIc is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b]furyl,
benzo [b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl .
On Ring D of formula IIc, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)3,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl) ,-NHSO2(isopropyl),-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu) CH3 ,-NHCOCH2N(CH3)2 ,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CK2N(CH3)2 ,
-NHCO(cyclopropyl) ,-NHCO(isobtyl),-NHCOCH2(morpholin-4-yl) ,-NHCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2(morpholin-4-yl) ,-NHCO-(t-butyl) ,-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OK,-O(C1-4 aliphatic)
such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).

Preferred formula IIc compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx and Ry are taken together with their
intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having O-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by Rx and
Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of
said ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(d) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring; and
(e) R3 is selected from-R,-halo,-OR, or-N(R4)2.
More preferred compounds of formula IIc have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;

(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
Even more preferred compounds of formula IIc
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;
(b) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;
(c) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NK-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

Preferred compounds of formula IIc include
compounds of formula IIc':

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;
Rx and Ry are taken together with their intervening atoms
to form a fused benzo ring, wherein each substitutable
ring carbon of said fused ring formed by Rx and Ry is
independently substituted by T-R3, or L-Z-R3,-
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,

-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(C)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having O-3 ring heteroatotns
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms ;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4):,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),

-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4) CON(R4) 2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R5)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R5)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6) 2N(R6) CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6) 2N(R6) N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
The ring formed when Rx and Ry of formula IIc'
are taken together may be substituted or unsubstituted.
Suitable substituents include-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4) CO2(optionally substituted C1-6 aliphatic),

-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, wherein R and
R4 are as defined above. Preferred Rx/Ry ring
substituents include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2, wherein R is
hydrogen or an optionally substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IIc' may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazoie ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIc'
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IIC include one or more of the following:-halo,-N(R4)2,-C1-4alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl).-CN,-SO2(C1-4 alkyl) ,-SO2NH2,-OC(O)NH2,-NH2SO2(C2-4 alkyl) ,-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl) group is methyl.
When the pyrazoie ring system of formula IIC'
is monocyclic, preferred R2 groups include hydrogen or a

substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include K, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIc' is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIc' is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo [b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, guinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIc', preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3l-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl) ,-NHSO2(isopropyl),-NKCOEt,-NHCOCH2NHCH3,-NKCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CH2N(CH3)2 ,
-NKCO(cyclopropyl),-NKCO(isobutyl),-NHCOCH2(morpholin-4-yl),-NKCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)

such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred formula IIc' compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(b) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(c) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2.
More preferred compounds of formula IIc' have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(b) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(c) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.

Even more preferred compounds of formula IIc'
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;
(b) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(c) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-; and
(d) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
"heterocyclic ring.
Other preferred compounds of formula IIc
include compounds of formula IIc":


or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;
Rx and Ry are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having O-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each
substitutable ring carbon of said fused ring formed by
Rx and Ry is optionally substituted by oxo, T-R3, or L-2-R3, and each substitutable ring nitrogen of said ring
formed by Rx and Ry is optionally substitued by R4;
provided that said fused ring formed by Rx and Ry is
other than benzo;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;

R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 tnembered, unsaturated or
partially unsaturated, ring having O-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4,-
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic) ,-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C-N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,

-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-/-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred rings formed by Rx and Ry of formula
IIc" include a 5-, 6-, or 7-membered unsaturated or
partially unsaturated ring having 1-2 heteroatoms, or a
partially unsaturated carbocyclo ring, wherein said Rx/Ry
ring is optionally substituted. This provides a bicyclic
ring system containing a pyrimidine ring. Examples of
preferred pyrimidine ring systems of formula IIc" are
shown below.


More preferred pyrimidine ring systems of
formula IIc" include IIc"-B, IIc-D, IIc-E, IIc-J, IIc-P,
and IIc-V, most preferably IIc-B, IIc-D, IIc-E, and IIc-J.
The ring formed when Rx and Ry of formula IIc"
are taken together may be substituted or unsubstituted.
Suitable substituents include-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2,-N(R4)2,-N(R4)-(CH2)2-4-R,

-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2 ,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, wherein R and
R4 are as defined above. Preferred Rx/Ry ring
substituents include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CK2)2-4-N(R4)2,-O(CK2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen
or an optionally substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IIc" may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIc"
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IIc" include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl),-SO2NH2,-OC(O)NH2,-NK2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl) is a

straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula IIc"
is monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIc" is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIc" is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIc", preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCK2N(R4)2,-N(R6) COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl),-NHSO2(isopropyl) ,-NHCOEt,-NKCOCH2NHCH3,-NHCOCH2N(CO2t-Bu) CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2 ,-NHCOCH2CH2CH2N(CH3)2 ,

-NHCO(cyclopropyl) ,-NHCO(isobutyl) ,-NHCOCH2(morpholin-4-yl) ,-NHCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl) ,-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic) 2 such as-NMe2, OH,-O(C1-4 aliphatic)
such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred formula IIc" compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx and Ry are taken together with their
intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having 1-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, or a partially unsaturated
6-membered carbocyclo ring, wherein each
substitutable ring carbon of said fused ring
formed by Rx and Ry is independently substituted
by oxo, T-R3, or L-Z-R3, and each substitutable
ring nitrogen of said ring formed by Rx and Ry is
independently substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit, and Ring D is a 5-7 membered
monocyclic or an 8-10 membered bicyclic aryl or
heteroaryl ring;
(c) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2.
More preferred compounds of formula IIc" have
one or more, and more preferably all, of the features
selected from the group consisting of:

(a) Rx and Ry are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring, wherein
each substitutable ring carbon of said fused
ring formed by Rx and Ry is independently
substituted by oxo, T-R3, or L-Z-R3, and each
substitutable ring nitrogen of said ring formed
by Rx and Ry is independently substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
Even more preferred compounds of formula IIc"
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx and Ry are taken together to form a pyrido,
piperidino, or cyclohexo ring, wherein each
substitutable ring carbon of said fused ring
formed by Rx and Ry is independently substituted
by oxo, T-R3, or L-Z-R3, and each substitutable
ring nitrogen of said ring formed by Rx and Ry is
independently substituted by R4;

(b) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring ;
(c) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.
Representative compounds of formula IIc are
shown below in Table 3.
Table 3.















In another embodiment, this invention provides
a composition comprising a compound of formula IIc, IIc' ,
or IIc", and a pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IIc, IIc', or IIc", or a
pharmaceutical composition thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,

which method comprises administering to the patient a
compound of formula IIc, IIc', or IIc", or a composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIc, IIc', or IIc", or a pharmaceutical composition
thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IIc, IIc', or IIc", or a pharmaceutical composition
thereof. This method is especially useful for diabetic
patients. Another method relates to inhibiting the
production of hyperphosphorylated Tau protein, which is
useful in halting or slowing the progression of
Alzheimer's disease. Another method relates to
inhibiting the phosphorylation of P-catenin, which is
useful for treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IIc, IIc', or IIc", or a composition
comprising said compound.
Another aspect of this invention relates to a
method of treating or preventing a Src-mediated disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula

IIc, IIc', or IIc", or a pharmaceutical composition
thereof.
Another aspect of the invention relates to
inhibiting Src activity in a patient, which method
comprises administering to the patient a compound of
formula IIc, IIc', or IIc", or a composition comprising
said compound.
Another aspect of this invention relates to a
method of treating or preventing an ERK-2-mediated
diseases with an ERK-2 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIc, IIc', or IIc", or a pharmaceutical composition
thereof.
Another aspect of the invention relates to
inhibiting ERK-2 activity in a patient, which method
comprises administering to the patient a compound of
formula IIc, IIc', or IIc", or a composition comprising
said compound.
Another aspect of this invention relates to a
method of treating or preventing an AKT-mediated diseases
with an AKT inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIc, IIc', or IIc", or a pharmaceutical composition
thereof.
Another aspect of the invention relates to
inhibiting AKT activity in a patient, which method
comprises administering to the patient a compound of
formula IIc, IIc', or IIc", or a composition comprising
said compound.
Another method relates to inhibiting Aurora-2,
GSK-3, Src, ERK-2, or AKT activity in a biological

sample, which method comprises contacting the biological
sample with the Aurora-2, GSK-3, Src, ERK-2, or AKT
inhibitor of formula IIc, IIc, or IIc", or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2, GSK-3, Src, ERK-2, or AKT.
Each of the aforementioned methods directed to
the inhibition of Aurora-2, GSK-3, Src, ERK-2, or AKT, or
the treatment of a disease alleviated thereby, is
preferably carried out with a preferred compound of
formula IIc, IIc', or IIc", as described above.
Another embodiment that is particularly useful
for treating Aurora-2-mediated diseases relates to
compounds of formula IId:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;
Q' is selected from-C(R6')2-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;
Rx and Ry are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having O-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each-substitutable ring carbon of said fused ring formed by
Rx and Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of said

ring formed by Rx and Ry is independently substituted
by R4;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain, wherein
when Q' is-C(R6')2-a methylene group of said C1-4
alkylidene chain is optionally replaced by-O-,-S-,-N(R4)-,-CO-,-CONH-,-NHCO-,-SO2-,-SO2NH-,-NHSO2-,-CO2-,-OC(O)-,-OC(O)NH-, or-NHCO2-;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having O-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,

-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-N02,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms ,-
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2 ;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,

-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6) 2N(R6) CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(Rs)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R6' is independently selected from hydrogen or a C1-4
aliphatic group, or two R6' on the same carbon atom are
taken together to form a 3-6 membered carbocyclic ring;
and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred rings formed by Rx and RY include a
5-, 6-, or 7-membered unsaturated or partially
unsaturated ring having O-2 heteroatoms, wherein said
Rx/Ry ring is optionally substituted. This provides a
bicyclic ring system containing a pyrimidine ring.
Examples of preferred pyrimidine ring systems of formula
IId are shown below.



More preferred pyrimidine ring systems of
formula IId include IId-A, IId-B, IId-D, IId-E, IId-J,
IId-P, and IId-V, most preferably IId-A, IId-B, IId-D,
IId-E, and IId-J.
The ring formed when Rx and Ry of formula IId
are taken together may be substituted or unsubstituted.
Suitable substituents include-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-4-R,

-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, R and R4 are
as defined above. Preferred Rx/Ry ring substituents
include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen or an optionally
substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IId may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IId
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IId include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl)is a

straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl)group is methyl.
When the pyrazole ring system of formula IId is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IId is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IId is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo [b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IId, preferred T-R5 or V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOK,-CONHMe,-CONHEt,-NH2,-NKAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl),-NHSO2(isopropyl),-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu)CH3 ,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2 ,-NHCOCH2CH2CH2N(CH3)2,

-NHCO(cyclopropyl),-NHCO(isobutyl),-NHCOCH2(morpholin-4-yl),-NHCOCH2CH2(morpholin-4-yl),-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic)such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)such as-OMe,
C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred Q' groups of formula IId include-C(R6')2-or 1,2-cyclopropanediyl, wherein each R6' is
independently selected from hydrogen or methyl. A more
preferred Q' group is-CH2-.
Preferred formula llc compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx and Ry are taken together with their
intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by Rx and
Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of
said ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit and wherein said methylene unit
is optionally replaced by-O-,-NK-, or-S-;
(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(d) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring; and

(e)R3 is selected from-R,-halo,-OR, or-N(R4)2.
More preferred compounds of formula IIc have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit and wherein said methylene unit
is optionally replaced by-0-, and Ring D is a
5-6 membered monocyclic ring or an 8-10 membered
bicyclic ring selected from an aryl or
heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-,-and
(e) Q' is-C(R6')2-or 1,2-cyclopropanediyl, wherein
each R6' is independently selected from hydrogen
or methyl.
Even more preferred compounds of formula llc
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;
(b) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;

(c) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-;
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(f) Q' is-CH2-.
Representative compounds of formula IId are
shown below in Table 4.
Table 4.





In another embodiment, this invention provides
a composition comprising a compound of formula IId and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IId or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IId or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a

therapeutically effective amount of a compound of formula IId or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula IId or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of β-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IId or a composition comprising said compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IId, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IId, as described
above.
Another embodiment of this invention relates to
compounds of formula IIIa:


or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Rx and Ry are independently selected from T-R3 or L-Z-R3;
R1 is T-(Ring D),-
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R*;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)20-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)C0N(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or

partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(«0)R,-N(R7)C0R,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each Rs is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C-N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,

-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)0-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred Rx groups of formula IIIa ""include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IIIa include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoalkoxy such as

dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The R2 and R2' groups of formula IIIa may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIIa
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IIIa include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl)is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl)group is methyl.
When the pyrazole ring system of formula IIIa
is monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include E, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,

methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIIa is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIIa is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIIa, preferred T-R5 or V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 memBered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl),-NHSO2(isopropyl),-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CH2N(CH3)2,
-NKCO(cyclopropyl),-NKCO(isobutyl),-NHCOCH2(morpholin-4-yl),-NHCOCH2CK2(morpholin-4-yl),-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic)such as-NHMe,-N(C1-4 aliphatic); such as-NMe2, OH,-O(C1-4 aliphatic)such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).

Preferred formula IIIa compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group;
(b) Ry is T-R3 or L-Z-R3, wherein T is a valence bond
or a methylene and R3 is-R,-N(R4):, or-OR;
(c) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(d) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(e) R2 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.
More preferred compounds of formula IIIa have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,
or-N(R4)2, wherein R is selected from hydrogen,
C1-6 aliphatic, or 5-6 membered heterocyclyl,
phenyl, or 5-6 membered heteroaryl;
(b) R1 is T-(Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;
(d) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(e) L is-O-,-S-, or-N(R4)-.
Even more preferred compounds of formula IIIa
have one or more, and more preferably all, of the
features selected from the group consisting of:

(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or
acetimido;
(b) Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl;
(c) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally substituted
with one to two groups selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6
aliphatic group,-OR,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)SO2R,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2; and
(d) R2 is hydrogen or a substituted or unsubstituted
C1-6 aliphatic, and L is-O-,-S-, or-NH-.
Representative compounds of formula IIIa are
shown below in Table 5.
Table 5.











In another embodiment, this invention provides
a composition comprising a compound of formula IIIa and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IIIa or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IIIa or a composition comprising said
compound.

Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIIa or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IIIa or a pharmaceutical composition thereof. This
method is especially useful for diabetic patients.
Another method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IIIa or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a Src-mediated disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIIa or a pharmaceutical composition thereof.
Another aspect of the invention relates to
inhibiting Src activity in a patient, which method

comprises administering to the patient a compound of
formula IIIa or a composition comprising said compound.
Another method relates to inhibiting Aurora-2,
GSK-3, or Src activity in a biological sample, which
method comprises contacting the biological sample with
the Aurora-2, GSK-3, or Src inhibitor of formula IIIa, or
a pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2, GSK-3, or Src.
Each of the aforementioned methods directed to
the inhibition of Aurora-2, GSK-3, or Src, or the
treatment of a disease alleviated thereby, is preferably
carried out with a preferred compound of formula IIIa, as
described above.
Another embodiment of this invention relates to
compounds of formula Illb:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Rx and Ry are independently selected from T-R3 or L-Z-R3;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently

substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently-substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C-N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or
-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10

ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)C02(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C-N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-0C(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R5)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(Rs)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)0-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the

nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred Rx groups of formula IIIb include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IIIb include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethy1amino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The R2 and R2' groups of formula IIIb may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIIb
compounds having a pyrazole-containing bicyclic ring
system:


Preferred substituents on the R2/R2' fused ring
of formula IIIb include one or more of the following: •-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl)is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl)group is methyl.
When the pyrazole ring system of formula IIIb
is monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIIb is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIIb is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, guinolinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, guinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoguinolinyl.
On Ring D of formula IIIb, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,-optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from

hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl),-NHSO2(isopropyl),-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CH2N(CH3)2,
-NHCO(cyclopropyl),-NHCO(isobutyl),-NHCOCH2(morpholin-4-yl),-NHCOCH2CH2(morpholin-4-yl),-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic)such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred formula IIIb compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group;
(b) Ry is T-R3 or L-Z-R3, wherein T is a valence bond
or a methylene and R3 is-R,-N(R4)2, or-OR;
(c) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit,-
(d) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(e) R2 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.
More preferred compounds of formula IIIb have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a)Ry is T-R3 or L-2-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,

or-N(R4)2, wherein R is selected from hydrogen,
C1-6 aliphatic, or 5-6 membered heterocyclyl,
phenyl, or 5-6 membered heteroaryl;
(b) R1 is T-(Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;
(d) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(e) L is-O-,-S-, or-N(R4)-.
Even more preferred compounds of formula IIIb
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or
acetimido,-
(b) Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
diaikylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl;
(c) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally substituted
with one to two groups selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6
aliphatic group,-OR,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)SO2R,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2; and

(d)R2 is hydrogen or a substituted or unsubstituted
C1-6 aliphatic, and L is-O-,-S-, or-NH-.
Representative compounds of formula IIIb are
shown below in Table 6.





In another embodiment, this invention provides
a composition comprising a compound of formula IIIb and a
pharmaceutically acceptable carrier.
Another, aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IIIb or a pharmaceutical composition
thereof;
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IIIb or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises

administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula IIIb or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula IIIb or a pharmaceutical composition thereof. This
method is especially useful for diabetic patients.
Another method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of p-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IIIb or a composition comprising said
compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IIIb, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IIIb, as described
above.

Another embodiment of this invention relates to
compounds of formula IIIc:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Rx and Ry are independently selected from T-R3 or L-Z-R3;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,

-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2 ,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C-NN(R4)2,-C-N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;

V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)0-,-N(R6)C0N(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred Rx groups of formula IIIc include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IIIc include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,

morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The R2 and R2' groups of formula IIIc may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIIc
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IIIc include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(1-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl). wherein the(C1-4 alkyl)is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl)group is methyl.
When the pyrazole ring system of formula IIIc
is monocyclic, preferred R2 groups include hydrogen or a

substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIIc is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIIc is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IIIc, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl),-NHSO2(isopropyl),-NKCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CH2N(CH3)2 ,
-NHCO(cyclopropyl),-NHCO(isobutyl),-NHCOCH2(morpholin-4-yl),-NHCOCH2CH2(morpholin-4-yl),-NHCOCK2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic)such as-NHMe,-N(d-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)

such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred formula IIIc compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group;
(b) Ry is T-R3 or L-Z-R3, wherein T is a valence bond
or a methylene and R3 is-R,-N(R4)2, or-OR;
(c) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(d) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(e) R3 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.
More preferred compounds of formula IIIc have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,
or-N(R4)2, wherein R is selected from C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl;
(b) R1 is T-(Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;
(d) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(e) L is-O-,-S-, or-N(R4)-.

Even more preferred compounds of formula IIIc
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or
acetimido;
(b) Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl;
(c) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally substituted
with one to two groups selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6
aliphatic group,-OR,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)SO2R,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2; and
(d) R2 is hydrogen or a substituted or unsubstituted
C1-6 aliphatic, and L is-O-,-S-, or-NH-.
Representative compounds of formula IIIc are
shown below in Table 7.






In another embodiment, this invention provides
a composition comprising a compound of formula IIIc and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IIIc or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IIIc or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIIc or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula

IIIc or a pharmaceutical composition thereof. This
method is especially useful for diabetic patients.
Another method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of β-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient:, which
method comprises administering to the patient a compound
of formula IIIc or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a Src-mediated disease
with a Src inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IIIc or a pharmaceutical composition thereof.
Another aspect of the invention relates to
inhibiting Src activity in a patient, which method
comprises administering to the patient a compound of
formula IIIc or a composition comprising said compound.
Another method relates to inhibiting Aurora-2,
GSK-3, or Src activity in a biological sample, which
method comprises contacting the biological sample with
the Aurora-2, GSK-3, or Src inhibitor of formula IIIc, or
a pharmaceutical composition thereof, in an amount
effective to Aurora-2, GSK-3, or Src.
Each of the aforementioned methods directed to
the inhibition of Aurora-2, GSK-3, or Src, or the
treatment of a disease alleviated thereby, is preferably

carried out with a preferred compound of formula IIIc, as
described above.
Another embodiment of this invention relates to
compounds of formula IIId:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Q' is selected from-C(R6')2-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;
Rx and Ry are independently selected from T-R3 or L-Z-R3;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-Rs, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain, wherein
when Q' is-C(R6')2-a methylene group of said C1-4
alkylidene chain is optionally replaced by-O-,-S-,-N(R4)-,-CO-,-CONH-,-NHCO-,-SO2-,-SO2NH-,-NHSO2-,-CO2-,-OC(O)-,-OC(O)NH-, or-NHCO2-;
Z is a C1-4 alkvlidene chain;

L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR ,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;

each R5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)C02(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2 ,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON{R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R6' is independently selected from hydrogen or a C1-4
aliphatic group, or two R6' on the same carbon atom are
taken together to form a 3-6 membered carbocyclic ring;
and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the

nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.
Preferred Rx groups of formula IIId include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IIId include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The R2 and R2' groups of formula IIId may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IIId
compounds having a pyrazole-containing bicyclic ring
system:


Preferred substituents on the R2/R2' fused ring
of formula IIId include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl), —SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl.)is a
straight, branched, or cyclic alkyl group. Preferably,
the(d-4 alkyl)group is methyl.
When the pyrazole ring system of formula IIId
is monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IIId is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IIId is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, guiholinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo [b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoguinolinyl.
On Ring D of formula IIId, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted d-e aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH3CH3CH2CH2N(R4)2 wherein R is selected from

hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl),-NHSO2(isopropyl),-NHCOEt,-NHCOCH2NHCH3 ,-NHCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2 ,-NHCOCH2CH2N(CH3)2 ,-NHCOCH2CH2CH2N(CH3)2,
-NHCO(cyclopropyl),-NHCOdsobutyl),-NHCOCH2(morpholin-4-yl),-NHCOCH2CH2(morpholin-4-yl),-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic)such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred Q' groups of formula IIId include-C(R6')2-or 1,2-cyclopropanediyl, wherein each R6' is
independently selected from hydrogen or methyl. A more
preferred Q' group is-CH2-.
Preferred formula IIId compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group;
(b) Ry is T-R3 or L-Z-R3, wherein T is a valence bond
or a methylene and R3 is-R,-N(R4)2, or-OR;
(c) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit and wherein said methylene unit
is optionally replaced by-O-,-NH-, or-S-;
(d) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(e) R2 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.

More preferred compounds of formula IIId have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,
or-N(R4)2, wherein R is selected from hydrogen,
C1-6 aliphatic, or 5-6 membered heterocyclyl,
phenyl, or 5-6 membered heteroaryl;
(b) R1 is T-(Ring D), wherein T is a valence bond;
(c) Ring D is a 5-6 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring;
(d) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;
(e) L is-O-,-S-, or-N(R4)-; and
(f) Q' is-C(R6')2-or 1,2-cyclopropanediyl, wherein
each R6' is independently selected from hydrogen
or methyl.
Even more preferred compounds of formula IIId
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or
acetimido;
(b) Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl;

(c) R2 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring, wherein Ring D is optionally substituted
with one to two groups selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6
aliphatic group,-OR,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)SO2R,-N(R6)COCH2CH2N(R4)2, or
-N(R6)COCH2CH2CH2N(R4)2;
(d) R2 is hydrogen or a substituted or unsubstituted
C1-6 aliphatic; and L is-O-,-S-, or-NH-; and
(e) Q' is-CH2-.
Representative compounds of formula IIId are
shown below in Table 8.





In another embodiment, this invention provides
a composition comprising a compound of formula IIId and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IIId or a pharmaceutical composition
thereof .
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IIId or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a

therapeutically effective amount of a compound of formula
IIId or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IIId or a pharmaceutical composition thereof. This
method is especially useful for diabetic patients.
Another method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of β-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IIId or a composition comprising said
compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IIId, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IIId, as described
above.
Another embodiment of this invention relates to
compounds of formula IVa:


or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Z1 is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein
one of Z1 or Z2 is nitrogen;
Rx and Ry are independently selected from T-R3 or L-Z-R3,
or Rx and Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused
ring formed by Rx and Ry is independently substituted
by oxo, T-R3, or L-Z-R3, and each substitutable ring
nitrogen of said ring formed by Rx and Ry is
independently substituted by R4;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;

T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-c(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C{R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4 ;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)C02(optionally substituted C1-6 aliphatic),-N(R4)N(R4):,-C=NN(R4)2,-C-N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2 ;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-COz-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R5)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)0C(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring; and

R8 is selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally
substituted C2-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2.
Preferred rings formed by Rx and Ry of formula
IVa include a 5-, 6-, or 7-membered unsaturated or
partially unsaturated ring having 0-2 heteroatoms,
wherein said Rx/Ry ring is optionally substituted. This
provides a bicyclic ring system containing a pyridine
ring. Preferred pyridine ring systems of formula IVa are
shown below.



More preferred pyridine ring systems of formula
IVa include IVa-A, IVa-B, IVa-D, IVa-E, IVa-J, IVa-P, and
IVa-V, most preferably IVa-A, IVa-B, IVa-D, IVa-E, and
IVa-J. Even more preferred pyridine ring systems of
formula IVa are those described above, wherein Z1 is
nitrogen and Z2 is CH.
Preferred Rx groups of formula IVa include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IVa include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoaikoxy such as

dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The ring formed when the Rx and Ry groups of
formula IVa are taken together may be substituted or
unsubstituted. Suitable-substituents-include •-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6
aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, R and R4 are as defined above. Preferred
Rx/Ry ring substituents include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen
or an optionally substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IVa may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IVa
compounds having a pyrazole-containing bicyclic ring
system:


Preferred substituents on the R3/R2' fused ring
of formula IVa include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl),-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl)is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl)group is methyl.
When the pyrazole ring system of formula IVa is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl., and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IVa is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IVa is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, guinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IVa, preferred T-R5 or V-2-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered

heteroaryl ring, or a 5-5 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl),-NHSO2(isopropyl),-NKCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu)CH3 ,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2 ,-NHCOCH2CH2CH2N(CH3)2,
-NHCO(cyclopropyl),-NHCO(isobutyl),-NHCOCH2(morpholin-4-yl),-NHCOCH2CH2(morpholin-4-yl),-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl),-NH(C1-4 aliphatic)such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred R8 groups of formula IVa, when
present, include R, OR, and N(R4)2. Examples of preferred
R9 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH,
N(CH3)2CH2CH2O,(piperidin-1-yl)CH2CH2O, and NH2CH2CH2O.
Preferred formula IVa compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a)Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group and Ry is
T-R3 or L-Z-R3, wherein T is a valence bond or a
methylene and R3 is-R,-N(R4)2, or-OR; or Rx and
Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-6 membered ring having 0-2
heteroatoms selected from oxygen, sulfur, or
nitrogen, wherein each substitutable ring carbon
of said fused ring formed by Rx and Ry is
independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said

ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(d) R2 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.
More preferred compounds of formula IVa have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,
or-N(R4)2, wherein R is selected from hydrogen,
C1-6 aliphatic, or 5-6 membered heterocyclyl,
phenyl, or 5-6 membered heteroaryl; or Rx and Ry
are taken together with their intervening atoms
to form a benzo, pyrido, cyclopento, cyclohexo,
cyclohepto, thieno, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by Rx and Ry is independently
substituted by oxo, T-R3, or L-Z-R3, and each
substitutable ring nitrogen of said ring formed
by Rx and Ry is independently substituted by R4 ;
(b) R1 is T-(Ring D), wherein T is a valence bond,
and Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;and

(d)R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
Even more preferred compounds of formula IVa
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or acetamido
and Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl; or Rx and
Ry are taken together with their intervening
atoms to form a benzo, pyrido, piperidino, or
cyclohexo ring, wherein said ring is optionally
substituted with-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-NO2-N(R4)2,-NR4COR,-NR4SO2R, or-SO2N(R4)2, wherein
R is hydrogen or an optionally substituted C1-6
aliphatic group;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl ring
optionally substituted with one or two groups
selected from-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2;

(c) R2 is hydrogen or a substituted or unsubstituted
group selected from aryl, heteroaryl, or a C1-6
aliphatic group, and R2' is hydrogen; and
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.
Representative compounds of formula IVa are
shown below in Table 9.



In another embodiment, this invention provides
a composition comprising a compound of formula IVa and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IVa or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a

compound of formula IVa or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IVa or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IVa or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of P-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IVa or a composition comprising said compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IVa, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of

a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IVa, as described
above.
Another embodiment of this invention relates to
compounds of formula IVb:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Z1 is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein
one of Z1 or Z2 is nitrogen;
Rx and Ry are independently selected from T-R3 or L-Z-R3,
or Rx and Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused
ring formed by Rx and Ry is independently substituted
by oxo, T-R3, or L-Z-R3, and each substitutable ring
nitrogen of said ring formed by Rx and Ry is
independently substituted by R4;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected

from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-Rs, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO,-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R')2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6

aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic) ,-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4) CO2(optionally substituted C1-6 aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4) CON(R4) 2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O) N(R4) 2 ;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6) C(O) O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6) N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)25O2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6) 2N(R6) CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7

on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring; and
R8 is selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4) CO2(optionally-substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4) SO2N(R4) 2,-N(R4)SO2R, or-OC(=O)N(R4)2.
Preferred rings formed by Rx and Ry of formula
IVb include a 5-, 6-, or 7-tnembered unsaturated or
partially unsaturated ring having 0-2 heteroatoms,
wherein said Rx/Ry ring is optionally substituted. This
provides a bicyclic ring system containing a pyrimidine
ring. Preferred pyrimidine ring systems of formula IVb
are shown below.



More preferred pyrimidine ring systems of
formula IVb include IVb-A, IVb-B, IVb-D, IVb-E, IVb-J,
IVb-P, and IVb-V, most preferably IVb-A, IVb-B, IVb-D,
IVb-E, and IVb-J. Even more preferred pyridine ring
systems of formula IVb are those described above, wherein
Z1 is nitrogen and Z2 is CH.
Preferred Rx groups of formula IVb include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IVb include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include

2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The ring formed when the Rx and Ry groups of
formula IVba are taken together may be substituted or
unsubstituted. Suitable substituents include-R, halo,
-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,
-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,
-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,
-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6
aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,
-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or
-OC(=O)N(R4)2, R and R4 are as defined above. Preferred
Rx/Ry ring substituents include-halo,-R,-OR,-COR,
-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2
-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen
or an optionally substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IVb may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IVb
compounds having a pyrazole-containing bicyclic ring
system:


Preferred substituents on the R2/R2' fused ring
of formula IVb include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl) ,-CN,-SO2(C1-4 alkyl) ,-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl) ,-NHC(O)(C1-4 alkyl) ,-C(O)NH2, and-CO(C1-4 alkyl) , wherein the(C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula IVb is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include hydrogen, methyl, ethyl,
propyl, , cyclopropyl, i-propyl, cyclopentyl,
hydroxypropyl, methoxypropyl, and benzyloxypropyl. A
preferred R2' group is hydrogen.
When Ring D of formula IVb is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IVb is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzofbjfuryl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalasinyl, quinazolinyl, guinoxazolinyl,
1,8-naphthyridinyl and imoquinolinyl.

