AU2006201262B2 - Pyrazole Compounds Useful As Protein Kinase Inhibitors - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Address for Service: Invention Title: Vertex Pharmaceuticals Incorporated CULLEN CO Patent Trade Mark Attorneys, 239 George Street Brisbane Qld 4000 Australia Pyrazole Compounds Useful As Protein Kinase Inhibitors The following statement is a full description of this invention, including' the best method of performing it, known to us: -1-

O

O

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^s FIELD OFTHE INVENTION (9 The present invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this invention relates to compounds that are inhibitors of GSK-3 and Aurora-2 protein kinases. The invention also relates to methods of treating diseases associated with these protein kinases, such as diabetes, cancer and Alzheimer's disease.

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 of extensive study is the protein kinases.

srotein kinases mediate intracellular signal tranaduction. They do this by effecting a phosphoryltransduction. They do this by effecting a phosphorylextracellular and other stimuli cause a variety of IND cellular responses to occur inside the cell. Examples of o such stimuli include environmental and chemical stress 0 C<K signals osmotic shock, heat shock, ultraviolet radiation, bacterial endotoxin, H202), cytokines (e.g.

iinterleukin-1 (IL-1) and tumor necrosis factor a (TNFr and growth factors granulocyte macrophagecolony-stimulating factor (GM-CSF), and fibroblast growth factor (FGF). An extracellular stimulus may effect one ID 10 or more cellular responses related to cell growth, Cl migration, differentiation, secretion of hormones, c-i -activation of transcription factors, muscle contraction, 1..

Sglucose metabolism, control of protein synthesis and o regulation of cell cycle.

Cl 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 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143, 1635-1646; Kimura et D0 al., J. Biol. chem., 1997, 272, 13766-13771.

o Glycogen synthase kinase-3 (GSK-3) is a (N serine/threonine protein kinase comprised of a and P isoforms that are each encoded by distinct genes [Coghlan et al., Chemistry Biology, 7, 793-803 (2000); Kim and Kimmel, Curr. Opinion Genetics Dev., 10, 508-514 (2000)].

GSK-3 has been implicated in various diseases including q diabetes, Alzheimer's disease, CNS disorders such as ID 10 manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; Sand Haq et al., J. Cell Biol. (2000) 151, 117]. These Sdiseases may be caused by, or result in, the abnormal Soperation 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 1-catenin, the translation initiation factor elF2B, as well as ATP citrate lyase, axin, heat shock factor-i, c-Jun, c-Myc, c-Myb, CREB, and CEPBa. 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. 303, 21-26 IN- (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); O Massillon et al., Biochem J. 299, 123-128 (1994)].

Cr 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 10 failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It o has also been reported that in patients with type II C0 diabetes, GSK-3 is overexpressed [WO 00/38675].

O Therapeutic inhibitors of GSK-3 are therefore potentially 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 0-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); Brownlees 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 p-catenin which is degradated after phosphorylation by GSK-3. Reduced levels of p-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death [Zhong etal., Nature, 395, 698-702 (1998); Takashima et al., PKAS, 90, 7789-93 (1993); Pei et al., L.

cNeuropathol. Exp, 56, 70-78 (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 tWO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)].

For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein o kinases have also been targeted for treating the same I diseases. However, the various protein kinases often act o 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-t activity and/or enhanced TGF-A activity. While p 3 8 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 role in cancer, diabetes, Alzheimer's disease and other diseases.

\O ID Ct Ci 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 and GSK-3. These -compounds have the general formula I:

^A

2 .0 or a pharmaceutically acceptable derivative or prodrug thereof, wherein: ZI to Z 4 are as described below; Ring A is selected from the group consisting of: F N a NeN Ry e.

S

N N RC RYANA a 4 f g N"kN

N-

'N

-6- 0 s Cq and R G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, 0 wherein said Ring C has one or two ortho substituents 'N independently selected from any substitutable nonoortho carbon position on Ring C is independently 10 substituted by -R 5 and two adjacent substituents on SRing C are optionally taken together with their (N intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -RO; 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 Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen.at each ortho carbon position of Ring D;

R

1 is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C 1 -6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally.substituted by up to three groups independently selected from halo, oxo, or -R 8 said C1-6 aliphatic group optionally ND substituted with.halo, cyano, nitro, or oxygen, or R 1 O and an adjacent substituent taken together with their C( intervening atoms form said ring fused to Ring C; CRX and R Y are independently selected from T-R 3 or R x and

SR

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable IN carbon on said fused ring formed by R X and RY is substituted by oxo or T-R 3 and any substitutable Cq nitrogen on said ring formed by RX and R' is IND substituted by R 4 oT is a valence bond or a C-.

4 alkylidene chain;

R

2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 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 carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4

R

3 is selected from -halo, -OR, -COR, -COCOR, -COCH 2 COR, -NO2, -CN, -S(0) 2 R, -SR,

-N(R

4 2

-CON(R

7 2 -S0 2

N(R

7 2

-N(R

7

)COR,

-N (R CO2(optionally substituted CI-6 aliphatic),

-N(R

4 N R4 2

-C=NN(R

4 2

-N(R

7

)CON(R

7

-N(R

7

)SO

2

N(R

7 2

-N(R

4

)SO

2 R, or -OC(=O)N(R 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, C 6 -i 0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR

7 -Co0 2

(C

1 s INDaliphatic), -CON(R') 2 or -SO 2 or two R' on the same 0 nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -COa 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 2

-CON(R')

2 -S0 2

N(R)

2

-N(R')COR,

-N dO2 (optionally substituted C 1 6 aliphatic)j

C.-N(R)N(R)

2

-C=NN(R

4 2 -C=N-OR, -N(R')CON(R') 2 IND 10 -N(R')SO 2

N(R)

2 -N(R')SOR, or -OC(=O)N(R) 2 or RS and an adjacent substituent taken together with their Cl intervening atoms form said ring fused to Ring C; V is -SO2-, -N(R')SO0 2 -COa-, -N(R 6

-N.(R')SO

2

N(R

6 -C(O)N(R 6 -C(R')2 3

S-,

-C(R

6

)SO

2 -C(Rt) 2

SO

2 2 2 -C(R6) 2

-C(R)

2 -c(R) 2

SO

2

N(R

6 or C 2 N CON (R 6 W is 2

-C(R)

2 -C(R6) 2 SO0-, 2

SO

2 2 SO2N(R)-, 2 -C0 2 C OC -C (R6) 0C(O)N(R6)-, 2N(R6)CO-, 2N C -C(R 6 2 N(Rr)N(R 6 2

N(R")SO

2 2 or -CON(R)-; each R' is independently selected from hydrogen or an optionally substituted C1.4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or an optionally substituted C1-6 aliphatic group, or two R' on the same nitrogen are taken together with the -9nitrogen to form a 5-8 membered heterocyclyl or \D heteroaryl ring; each R 8 is independently selected from an optionally c( substituted C 1 4 aliphatic group, -OR 6

-SR

6

-COR

6

-SO

2

R

6

-N(R

6 2

N

(R

6 -CN, -NO 2

-CON(R)

2 or G -CO2R 6 and

R

9 is selected from halo, -OR, -C0 2 R, -COCOR,

-NO

2 -CN, -SO 2 R, -SR, -N(R 4 2

-CON(R')

2

-SO

2

N(R

4 2

-N(R

4 )COR, -N CO2 (optionally ND 10 substituted CIj- aliphatic), -N(R 4 )N(R4)2, -C=NN(R) 2 -C=N-OR, CON 2 SO2N(R -N(R' SO 2 R, or 0D -OC(=0)N(R 4 2 SAs used herein, the following definitions shall Sapply 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 CI-C 2 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 00 straight and branched chains containing two to twelve 0 carbon atoms. The term "cycloalkyl" used alone or as part of a larger moiety shall include cyclic C 3

-C

12 hydrocarbons which are completely saturated, but which C( 5 are not aromatic.

The terms "haloalkyl", "haloalkenyl" and O "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case may be, substituted with one or more halogen atoms. The C- term "halogen" means F, Cl, Br, or I.

S 10 The term "heteroatom" means nitrogen, oxygen, or C-i 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 0-3 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", "carbocyclyl", "carbocyclo", or "carbocyclic" as used herein means an aliphatic ring system having three to fourteen members.

The terms "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The terms "carbocycle", "carbocyclyl", "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 -11five to fourteen members, such as phenyl, benzyl, Sphenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2o 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 1-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl. Also included within the scope of the term "aryl", as it is usedherein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, 0 such as in an indanyl, phenanthridinyl, or INDtetrahydronaphthyl, where the radical or point of o 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 3-1Hbenzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2tetrahydropyranyl, 3-tetrahydropyranyl, 4tetrahydropyranyl, [1,31-dioxalanyl, [1,3]-dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzathiolanyl, and benzothianyl. Also included within the scope of the term -12- "heterocyclyl"or "heterocyclic", as it is used herein, IN is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic (N 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 1 0 optionally substituted.

The term "heteroaryl", used alone or as part of 0 a larger moiety as in "heteroaralkyl" or ID"heteroarylalkoxy", refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, N-imidazolyl, 2imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-isoxazolyl, 4isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1-pyrrolyl, 2pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl, indolyl, 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 -13used interchangeably with the term "heteroaryl ring" or IN the term "heteroaromatic".

o An aryl (including aralkyl, aralkoxy, aryloxyalkyl -and the like) or heteroaryl (including S 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, -Ro, -ORO, -SRO, 1,2-methylene-dioxy, IO 10 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl C- substituted Ph, substituted -O(Ph), 0

-CH

2 (Ph) substituted -CH2 (Ph) -HCH 2 (Ph) substituted N -CH2CH 2

-NO

2 -CN, -N(RO) 2 -NROC(o)Ro, -NROC(O)N(RO) 2 -NRC0 2 R, -NR 0

NR

0 C(o)R 0 -NRNROC(o)N(Ro) 2

-NRONROCO

2

RO,

-C(0)C (O)Ro, CH 2 C -CO2R0, -C -C(O)N(RO) 2

-OC(O)N(RO)

2 -S(O)2R0, -SO 2

N(RO)

2

-NR

0

SO

2 N (R) 2

-NROSO

2

R

0 2 2

-(CS

2

)YNHC(O)RO,

(CH

2 yNHC CH wherein RO is hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl substituted Ph, substituted -O(Ph),

-CH

2 or substituted -CH 2 y is 0-6; and V is -a linker group. Examples of substituents on the aliphatic group or the phenyl ring of RD 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 -14ring include those listed above for the unsaturated s carbon of an aryl or heteroaryl group and the following: =NNHR*, =NN(R') 2 =NNHC(O)R', =NNHCO (alkyl), C1 =NNHS02(alkyl), or 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, IO 10 alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, o hydroxy, haloalkoxy, or haloalkyl.

I0 Suitable substituents on the nitrogen of a nono aromatic heterocyclic ring include -N(R 2 -co 2 -C CH 2 C R, -SO 2 R, -SO 2 N(R 2 2 2 and -NR 4

SO

2 R wherein R* is hydrogen, an aliphatic group, a substituted aliphatic group, phenyl substituted Ph, substituted CH 2 substituted CHl 2 (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 -CHa-, -C(0)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 Sinclude a saturated or unsaturated C1.; alkylidene chain O which is optionally substituted, and wherein one or two C saturated carbons of the chain are optionally replaced by -CONH-, -CONHNH-, -CO2-, G -NHC02-, -NHCONH-, -OC(0)NH-, -NHNH-, -NHCO-, -S02-, -SO 2 NH-, or -NHSO-.

The term "alkylidene chain" refers to an optionally substituted, straight or branched carbon chain C\ 10 that may be fully saturated or have one or more units of C- unsaturation. The optional substituents are as described 0 above for an aliphatic group.