On Ring D of formula IVb, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6) COCH2CH2N(R4) 2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl) ,-NHSO2(isopropyl),-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CH2N(CH3)2,
-NHCO(cyclopropyl) ,-NHCO(isobutyl),-NHCOCH2(morpholin-4-yl) ,-NHCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl) ,-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)
such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic) .
Preferred R8 groups of formula IVb, when
present, include R, OR, and N(R4)2. Examples of preferred
R8 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH,
N(CH3)2CH2CH2O,(piperidin-1-yl)CH2CH2O, and NK2CH2CH2O.
Preferred formula IVb compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group and Ry is
T-R3 or L-Z-R3, wherein T is a valence bond or a
methylene and R3 is-R,-N(R4)2, or-OR; or Rx and
Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially

unsaturated, 5-6 membered ring having 0-2
heteroatoms selected from oxygen, sulfur, or
nitrogen, wherein each substitutable ring carbon
of said fused ring formed by Rx and Ry is
independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said
ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D) , wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(d) R2 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.
More preferred compounds of formula IVb have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,
or-N(R4)2, wherein R is selected from hydrogen,
C1-6 aliphatic, or 5-6 membered heterocyclyl,
phenyl, or 5-6 membered heteroaryl; or Rx and Ry
are taken together with their intervening atoms
to form a benzo, pyrido, cyclopento, cyclohexo,
cyclohepto, thieno, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by Rx and Ry is independently
substituced by oxo, T-R3, or L-Z-R3, and each
substitutable ring nitrogen of said ring formed
by Rx and Ry is independently substituted by R4;

(b) R1 is T-(Ring D), wherein T is a valence bond,
and Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
Even more preferred compounds of formula IVb
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or acetamido
and Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl; or Rx and
Ry are taken together with their intervening
atoms to form a benzo, pyrido, piperidino, or
cyclohexo ring, wherein said ring is optionally
substituted with-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-NO2-N(R4)2,-NR4COR,-NR4SO2R, or-SO2N(R4)2, wherein
R is hydrogen or an optionally substituted C1-6
aliphatic group;

(b) R1 is T-(Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl ring
optionally substituted with one or two groups
selected from-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6) COCH2CH2CH2N(R4)2 ;
(c) R2 is hydrogen or a substituted or unsubstituted
group selected from aryl, heteroaryl, or a C1-6
aliphatic group, and R2' is hydrogen; and
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.
Representative compounds of formula IVb are
shown below in Table 10.




In another embodiment, this invention provides
a composition comprising a compound of formula IVb and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IVb or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IVb or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IVb or a pharmaceutical composition thereof

One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IVb or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of β-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IVb or a composition comprising said compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IVb, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IVb, as described
above.
Another embodiment of this invention relates to
compounds of formula IVc:


or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Z1 is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein
one of Z1 or Z2 is nitrogen;
Rx and Ry are independently selected from T-R3 or L-Z-R3,
or Rx and Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused
ring formed by Rx and Ry is independently substituted
by oxo, T-R3, or L-Z-R3, and each substitutable ring
nitrogen of said ring formed by Rx and Ry is
independently substituted by R4;
R1 is T-(Ring D) ,-
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;

Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6) N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6) 2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6) =NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6) 2N(R6) SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2 is
independently substituted by R4 ;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic) ,-N(R4) N(R4) 2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7) SO2N(R7) 2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic) ,-CON(R7)2,
or-SO2R7;

each H5 is independently selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted d-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6) N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6) =NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,-C(R6)2N(R6)CON(R6)-, or-CON(R6)-,-
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring; and
R8 is selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally

substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2/-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2.
Preferred rings formed by Rx and Ry of formula
IVc include a 5-, 6-, or 7-membered unsaturated or
partially unsaturated ring having 0-2 heteroatoms,
wherein said Rx/Ry ring is optionally substituted. This
provides a bicyclic ring system containing a pyridine
ring. Preferred pyridine ring systems of formula IVc are
shown below.



More preferred pyridine ring systems of formula
IVc include IVc-A, IVc-B, IVc-D, IVc-E, IVc-J, IVc-P, and
IVc-V, most preferably IVc-A, IVc-B, IVc-D, IVc-E, and
IVc-J. Even more preferred pyridine ring systems of
formula IVc are those described above, wherein Z1 is
nitrogen and Z2 is CH
Preferred Rx groups of formula IVc include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IVc include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoalkoxy such as

dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The ring formed when the Rx and Ry groups of
formula IVc are taken together may be substituted or
unsubstituted. Suitable substituents include-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2)2-4-N(R4)2,-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally substituted C1-6
aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, R and R4 are as defined above. Preferred
Rx/Ry ring substituents include-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen
or an optionally substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IVc may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IVc
compounds having a pyrazole-containing bicyclic ring
system:


Preferred substituents on the RVR2' fused ring
of formula IVc include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2(C1-4 alkyl) ,-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl) ,-C(O)NH2, and-CO(C1-4 alkyl), wherein the(C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the(C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula IVc is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubstituted group selected from aryl,
heteroaryl, or a d-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,
methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IVc is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IVc is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo [b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, guinazolinyl, quinoxazolinyl,
1, 8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IVc, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6) COCH2CH2N(R4) 2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered

heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl) ,-NHSO2(isopropyl) ,-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N(CO2t-Bu) CH3,-NHCOCH2N(CH3)2 ,-NHCOCH2CH2N(CH3)2 ,-NHCOCH2CH2CH2N(CH3)2 ,
-NHCO(cyclopropyl),-NHCO(isobutyl),-NHCOCH2(morpholin-4-yl) ,-NHCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2(morpholin-4-yl),-NHCO2(t-butyl) ,-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)
such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2(C1-4
aliphatic).
Preferred R8 groups of formula IVc, when
present, include R, OR, and N(R4)2. Examples of preferred
R8 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH,
N(CH3)2CH2CH2O,(piperidin-1-yl)CH2CH2O, and NH2CH2CH2O.
Preferred formula IVc compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group and Ry is
T-R3 or L-Z-R3, wherein T is a valence bond or a
methylene and R3 is-R,-N(R4)2, or-OR; or Rx and
Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-6 membered ring having 0-2
heteroatoms selected from oxygen, sulfur, or
nitrogen, wherein each substitutable ring carbon
of said fused ring formed by Rx and Ry is
independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said

ring formed by Rx and Ry is independently
substituted by R*;
(b) R1 is T-(Ring D) , wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(d) R2 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.
More preferred compounds of formula IVc have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,
or-N(R4)2, wherein R is selected from hydrogen,
C1-6 aliphatic, or 5-6 membered heterocyclyl,
phenyl, or 5-6 membered heteroaryl; or Rx and Ry
are taken together with their intervening atoms
to form a benzo, pyrido, cyclopento, cyclohexo,
cyclohepto, thieno, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by Rx and Ry is independently
substituted by oxo, T-R3, or L-Z-R3, and each
substitutable ring nitrogen of said ring formed
by Rx and Ry is independently substituted by R4;
(b) R1 is T-(Ring D) , wherein T is a valence bond,
and Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;and

(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
Even more preferred compounds of formula IVc
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or acetamido
and Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl; or Rx and
Ry are taken together with their intervening
atoms to form a benzo, pyrido, piperidino, or
cyclohexo ring, wherein said ring is optionally
substituted with-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-NO2-N(R4)2,-NR4COR,-NR4SO2R, or-SO2N(R4)2, wherein
R is hydrogen or an optionally substituted C1-6
aliphatic group;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl ring
optionally substituted with one or two groups
selected from-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2 ,-N(R6)COCH2CH2N(R4)2, or-N(R6) COCH2CH2CH2N(R4)2 ;

(c) R2 is hydrogen or a substituted or unsubstituted
group selected from aryl, heteroaryl, or a C1-6
aliphatic group, and R2' is hydrogen; and
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.
Representative compounds of formula IVc are
shown below in Table 11.



In another embodiment, this invention provides
a composition comprising a compound of formula ivc and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitory which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula JVc or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient

which method comprises administering to the patient a
compound of formula IVc or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IVc or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula
IVc or a pharmaceutical composition thereof. This method
is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of β-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IVc or a composition comprising said compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IVc, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.

Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IVc, as described
above.
Another embodiment of this invention relates to
compounds of formula IVd:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein:
Z1 is nitrogen or C-R8 and Z2 is nitrogen or CH, wherein
one of Z1 or Z2 is nitrogen;
Q' is selected from-C(R6')2-, 1,2-cyclopropanediyl, 1,2-cyclobutanediyl, or 1,3-cyclobutanediyl;
Rx and Ry are independently selected from T-R3 or L-Z-R3,
or Rx and Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3 ring
heteroatoms selected from oxygen, sulfur, or nitrogen,
wherein each substitutable ring carbon of said fused
ring formed by Rx and Ry is independently substituted
by oxo, T-R3, or L-Z-R3, and each substitutable ring
nitrogen of said ring formed by Rx and Ry is
independently substituted by R4;
R1 is T-(Ring D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heter.oatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each
substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain, wherein
when Q' is-C(R6')2-a methylene group of said Cx-4
alkylidene chain is optionally replaced by-O-,-S-,-N(R4)-,-CO-,-CONH-,-NHCO-,-SO2-,-SO2NH-,-NHSO2-,-CO2-,-OC(O)-,-OC(O)NH-, or-NHCO2-;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6),CO-,-N(R6) C(O) O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6) N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6) =NW(R6)-,-C(R5)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6) 2N(R6) SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 membered, unsaturated or'
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2' is
independently substituted by R4;

R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,-N(R7)CO2(C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R7)CON(R7)2,-N(R7-)SO2N(R7)2,-N(R4)SO2R, or-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;
each R4 is independently selected from-R7,-COR7,
-CO2(optionally substituted C1-6 aliphatic),-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4) CO2(optionally substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4) CON(R4) 2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4) 2 ;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6) N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,
-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,

-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C3-4 aliphatic group, or two R6
groups on the same nitrogen, atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring;
each R6' is independently selected from hydrogen or a C1-4
aliphatic group, or two R6' on the same carbon atom are
taken together to form a 3-6 membered carbocyclic ring;
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring; and
R8 is selected from-R, halo,-OR,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2(optionally
substituted C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2.
Preferred rings formed by Rx and Ry of formula
IVd include a 5-, 6-, or 7-membered unsaturated or
partially unsaturated ring having 0-2 heteroatoms,
wherein said Rx/Ry ring is optionally substituted. This
provides a bicyclic ring system containing a pyridine
ring. Preferred pyridine ring systems of formula IVa are
shown below.



More preferred pyridine ring systems of formula
IVd include IVd-A, IVd-B, IVd-D, IVd-E, IVd-J, IVd-P, and
IVd-V, most preferably IVd-A, IVd-B, IVd-D, IVd-E, and
IVd-J. Even more preferred pyridine ring systems of
formula IVd include those described above, wherein Z1 is
nitrogen and Z2 is CH.
Preferred Rx groups of formula IVd include
hydrogen, alkyl-or dialkylamino, acetamido, or a C1-4
aliphatic group such as methyl, ethyl, cyclopropyl, or
isopropyl.
Preferred Ry groups of formula IVd include T-R3
or L-Z-R3 wherein T is a valence bond or a methylene, L is-O-,-S-, or-N(R4)-,-C(R6)2O-,-CO-and R3 is-R,-N(R4)2, or-OR. Examples of preferred Ry groups include
2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl,
morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino such as
methoxyethylamino, alkoxyalkyl such as methoxymethyl or
methoxyethyl, alkyl-or dialkylamino such as ethylamino
or dimethylamino, alkyl-or dialkylaminoalkoxy such as
dimethylaminopropyloxy, acetamido, optionally substituted
phenyl such as phenyl or halo-substituted phenyl.
The ring formed when the Rx and Ry groups of
formula IVd are taken together may be substituted or
unsubstituted. Suitable substituents include-R, halo,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-OR,-N(R4)-(CH2) 2-4-N (R4) 2,-N(R4)-(CH2)2-4-R,-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,-N(R4)CO2 (optionally substituted C1-6
aliphatic),-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(=O)N(R4)2, R and R4 are as defined above. Preferred
Rx/Ry ring substituents include-halo,-R,-OR,-COR,

-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R, ,-NO2-N(R4)2,-NR4COR,-NR4SO2R,-SO2N(R4)2 wherein R is hydrogen
or an optionally substituted C1-6 aliphatic group.
The R2 and R2' groups of formula IVd may be
taken together to form a fused ring, thus providing a
bicyclic ring system containing a pyrazole ring.
Preferred fused rings include benzo, pyrido, pyrimido,
and a partially unsaturated 6-membered carbocyclo ring.
These are exemplified in the following formula IVd
compounds having a pyrazole-containing bicyclic ring
system:

Preferred substituents on the R2/R2' fused ring
of formula IVd include one or more of the following:-halo,-N(R4)2,-C1-4 alkyl,-C1-4 haloalkyl,-NO2,-O(C1-4
alkyl),-CO2(C1-4 alkyl),-CN,-SO2 (C1-4 alkyl),-SO2NH2,-OC(O)NH2,-NH2SO2(C1-4 alkyl),-NHC(O)(C1-4 alkyl) ,-C(O)NH2, and-CO(C1-4 alkyl), wherein the (C1-4 alkyl) is a
straight, branched, or cyclic alkyl group. Preferably,
the (C1-4 alkyl) group is methyl.
When the pyrazole ring system of formula IVd is
monocyclic, preferred R2 groups include hydrogen or a
substituted or unsubsticuted group selected from aryl,
heteroaryl, or a C1-6 aliphatic group. Examples of such
preferred R2 groups include H, methyl, ethyl, propyl, ,
cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl,

methoxypropyl, and benzyloxypropyl. A preferred R2' group
is hydrogen.
When Ring D of formula IVd is monocyclic,
preferred Ring D groups include phenyl, pyridyl,
pyridazinyl, pyrimidinyl, and pyrazinyl.
When Ring D of formula IVd is bicyclic,
preferred bicyclic Ring D groups include naphthyl,
tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl,
indolyl, isoindolyl, indolinyl, benzo[b]furyl,
benzo[b]thiophenyl, indazolyl, benzothiazolyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl,
1,8-naphthyridinyl and isoquinolinyl.
On Ring D of formula IVd, preferred T-R5 or
V-Z-R5 substituents include-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, and-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected from
hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered
heteroaryl ring, or a 5-6 membered heterocyclic ring.
More preferred R5 substituents include-Cl,-Br,-F,-CN,-CF3,-COOH,-CONHMe,-CONHEt,-NH2,-NHAc,-NHSO2Me,-NHSO2Et,-NHSO2(n-propyl) ,-NHSO2 (isopropyl) ,-NHCOEt,-NHCOCH2NHCH3,-NHCOCH2N (CO2t-Bu)CH3,-NHCOCH2N(CH3)2,-NHCOCH2CH2N(CH3)2,-NHCOCH2CH2CH2N(CH3)2,
-NHCO(cyclopropyl) ,-NHCO (isobutyl) ,-NHCOCH2 (morpholin-4-yl),-NHCOCH2CH2(morpholin-4-yl) ,-NHCOCH2CH2CH2 (morpholin-4-yl),-NHCO2(t-butyl) ,-NH(C1-4 aliphatic) such as-NHMe,-N(C1-4 aliphatic)2 such as-NMe2, OH,-O(C1-4 aliphatic)
such as-OMe, C1-4 aliphatic such as methyl, ethyl,
cyclopropyl, isopropyl, or t-butyl, and-CO2 (C1-4
aliphatic).

Preferred R8 groups of formula IVd, when
present, include R, OR, and N(R4)2. Examples of preferred
R8 include methyl, ethyl, NH2, NH2CH2CH2NH, N(CH3)2CH2CH2NH,
N(CH3)2CH2CH2O, (piperidin-1-yl)CH2CH2O, and NH2CH2CH2O.
Preferred-Q' groups of formula IVd include-C(R6')2-or 1,2-cyclopropanediyl, wherein each R6' is
independently selected from hydrogen or methyl. A more
preferred Q' group is-CH2-.
Preferred formula IVd compounds have one or
more, and more preferably all, of the features selected
from the group consisting of:
(a) Rx is hydrogen, alkyl-or dialkylamino,
acetamido, or a C1-4 aliphatic group and Ry is
T-R3 or L-Z-R3, wherein T is a valence bond or a
methylene and R3 is-R,-N(R4)2, or-OR; or Rx and
Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-6 membered ring having 0-2
heteroatoms selected from oxygen, sulfur, or
nitrogen, wherein each substitutable ring carbon
of said fused ring formed by Rx and Ry is
independently substituted by oxo, T-R3, or L-Z-R3, and each substitutable ring nitrogen of said
ring formed by Rx and Ry is independently
substituted by R4,-
(b) R1 is T-(Ring D) , wherein T is a valence bond or
a methylene unit and wherein said methylene unit
is optionally replaced by-O-,-NH-, or-S-;
(c) Ring D is a 5-7 membered monocyclic or an 8-10
membered bicyclic aryl or heteroaryl ring; and
(d) R2 is-R or-T-W-R6 and R2' is hydrogen, or R2 and
R2' are taken together to form an optionally
substituted benzo ring.

More preferred compounds of formula IVd have
one or more, and more preferably all, of the features
selected from the group consisting of:
(a) Ry is T-R3 or L-Z-R3 wherein T is a valence bond
or a methylene and R3 is selected from-R,-OR,
or-N(R4)2, wherein R is selected from hydrogen,
C1-6 aliphatic, or 5-6 membered heterocyclyl,
phenyl, or 5-6 membered heteroaryl; or Rx and Ry
are taken together with their intervening atoms
to form a benzo, pyrido, cyclopento, cyclohexo,
cyclohepto, thieno, piperidino, or imidazo ring,
wherein each substitutable ring carbon of said
fused ring formed by Rx and Ry is independently
substituted by oxo, T-R3, or L-Z-R3, and each
substitutable ring nitrogen of said ring formed
by Rx and Ry is independently substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond,
and Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring;
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-; and '
(e) Q' is-C(R6')2-or 1,2-cyclop ropanediyl, wherein
each R6' is independently selected from hydrogen
or methyl.

Even more preferred compounds of formula IVd
have one or more, and more preferably all, of the
features selected from the group consisting of:
(a) Rx is hydrogen methyl, ethyl, propyl,
cyclopropyl, isopropyl, methylamino or acetamido
and Ry is selected from 2-pyridyl, 4-pyridyl,
pyrrolidinyl, piperidinyl, morpholinyl,
piperazinyl, methyl, ethyl, cyclopropyl,
isopropyl, t-butyl, alkoxyalkylamino,
alkoxyalkyl, alkyl-or dialkylamino, alkyl-or
dialkylaminoalkoxy, acetamido, optionally
substituted phenyl, or methoxymethyl; or Rx and
Ry are taken together with their intervening
atoms to form a benzo, pyrido, piperidino, or
cyclohexo ring, wherein said ring is optionally
substituted with-halo,-R,-OR,-COR,-CO2R,-CON(R4)2,-CN,-O(CH2)2-4-N(R4)2,-O(CH2)2-4-R,-NO2-N(R4)2,-NR4COR,-NR4SO2R, or-SO2N(R4)2, wherein
R is hydrogen or an optionally substituted C1-6
aliphatic group;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl ring
optionally substituted with one or two groups
selected from-halo,-CN,-NO2,-N(R4)2,
optionally substituted C1-6 aliphatic,-OR,-C(O)R,-CO2R,-CONH(R4) ,-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2 ,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2;
(c) R2 is hydrogen or a substituted or unsubstituted
group selected from aryl, heteroaryl, or a C1-6
aliphatic group, and R2' is hydrogen; and
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6

membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-;
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,.-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(f) Q' is-CH2-.
Representative compounds of formula IVd are
shown below in Table 12.



In another embodiment, this invention provides
a composition comprising a compound of formula IVd and a
pharmaceutically acceptable carrier.
Another aspect of this invention relates to a
method of treating or preventing an Aurora-2-mediated
disease with an Aurora-2 inhibitor, which method
comprises administering to a patient in need of such a
treatment a therapeutically effective amount of a
compound of formula IVd or a pharmaceutical composition
thereof.
Another aspect of this invention relates to a
method of inhibiting Aurora-2 activity in a patient,
which method comprises administering to the patient a
compound of formula IVd or a composition comprising said
compound.
Another aspect of this invention relates to a
method of treating or preventing a GSK-3-mediated disease
with a GSK-3 inhibitor, which method comprises
administering to a patient in need of such a treatment a
therapeutically effective amount of a compound of formula
IVd or a pharmaceutical composition thereof.
One aspect of this invention relates to a
method of enhancing glycogen synthesis and/or lowering
blood levels of glucose in a patient in need thereof,
which method comprises administering to the patient a
therapeutically effective amount of a compound of formula .
IVd or a pharmaceutical composition thereof. This method

is especially useful for diabetic patients. Another
method relates to inhibiting the production of
hyperphosphorylated Tau protein, which is useful in
halting or slowing the progression of Alzheimer's
disease. Another method relates to inhibiting the
phosphorylation of P-catenin, which is useful for
treating schizophrenia.
Another aspect of this invention relates to a
method of inhibiting GSK-3 activity in a patient, which
method comprises administering to the patient a compound
of formula IVd or a composition comprising said compound.
Another method relates to inhibiting Aurora-2
or GSK-3 activity in a biological sample, which method
comprises contacting the biological sample with the
Aurora-2 or GSK-3 inhibitor of formula IVd, or a
pharmaceutical composition thereof, in an amount
effective to inhibit Aurora-2 or GSK-3.
Each of the aforementioned methods directed to
the inhibition of Aurora-2 or GSK-3, or the treatment of
a disease alleviated thereby, is preferably carried out
with a preferred compound of formula IVd, as described
above.
The compounds of this invention may be prepared
in general by methods known to those skilled in the art
for analogous compounds, as illustrated by the general
Schemes I-VII, the general methods that follow, and by
the preparative examples below.

Scheme I

Reagents: (a) EtOH, Et3N, room temperature; (b) R1-QH (Q =
S, NH or O) or R1-CH2-M/catalyst (M is Al or Mg or Sn,
catalyst = Pd° or Ni°)
Scheme I above shows a general route for the
preparation of the present compounds. The dichlorinated
starting material 1 may be prepared using methods similar
to the those reported in J. Indian. Chem. Soc., 61, 690-693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994).
The reaction of 1 with aminopyrazole (or aminoindazole) 2
in a manner as described in Bioorg. Med. Chem. Lett, 10,
11, 1175-1180, (2000) or in J. Het. Chem, 21, 1161-1167,
(1984) provides the versatile monochloro intermediate 3.
Conditions for displacing the chloro group of 3 by Ra-Q
will depend on the nature of the Q linker moiety and are
generally known in the field. See, for example, J. Med.
Chem, 38, 14, 2763-2773,' (1995) (where Q is an N-Link),
or Chem. Pharm. Bull., 40, 1, 227-229, (1992) (S-Link),
or J. Het. Chem., 21, 1161-1167, (1984) (O-Link) or
Bioorg. Med. Chem. Lett, 8, 20, 2891-2896, (1998) (C-Link).


Reagents: (a) POCl3, Pr3N, 110°C; (b) EtOH, Et3N, room
temperature.
Scheme II above shows an alternative route for
the preparation of the present compounds. The starting
material 4 may be prepared in a manner similar to that
described for analogous compounds. See Chem. Heterocycl.
Compd., 35, 7, 818-820 (1999) (where Q is an N-Link),
Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (N-Link),
Pestic. Sci, 47, 2, 103-114 (1996) (O-Link), J. Med.
Chem., 23, 8, 913-918 (1980) (S-Link), or Pharmazie, 43,
7, 475-476 (1988) (C-Link). The chlorination of 4
provides intermediate 5. See J. Med. Chem., 43, 22,
4288-4312 (2000) (Q is an N-Link), Pestic. Sci, 47, 2,
103-114 (1996) (O-Link), J. Med. Chem., 41, 20, 3793-3803
(1998) (S-Link), or J. Med. Chem., 43, 22, 4288-4312
(2000) (C-Link). Displacement of the 4-Cl group in
intermediate 5 with aminopyrazole (or aminoindazole) 2 to
provide compounds of this invention may be performed
according to known methods for analogous compounds. See
J. Med. Chem., 38, 14, 2763-2773 (1995) (where Q is an N-Link) , Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997) (0-Link) , Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000)
(S-Link), or J. Med. Chem., 41, 21, 4021-4035 (1998) (C-Link).

Scheme III

Reagents: (a) POCl3; (b) EtOH, Et3N, room temperature; (c)
Oxone; (d) R2-QH (Q = S, NH or O) or R1-CH2-M/catalyst (M
is Al or Mg or Sn, catalyst = Pd° or Ni°)
Scheme III above shows another alternative
route for preparing the present compounds. The starting
material 6 may be chlorinated to provide intermediate 7.
Displacement of the 4-chloro group in 7 with
aminopyrazole (or aminoindazole) 2 gives intermediate 8
which, upon oxidation of the methylsulfanyl group,
provides the methylsulfone 9. The methylsulfonyl group
of 9 may be displaced readily with R1-QH to give the
desired product I. See J. Am. Chem. Soc, 81, 5997-6006
(1959) (where Q is an N-Link)or in Bioorg. Med. Chem.
Lett., 10, 8, 821-826 (2000) (S-Link).


Reagents: (a) POCl3; (b) EtOH, Et3N, room temperature; (c)
Ry-H (R = S, NH or 0) ; (d) oxone; (e) R1-QH (Q = S, NH or
0) or R1-CH2-M/catalyst (M is Al or Mg or Sn, catalyst =
Pd° or Ni°)
Scheme IV above shows a general route for the
preparation of the present compounds wherein Ry is a group
attached to the pyrimidine core via a nitrogen, oxygen or
sulfur heteroatom. The starting 4,6-dihydroxy-2-methylsulfanylpyrimidine 10 may be prepared as described
in J. Med. Chem. , 27, 12, 1621-1629 (1984). The chloro
groups of intermediate 11 may be displaced sequentially
with aminopyrazole (or aminoindazole) 2 and then with
another amine (or alcohol or thiol) following procedures
similar to those reported in US Patent 2585906 (ICI,
1949) . The methylsulfanyl group of 13 may then be
oxidized to provide the methylsulfone 14. Displacement
of the methylsulfonyl group of 14 gives the desired
product II.


Scheme V above shows general routes for the
preparation of compounds of formulae IVa, IVb, IVc, and
IVd. Steps (a) and (b) are analogous to the
corresponding steps described in Scheme I above. See
Indian J. Chem. Sect. B, 34, 9, 1995, 778-790; J. Chem.
Soc, 1947, 899-905; J. Chem. Soc. , 34, 9, 1948, 777-782;
and Indian J. Chem., 1967, 467-470.
The synthetic transformations shown in Schemes
I-IV above are further illustrated by the following
methods.


Scheme VI above shows a general route for
preparing the aryl guanidine intermediate used to prepare
compounds where Q is-C(R6')2-. The mono-or bis-alkylation of 19 at step (a) to prepare compound 20 can
be achieved by using methods substantially similar to
those described by Jeffery, J. E., et al, J. Chem Soc,
Perkin Trans 1, 1996 (21) 2583-2589; Gnecco, D., et al,
Org Prep Proced Int, 1996, 28 (4), 478-480; Fedorynski,
M. and Jonczyk, A., Org Prep Proced Int, 1995, 27 (3),
355-359; Suzuki, S, et al, Can J Chem, 1994, 71 (2) 357-361; and Prasad, G., et al, J Org Chem, 1991, (25), 7188-7190. The method of step (b) to prepare compound 21 from
compound 2 0 can be achieved by using methods
substantially similar to those described by Moss, R. , et
al, Tetrahedron Lett, 1995, (48), 8761-8764 and
Garigipati, R., Tetrahedron Lett, 1990, (14), 1969-1972.
The aryl guanidine intermediates prepared
according to Scheme VI may then be used to prepare the
compounds of this invention by the methods described .in
the above Schemes I-V and by methods known to one skilled
in the art.