ND A combination of substituents'or variables is o 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; 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 of 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 "1C- or 1C-enriched carbon are within the scope of this invention.

-16- Compounds of formula I or salts thereof may be IND formulated into compositions. In a preferred embodiment, 0 the composition is a pharmaceutical composition. In one 0 (N embodiment, the composition comprises an amount of the ct protein kinase inhibitor effective to inhibit a protein kinase, particularly GSK-3, in a biological sample or in a patient. In another embodiment, compounds of this ci invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor IN 10 effective to treat or prevent a GSK-3-mediated condition ci and a pharmaceutically acceptable carrier, adjuvant, or 0q vehicle, may be formulated for administration to a cO Ipatient.

oThe term "GSK-3-mediated condition" or ci "disease", as used herein, means 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, AIDSassociated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis 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 -17phosphorylation of 0-catenin, which is-useful for IND treating schizophrenia.

o Another aspect of the invention relates to C inhibiting GSK-3 activity in a.biological sample, which method comprises contacting the biological sample with a SGSK-3 inhibitor of formula I.

C- 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 S0 10 compound of formula I or a composition comprising said compound.

*g Another aspect of this invention relates to a C) IN method of treating or preventing an Aurora-2-mediated o 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 condition" or "disease", as used herein, means any disease or other deleterious condition in which-Aurora is known to play a role. The term "Aurora-2-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor.

Such conditions include, without limitation, cancer. The term "cancer" includes, but is not limited to the following cancers: colon and ovarian.

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 treating or preventing a CDK-2-mediated -18diseases with a CDK-2 inhibitor, which method comprises IND administering to a patient in need of such a treatment a 0 therapeutically effective amount of a compound of formula C( I or a pharmaceutical composition thereof.

The term "CDK-2-mediated condition" or S"disease", as used herein, means any disease or other r deleterious condition in which CDK-2 is known to play a role. The term "CDK-2-mediated condition" or "disease" C also means those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such ci conditions include, without limitation, cancer, 0 Alzheimer's disease, restenosis, angiogenesis, I ;glomerulonephritis, cytomegalovirus, HXV, herpes, 0 o psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M.

and Lane, Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani, Wang, Wu, Francis, R. and Pestell, Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett, Current Opinion in Oncologic, Endocrine Metabolic Investigational Drugs, 2, 40-59 (2000).

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 term "ERK-mediated condition", as used herein means any disease state or other deleterious -19condition in which ERK is known to play a role. The term IND "ERK-2-mediated condition" or "disease" also means those o diseases or conditions that are alleviated by treatment Ci with a ERK-2 inhibitor. Such conditions include, without C 5 limitation, cancer, stroke, diabetes, hepatomegaly, Scardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, ID 10 inflammation, neurological disorders and hormone-related ci -i diseases. The term ucancer" includes, but is not limited 0 to the following cancers: breast, ovary, cervix, IN prostate, testis, genitourinary tract, esophagus, larynx, 0 o glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoia, 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, colonrectum, 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, 651; Crews et al., 1992, Science 258, 478; 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 10952; Oliver et al., 1995, Proc. Soc. Exp. Biol. Med.

210, 162; Moodie et al., 1993, Science 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; Whelchel et al., 1997, o Am. J. Respir. Cell Mol. Biol. 16, 589].

(N Another aspect of the. invention relates to inhibiting ERK-2 activity in a biological sample or a Spatient, which method comprises administering.to the patient a compound of formula I or a composition comprising said compound.

i Another aspect of this invention relates to a I0 10 method of treating or preventing an AKT-mediated diseases ci with an AKT inhibitor, which method comprises 0 administering to a patient in need-of such a treatment a o therapeutically effective amount of a compound of formula SI or a pharmaceutical composition thereof.

ci The term "AKT-mediated condition", as used herein, means any disease state or other deleterious condition in which AKT is known to play a role. The term "AKT-mediated condition" or '"disease" also means 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, Nature, pp. 33-34, 1990; Zang, Q. et al, Oncogene, 19 2000; Kazuhiko, et al, The Journal of Neuroscience, 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 -21with a Src inhibitor, which method comprises O administering to a patient in need of'such a treatment a Stherapeutically effective amount of a compound of formula N I or a pharmaceutical composition thereof.

The term "Src-mediated condition", as used Sherein means any disease state or other deleterious condition in which Src is known to play a role. The term "Src-mediated condition" or "disease" also means those diseases or conditions that are alleviated by treatment O0 10 with a Src inhibitor. Such conditions include, without limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and SPaget's disease. Src protein kinase and its implication o 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 (1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin..Cancer Res., 5, 2164 (1999); Staley, Cell 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.

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 -22which does not destroy the pharmacological activity IND thereof.

0 The term "patient" includes human and Cl veterinary subjects.

The term "biological sample", as used herein, Sincludes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro ci assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, I0 10 tears, or other body-fluids or extracts thereof.

The amount effective to inhibit protein kinase, for example, GSK-3 and Aurora-2, is one that measurably IN inhibits the kinase activitywhere compared to the o activity of the enzyme in the absence of an inhibitor.

ci 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 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 of the present invention may be administered orally, parenterally, by inhalation -23spray, topically, rectally, nasally, buccally, vaginally ND or via an implanted reservoir. The term "parenteral" as 0 o used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional Sand intracranial injection or infusion techniques.

Preferably, the compositions are administered orally, intraperitoneally or intravenously.

C Sterile injectable forms of the compositions of ND 10 this invention may be aqueous or oleaginous suspension.

These suspensions may be formulated according to C techniques known in the art using suitable dispersing or Swetting agents and suspending agents. The sterile o injectable.preparation may also be a sterile injectable solution or suspension in a non-toxic parenterallyacceptable 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 monoor di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceuticallyacceptable 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 -24which are commonly used in the manufacture of IND pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of- N 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 IN0 10 include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.

SFor oral administration in a capsule form, useful Sdiluents include lactose and dried cornstarch. When Saqueous 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 nonirritating 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.

I Topically-transdermal patches may also be used.

O For topical applications, the pharmaceutical Cl compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in Sone or more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid .C petrolatum, white petrolatum, propylene glycol, IN 10 polyoxyethylene, polyoxypropylene compound, emulsifying C-l wax and water. Alternatively, the pharmaceutical 0 compositions can be formulated in a suitable lotion or

N

cream containing the active components suspended or o dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral-oil, sorbitan monostearate, polysorbate cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may 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 benzylalkonium 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 to 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, -26fluorocarbons, and/or other conventional solubilizing or ND dispersing agents.

O In addition to the compounds of this invention, C( pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in Scompositions to treat or prevent the above-identified diseases or disorders.

ci A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ND 10 ester, salt of an ester or other derivative of a compound of this invention which, upon administration to a Srecipient, is capable of providing, either directly or N0 indirectly, a compound of this invention or an o 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 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 the brain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, esters, amino acid esters, phosphate esters, metal salts and sulfonate esters.

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, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, -27fumarate, glucoheptanoate, glycerophosphate, glycolate, \D hemisulfate, heptanoate, hexanoate, hydrochloride, 0 hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, C lactate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, 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 ID 10 themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in C] obtaining the compounds of the invention and their O pharmaceutically acceptable acid addition salts.

o Salts derived from appropriate bases include alkali metal sodium and potassium), alkaline earth metal magnesium), ammonium and 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 of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and -28the judgment of the treating physician and the severity \D of the particular disease being treated. The amount of the inhibitor will also depend upon the particular Cl compound in the composition.

5 Depending upon the particular protein kinase- Smediated condition to be treated.or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered Stogether with the inhibitors of this invention. For S. 10. example, in the treatment of diabetes other anti-diabetic Cl -4 agents may be combined with the GSK-3 inhibitors of this 0 invention to treat diabetes. Theseagents include, NO without limitation, insulin or insulin analogues, in 0 injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and sulfonyl ureas.

Other examples of agents the inhibitors of this invention may also be combined with include, without limitation, chemotherapeutic agents or other antiproliferative agents such as adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives; antiinflammatory agents such as corticosteroids, TNF blockers, IL-I RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors such as acetylcholinesterase inhibitors, MAO inhibitors, interferons, anticonvulsants, 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 -29for treating liver disease such as corticosteroids, k0 cholestyramine, interferons, and anti-viral agents; O agents for treating blood disorders such as c<l corticosteroids, anti-leukemic agents, and growth c 5 factors; and agents for treating immunodeficiency Sdisorders such as gamma globulin.

r Those additional agents may be administered Cl separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen.

IN 1 0 Alternatively, those agents may be part of a single Cl -i dosage form, mixed together with the protein kinase Sinhibitor of this invention in a single composition.

IN Compounds of this invention may exist in o alternative tautomeric forms, as in tautomers 1 and 2 Cl| 15 shown below. Unless otherwise indicated, the representation of either tautomer is meant to include the other.

H N A

A

1Z 2 RX and RY (at positions Z 3 and Z 4 respectively) may be taken together to form a fused ring, providing a.

bicyclic ring system containing Ring A. Preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said Rx/Ry ring is optionally substituted.

Examples of Ring A systems are shown below by compounds I-A through I-DD, wherein Z is nitrogen or C(R) and Z 2 is nitrogen or C(H).

KN

I-A

1.-C

I-D

HN31

H

Me)

HN>

I-H I-F I-H I-I I-K I-L

N

CjSS tQN I-0~ I-Nq -31- HN HINH34 NO 'NAZs I-P 1-0 I-fl HNh

HNO

Vai Q4 OCtt TaS

I-T

0

HNN

I-v I-w I-x HN~ HN

N-Z

1-I IX -hA I-BE I-cc

I-DD

Preferred bicyclic Ring'A systems include I-A, and I-M, more preferably I-A, I-B 1 I-C, I-F, and I-H, and mo -st preferably I-A, I-B, -and I-H.

-32- In the monocyclic Ring A system, preferred R

X

\D groups, when present, include hydrogen, alkyl- or o dialkylamino, acetamido,. or a C-.4 aliphatic group such as C( methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred R Y groups, when present, include T-R 3 wherein T is a valence bond or a methylene, and R 3 is 2 or -OR. Examples of preferred R Y include 2-pyridyl, 4pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, C isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, C) 10 optionally substituted phenyl such as phenyl or halosubstituted phenyl, and methoxymethyl.

C In the bicyclic Ring A system, the ring formed IN when R x and R y are taken together may be substituted or 0 unsubstituted. Suitable substituents include halo, -OR,

-CO

2 R, -COCOR, -CN, -SOzR, -SR, 2

-CON(R

4 2 -S0 2

N(R

4 2

-N(R')COR,

CO

2 (optionally substituted C-e 6 aliphatic), -N (R 4 N (R 4 -C=NN -C=N-OR, -N CON 2, -N(R4)S02N (R 4 2

-N(R

4 )S0 2 R, or -OC(=O)N(R 4 2 wherein R and

R

4 are as defined above. Preferred R/Ry ring substituents include -halo,' -OR, -COR, -CO 2

R,

-CON(R')a, -CN, or 2 wherein R is hydrogen or an optionally substituted Ci-a aliphatic group.