Scheme VII above shows a general method that
may be used to prepare compounds of formula II wherein Q

is 1,2-cyclopropanediyl. Compound 26 may then be used to
prepare the desired amino-pyrazole compounds using the
methods described above at Scheme I step (b).
Method A. To a solution of 2,4-dichloroquinazoline (12.69g, 63mmol) and 3-amino-5-methylpyrazole (6.l8g, 63mmol) in ethanol (220mL) is
added triethylamine (8.l3mL, 63mmol) and the reaction
mixture is stirred for 3 hours at room temperature. The
pale yellow precipitate is then collected by filtration,
washed with cold ethanol and dried under vacuum to give
(2-chloroguinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared (2-chloroquinazolin-4-yl)-(5-methyl-2iI-pyrazol-3-yl)-amine (155 mg, 0.6 mmol) and
3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed in
tert-butanol (3 mL) over 20 h. The mixture is
concentrated in vacuo and the residue is suspended in
EtOH/H2O (lmL/3mL) . K2CO3 (83 mg, 0.6 mmol) is added and
the suspension is stirred for 2h at room temperature.
The solid that forms is collected and dried under vacuum
to give the product [2-(3-chlorophenylamino)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method B. Sodium hydride (45 mg, 1.12 mmol) in
THF (2 mL) is treated with 3-methoxyphenol (0.94g, 7.6
mmol) and the reaction mixture is stirred until
effervescence ceases. The THF is removed in vacuo and
the above-prepared (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (150 mg, 0.51 mmol)) is added.'
The reaction mixture is stirred at 10 0°C for 2 0 h, then
poured into aqueous K2CO3 and stirred for 2h at room
temperature. The solid that forms is collected and re-crystallized from ethanol to give the product [2-(3-

methoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method C. To a solution of 4-hydroxy-2-phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus
oxychloride (10mL) is added tripropylamine (3.02 mL, 15.8
mmol) and the reaction mixture is heated for 3 0 minutes
at 110°C. The excess phosphorus oxychloride is
evaporated in vacuo, the residue is poured on ice cold
aqueous NaHCO3 and extracted with ethyl acetate. The
organic layer is washed with brine, dried, filtered and
evaporated. The resulting residue is purified on flash
chromatography (SiO2, hexane /AcOEt gradient) to give 4-chloro-2-phenoxymethylquinazoline.
To a solution of the above 4-chloro-2-phenoxymethylquinazoline (0.5 g, 1.8 5 mmol) in THF (3 0
mL) is added 3-amino-5-cyclopropylpyrazole (0.47 g, 3.69
mmol) and the reaction mixture is heated at 65°C for 24
hours. Solvent is evaporated and ethanol is added. A
white solid forms and is collected by filtration and
dried under vacuum to give (5-cCyclopropyl-2H-pyrazol-3-yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine.
Method D. To a solution of the above-prepared
(2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (123 mg, 0.43 mmol) in THF (5 mL) is added
NiCl2(dppp) (12 mg, 2.1.10-5 mol) , followed by 1M
benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol).
The solution is heated at 50°C for 2 0 hours and the
reaction mixture is then quenched with aqueous NH4Cl and
the product extracted in ethyl acetate. The solvent is
evaporated and the residue purified by flash
chromatography to yield the desired (2-benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

Method E. A solution of (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (200 mg, 0.77 mmol)
and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed
in tert-butanol (3 mL) over a 20 hour period.
Diethylether (10 mL) is added to the mixture and a solid
forms that is collected by filtration. This solid is
suspended in EtOH/H2O lmL/3mL), then K2CO3 (110 mg, 0.8
mmol) is added and the suspension is stirred for 2h at
room temperature. A solid forms and is collected and
dried under vacuum to give the product [2-(4-acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method F. To a solution of 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500 mg, 2.4 6 mmol) and 3-amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF
(10mL) is added triethylamine (0.357 mL, 2.5 6 mmol)
followed by sodium iodide (368 mg, 2.46 mmol) and the
reaction mixture is heated at 90 °C for 2 0 h. The
reaction mixture is partitioned between ethyl acetate and
aqueous saturated NaHCO3. The organic layer is washed
with brine and evaporated in vacuo. The residue is
purified by flash chromatography (SiO2, hexane/AcOEt
gradient) to give (2-chloro-5,6, 7, 8-tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
The above-prepared (2-chloro-5 , 6 , 7, 8-tetrahydroguinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine is reacted with 2-naphthalene mercaptan as
described in Method L to yield the desired (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine.
Method G. A solution of (5-cyclopropyl-2H-pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl)-guinazolin-4-yl]-amine (110 mg, 0.26 mmol) in a mixture

of THF/water (1/1, 10 mL) is treated with 1M LiOH (0.75
mL, 0.75 mmol). The mixture is stirred for 20 hours at
room temperature and then neutralized with 1M HC1 (0.75
mL, 0.75 mmol) . A solid forms and is collected by-filtration to afford the desired [2-(3-
carboxyphenylsulfanyl)-guinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.
Method H. A solution of [2-(4-acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10"5 mol) in
dichloroethane (3 mL) is treated with 1M BBr3 in
dichloromethane (222 J1L, 2.21.10"4 mol). The mixture os
heated at 80 °C for 4 hours before 1M BBr3 in DCM (222 |1L,
2.21.10"* mol) is added. The reaction mixture is heated
at 80 °C for a further 3 hours. The solvent is evaporated
and methanol is added to the residue to quench residual
BBr3. The solvent is evaporated in vacuo and this
operation repeated 3 times. 1M HC1(2 mL) is added to the
solid residue and the suspension stirred at room
temperature for 15 hours. The solid is collected by
filtration and suspended in a mixture water/EtOH (3/1, 8
mL) . The mixture is neutralized with NaHCO3 and stirred
for 2 hours at room temperature. The solid is then
collected by filtration, rinsed with water and diethyl
ether to give the desired [2-(4-acetamidophenylsulfanyl)-7-hydroxy-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method I. To a solution of [2-(4-acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (32 mg, 7.87.10-5 mol) in
DMF (1 mL) is added potassium carbonate (65 mg, 4.72.10-4
mol) and the reaction mixture is heated to 8 0 °C. N-(3-

chloropropyl)morpholine (39 mg, 2.3 6.10-4 mol) is then
added, and the mixture is stirred at 80 °C for 4 hours,
cooled to room temperature and the solvent is evaporated.
The resulting residue is purified by flash chromatography
to afford the desired [2-(4-acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-propoxy)-guinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method J. To a solution of [2-(4-acetamido-
phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (147 mg, 3.38.10-4 mol) in methanol (5
mL) is added Pd/C 10% (40 mg) and the reaction mixture is
treated with hydrogen at balloon pressure at 45 °C for 20
hours. The catalyst is filtered through a pad of celite
which is then washed with dilute HC1. The combined
yellow filtrate is evaporated and the resulting solid
residue is crystallized from methanol to afford the
desired [2-(4-acetamido-phenylsulf anyl)-7-hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method K. [2-(4-Acetamido-phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine
(182 mg, 4.18.10-4 mol) is dissolved in a mixture
EtOH/water/AcOH (25/10/1, 36 mL) and the reaction is
heated at 90 °C. Iron powder (93 mg) is added and the
mixture is stirred at 90 °C for 4 hours, cooled to room
temperature and filtered through a pad of celite. The
pad is washed with methanol and the combined filtrate is
concentrated in vacuo. The residue is purified by flash
chromatography (SiO2, DCM/MeOH gradient) to give the
desired [2-(4-acetamido-phenylsulfanyl)-7-aminoguinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method L. To a solution of 2,4-dichloro-6-phenyl-pyrimidine (3 00 mg, 1.33 mmol) and 3-amino-5-methylpyrazole (129 mg, 1.33 mmol) in DMF (7 mL) is added
triethylamine (195 µL, 1.40 mmol) followed by sodium
iodide (200 mg, 1.33 mmol) and the reaction mixture is
stirred for 15 hours at 90 °C. The resulting solution is
partitioned between ethyl acetate and water and the
organic phase washed with brine, dried over MgS04 then
concentrated in vacuo. The residue is triturated in
methanol and the resulting white solid collected by
filtration to afford (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (236 mg, 62%).
The above prepared (2-chloro-6-phenyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60 mg,
0.21 mmol) is combined with 4-acetamidothiophenol (176
mg, 1.05 mmol) in tert-butanol (5 mL) and the mixture
heated at reflux for 20 hours. The reaction mixture is
cooled to room temperature and partitioned between ethyl
acetate and aqueous NaHCO3. The organic layer is washed
with brine, dried over MgSO4 and concentrated in vacuo.
The resulting residue is purified by flash chromatography
(SiO2, DCM/MeOH gradient) to afford [2-(4-acetamido-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (74 mg, 85%)
Method M. To a suspension of 4,6-dihydroxymercaptopyrimidine (8 g, 55 mmol) in a mixture
of EtOH/water (1/1, 140 mL) is added NaOH (2.33 g, 58.3
mmol) followed by 4-methoxybenzyl chloride (7.90 mL, 58.3
mmol). The solution is stirred for 1.5 hours at 60 °C
and then at room temperature for a further 6 hours. The
resulting white precipitate is collected by filtration to
give 4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine.

The above-prepared 4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl)-pyrimidine (2.5 g, 9.46 mmol) is
suspended in POCl3 (20 mL) , and tripropylamine (3.60 mL,
18.9 mmol) is added dropwise to the mixture. T he
reaction is then heated at 110 °C for 4 hours. The brown
solution is cooled to room temperature and the solvent is
evaporated. The residue is poured on ice cold NaHC03 and
the product is then extracted with ethyl acetate. The
organic phase is dried over MgSO4, concentrated in vacuo
and the residue is purified by flash chromatography (SiO2,
hexane/AcOEt gradient) to give 4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine.
To a solution of above-prepared 4,6-dichloro-2-(4-methoxy-benzylsulfanyl)-pyrimidine (915 mg, 3.04 mmol)
and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH
(20 mL) is added diisopropylethylamine (0.56 mL, 3.19
mmol) followed by sodium iodide (455 mg, 3.04 mmol). The
reaction mixture is stirred for 15 hours at 12 0 °C. The
solvent is removed in vacuo and the residue is purified
by flash chromatography (SiO2, hexane/AcOEt gardient) to
give [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10
mL) is heated at 130 °C for 15 hours. The solvent is
then removed in vacuo and the residue is purified by
flash chromatography (SiO2, dichloromethane/MeOH gradient)
to give the desired product [2-(4-methoxy-benzylsulfanyl)-6-(4-methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method N. A solution of [2-(4-acetamido-phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-

methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10-4 mol) in
dichloroethane (5 mL) is treated with 1M BBr3 in DCM (896
µL, 8.96.10-4 mol) . The mixture is then heated at 8 0 °C
for 4 hours before 1M BBr3 in DCM (896 µL, 8.96.10-4 mol)
is added. The reaction mixture is then heated at 80 °C
for a further 3 hours. The solvent is evaporated and
methanol is added to the residue to quench any residual
BBr3. The solvent is evaporated in vacuo and this
evaporation step is repeated 3 times. 1M HCl(8mL) is
added to the solid residue and the suspension is stirred
at room temperature for 15 hours. The solid is collected
by filtration and suspended in a mixture of water/EtOH
(3/1, 24 mL). The mixture is neutralized with NaHCO3 and
stirred for 2 hours at room temperature. The solid is
then collected by filtration, rinsed with water and with
diethyl ether to give [2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
To a solution of the above-prepared [2-(4-acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (70 mg, 1.62.10-4
mol) in DMF (3 mL) is added potassium carbonate (134 mg,
9.71.10-4 mol). The reaction mixture is heated to 80°C
before l-dimethylamino-3-chloropropane hydrochloride (77
mg, 4.86.10-4 mol) is added. The mixture is stirred at
80°C for 4 hours, cooled to room temperature and the
solvent is evaporated. The residue is purified by flash
chromatography to afford the desired product {2-(4-acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino-propoxy)-phenyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine.
Method O. To a solution of [6-methoxycarbonyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-

methyl-2H-pyrazol-3-yl)-amine (2g, 4.85 mmol) in THF (100
mL) is added lithium borohydride (0.32 g, 14.5 mmol).
The reaction mixture is stirred at 5 0°C for 1.5 hours.
The reaction is then quenched with dilute HC1 and
extracted with ethyl acetate. The organic layer is
successively washed with aqueous saturated NaHCO3 and
brine, dried over MgSO4 and evaporated. The solid residue
is triturated in ethyl acetate and the resulting white
solid is collected by filtration to give the desired
product [6-hydroxymethyl-2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
Method P. To a solution of 4, 6-dichloro-2-methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5-methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is
added diisopropylethylamine (4.69 mL, 26.9 mmol) followed
by sodium iodide (3.84 g, 25.6 mmol). The reaction
mixture is stirred for 15 hours at 12 0 °C. The solvent
is then removed in vacuo and the residue is purified by
"flash chromatography (SiO2, hexane/AcOEt gradient) to give
[6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (2.42 g,
9.4 6 mmol) is heated in morpholine (10 mL) at 13 0 °C for
15 hours. The solvent is then removed in vacuo and the
solid residue is triturated in EtOH and collected by
filtration to give [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
To a suspension of the above-prepared [2-methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.63 mmol) in MeOH
(10 mL) is added a solution of oxone (3.0 g) in water (10

mL). The reaction mixture is stirred at room temperature
for 15 hours and most of the solvent is evaporated. The
residue is partitioned between DCM and aqueous saturated
NaHCO3-The organic layer is washed with brine, dried,
filtered and evaporated. The residue is triturated in
MeOH and the resulting white solid is collected by
filtration to give [2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
The above-prepared [2-methylsulfonyl-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (178 mg, 0.52 mmol) and 4-acetamidothiophenol
(176 mg, 1.05 mmol) are refluxed in tert-butanol (5 mL)
over 20 h. The reaction mixture is cooled to room
temperature and partitioned between ethyl acetate and
aqueous NaHCO3. The organic layer is washed with brine,
dried over MgSO4 and concentrated in vacuo. The residue
is purified by flash chromatography to give the desired
product [2-(4-acetamidophenylsulfanyl)-6-(morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.
In order that the invention described herein
may be more fully understood, the following examples are
set forth. It should be understood that these examples
are for illustrative purposes only and are not to be
construed as limiting this invention in any manner.
SYNTHETIC EXAMPLES
The following HPLC methods were used in the
analysis of the compounds as specified in the Synthetic
Examples set forth below. As used herein, the term "Rt"
refers to the retention time observed for the compound
using the HPLC method specified.

HPLC-Method A:
Column: CI8, 3 µm, 2.1 X 50 mm, "Lighting" by Jones
Chromatography.
Gradient: 100% water (containing 1% acetonitrile,
0.1% TFA) to 100% acetonitrile (containing 0.1% TFA)
over 4.0 min, hold at 100% acetonitrile for 1.4 min
and return to initial conditions. Total run time 7.0
min. Flow rate: 0.8 mL/min.
HPLC-Method B:
Column: C18, 5 µm, 4.6 X 150 mm "Dynamax" by Rainin
Gradient: 100% water (containing 1% acetonitrile,
0.1% TFA) to 100% acetonitrile (containing 0.1% TFA)
over 20 min, hold at 100% acetonitrile for 7.0 min
and return to initial conditions. Total run time
31.5 min. Flow rate: 1.0 mL/min.
HPLC-Method C:
Column: Cyano, 5 µm, 4.6 X 150 mm "Microsorb" by
Varian.
Gradient: 99% water (0.1% TFA), 1% acetonitrile
(containing 0.1% TFA) to 50% water (0.1% TFA), 50%
acetonitrile (containing 0.1% TFA) over 20 min, hold
for 8.0 min and return to initial conditions. Total
run time 30 min. Flow rate: 1.0 mL/min.
HPLC-Method D:
Column: Waters (YMC)' ODS-AQ 2.0x50mm, S5, 120A.
Gradient: 90% water (0.2% Formic acid),, 10%
acetonitrile (containing 0.1% Formic acid) to 10%
water (0.1% formic acid), 90% acetonitrile
(containing 0.1% formic acid) over 5.0 min, hold for

0.8 min and return to initial conditions. Total run
time 7.0 min.
Flow rate: 1.0 mL/min.
HPLC-Method E:
Column: 50x2.0mm Hypersil C18 BDS;5 µm
Gradient: elution 100% water (0.1% TFA), to 5% water
(0.1% TFA), 95% acetonitrile (containing 0.1% TFA)
over 2.1 min, returning to initial conditions after
2.3 min.
Flow rate: 1 mL/min.
Example 1 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-,
quinazolin-4-yl)-amine (IIa-1): Prepared in a manner
similar to the above described Method E to afford a pale
yellow solid, mp >300°C (dec); 1H NMR (DMSO) δ 2.07(3H,
s) , 5.54(1H, s) , 7.38(1H, m) , 7.56-7.45(4H, m) , 7.65(2H,
m) , 7.73 (1H, m) , 8.55(1H, d) , 10.43(1H, s) , 12.05(1H, br
s) ; IR (solid) 3259, 3170, 3109, 1618, 1594, 1565, 1525,
1476; MS 334.0 (M+H)+
Example 2 [2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-2) : Prepared in a
manner similar to the above described Method E to afford
a pale yellow solid, mp 259-260°C; 1H NMR (DMSO) δ 2 .12
(3H, s) , 5.40 (1H, s) , 7.60 (1H, t) , 7.64 (2H, d) , 7.76
(3H, d), 7.92 (1H, t), 8.70.(1H, d) 11.50 (1H, br s); IR
(solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339,
1286, 1219; MS 368.0 (M+H)+
Example 3 [2-(2, 4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-3): Prepared in

a manner similar to the above described
afford a pale yellow solid, mp 258-259°C;
2.12 (3H, S) , 5.40 (1H, s) , 7.54 (1H, t),
7.68 (1H, d), 7.86 (1H, t), 7.92 (1H, d),
8.66 (1H, d) 11.20 (1H, br s) ; IR (solid)
1551, 1488, 1435, 1410, 1339, 1284, 1217;
Example 4 [2-(4-Methoxyphenylsulfanyl)-q
(5-methyl-2H-pyrazol-3-yl)-amine (IIa-4) :
manner similar to the above described Met
a pale yellow solid, mp 264-268°C; 1H NMR
(3H, s) , 3.85 (3H, s) , 5.43 (1H, s) , 7.11
(1H, t) , 7.61 (3H, d) , 7.84 (3H, t) , 8.63
(1H, br s), 12.30 (1H, br s); IR (solid)
1552, 1492, 1404, 1340, 1292, 1249, 1219,
3 64.1 (M+H)+
Example 5 [2-(2-Ethylphenylsulfanyl)-qui
methyl-2H-pyrazol-3-yl)-amine (IIa-5): P:
manner similar to the above described Me1
a pale yellow solid, mp 205-208°C; 1H NMF
(3H, s), 5.19 (1H, s) , 7.38 (1H, t) , 7.5:
7.68 (2H, d) , 7.90 (1H, t) , 8.68 (1H, d)
3262, 2967, 1632, 1605, 1558, 1492, 1434
1294, 1224, 1162; MS 362.1 (M+H)+
Example 6 {2-[2 , 4-Bis (trifluoromethyl) ph
quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-;
(IIa-6): Prepared in a manner similar to
described Method E to afford a pale yell
>300°C; 1H NMR (DMSO) δ 1.98 (3H, s) , 5.
(1H, t) , 7.59 (2H, d), 7.84 (1H, d) , 8.3

(2H, s), 8.66 (1H, d), 10.73 (1H, br E
1628, 1603, 1577, 1548, 1512, 1493, 144
1275, 1196, 1124; MS 470.1 (M+H) +
Example 7 02-(2-Chlorophenylsulfanyl)-q
(5-methyl-2H-pyrazol-3-yl)-amine (IIa-7
manner similar to the above described M
a pale yellow solid, mp 262-263°C; 1H NI
(3H, s) , 5.35 (1H, s) , 7.52 (2H, t) , 7.
(1H, d) , 7.83 (1H, t) , 7.88 (1H, d), 8.
(1H, br s); IR (solid) 1621, 1603, 1569
1448, 1400, 1376, 1336, 1288, 1208; MS :
Example 8 [2-(2,3-Dichlorophenylsulfany
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (I:
a manner similar to the above described
afford a pale yellow solid, mp >3 00°C;
2.05 (3H, s), 5.34 (1H, s), 7.50 (2H, m)
7.75 (1H, t), 7.88 (2H, m), 8.62 (1H, d)
s) ; IR (solid) 1632, 1609, 1561, 1532, 1
1380, 1345, 1298, 1228, 1162, 1125; MS 4
Example 9 [2-(3-Chlorophenylsulfanyl)-qu
(5-methyl-2H-pyrazol-3-yl)-amine (IIa-9)
manner similar to the above described Me
a pale yellow solid, mp 248-249°C; 1H NM
(3H, s) , 5.42 (1H, s) , 7.55 (2H, m), 7.6
(1H, 9), 7.85 (1H, t) , 8.62 (1H, d), 11.
(solid) 1628, 1611, 1551, 1487, 1432, 14
1217, 1165; MS 368.0 (M+H)+

Example 10 [2-(l-Methylimidazol-2-ylsulf
4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (
in a manner similar to the above describ
afford an off white solid, mp 255-256°C;
2.19 (3H, S), 3.59 (1H, s), 5.51 (1H, s)
7.45 (1H, t) , 7.57 (1H, s) , 7.59 (1H, d)
8.57 (1H, d) , 10.57 (1H, s) , 12.13 (1H,
1628, 1565, 1550, 1532, 1492, 1430, 1376
1278, 1211; MS 338.2 (M+H)+
Example 11 [2-(2-Hydroxyphenylsulfanyl)-(5-methyl-2H-pyrazol-3-yl)-amine(IIa-11
manner similar to the above described Me-a pale yellow solid, mp 273-275°C; 1H NMI
(3H, s), 5.41 (1H, s), 6.99 (1H, t) , 7.0
(1H, t) , 7.57-7.62 (2H, m) , 7.73 (1H, d)
8.71 (1H, d) , 10.29 (1H, br s), 11.66 (13
(solid) 1623, 1597, 1552, 1485, 1442, 14
1289, 1221, 1165; MS 350.1 (M+H)+
Example 12 [2-(2, 4-Difluorophenylsulfany
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (II
in a manner similar to the above describe
afford a pale yellow solid, mp 256-258°C,
2.10 (3H, s), 5.41 (1H, S), 7.33 (1H, t),
m) , 7.65 (1H, d), 7.82-7.91 (2H, m), 8.6:
(1H, br s); IR (solid) 1626, 1608, 1556,
1341, 1288, 1270, 1219, 162, 1140; MS 3.
Example 13 [2-(3, 4-Dimethoxyphenylsulfany
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa
in a manner similar to the above describe
afford a pale yellow solid, mp 229-232°C.

2.05 (3H, s), 3.70 (3H, s), 3.85 (3H, s
6.9.5 (1H, d) , 7.30 (2H, d) , 7.60.(1H, t
7.94 (1H, t), 8.72 (1H, d), 11.56 (1H,
1625, 1607, 1551, 1503, 1436, 1404, 134!
1237, 1218, 1161, 11377 MS 394.1 (M+H)+
Example 14 [2-(3-Methylphenylsulfanyl)-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-1
manner similar to the above described M
a pale yellow solid, mp 249-250°C; 1H N
(3H, s) , 2.36 (3H, s) , 5.31 (1H, s), 7.
7.58 (3H, m), 7.61 (1H, d), 7.88 (1H, t
11.66 (1H, br s); IR (solid) 1617, 1587.
14414, 1387, 1341, 1283, 1221, 1162, 11
Example 15 [2-(2-Methoxyphenylsulfanyl)
(5-methyl-2H-pyrazol-3-yl)-amine (IIa-1
manner similar to the above described Me
a pale yellow solid, mp 237-239°C; 1H NM
(3H, B) , 3.71 (3H, s) , 5.35 (1H, s) , 7.
(1H, d), 7.55 (1H, t), 7.60-7.67 (3H, m)
8.66 (1H, d), 11.20 (1H, br s); IR (sol:
1561, 1480, 1430, 1405, 1344, 1292, 1276
364.1 (M+H)+
Example 16 [2-(2-Naphthalenylsulfanyl)-c
(5-methyl-2H-pyrazol-3-yl)-amine(IIa-16
manner similar to the above described Me
a pale yellow solid, mp 267-270°C; 1H NM
(3H, s), 5.09 (1H, s), 7.57 (1H, t), 7.6
7.90 (1H, t), 8.07 (3H, t), 8.40 (1H, s)

11.28 (1H, br s); IR (solid) 1624, 1606,
1435, 1407, 1341, 1285, 1216, 1158; MS 38
Example 17 [2-(2, 6-Dichlorophenylsulfanyl
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa
in a manner similar to the above describe
afford a pale brown solid, mp >300°C; 1H
(3H, S), 5.49 (1H, s), 7.49 (1H, t), 7.59
7.76 (2H, d) , 7.81 (1H, d) , 8.60 (1H, d) ,
IR (solid) 1618, 1599, 1565, 1533, 1486,
1361, 1344, 1285, 1246, 1216, 1188, 1172;
Example 18 [2-(3,4-Dichlorophenylsulfanyl
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa
in a manner similar to the above describe
afford a pale yellow solid, mp 268-272°C;
2.11 (3H, s), 5.47 (1H, s), 7.56 (1H, t),
m) , 7.83 (2H, d) , 7.88 (1H, t) , 8.05 (1H,
d); IR (solid) 1628, 1607, 1556, 1488, 14
1367, 1341, 1288, 1216, 1166; MS 402.0
Example 19 [2-(Benzimidazol-2-ylsulfanyl)
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa
in a manner similar to the above describe
afford a pale grey solid, mp 192-196°C; 1
1.60 (3H, s) , 5.48 (1H, s) , 7.44 (2H, m),
7.69 (2H, d), 7.76 (2H, m), 7.85 (1H, t),
10.79 (1H,S); IR (solid) 1618, 1606, 156
1411, 1395, 1369, 1343, 1288, 1273, 1170;
Example 20 [2-(2-Aminophenylsulfanyl)-qui
(5-methyl-2H-pyrazol-3-yl)-amine (IIa-20)

manner similar to the above described M
a bright yellow solid, mp 257-259°C; 1H
2.30 (3H, 2xbr s), 6.10 (1H, br s), 7.1
8.60 (1H, br s), 9.80 (1H, br s), 10.
(solid) 1623, 1591, 1567, 1538, 1496, 1
Example 21 (5-Cyclopropyl-2H-pyrazol-3-;
phenylsulfanyl-quinazolin-4-yl)-amine (
in a manner similar to the above describ
afford a yellow solid, mp 233-236°C; 1H
(2H, d) , 0.98 (2H, d) , 1.67 (1H, m) , 5.
7.73 (7H, m), 7.89 (1H, t) , 8.68 (1H, d)
s); IR (solid) 1629, 1606, 1577, 1546, 3
1413, 1370, 1291, 1219; MS 360.3 (M+H)+
Example 22 (5-Cyclopropyl-2H-pyrazol-3-y
methoxycaxbonylphenylsulfanyl)-quinazoli
(IIa-22): Prepared in a manner similar t
described Method E to afford a white sol
1H NMR (DMSO) δ 0.52 (2H, m) , 0.86 (2H, t
3.86 (3H, s), 5.60 (1H, s), 7.45 (1H, t)
7.66 (1H, t), 7.76 (1H, t) , 7.93 (1H, d)
8.18 (1H, s), 8.57 (1H, d), 10.48 (1H, b
br s); IR (solid) 1724, 1617, 1593, 1567
1432, 1400, 1361, 1343, 1283, 1260, 1218
418.3 (M+H)+
Example 23 (5-Cyclopropyl-2H-pyrazol-3-yl
methylphenylsulfanyl)-guinazolin-4-yl]-an
Prepared in a manner similar to the above
Method E to afford a white solid, mp 241-(DMSO) δ 0.55-0.63 (2H, m), 1.87-1.97 (1H

(1H, m), 2.35 (3H, s), 5.72 (1H, s), 7.3C
7.68-7.78 (1H,m), 8.50-8,60 (1H, d), 10.2
(1H, S); IR (solid) 1617, 1594, 1568, 152
1344, 1287, 1176, 758, 665,656; MS (M+H)+
Example 24 (5-Cyclopropyl-2H-pyrazol-3-yl
methoxyphenylsulfanyl)-quinazolin-4-yl]-a
Prepared in a manner similar to the above
Method E to afford a white solid, mp 232
(DMSO) δ 0.55-0,62 (2H, m) , 0.88-0.97 (2E
(1H, m), 3.79 (3H, s), 5.79 (1H, s), 7.08
7.29 (2H, m) , 7.40-7.50 (2H, m) , 7.60 (II
t), 8.57 (1H, d), 10.40 (1H, s), 12.04
(solid) 3100, 1618, 1592, 1567, 1527, 14
1284, 1246, 1231, 1171, 1041, 1.001, 969,
667; MS (M+H)+
Example 25 (5-Cyclopropyl-2H-pyrazol-3-y]
dimethoxyphenylsulfanyl)-quinazolin-4-yl]
Prepared in a manner similar to the above
Method E to afford a white solid, mp 250-
(DMSO) δ 5 0.54-0.60 (2H, m) , 0.83-0.91 (2E
(1H, m) , 3.79 (3H, s) , 3.85 (3H, s) , 5.7E
(1H, d), 7.20-7.26 (2H, m), 7.45 (1H, t),
7.77 (1H, t), 8.55 (1H, d), 10.45 (1H, s)
IR (solid) 1617, 1593, 1567, 1530, 1504,
1439, 1398, 1364, 1347, 1288, 1269, 1250,
1169, 1138, 1037, 1020, 997, 972, 882, 84
75 0; MS (M+H) +
Example 26 [2-(3-Carboxyphenylsulfanyl)-c
(5-cyclopropyl-2H-pyrazol-3-yl)-amine(II
from IIa-22 according to Method G to affc

solid, mp >300°C; 1H NMR (DMSO) δ 0.53
d) , 1.65 (1H, m), 5.37 (1H, s), 7.55 (1
t) , 7.81 (1H, d), 7.88 (1H, t) , 7.95 (1
d) , 8.15 (1H, s), 8.71 (1H, d), 11.32 (
(solid) 1702, 1626/ 1609, 1559, 1490, 1
1222, 1170; MS 4 04.7(M+H)+
Example 27 (5-Cyclopropyl-2H-pyrazol-3-2-ylsulfanyl)-quinazolin-4-yl]-amine (r
in a manner similar to the above descri
afford an off-white solid, mp 285-288°C
0.25 (2H, br s), 0.52 (2H, br s), 0.87
br s), 7.42-7.77 (4H, m), 8.00 (3H, m
s) , 8.56 (1H, br d), 10.42 and 11.88 (11
(solid) 1615, 1592, 1562, 1527, 1476, 1
1240, 1216, 1167, 1158, 1142, 1128, 996,
410.7(M+H)+
Example 2 8 (5-Cyclopropyl-2H-pyrazol-3-y
difluorophenylsulfanyl)-quinazolin-4-yl]
Prepared in a manner similar to the abov
Method E to afford an off-white solid,
NMR (DMSO) δ 0.61 (2H, m) , 0.91 (2H, m) ,
5.67 (1H, m), 7.24-7.28 (1H, m), 7.44-7.
7.81 (2H, brm), 8.55 (1H, m), 10.47 and
s)/ IR (solid) 1614, 1598, 1565, 1525, 1
1366, 1345, 1285, 1267, 1243, 1213, 1168
1026,. 995, 968; MS 396 . 6 (M+H)+
Example 29 (5-Cyclopropyl-2H-pyrazoal-3-yl
(naphthalen-2-ylsulfanyl)-5,6,7, 8-tetrahy
yl]-amine (IIa-29) : Prepared in a manner

above described Method F to afford a w
244°C; 1H NMR (DMSO) δ 0.13 (2H,s), 0.4
s) , 1.73 (4H, s) , 2.42 (2H, s) , 2.58 (
s) , 7.58 (2H, d) , 7.61 (2H, d), 7.97 (
s) , 8.56 (1H, s) , 11.63 (1H, s) ; IR (s
1514, 1477, 1423, 1333, 1279, 1251, 99
651; MS 414.7(M+H)+
Example 3 0 (5-Cyclopropyl-2H'-pyrazol-3
dichlorophenylsulfanyl)-quinazolin-4-yl
Prepared in a manner similar to the abc
Method E to afford an off-white solid,
NMR (DMSO) δ 0.60 (2H, d) , 0.93 (2H, d)
5.54 (1H, S), 7.47 (2H, m), 7.57 (1H, C
7.86 (2H, d), 8.57 (1H, d), 10.48 (1H,
IR (solid) 1616, 1601, 1570, 1528, 1486
1367, 1335, 1285, 1246, 1210, 1159, 114
1021, 997; MS 428.6(M+H)+
Example 31 [2-(3-Chlorophenylsulfanyl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (
in a manner similar to the above descri
afford an off-white solid, mp 235-238°C
0.58 (2H, d), 0.92 (2H, d), 1.75 (1H, m
7.44 (1H, t), 7.50-7.63 (4H, m), 7.73
(1H, t), 8.57 (1H, d) , 10.46 (1H, s), 1
(solid) 1616, 1593, 1562, 1528, 1479, 1-1343, 1286, 1244, 1216, 1176, 1067, 105
394.7 (M+H)+
Example 32 [2-(2-Chlorophanylsulfanyl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (1

in a manner similar to the above descr
afford an off-white solid, mp 255-257°
0.59 (2H, d) , 0.91 (2H, d), 1.71 (1H,
7.45 (2H, m) , 7.57 (1H, m), 7.69 (1H,
7.85 (1H, d), 8.56 (1H, d), 10.43 (1H,
IR (solid) 1619, 1596, 1564, 1529, 148
1370, 1343, 1289, 1246, 1218, 1165, 11
1030, 997; MS 394.7(M+H)+
Example 3 3 (5-Cyclopropyl-2H-pyrazol-3
dimethylphenylsulfanyl)-quinazolin-4-y
Prepared in a manner similar to the ab
Method E to afford an off-white solid,
NMR (DMSO) δ 0.56 (2H, m), 0.90 (2H, m
2.26 and 2.29 (6H, 2 x s) , 5.75 (1H, b
7.35-7.55 (4H, m), 7.74 (1H, m), 8.54
and 12.06 (2H, 2 x br s) ; IR (solid) 1
1526, 1479, 1459, 1404, 1366, 1343, 12;
1167, 1145, 1017, 996, 966; MS 388.3 (M
Example 34 [2-(Benzimidazol-2-ylsulfany
yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-am:
Prepared in a manner similar to the abc
Method E to afford an off-white solid,
NMR (DMSO) δ 0.44 (2H, m) , 0.71 (2H, m)
5.72 (1H, m), 7.23 (2H, m) , 7.51-7.81
m), 10.59, 12.06 and 13.17 (3H, 3 x br
1617, 1601, 1572, 1532, 1485, 1402, 137
1273, 1209, 1168, 1024, 1010, 965; MS 4
Example. 3 5 (5-Cyclopropyl-2H-pyrazol-3-methoxycarbonylphenylsulfanyl)-quinazol