R

2 and R' 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: -33- IND

H

VaN e-Z N..N N -§N PAZI% H H NH ,and Preferred substituents on the R 2 /R 2 fused ring Clinclude one or more of. the following: -halo, -N (R 4 2 -CI-3 IND 5 alkyl, -C- 3 haloalkyl, -NO 2 -O (C- 3 alkyl) -C0 2

(C

3 alkyl), -CN, -S0 2

(C

1 3 alkyl), -SO 2 Nn 2

-OC(O)N"

2 Wi 2 S0 2

(C

1 L 3 al kyl) NHC (C 1 al kyl), -C(ON and -O(l NO 3 alkyl) wherein the' (C 1 3 alkyl) is most preferably 0 methyl.

When-the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, C3., aliphatic, al koxycarbonyl, (tin) substituted phenyl., hydroxyalkyl, alkoxy~ilkyl, aminocarbonyl,.mono- or dialkylaminocarbony., aminoalkyl, alkylaminoalkyl,' dialkylaminoalkyl, phenylaminocarbonyl,'and

(N-

heterocyclylpoarbonyl. Examples of such preferred R 2 stibstituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-buty2, cyclopentyl, phenyl, C02H1 C0 2 C11 3 023011, CH20CR3, CH3CH2CR42OM, C1120{2CH200M3,

CE

2

CH

2

OI

2 00H 2 Ph, CH2CHaCH 2

NE

2

CH

2

CH

2

CI{

2 NHCOOC (CHO CON1CH (CM 3 2

CONROH

2

CH=CH

2

CONHCH

2 11 2 00 3

CONHCH

2 Ph, CONH(cyclohexyl), CON(Et) 2 CON(0M 3

)CH

2 Ph, CONH(n-C 3 2 7 CON(Et)011 2 011 2

CONHCM

2

CIH(C!H

3 2 CON(n-C 3 2 7 2 C0(3methoxymethylpyrrolidi-i-yl), CONH(3-tolyl), CONE C4tolyl) 00112013, CO(morpholinl-yl), 00(4-methylpiperazin- 1-yl), CONHCM 2

CH

2 OH, 00N11 2 and CO(piperidin-l-yl). A p referred R 2 group is hydrogen.

-34- An embodiment that is particularly useful for IND treating GSK3-mediated diseases relates to compounds of formula II:

.HNN

CMRY

or a pharmaceutically acceptable derivative or prodrug Sthereof, wherein; ND Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, 0 pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring,.

wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8

R

1 is selected from -halo, -CN, -NOa, T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Cz- 6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R e said Ci-s aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R' and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; Rx and R Y are independently selected from.T-R 3 or Rx and k R y are taken together with their intervening atoms to o form a fused, unsaturated or partially unsaturated, 5-8 C 1membered ring having 0-3 ring heteroatoms selected from Soxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and Ry is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by Rx and R y is substituted by R 4 \D T is a valence bond or a CI- alkylidene chain;

R

2 and -R 2 are independently selected from -T-W-R 6 or

SR

2 and R 2 are taken together with their intervening IN atoms to form a fused, 5-8 membered, unsaturated or o partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each.

substitutable carbon on said fused ring formed by R 2 and R 2 is.substituted by halo, oxo, -CN, -NO, -R 7 or

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R4;

R

3 is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0)2R, -SR,

-N(R

4 2

-CON(R

7 2

-SO

2

N(R)

2

-N(R

7

)COR,

-N CO 2 (optionally substituted C1- aliphatic),

-N(RN(RI)

2

-C=NN(R

4 -C=N-OR, CON(R) 2

-N(R

7

)SO

2

N(R

7 2

-N(R

4

)SO

2 R, or -OC(=0)N(R 7 )2; each R is independently selected from hydrogen or an optionally substituted group selected from C.Ialiphatic', C-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected-from -R 7

-COR

7 -CO (optionally substituted C 1 -6 aliphatic), -CON(Rb2, or -SO 2

R

7 or two R 4 on the same nitrogen are taken -36together to form a 5-8 membered heterocyclyl or heteroaryl ring; o each R 5 is independently selected from *halo, -OR, 0 c-I -CC=Q)R, -CO 2 R, -COCOR, -N102, -CN, -SO 2 R, -SR, -1(R 4 2 -0011(R 4 2 -80 2

N(R

4 2

-N(R)COR,

CO

2 (optionally substituted C1_, aliphatic), -N(R 4

N(R

4 2 -C441N(Rfl 2 -0=11-OR, -N(Rt)CON(n 4 2 Cl -NCRt)S 2

N(R

4 2 -N(Rt)SO 2 R, or 2 or Rt 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; is -S2- -N(R 6 )So 2 -S0 2 o C02-, -NOI')C(o)o-, -N(R')s0 2 0 -C(0)11(R 6 -OCCO)N(a 6 -C(R'ho0-, -CCRi) S-, 3 S0-, -C(R6) 2 S0 2 -C(R'L2SO 2 2 2 gNCR 6

-CCPY)

2 11Ca 6

-C(R')=NN(R

6 -C(R6) -C CR 6 i) 2

N(R

6 N 2 1(R 6 SO2N or -C(R6) 2 ,N(R)CON(R') W1 is 2 2

-CCR')

2 S0-, 2 s0 2 2 ,S0 2 -C(R6) 2

N(R

6 CO3-, -C CR)OC

-C(R)

2 N( R 6

CO-,

2 N -C CR 6 -C(R0) 2 N(R) -CC(R') 2 N(R) S0 2 N (R) -C (Rt) 31 R6) CON (it) or -0011CR')-.; each R6' is independently selected from hydrogen, an optionally substituted C:-4 aliphatic group, or two R6' groups on the same nitrogen atom are taken together with the nitrogen- atom to'fornia heterocycyl. or heteroaryl ring; 'each' R7 is independently selected from hydrogen or an optionally substituted C 1 6 aliphaticegroup, or two it7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and 3 7each R' is independently selected from an optionally NO substituted C 1 4 aliphatic group, -SR 6

-COR',

o -S0 2

R

6 2 N 2 -CN, -NO 2

-CON(R').

2 or -C0O 2

R'.

When the Rx and RY groups of formula II are taken together to form a fused ring, preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said Rx/RY ring is optionally substituted. This IND 10 provides a bicyclic ring system- containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula 11 are the mono- and bicyclic systems shown below.

H

HN HN7 HN 11-A II-B II-C HN' HN3 HN>1? R 4 XI-D I-E Il-F HNt> HN' HN

HA

I t II- t y t-U3 It-H fl I-I -38- HNZ HN' HN,

\O

II-J

-L

a -5 -Na I-N .1-I ci V.0X Ci (NN

II-P

More preferred pyrimidine ring systems of formula I include Il-A, SI-B, Il-C, Il-F, and Il-H, most preferably Il-A, Il-B, and Il-H.

In the monocyclic pyrimidine ring system of formula II, preferred RX groups include hydrogen, alkylor dialkylamino, acetamido, or a C.- 4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred RY groups include T-R 3 wherein T is a valence bond or a methylene, and-R 3 is -N(R 4 or -OR. When R3 is -R or -OR, a preferred R is an optionally substituted group selected from C 1 -6 aliphatic, phenyli or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl -39such as phenyl or halo-substituted phenyl, and methoxymethyl.

o In the bicyclic pyrimidine ring system of 0 formula II, the ring formed when R and Ry are taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR,

-CO

2

R,

-COCOR, -NO 2 -CN, -SOa 2 R, -SR, -N(R 4 2

-CON(R')

2 Ci -S0 2

N(R

4 2 -N(R')COR, -N(R 4 CO0 2 (optionally substituted aliphatic), 2

-C=NN(R')

2 -C=N-OR, -N(R')CON(R') 2

-N(R')SO

2 N 2

-N(R')SO

2 R, or

-OC(=O)N(R)

2 wherein R and are as defined above.

o Preferred RX/RY ring substituents include -halo, -OR, -COR, -CO 2 R, -CON(R 4 2 -CN, or -N(R 4 2 wherein R is an optionally substituted C 1 -s aliphatic group.

C 15 The R' and R 2 groups of formula II 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 II.compounds having a pyrazole-containing bicyclic ring system:

H

HN HN N f) Fix NN Nl I QCNH NH NH H RY IN Z -N Sand Preferred substituents on the R'/R 2 fused ring of formula II include one or more of the following: -halo, 2

-C

1 .4 alkyl, haloalkyl, -NO 2 -O(Ci-4 alkyl), -CO 2

(C

1 aikyl), -CN, -so alkyl), -S0 2

NH

2

-OC(O)NH

2

-NH

2

SO

2

(C

1 4 alkyl), -NC(O) (C1-.

4 alkyl), -C(0)NH 2 and -CO(C-.

4 alkyl), wherein the 4 alkyl) is a straight, branched, or cyclic alkyl group.' Preferably, \O Sthe (CI.

4 alkyl) group is methyl.

SWhen the pyrazole ring system of formula II is monocyclic, preferred R 2 groups include hydrogen, a Ssubstituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -s aliphatic group. Examples of such C preferred R 2 groups include methyl, t-butyl, -CH 2 0CH 3 cyclopropyl, furanyl, thienyl, and phenyl. A preferred 10 R 2 group is hydrogen.

C. More preferred ring systems of formula II are o the following, which may be substituted as described above, wherein R 2 and R 2 are taken together with the Spyrazole ring to form an indazole ring; and RX and RY are C 15 each methyl, or RX and R y are taken together with the pyrimidine ring to form a quinazoline or tetrahydroquinazoline ring: NH H HN HN HN

H

3 C N 0t"Ot

H

3 C A® II-Aa II-Ba II-Ha Particularly preferred are those compounds of formula II-Aa, II-Ba, or II-Ha wherein ring C is a phenyl ring and.R 1 is halo, methyl, or trifluoromethyl.

Preferred formula II Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system. Preferred fused rings include a benzo or pyrido ring. Such rings preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C'systems include

LO

naphthyl, quinolinyl and isoquinolinyl.

0 An important feature of the formula II S compounds is the R 1 ortho substituenton'Ring C. An ortho position on Ring C or Ring D is defined relative to the position where Ring A is attached. Preferred R 1 groups C include -halo, an optionally substituted C16- aliphatic group, phenyl, -COR', -CN, -SO 2 -SO2NH 2 7COR 4 -CONH, -NHCOR', -OC(O)NH 2 or -NHSO 2 When R' is Ci an optionally substituted.C,- 6 aliphatic group, the most o preferred optional substituents are halogen. Examples of IND preferred R1 groups include -CF 3 -Cl, -CN, -COCH 3

-OCH

3 -OH, -CH2CH 3

-OCH

2

H

3

-COH

3

-F

2 a 3 cyclohexyl, t- 15 butyl, isopropyl; cyclopropyl, -CCH, -OmC-CH 3 -S20t 3

-SO

2

NH

2

-N(CH

3 2 -C0 2 0CH 3

-CONH

2

-NHCOCH

3

-OC(O)NH

2

-NHSO

2

CH

3 and -OCF 3 On Ring C of formula II, preferred R substituents, when present, include -halo, -CN, -N0 2 optionally substituted Cz-g aliphatic group, -OR, -C -CO 2 R, -CONH(R), -N(R)COR, -SOzN(R) 2 and

-N(R')SO

2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3 -Ni2, -NH(C.-4 aliphatic), aliphatic) 2 aliphatic), C, 4 aliphatic, and

-CO

2 (C-4 aliphatic). Examples of such preferred substituents include -Cl, -CN, -CF 3

-NH

3 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl-, tbutyl, and -CO 2 Et.