(IIa-35): Prepared in a manner similar
described Method E to afford an off-wh
246°C; 1H NMR (DMSO) δ 0.47 (2H, br s) ,
1.62 (1H, m), 3.85 (3H, s), 5.69 (1H,]
m) , 7.58 (1H, m) , 7.76-7.81 (3H, m) , 8
8.57 (1H, m), 10.48 and 12.11 (2H, 2 x
1721, 1712, 1616, 1596, 1572, 1564, 15:
1404, 1360, 1346, 1277, 1181, 1114, 11
418.2(M+H)+
Example 3 6 [2-(4-Acetamido-phenylsulfar
yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-ami
Prepared in a manner similar to the abc
Method E to afford an off-white solid,
NMR (DMSO) 6 0.57 (2H, m), 0.83 (2H, m)
2.02 (3H, s), 5.73 (1H, br s), 7.41 (1H
(3H, m) , 7.73-7.75 (3H, m) , 8.54 (1H, m
and 11.98 (3H, 3 x br s) ; IR (solid) 16
1586, 1572, 1564, 1529, 1482, 1387, 134
1243, 1221, 1162, 1005, 968; MS 417.2 (M
Example 37 (5-Cyclopropyl-2H-pyrazol-3-(naphthalen-1-ylsulfanyl)-quinazolin-4-37) : Prepared in a manner similar to th
Method E to afford an off-white solid,
NMR (DMSO) δ 0.46-0.47 (2H, m), 0.87-0.
(1H, m), 5.01 (1H, m), 7.42 (1H, m), 7.
7.64 (1H, m) , 7.75 (1H, m) , 7.98 (1H, m
8.17 (1H, m), 8.28 (1H, m), 8.50 (1H, m
s), 11.84 (IH, br s); IR (solid) 1615,
1483, 1401, 1362, 1343, 1285, 1242, 121
MS 410.2(M+H)+

Example 38 [2-(4-Acetamidophenylsulfan
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (
in a manner similar to the above descr
afford an white solid, mp 268-271°C; 1l
(3H, s) , 2.09 (3H, s) , 5.56 (1H, s) , 7
(3H, m) , 7.75 (3H, d) , 8.55 (1H, d) , 1
(1H, s) , 12.03 (1H, s) ; IR (solid) 166
1572, 1531, 1438, 1397, 1370, 1358, 13
1278, 1265, 1245, 1216, 1161, 1006, 96
Example 3 9 [2-(4-Methanesulfonylamino-1
quinazolin-4-yl]-(5-methyl-2H-pyrazol-
39) : Prepared in a manner similar to t1
Method E to afford an off-white solid,
NMR (DMSO) δ 2.15 (3H, s), 2.61 (3H, s
6.91 (2H, d), 7.22 (2H, d), 7.36 (1H,
7.69 (1H, S), 8.53 (1H, d), 10.31 (1H,
IR (solid) 1621, 1602, 1584, 1567, 1528
1287, 1253, 1207, 1179, 1102, 1091, 98
Example 4 0 [2-(4-Acetamidophenylsulfany
guinazolin-4-yl]-(5-methyl-2H-pyrazol-3
40): Prepared in a manner similar to th
Method E to afford a white solid, mp 29
(DMSO) 5 2.01 (3H, s) , 2.09 (3H, s) , 3.
(1H, s) , 6.96 (1H, s) , 6.99 (1H, d) , 7.
(2H, d) , 8.45 (1H, d) , 10.21 (1H, s) , 1
11.99 (1H, s); IR (solid) ; MS 421.2(M+
Example 41 [2-(4-Acetamidophenylsulfany
4-yl-propoxy)-quinazolin-4-yl]-(5-methy

yl)-amine (IIa-41) .-Prepared in a mann
above described Method E to afford a w]
264 °C; 1H NMR (DMSO) δ 1.94 (2H, quint.
2.09 (3H, s) , 2.38 (4H, s) , 2.45 (2H, t
4.11 (2H, t), 5.60 (1H,s), 7.24 (1H, c
7.57 (2H, d), 7.73 (2H, d), 8.07 (1H, c
10.24 (1H, s) , 12.02 (1H, br s); IR (sc
2954, 2918, 2845, 1663, 1609, 1586, 152
1332, 1268, 1254, 1159, 1136, 1114, 105
534.4(M+H)+
Example 42 [2-(4-Methoxycarbonylphenyls
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3
42): Prepared in a manner similar to th
Method E to afford an off-white solid,
NMR (DMSO) δ 1.95 (3H, s) , 3.89 (3H, s)
7.39 (1H, br s), 7.51 (1H, br s), 7.70
(2H, d), 8.04 (2H, d), 8.51 (1H, br s) ,
12.03 (1H, br s); IR (solid) 1718, 1618
1531, 1481, 1434, 1395, 1362, 1342, 128'
1156, 1116, 1018, 1003, 968 ; MS 392.2(1
Example 43 [2-(4-Carboxyphenylsulfanyl)
(5-methyl-2H-pyrazol-3-yl)-amine(IIa-43
manner similar to the above described Me
an off-white solid, mp 263-265°C; 1H NMR
(3H, S) , 5.50 (1H, s) , 7.46 (1H, t), 7.€
(3H, m) , 8.02 (2H, d) , 8.58 (1H, d) , 10.
(1H, br s); IR (solid) 1623, 1605, 1574,
1490, 1401, 1349, 1318, 1285, 1249, 1216
1088, 1018/ MS 378.2(M+H)+

Example 44 [2-(4-Acetamidophenyls
quinazolin-4-yl]-(5-methyl-2H-pyra
44): Prepared in a manner similar
Method E to afford an off-white sc
NMR (DMSO) 1.99 (3H, s), 2.10 (3H,
(1H, s), 7.31 (1H, d), 7.38 (1H, t
(2H, d), 8.11 (1H, d), 10.28 (1H,
12.11 (1H, br s); IR (solid) 3234,
1618, 1591, 1536, 1481, 1459, 1390
1267, 1249, 1158, 1058, 985, 830;
Example 45 [2-(4-Acetamidophenylsul
4-yl-propoxy)-quinazolin-4-yl]-(5-1
yl)-amine (IIa-45): Prepared from :
Method I to afford an off-white so]
NMR (DMSO) δ 2.02 (3H, s), 2.09 (3E
quint.), 3.16 (2H, m), 3.36 (4H,m),
(2H, m), 5.58 (1H, s), 7.22-7.29 (2
7.76 (2H, d) , 8.07 (1H, d) , 10.26 (
s) , 12.06 (1H, br s); IR (solid) 16
1486, 1391, 1336, 1254, 1109, 1063,
Example 46 [2-(4-Bromophenylsulfany
(5-methyl-2H-pyrazol-3-yl)-amine(I
manner similar to the above describe
an off-white solid, mp >300°C; 2H N
s), 5.63 (1H, br s), 7.44 (1H, m),
7.69-7.77 (3H, m) , 8.56 (1H, m) , 10.
x br s); IR (solid) 1615, 1597, 1565
1362, 1339, 1285, 1218, 1158, 1034,
412.1/414.1(M+H)+

Example 47 [2-(3-Bromophenylsulfan
(5-methyl-2H-pyrazol-3-yl)-amine (
manner similar to the above descri
an off-white solid, mp 280-281°C;
(3H, s) , 5.54 (1H, br s) , 7.46 (1H
m) , 7.75-7.88 (3H, m), 8.81 (1H, m
(2H, 2 X br s); IR (solid) 1617, If
1399, 1362, 1342, 1282, 1200, 1168,
967; MS 412.2/414.2(M+H) +
Example 48 [2-(4-Isopropanesulfony]
quinazolin-4-yl]-(5-methyl-2H-pyraz
48). Prepared in a manner similar t
Method E to afford a white solid, m
(DMSO) δ 1.26 (6H, d), 2.13 (3H, s)
(2H, d), 7.41 (1H, t), 7.54 (1H, d)
(1H, t) , 8.53 (1H, d) , 10.16 (1H, s
12.07 (1H, br s); IR (solid) 1613,
1482, 1384, 1364, 1346, 1320, 1290,
1169, 1141, 1084, 1056, 1019, 999, :
455.2(M+H)+
Example 49 [2-(4-Isobutyrylamino-phe
quinazolin-4-yl]-(5-methyl-2H-pyrazc
49): Prepared in a manner similar tc
Method E to afford an off-white soli
NMR (DMSO) δ 1.12-1.13 (6H, m) , 1.99
m) , 5.52 (1H, br s) , 7.41 (1H, m) , 7
7.72-7.77 (3H, m), 8.54 (1H, m), 10.
(3H, 3 x br s); IR (solid) 1704, 168
1516, 1481, 1395, 1358, 1341, 1286,
1052, 1032, 1006, 969; MS 419.3(M+H)

Example 50 (5-Methyl-2H-pyrazol-3-yl)-[
propionylamino-phenylsulfanyl)-quinazol
(IIa-50): Prepared in a manner similar
described Method E to afford an off-whi
282°C; 1H NMR (DMSO) 5 1.11-1.13 (3H, m
2.33 (2H, m), 5.51 (1H, br s), 7.41 (IE
(3H, m), 7.71-7.78 (3H, m), 8.54 (1H, n
and 12.04 (3H, 3 x br s); IR (solid) 16
1571, 1527, 1476, 1398, 1358, 1341, 12E
1155, 1006, 969; MS 405.3(M+H)+
Example 51 [2-(4-cyclopropanecarbonylan
phenylsulfanyl)-quinazolin-4-yl]-(5-met
yl)-amine (IIa-51): Prepared in a manne
above described Method E to afford an c
300-303°C; 1H NMR (DMSO) δ 0.82-0.84 (4:
m) , 2.01 (3H, s) , 5.55 (1H, br s) , 7.3S
7.53-7.57 (2H, m), 7.72-7.77 (2H, m), 8
10.40, 10.46 and 12.03 (3H, 3 X br s);
1614, 1591, 1560, 1526, 1480, 1432, 13S
1240, 1194, 1177, 1152, 997; MS 417.2(1
Example 52 [2-(4-Acetamido-phenylsulfar
hydroxyquinazolin-4-yl]-(5-methyl-2H-py
(IIa-52): tan solid, mp 258-259°C; 1H N
(3H, s), 2.09 (3H, s) , 5.45 (1H, s) , 7.
(1H, t), 7.57 (2H, d) , 7.75 (2H, d) , 7.
(1H, s), 10.22 (1H, s), 10.26 (1H, s),
IR (solid) 3295, 3272, 3181, 3109, 1654
1482, 1459, 1386, 1368, 1314, 1268, 114
MS 407.2(M+H)+

Example 53 [2-(4-Acetamido-phenylsulfa
nitroquinazolin-4-yl]-(5-methyl-2H-pyr
(IIa-53) : Prepared in a manner similar
described Method-E to afford a yellow
5 2.02 (3H, s), 2.09 (3H, s), 5.54 (1H
7.75 (2H, d) , 8.08 (1H, d) , 8.22 (1H,
10.24 (1H, s) , 10.85 (1H, s), 12.15 (1:
MS 436.2(M+H)+
Example 54 (5-Methyl-2H-pyrazol-3-yl)-sulfonylamino)-phenylsulfanyl]-quinazo:
(IIa-54) : Prepared in a manner similar
described Method E to afford a white sc
1H NMR (DMSO) δ 0.95 (3H, t) , 1.71 (2H,
3.18 (2H, t), 5.70 (1H, s), 7.31 (2H, c
7.52 (1H, d) , 7.58 (1H, d) , 7.73 (1H, t
,10.16 (1H, s) , 10.42 (1H, S), 12.07 (I
1615, 1594, 1563, 1530, 1481, 1389, 136
1291, 1245, 1147, 969; MS 455.2(M+H)+
Example 55 [2-(4-Ethylsulfonylamino-phe
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3
(IIa-55) : Prepared in a manner similar
described Method E to afford an off-whi
280°C; 1H NMR (DMSO) δ 1.28 (3H, t), 2.
(2H, m), 5.76 (1H, s), 7.36 (2H, d), 7.
(1H, d), 7.65 (1H, d), 7.80 (1H, t), 8.
(1H, s), 10.49 (1H, s), 12.13 (1H, s);
1597, 1564, 1532, 1506, 1485, 1455, 138
1323, 1294, 1218, 1150, 1033, 1016, 998
441.2(M+H)+

Example 56 [2-(4-Acetamido-phenylsulfa
hydroxyaminoquinazolin-4-yl]-(5-methyl
amine (IIa-56): Prepared from IIa-53 a
J to afford a yellow solid; 1H NMR (DM,
2.11 (3H, s) , 5.19 (1H, s) , 6.88-6.91
d), 7.85 (2H, d), 8.44 (1H, d), 9.27 (
(1H, s), 11.38 (1H, s), 14.58 (1H, br
422.2(M+H)+
Example 57 [2-(4-Isobutanecarbonylamin
quinazolin-4-yl]-(5-methyl-2H-pyrazol-57): Prepared in a manner similar to t
Method E to afford a white solid, mp 2
(DMSO) δ 0.95-0.97 (6H, m) , 2.00 (3H,
2.23-2.25 (2H, m), 5.56 (1H, s), 7.41
(3H, m) , 7.72-7.78 (3H, m) , 8.54 (1H,
and 12.03 (3H, 3 x br s) ; IR (solid) 1'
1599, 1566, 1530, 1483, 1432, 1394, 13
1287, 1242, 1216, 1167, 1151, 1003, 96
Example 58 [2-(4-tert-Butoxycarbonylam:
phenyl sulfanyl)-quinazolin-4-yl]-(5-met
yl)-amine (IIa-58): Prepared in a manne
above described Method E to afford a wl
246°C; 1H NMR (DMSO) δ 1.50 (9H, s), 1.
(1H, s), 7.07 (2H, br s), 7.36 (1H, br
7.58 (2H, d), 8.12 (1H, br s), 9.58 (II
br s); IR (solid) 1701, 1593, 1559, 153
1365, 1346, 1308, 1288, 1237, 1154, 10E
449.2(M+H)+

Example 59 [2-(4-Acetamido-phenylsulfa
aminoquinazolin-4-yl]-(5-methyl-2H-pyra
(IIa-59): Prepared from IIa-53 accordin
afford an off-white solid, mp 264-265
1.99 (3H, S), 2.09 (1H,s), 5.53 (1H,
6.47 (1H, s), 6.68 (1H, d) , 7.52 (2H, C
8.15 (1H, d) , 9.83 (1H, br s), 10.19 C
br s); IR (solid); MS 406.2(M+H)+
Example 60 (5-Methyl-2H-pyrazol-3-yl)-{
4-yl-acetylamino)-phenylsulfany1]-quina
(IIa-60): Prepared in a manner similar
described Method E to afford an off-whi
267 °C; 1H NMR (DMSO) δ 2.03 (3H, s), 2
(2H,s), 3.69 (4H, m), 5.58 (1H, s), 7.4
7.62 (3H, m), 7.75 (1H, t), 7.80 (2H, c
10.02 (1H, s), 10.41 (1H, s), 12.03 (1H
1686, 1598, 1564, 1533, 1515, 1484, 138
1291, 1113, 868, 801, 773; MS 476.4(M+H
Example 61 (5-Cycloprpyl-2H-pyrazol-3-y
methylsulfonylamino-phenylsulfanyl)-qui
amine (IIa-61): Prepared in a manner si
described Method E to afford a white so
1H NMR (DMSO) δ 0.61 (2H, s), 0.92 (2H,
s), 2.98 (3H,s), 5.90 (1H, s), 7.23 (2H
t) , 7.54 (3H, m) , 7.72 (1H, t) , 8.55 (1
br s), 10.38 (1H, s), 11.99 (1H, s); IR
1605, 1573, 1532, 1494, 1455, 1375, 134
1232, 1143, 1113, 985, 972; MS 453.3(M+1

Example 62 [2-(4-Amino-phenylsulfanyl)
(5-methyl-2H-pyrazol-3-yl)-amine (Ila-manner similar to the above described J
an off-white solid, mp >300°C; 1H NMR (
S) , 5.58 (1H, s) , 6.78 (2H, d) , 7.36 C
m) , 7.94 (1H, t) , 8.74 (1H, d) , 11.82
(solid) 1615, 1591, 1561, 1532, 1495, :
1344, 1288, 1244, 1148, 966; MS 349.2(
Example 63 [2-(4-Acetamido-phenylsulfa
yl]-(2H-pyrazol-3-yl)-amine (IIa-63): I
manner similar to the above described I
a white solid, 1H NMR (DMSO) δ 2.11 (3H
7.31-7.68 (8H, m) , 8.54 (1H, s), 10.17
(1H, s) , 12.38 (1H, s) ; IR (solid); MS
Example 64 (5-Methyl-2H-pyrazol-3-yl)-{
4-yl-butyryl amino)-phenyl sulfanyl]-quin
(IIa-64) : Prepared in a manner similar
described Method E to afford a white sc
1H NMR (DMSO) δ 1.77 (2H, m) , 2.00 (3H,
m) , 3.57 (4H, m) , 5.54 (1H, s) , 7.39-7.
(1H, br m) , 10.15 (1H, s) , 10.41 (1H, s
s) ; IR (solid); MS 504.3(M+H)+
Example 65 (5-Methyl-2H-pyrazol-3-yl)-{
4-yl-ethylcarbamoyl)-phenylsulfanyl]-qu
amine (IIa-65) : Prepared in a manner si:
described Method E to afford a white so
1H NMR (DMSO) δ 1.97 (3H, s), 2.43 (4H,
s), 3.42 (2H, m), 3.58 (4H, br s), 5.52
(1H, t) , 7.55 (1H, d) , 7.76 (3H, m) , 7.1

(2H, m), 10.45 (1H, s), 12.05 (1H, br
1637, 1618, 1596, 1568, 1530, 1484, 13
1286, 1247, 1216, 1159, 1116, 1006, 96
Example 66 [8-Methoxy-2-(4-methylsulfo
phenylsulfanyl)-quinazolin-4-yl]-(5-me
yl)-amine (Ila-66): Prepared in a mann
above described Method E to afford an
275-277 °C; 1H NMR (DMSO) δ 2.10 (3H, S
3.89 (3H, S), 5.58 (1H, s), 7.24 (1H,
m) , 7.60 (2H, d) , 8.07 (1H, d) , 10.13
(1H, S), 12.03 (1H, s) ; IR (solid) 337
1531, 1481, 1467, 1344, 1326, 1271, 12
993, 975, 924, 829; MS 457.2(M+H)+
Example 67 {2-[4-(2-Dimethylamino-ethy3
phenylsulfany]-quinazolin-4-yl}-(5-met
yl)-amine (IIa-67): Prepared in a manne
above described Method E to afford a wh
193°C; 1HNMR (DMSO) δ 1.99 (3H, s) , 2.
(2H, t) , 3.40 (2H, q) , 5.56 (1H, s) , 7.
(1H, d) , 7.77 (3H, m) , 7.92 (2H, d) , 8.
(1H, s), 12.04 (1H, br s); IR (solid) 1
1561, 1525, 1481, 1419, 1395, 1361, 133
1214, 1165, 1004, 969; MS 448.3(M+H)+
Example 68 {2-[4-(2-Dimethylamino-acety
phenyl sulfanyl]-guinazolin-4-yl}-(5-met
yl)-amine (IIa-68): Prepared in a manne
above described Method E to afford a wh
243°C; 1H NMR (DMSO) δ 2.00 (3H, s), 2.3
(2H, s) , 5.60 (1H, S) , 7.40 (1H, t) , 7.

(1H, t ), 7.76 (2H, d) , 8.58 (1H, d),
10.42 (1H, s), 11.99 (1H, s).; IR (sol
1601, 1571, 1509, 1485, 1420, 1397, 13
1243, 1215, 1161, 970, 847, 813, 765,
434.3(M+H)+
Example 69 [8-Hydroxy-2-(4-methylsulfo
phenylsulfany 1)-quinazolin-4-yl]-(5-me
yl)-amine (IIa-69) : pale green solid,
(DMSO) 5 2.10 (3H, s), 3.09 (3H, s), 5
(1H, d), 7.24 (1H, t), 7.31 (2H, d), 7
(1H, d) , 9.32 (1H, s), 10.16 (1H, s) ,
12.02 (1H, s); IR (solid) 3256, 1596,
1317, 1334, 1296, 1267, 1146, 993, 968
443.2(M+H)+
Example 70 {2-[4-(3-Dimethyl amino-prop
phenylsulfanyl]-quinazolin-4-yl}-(5-me
yl)-amine (IIa-70): Prepared in a mann
above described Method E to afford a p.
213°C; 1H NMR (DMSO) δ 1.48 (2H, m) , 2.
(6H,s), 2.38 (2H, br s) , 2.93 (2H, s) ,
(1H, t), 7.62 (1H, d), 7.80 (3H, m), 8
(1H, d) 8.74 (1H, s) , 10.50 (1H, s) , 1
(solid) 1682, 1618, 1595, 1567, 1528, 1
1344, 1285, 1247, 1219, 1172, 1084, 10
462.3(M+H)+
Example 71 {2-[4-(3-Dimethyl amino-prop
phenylsulfanyl]-guinazolin-4-yl}-(5-met
yl)-amine (IIa-71): Prepared in a manne
above described Method E to afford an c
280°C (dec); 1H NMR (DMSO) δ 2.09 (3H,

2.93 (2H, m), 3.10 (2H, m), 5.64 (1H,
7.59-7.70 (3H, m), 7.80-7.87 (3H, m),
1H, s) , 10.48 (1H, s), 12.15 (1H, s) .
1619, 1598, 1586, 1571, 1534, 1515, 14
1348, 1286, 1178, 1162, 764; MS 448.4(1
Example 72 [2-(4-Acetamido-phenylsulfa
quinazolin-4-yl]-(5-cyclopropyl-2H-pyr
(IIa-72): Prepared in a manner similar
described Method E to afford an off-wh:
268°C; 1H NMR (DMSO) δ 0.49-0.56 2H, m
m) , 1.55-1.70 (1H, m) , 2.06 (3H, s) , 3.
(1H, s) , 7.25 (1H, d) , 7.33 (1H, t) , 7.
(2H, d), 8.07 (1H, d), 10.17 (1H, s), 3
11.94 (1H, br s); IR (solid) 3250, 1673
1536, 1480, 1460, 1396, 1373, 1335, 125
1071, 1011, 984, 869, 815; MS 447.4(M+
Example 73 [2-(4-Acetamidophenylsulfany
dimethylamino-propoxy)-quinazolin-4-yl]
pyrazol-3-yl)-amine (IIa-73): Prepared
similar to the above described Method E
white solid, mp 170-172°C; 1H NMR (DMSO
quint.), 2.03 (3H, s), 2.09 (3H, s), 2.
(2H, t) , 4.10 (2H, t) , 5.59 (1H, s) , 7.
(1H, t) , 7.57 (2H, d) , 7.73 (2H, d) , 8.
(1H, s) , 10.24 (1H, s), 12.02 (1H, br s
3234, 3108, 1675, 1614, 1592, 1531, 148
1338, 1316, 1253, 1161, 1137, 1062, 103
MS 492.4(M+H)+
Example 74 [2-(4-Acetamidophenylsulfany.
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3

(IIa-74): Prepared from IIa-40 accordi
afford an off-white solid, mp 246-248°
2.00 (3H, s), 2.08 (3H, s), 5.52 (1H,
6.87 (1H, d), 7.54 (2H, d), 7.72 (2H, c
10.06 (1H, S), 10.17 (1H, S) , 10.37 (H,
s); IR (solid) 1661, 1633, 1594, 1572,
1389, 1359, 1298, 1223, 1176, 1148, 10E
965; MS 407.4(M+H)+
Example 75 [2-(4-Acetamidophenylsulfany
dimethylamino-propoxy)-quinazolin-4-yl]
pyrazol-3-yl)-amine (IIa-75): Prepared
similar to the above described Method I
white solid, mp 249-250°C; 1H NMR (DMSO
quint.), 2.01 (3H, s) , 2.09 (3H, s), 2.
(2H, m) , 4.12 (2H, t) , 5.55 (1H, s) , 6.
(1H, d), 7.55 (2H, d), 7.73 (2H, d), 8.
(1H, s), 10.23 (1H, s), 11.98 (1H, br s
3272, 1677, 1615, 1571, 1558, 1530, 150:
1394, 1344, 1320, 1292, 1263, 1222, 116
1005, 967, 864, 844; MS 492.4(M+H)+
Example 76 (2-{4-[2-(tert-Butoxycarbonyl
acetylamino]-phenylsulfanyl}-quinazolin-2H-pyrazol-3-yl)-amine(IIa-76) : Prepare
similar to the above described Method E
solid, mp 228-229°C (dec); 1H NMR (DMSO
1.40 (3H, s), 2.02 + 2.03 (3H, 2xs), 2.8
2xs), 4.01 +4.02 (2H, 2xs), 5.52 + 5.57
(1H, t), 7.55-7.63 (3H, m), 7.75-7.80 (3
(lH,d), 10.28 + 10.30 (1H, 2xs), 10.45 (
(1H, s).; IR (solid) 1698, 1683, 1653, 1

1538, 1532, 1507, 1488, 1457, 1418, 13
1307, 1287, 1246, 1151, 842, 827, 759;
Example 77 {2-[4-(2-Methylamino-acetyl
phenylsulfanyl]-quinazoli-n-4-yl}-(5-me
yl)-amine (IIa-77): Prepared in a mann
above described Method E to afford a w
244°C; 1H NMR (DMSO) δ 2.01 (3H, s) , 2.
(2H, s), 5.58 (1H, s), 7.45 (1H, t), 7
7.75 (1H, t) , 7.80 (2H, d) , 8.55 (1H,
s) , 10.42 (1H, s) , 12.02 (1H, s) ; IR (
1598, 1570, 1525, 1483, 1417, 1363, 13'
1247, 1160, 966, 827, 804, 784, 763, 7:
420.4 (M+H)+
Example 78 [2-(4-Acetamidophenylsulfan}
quinazolin-4-yl]-(5-methyl-2H-pyrazol-
78): Prepared in a manner simiar to tH
Method E to afford a white solid, mp 25
(DMSO) 52.01 (3H, s) , 2.09 (3H, s) , 5.
(1H, t), 7.57-7.68 (3H, m), 7.75 (2H,
10.28 (1H, S), 10.75 (1H, s); 19F NMR
(solid) 1690, 1670, 1637, 1609, 1588, 3
1456, 1434, 1395, 1366, 1332, 1315, 125
1032, 838, 829, 808, 744; MS 409.4 (M+H)
Example 79 (1H-Indazol-3-yl)-(2-phenyls
quinazolin-4-yl)-amine (IIa-79): Prepar
similar to the above described Method E
solid. 1H NMR (DMSO) δ 7.07 (m, 3H) , 7.:
(d, 2H), 7.39 (t, 1H), 7.52 (dd, 1H), 7

(d, 1H), 7.56 (t, 1H), 7.83 (t, 1H) , 8.
(S, 1H), 12.85 (s, 1H); MS 370.1 (M+H)+
Example 80 {2-[(2-Hydroxyethyl)phenylan
yl}-(5-methyl-2H-pyrazol-3-yl)-amine (1
a manner similar to the above describee
afford a brown solid, mp 217°C; 1H NMR
s), 3.69 (2H, t), 4.05 (2H, t), 5.00 (1
1H, br s) , 7.09 (1H, m) , 7.25-7.40 (4K
(2H, m), 7.54 (1H, m), 8.34 (1H, m), 1C
(1H, br s) ; IR (solid) 3395, 3155, 3052
1598, 1577, 1475, 1434, 1393; MS 361.2
Example 81 [2-(Methylphenylamino)-quina
methyl-2H-pyrazol-3-yl)-amine (IIc-2):
manner similar to the above described M
a white solid, mp 154-156°C; 1H NMR (DM;
3.5K3H, s) , 5.70(1H, s), 7.13(1H, m) ,
7.48-7.37 (3H, m), 7.58 (1H, m), 8.38 (
s) , 11.91 (1H s); IR (solid) 1621, 1598
1494, 1473, 1396, 1374; MS 331.0 (M+H)+
Example 82 (5-methyl-2H-pyrazol-3-yl)-{
(pyridin-3-ylmethyl)amino]-quinazolin-4
(IIc-3): Prepared in a manner similar
described Method A to afford a yellow
NMR(DMSO) δ 0.45 (2H, s), 0.84 (2H, s),
3.16 (3H, s), 4.93 (2H, s), 6.18 (1H, b:
t), 7.34 (2H, S), 7.55 (1H, t), 7.64 (11
d), 8.45 (1H, s), 8.52 (1H, s), 10.03
s) ; IR (solid) 3104, 2995, 2936, 1618,
1518, 1477, 1409, 1386, 1350, 1300, 101f
MS 3 72.3 (M+H)+

Example 83 (5-Methyl-2H-pyrazol-3-yl)-quinazolin-4-yl)-amine (IIc-4): Prepare
similar to the above described Method
solid; 1H NMR (DMSO @60°C) δ 2.27 (3H, s
6.92(1H, m) , 7.31(3H, m), 7.53(1H, m) ,
(2H, m), 8.37 (2H, d), 9.16 (1H, br s),
12.15 (1H, br s); IR (solid) 1623, 1603
1478; MS 317.0 (M+H) +
Example 84 (2-Benzylamino-quinazolin-4-pyrazol-3-yl)-amine (IIc-5) : Prepared i
to the above described Method A to affc
mp 225-227°C; 1H NMR (DMSO)δ 8 2.20 (3H,
7.18 (1H, s), 7.43-7.60(8H, m), 8.22 (1
br s) , 12.05 (1H, br s) ; IR (solid) 16
1538, 1511; MS 331.0 (M+H)+
Example 85 (2-Cyclohexylamino-quinazoli
2H-pyrazol-3-yl)-amine (IIc-6) : Prepare
similar to the above described Method A
white solid, mp 280°C (dec); 1H NMR (DJ
1.44(5H, m) , 1.56 (1H, m) , 1.71(2H, m) ,
2.26(3H, s) , 3.75(1H, s), 6.63 (1H, br
7.28 (1H, s) , 7.51(1H, m) , 8.26(1H, s) ,
12.08(1H, br s), 12.75(1H, br s) ,-IR (s
1619, 1596, 1569, 1522, 1482; MS 323.0
Example 8 6 [2-(2,3-Dihydrobenzo[1,4] dio
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3
(IIc-7) .-Prepared in a manner similar t
described Method A to afford an off-gre

>250°C; 1H NMR (DMSO) δ 2.23 (3H, s) , 4
(1H, br s), 6.76 (1H; d), 7.16 (1H, t)
7.39 (1H, d), 7.57 (1H, t), 7.66 (1H,
9.07 (1H, br s) , 10.20 (1H, br s) , 12.
(solid) 3445, 3045, 2968, 2927, 2868,
1559, 1509, 1441, 1377, 1073; MS 375.1
Example 87 (2-Cyclohexylmethylamino-qu
methyl-2H-pyrazol-3-yl)-amine (IIc-8):
manner similar to the above described I
a white solid, mp 211°C; 1H NMR (DMSO)
m), 1.50-1.85 (6H, m), 2.22 (3H, s), 3.
7.00 (1H, br s), 7.06 (1H, br s), 7.29
(1H, t) , 8.26 (1H, br s), 9.97 (1H, br
s), 12.75 (1H, br s); IR (solid) 3333,
1627, 1609, 1577, 1540, 1508, 1449, 142
33 7.4 (M+H)+
Example 88 [2-(1H-Indazol-6-ylamino)-qu
methyl-2H-pyrazol-3-yl)-amine (IIc-9) :
manner similar to the above described M
an off-white solid, mp >250°C; 1H NMR (:
s), 5.93 and 6.8 9 (1H, 2xbr s), 7.05-8.
8.90 (2H, m), 9.25 and 9.97 (1H, 2xbr s
(1H, 2xbr s), 12.15 and 12.80 (2H, 2xbr
3456, 3315, 2923, 1613, 1600, 1577, 154
(M+H)+
Example 89 (5-Methyl-2H-pyrazol-3-yl)-[
ylmethylamino)-quinazolin-4-yl]-amine (
in a manner similar to the above descri:
afford an off-white solid, mp 218°C; 1H

(3H, s), 4.59 (2H, s), 6.30 (1H, br s),
7.33 (2H, s), 7.54 (1H, s), 7.78 (1H,
6.43 (1H, s), 8.61 (1H, s), 10.0 (1H,
br s); IR (solid) 3308, 2945, 2919, 285
1577, 1552, 1501, 1475, 1449, 1383; MS
Example 90 [2-(3-Chlorophenylamino)-qui
methyl-2H-pyrazol-3-yl)-amine (IIc-11) :
manner similar to the above described N
an off-white solid, mp >250°C, 1H NMR (
s), 5.30-6.98 (1H, m) , 6.96 (1H, s) , 7.
(1H, s), 7.67 (1H, s), 7.77 (1H, s), 8.
(1H, s), 9.35 and 10.00 (1H, 2xbr s), 1
(1H, 2xbr s), 12.20 and 12.82 (1H, 2xbr
3447, 3078, 2945, 2914, 2863, 1618, 160
1472, 1440, 1403, 1372; MS 351.1 (M+H)+
Example 91 [2-(4-Chlorophenylamino)-qui
methyl-2H-pyrazol-3-yl)-amine (IIc-12):
manner similar to the above described M
an off-white solid, mp >250°C; 1H NMR (I
s), 5.20-6.80 (1H, m), 7.26 (1H, s), 7.
1H, s), 7.66 (1H, s) , 7.99 (2H, d) , 8.
and 9.93 (1H, 2xbr s) , 10.13 and 10.55
12.19 and 12.81 (1H, 2xbr s) ,-IR (solid
2957, 1618, 1600, 1586, 1572, 1550, 150-1413, 1367; MS 351.1 (M+H)+
Example 92 [2-(4-Fluorobenzylamino)-qui
methyl-2H-pyrazol-3-yl)-amine (IIc-13):
manner similar to the above described Me
a white solid, mp 216°C; 1H NMR (DMSO) δ

4.56 (2H, d) , 6.30 (1H, br s) , 7.05-7.
(1H, d) , 7.42 (2H, s), 7.54 (1H, t), 8
and 10.34 (1H, 2xbr s), 12.09 and 12.7
(solid) 3333, 2854, 1632, 1609, 1577,
MS 349.3 (M+H)+
Example 93 {2-[2-(2-Hydroxyethyl) phenyl
4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine
in a manner similar to the above descri
afford a white solid, mp 222°C; 1H NMR
s) , 2.80 (2H, t) , 3.61 (2H, t) , 4.87 (1
(1H, br s), 7.30-7.53 (5H, m) , 7.63 (1P
t), 8.68 (1H, d), 10.11 (1H, br s) , 11.
12.49 (1H, br s) , 13.50 (1H, br s) ; IR
3171, 3111, 3084, 1636, 1577, 1559, 15C
1340, 1058; MS 361.3 (M+H)+
Example 94 [2-(4-Cyanomethylphenylaminc
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (I
in a manner similar to the above descri
afford an off-white solid, mp >250°C; 1.
(3H, s), 4.09 (2H, s), 6.28 (1H, br s),
7.48 (1H, t) , 7.57-7.63 (3H, m) , 7.87 (
s), 11.56 (1H, s), 12.63 (1H, br s), 13
(solid) 3294, 3271, 3093, 1641, 1586, 1
1481, 1413, 1336, 1158, 999; MS 356.2 (
Example 95 [2-(3-Hydroxymethylphenylami:
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (I
in a manner similar to the above descri
afford an off-white solid, mp >250°C;
(3H, s), 4.53 (2H, s), 5.22 (1H, br s),
7.24 (1H, d) , 7.33-7.53 (4H, m) , 7.61

t) , 8.67 (1H, d), 10.61 (1H, br s), 11
12.59 (1H, br s), 13.10 (1H, br s); IR
3209, 3108, 3071, 2975, 2916, 1632, 16
1485, 1421, 1371, 1348, 1046, 1005, 81
Example 96 [2-(3-Hydroxyphenylamino)-q-methyl-2ir-pyrazol-3-yl)-amine (IIc-17)
manner similar to the above described ]
a white solid, mp >250°C; 1H NMR (DMSO)
6.42 (1H, br s), 6.72 (1H, d), 6.97 (21
t), 7.47 (1H, t), 7.60 (1H, d), 7.85 C
d) , 9.76 (1H, s) , 10.53 (1H, s), 11.53
(1H, br s), 12.99 (1H, br s); IR (solid
2893, 2817, 1654, 1588, 1541, 1490, 141
1154, 1004; MS 333.2 (M+H)+
Example 97 (5-Cyclopropyl-2H-pyrazol-3-phenylamino-quinazolin-4-yl)-amine (IIc
a manner similar to the above described
afford an off-white solid, mp 234°C; 1H
(2H, s), 0.92 (2H, s), 1.91 (1H, s), 5.
2xbr s), 6.94 (1H, t), 7.30 (3H, m), 7
(1H, s), 7.91 (2H, d), 8.27 (1H, s), 9.
2xbr s), 10.07 and 10.52 (1H, 2xbr s),
(1H, 2xbr s); IR (solid) 3443, 1622, 15
1486, 1449, 1413, 1376, 1340, 1235, 117
343.2 (M+H)+
Example 98 (5-Cyclopropyl-2H-pyrazol-3-methylphenylamino)-quinazolin-4-yl]-ami
Prepared in a manner similar to the abo
Method A to afford an off-white solid,
(DMSO) δ 0.72 (2H, s), 0.92 (2H, s), 1.:

(3H, s), 6.20 (1H, br s) , 6.80 (1H, d)
7.27 (1H, br s) , 7.51 (1H, br s) , 7.5
(1H, br s), 9.50 (1H, br s) , 10.44 (1H
s); IR (solid) 3303, 1618, 1581, 1554,
1436, 1413, 1372, 1336, 1240, 990; MS
Example 99 (5-Cyclopropyl-2ir-pyrazol-3
methoxypyridin-3-ylamino)-quinazolin-4
(IIc-20): Prepared in a manner similar
described Method A to afford a pink so
NMR (DMSO) 5 0.72 (2H, s), 0.91 (2H, S
3.85 (3H, s) , 6.20 (1H, br s) , 6.82 (1
S), 7.48 (1H, m), 7.66 (1H, t), 8.13 (
(1H, br s) , 8.61 (1H, br s) , 9.50 (1H,
br s), 12.55 (1H, br s); IR (solid) 34
1604, 1577, 1554, 1481, 1422, 1386, 13
1035, 985, 821; MS 374.2 (M+H)+
Example 100 (5-Cyclopropyl-2H-pyrazol-ylamino)-quinazolin-4-yl]-amine(IIc-2
manner similar to the above described
a pale brown solid, mp 199-204 °C; 1H NM
(2H, br s) , 0.91 (2H, br s) , 1.90 (1H,
2.68 (1H, m), 2.83 (3H, m) , 6.46 (1H, b
d), 7.26 (1H, br s) , 7.50 (1H, d) , 7.6
(1H, br s), 8.45 (1H, br s) , 9.70 (1H,
br s), 12.30 and 12.80 (1H, 2xbr s); IF
1601, 1572, 1552, 1495, 1474, 1439, 142
1363, 1319, 1267; MS 383.3 (M+H)+
Example 101 (5-Cyclopropyl-2H-pyrazol-3
6-ylamino)-quinazolin-4-yl]-amine(IIc-
manner similar to the above described M

a dark brown solid, mp >3 00°C; 1H NMR (
br s), 0.89 (2H, br s), 1.88 (1H, m) , E
2xbr s), 6.35 (1H, s), 7.22 (3H, br s),
7.65 (1H, s) , 8.35 (2H, br s) , 8.86, 9.
3xbr s) , 10.-49, 12.12 and 12.84 (1H, 33
1H); IR (solid) 1623, 1603, 1571, 1549,
1419, 1383, 1336, 1264, 1250, 1238; MS
Example 102 [2-(4-Acetamido-3-methylphe
quinazolin-4-yl]-(5-cyclopropyl-2H-pyra
(IIc-23): Prepared in a manner similar
described Method A to afford an off-whi
>188°C (dec); 1H NMR (DMSO) δ 0.72 (2H
br s), 1.92 (1H, m), 2.03 (3H, s), 2.
6.69 (1H, 2xbr s), 7.22 (2H, br s), 7.4
(3H, m), 8.35 (1H, br s), 9.01, 9.59 an
s), 9.19 (1H, s), 10.53, 12.16 and 12.8
(solid) 1637, 1624, 1578, 1542, 1502, 1
1343, 1320, 1307, 1250; MS 414.4 (M+H)+
Example 103 [2-(4-Chloro-3-methylphenyl
4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-a
Prepared in a manner similar to the abo
Method A to afford a pale brown solid,
NMR (DMSO) 5 0.69 (2H, br s), 0.94 (2H,
m), 2.32 (3H, s), 5.89 and 6.63 (1H, 2x
m) , 7.49 (1H, m) , 7.65 (1H, m) , 7.80 (1
(1H, s) , 8.40 (1H, br s) , 9.17, 9.81 an
s) , 10.58, 12.19 and 12.78 (1H, 3xbr s)
1578, 1549, 1475, 1419, 1397, 1365, 133:
1238, 1187, 1139; MS 391.4 (M+H)+

Example 104 (5-Cyclopropyl-2H-pyrazol-;
ethylphenylamino)-quinazolin-4-yl]-ami
Prepared in a manner similar to the ab
Method A to afford a pale brown solid,
NMR (DMSO) δ 0.72 (2H, br s) , 0.91 (2H,
t) , 1.91 (1H, m) , 2.58 (2H, q) , S.81 a
s) , 7.15 (2H, d) , 7.22 (1H, s) , 7.47
S) , 7.78 (2H, S) , 8.36 (1H, br.s), 9.0
(1H, 3xbr s), 10.49, 12.2 0 and 12.80 (
(solid) 1603, 1574, 1546, 1509, 1497,
1386; MS 371.5 (M+H)+
Example 105 (5-Cyclopropyl-2H-pyrazol-propylphenylamino)-quinazolin-4-yl]-ami
Prepared in a manner similar to the abc
Method A to afford an off-white solid,
NMR (DMSO) 6 0.72 (2H, br s) , 0.91 (5H,
1.90 (1H, m), 2.58 (2H, q), 5.81 and 6.
7.12 (2H, d) , 7.21 (1H, s), 7.47 (1H, s
7.77 (2H, s), 8.36 (1H, br s), 9.01, 9.
3x br s), 10.51, 12.17 and 12.80 (1H, 3
1595, 1571, 1545, 1499, 1477, 1442, 141
(M+H)+
Example 106 (5-Cyclopropyl-2H-pyrazol-3
hydroxyethyl) phenylamino]-quinazolin-4-(IIc-27) : Prepared in a manner similar
described Method A to afford a pale bro
256°C; 1H NMR (DMSO) δ 0.73 (2H, br s),
(1H, m) , 2.69 (2H, t) , 3.60 (2H, q), 4
and 6.65 (1H, 2xbr s) , 7.15 (2H, d), 7.
(1H, s) , 7.63 (1H, S) , 7.77 (2H, s) , 8.

9.05, 9.69 and 10.02 (1H, 3xbr s), 10.
(1H, 3xbr s) ; IR (solid) 1632, 1569, 1!
1434, 1402, 1371, 1267, 1231; MS 387.4
Example 107 (5-Cyclopropyl-2H-pyrazol-:
phenetylamino-quinazolin-4-yl)-amine (:
in a manner similar to the above descr:
afford a white solid, mp >250°C; 1H NMF
m) , 0.84 (2H, ,m), 1.83 (1H, m) , 2.90 (:
m) , 6.2.9 (1H, br s) , 7.01 (1H, t),7.1:
7.48 (1H, t), 8.42 (1H, s) , 10.91 1H,
br s); IR (solid) 2922, 1650, 1627, 15
1482, 1395, 1368, 1004, 832; MS 371.3
Example 108 [2-(2-Cyclohexylethylamino;
(5-cyclopropyl-2H-pyrazol-3-yl)-amine
in a manner similar to the above descr:
afford a white solid, mp >250°C; 1H NME
s), 0.80-1.00 (4H, m), 1.05-1.30 (4H, r
m), 1.55-1.80 (5H, m) , 1.87 (1H, s), 5
s) , 7.04 (1H, S) , 7.25 (1H, s) , 7.49 C
s), 10.06 (1H, br s) , 11.93 (1H, br s),
2920, 2852, 1618, 1600, 1568, 1550, 14(
1367, 1258, 1008, 985; MS 377.4 (M+H)+
Example 109 [2-(4-Carboxymethoxypheny 1
4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-s
Prepared in a manner similar to the abc
Method A to afford a yellow solid, mp ;
(DMSO) 0.72 (2H, m), 0.91 (2H, m), 1.9C
(2H, s), 6.24 (1H, s), 6.88 (2H, s) , .
(1H, m), 7.62 (1H, m), 7.78 (2H, m), 8.
(1H, s) , 10.25 (1H, s) , 11.70 (m, br S

1663, 1595, 1563, 1509, 1422, 1331, 12
999; MS 417.3 (M+H)+
Example 110 [2-(4-Cyanome thylphenylamin
yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-ami
Prepared in a manner similar to the abc
Method A to afford a white solid, mp 2
6 0.74 (2H, m), 0.93 (2H, m), 1.92 (1H,
5.82 and 6.65 (1H, 2xbr s), 7.29 (3H,
7.66 (1H, m), 7.92 (2H, m), 8.39 (1H, n
(1H, 2xbr s), 9.90 and 10.56 (1H, 2xs),
(1H, 2xbr s); IR (solid) 1641, 1622, 15
1513, 1486, 1463, 1408, 1372, 985, 821;
Example 111 [2-(Benzothiazol-6-ylamino)
(5-cyclopropyl-2H-pyrazol-3-yl)-amine (
in a manner similar to the above descri
afford an off-white solid, mp 255-256°C
0.73 (2H, m), 0.92 (2H, m), 1.92 (1H, m
(1H, 2xbr s), 7.27 (1H, br s), 7.59 1H
br s), 7.79 (1H, br s) , 7.98 (1H, br s)
8.97 (1H, br s), 9.19 (1H, s), 9.58 and
s), 10.57, 12.21 and 12.85 (1H, 3xbr s)
1592, 1575, 1512, 1472, 1411, 1377, 133
(M+H) +
Example 112 (5-Cyclopropyl-2H-pyrazol-3
dimethylpheny1amino)-quinazolin-4-yl]-a
Prepared in a manner similar to the abo-
Method A to afford a white solid, mp 24.
(DMSO) 6 0.72 (2H, br s) , 0.90 2H, br
2.18 (3H, s) , 2.23 (3H, s) , 5.77 and 6.

7.09 (1H, d), 7.23 (1H, br s), 7.47 (II
br s), 7.64 (1H, br s), 8.36 (1H, br s)
10.07 (1H, 3xbr s), 10.49, 12.31 and i
IR (solid) 1620, 1600, 1574, 1552, 149
1416, 1385,-1262; MS 371.5 (M+H)+
Example 113 (5-Cyclopropyl-2H-pyrazol-2
phenoxyethylamino)-quinazolin-4-yl]-ami
Prepared in a manner similar to the abc
Method A to afford a white solid, mp 2C
5 0.70 (2H, m) , 0.88 (2H, m) , 1.87 (1H,
4.16 (2H, s), 5.75 and 6.70 (1H, 2xbr s
6.90-7.20 (3H, m) , 7.20-7.45 (3H, m)
(1H, br s), 8.32 (1H, s), 9.95 and 10.3
and 12.75 (1H, 2xbr s) ; IR (solid) 3434
1572, 1554, 1499, 1476, 1422, 1399, 13E
1226, 1212, 1052, 829; MS 387.4 (M+H)+
Example 114 (5-Cyclopropyl-2H-pyrazol-3
2-methylamino)-quinazolin-4-yl]-amine (
in a manner similar to the above descri
afford a white solid, mp 212°C; 1H NMR
m) , 0.90 (2H, m) , 1.86. (1H, m), 4.74 (2
6.66 (1H, 2xbr s) , 6.95 (1H, s), 6.90-7.20-8.45 (5H, m), 9.94 and 10.40 (1H,
12.71 (1H, 2xbr s); IR (solid) 3444, 29
1600, 1559, 1500, 1481, 1418, 1390, 135
1263, 1217, 1185, 1149, 990, 821; MS 36
Example 115 [2-(4-Carboxymethylphenylam
yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-ami
Prepared in a manner similar to the abo
Method A to afford a brown solid, mp >2

(DMSO) δ 0.64 (2H, br s), 0.92 (2H, m).
3.50 (2H, s), 5.76 and 6.54 (1H, 2xs) ,
(1H, m), 7.49 (1H, d), 7.64 (1H, t), 7
(1H, m), 10.27 and 12.25 (1H, 2xbr s);
1591, 1555,-1512, 1489, 1428, 1411, 13'
Example 116 (5-Cyclopropyl-2H-pyrazol-:
indazol-5-ylamino)-quinazolin-4-yl]-am:
Prepared in a manner similar to the abc
Method A to afford a purple solid, mp
(DMSO) 5 0.69 (2H, br s), 0.90 (2H, m),
5.86 and 6.58 (1H, 2xs), 7.22 (1H, s),
(2H, m), 8.01 (1H, s), 8.37 (2H, s), 8.
(1H, 3xbr s), 10.01, 10.68 and 12.38 (J
(1H, s); IR (solid) 1626, 1605, 1576, 3
1476, 1447, 1431, 1416, 1393, 1261, 122
Example 117 (5-Cyclopropyl-2H-pyrazol-3
3-ylmethylamino)-quinazolin-4-yl]-amine
Prepared in a manner similar to the abc
Method A to afford a yellow solid, mp 1
5 0.69 (2H, m), 0.89 (2H, m), 1.86 (1H,
5.76, 6.22 and 6.66 (1H, 3xbr s), 7.10
(2H, s) , 7.54 (1H, S) , 7.78 (1H, s) , 8.
(1H, s), 8.61 (1H, s), 10.00 and 10.32
and 12.63 (1H, 2xbr s); IR (solid) 2927
1600, 1577, 1536, 1477, 1418, 1332, 125
(M+H)+
Example 118 (5-Cyclopropyl-2H-pyrazol-3
methoxycarbonylphenylamino)-guinazolin-
(IIc-39): Prepared in a manner similar

described Method A to afford a white s
1H NMR (DMSO) δ 0. 73 (2H, br s) , 0.91 (
m) , 3.88 (3H, s) , 5.99 and 6.79 (1H, 2:
7.46 (3H, m), 7.68 (1H, s) , 8.36 (1H,
9.36, 9.84 and 10.00 (1H, 3xbr s), 10.
(1H, 3xbr s) ; IR (solid) 1716, 1615, 1:
1473, 1432, 1416, 1379, 1334, 1298, 12'
1142, 1110, 1020, 985; MS 401.3 (M+H)+
Example 119 [2-(3-Carboxyphenylamino)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine
in a manner similar to the above descr:
afford an off-white solid, mp 298-302°(
0.73 (2H, br s) , 0.91 (2H, m), 1.90 (II
S), 7.35 (1H, t), 7.50 (2H, d) , 7.66 C
m) , 8.41 (1H, d) ; IR (solid) 1661, 159
1517, 1486, 1424, 1385; MS 387.3 (M+H)+
Example 120 (5-Cyclopropyl-2H-pyrazol-2
ethylphenylamino)-quinazolin-4-yl]-amir
Prepared in a manner similar to the abc
Method A to afford an off-white solid,
NMR (DMSO) δ 0.73 (2H, br s) , 0.91 (2H,
t) , 1.90 (1H, m) , 2.62 (2H, d) , 5.81 an
S) , 6.78 (lH,d), 7.20 (2H, s), 7.48 (1H
S), 7.69 (1H, s), 7.81 (1H, s), 8.38 (1
9.74 and 10.03 (1H, 3 x br s), 10.55, 1
(1H, 3 x br s) ; IR (solid) 1614, 1580,
1471, 1433, 1409, 1374, 1340, 1240, 118
371.3 (M+H)+

Example 121 (5-Cyclopropyl-2H-pyrazol-dimethylphenylamino)-quinazolin-4-yl]-Prepared in a manner similar to the ab
Method A to afford an off-white solid,
NMR (DMSO) δ 0.58 (2H,brs),t) 0.86 (2H
s) , 2.11 (3H, brs), 2.28 (3H, s) , 5.7
br s,), 7.01 (1H, s) , 7.11 (1H, t) , 7.
(1H, d), 7.56 (1H, s) , 8.36 (1H, br s)
9.98 (1H, 3 x br s) , 10.48, 12.04 and
s); IR (solid) 1622, 1603, 1573, 1552,
1428, 1412, 1384, 1268; MS 371.4 (M+H)+
Example 122 (5-Cyclopropyl-2H-pyrazol-dimethoxyphenylamino)-quinazolin-4-yl]
Prepared in a manner similar to the abc
Method A to afford a grey solid, mp 14
0.69 (2H, S) , 0.86 (2H, d) , 1.89 (1H, r
3.67 (3H, s), 5.76 (1H, br s), 6.12 C
s), 6.66 (1H, d), 6.94 (1H, d), 7.27 C
d), 7.68 (1H, t), 8.45 and 9.36 (1H, b
9.42 and 10.54 (1H, s, rotamers), 12.2
s, rotamers); IR (solid) 3331, 3000, 2
1627, 1604, 1577, 1536, 1509, 1463, 144
1259, 1232, 1200, 1027; MS 403.8.(M+H)+
Example 123 (5-Cyclopropyl-2H-pyrazol-methoxyphenylamino)-quinazolin-4-yl]-an
Prepared in a manner similar to the abc
Method A to afford a grey solid, mp 207
(DMSO) 8 0.73 (2H, br s), 0.91 (2H, br
3.77 (3H, s), 5.81 and 6.71 (1H, 2 X br
7.19-7.85 (7H, m), 8.34 (1H, s), 9.08

(1H, 3 x br s), 10.56, 12.16 and 12.82
(solid) 1611, 1580, 1549, 1533, 1498, 1
1374, 1337, 1253, 1204, 1180, 1157, 114
992; MS 373.7 (M+H)+
Example 124 (5-Methyl-2H-pyrazol-3-yl)-5,6,7, 8-tetrahydroquinazolinin-4-yl)-am
Prepared in a manner similar to the abo
Method C.
Example 125 12-(Biphenyl-3-ylamino)-qui
cyclopropyl-2H-pyrazol-3-yl)-amine (IIc
a manner similar to the above described
afford a pale brown solid, mp 153°C; 1H
(2H, s) , 0.90 (2H, d) , 1.89 (1H, m), 5.
br s, rotamers) , 7.25 (2H, d) , 7.32 (2
t) , 7.68 (3H, m), 8.00 (1H, d) , 8.22 (1
(1H, br s) , 9.20 and 9.89 (1H, br s, ro
10.46 (1H, s, rotamers), 12.17 and 12.8
rotamers); IR (solid) 3333, 1627, 1609,
1472, 1449, 1426, 1335, 1248, 1216, 110.
419.3 (M+H)+
Example 126 (5-Cyclopropyl-2H-pyrazol-3
phenylprop-1-ylamino)-quinazolin-4-yl]-Prepared in a manner similar to the abo
Method A to afford a white solid, mp 18
6 0.71 (2H, S),.0.91 (2H, s), 1.89 (3H,
3.37 (2H, s) , 5.76 and 6.66 (1H, br s, :
7.60 (8H, m), 8.10-8.40 (1H, m), 9.89 i
s, rotamers), 12.10 and 12.75 (1H, br s,
(solid) 1622, 1595, 1572, 1545, 1499, 1*.
1367, 1048, 997, 829; MS 385.4 (M+H)+

Example 127 [2-(4-acetamido-3-methylph
quinazolin-4-yl]-(5-methyl-2H-pyrazol-(IIc-48): Prepared in a manner similar
described Method-A to-afford a pale br
251°C; 1H NMR (DMSO) δ 2.04 (3H, s) , 2
(3H, s), 5.92 and 6.80 (1H, br s, rota
s) , 7.48 (1H, s) , 7.64 (1H, s) , 7.73 (
s), 9.05 and 9.74 (1H, br s, rotamers)
10.05 and 10.54 (1H, br s, rotamers),
(1H, br s, rotamers) ; IR (solid) 3309,
1604, 1577, 1536, 1504, 1468, 1423, 14
1304, 1259, 1223, 1100, 1009, 864; MS
Example 12 8 (5-Cyclopropyl-2H-pyrazol-ylamino)-quinazolin-4-yl]-amine (IIc-4
manner similar to the above described
a brown solid, mp 233-234°C; 1H NMR (DI
0.84 (2H, s) , 1.83 (1H, s) , 2.91 (2H,
4.72 (1H, s), 6.07 (1H, br s), 7.00-7.
(1H, s), 10.30 (1H, br s), 12.24 (1H,
3425, 2941, 2836, 1622, 1595, 1572, 15
1426, 1394, 1248, 1025, 1007, 870, 833
Example 129 [2-(3-Methylphenylamino)-g
methyl-2£T-pyrazol-3-yl)-amine (IIc-50)
manner similar to the above described :
an off-white solid, mp 240-242°C; 1H NT
(3H, s), 2.30 (3H, s) , 5.95 (1H, br s)
7.10-7.35 (2H, m), 7.48 (1H, s), 7.55-
(1H, s) , 9.05 and 9.74 (1H, br s, rota
10.55 (1H, br s, rotamers), 12.14 and

rotamers); IR (solid) 3443, 2914, 2859,
1536, 1481, 1445, 1408, 1372, 1330, 126
1166, 1139, 993, 838, 806; MS 331.3 (M+
Example 13 0 [2-(2-Chloro-5-methylphenyl
4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine
in a manner similar to the above descri
afford a grey solid, mp 246-247°C; 1H Nl
(3H, s), 2.31 (3H, s), 6.37 (1H, br s),
7.23 (1H, s) , 7.37 (1H, d) , 7.4.3 (1H, d
7.97 (1H, s) , 8.19 (1H, s), 8.42 (1H, b
br s), 12.19 (1H, br s); IR (solid) 340
1627, 1591, 1573, 1545, 1513, 1486, 146
1332, 1291, 1259, 1182, 1000, 827; MS 3
Example 131 (5-Cyclopropyl-2H-pyrazQl-3
(morpholin-1-yl)phenylamino]-quinazolin
(IIc-52) .-Prepared in a manner similar
described Method A to afford a grey sol:
1H NMR (DMSO) δ 0.71, (2H, s), 0.90 (2H,
3.05 (4H, s) , 3.75 (4H, s) , 5.78 and 6.
rotamers), 6.93 (2H, s) , 7.20 (1H, s) ,
7.50-7.90 (3H, m) , 8.39 (1H, s) , 8.95 a
rotamers), 10.07 and 10.47 (1H, br s, re
and 12.81 (1H, br s, rotamers); IR (sol:
2972, 2959, 2936, 2918, 1618, 1577, 155
1445, 1413, 1382, 1264, 1223, 1150, 1105
823; MS 428.3 (M+H)+
Example 13 2 [2-(Benzothiazol-6-ylamino)-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-53
manner similar to the above described Me
an off-white solid, mp 236-239°C; 1H NMR

(3H, s), 6.35 (1H, br s), 7.22 (1H, t)
7.62 (1H, t), 7.76 (1H, d), 7.98 (1H, .
9.05 (1H, s), 9.17 (1H, s), 9.59 (1H,
brs), 12.35 (1H, br s) ; IR (solid) 16.
1546, 1505, 1473, 1441, 1417, 1385, 13
1253, 1192, 1130; MS 374.1 (M+H)+
Example 133 [2-(3 ,4-Dimethylphenylamin
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (
in a manner similar to the above descri
afford an off-white solid, mp 249-251°
2.18 (3H, br s) , 2.21 (3H, br s), 2.24
and 6.80 (1H, 2 x br s), 7.05 (1H, br
s) , 7.46 (1H, br s) , 7.64 (3H, br s) ,
9.00, 9.51 and 9.73 (1H, 3 x br s) , 10
12.17 (1H, 3 x br s) ; IR (solid) 1616,
1473, 1452, 1413, 1368, 1334, 1294, 12'
1170, 1139; MS 345.3 (M+H)+
Example 134 [2-(3-Ethylphenylamino)-qu;
methyl-2H-pyrazol-3-yl)-amine (IIc-55)
manner similar to the above described I
an off-white solid, mp 238-239°C; 1H NM
(3H, t) , 2.25 (3H, br s) , 2-61 (2H, q) ,
(1H, 2 x br s), 6.78 (1H, d), 7.21 (2H,
br s) , 7.65 (1H, s) , 7.72 (1H, s), 7.8C
(1H, br s), 9.09, 9.58 and 10.10 (1H, 2
12.26 and 12.81 (1H, 3 x br s); IR (sol
1535, 1471, 1441, 1407, 1377, 1341, 12'
1167, 1139, 995; MS 345.5 (M+H)+
Example 135 [2-(3-Methoxyphenylamino)-c
(5-methyl-2H-pyrazol-3-yl)-amine (IIc-5

manner similar to the above described
an off-white solid, mp 212-215°C; NM
(3H, br s) , 3.77 (3H, s) , 5.92 and 6.84
6.55 (1H, d), 7.13 (2H, m) , 7.41-7.50 (
s), 7.77 (1H, s) , 8.41 (1H, br s), 9.10
(1H, 3 x br s), 10.55, 12.13 and 12.82
(solid) 1610, 1576, 1532, 1494, 1468, 1
1256, 1201, 1159; MS 347.4 (M+H)+
Example 13 6 [2-(4-Acetamido-3-cyanophen
quinazolin-4-yl]-(5-methyl-2H-pyxazol-3
(IIc-57) : Prepared in a manner similar
described Method A to afford an off-whi
296°C; 1H NMR (DMSO) δ 2.08 (3H, s), 2.2
(1H, br s) , 7.27 (1H, s), 7.43 (1H, d) ,
7.68 (1H, s) , 8.04 (1H, d) , 8.45 (2H, S
12.18 (2H, 3 x br s), 10.00 (1H, s); IR
1583, 1558, 1237, 1508, 1477, 1446, 141:
1292, 1259, 1241, 1180, 1162, 1142, 110!
399.2 (M+H)+
Example 13 7 [2-(2-Methoxybiphenyl-5-yla
4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine
in a manner similar to the above descril
afford a white solid, 222-223°C; 1H NMR
s), 3.75 (3H, s), 6.82 (1H, br s), 7.05-7.15-7.25 (1H, m) , 7.30-7.36 (1H, m) , 7.
7.49-7.55 (2H, m), 7.55-7.70 (1H, m), 7.
7.90-8.02 (1H, m), 8.30-8.50 (1H, m); IR
1604, 1574, 1556, 1496, 1473, 1444, 1403
1234, 1182, 1018, 824, 806, 755, 698; MS

Example 138 [2-(4-Acetamidophenylami.no)
(5-methyl-2H-pyrazol-3-yl)-amine (IIc-5
manner similar to the above described 1
an off-white solid, mp 253-256°C; 1H NM
(3H, s), 2.25 (3H, br s) , 5.92 and 6.7
7.21 (1H, s) , 7.49 (3H, s), 7.63 (1H, s
8.38 (1H, br s) , 9.03 and 10.05 (1H, 2
S), 12.13 and 12.80 (1H, 2 x br s) ; IR
1635, 1617, 1574, 1535, 1512, 1486, 142
1316, 1268, 1231, 1184, 1119, 1101; MS
Example 13 9 [2-(4-text-Butoxycarbonylan
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3
(IIc-60): Prepared in a manner similar
described Method A to afford an off-whi
242°C; 1H NMR (DMSO) δ 1.48 (9H, s), 2.:
(1H, br s) , 7.12 (1H, s), 7.36 (3H, s),
7.67 (2H, d) , 8.30 (1H, d) , 9.14 (2H, b
12.19 (1H, 2 X br s); IR (solid) 1698,
1475, 1443, 1405, 1371, 1310, 1241, 116
432.1 (M+H)+
Example 140 [2-(4-Cyanophenylamino)-qui
methyl-2H-pyrazol-3-yl)-amine (IIc-61):
manner similar to the above described 14
an off-white solid, mp 293-298°C; 1H NMI
(3H, S), 6.50 (1H, br s), 7.27 (1H, s),
7.64 (1H, s) , 7.71 (2H, d), 8.40 (1H, s
s), 10.34 (1H, br s), 12.33 (1H, br s);
1605, 1571, 1517, 1505, 1469, 1418, 133'
1000; MS 342.1 (M+H)+