Preferred formula II compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring C'is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring.C and two adjacent substituents thereon form a bicyclic ring -42system, the bicyclic ring system is selected from a I naphthyl, quinolinyl or isoquinolinyl ring; o

R

x is hydrogen or Ci.- aliphatic and R Y is C' T-R 3 or RX and R .are taken together with their S 5 intervening atoms to form an optionally substituted 5-7 Smembered unsaturated or partially unsaturated ring having 0-2 ring nitrogens;

R

1 is -halo, an optionally substituted CI-6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO2R 6

-SO

2

NH

2

-N(R

6

-CO

2

R

6 -CONHa, -NHCOR 6 -OC(0)NH 2 or -NHSO 2

R

6 c and o

R

2 is.hydrogen and R 2 is hydrogen or a 0 'substituted or unsubstituted group selected from aryl, Sheteroaryl, or a CI-s aliphatic group, or R 2 and R 2 are c 15 taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula II have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring; Rx is hydrogen or methyl and R Y is -R,

N(R

4 or -OR, or R x and R y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclo -ring optionally substituted with halo,. -OR, -CO2R, -COCOR,

-NO

2 -CN, -SOaR, -SR, -N(R 4 2 -CON(R4) 2 -S0 2

N(R

4 2

-N(R

4 COR, CO2 (optionally substituted Ci-6 aliphatic), -N(R 4 2

-C=NN(R')

2 -C=N-OR, N(R')CON(R 4 2

-N(R

4

)SO

2

N(R

4 2 -N(R4)SO 2 R, or 2; -43- R' is -halo, .a CI-6 haloaliphatic group, a

C

1 -6 aliphatic group, phenyl, or -CN;

\O

o R 2 is hydrogen and R 2 is hydrogen or a C substituted or unsubstituted group selected from aryl, or a C2r- aliphatic group, or R 2 and R 2 are taken together Swith their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially C unsaturated 6-membered carbocyclo ring; and each R 5 is independently selected from c 10 -halo, -CN, -N02, 2 optionally substituted Ci.- Ci aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N(R')COR,

o -SO 2

N(R

2 or -N(R')SO 2

R.

Even more preferred compounds of formula II I have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl ring optionally substituted by -R; Rx is hydrogen or methyl and R Y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or Rx and R y are taken together with their intervening atoms to form an optionally substituted benzo ring or partially unsaturated 6-membered carbocyclo ring;

R

1 is -halo, a Ci- 4 aliphatic group optionally substituted with halogen, or -CN;

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally-substituted with -halo, 2 -Ci-4 alkyl, -CI-4 haloalkyl, -NO2, 4 alkyl) -CO (CN 4 alkyl), -N, -S02(C 1 4 alkyl), -SO 2

NH

2 -OC(0)NH 2

-NHSO

2

(CI-

4 alkyl) -NHC(0) alkyl), -C(0)NH2, or -CO(C1-4 alkyl), wherein -44the (C 1 4 alkyl) is a straight, branched, or cyclic alkyl group; and each R 5 is independently selected from -Cl, -CN, -CF3, -NH2, -NH(C, 4 aliphatic), -N(C 1 -4 aliphatic) 2 -0(C 1 4 aliphatic), C, 4 aliphatic, and -CO0(C:.

4 aliphatic).

Representative compounds of formula II are shown below in Table 1.

Tablel".

CH

3 H3CIN

CI

H

3

CN

II-1

F

HN

IIN

CI

11-4 HN9

H

NI

II-2

F

HSH

II-5

F

N CF 3 II-8

F'

H

I CF3 HNr)>,.b 11-3 F

FZ

HN

II-6

F

H

N CF3 WIb II-7 FsC OC)tN

CF

3 94H K0hN CF.9

N#KOI

11-13 HN~Jj 4 -N CF 3

NO

H

3

C

'I-19

NCF

3 11-12 11-14 -tipH

HN

11-.17 11-20 QF' HC~

HN

F

'I-iH

NO

11-21 -46- 11-22 11-23 F HSCXI N CF3 HCIN l HfC) 1130 N r HsC bN

CF

3 H 3C N11- 11-24 11-25 11-26 11-27

F,

HSCtN

CF

HC

11-28 Fn

H

3

CN

11-31

CH

3 kN F 11-34

HN-I

HfC I N CI N16 11-29 11-30 HfH 11-32

CH

3

HN

0013 11-35 CH3 HN

J

NCHs 11-33

OH

3 HN 1'NP 11-36 -47-

OH

3 HN

N~Y

11-37

OH

3 HNHe-r 11-40

OH

3 c

HN

3 0 11-38

OH

3

HN

t Pq

NCF

3 N.I0 11-41 O

H

3 11-44

N~Y

11-47

.OCH

HN

11-39

OK

3 HN4JP

H

Oh N C2H Nv 11-42

OH

3 HN f

W

N

11-45 N F 11-48

OH

3

HNAJPNH

OtN 11-43 HN 2 11-46 -48-

CH

3 HN

C

11-49 0 N CF 3 11-52

HNL?

vc N CF 3

NO

HN td

NCF

3 11-53

HN

CF

3

H

HNLY

tN CF,

CNO

11-59

HN

OH

HN'*

11-54 N H yjN CF 3 11-57

HN

N 'It -49- I13C

HN

cNt CF 3

N$Y

11-64

FSH

HN

11-62

F

3 C r 11 CF 3 11-65 (jN Cl

NN~

11-63

CF

8 11-66 H

N

11-72 0 HN2 11-67 0 2

N

11-70 Nit CF 3 311-68 11-71

H

2

N

H N2N N CF 3 11-73

FF

9NH 11-74 F

CI

'NJIs 11-76 F'A6

HN

N1-75

N

11-75.

HrZ 11-8

F

KIN OF 3 11-81 11-79 Br N CF 3 11-82 11-83 -51-

F

F

oHN CIp

CF

3 11-88

F?

OCHj'1O 11-91 F

F

11-94

CF

11-86

CF

NkO HN2

NCF

3 11-92

MNN

-N95 IJI-87 NCF3

OCH

3 Ltl 11-90 NtfCFS 11-93

NH

2 C0 -52-

IND

9NH 11-97

OH

3 11-100 N00F 3

OH

3 11-103 9 ON F 3 SI-s 11-99 HN -1P

NCF

6 11-101 HN2H vQJ N OCF 3

OH

3 11-104

HZ

11-102

OH

3

H

3 0 -kV 11-10s

OH

3

HHX

NNY

11-106

F

jj CF 3 11-107 HN (JE CF3 11-108 -53-

F,

~N OF 3 11-109

FZ_

HN11

CIH

1111 II-~ 111 11-113 11-114 HN2P ,NC46

HN

11-117

F'

11-115 F

Z

HZ

qN Cl 11-119 11-120 -54- Nqt

H

H N-16 11-123 11-121 11-122 1-2

F

ciH ci HN N CF

NCF

3 11-125 11-124 11-126 11-127 11-128' 11-129 11-130 11-131 11-132

CH

3

HN

4 p Fs 3

C

F

8

SC

11-135 11-133 11-134

OH

3 11-136 11-137 11-138

HN

2 H I1H AcNHZ" 11-140

HN

2

N,

H

3 C

,'N

MeSO 2

NH

11-139 11-141

H

3

C

<N N 11-142 11-143 11-144 -56-

HN

11-145 11-146 11-147 11-148 HNXt

A$

11-151 HN.M8 9 pH r- HN" 11-154 11-149 11-150

N

1 N CF 3 NH 8 2

N

11-153 HNi HNZ)(IN CF.

11-156 11-152

N

-S7-

NNH

2 NK~ p I

NYQ

H2N

H

2

N

11-157 11-158

N

Me0Q{>%SN 11-160

HN

N.tS -NtNCFs Et--N N~Y 11-161

HN

11-162

YNN

N- NC Fs N126 11-163 N CF 3 Hsc H NC Cbz 00 N

H

11-166 11-167 -11-168 -58- 11-169 11-172 Cbz.N4

F

11-175 11-270 og~o

HN.-L&

H3C~ t

F

11-173

HN

2 H2N 4>

F

11-176 11-179 HN2P

H

11-271 HN2P 11-174 11-177 ,jr2%

N

11-178 11-180 -59- JtNN

N~C

O H~ CFAC

N

ON NN 11-184 HN d9JH Ac 11-182 11-183 (ji 11-185 11-166 CHrNQ C 3 11-189 11-188 11-191 HN

H

Y12 11-190 Va 0 0 ci ci 11-193 11-194 11-195

HN

I 'N Cl N N4"

H

11-196 H~jNC H-IN:saN 11-197 0 lb 19

HN

11-202

HZ

Me.N

CI

11-200 11-203 MeX 4 N CI

H

2

NQ

2

SN

Ir-201 11-204 -61- HN9NNV 11-205 11-206 11-208

NN

11-211 11-214 11-209

HN

4 11-212 11-207

HNH

11-210 _NH 11I-23 11-216 a

Q)

11-215 -62- WN c 11-217 11-220 H3

I

11-218 HN2N Qhj2H 11-221 NN Cl

NN

11-219 H9H 11-222 Me 11-225 tOMe

HN

HN

Me 11-223 F

TF

HNTV

11-224 11-226 11-227 11-228 -63-

F

11-229 HN2P otN t.Bu 11-232 Fn N' C(O)NH 2 11-235 F' H 3N 11-230 11-231

H

t-Bu 11-233 'LN NH2 11-236

:FH

NH

2 11-239 I1-234

NHN

11-237 H2 11-240 11-238 -64n ,'>2k1U r4 II-241

(N

ci' 0 ND

IN

<D

0 0 ci II-244 II-242

HN-N

aN II-245 itN S02NHa II-248

H

H3C N CF II-251 11-243 II-243 -HN H CIN NO 2 11-246 HN 1H ON N(Me) 2 11-249 II-247

F

N SO 2 N(Me) 2 1-250 In another embodiment, this invention provides a composition comprising a compound of formula II and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically IND effective amount of a composition comprising a compound o of formula II.

C Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 S inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula II.

s0 1 0 Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of o glucose in a patient in need thereof, comprising NO administering to said patient a therapeutically effective Samount of a composition comprising a compound of formula II. This method is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula II. This method is'especially useful in halting or slowing the progression of Alzheimer's disease.

Another aspect relates to a method of inhibiting the phosphorylation of P-catenin in a patient in need .thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula II. This method is especially.useful for treating schizophrenia..

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula II.

-66- Another aspect relates to a method of treating \O a disease that is alleviated-by treatment with an Aurora C inhibitor, said method comprising the step of

C

N administering to a patient in need of such a treatment a therapeutically effective amount of a composition Scomprising a compound of formula II. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a C\ 10 method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically 0 effective amount of a composition comprising a compound IN of formula II.

o Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula II. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulqnephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula II, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora or CDK-2, or the treatment .of a disease alleviated thereby, is preferably -67carried out with a preferred compound of formula II, as O described above.

0 Another embodiment of this invention relates to (C compounds of formula III:

HN

Rx N

III

0 or a pharmaceutically acceptable derivative or prodrug NO thereof, wherein: o Ring D is a 5-7 membered monocyclic ring or 8-10o'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 Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or heteroaryl ring, -R s is hydrogen at each ortho carbon position of Ring D;

R

x and R y are taken together with their intervening atoms to form a fused, benzo ring or.a 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by Rx and R Y is substituted by oxo or T-R 3 T is a valence bond or a C..

4 alkylidene chain;

R

2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 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 -68substitutable carbon on said fused ring formed by R' IND and R 2 is substituted by halo, oxo, -ON, -NO 2 -R7, or o and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4

R

3 is selected from -halo,

-CO

2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(O) 2 a, -SR, 2

,.-CON(R

4 2

-SO

2

N(R&)

2 -N(R 4

)COR,

-N (K 4 002 (optionally substituted C1.6 aliphatic), -N(RtN(R 4 2

-C=NN(R')

2 -C=N-OR, -N(R 4

)CON(R)

2

-N(R

4 )SoN(R 4 2

-N(R)S

2 R, or -OC(=O)N(R 4 2 each R is independently selected from hydrogen or an Cl optionally substituted group selected from C1-b IND aliphatic, aryl, a heteroaryl ring having 5-10 ringatoms, or a heterocyclyl ring having 5-10 ring atoms; each K 4 is independently selected from -Ra 7 -Coat, -CO (optionally substituted C3_r aliphatic),

-CON(R

7 2 or -S0 2

R

7 or two R 4 on the same'nitrogen are taken together to form a 5-8 membered heterocyclyl or is heteroaryl ring; each R 5 is independently selected from *halo, -OR,

-CO

2 R, -COCOR, -NO 2 -cit -SO 2 R, -BR,

-CON(R

4 2

-SO

2

N(R)

2

-N(K

4

)COR,

-N (R 4 )0Co 2 (optionally substituted 0 -6 aliphatic),

-N(R')N(R

4 2

-C=NN(R

4 2 -C=N-0R, -N(R')CON(R) 2

-N(R

4 )So 2

N(R

4 2

-N(R

4 )S0 2 R, or -0C(O)W(R4)3; V is -S-i -SO, -S02-, N(R 6 )S0 2

-SO

2 N(R6)-,

-N(R

6 -COg-,

-N(R

6

-N(R)CON(R

6 -N(0Z)SO 2

N(R

6

-N(R

6 )i(R 6 -C(O)N(a 6 -OC(O)N(a 6

-C(R

6 2 0-,p C(R6)2S-,

-C(R

6 2 SO-, -C(R 6 2

SO

2

-C(R

6 2 So 2 2

N(R

6

-C(R

6 2

N(R

6 -C(R6) 2 NN(R6)-,

-N(

6 2 1 6 )N(a 6

-C(R

6 2

N(R

6

)'SO

2 or

-C(R

6 2

N(R)CON(R

6 -69- W is -C(R) 2 -C(R6)2S-, 2 SO-, 2 S02-,

IND-C(R)

2 SO0 2

-C(R

6 2

-CO

2 o -C(R 6 -C(R')OC(o)N(R 6

-C(R

6 2

N(R

6

)CO-,

cl -C(R 6 2 N(R')C 2 N(R)so 2

N(R

6 -C (R 6 2 CON (R 6 or CON(R) each'R 6 is independently selected from hydrogen or an optionally substituted C 1 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together IN 10 with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and 0 each R' is independently selected from hydrogen or an IND optionally substituted Cl- aliphatic group, or two R' o -on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Preferred formula III Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. When two adjacent substituents on Ring D are taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula III Ring D bicyclic rings include 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred R 5 substituents on Ring D of formula Il3 include halo, oxo, CN, -NO 2

-N(R)

2

-CO

2 R, -CONH(R'),

-N(R

4 COR, -SO 2

N(R)

2

SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6 aryl, or C 1 aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, -OR, or a substituted or unsubstituted INDgroup selected from 5-6 membered heterocyclyl, Cs-o aryl, or C 1 i. aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, CH 2

CH

2 0H, pyrrolidinyl, OPh, CF3,.cCR, C1, Br, F, I, NH 2 C(0)CH 3 i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

Preferred rings formed when the R' and RY groups of formula III are taken together to form a fused ring IN 10 include a or 7-membered unsaturated or partially unsaturated carbocyclo ring, wherein any substitutable carbon on said fused ring is substituted by oxo or T-R 3

\O

Examples of preferred bicyclic ring systems are shown below.

R

2

NH

tNH HNN III-A III-B IlI-C HN- HN3? III-P III-I Preferred substituents on the RE/XRY fused ring of formula III include oxo, halo, -OR, -CO 2

R,

-COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R) 2

-CON(R')

2

-SO

2

N(R)

2 -N(R')COR, -N(R')CO0 2 (optionally substituted C1-6 aliphatic),

-C=NN(R

4 2 -C=N-OR, -N(R')CON(R 4 2 -N(R )SO 2 N(R 4 2

-N(R

4 )S0 2 R, or -71- -OC 4 2 wherein. R and R' are as def ined above.

IND* More preferred substituents on. the Rx/RY fused ring include halo, CN, oxo, C1_ 6 alkyl, C:L- alkoxy, (C2- 6 (Nalkyl) carbonyl, (C 1 6 alkyl) sulf onyl, mono- or ct dialkylamino, mono- or diallcylaminocarbonyl, mono- or dialkylaminocarbonylox, or 5-6 membered heteroaryl.

Examples of such preferred substituents include methoxy, methyl, isopropyl, methylsulfonyl, cyano, chioro, pyrrolyl, methoxy, ethoxy, ethylamino, acetyl, and IND 10 acetamido.

Preferred R 2 subs tituents of formula XII include 0 hydrogen, C3,- 4 aliphatic, alkoxycarbonyl, (un)substituted IND phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, monoo or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, is dialkylaminoalkyl, phenylaminocarbonyl,'and

(N-

heterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, 'isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO 3

H,

Co2Ce 3 Cx 2 oH, CR 2

OCH

3

CH

2 aI 2 aI 2 OH, OR 2

OH

2

GH

2

OCH

3

CM

2 a1 2

CM

2 0CH 2 Ph, CH 2

CM

2

CH

2

NM

2

CH

2

CH

2

CH

2 NHCOOC (ON 3 3 CONHCR (OH 3 2

CONNOH

2 CH=0H 2

CONHCH

2

CH

2

OCH

3

CONHOH

2 Pb, CON (cyclohexyl) CON (Et) 2 CON (CH 3

CH,

2 Ph, CONH (n-0 3 CON (Et) OR 2 OH2CH 3

OONRCH

2 CH CON (n-C 3

H

7 Co (3methoxymethylpyrrolidi n-a-ylj, OON(3-tolyl), OONH(4tolyl), CON14CH 3 CO(morpholin-1-yl), 00(4-methyipiperazinl-yl) CONHCH 2

CH

2 OH, dowi 2 and CO (piperidin-l-yl).

-when the R 2 and R 2 groups of formula III are taken together to form a ring, preferred R 2 ring systems containing the pyrazole ring include benzo, 30 pyrido, pyrimido, 3-oxo-2H-pyridazino, and a partially unsaturated 6-membered carbocyclo ring.' Examples of such preferred R 2

/R

2 ring systems containing the pyrazole ring include the following: -72- N0 0 N N o H H H C H, and H Preferred substituents on the R 2

/R

2 fused ring

\O

Ci of formula III include one or more of the following: o" -halo, -N 2

-C

1 4 alkyl, -C 1 4 haloalkyl, -NO 2 -0 (C-4 \O alkyl), -co0 2

(C

1 -4 alkyl) -CN, -S0 2

(C

1 4 alkyl), -SO 2

NH

2 o -OC(O)NH 2

-NH

2

SO

2

(C

1 4 alkyl), -NHC(O) (C3.

4 alkyl), C 10 -C(O0)NH 2 and -CO(Cc-, alkyl), wherein the (C 1 .4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C-4 alkyl) group is methyl.

Preferred formula III compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, .pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; RX and R are taken together with their intervening- atoms to form an optionally substituted benzo ring or a 5-7 membered carbocyclo ring; and

R

2 is hydrogen or methyl and R 2 is T-W-R' or R, wherein W is -C(R 6 2

-C(R)

2

N(R

6 -C0 2

-C(R

6

-C(R

6 2

N(R

6

-C(R

6 2 or -CON(R6)-, and R is an optionally substituted group -73selected from C.-6 aliphatic or phenyl, or R 2 and R 2 are IN .taken together with their intervening atoms to form a O substituted or unsubstitutedbenzo, pyrido, pyrimido, or Cr partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula III have Sone or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, .O 10 piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- C tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, O 2,3-dihydro-IH-isoindolyl, 2, 3-dihydro-lH-indolyl, I\ isoquinolinyl, quinolinyl, or naphthyl; 0 o Rx and R Y are taken together with their intervening atoms to form a benzo ring or a 5-7 membered carbocyclo ring optionally substituted with oxo, halo, -OR, -CO2R, -COCOR, -NO 2 -CN, -S(O)R, -S0 2 R, -SR, 2

-CON(R

4 -SOaN(R 4 2

-OC(=O)R,

-N(R COR, -N(R C02 (optionally substituted C 1 -6 aliphatic), -C=NN(R4)2, -C=N-OR, -N(R 4

)CON(R

4 2 -N(R')SOaN(R 4 2

-N(R

4 )S0 2 R, or N (R 4 2 and each R 5 is independently selected from halo, oxo, CN, NOa, -N(R 4 -C02R, -CONH(R 4

-N(R')COR,

-SO

2 N(R4) 2 -N(R4)SO 2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C 6 -lo aryl, or Ci-_ aliphatic.

Even more preferred compounds of formula III have one or more, and more preferably all, .of the features selected from the group consisting of:

R

x and R 7 are taken together with their intervening atoms to form a benzo or 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN,.oxo, Ci-6 alkyl, Ci-s alkoxy, (Ci- 6 alkyl)carbonyl, alkyl)sulfonyl, mono- or dialkylamino, mono- or -74dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, .O or 5-6 membered heteroaryl; O each R 5 is independently selected from C- -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from 5-6 Smembered heterocyclyl, C6-10 aryl, or C.z- aliphatic; and

R

2 is hydrogen and R 2 is selected from R 2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is

-C(R

6 2

-C(R

6 2 N R 6 -C0 2 -C(R)OC 10 -C(R 6 N (R 6 CO-, or -CON(R6)-, and R is an optionally substituted group selected from C 1 i- aliphatic or phenyl, o or R 2 and R 2 are taken together with their intervening NO atoms to form a benzo, pyrido, or partially unsaturated S6-membered carbocyclo ring optionally substituted with

C

N 15 -halo, -N(R 4 -C-4 alkyl, -C 1 4 haloalkyl, -NO 2 -0(C_-4 alkyl) -C0 2

(C-

4 alkyl), -CN, -SO(CC:- 4 alkyl), -S02NH 2 -OC(0) NH 2

-NH

2

SO

2 (C-4 alkyl), -NHC alkyl),

-C(O)NH

2 or -CO(C-.4 alkyl), wherein the alkyl) is a straight, branched, or cyclic alkyl group.

Representative compounds of formula III are set forth in Table 2 below.

Table 2 H H H HN HNI HNN H III-1 III-2 III-3 91at-"'l

NO

TPT-I I Ht 4

NH

El -III

ST

SI -111 HN jNH 8 H3 T III ZI-IlI 01-11I 6-1ll (9 8-111 L111 9-1l1 S-I"i rv-III

H

CHO

111-19

OH

3

HN*H

;11 11% 111-20 CH~SQ2 111-23

OH

3

HN

CH

3

NH,

OH

3 111-22 HN

H

3

C

111-25 111-21

OH

3

HN

111-24

CR

3

HN<N

0 111I-27 111-26

OH

3

HN<

111-28

CR

3 HN4* 111-31

OH

3 111-29

OH

3

HNJ?

111-32

OK

3 111-30

OH

3 4,*

-H

111-33 -77-

IND

CA

111-34.