Example 141 (5-Methyl-2H-pyrazol-3-yl)
dihydro-4aH-benzo[c]chromen-2-ylaxmino)
amine (IIc-62): Prepared in a manner s
described Method A to afford a pale ye
298°C; 1H NMR (DMSO) δ 1.72 (3H, br s),
7.50 (1H, t) , 7.66 (2H, t), 7.75 (1H,
7.77 (1H, t), 8.26 (1H, d), 8.33 (1H,
m), 10.55 (1H, s), 11.55 (1H, s), 12.4
(solid) 1707, 1629, 1607, 1579, 1540,
1446, 1428, 1417, 1346, 1332, 1298, 12
1114, 998, 816, 793, 766, 758, 710, 68
Example 142 [2-(Biphenyl-3-ylamino)-qu
methyl-2H-pyrazol-3-yl)-amine (IIc-63)
manner similar to the above described
a pale brown solid, mp 206-207°C; 1H NM
(3H,s), 6.80 (1H, br s), 7.24-7.27 (2H
(2H, m), 7.48-7.52 (3H, m), 7.67-7.69
m), 8.26 (1H, m), 8.42 (1H, m), 9.30 (
(1H, br s), 12.13 (1H, br s) ; IR (soli
1544, 1498, 1479, 1414, 1384, 1251, 12
(M+H)+
Example 143 [2-(4-Methoxycarbonylmethy:
methylphenylamino)-quinazolin-4-yl]-(5
3-yl)-amine (IIc-64): Prepared in a ma:
above described Method A to afford a wl
246°C; 1H NMR (DMSO) δ 2.23 (3H, s), 2.
(3H, s) , 3.64 (2H, s) , 5.99 (0.5H, br
s), 7.10 (1H, m), 7.25 (1H, m), 7.50 C
(3H, m), 8.44 (1H, m), 9.10 (0.5H, br
s) , 10.11 (0.5H, br s) , 10.56 (0.5H, b1

br s) , 12.90 (0.5H, br s); IR (solid) 1
1581, 1554, 1538, 1508, 1490, 1446, 143
1306, 1257, 1244, 1204, 1146, 1016, 99E
MS 403.4 (M+H)+
Example 144 [2-(4-Carboxymethyl-3-methy
quinazolin-4-yl]-(5-methyl-2H-pyrazol-2
(IIc-65): A solution of [2-(4-methoxyca
methylphenylamino)-quinazolin-4-yl]-(5-3-yl)-amine (IIc-64, 2 00 mg, 0.5 mmol)
methanol/water (3/1, 8 mL) was treated
mL, 2 mmol). The mixture was heated at
and then neutralised with 1M HCl (2mL,
solid that formed was collected by filt
the title compound (185 mg, 95%) as a p
mp 245°C (dec); 1H NMR (DMSO) δ 2.27 (
S), 6.49 (1H, S), 7.13 (1H, d), 7.26 (1
d), 7.62-7.78 (3H, m) , 8.42 (1H, d), 9.
(1H, s), 12.36 (1H, s) ; IR (solid) 166C
1504, 1427, 1385, 810, 776, 751, 693; N
Example 14 5 [2-(4-Aminophenylamino)-qui
methyl-2H-pyrazol-3-yl)-amine (IIc-66):
(4-tert-Butoxycarbonylamino-phenylaminc
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (I
0.232 mmol) in a mixture of DCM/TFA (5/
stirred for 2 hours at room temperature
were removed in vacuo and the residue t
aqueous K2CO3. The resulting solid was
filtration and washed with diethyl ethe
(69 mg, 90%) as an off-white solid, mp
(DMSO) δ 2.24 (3H, s), 6.33 (1H, br s),
7.48 (3H, m), 7.58 (1H, d), 7.86 (1H, t

10.86 (1H, br s), 11.46 (1H, s). IR (sc
1496, 1433, 1415, 1187, 1129; MS 332.4
Example 14 6 [2-(4-Bromophenylamino)-qui
methyl-2H-pyrazol-3-yl)-amine (IIc-67):
manner similar to the above described
an off-white solid, mp 290-293°C; 1H NM
(3H, s), 6.71 (1H, br s), 7.22 (1H, m) ,
m), 7.66 (1H, m), 7.92-7.94 (2H, m), 8.
10.11 and 12.13 (3H, 3 x br s); 1R (sc
1548, 1486, 1436, 1409, 1372, 1238, 118
997; MS 395.1/397.1 (M+H)+
Example 147 [2-(4-Isobutyrylamino-pheny
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3
68): Prepared in a manner similar to th
Method A to afford a yellow solid, mp 1
(DMSO) δ 1.11 (6H, d) , 2.15 (3H, s) , 2.
(1H, br s), 7.41 (1H, d), 7.46 (1H, t),
7.71 (2H, d) , 7.84 (1H, t) , 8.64 (1H, d
10.34 (1H, br s) , 11.47 (1H, br s) , 12.-(solid) 1676, 1653, 1585, 1561, 1512, 1-1199, 1177, 1128; MS 402.3 (M+H)+
Example 148 (5-Ethyl-2H-pyrazol-3-yl)-[1
pyrazol-3-ylamino)-quinazolin-4-yl]-amin
solution of 2,4-dichloroquinazoline (0.5
3-amino-5-ethylpyrazole (558 mg, 5.02 mn
(10mL) was added triethylamine (0.35mL,
resulting mixture was stirred for 3 hour
temperature. The resulting pale yellow
collected by filtration, washed with col
dried under vacuum to afford IIc-69 (306

off-white solid, mp 248-252°C; 1H NMR
6H) , 2.72 (m, 4H) , 6.12 (br.s, 1H), 6.
1H), 7.58 (t, 1H), 7.74 (d, 1H), 7.90
1H) ; IR (solid) 1639, 1602, 1591, 1555
(M+H)+
Example 14 9 (1H-Indazol-3-yl)-(2-pheny:
4-yl)-amine (IIc-70) : Prepared in a ma
above described Method A to afford a wl
(DMSO) 5 6.90 (m, 3H), 7.11 (t, 1H), 7.
(t, 1H), 7.57 (m, 1H), 7.62 (d, 1H), 7.
(d, 1H), 7.93 (t, 1H), 8.59 (d, 1H), 13
13.15 (S, 1H); MS 353.2 (M+H)+
Example 15 0 (1H-Indazol-3-yl)-[2-(3-trifluoromethylphenylamino)-quinazolin-
(IIc-71): Prepared in a manner similar
described Method A to afford a pale yel
(DMSO) 8 7.00 (t, 1H), 7.02 (d, 1H), 7.
(td, 1H), 7.56 (m, 3H), 7.61 (d, 1H), 7
(t, 1H), 8.60 (d, 1H), 10.61 (br. s, 1H
1H), 13.12 (s, 1H); MS 421.2 (M+H)+
Example 151 (1H-Indazol-3-yl)-[2-(4-
trifluoromethylphenylamino)-quinazolin-
(IIc-72) : Prepared in a manner similar
described Method A to afford a pale yel
(DMSO) δ 7.08 (t, 1H), 7.16 (d, 2H), 7.4
(t, 1H), 7.6 (t, 2H), 7.69 (d, 1H), 7.9
(d, 1H) , 10.82 (br. s, 1H), 11.50 (br. s
1H); MS 421.2 (M+H)+

Example 152 [2-(Adamantan-2-ylamino)-q.
(1H-indazol-3-yl)-amine (IIc-73): Preps
similar to the above described Method ?
solid. 1H NMR (DMSO) δ 0.83 (br. s, 1H)
1.44 (m, 4H) , 1.55 (m, 3H) , 1.63 (s, 2H
1.82 (s, 1H) , 1.84 (s, 1H) , 3.56 (m, 1H
7.41 (t, 1H) , 7.51 (t, 1H) , 7.54 (d, 1H
7.69 (d, 1H) , 7.90 (t, 1H) , 8.45 (d, 1H
11.60 (s, 1H) , 13.10 (s, 1H) ; MS 411.3
Example 153 (1H-Indazol-3-yl)-(2-methyl
quinazolin-4-yl)-amine (IIc-74): Prepar
similar to the above described Method A
solid; 1H NMR (DMSO) δ 3.27 (s, 1H) , 6.
(t, 2H) , 7.04 (t, 1H) , 7.14 (d, 2H) , 7.
(m, 2H) , 7.48 (d, 1H) , 7.54 (d, 1H) , 7.
(d, 1H), 10.11 (s, 1H), 12.71 (s, 1H); :
Example 154 [2-(2-Chloro-phenyl)-amino-
(1H-indazol-3-yl)-amine (IIc-75): Prepa
similar to the above described Method A
solid. 1H NMR (DMSO) δ 6.81 (t, 1H) , 6.8
(t, 1H) , 7.34 (dd, 1H) , 7.35 (t, 1H), 7
(d, 1H) , 7.56 (d, 1H), 7.63 (d, 2H), 7.
(d, 1H), 8.46 (d, 1H), 10.37 (s, 1H), 1
387.1 (M+H)+
Example 155 (1H-Indazol-3-yl)-[2-(2-
trifluoromethylphenylamino)-quinazolin-4
76): Prepared in a manner similar to the
Method A to afford a white solid; 1H NMR
1H), 7.20 (m, 1H), 7.32 (m, 1H), 7.36 (t

1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.61
1H), 7.69 (d, 1H), 7.95 (t, 2H), 8.62
1H) , 11.62 (s, 1H) , 13.03 (s, 1H) ; MS.
Example 156 [2-(4-Cyanomethylphenylamin
yl]-(1H-indazol-3-yl)-amine (IIc-77) : ]
manner similar to the above described I
a white solid; 1H NMR (DMSO) δ 13.16 (s
s, 1H) , 10.38 (br. s, 1H) , 8.58 (d, 1H)
7.67 (t, 2H) , 7.61 (d, 1H) , 7.56 (m, 11
7.22 (m, 2H) , 7.08 (t, 1H) , 6.86 (m, 2P
MS 392.2 (M+H)+.
Example 157 [2-(4-Chlorophenylamino)-5,
tetrahydroguinazolinin-4-yl]-(5-methyl-amine (IIc-78): Prepared in a manner si
described Method C; MS 355.5 (M+H)+
Example 158 (5-Methyl-2H-pyrazol-3-yl)-6,7,8,9-tetrahydro-5H-cycloheptapyrimid
(IIc-79): Prepared in a manner similar
described Method C; MS 33 5.3 (M+H)+
Example 159 [2-(Benzimidazol-2-ylamino)
tetrahydro-pyrido [3,4-d] pyrimidin-4-yl]
pyrazol-3-yl)-amine (IIc-80): Prepared :
similar to the above described Method C
Example 160 (7-Benzyl-2-phenylamino-5,6
pyrido [3,4-d]pyrimidin-4-yl)-(5-methyl-
amine (IIc-81): Prepared in a manner sir
described Method C; MS 412.1 (M+H)+

Example 161 [6-Benzyl-2-(4-chloropheny
tetrahydro-pyrido[4,3-d]pyrimidin-4-yl
pyrazol-3-yl)-amine (IIc-82): Prepared
similar to the above described Method
Example 162 [2-(Benzimidazol-2-ylamino
tetrahydro-pyrido[4,3-d]pyrimidin-4-yl
pyrazol-3-yl)-amine (IIc-83): Prepared
similar to the above described Method
Example 163 (6-Benzyl-2-phenylamino-5,
pyrido[4,3-d]pyrimidin-4-yl)-(5-methyl
amine (IIc-84): Prepared in a manner s
described Method C; MS 411.9 (M+H)+
Example 164 (5-Methyl-2H-pyrazol-3-yl)
5,6,7,8-tetrahydro-pyrido[3,4-d]pyximic
(IIc-85): Prepared in a manner similar
described Method C; MS 322.3 (M+H)+
Example 165 [2-(4-Cyanbmethylphenylamin
yl]-(1H-pyrazolo[3,4-b]pyridin-3-yl)-an
Prepared in a manner similar to the abc
Method A to afford an off-white solid;
13.65 (s, 1H), 12.82 (br. s, 1H), 11.65
(dd, 2H) , 8.12 (d, 1H) , 7.88 (m, 1H) , 7
(m, 1H), 7.30 (m, 2H), 7.09 (m, 1H), 6.
(s, 2H); MS 3 93.1 (M+H)+.
Example 16 6 [2-(4-Cyanobenzylamino)-qui
pyrazolo[3,4-b]pyridin-3-yl)-amine (IIc
a manner similar to the above describee
afford an off-white solid; 1H NMR (DMSO

12.82 (br. s, 1H) , 11.70 (br. s, 1H) ,
(d, 1H) , 7.92 (t, 1H) , 7.59 (m, 4H) , 6
(m, 1H) , 4.23 (s, 2H) ; MS 393.1 (M+H)+.
Example 167 [2-(4-Cyanamethylphenylami
yl]-(4-fluoro-1H-indazol-3-yl)-amine C
in a manner similar to the above descr.
afford a white solid; 1H NMR (DMSO) δ 1
(br. s, 1H) , 10.64 (br. s, 1H) , 8.56 (
1H) , 7.67 (d, 1H) , 7.58 (t, 1H), 7.46
1H) , 7.14 (m, 2H) , 6.85 (dd, 3H), 3.88
(M+H)+.
Example 168 [2-(4-Cyanophenylamino)-qu
indazol-3-yl)-amine (IIc-89) : Prepared
similar to the above described Method i
solid; 1H NMR (DMSO) δ 13.14 (s, 1H), 1
10.51 (br. s, 1H) , 8.59 (d, 1H) , 7.91
3H) , 7.56 (t, 1H) , 7.50 (m, 2H) , 7.45
2H) , 7.08 (t, 1H) ; MS 378.2 (M+H)+.
Example 169 [2-(4-Cyanobenzylamino)-qu:
indazol-3-yl)-amine (IIc-90) : Prepared
similar to the above described Method 2
solid; 1H NMR (DMSO) δ 13.12 (s, 1H) , 1
11.60 (br. s, 1H) , 8.57 (d, 1H) , 7.91
1H) , 7.55 (m,5H), 7.38 (t, 1H) , 6.89 (t
d, 2H) , 4.19 (s, 2H); MS 392.2 (M+H)+.
Example 170 (5-Cyclopropyl-2H-pyrazol-2
(naphthalen-2-yloxy)-quinazolin-4-yl]-A
Prepared in a manner similar to the abc

Method B to afford a white solid, rap 32
(DMSO) δ-0.05-0.07 (2H, m), 0.50-0.68
(1H, m) , 5.68 (lH,s), 7.40-7.50 (2H, m)
m), 7.70-7.80 (2H, m), 7.82-8.08 (3H, m
10.58 (1H, s), 12.07 (1H, s); IR (solid
1575, 1554, 1508, 1480, 1410, 1385, 132
1212, 1166, 830, 819, 758; MS 394.4 (M+
Example 171 (5-Methyl-2H-pyrazol-3-yl)-
yloxy)-quinazolin-4-yl]-amine (IIb-2):
manner similar to the above described M
a pale brown solid, mp >300°C; 1H NMR (1
s), 5.65 (1H, s), 7.96 (2H, br s), 7.55
(2H, m), 7.92 (1H, d), 8.00 (2H, m), 8.
(1H, s), 11.99 (1H, s); IR (solid) 1625
1556, 1479, 1377, 1315, 1250, 1236, 121
368.7(M+H)+
Example 172 (5-Methyl-2H-pyrazol-3-yl)-
quinazolin-4-yl)-amine (IIb-3): Prepare
similar to the above described Method B
solid, mp 287-290°C; 1H NMR (DMSO) δ 2.1
(1H, s), 7.23 (2H, d), 7.29 (1H, t), 7.
7.53 (3H, m), 7.85 (1H, t), 8.58 (1H, d
12.11 (1H, s); IR (solid) 1622, 1602, 1
1477, 1454, 1402, 1373, 1316, 1249, 120
318.3(M+H)+
Example 173 (5-Cyclopropyl-2H-pyrazol-3
tetrahydronaphthalen-2-yloxy)-quinazoli
(IIb-4) : Prepared in a manner similar t
described Method B to afford a solid, m

(DMSO) δ 0.40-0.50 (2H, m) , 0.89-0.96
(5H, m), 2.70-2.83 (4H, m), 5.88 (1H,
m), 7.12 (1H, d) , 7.39 (lH,t), 7.58 (1
t), 8.58 (1H, d), 10.54 (1H, s), 12.20
(solid) 1731, 1641, 1614, 1570, 1506,
1362, 1340, 1240, 880, 831, 812, 776,
Example 174 (5-Cyclopropyl-2H-pyrazol-
methylphenoxy)-quinazolin-4-yl]-amine
in a manner similar to the above descr
afford an off-white solid, mp 283-284°
0.49-0.53 (2H, m), 0.89-0.96 (2H, m), :
2.40 (3H, s), 5.82 (1H, s), 7.03 (1H,
7.15 (1H, d) , 7.35-7.46 (2H, m), 7.58
t) , 8.62 (1H, d) , 10.58 (1H, s), 12.25
(solid) 1622, 1604, 1576, 1557, 1483,
1253, 1189, 1158, 997, 842, 789, 763; I
Example 175 [2-(3-Methoxyphenoxy)-quins
methyl-2H-pyrazol-3-yl)-amine (IIb-6) :
manner similar to the above described r
a white solid, mp 277-278°C; 1H NMR (DK
3.78 (3H, s), 6.00 (1H, s) , 6.77-6.90
(2H, m), 7.52 (1H, d), 7.70 (1H, t), 8.
(1H, s), 12.10 (1H, s) ; IR (solid) 1623
1556, 1487, 1456, 1430, 1373, 1316, 12E
1046, 1022, 833, 760; MS 348.4 (M+H)+
Example 176 [2-(3,4-Dimethoxyphenoxy)-c
(5-methyl-2H-pyrazol-3-yl)-amine (IIb-7
manner similar to the above described N
an off-white solid, mp 277-278°C; 1H NM

(3H, s) , 3.70 (3H, s), 3.78 (3H, s), 5
6.77 (1H, m), 6.90 (1H, s), 7.00 (1H, .
m) , 7.58 (1H, d), 7.70-7.78 (1H, m) , 8
(1H, s) , 12.19 (1H, s); IR (solid) 16
1557, 1509, 1481, 1436, 1409, 1382, 13
1227, 1195, 1180, 1158, 1120, 1029, 96
767,753; MS 378.4 (M+H)+
Example 177 [2-(Benzo[1,3]dioxol-5-ylo3
yl]-(5-methyl-2H-pyrazol-3-yl)-amine(2
a manner similar to the above described
afford an off-white solid, mp 296-299°C
(DMSO) 5 2.13 (3H, s), 6.05 (1H, s), 6.
(1H, d), 6.90 (1H, s) , 6.98 (1H, d) , 7.
(1H, d), 7.70 (lH,t), 8.58 (1H, d), 10.
(solid) 1602, 1577, 1538, 1508, 1499, 1
1377, 1323, 1251, 1241, 1169, 1121, 103
863, 813, 752; MS 362.4 (M+H)+
Example 178 [2-(3-Methoxycarbonylphenox
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (I
a manner similar to the above described
afford an off-white solid, mp 269-270°C
2.05 (3H, S), 3.90 (3H, s), 5.88 (1H, s
m), 8.50-8.65 (1H, m), 10.65 (1H, s); I
1626, 1605, 1578, 1559, 1507, 1429, 137
1272, 1255, 1204, 1185, 1096, 1021, 990
MS 3 62.4 (M+H)+
Example 179 (5-Cyclopropyl-2H-pyrazol-3
phenoxymethyl-quinazolin-4-yl)-amine (I:
a manner similar to the above described
afford a pale yellow solid, mp 265-267°

0.67 (2H, m), 0.93 2H, m), 1.87 (1H,
6.55 (1H, br s) , 6.90-7.02 (3H, m) , 7
7.54 (1H, m) , 7.74-7.83 (2H, m), 8.61
br s), 12.18 (1H, br s); MS 358.4 (M+H
Example 180 (2-Benzyloxymethyl-quinazo
cyclopropyl-2H-pyrazol-3-yl)-amine (II
manner similar to the above described I
a white solid, mp 211-213°C; 1H NMR (D
0.90 (2H, m), 1.86 (1H, m) , 4.63 (2H,
6.71 (1H, s) , 7.28-7.54 (6H, m), 7.76-
(1H, m) , 10.41 (1H, s), 12.19 (1H, s) ;
Example 181 (2-Benzyl-quinazolin-4-yl)
pyrazol-3-yl)-amine (IId-3): Prepared :
to the above described Method D to affc
mp 219-221°C; 1H NMR (DMSO) δ 0.66 (2H,
1.87 (1H, m), 4.11 (2H, S), 6.31 (1H,
m), 7.71-7.79 (2H, m), 8.55 (1H, m) , 1C
(1H, s); MS 342.7 (M+H)+
Example 182 (5-Cyclopropyl-2H-pyrazol-
quinazolin-4-yl)-amine (IId-4): Prepare
similar to the above described Method C
solid, mp 289-290°C; 1H NMR (DMSO) δ 2.
(3H, S), 6.73 (1H, s) , 7.75 (2H, q) , 8.
(1H, s), 11.94 (1H, s), 12.65 (1H, s);
1636, 1607, 1579, 1479, 1407, 769, 668;
Example 183 [2-(4-Chlorophenoxymethyl)-
tetrahydro-5H-cycloheptapyrimidin-4-yl]
pyrazol-3-yl)-amine (IId-5): Prepared i

to the above described Method C to aff
1H NMR (DMSO) δ1.58 (2H, m) , 1.68 (2H,
2.20 (3H, s) , 2.90 (2H, m) , 3.00 (2H, i
6.15 (1H, s), 7.15 (2H, d), 7.40 (2H, i
MS 3 84.3 (M+H)+.
Example 184 [2-(4-Chlorophenoxymethyl)
tetrahydro-quinazolin-4-yl]-(5-methyl-
amine (IId-6): Prepared in a manner sir
described Method C to afford a white sc
51.80 (4H, m) , 2.15 (3H, s) , 2.55 (2H,
(2H, m) , 5.25 (2H, s) , 6.12 (1H, s) , 7.
(2H, d) , 9.80 (1H, br) ; MS 370.2 (M+H)+
Example 18 5 (5-Cyclopropyl-2H-pyrazol-
(naphtalen-2-ylsulfanyl)-6-phenylpyrimi
(IIIa-1) .-Prepared in a manner similar
described Method L to afford a white sc
1H NMR (DMSO) δ 0.21 (2H, br s) , 0.56 (.
(1H, br m), 5.35 (1H, br s), 7.02 (1H,
m), 7.59 (2H, m), 7.73 (1H, d), 7.88 (2
m), 8.30 (1H, m), 10.01 (1H, s), 11.75
(solid); MS 436.7(M+H)+
Example 18 6 (5-Cyclopropyl-2H-pyrazol-3
methoxycarbonyl-phenylylsulfanyl)-6-phe
yl]-amine (IIIa-2) : Prepared in a manne
above described Method L to afford a wh
129°C; 1H NMR (DMSO) δ 0.52 (2H, m) ,
(1H, m) , 3.87 (3H, s) , 5.47 (1H, s), 7.
7.49 (3H, m) , 7.67 (1H, m) , 7.87 (2H, m

8.09 (1H, m), 8.23 (1H, m), 10.07 (1H,
IR (solid); MS 444.7(M+H)+
Example 18 7 (5-Cyclopropyl-2H-pyrazol-:
(naphthalen-2-ylsulfanyl)-pyrimidin-4-]
Prepared in a manner similar to the abc
Method L to afford a white solid, mp 2
(DMSO) δ 0.21 (2H, br s), 0.55 (2H, br
m) , 5.31 (1H, br s), 6.55 (1H, br s),
7.99-8.03 (4H, m), 8.25 (1H, s), 9.94
br s); IR (solid); MS 360.7(M+H)+
Example 18 8 (5-Cyclopropyl-2H-pyrazol-
dimethyl-2-(naphthalen-2-ylsulfanyl)-py
amine (IIIa-4). Prepared in a manner Si
described Method L to afford a white sc
NMR (DMSO) δ 0.14 (2H, d), 0.45 (2H, d)
2.05 (3H, s), 2.27 (3H, s), 5.26 (1H, s
7.99 (3H, d), 8.21 (1H, s), 8.66 (1H, s
IR (solid) 1560, 1508, 1478, 1288, 1176
740, 669; MS 388.7(M+H)+
Example 189 (5-Cyclopropyl-2H-pyrazol-3
(naphthalen-2-ylsulfanyl)-pyrimidin-4-y
Prepared in a manner similar to the abc
Method L to afford a white solid, mp 19
δ 0.21 (2H, d), 0.51 (2H, d), 0.78 (1H,
5.40 (1H, s), 7.57 (2H, d), 7.62 (1H, 6
7.97 (3H, d), 8.22 (1H, s), 8.88 (1H, s
IR (solid) 1738, 1583, 1563, 1488, 1460
808, 656; MS 374 . 2 (M+H)+.

Example 190 (5-Cyclopropyl-2H-pyrazol-2
(naphthalen-2-ylsulfanyl)-pyrimidin-4-y
Prepared in a manner similar to the abc
Method L to afford a white solid, mp 23
5 0.15 (2H, s) , 0.51 (2H, s), 0.92 (1H,
5.22 (1H, S), 7.60 (2H, s), 7.67 (1H, C
8.24 (1H, s), 9.79 (1H, s), 11.60 (1H,
1586, 1508.7, 1485, 1282, 1180, 815, 78
MS 3 74.2(M+H)+
Example 191 (5-Cyclopropyl-2H-pyrazol-3
(morpholin-4-yl)-2-(naphthalan-2-ylsulf
yl]-amine(IIIa-7): To a solution of 2,
trichloropyrimidine (600 mg, 3.27 mmol)
cyclopropylpyrazole (403 mg, 3.27 mmol)
was added triethylamine (456 µL, 3.27 m
reaction mixture was stirred for 15 hou
temperature. The solvent was evaporate
was purified by flash chromatography (S
gradient) to afford (5-cyclopropyl-2H-p
dichloropyrimidin-4-yl)-amine (705 mg,
To a solution of (5-cycloprop
yl)-(2,6-dichloropyrimidin-4-yl)-amine
mmol) and 2-naphthalenethiol (125 mg, 0
tert-butanol (5 mL) was added triethyla
mmol) and the resulting mixture was heat
15 hours. The reaction mixture was coo
temperature and partitioned between ethy
aqueous NaHCO3. The organic layer was w
dried over MgSO4 and concentrated in vac
was purified by flash chromatography (Si
gradient) to afford [6-chloro-2-(naphtha

ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopr
yl)-amine.
The above formed [6-chloro-2
ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopr
yl)-amine (70 mg, 1.78.10-4 mol) was d:
morpholine (3 mL) and the mixture heat
hours. The solvent was evaporated and
purified by flash chromatography to af
63%) as a white solid, mp 118-120°C;
0.91 (4H, 4xm) , 1.28 and 1.78 (1H, 2xrr
3.60 (6H, m), 5.38-6.16 (2H, br m), 7.
7.95-8.02 (3H, m), 8.19 and 8.23 (1H,
(1H, 2xbr s), 11.71 and 11.84 (1H, 2xt
MS 445.2(M+H)+
Example 192 (5-Cyclopropyl-2H-pyrazol-
methylpiperazin-4-yl)-2-(naphthalen-2-
pyrimidin-4-yl]-amine (IIIa-8): Prepar
substantially similar to the method de
compound IIIb-7 to afford a white soli
NMR (DMSO) δ 0.35-0.91 (4H, 4xm), 1.31
2xm), 2.17 and 2.19 (3H, 2xs), 2.29 (4
m) , 3.61 (2H, m), 5.38-6.20 (2H, br m)
m) , 7.95-8.02 (3H, m) , 8.17 and 8.23 (
9.32 (1H, 2xbr s), 11.71 and 11.85 (1H
(solid) ; MS 458.3 (M+H) +
Example 193 [6-(2,6-Dimethylphenyl)-2-
ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-
amine (IIIa-9): Prepared in a manner s
described Method L to afford an off-wh
152°C; 1H NMR (DMSO) δ 2.10 (6H, s), 2.
and 6.31 (1H, 2x br s), 7.03 (3H, s),

(2H, t) , 7.69 (1H, d) , 7.99 (3H, d), 8
(1H, s) , 11.67 (1H, br s) ; IR (solid)
1365, 1229, 1217, 1205; MS 438.3(M+H)+
Example 194 [6-(2-Methylphenyl)-2-(napl
ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-
amine (IIIa-10): Prepared in a manner
above described Method L to afford a w
214°C; 1H NMR (DMSO) δ 1.41 (3H, s), 2
and 6.55 (1H, 2x br s), 7.34 (5H, m),
(1H, d), 7.99 (3H, t), 8.30 (1H, s), 9
(1H, br s); IR (solid) 2356, 1615, 158
822, 761; MS 424.0(M+H)+
Example 195 [2-(4-Acetamido-phenylsulf
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3
11): Prepared in a manner similar to
Method L to afford a white solid, mp
(DMSO) δ 2.01 (3H, s) , 2.08 (3H, s) , 5
(1H, br s), 7.49-7.88 (9H, m), 10.00 C
(1H, s), 11.86 (1H, br s) ; MS 417.2(M+
Example 196 (5-Methyl-2H-pyrazol-3-yl)
ylsulfanyl)-6-phenyl-pyrimidin-4-yl]-a
Prepared in a manner similar to the ab
Method L to afford a white solid, mp 2
(DMSO) δ 1.39 (3H, br s), 5.12 (1H, br
s), 7.50 (3H, m), 7.62-7.63 (2H, m), 7
(2H, m), 8.03-8.05 (3H, m), 8.31 (1H,
11.73 (1H, br s) ; IR (solid) ; MS 410
Example 197 [2-(4-Isobutyrylylamino-ph
phenylpyrimidin-4-yl]-(5-methyl-2H-pyr