OH3

NH

Nt 111-37

HNJJ

tNN

H

111-40

OH

3 111-35

OH

3

HN

111-41

OH

3 gcI 111-36

OH

3 111-39 k 111-42

OH

3 gn*

,,H

111-43

HN

111-46 111-44

OH

3 HN4* tH N N 111-47

OH

3

HN*$

N HNQM 111-45

OH

3

HN~H

111-48 -78-

OH

3

HN*&

111-49

OH

3

HN*

111-52

CH%

HN<Nl 111-55 CH3

LIH

"II-so

OH

3

HN<(IN

111-53 91%

HN

N

111-56

OH

3

HNH

111-59

OH

3 111-62

OH

3 N

~F

F

OH

3 OtN H

N

111-54

OH

3 HN 1 tNH3 111-57 1"-58 111-61 -79- HNQ l

H

111-64

H

3 0

H

CH

2

CH

3 4 HN e N

HIE

OH

3 HN6 111-66 111-67 111-E8 111-69 HNt

H

111-70 111-71 111-72 C0 2 0H 3 HN4* 111-73

CH

2 0H

NH

111-74 0H 2 00H 3 HNt 111-75 Hc lN

NH

H1 oll 111-76 111-77 111-78

NH

2

HNX

111-79 III-so o) )-CH 3 (j~NH 111-81 0arC) 111-82

OCH

3 o r-, H4 111-83 o ,r-CH 3

HN

111-86 111-84 0Q

NN

0H ei 111-87 -81- 111-88 111-8911-9 111-90

CH

3

H

111-9

OH

3

H

tN4- 111-92

OH

3

HN$

III)-9NS o0

N"I-CH

111-93

N

HNW

111-97 111-96

O,,H

111-99 -82- -Es- VTT-111

"NH

CHO

Itt-III Ell-III Ett-II 6 H0 oil-III 601-I"1 H 2 HO CHO.

oNH

CHO

LOT-III

SOT-III Vol-III HNh

N,

or>

HN-

owJ

NH

EHO

tOT-III HNt

NH

is EO-IIll

ON

~NH

ONN

0y.

H ZOt-III 111-115 111-118 Hi~

N

111-121

CH

2 0H 111-124

HN$

III-a27 111-116 WHi 111-119 00 2

CH

3

HN*

111-122

CONH

2

HN'

W,,N

H

111-125

F

3 0 4, 111-128 111-117 Hi 111-120 0

HA

N 1 3 111-123 111-126 111-129 -84-

F

H

111-131 HNNNf 111-122 111-130 111-133 111-134 111-135 MeOt% 111-136

F

3 C N N4 HN N 111-138 111-137

H

(NN N L=1 111-141 111-139 111-140 0 HNA HN^ HN- H N C 'N H

NX

6 CHV 3 NV -S 111ii-142 III-143 III-144 i-(A r~~l HN"^r, N HN NN MeMe 0 5I-145 111-146 In another embodiment, this invention provides a composition comprising a compound of formula III and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

I

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula III.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of -a composition comprising a compound of formula -86- III. This. method is especially useful for diabetic D patients.

0 Another aspect relates to a method of (C .inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising Sadministering to said patient a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

IN 1 0 Another aspect relates to a method of inhibiting the phosphorylation.of D-catenin in a patient C in need thereof, comprising administering to said patient oN a therapeutically effective amount of a composition o comprising a compound of formula III. This method is especially useful for treating schizophrenia.

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for treating cancer, such as colon, .ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

Another aspect relates to a method of treating ND a disease that is alleviated by treatment with a CDK-2 O inhibitor, said method comprising the step.of Ci administering.to a patient in need of such a treatment a t 5 therapeutically effective amount of a composition >comprising a compound of formula III. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, Scytomegalovirus,.HIV, herpes, psoriasis, atherosclerosis, IND 10 alopecia, and autoimmune diseases such as rheumatoid ci arthritis.

One aspect of this invention relates to ,a I0 method of inhibiting Src activity in a patient, o comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula III.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a Src inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula III. This method is especially useful for treating hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease.

Another method relates to inhibiting GSK-3,. Aurora, CDK-2, or Src activity in a biological sample, which method comprises contacting the biological sample with the GSK-3, Aurora, CDK-2, or Src inhibitor of formula III, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora, CDK-2, or Src.

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora, CDK-2, or Src, or the -88treatment of a disease alleviated thereby, is preferably ND carried out with a preferred compound of formula III, as o described above.

(1 Compounds of formula III, wherein R 2 is C 5 hydrogen and RX and RY are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system, are also inhibitors of ERK-2 and ci AKT protein kinases.

Accordingly, another method of this invention I 10 relates to a method of inhibiting ERK-2 or AKT activity in a patient, comprising administering to the patient a 0 therapeutically effective amount of a composition ci IN comprising a compound of formula I, wherein R 2 is Shydrogen and R 1 and R Y are taken together with the 1S pyrimidine ring to form an optionally substituted quinazoline ring system.

Another aspect relates ,to a method of treating a disease that is alleviated by treatment with a ERK-2 or AKT inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount' of a composition comprising a compound of formula III, wherein R 2 is hydrogen and RX and R Y are taken together with the pyrimidine ring to form an optionally substituted quinazoline ring system. This method is especially useful for treating cancer, stroke, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, restenosis, psoriasis, allergic disorders including asthma, inflammation, and neurological disorders.

Another embodiment of this invention relates to compounds of formula IV: 89- I L NH 0

HN

N

N

IV

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: IN Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, beteroaryl, o 5 heterocyclyl or carbocyclyl, said heteroaryl or IN heterocyclyl ring having 1-4 ring heteroatoms selected O from nitrogen, oxygen or sulfur, wherein Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R, provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D;

R

x and R y are independently selected from T-R 3 or Rx and

R

y are-taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring is optionally and independently substituted by T-R 3 and any substitutable nitrogen on said ring is substituted by 4; T is a valence bond or a C 1 -4 alkylidene chain; R2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R are taken together with their intervening atoms to'form a fused, 5-8 membered, unsaturated or partially unsaturated, ring containing 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein said fused ring is optionally substituted by up IND to three groups independently selected from halo, oxo, -CN, -NO 2 or -V-R6; c R'is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -S(0) 2 R, -SR, 2, CON(R') 2

-SO

2 N 2 -N(R')COR,

-N(R

4

)CO

2 (optionally substituted Cj-_ aliphatic),

N(R)

2

-C=NN(R')

2 -C=N-OR, -N(Rf)CO(Rf) 2 N(R 4

SO

2 SO 2 R, or IND each R is independently selected from hydrogen or an optionally substituted group selected from C- 6 aliphatic, C-.

1 0 aryl, a heteroaryl ring having 5-10 IN ring atoms, or a heterocyclyl ring having 5-10 ring o atoms; each R' is .independently selected from -R -COR', S -CO 2 (optionally substituted

C

1 aliphatic), -CON(R') 2 or -SO 2 or two R4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 2

-CON(R')

2

-SO

2

N(R

4 2

-N(R)COR,

C0 2 (optionally substituted Ci.e aliphatic); -N(Rt)N(R 4 2

-C=NN(R')

2 -C=N-OR, -N(R')CON(R 2

SO

2 N 2 -N(R 4 SO2R, or -OC 2; V is -N(R')S0 2

-SO

2

N(R

6 -CO2-, -N(R 6)CO-, C O-, -1T (R6) CON SO2N -N(R6)N (R6)_

-C(R)

2

-C(R)

2

S-,

2 so-, -C(R)2So0 2

-C(R

6 2 So 2

N(R

6

-C(R

6 2

N(R

6

-C(R

6 2 2

-C(R

6

-C(R

6 2 2 or -C(R6) 2 N(R) CON (R6) -91- W is 2

-C(R)

2

-C(R

6

SO

2 D-C 2so 2 2

N(R

6

-CO

2

-C(R

6

-C(R

6

-C(R

6 2 aN(R')CO-, Cl 2

-C(R

6 6

)N(R

6

-C(R

6

),N(RR')SO

2

N(R

6 2

N(R

6

)CON(R

6 or each R 6 is independently selected from hydrogen or an optionally substituted C.4 aliphatic group, or two R 6 cl.groups on the same nitrogen atom are taken together O 10 with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and Cl each R' is independently selected from hydrogen or an oN optionally substituted C-6 aliphatic group, or two R' o on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl ring or heteroaryl.

Preferred formula IV Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings. Preferred formula IV Ring D bicyclic rings include 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1HR-indolyl, isoquinolinyl,. quinolinyl, and naphthyl. Examples of more preferred Ring D bicyclic rings include naphthyl and isoquinolinyl.

Preferred substituents on Ring D of formula IV include halo, oxo, CN, -NO 2 2

-CO

2 R, -CONH(R'), -N(R)COR, -SO 2

N(R')

2 -N(R)SOaR, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered. heterocyclyl, Cs-jo aryl, or Cl' aliphatic. More preferred R 5 substituents include -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, CO6.0 aryl, -92or C 1 6 aliphatic. Examples of Ring D substituents LC) include -OH, phenyl, methyl, CH 2 H, CH 2

CH

2

H,

0 o2 pyrrolidinyl, OPh, CF 3 CiCH, Cl, Br, F, I, NH 2

C(O)CH

3 i-propyl, tert-butyl, SEt, OMe, N(Me) 3 methylene dioxy, and ethylene dioxy.

When the. RX and Ry groups of formula IV are taken together to form a fused ring, preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms. This IND 10 provides a bicyclic ring system containing the pyrimidine ring. Examples of preferred pyrimidine ringasystems of formula IV are the mono- and bicyclic systems shown \O IND o below.

0 HN' HN'

HN'-

NN

c R 4 Nt HtN, N N Me IV-D TV-E

IV-G

HN1 HN' HNZ N 'NsS me 1N')N N:

'-Y

IV-H IV-J

IV-K

HN* HNZ HN Z

UNN

V- I-N IV-L IV-M

IV-N

-93-

N~

HN

HNt 0tN 'v-s

HNA

17A 17-P IV- Q HNtZ 'v-s HNt1 IV- 7 17-BB

IV-T

<N

R iv- z

H?'

iv-cc -94- IND H HNN

SN

IV-DD

More preferred pyrimidine ring systems of formula IV include IV-E, IV- V-H, IV-J, IV-K, IV-L, IV-M, IV-T, and IV-U.

IN In the monocyclic pyrimidine ring system of formula IV, preferred Rx groups include hydrogen, amino, C< nitro, alkyl- or dialkylamino, acetamido, or a C 1 -4 Io 10 aliphatic group such as methyl, ethyl, cyclopropyl, Sisopropyl or t-butyl. Preferred R Y groups include T-R 3 wherein T is a valence bond or a methylene, and R 3 is -R, -N(R4)2, or -OR. When R 3 is -R or -OR, a preferred R is an optionally substituted group selected from Ci.aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R y groups include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl, methoxyphenyl, trimethoxyphenyl, or halo-substituted phenyl, and methoxymethyl.

In the bicyclic pyrimidine ring system of formula IV, the ring formed when Rx and R y are taken together may be substituted or unsubstituted. Suitable substituents include halo, -OR,

-CO

2

R,

-COCOR,.-NO

2 -CN,

-SO

2 R, -SR, -N(R 4 2

-CON(R

4 2

-SO

2 Na(R 4

-N(R

4 COR, -N(R 4 )C0 2 (optionally substituted

C

1 -6 aliphatic),

-N(R')N(R

4 2

-C=NN(R

4 2 -C=N-OR, -N(R')CON(R 4 2

-N(R

4 )S0 2

N(R

4 2

-N(R

4 )SO2R, or 2 wherein R and R 4 are as defined above for compounds of formula IV. Preferred R 1

/R

Y

ring substituents include -halo, -OR, -COR, -CO 2

R,

O -CON(R') 2 -CN, or -N(R 4 2 wherein R is a substituted or o unsubstituted C,_s aliphatic group.

C The R 2 and R 2 groups of formula IV 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 C exemplified in the following formula IV compounds having- NO 10 a pyrazole-containing bicyclic ring system: 0

H

N N N H DNH H NH RY N DNNN S, and Preferred substituents on the R2/R 2 fused ring of formula IV include one or more of the following: -halo, -N(R -Ci-4 alkyl, -CI-4 haloalkyl, -NO2, -0(C1-, alkyl), -CO2(Ci-4 alkyl)., -CN, -S02 (Ci-4 alkyl), -SO2NH2, -OC NH, -NH2SO(Ci-4 alkyl), -NHC alkyl), -C(0)NH2, and -CO(CI-4 alkyl), wherein the (Ci-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (CI-4 alkyl) group is methyl.