(IIIa-13): Prepared in a manner simila
described Method L to afford an off-wh
202 °C; 1H NMR (DMSO) δ 1.05-1.13 (6H, n
2.65 (1H, m) , 5.37 (1H, br s) , 6.93 (i:
(5H, m), 7.78-7.90 (4H, m), 9.99, 10.1
X br s); IR (solid) 1676, 1614, 1586,
1395, 1299, 1262, 1242, 1214, 1168, 10
445.3(M+H)+
Example 198 [6-(4-Methylpiperazin-1-yl
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3
14) : Prepared in a manner similar to t
Method M to afford an off-white solid;
2.18 (3H, s) , 2.20 (3H, s) , 2.36 (4H, I
3.46 (4H, m), 5.91 (1H, s), 6.41 (1H, 3
s) , 11.87 (1H, s) ; IR (solid); MS 320.:
Example 199 (5-Methyl-2H-pyrazol-3-yl)
propionylamino-phenylsulfanyl)-pyrimid:
(IIIa-15) : Prepared in a manner similar
described Method L to afford a pale pi
206°C; 1H NMR (DMSO) δ 1.09-1.13 (3H, m
2.33-2.37 (2H, m) , 5.40 (1H, br s) , 6.5
(3H, m) , 7.56-7.58 (2H, m) , 7.76-7.78
m) , 9.99, 10.15 and 11.85 (3H, 3 X br
1678, 1623, 1580, 1534, 1496, 1453, 13S
1203, 1119, 1049, 1030, 1004; MS 431.2 1
Example 200 [2-(4-Cyclopropanecarbonyl
phenylsulfanyl)-6-phenylpyrimidin-4-yl]
pyrazol-3-yl)-amine (IIIa-16): Prepared
similar to the above described Method I

white solid, rap 253-255°C; 1H NMR (DMSO
m), 1.83 (1H, m), 2.00 (3H, s), 5.41 (1
(1H, br s), 7.42-7.50 (3H, m), 7.56-7.5
7.78 (2H, m), 7.89 (2H, m), 9.99, 10.47
X br s); IR (solid) 1672, 1621, 1591, 1
1495, 1448, 1405, 1390, 1312, 1254, 124
1179, 1119.2, 1005, 959; MS 443.2(M+H)+
Example 201 (5-Methyl-2H-pyrazol-3-yl)-
(propane-1-sulfonylamino)-phenylsulfany
yl}-amine (IIIa-17): Prepared in a mann
above described Method L to afford an c
232-235°C; 1H NMR (DMSO) δ 0.94 (3H, t)
2.12 (3H,s), 3.13 (2H, t), 5.59 (1H, s)
7.49 (3H, s), 7.59 (2H, d), 7.85 (2H, S
s), 10.16 (1H, s), 12.05 (1H, br s); IR
1587, 1545, 1525, 1496, 1455, 1311, 125
1186, 1140, 1032, 1001, 934; MS 481.2(M
Example 202 [2-(4-Ethanesulfonylamino-p
phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyr
(IIIa-18): Prepared in a manner similar
described Method L to afford a pale yel
254°C; 1H NMR (DMSO) δ 1.21 (3H, t), 2.
(2H, q), 5.59 (1H, s), 7.32 (2H, d), 7.
(2H, d), 7.85 (2H, s), 9.99 (1H, br s),
11.90 (1H, br s); IR (solid) 1621, 1585
1495, 1455, 1315, 1257, 1208, 1142, 104
932; MS 467.2(M+H)+
Example 203 [2-(4-Acetamldophenyl-sulfa
methylphenyl)-pyrimidin-4-yl]-(5-methyl

amine (IIIa-19): Prepared in a manner
above described Method L to. afford a v
214°C; 1H NMR (DMSO) δ 2. 01 (3H, s) , 2
(3H, s), 5.43 (1H, s) , 6.56 (1H, br s)
m), 10.00 (1H, br s) , 10.23 (Iff, s), 1
(solidl701, 1S34, 1588, 1555, 1496, 13
1169, 823, 803; MS 431.4(M+H)+
Example 2 04 [2-(4-Isobutanecarbonylami
sulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-
3-yl)-amine (IIIa-20) : Prepared in a m
the above described Method L to afford
solid, mp 241-243 °C; 1H NMR (DMSO) δ 0.
2.00 (3H, s), 2.11 (1H, m), 2.23-2.25
br s), 6.95 (1H, br s) , 7.50-7.58 (5H,
m), 10.00, 10.13 and 11.84 (3H, 3 x br
1660, 1628, 1589, 1575, 1543, 1525, 14
1357, 1314, 1301, 1251, 1206, 1108, 99
Example 205 [2-(4-Acetamido-phenyl-sul
phenyl-pyrimidin-4-yl]-(5-methyl-2H-py
(IIIa-21) : Prepared in a manner simila:
described Method L to afford a pale pii
277°C; 1H NMR (DMSO) δ 1.98 (3H, s) , 2.
(1H, br s), 7.47-7.55 (7H, m), 7.72-7.'
10.20 and 11.87 (3H, 3 x br s) ; IR (so
1555, 1540, 1519, 1493, 1393, 1375, 13(
1176, 1148, 1045, 1011, 969; MS 431.2
Example 206 [2-(4-Acetamido-phenyl-sull
methoxyphenyl)-pyrimidin-4-yl]-(5-methy
yl)-amine (IIIa-22) : Prepared in a manr

above described Method L to afford an c
241-245°C; 1H NMR (DMSO) δ 1.99 (3H,s),
(3H, s), 5.44 (1H, s), 7.03 (2H, d), 7.
(2H, S), 7.83 (2H, s), 10.12 (1H, s), 3
11.84 (1H, s); IR (solid) 1627, 1606,
1257, 1181, 830; MS 447.2 (M+H)+
Example 207 [6-(3-Acetamidophenyl)-2-(
phenyl-sulfany1)-pyrimidin-4-yl]-(5-met
yl)-amine (IIIa-23) .-Prepared in a manr
above described Method L to afford a b
230°C; 1H NMR (DMSO) δ 2.01 (3H, s), 2
(1H, s) , 6.99 (1H, br s) , 7.41 (1H, t),
m) , 3.71-3.76 (3H, m) , 8.19 (1H s) , 10.
s) , 10.23 (1H, s) , 12.20 (1H, br s) ; IR
1573, 1533, 1488, 1372, 1318, 1297, 827
(M+H)+
Example 208 [2-(4-Isopropanesulfonylami
sulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-m
3-yl)-amine (IIIa-24): Prepared in a ma
the above described Method L to afford
255-257°C; 1H NMR (DMSO) δ 1.28 (6H, d) ,
(1H, S), 5.60 (1H, s) , 7.36 (2H, d), 7.
(2H, d) , 7.85 (2H, s) , 10.00 (1H, br s)
11.92 (1H, br s); IR (solid) 1625, 1587
1525, 1495, 1313, 1295, 1257, 1234, 113
481.2 (M+H)+
Example 209 {2-[4-(2-Dimethylamino-acet
phenylsulfanyl]-6-phenyl-pyrimidin-4-yl
pyrazol-3-yl)-amine (IIIa-25): Prepared

similar to the above described Method
white solid, mp 213-215°C; 1H NMR (DMS
2.31 (6H, s), 3.15 (2H, s), 5.45 (1H,
S), 7.46-7.51 (3H, m), 7.59 (2H, d), 7
9.98 (1H, S), 10.05 (1H, s); IR (solid
1571, 1509, 1480, 1456, 1304, 1284, 12
1181, 1156, 987, 833, 782, 754, 695; M
Example 210 [2-(3-Chloro-benzylsulfany
yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazo
(IIIa-26): Prepared in a manner simila
described Method M to afford a white s
1H NMR (DMSO) δ 2 . 17 (3H, s), 3.40-3.5C
(4H, m), 4.30 (2H, s), 5.95 (1H, brs),
7.23-7.55 (4H, m), 9.31 (1H, s) , 11.89
(solid) 1557, 1476, 1442, 1401, 1314,
MS 417.4 (M+H)+
Example 211 [2-(3-Chloro-benzylsulfanyl
ethylamino)-pyrimidin-4-yl]-(5-methyl-
amine (IIIa-27): Prepared in a manner
above described Method M to afford a w
102°C; 1H NMR (DMSO) δ 2.15 (3H, s) , 3
3.41 (4H, m), 4.29 (2H, s), 5.78 (1H, 1
brs), 7.10 (1H, brs), 7.21-7.50 (4H, m)
IR (solid) 1598, 1555, 1527, 1336, 1293
783; MS 405.4 (M+H)+
Example 212 [2-Benzylsulfanl-6-(4-meth
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
(IIIa-28): Prepared in a manner similar
described Method M to afford a yellow c

5 2.23 3H, s), 2.28 (3H, s) , 2.31-2.6
3.65 (4H, m) , 4.38 (2H, s) , 5.83 (1H,
S), 7.17-7.49 (5H, m) , 7.98-8.18 (1H, 1
1555, 1494, 1371, 1315, 1286, 1233, 99:
709; MS 396.4 (M+H)+
Example 213 [2-Benzylsulfanyl-6-morpho
4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine
Prepared in a manner similar to the abc
Method M to afford an off-white foam;
2.31 (3H, s), 3.39-3.80 (8H, m), 4.39
s) , 6.25 (1H, brs), 7.20-7.50 (5H, m),
(solid) 1557, 1486, 1442, 1314, 1229, 1
698; MS 383.4 (M+H)+
Example 214 [2-(3-Chloro-benzylsulfanyl
methylpiperazin-1-yl)-pyrimidin-4-yl]-(
pyrazol-3-yl)-amine (IIIa-30): Prepared
similar to the above described Method M
foam; 1H NMR (CDCl3) δ 2.31 (3H, s) , 2.3
2.51 (4H, m), 3.56-3.69 (4H, m), 4.34 (
s) , 6.29 (1H, brs), 6.89 (1H, s) , 7.18-
(solid) 1553, 1514, 1484, 1446, 1277, 1
430.4 (M+H)+
Example 215 [2-(4-methoxy-benzylsulf any
methylpiperazin-1-yl)-pyrimidin-4-yl]-(
pyrazol-3-yl)-amine(IIIa-31): Prepared
similar to the above described Method M
yellow oil; 1H NMR (CDCl3) δ 2.28 (3H, S
2.44-2.45 (4H, m), 3.62 (4H, m), 3.80
s), 5.32 (1H, s), 6.28 (1H, br s), 6.83

7.34-7.36 (2H, m) ; IR (solid) 1659, 15
1449, 1366, 1318, 1302, 1277, 1230, 11
999, 973, 948; MS 443.4 (M+H)+
Example 216 [2-(4-Acetamido-phenyl-sul
butyl-pyrimidin-4-yl]-(5-methyl-2H-pyri
(IIIa-32): Prepared in a manner simila
described Method L to afford a white s
1H NMR (DMSO) δ 1.10 (3H, br s), 1.20
s) , 2.35 (2H, q) , 5.35 (1H, br s) , 6.5
(2H, d), 7.75 (2H, d), 10.1 (1H, br s)
12.1 (1H, br S); IR (solid); MS (M+H)+
Example 217 (5-Cyclopropyl-2H-pyrazol-
(4-propionylamino-phenyl-sulfanyl)-pyr
(IIIa-33): Prepared in a manner simila
described Method L to afford an off-wh
209°C; 1H NMR (DMSO) δ 0.52 (2H, m), 0.
1.10 (3H, m), 1.65 (1H, br s), 2.33-2.
(1H, br s), 7.03 (1H, br s), 7.47 (3H,
m), 7.76-7.77 (2H, m), 7.88-7.98 (2H, r
and 11.86 (3H, 3 x br s) ; IR (solid)
1539, 1520, 1485, 1459, 1418, 1395, 13(
1215, 1161, 1071, 990; MS 457.4 (M+H)4
Example 218 [2-(3-Chloro-benzylsulfany]
yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazc
(IIIa-34): Prepared in a manner simila:
described Method M to afford a white sc
1H NMR (DMSO) δ 1.40-1.64 (6H, m) , 2.13
(4H, m), 4.27 (2H, s), 5.85 (1H, br s),
7.23-7.41 (3H, m), 7.48 (1H, s), 9.18 (

s) ; IR (solid) 1598, 1546, 1483, 1398,
79 8, 779; MS 415.4 (M+H)+
Example 219 (5-Methyl-2H-pyrazol-3-yl)
(morpholinesulfonyl)-benzylsulfanyl]-6
-pyrimidin-4-yl}-amine (IIIa-35): Prepa
similar to the above described Method
solid; 1H NMR (DMSO) δ 2.24 (3H, s), 2.
3.29-3.36 (4H, m), 3.48-3.57 (4H, m) ,2
4.43 (2H, s) , 5.82-6.10 (2H, m) , 7.50-
(solid) 1550, 1483, 1441, 1346, 1308, 3
941, 726; MS 532.5 (M+H)+
Example 220 {6-(2-Methoxy-ethylamino)-2
(morpholinesulfonyl)-benzylsulfanyl]-py
methyl-2H-pyrazol-3-yl)-amine (IIIa-36)
manner similar to the above described
a white solid, mp 193-195°C; 1H NMR (DM,
2.79-2.89 (4H, m) , 3.34 (3H, s) , 3.40-3
3.67 (4H, m), 4.41 (2H, s), 5.76-5.72 (
brs), 7.10 (1H, brs), 7.61-7.74 (4H, m)
11.81 (1H, brs); IR (solid) 1593, 1555,
1255, 1160, 1107, 936; MS 520.5 (M+H)+
Example 221 {6-(4-methylpiperazin-1-yl)
(morpholinesulfonyl)-benzylsulfanyl]-py
methyl-2H-pyrazol-3-yl)-amine (IIIa-37)
manner similar to the above described M
a, white solid, mp 206-207°C; 1H NMR (DMS
2.20 (3H, s), 2.26-2.40 (4H, m), 2.78-2
3.49 (4H, mf, 3.56-3.67 (4H, m) , 4.41 0
brs), 6.42 (1H, brs), 7.60-7.74 (4H, m) .

11.89 (1H, brs); IR (solid) 1583, 1558
1160, 1112, 998, 969, 926; MS 545.5 (M
Example 222 [6-Methoxymethyl-2-{4-prop
sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H
amine (IIIa-38): Prepared In a manner
above described Method L to afford a w
(DMSO) δ 1.03-1.14 (3H, m) , 2.00 (3H,
m), OMe under DMSO, 4.22 (2H, m), 5.26
(1H, brs), 7.44-7.56 (2H, m), 7.68-7.8
(1H, brs), 10.11 (1H, s), 11.79 (1H, b
1670, 1593, 1517, 1479, 1393, 1360, 12
399.4 (M+H)+
Example 223 [2-(4-Methoxycarbonyl-phen
methoxymethyl-pyrimidin-4-yl]-(5-methy
amine (IIIa-39): Prepared in a manner ,
above described Method L to afford a w
205°C; 1H NMR (DMSO) δ 1.89 (3H, brs),
under DMSO, 4.23 (2H, s), 5.22 (1H, br,
7.70-7.81 (2H, m) , 7.96-8.06 (2H, m), :
11.85 (1H, brs); IR (solid) 1721, 1621
1289, 1271, 1178, 1119, 1109, 997, 841
Example 224 [2-(3,5-Dimethoxy-benzylsu.
morpholin-4-yl-pyrimidin-4-yl]-(5-meth:
yl)-amine(IIIa-40): Prepared in a ma
above described Method M to afford a wl
(DMSO) δ 2.15 (3H, s), 3.40-3.49 (4H, n
m), 4.25 (2H, s) , 5.88 (1H, brs), 6.31
(1H, s) , 11-86 (1H, s);IR (solid) 158'.
1439, 1315, 1232, 1205, 1159, 1144; MS

Example 225 [2-(3,5-Dimethoxy-benzylsul
pyrrolidin-4-yl-pyrimidin-4-yl]-(5-meth
yl)-amine (111a-41): Prepared in a mann
above described Method M to afford a wh
(DMSO) δ 1.80-1.97 {4H, m), 2.15 (3H, s
m), 3.69 (6H, s), 4.26 (2H, s), 5.85 (1
brs), 6.35 (1H, brs), 6.60 (2H, s), 9.1
(1H, s); IR (solidl598, 1560, 1474, 147
1207, 1136, 1050; MS 427.4 (M+H)+
Example 226 (5-Methyl-2H-pyrazol-3-yl)-2-(naphth.alene-2-ylmethylsulfanyl)-pyri:
(IIIa-42): Prepared in a manner similar
described Method M to afford an off-whi
(DMSO) δ 2.15 3H, s) , 3.37-3.50 (4H, m
m), 4.48 (2H, s), 5.88 (1H, brs), 6.40
7.60 (3H, m), 7.78-7.95 (4H, m), 9.30 (
brs); IR (solid) 1607, 1555, 1484, 1441
1308, 1231, 1179, 1112; MS 433.4 (M+H)+
Example 227 {2-(4-Acetamido-phenyl-sulf.
dimethylamino-propoxy)-phenyl]-pyrimidi
2H-pyrazol-3-yl)-amine(IIIa-43): Prepa
similar to the above described Method N
solid, mp 219-222°C; 1H NMR (CDCl3) δ.1.
2.14 (3H, s), 2.18 (3H, s), 2.30 (6H, s
4.09 (2H, t) , 5.56 (1H, s) , 6.80 (1H, b:
d) , 7.60 (2H, d) , 7.68-7.78. (3H, m) , 7.1
(solid) 1606, 1590, 1512, 1482, 1309,
1178, 1151, 1055, 989, 824, 711, 690, 6
(M+H)+

Example 228 [2-(4-Acetamidophenylsulfa
4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyr
(IIIa-44): Prepared in a manner simila
described Method P to-afford a white s
(M+H)+
Example 229 [6-Hydroxymethyl-2-(4-prop
sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H
amine (IIIa-45): Prepared from IIIa-48
Method O to afford a white solid; 1H NM
1.18 (3H, m) , 1.96 (3H, brs) , 2.29-2.41
4.40 (3H, m), 5.20-5.46 (2H, m), 6.56
d) , 7.79 (2H, d), 9.90 (1H, brs) , 10.11
(1H, brs); MS 385.4 (M+H)+
Example 230 [2-(4-Acetamido-phenyl-sul
yl]-(5-methyl-2H-pyrazol-3-yl)-amine (1
in a manner similar to the above descri
afford an off-white solid, mp 249-250°C
1.99 (3H, s), 2.08 (3H, s), 5.38 (1H,
S) , 7.50 (2H, d) , 7.71 (2H, d) , 7.98 (3
br s), 10.19 (1H, br s), 11.83 (1H, br
1657, 1609, 1584, 1515, 1494, 1468, 13S
1330, 1316, 1201, 1175, 1157, 1027, 993
Example 231 [6-(1-Butoxycarbonyl)-2-(4-
phenyl-sulfanyl)-pyrimidin-4-yl]-(5-met
yl)-amine (IIIa-47): Prepared in a mann
above described Method L to afford a ye
(DMSO) δ 0.90-0.98 (3H, m), 1.03-1.12 (
(2H, m), 1.60-1.71 (2H, m), 1.94 (3H, b

(2H, m), 4.20-4.30 (2H, m) , 5.25 (1H, I
brs), 7.49-7.55 (2H, m), 7.72-7.81 (2H,
brs), 10.32 (1H, brs), 11.89 (1H, brs);
1679, 1622, 1584, 1517, 1489, 1284, 117
Example 232 [6-Methoxycarbonyl-2-(4-prc
phenyl-sulfanyl)-pyrimidin-4-yl]-(5-met
yl)-amine(IIIa-48): Prepared in a mann
above described Method L to afford a ye
(DMSO) δ 1.10 (3H, t) , 1.94 (3H, brs),
(3H, s), 5.22 (1H, brs), 7.05 (1H, s),
(2H, d), 10.18 (1H, brs), 10.38 (1H, br
brs).; IR (solid) 1741, 1679, 1617, 158
1374, 1284, 1250; MS 413.4 (M+H)+
Example 233 (5-Methyl-2H-pyrazol-3-yl)-
phenylamino-pyrimidin-4-yl)-amine (IIIc
MS 343.4(M+H)+
Example 234 (5-Cyclopropyl-2H-pyrazol-3
phenylamino-pyrimidin-4-yl)-amine (IIIc
mp 267-269°C; 1H NMR (DMSO) δ 0.63 (2H,
1.87 (1H,m), 6.07 (1H, s), 6.84 (1H, br
7.33-8.05 (9H, m), 10.52 (1H, br s), 11
12.53 (1H, br s); IR (solid); MS 369.7
Example 235 (5-Cyclopropyl-2H-pyrazol-3
methylphenylamino)-6-phenyl-pyrimidin-4
3): white solid, mp 267-270°C; 1H NMR (I
m) , 0.94 (2H, m) , 1.87 (1H,m), 2.36 (3H
s), 6.81 (1H, br s), 7.03 (1H, m), 7.29
10.43 (1H, br s) , 11.12 (1H, br s) , 12.
(solid); MS 3 83.7 (M+H)+

Example 236 [2-(4-cyanome thylphenylami
pyrimidin-4-yl]-(5-cyclopropyl-2H-pyra
(IIIc-4): pale yellow solid, mp 294-29
0.64 (2H, m), 0.97 (2H, m), 1.89 (1H,
6.07 (1H, s), 6.87 (1H, br s), 7.40 (2
(5H, m), 7.95 (2H, m), 10.51 (1H, br s
s), 12.57 (1H, br s); IR (solid); MS 4
Example 237 (5-Cyclopropyl-2H-pyrazol-
(pyridin-3-ylmethylamino)-pyrimidin-4-
off-white solid, mp 191-193°C; 1H NMR
m), 0.89 (2H, m), 1.83 (1H, m), 4.59 (
br s), 6.76 (1H, br s), 7.32-7.56 (5H,
7.88-7.97 (2H, m), 8.43 (1H, m), 8.61
brs), 11.93 (1H, br s) ,-IR (solid); M
Example 238 [2-(3-Chlorophenyl)amino-6
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3
6) : Off-white solid; 1H NMR (CD3OD) δ 5
(1H, s), 6.90 (1H, d), 7.18 (1H, t), 7
(1H, t) , 7.82 (1H, s) , 8.18 (1H, d) , 8
(1H, s) ; MS 422.1 (M+H)+
Example 239 [2-(3-Chlorophenyl)amino-6
trimethoxyphenyl)-pyrimidin-4-yl]-(5-m
yl)-amine (IIIc-7): white solid; MS 46
Example 240 (5-,Methyl-2H-pyrazol-3-yl)
sulfamoylphenylamino)-6-(3,4,5-trimeth
pyrimidin-4-yl]-amine (IIIc-8): white
(M+H)+

Example 241 [2-(4-Chlorophenyl) amino-6-
4-yl]-[5-(furan-2-yl)-2H-pyrazol-3-yl]
white solid; MS 3 67.1 (M+H)+
Example 242 [2-(Benzimidazol-2-ylamino-
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
10): MS 335.5 (M+H)+
Example 243 [2-(4-Chlorophenyl)amino-6-
4-yl]-(5-phenyl-2H-pyrazol-3-yl)-amine
377.5(M+H)+
Example 244 [2-(4-Chlorophenyl)amino-6-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine(I
(M+H)+
Example 245 (5-tert-Butyl-2H-pyrazol-3-
chlorophenyl) amino-6-(3-nitrophenyl)-py
amine (IIIc-13): off-white solid; 1H NMI
(9H, s), 6.18 (1H, S), 7.04 (1H, s), 7.
(1H, t), 7.58 (1H, d), 7.82 (1H, t), 7.
(1H, d), 8.40 (1H, d), 8.90 (1H, s); MS
Example 246 [2-(3-Chlorophenyl)amino-6-
pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-
(IIIc-14): δ off-white solid; 1H NMR (CI
s), 7.12 (1H, d), 7.30-7.45 (5H, m), 7
(2H, d) , 7.78 (1H, t) , 7.88 (1H, s), 8
(1H, d) , 8.85 (1H, s).; MS 484.1 (M+H)+
Example 247 [5-(Furan-2-yl)-2H-pyrazol-
phenylamino-pyrimidin-4-yl)-amine (IIIC
(M+H)+

Example 248 [2-(Benzimidazol-2-ylamino;
pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-
16): MS 383.2 (M+H)+
Example 24 9 [2-(Benzimidazol-2-ylamino
pyrimidin-4-yl]-[5-(Furan-2-yl)-2H-pyr
(IIIC-17): MS 373.4 (M+H)+
Example 250 [2-(4-Chlorophenylamino)-6
-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine
315.4 (M+H)+
Example 251 [2-(4-Chlorophenyl)amino-5,
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
19) : MS 329.4 (M+H) +
Example 252 (5,6-Dimethyl-2-phenylaminc
(5-methyl-2H-pyrazol-3-yl)-amine (IIIc-
(M+H)+
Example 253 [2-(4-Chlorophenyl)amino-6-
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
21): MS 345.1 (M+H)+
Example 254 [2-(Benzimidazol-2-ylamiho)
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
22): MS 351.2 (M+H)+
Example 255 (6-Methoxymethyl-2-phenylan
yl)-(5-methyl-2H-pyrazol-3-yl)-amine (3
(M+H) +

Example 256 (6-Methyl-2-phenylamino-py
methyl-2H-pyrazol-3-yl)-amine(IIIc-24)
Example 257 [2-(2-Chlorophenoxymethyl)-
pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-
1): MS 392.1 (M+H)+
Example 258 [2-(2-Chlorophenoxymethyl)-
pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyre
(IIId-2) : MS 382.1 (M+H)+
Example 259 (6-methyl-2-phenoxymethyl-p
phenyl-2H-pyrazol-3-yl)-amine(IIId-3):
Example 260 [5-(Furan-2-yl)-2H-pyrazol-
phenoxymethyl-pyrimidin-4-yl)-amine (II
(M+H)+
Example 261 [5-(Furan-2-yl)-2H-pyrazol-
phenylsulfanylmethyl-pyrimidin-4-yl)-am
364.1 (M+H)+
Example 262 [6-Methyl-2-(4-methyl-pheny
pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-
6) : MS 388.1 (M+H)+
Example 263 [5-(Furan-2-yl)-2H-pyrazol-
(4-methyl-phenylsulfanylmethyl)-pyrimid
(IIId-7): MS 378.1 (M+H)+
Example 264 [2-(4-Fluoro-phenoxymethyl)
pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-
8): MS 376.2 (M+H)+

Example 265 [2-(4-Fluoro-phenoxymethyl)
pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyr
(IIId-9): MS 366.2 (M+H)+
Example 266 (6-Ethyl-2-phenylsulfanylme
yl)-(5-methyl-2H-pyrazol-3-yl)-amine (1
(M+H)+
Example 267 (6-Ethyl-2-phenoxymethyl-p
methyl-2H-pyrazol-3-yl)-amine (IIId-11)
Example 268 [6-Ethyl-2-(4-fluorophenoxy
4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine
328.2 (M+H)+
Example 269 [6-Ethyl-2-(1-methyl-1-pher
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
13): MS 322.2 (M+H)+
Example 270 [2-(4-Chlororophenoxymethyl
pyrimidin-4-yl]-(5-phenyl-2H-pyrazol-3-
14): MS 3 92.2 (M+H)+
Example 271 [2-(4-Chlororophenoxymethyl
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
15): MS 330.2 (M+H)+
Example 272 [2-{4-Chlororophenoxymethyl
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-
16): white solid; 1H NMR (DMSO) δ 2.20
s), 4.49 (2H, S), 5.20 (2H, s), 6.05 (1
d), 7.33 (2H, d), 10.55 (1H, br) ; MS 36

Example 273 [2-(4-Chlororophenoxymethyl
pyrimidin-4-yl]-[5-(furan-2-yl)-2H-pyra
(IIId-17): MS 382.2 (M+H)+
Example 2 74 (5-Methyl-2H-pyrazol-3-yl)-
phenylsulfanylmethyl-5, 6, 7, 8-tetrahydro
amine (IId-7) : MS 352.5 (M+H) +
Example 275 [2-(4-Methylphenylsulfanyln
te trahydro-5H-cycloheptapyrimidin-4-yl]
pyrazol-3-yl)-amine (IId-8):MS 380.2 (M
Example 276 [2-(1-Methyl-1-phenyl-ethyl
tetrahydro-5H-cycloheptapyrimidin-4-yl]
pyrazol-3-yl)-amine (IId-9) :
MS 362.3 (M+H)+
Example 277 [2-(2, 6-Dichlorobenzyl)-5, 6
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3
10): MS 388.1 (M+H) +
Example 278 [7-Benzyl-2-(2, 6-dichlorobe
tetrahydropyrido [3, 4-d] pyrimidin-4-yl]-
pyrazol-3-yl)-amine (IId-II) : MS 479.5
Example 279 [6-Benzyl-2-(4-chlorophenoxy
tetrahydro-pyrido [4,3-d] pyrimidin-4-yl]
pyrazol-3-yl)-amine (IId-12): MS 461.2
Example 280 [2-(4-Chlorophenoxymethyl)-
tetrahydro-pyrido [4, 3-d]pyrimidin-4-yl]-
pyrazol-3-yl)-amine (IId-13): MS 371.3

Example 2 81 [2-(2, 6-Dichlorobenzyl)-6-
yl]-{5-methyl-2H-pyrazol-3-yl)-amine (:
(M+H)+
Example 282 [2-(2,6-Dichlorobenzyl)-5,
pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-19):
white solid; 1H NMR (DMSO) □ 8.50
d) , 7.3-7.1 (3H, m) , 5.25 (1H, s) , 4.K
(3H, s), 2.10 (3H, s), 1.80 {3H, s); M
Example 283 (1H-Indazol-3-yl)-[2-(2-ph
quinazolin-4-yl]-amine (IId-16) :1HNMR
12.0(1H, s) , 8.76(1H, m) , 8.10(1H, m) ,
7.75(1H, m), 7.61(1H, m) 7.41(1H, m) , '
7.20(2H, m) , 7.12{2H, m) , 2.35(2H, m) ,
1.35(1H, m) ; MS: m/z, 378.1 MH+; HPLC I
Example 284 (7-Fluoro-1H-indazol-3-yl) -
cyclopropyl)-guinazolin-4-yl]-amine (I
13.8(1H, s), 12.05(1H, s) , 8.75(1H, m) ,
7.85(2H, m) , 7.60(1H, m) , 7.35(3H, m)
2.35(2H, m) , 1.60I1H, m) , 1.35(1H, m) ;
MH+; HPLC Rt=3.26 min.
Example 285 5-Fluoro-1H-indazol-3-yl)
-cyclopropyl)-quinazolin-4-yl]-amine (I)
13.3(1H, s), 12.0 (1H, s), 8.75(1H, m) ,
7.85(2H, m) , 7.65(2H, m) , 7.35(3H, m)
7.10(2H, m) 2.40 (2H, m), 1.65(1H, m) ,
m/z, 396.1 MH+; HPLC Rt=3.26 min.