When the pyrazole ring system of formula IV is monocyclic, preferred R 2 groups include hydrogen, a substituted or unsubstituted group selected from aryl, heteroaryl, or a C-6 aliphatic group. Examples of such preferred R 2 groups include methyl, t-butyl, -CH20CH3, cyclopropyl, furanyl, thienyl, and phenyl. A preferred

R

2 group is hydrogen.

-96- Preferred formula IV compounds have one or \qD more, and more preferably all,'of the features selected 0 from the group consisting of:

C

N Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, S.piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1 ,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- C dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or I\ 10 naphthyl ring;

R

X is hydrogen or C 1 -4 aliphatic and R is T- 0 R 3 or R x and R y are taken together with their intervening IN atoms to form an optionally substituted 5-7 membered o unsaturated or partially unsaturated ring having 1-2 ring heteroatoms; and

R

2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is -C(R) 2

-C(R

6 2

N(R

6 -C02-,

-C(R

6

-C(R

6 3

N(R

6

-C(R

6 or

-CON(R

6 and R is an optionally substituted group selected from Ci-6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula IV have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl,.or naphthyl;

R

X is hydrogen or methyl and R Y is -R,

N(R

4 2 or -OR, or R x and R

Y

are taken together with their -97intervening atoms to form a 5-7 membered unsaturated or \D partially unsaturated ring having 1-2 ring nitrogens, Swherein said ring is optionally substituted with -R, C halo, oxo, -OR, -C02R, -COCOR, -N0O, -CN, -S(O)R, -S0 2 R, -SR, -N(R4) 2 -CON(R4)2, -SO 2 -OC(=0)R, G -N (R')COR, CO 2 (optionally substituted C 1 -6 aliphatic), -N (R N 2, -C=NN(R 4 2 -C=N-OR, -N(R 4

CON(R

4 2

-N(R')SO

2

N(R

4 2

-N(R

4

SO

2 R, or -OC(=0)N(R 4 2 and each R 5 is independently selected from halo, I0 10 oxo, CN, NO 2 2 -COR, -CONH(R'), -N(R')COR,

-SO

2

-N(R

4 SOaR,. -SR, -OR, or a substituted -or unsubstituted group selected from 5-6 membered S theterocyclyl, C 6 -o 1 aryl, or C- 6 aliphatic.

SEven more preferred compounds of formula IV have one or more, and more preferably all, of the features selected from the group consisting of:

R

x and R Y are taken together with their intervening atoms to form a 6-membered unsaturated or -partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, Ci-. alkyl, Ci-6 alkoxy, (C 1 6 alkyl)carbonyl, alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Ci-lo aryl, or C 1 i- aliphatic; and

R

2 is hydrogen and R 2 is T-W-R 6 or R, wherein W is. -C (R -C(R 6

N(R

6 -CO, -CO-,

-C(R

6

-C(R

6 or -CON(R 6 and R is an optionally substituted group selected from C 1 aliphatic or phenyl, or R' and R 2 are. taken together with their intervening atoms to form a.benzo, pyrido, or partially unsaturated 6-membered carbocyclo ring optionally -98substituted with -halo, oxo, -N(R 4 2 _C2-4 alkyl, -01.4 haloaliyl, -N0, -O(Ci-..alkyl), -C0 2

(C>

4 alkyl)., -CN,

-SO

2 (CI-4 alkyl), -S0 2

NH

2 -OC(O)NB, -NH 2 S0 2 .(c 1 4 alkyl), -NHC(o) (01-4 alkyl), -C(O)NH 2 or' -CO(Cj-4 alkyl) wherein the (Cl-4 alkyl) is a straight, branched, or cyclic alkyl group.

Representative compounds of formula IV are set forth in Table 3 below.

Table 3.

HN*

eIv-N

OH

3

HN

OMe IV-2

OH

3 AcNH IV-3

CH

3 H2N Iv-6 N O H 3 IV- 6 IV-4 IV-S

OK

3

H

3C

N

IV-7 IV-B -99- IV-1o0lT1 IV-1 IV- 12

H

3

CH

N

H

3 0 IV-13 IV-14 2N

CH

3

N

HCJY

0 IV-17

CH

3 H 3

CH

CH

3 IV-18 IV-21 -100- CHs

HN.,

H

Meo IV-22 CHs

HNH

Hf- H3CHNN1.

CH

3

H

3

C,

IV-23

CH

3

HNIV-

IV-26

CH

3

HN*H

N

H

3 C N IV-24

CH

3 HN

H

t t

N

CIoH 3 IV-27 HNj H MeO N IV-28

CH

3 aHN HNI-1 IV-31

CH

3

HN

H

s-N IV-29

HN

IV-32 IV-32

CH

3

HNI*H

HN

H

CH

3 H HNA$

H

&-H3 IV-33 In another embodiment, this invention provides a composition comprising a compound of. formula IV and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically -101effective amount of a composition comprising a compound NO of formula IV.

0 Another aspect relates to a method of treating Sa disease that is alleviated by treatment with a GSK-3

S

5 inhibitor, said method comprising the step of administering.to.a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula IV.

C( Another aspect relates to a method of enhancing

N

O 10 glycogen synthesis and/or lowering blood'levels of glucose in a patient in need thereof, comprising (C administering to said patient a therapeutically effective Samount of a composition comprising a compound of formula o IV. This method is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

Another aspect relates to a method of inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient r a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for treating schizophrenia.

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula IV.

-102- Another aspect relates to a method of treating IND a disease that is alleviated by treatment with an Aurora 0D inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a I 10 method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound

VO

Iof formula IV.

oAnother aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula IV. This method is especially useful for treating cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula IV, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora or CDK-2, or the treatment of a disease alleviated thereby, is preferably -103carried out with a preferred compound of formula IV, as described above.

Another embodiment of this invention relates to compounds of formula V: H NH HN N RxZ

V

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is N, CRa, or CH and Z 2 is N or CH, provided that one of Z' and Z 2 is nitrogen; G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered.ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 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 -104from nitrogen, oxygen or sulfur, wherein Ring D is IND substituted at any substitutable ring carbon by oxo or

S-R

s and at any substitutable ring nitrogen by -R 4 ^C provided that when Ring D' is a six-membered aryl or 5 heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D; SR is selected from -halo, -CN, -N02, T-V-R 6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, V0 10 and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, C oxo, or -R8, said Ci-6.aliphatic group optionally o substituted with halo, cyano, nitro, or oxygen, or R 1 0 .and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; Rx and R 7 are independently selected from T-R 3 or Rx and

R

y are taken together with .their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R" and R y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring, formed by R.and R y is substituted by R4; T is a valence bond or a C1.4 alkylidene chain;

R

2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 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 carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R4; -105-

R

3 is selected from -halo, -OR, -CO 2

R,

SCOCOR,. -COOH 2 COR, -NO 2 1 -CN, -S(0) 2 R, -SR, 0N,(R 4 2

-CON(R

7 2 -S0 2 N(R7) 2 -N(R')COR, -N (R7) CO 2 (optionally substituted CI-6 aliphatic),

-N(R

4 2 -CnNN(R) 3 -C=N-OR, -N(R 7

)CO(R')

2 -N(R)So 2

N(R)

2

-N(R

4 0 2 R, or -OC 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -6 cl aliphatic, C 6 10 aryl, a'heteroaryl ring having 5-10 Va ring atoms, or a heterocyclyl ring having 5-10 ring atoms; eachR 4 .is independently selected from -R7, -COR 7 Cl -C0 2 (optionally substituted CI 6 aliphatic), -CON(R7) 2 o or -S0 2

R

7 or two R' on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each RS is independently selected from halo, -OR, -CC=O)R, -C0 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR,

NCR

4 2 -CON(R) -S0 2

N(R

4 2 -OC(cO)R, -N(RtCOR, -N (R 4

CO

2 (optionally substituted

C

1 6 aliphatic), -N(Rt)N(R') 2

-C=NN(R

4 2 -C=N-OR, -N(RflCON(a') 2

-N(R

4

)SO

2

NR')

2

-N(R

4 )S0 2 R, or -OC(=O)N(R 4 2 or R5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -502-, -N(R 6 )S0 2 -S0 2 N(R6)-,

-NCR

6 -C0 2

-N(R

6

-N(R

6 -N(R")S0 2

N(R

6 -N(Rj)N(R 6

-C(O)N(R

6

-OC(O)N(R

6

-C(R

6 2

-C(R)

2

S-,

-C(R

6 2

-C

6 2

SO

2

-C(R

6 2 S0 2

N(R

6

-C(R

6 2

N(R

6 -C(R6) 2

N(R

6

-C(R

6 2

N(R

6

-C(R

6

=NN(R

6

-C(

6

-C(R)

2 N (R6')NCR 6 -J or

-C(R

6

")N(CR

6 CON (R 6 W is -C(R 6 2

-C(R

6 2

-C(R

6 2 -CCR' 2 S0 2

-C(R

6 2 S0 2

-C(R

6

),N(R

6 -C02-, -106-

-C(R

6 -C(RG)0C(0)N(R6)-, 2 N(R6)Co-, N-c 2N(R)C(0)o-, -c (R 6 -C N-O-,

-C(R

6 2 -C(R 6 N SO2N (R6), 2 N(R)CON(R or -CON(R')each RI is independently selected from hydrogen, an optionally substituted C.4 aliphatic group, or two R groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or an optionally. substituted C2_ aliphatic group, or two R 7 on the same nitrogen arie taken together with the INDnitrogen to form a 5-8 membered heterocyclyl or o heteroaryl ring; each Re is independently selected from an optionally substituted Ci14 aliphatic group, -OR 6 -SR, -COR', -S02R', -N(R6) 2 -N(It )N(R6) 2 -CN, -NO 2 or -C0 2

R

6 and Ra is selected from halo, -OR,

-CO

2 R, -COCOR,

-NO

2 -CN,

-SO

2 R, -SR, -N(R 4 2

-CON(R')

2

-SO

2

N(R')

2 -OC R, -N COR, CO0 (optionally substituted C, aliphatic),

-N(R')N{R

4 2, -C=NN(R 2 -C=N-OR,

-N(R

4

)CON(R')

2 -N(R)S0 2 N(R4) 2 -N(R 4

)SO

2

R,

-OC(=0)N(R4)2, or an optionally substituted group selected from Cx-6 aliphatic, C,_o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10-ring atoms.

Compounds of formula V may be represented by specifying 21 and Z2 as shown below: -107- 2

R

2 2 IND R H R' NHH HN dHN N HN N N N R "R R" I G N G ,anG and Va Vb Vc C- When the R x and RY groups of formula V are taken

\O

IN 5 together to form a fused ring, preferred RX/RY rings include a or 8-membered unsaturated or C^ 'partially unsaturated ring having 0-2 heteroatoms, Swherein said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Examples of preferred bicyclic ring systems of formula V are shown below.

R 2

IH

A

2 Va-A Vb-A Ve-A HN HNZ HN is c s Va-B Vb-B Vc-B -108- Ut Va-C CA HNt IN FNo

CIA

VB -c V C Va-n vt-n Va-D VaN Va

HN

Va -J Vb-H Va-H

HN-,

Va

F

Vt -F Hr? Qtt (Nt Va -3 -109- Va -K HN

N"

Va -L HN Z rN Va-N N% 0 Va -0 HNt1 NoN

RA

V K Vb -K Vb- L V- L ib -N Va

HMN

vb -N V N 1b -o Va -0 -110- HNk? HN31 HN3 CNN N N (N _j51NN/( Va-P' Vb-P Va-P More preferred bicyclic ring systems of formula V include Va-A, Vb-A, Va-A, Va-B, Vb-B, Vc-B, Va-D, Vb-D, Vc-D, Va-E, Vb-E, VC-E, Va-J, Vb-J, VcJ, Va-K, Vb-K, Vc-K, Va-L, Vb-L, Va-L, Va-K, Vb-M, and Vc-M, most preferably Va-A, Vb-A, Va-A, Va-B, Vb-B, and VC-B.