Example 286 (5-Methyl-llf-pyrazol-3~yl)
cyclopropyl)-quinazolin-4-yl]-amine (I
12.8 (1H, s), 11.90(1H, s), 8.80(13, m)
7.85(2H, m), 7.30-7.20(5H, m), 6.55 (II
2.55(1H, m) , 2.35 (3H,S) 2.00(2H, m) ; I
HPLC Rt=3 .13 min.
BIOLOGICAL TESTING
The activity of the compounds
inhibitors may be assayed in vitro, in
line. In vitro assays include assays t
inhibition of either the phosphorylatic
ATPase activity of the activated protei
Alternate in vitro assays quantitate the
inhibitor to bind to the protein kinase
binding may be measured by radiolabelli
prior to binding, isolating the inhibit
complex and determining the amount of r
Alternatively, inhibitor binding may be
running a competition experiment where
incubated with the protein kinase bound
radioligands.
BIOLOGICAL TESTING EXAMPLE
Ki DETERMINATION FOR THE INHIBIT
Compounds were screened for
inhibit GSK-3β (AA 1-420) activity usin
coupled enzyme system (Fox et al. (1998
2249). Reactions were carried out in a
containing 100 mM HEPES (pH 7.5), 10 mM
300 µM NADH, 1 mM DTT and 1.5% DMSO. F
concentrations in the assay were 20 µM
Chemicals, St Louis, MO) and 300 µM pep

(HSSPHQS(PO3H2)EDEEE, American Peptide,
Reactions were carried out at 30°C an
Final concentrations of the components
enzyme system were 2.5 mM phosphoenolp
NADH, 30 µg/ml pyruvate kinase and 10
dehydrogenase.
An assay stock buffer soluti
containing all of the reagents listed
exception of ATP and the test compound
assay stock buffer solution (175 µl) w
96 well plate with 5 µl of the test co
at final concentrations spanning 0.002
for 10 min. Typically, a 12 point tit
conducted by preparing serial dilution
compound stocks) with DMSO of the test
daughter plates. The reaction was ini
addition of 20 µl of ATP (final concen
Rates of reaction were obtained using
Spectramax plate reader (Sunnyvale, CA
30°C. The Ki values were determined fr
a function of inhibitor concentration.
The following compounds were
values less than 0.1 µM for GSK-3: IIa
IIa-9, IIa-11, IIa-12, IIa-17, IIa-l8,
Ila-26, IIa-28, IIa-30 through IIa-32,
IIa-46, IIa-47, IIa-61, IIc-3, IIc-6, :
through IIc-12, IIc-15, IIc-1B, IIc-20
IIc-24, IIc-25, IIc-27, IIc-30 through
IIc-39, IIC-42, IIc-53, IIc-61, IIc-67
IIb-1, IIb-3, IIb-5, IIb-8, IId-l, III;
6, IIIa-17, IIIa-1B, IIIa-24, IIIa-27,
IIIc-5, IIIc-9, IIIc-11, IIIc-12, IIIc-

19, IIIc-21, IIIc-24, IIIb-1 through II
through IIIb-10, IIIb-13, IIIb-14, IIIc
14, and IId-19.
The following compounds were
values between 0.1 and 1.0 µM for GSK-2
IIa-5, IIa-7, IIa-14, IIa-15, IIa-20, I
through IIa-36, IIa-38, IIa-41, IIa-42,
IIa-55, IIa-62, IIa-63, IIa-66, IIa-69,
IIc-2, IIc-4, IIc-5, IIc-7, II-9, IIc-
16, IIc-17, IIc-19, IIc-23, IIc-26, IIc
33, IIc-34, IIC-40, IIc-41, IIc-43 thrc
through IIc-52, IIc-54 through IIc-57,
through IIc-66, IIc-72, IIc-75, IIc-76,
IIb-7, IIb-9, IId-2, IId-5, IId-6, IIIa
5, IIIa-7, IIIa-8, IIIa-10, IIIa-11, II
IIIa-23, IIIa-26, IIIa-29, IIIa-30, III
IIIa-34, IIIa-37, IIIa-42, IIIc-1, IIIc
23, IIIb-7, IIIb-11, IIIb-12, IIIb-15,
IId-17, and IId-18.
The following compounds were
values between 1.0 and 7.0 µM for GSK-3
IIa-25, IIa-40, IIa-45, IIa-49, IIa-50
IIa-64, IIa-65, IIa-67, IIa-68, IIa-71,
IIa-76, IIa-77, IIa-81, IIc-58, Hc-60,
through IIc-71, IIc-74, IId-3, IId-4, I
IIIa-21, IIIa-28, IIIa-35, IIIa-36, III
IIIa-43, IIIa-45, IIIa-49, IIIc-10, III
IIIc-22.
BIOLOGICAL TESTING EXAMP
KI DETERMINATION FOR THE INHIBITIO
Compounds were screened in th
for their ability to inhibit Aurora-2 u

coupled enzyme assay (Fox et al (1998)
2249).
To an assay stock buffer solu
0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT,
phosphoenolpyruvate, 300 mM NADH, 30 mg
kinase, 10 mg/ml lactate dehydrogenase,
800 uM peptide (LRRASLG, American Pepti
was added a DMSO solution of a compound
invention to a final concentration of 3
resulting mixture was incubated at 3 0 "
reaction was initiated by. the addition
Aurora-2 stock solution to give a final
70 nM in the assay. The rates of react
by monitoring absorbance at 340 nm over
time at 30 °C using a BioRad Ultramark
(Hercules, CA) . The Ki values were det
rate data as a function of inhibitor cc
The following compounds were
values less than 0.1 µM for Aurora-2: 1
18, IIa-21 through IIa-64, IIa-66, IIa-
through IIa-78, IIa-81, IIc-1 through 1
through IIc-44, IIc-46 through IIc-61,
IIc-65, IIc-67 through IIc-69, IIb-1 th
through IId-3, IIIa-1 through IIIa-8,
IIIa-13, IIIa-15 through IIIa-32, IIIa-
41, IIIa-44 through IIIa-49, IIIc-1 th
12, and IIIc-15.
The following compounds were
values between 0.1 and 1.0 µM for Auron
65, IIa-67, IIa-70, IIa-80, IIc-14, IIc
IIIa-14,-IIIa-33 through IIIa-35, IIIc
1, IIIb-2, IIIb-7, IIIb-10 through III
IIIb-16, and IIId-20.

The following compounds were
values between 1.0 and 10.0 µM for Aun
71, IIc-75, IIc-76, IId-4, IIIa-42, II:
IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14.
BIOLOGICAL TESTING EXAMI
CDK-2 INHIBITION ASSi
Compounds were screened in t
for their ability to inhibit CDK-2 usin
coupled enzyme assay (Fox et al (1998)
2249).
To an assay stock buffer soli
0.1M HEPES 7.5, 10 mM MgCl2, 1 mM DTT,
phosphoenolpyruvate, 300 mM NADH, 30 mg
kinase, 10 mg/ml lactate dehydrogenase,
100 µM peptide (MAHHHRSPRKRAKKK, Americ
Sunnyvale, CA) was added a DMSO solutic
the present invention to a final concer
The resulting mixture was incubated at
The reaction was initiated by
10 uL of CDK-2/Cyclin A stock solution
concentration of 25 nM in the assay. T
reaction were obtained by monitoring ab
over a 5-minute read time at 30 °C usin
Ultramark plate reader (Hercules, CA) .
determined from the rate data as a func
concentration.
The following compounds were
values less than. 1 µM for CDK-2: IIa-14
IIc-25, IIc-27, IIc-32, IIc-53, and III

The following compounds were
values between 1.0 and 20.0 µM for CDK-
IIa-44, IIa-52, and IIa-54.
BIOLOGICAL TESTING EXAMI
ERK INHIBITION ASSAY
Compounds were assayed for tl
ERK2 by a spectrophotometric coupled-e
al (1998) Protein Sci 7, 2249). In th
concentration of activated ERK2 (10 nM)
with various concentrations of the com
%) for 10 min. at 30°C in 0.1 M HEPES t
containing 10 mM MgCl2, 2.5 mM phosphoe
µM NADH, 150 µg/mL pyruvate kinase, 5 0
dehydrogenase, and 200 µM erktide pept
was initiated by the addition of 65 µM
decrease of absorbance at 340 nM was mg
was evaluated from the rate data as a
inhibitor concentration.
The following compounds were
values less than 1 µM for ERK-2: IIc-15
IIc-53, and IIIc-4.
The following compounds were
values between 1.0 and 20.0 µm for ERK-
and IIa-36.
BIOLOGICAL TESTING EXAM
AKT INHIBITION ASSA
Compounds were screened for t
inhibit AKT using a standard coupled er
al., Protein Sci., (1998) 7, 2249). As
out in a mixture of 100 mM HEPES 7.5, 1

NaCl , 1 mM DTT and 1.5% DMSO. Final
concentrations in the assay were 170
Chemicals) and 200 uM peptide (RPRAATF,
Sunnyvale, CA). Assays were carried
nM AKT. Final concentrations of the cc
coupled enzyme system were 2.5 mM phos
300 µM NADH, 30 µg/ML pyruvate kinase a
lactate dehydrogenase.
An assay stock buffer solutic
containing all of the reagents listed a
exception of AKT, DTT, and the test com
56 µl of the stock solution was placed
plate followed by addition of 1 µl of 2
containing the test compound (final com
concentration 30 µM). The plate was pr
about 10 minutes at 30oC and the reacti
addition of 10 µl of enzyme (final conc
and 1 mM DTT. Rates of reaction were o
BioRad Ultramark plate reader (Hercules
minute read time at 30oC. Compounds sh
50% inhibition versus standard wells co
mixture and DMSO without test compound
determine IC50 values.
The following compounds were .
values between 1.0 and 20.0 µM for AKT-
IIc-25, IIc-27, IIc-31, IIc-32, IIc-37,
and IIc-53.
BIOLOGICAL TESTING EXAMPI
SRC INHIBITION ASSAY
The compounds were evaluated a
human Src kinase using either a radioact
or spectrophotometric assay.

Src Inhibition Assay A: Radioactive
The compounds were assayed a
full length recombinant human Src kina;
Biotechnology, cat. no. 14-117) expres:
from baculo viral cells. Src kinase a
monitored by following the incorporate
into the tyrosine of a random poly Glu
substrate of composition, Glu:Tyr = 4:
P-0275) . The following were the final
the assay components: 0.05 M HEPES, pH
mM DTT, 0.25 mg/ml BSA, 10 µM ATP (1-2
reaction) , 5 mg/ml poly Glu-Tyr, and 1
recombinant human Src kinase. In a typ
the reaction components with the except
pre-mixed and aliquoted into assay plat
Inhibitors dissolved in DMSO were addec
give a final DMSO concentration of 2.5
was incubated at 30 °C for 10 min befor
reaction with 33P-ATP. After 20 min of
reactions were quenched with 150 µl of
trichloroacetic acid (TCA) containing
quenched samples were then transferred
filter plate (Whatman, UNI-Filter GF/F
Filter, cat no. 7700-3310) installed or
vacuum manifold. Filter plates were wa
with 10% TCA containing 20 mM Na3PO4 and
methanol. 200µl of scintillation fluid
each well. The plates were sealed and
radioactivity associated with the filte
on a TopCount scintillation counter. 1
incorporated was plotted as a function
concentration. The data was fitted to
inhibition kinetics model to get the Ki

Src Inhibition Assay B: Spectrophe
The ADP produced from ATP by
recombinant Src kinase-catalyzed phosph
Glu-Tyr substrate was quanitified using
assay (Fox et al (1998) Protein Sci 7,
assay one molecule of NADH is oxidised
molecule of ADP produced in the kinase
disappearance of NADH can be convenient
ntn.
The following were the final
the assay components: 0.025 M HEPES, pH
2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and
recombinant human Src kinase. Final con
components of the coupled enzyme system
phosphoenolpyruvate, 200 µM NADH, 30 µg
kinase and 10 µg/ml lactate dehydrogena
In a typical assay, all the r
with the exception of ATP were pre-mixe
into assay plate wells. Inhibitors dis
were added to the wells to give a final
of 2.5%. The assay plate was incubated
before initiating the reaction with 100
absorbance change at 340 nm with time,
reaction, was monitored on a molecular
reader. The data of rate as a function
concentration was fitted to compettive
kinetics model to get the Ki for the cor
The following compounds were
value of 100nM on SRC: IIa-8, IIa-21,
IIa-27, IIa-28, IIa-30 through IIa-33,
5, IIc-3, IIc-8, IIc-10, IIc-13, IIc-15
IIc-21 through IIc-24, IIc-31 through I:

through IIc-39, IIc-41 through IIc-44,
IId-2, IIIa-1, IIIa-6 through IIIa-8,
IIIa-30, and IIIc-1 through IIIc-5.
The following compounds were
value of between 100nM and 1µM for SRC
IIa-7, IIa-9, IIa-12, IIa-14, IIa-22,
IIa-29, IIa-34 through IIa-42, IIa-46,
through IIa-52, IIa-56, IIa-57, IIa-59
IIa-66, IIa-67, IIa-69, IIa-72, IIa-73
IIb-8, IIc-4 through IIc-7, IIc-9, He
14, IIc-16, IIc-17, IIc-20, IIc-25 thr
36, IIc-40, IIc-46 through IIc-50, He
IIc-63 through IIc-65, IIc-67, IIc-69,
through IIIa-5, IIIa-11, IIIa-14 throu
through IIIa-24, IIIa-31, IIIa-33, III
through IIIa-43, and IIIa-47.
The following compounds were
value of between 1µM and 6µM for SRC:
IIa-44, IIa-45, IIa-48, IIa-54, IIa-55
IIa-68, IIa-70, IIa-71, IIa-74, IIa-77
IIb-3, IIb-9, IIc-1, IIc-2, IIc-66, II
IIIa-21, IIIa-25, IIIa-34, IIIa-36, II
While we have presented a nui
of this invention, it is apparent that
construction can be altered to provide
which utilize the compounds and methods
invention. Therefore, it will be appre
scope of this invention is to be define
claims rather than by the specific embc
been represented by way of example.

WE CLAIM:
1. Pyrazole compounds of formula IIa:

or a pharmaceutically acceptable derivative or prodrug
thereof, wherein;
Rx and Ry are taken together with their intervening atoms
to form a fused, unsaturated or partially unsaturated,
5-7 membered ring having 0-3 ring heteroatoms selected
from oxygen, sulfur, or nitrogen, wherein each
substitutable ring carbon of said fused ring formed by
Rx and Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of said
ring formed by Rx and Ry is independently substituted
by R4;
R1 is T-(Ring D);
Ring D is a 5-7 membered monocyclic ring or 8-10 membered
bicyclic ring selected from aryl, heteroaryl,
heterocyclyl or carbocyclyl, said heteroaryl or
heterocyclyl ring having 1-4 ring heteroatoms selected
from nitrogen, oxygen or sulfur, wherein each
substitutable ring carbon of Ring D is independently
substituted by oxo, T-R5, or V-Z-R5, and each

substitutable ring nitrogen of Ring D is independently
substituted by-R4;
T is a valence bond or a C1-4 alkylidene chain;
Z is a C1-4 alkylidene chain;
L is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,-N(R6)-,-CO-,-CO2-,-N(R6)CO-,-N(R6)C(O)O-,-N(R6)CON(Rs)-,-N(R6)SO2N(R6)-,-N (R6)N(R6)-,-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,
-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C (R6)2N(R6)-,
-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C (R6)=NN(R6)-,
-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or
-C(R6)2N(R6)CON(R6)-;
R2 and R2' are independently selected from-R,-T-W-R6, or
R2 and R2' are taken together with their intervening
atoms to form a fused, 5-8 merabered, unsaturated or
partially unsaturated, ring having 0-3 ring heteroatoms
selected from nitrogen, oxygen, or sulfur, wherein each
substitutable ring carbon of said fused ring formed by
R2 and R2' is independently substituted by halo, oxo,
-CN,-NO2,-R7, or-V-R6, and each substitutable ring
nitrogen of said ring formed by R2 and R2 is
independently substituted by R4;
R3 is selected from-R,-halo,-OR,-C(=O)R,-CO2R,
-COCOR,-COCH2COR,-NO2,-CN,-S(O)R,-S(O)2R,-SR,
-N(R4)2,-CON(R7)2,-SO2N(R7)2,-OC(=O)R,-N(R7)COR,
-N(R7)CO2(C1-6 aliphatic) ,-N(R4)N(R4)2,-C=NN(R4)2,
-C-N-OR, -N(R7)CON(R7)2,-N(R7)SO2N(R7)2,-N(R4)SO2R, or
-OC(=O)N(R7)2;
each R is independently selected from hydrogen or an
optionally substituted group selected from C1-6
aliphatic, C6-10 aryl, a heteroaryl ring having 5-10
ring atoms, or a heterocyclyl ring having 5-10 ring
atoms;

each R4 is independently selected from-R7,-COR7,
-CO2 (optionally substituted C1-6 aliphatic) ,-CON(R7)2,
or-SO2R7;
each R5 is independently selected from-R, halo,-OR,
-C(=O)R,-CO2R,-COCOR,-NO2,-CN,-S(O)R,-SO2R,-SR,
-N(R4)2,-CON(R4)2,-SO2N(R4)2,-OC(=O)R,-N(R4)COR,
-N(R4)CO2 (optionally substituted C1-6 aliphatic),
-N(R4)N(R4)2,-C=NN(R4)2,-C=N-OR,-N(R4)CON(R4)2,
-N(R4)SO2N(R4)2,-N(R4)SO2R, or-OC(O)N(R4)2;
V is-O-,-S-,-SO-,-SO2-,-N(R6)SO2-,-SO2N(R6)-,
-N(R6)-,-CO-, -CO2-,-N(R6)CO-,-N(R6)C(O)O-,
-N(R6)CON(R6)-,-N(R6)SO2N(R6)-,-N(R6)N(R6)-,
-C(O)N(R6)-,-OC(O)N(R6)-,-C(R6)2O-,-C(R6)2S-,
-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,
-C(R6)2N(R6)C(O)-,-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,
-C(R6)=N-O-,-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-, or
-C(R6)2N(R6)CON(R6)-;
W is-C(R6)2O-,-C(R6)2S-,-C(R6)2SO-,-C(R6)2SO2-,-C(R6)2SO2N(R6)-,-C(R6)2N(R6)-,-CO-,-CO2-,-C(R6)OC(O)-,-C(R6)OC(O)N(R6)-,-C(R6)2N(R6)CO-,
-C(R6)2N(R6)C(O)O-,-C(R6)=NN(R6)-,-C(R6)=N-O-,
-C(R6)2N(R6)N(R6)-,-C(R6)2N(R6)SO2N(R6)-,
-C(R6)2N(R6)CON(R6)-, or-CON(R6)-;
each R6 is independently selected from hydrogen or an
optionally substituted C1-4 aliphatic group, or two R6
groups on the same nitrogen atom are taken together
with the nitrogen atom to form a 5-6 membered
heterocyclyl or heteroaryl ring; and
each R7 is independently selected from hydrogen or an
optionally substituted C1-6 aliphatic group, or two R7
on the same nitrogen are taken together with the
nitrogen to form a 5-8 membered heterocyclyl or
heteroaryl ring.

2. The compound as claimed in claim 1, wherein said
compound as one or more features selected from the group
consisting of:
(a) Rx and Ry are taken together with their
intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by Rx and
Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of
said ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D), wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring,-
(d) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring,-and
(e) R3 is selected from-R,-halo,-OR, or-N(R4)2.
3. The compound as claimed in claim 2, wherein:
(a) Rx and Ry are taken together with their
intervening atoms to form a fused, unsaturated
or partially unsaturated, 5-6 membered ring
having 0-2 heteroatoms selected from oxygen,
sulfur, or nitrogen, wherein each substitutable
ring carbon of said fused ring formed by Rx and
Ry is independently substituted by oxo, T-R3, or
L-Z-R3, and each substitutable ring nitrogen of

said ring formed by Rx and Ry is independently
substituted by R4;
(b) R1 is T-(Ring D) , wherein T is a valence bond or
a methylene unit;
(c) Ring D is a 5-7 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(d) R2 is-R or-T-W-R6 and R2' is hydrogen; or R2 and
R2' are taken together to form an optionally
substituted benzo ring; and
(e) R3 is selected from-R,-halo,-OR, or-N(R4)2-.
4. The compound as claimed in claim 2, wherein said
compound has one or more features selected from the group
consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;
(b) R1 is T-(Ring D), wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
5. The compound as claimed in claim 4, wherein:

(a) Rx and Ry are taken together to form a benzo,
pyrido, cyclopento, cyclohexo, cyclohepto,
thieno, piperidino, or imidazo ring;
(b) R1 is T-(Ring D) , wherein T is a valence bond and
Ring D is a 5-6 membered monocyclic ring or an
8-10 membered bicyclic ring selected from an
aryl or heteroaryl ring;
(c) R2 is-R and R2' is hydrogen, wherein R is
selected from hydrogen, C1-6 aliphatic, phenyl, a
5-6 membered heteroaryl ring, or a 5-6 membered
heterocyclic ring; and
(d) R3 is selected from-R,-halo,-OR, or-N(R4)2,
wherein R is selected from hydrogen, C1-6
aliphatic, or 5-6 membered heterocyclyl, phenyl,
or 5-6 membered heteroaryl, and L is-O-,-S-,
or-N(R4)-.
6. The compound as claimed in claim 4, wherein said
compound has one or more features selected from the group
consisting of:
(a) Rx and Ry are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;
(b) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;
(c) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-,-and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,

-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,
-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,
-NR6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or
-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.
7. The compound as claimed in claim 6, wherein:
(a) Rx and Ry are taken together to form a benzo,
pyrido, piperidino, or cyclohexo ring;
(b) R1 is T-Ring D, wherein T is a valence bond and
Ring D is a 5-6 membered aryl or heteroaryl
ring;
(c) R2 is hydrogen or C1-4 aliphatic and R2' is
hydrogen;
(d) R3 is selected from-R,-OR, or-N(R4)2, wherein
R is selected from hydrogen, C1-6 aliphatic, 5-6
membered heterocyclyl, phenyl, or 5-6 membered
heteroaryl, and L is-O-,-S-, or-NH-; and
(e) Ring D is substituted by up to three
substituents selected from-halo,-CN,-NO2,
-N(R4)2, optionally substituted C1-6 aliphatic
group,-OR,-C(O)R,-CO2R,-CONH(R4),-N(R4)COR,
-N(R4)CO2R,-SO2N(R4)2,-N(R4)SO2R,-N(R6)COCH2N(R4)2,-N(R6)COCH2CH2N(R4)2, or
-N(R6)COCH2CH2CH2N(R4)2, wherein R is selected
from hydrogen, C1-6 aliphatic, phenyl, a 5-6
membered heteroaryl ring, or a 5-6 membered
heterocyclic ring.

8. A compound selected from the group consisting
of:
(5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-
quinazolin-4-yl)-amine;
[2-(4-Chlorophenylsulfanyl)-guinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
[2-(2,4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine ;
[2-(4-Methoxyphenylsulfanyl)-guinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(2-Ethylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
{2-[2, 4-Bis(trifluoromethyl)phenylsulfanyl]-quinazolin-
4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(2-Chlorophenylsulfanyl)-guinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
[2-(2, 3-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(3-Chlorophenylsulfanyl)-guinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
[2-(l-Methylimidazol-2-ylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine ;
[2-(2-Hydroxyphenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(2,4-Difluorophenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(3,4-Dimethoxyphenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(3-Methylphenylsulfanyl)-quinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
[2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;

[2-(2-Naphthalenylsulfanyl)-quinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
[2-(2, 6-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(3, 4-Dichlorophenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine ;
[2-(Benzimidazol-2-ylsulfanyl)-guinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(2-Aminophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
(5-Gyclopropyl-2H-pyrazol-3-yl)-(2-phenylsulfanyl-
quinazolin-4-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-
methoxycarbonylphenylsulfanyl)-guinazolin-4-yl]-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-
methylphenylsulfanyl)-quinazolin-4-yl]-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3-
methoxyphenylsulfanyl)-quinazolin-4-yl]-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-
dimethoxyphenylsulfanyl)-quinazolin-4-yl]-amine;
[2-(3-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-
cyclopropyl-2H-pyrazol-3-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphtalen-2-
ylsulfanyl)-quinazolin-4-yl]-amine;
(5-Cyclopropyl-2H-pyrazdl-3-yl)-[2-(2,4-
difluorophenylsulfanyl)-quinazolin-4-yl]-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2-
ylsulfanyl)-5,6,7,8-tetrahydroguinazolin-4-yl]-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,3-
dichlorophenylsulfanyl)-quinazolin-4-yl]-amine;
[2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-
cyclopropyl-2H-pyrazol-3-yl)-amine;

[2-(2-Chlorophenylsulfanyl)-quinazolin-4-yl]-(5-
cyclopropyl-2H-pyrazol-3-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4-
dimethylphenylsulfanyl)-quinazolin-4-yl]-amine;
[2-(Benzimidazol-2-ylsulfanyl)-guinazolin-4-yl]-(5-
cyclopropyl-2H-pyrazol-3-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4-
methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-amine;
[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(5-
cyclopropyl-2H-pyrazol-3-yl)-amine;
(5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-1-
ylsulfanyl)-quinazolin-4-yl]-amine;
[2-(4-Acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Methanesulfonylamino-phenylsulfanyl)-guinazolin-
4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin-4-yl-
propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-
amine;
[2-(4-Methoxycarbonylphenylsulfanyl)-quinazolin-4-yl]-
(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Carboxyphenylsulfanyl)-quinazolin-4-yl]-(5-
methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamidophenylsulfanyl)-8-methoxy-quinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamidophenylsulfanyl)-7-(3-morpholin-4-yl-
propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-
amine;
[2-(4-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;

[2-(3-Bromophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
[2-(4-Isopropanesulfonylamiho-phenylsulfanyl)-
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Isobutyrylamino-phenylsulfanyl)-quinazolin-4-yl]-
(5-methyl-2H-pyrazol-3-yl)-amine;
(5-Methyl-2H-pyrazol-3-yl)-[2-(4-propionylamino-
phenylsulfanyl)-quinazolin-4-yl]-amine;
[2-(4-cyclopropanecarbonylamino-phenylsulfanyl)-
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamido-phenylsulfanyl)-8-hydroxyquinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamido-phenylsulfanyl)-7-nitroguinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(propane-1-
sulfonylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;
[2-(4-Ethylsulfonylamino-phenylsulfanyl)-guinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamido-phenylsulfanyl)-7-
hydroxyaminoguinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Isobutanecarbonylamino-phenylsulfanyl)-
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-tert-Butoxycarbonylamino-phenylsulfanyl)-
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamido-phenylsulfanyl)-7-aminoguinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-raorpholin-4-yl-
acetylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;
(5-Cycloprpyl-2H-pyrazol-3-yl)-[2-(4-
methylsulfonylamino-phenylsulfanyl)-quinazolin-4-yl]-
amine;

[2-(4-Amino-phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-
2H-pyrazol-3-yl)-amine;
[2-(4-Acetamido-phenylsulfanyl)-quinazolin-4-yl]-(2H-
pyrazol-3-yl)-amine;
(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(4-morpholin-4-yl-
butyrylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine;
(5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin-4-yl-
ethylcarbamoyl)-phenylsulfanyl]-guinazolin-4-yl}-amine;
[8-Methoxy-2-(4-methylsulfonylamino-phenylsulfanyl)-
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
{2-[4-(2-Dimethylamino-ethylcarbamoyl)-phenylsulfanyl]-
quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;
{2-[4-(2-Dimethylamino-acetylamino)-phenylsulfanyl]-
quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;
[8-Hydroxy-2-(4-methylsulfonylamino-phenylsulfanyl)-
quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
{2-[4-(3-Dimethylamino-propylcarbamoyl)-
phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-
yl)-amine;
{2-[4-(3-Dimethylamino-propionylamino)-phenylsulfanyl]-
quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamido-phenylsulfanyl)-8-methoxy-quinazolin-4-
yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamidophenylsulfanyl)-8-(3-dimethylamino-
propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-
amine;
[2-(4-Acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamidophenylsulfanyl)-7-(3-dimethylamino-
propoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-
amine;

(2-{4-f2-{tert-Butoxycarbonyl-methyl-amino)-
acetylamino]-phenylsulfanyl}-quinazolin-4-yl)-(5-methyl-
2H-pyrazol-3-yl)-amine;
{2-[4-{2-Methylamino-acetylamino)-phenylsulfanyl]-
quinazolin-4-yl}-(5-methyl-2H-pyrazol-3-yl)-amine;
[2-(4-Acetamidophenylsulfanyl)-8-fluoro-guinazolin-4-
yl]-(5-methyl-2H-pyrazol-3-yl)-amine; and
(1H-Indazol-3-yl)-(2-Phenylsulfanyl-quinazolin-4-yl)-
amine.
9. A composition comprising a compound as claimed
in any one of claims 1-8, and a pharmaceutically
acceptable carrier.
10. The composition as claimed in claim 9,
comprising an additional therapeutic agent.
11. The composition as claimed in claim 9, wherein
said composition is formulated for administration to
a human.
12. A method of inhibiting Aurora-2, GSK-3, CDK-2
or Src activity in a biological sample comprising
the step of contacting in vitro said biological
sample with a compound as claimed in any one of
claims 1-8.
13. A composition as claimed in claim 9 for
inhibiting Aurora-2 activity in a patient.
14. A composition as claimed in claim 10, for
inhibiting Aurora-2 activity in a patient.

15. A composition as claimed in claim 9 for
treating an Aurora-2 mediated disease.
16. The composition as claimed in claim 15,
wherein said disease is selected from colon,
breast, stomach or ovarian cancer.
17. A composition as claimed in claim 10 for
treating an Aurora-2 mediated disease.
18. A composition as claimed in claim 17, wherein
said composition comprises an additional therapeutic
agent which is a chemotherapeutic agent.
19. A composition as claimed in claim 9, for
inhibiting GSK-3 in a patient.
20. A composition as claimed in claim 10, for
inhibiting GSK-3 in a patient.
21, A composition as claimed in claim 9 for treating
a GSK-3 mediated disease.
22. The composition as claimed in claim 21, wherein
said GSK-3-mediated disease is selected from
diabetes, Alzheimer's Disease, Huntington's disease,
Parkinson's Disease, AIDS-associated dementia,
amyotrophic lateral sclerosis (AML), multiple
sclerosis (MS), schizophrenia, cardiomycete
hypertrophy, reperfusion/ischemia, or baldness.

23. The composition as claimed in claim 21, wherein
GSK-3-mediated disease is diabetes.
24. A composition as claimed in claim 9, for
enhancing glycogen synthesis or lowering blood
levels of glucose in a patient in need thereof.
25. A composition as claimed in claim 9 for
inhibiting the production of hyperphosphorylated Tau
protein in a patient.

26. A composition as claimed in claim 9, for
inhibiting the phosphorylation of β-catenin.
27. A composition as claimed in claim 9, for
inhibiting CDK-2 activity in a patient.
28. A composition as claimed in claim 9, for
treating CDK-2-mediated disease.
29. A composition as claimed in claim 9, for
inhibiting Src activity in a patient.
30. A composition as claimed in claim 9, for
treating Src-mediated disease.

This invention describes
novel pyrazole compounds of formula (IIA):
wherein R1 is T-Ring D, wherein Ring D
is 5-7 membered monocyclic ring or 8-10
membered bicyclic ring selected from aryl,
heteroaryl, heterocyclyl or carbocyclyl; Rx and
Ry are taken together with their intervening
atoms to form a fused, unsaturated or partially
unsaturated, 5-7 membered ring having 0-3
heteroatoms; and R2 and R2' are as described
in the specification. The compounds are useful
as protein kinase inhibitors, especially as

inhibitors of Aurora-2 and GSK-3, for treating diseases such as cancer, diabetes and Alzheimer's disease.

Documents:

796-KOLNP-2003-FORM-27.pdf

796-kolnp-2003-granted-abstract.pdf

796-kolnp-2003-granted-assignment.pdf

796-kolnp-2003-granted-claims.pdf

796-kolnp-2003-granted-correspondence.pdf

796-kolnp-2003-granted-description (complete).pdf

796-kolnp-2003-granted-examination report.pdf

796-kolnp-2003-granted-form 1.pdf

796-kolnp-2003-granted-form 18.pdf

796-kolnp-2003-granted-form 3.pdf

796-kolnp-2003-granted-form 5.pdf

796-kolnp-2003-granted-gpa.pdf

796-kolnp-2003-granted-reply to examination report.pdf

796-kolnp-2003-granted-specification.pdf

796-kolnp-2003-granted-translated copy of priority document.pdf


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Patent Number 228789
Indian Patent Application Number 796/KOLNP/2003
PG Journal Number 07/2009
Publication Date 13-Feb-2009
Grant Date 11-Feb-2009
Date of Filing 19-Jun-2003
Name of Patentee VERTEX PHARMACEUTICALS INCORPORATED
Applicant Address 130 WAVERLY STREET, CAMBRIDGE, MA
Inventors:
# Inventor's Name Inventor's Address
1 BEBBINGTON DAVID 6 LINDEN CLOSE, NEWBURY BERKSHIRE, BERKSHIRE R6141QA
2 CHARRIER JEAN-DAMIEN VERTEX PHARMACEUTICALS, FRANCE, INC., COTTAGE WING, STATION ROAD, SOUTHAM, BISHOPS ITCHINGTON, OXFORDSHIRE CV47 2QB
3 DAVIES ROBERT 65 ORIENT AVENUE, ARLINGTON, MA 02474
4 GOLEC JULIAN 8 MANOR FARM, CHAPEL ROAD, ASHBURY, WILTSHIRE SN6 8LS
5 KAY DAVID 4 CHURCH PATH, PURTON, WILTSHIRE SN5 9DR
6 KNEGTEL RONALD 92 ANDERSEY WAY, ABINGDON, WILTSHIRE OX14 5NW
7 PATEL SANJAY 2 ALLDER CLOSE, ABINGDON, WILTSHIRE OC14 1YG
PCT International Classification Number C07D 403/12
PCT International Application Number PCT/US2001/51120
PCT International Filing date 2001-12-19
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/257,887 2000-12-21 U.S.A.
2 60/286,949 2001-04-27 U.S.A.