In the monocyclic pyridine ring system of formula V, preferred RX groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C.4.aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred RY groups include T-R 3 wherein T is a valence bond or a methylene, and R3 is 2 or -OR. When R3 is -R or -OR, a preferred R is an optionally substituted group selected from C 1 6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred RY include 2-pyridyl, 4-pyridyl, piperidinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl, and methoxymethyl.

In the bicyclic ring system of formula V, the ring formed when RX and RY are taken together may be substituted or unsubstiruted. Suitable substituents include halo, -OR, -Co 2 R, -COCOR, -NO 2

-CN,

-So 2 R, -SR, -N(Rt)2, -CON(R') 2

-SO

2

N(R')

2

-N(R

4 )COR, -N(Rf)CO 2 (optionally substituted C4 aliphatic) i 2

-C=NN(R')

2

-C=N-OR,

N(R

4

)CON(R

4 2 -N(R )SO 2

N(R')

2

-N(R')SO

2 R, or 2 wherein-R and R' are as defined above.

-111- Preferred RX/RY ring substituents include -halo, -OR, IND -COR, -CO 2 R, -CON(R 4 2 -CN, or -N(R 4 2 wherein R is an 0 Soptionally substituted C1i- aliphatic group.

The R 2 and R 2 groups of formula V may be taken together to form a fused ring, thus providing a bicyclic Sring system containing a pyrazole ring. Preferred fused C< rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are C exemplified in the following formula V compounds having a NO 10 pyrazole-containing 6icyclic ring system: N t ,ian -NHS(C alkyl), alkyl) and Preferred substituents on the fused ring of formula V include one or more of the following: -halo, 3 -0.4 alkyl, -Ci-4 haloalkyl, -NO 2 -0 (C.4 alkyl) -CO3 4 alkyl), -CN, -SO 2 (0-4 alkyl) -SOaNH, -OC (0)NH 2

S-NH

2

SO

2 (Cr4 alkyl) -NHC(0) (C1-4 alkyl) -C (O)NHa, and

-CO(C-.

4 alkyl), wherein the (Cl-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (Ci- 4 alkyl) group is methyl.

When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, C-.4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyi, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, -112isopropyl, propyl, t-butyl, cyclopentyl, phenyl, C0 2

H,

N CO2CH 3 CH20H, CH 2 0CH 3 CH2C2CH20H, CH 2

CH

2

CH

2

CH

2

CH

2

OCH

2 Ph, CH 2

CHCH

2 NH2, CS 2

CH

2

CH

2 NHCOOC (CH3)3, CONHCH (C3)2, CONHCH 2

CHCH

2

CONHCH

C

HH

2

OCH

3

CONHCH

2 Ph, CONH(cyclohexyl), CON(Et) 2

CON(CH

3

)CH

2 Ph, CONH(n-C 3

H

7 CON(Et)CH2C121H3, CONHCH2CH (CCH3)32, CON(n-C 3

H)

2 CO (3methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4tolyl), CONXCH 3 CO(morpholin-1-yl), CO(4-methylpiperazinl -yl) CONHCH 3 OH20H, CONH2, and CO(piperidin-1-yl).

A

IND 10 preferred group is hydrogen.

More preferred ring systems of formula V are 0 the following, which may be substituted as described IN above, wherein R' and R 2 are taken together with the' o pyrazole ring to form an optionally substituted indazole ring; and RX and RY are each methyl, or RX and RY are taken together with the pyridine ring to form an optionally substituted quinoline, isoquinoline, tetrahydroquinoline or tetrahydroisoquinoline ring: 9 NH 9 NH NH HN N I-N Ni HN N 0;1 1 ICZ2 Z2 H 3 C 1 Z V-Aa V-Ba V-Ha When G is Ring C, preferred formula V Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions 'of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred -113- R1 groups include -halo, an optionally substituted Cl-g aliphatic group, phenyl, -COR 6 -CN, -SO1R, -SO0N1 2 2 -C0AR 6 -CONH, -NHCOR6, -OC(O)NH 2 or -NHSO 2 R6.

SWhen R' is an optionally substituted C-6 aliphatic group, the most preferred optional substituents are halogen.

Examples of.preferred R 1 groups include -CF 3 -C1, -F, -CN, -COCH 3 -0CH3, -OH, -CH2CH 3

-OCH

2 1CH3, -CH3, -CF 2

CH

3 cyclohexyl, t-butyl,,isopropyl, cyclopropyl, -CCH, C -CC-CM 2 -S0 2

CH

3 -S0 2

NH

2

-N(CH

3 2 -C0 3

H

3

-CONH

2

NO

S 10 -NHCOCH 3

-OC(O)NH

2

-NHSO

2

CH

3 and -OCF 3 On Ring C preferred R5 substituents, when Cl present, include -halo, -CN, -NO 2 2 optionally o, substituted C1-6 aliphatic group, -OR, -COR,

-CONH(R

4 -N(R)COR, -SO 2

N(R)

2 and -N(R)SO 2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3 -NH2, -NH(CI-4 aliphatic), -N(CI-4 aliphatic)2, -0(Cl.4 aliphatic), C1..4 aliphatic, and -C02(C,4 aliphatic).

Examples of such preferred R 5 substituents include -C1, -CN, -CF 3 -NHa, -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et.

When G is Ring D, preferred formula V Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

When two adjacent substituents on Ring D are taken together to form a fused ring, the Ring D system.is bicyclic. Preferred formula V Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H- indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on Ring D of formula V include one or more of the following: halo, oxo, CN, -NO 2 -114- 2 -C0 2 R, -CONH(R),

-N(R

4 )COR; -SO 2

N(R)

2

-N(R

4

)SOR,

IN -SR, -OR, or substituted or unsubstituted group 0 selected from 5-6 membered heterocyclyl, C 6 -io aryl, or C 1 -s c aliphatic. More preferred Ring D substituents include S -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted .group selected from 5-6 membered heterocyclyl, C-1o aryl, or Cs. aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH 2 OH, CH 2

CH

2 o0H, pyrrolidinyl, OPh, CF 3 CH, C1, O 10 Br, F, I, NH 2 C(O)CH,; i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

0 Preferred formula V compounds have one or more, C' and more preferably all, of the features selected from o the-group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R' is -halo, an optionally substituted C3,s aliphatic group, phenyl, -COR', -OR 6 -CN, -SOR 6

-SO

2 NH,, -N(R 6

-CO

2

R,

-CONH

2 -NHCOR', -OC NH 2 or -NHSO 2 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-rH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

1 is hydrogen or C1..4 aliphatic and RI is T-

R

3 or RX and Ry are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and -115-

R

2 is hydrogen and'R 2 is hydrogen or a s substituted or unsubstituted group selected from aryl, o heteroaryl, or a C 1 i- aliphatic group, or R 2 and R 2 are CA taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or Spartially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula V have one or more, and more preferably all, of the features selected from the group consisting of: I0N 10 Ring C is a phenyl or pyridinyl ring, -i optionally substituted-by -R 5 wherein when Ring C and two 0 adjacent substituents thereon form a bicyclic ring o system, the bicyclic ring system is a naphthyl ring, and o R is -halo, a Ci.- haloaliphatic group, a CI-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl,. 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx is hydrogen or methyl and R Y is -R,

N(R

4 2 or -OR, or R x and R Y are taken together with their intervening atoms to form a benzo ring or a 5-7 membered partially unsaturated carbocyclo ring, said benzo or carbocyclo ring optionally substituted with halo, -OR, C0 2 R, -COCOR, -NO 2 -CN, -SO2R, -SR, -N(R 4 2

-CON(R')

2

-SO

2

N(R

4 2

N(R

4

)COR,

CO

2 (optionally substituted Ci6 aliphatic), -N(R4)N(R') 2

-C=NN(R

4 2 -C=N-OR, -N(R 4

)CON(R

4 2

-N(R

4

)SO

2

N(R

4 2 -N(R'SOR, or -OC(=O)N(R)2;

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or a C1-s aliphatic group, or R 2 and R 2 are taken together -116with their intervening atoms to form a substituted or ID unsubstituted benzo, pyrido, pyrimido or partially Sunsaturated 6-membered carbocyclo ring; and S(d) Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2 S optionally substituted

C

1 6 aliphatic group, -OR,

-CO

2 R, -CONH(R), -N(R COR, -SO 2

N(R

4 or

-N(R

4

SOR.

Even more preferred compounds of formula v have kC 10 one or more, and more preferably all, of the features selected from the group consisting of: o(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by -R s wherein when Ring C and two Sadjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R is -halo, a C 1 4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;-

R

x is hydrogen or methyl and R y is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or.phenyl, or R x and R

Y

are taken together with their intervening atoms to.form a benzo ring or a 6-membered partially unsaturated carbocyclo ring optionally substituted with halo, CN, oxo, Ci,3 alkyl, C, alkoxy,

(C_

6 alkyl)carbonyl, (C1-.

alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; -117-

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -C 1 alkyl,

-C

1 -4 haloalkyl, -NO 2 -0(CI- 4 alkyl) -CO, (Cx-4 alkyl) -CN, -SO2(CI-4 alkyl) -SO 2

NH

2 OC(0)NHA, -NH 2

SO

2 (CI-4 alkyl), -NHC(O) (C 1 -4 alkyl), -C(0)NH 2 or -CO(C..

4 alkyl), wherein the alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -Cl, -CN, -CF 3

-NH

2

-NH(C

1 -4 aliphatic), -N(C 1 -4 aliphatic) 2 -0(C-4 aliphatic), C 1 -4 aliphatic, and -C0 2

(C

1 4 aliphatic).

Representative compounds of formula V are set forth in Table 4 below.

Table 4.

'I

CH3 HN

NNH

V-1

CH

3 HN H

-IHN

V-4 N CF V-2 V-5 HN O "jN CF3 V-3 H N

H

HNV-

V-6 -118-

F

V- 8 V-7 v-aa

O

3 Ht V-9l H N vN-i

HNJ

-s

OH

3 HN V-13 V- 14 V-16 V-17 -119-

HCX>

0 V-22

F

V-21.

V- 20 V-23 V-24 V- 25 V- 26 HN9-N V- 27 HN9-KN F 3

C

V-3D V-28 V-29 -120- V-31 V-32 V-33

CI

V-34 V-35

H

3

C

Fs 3

C

V-37 -38 V-38

F

H

3 N

II

V-36

F

HN

F 3

C

V-39

F

V-42 V-41 -122- V-43 V-44 V-46 V-47 2NH V-48 V-49

HN

V- 52 V-50

HNP-OH

tN F3ac V-5 3 V-51

F

3

C

V-54 -122-

F

3 (3 ciHNd

HN

2

NN',

-N AN V-59 HN~h HNP&WN HN<N cHc H0x~

F

3 C FC FCl 5V-58 V-59

CH

3 OH 3 HN HN 8N$O-4N H -N F0 3 F 3 0 V-61 V-62 -123-

F

Va HNQN -3 F 3

C

V-67 V-68 In another embodiment, this invention provides a composition compris-ing a compound of formula V and a NO pharmaceutically acceptable carrier.

one aspect of this invention relates to a Cimethod of inhibiting GSK-3 activity in a patient, k

NO

o comprising administering to the patient a therapeutically 010 effective amount of a composition comprising a compound of formula V.

Another aspect relates to a method of treating a disease that is-alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comnprising a compound of formula V.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for diabetic patients.- Another aspect relates to a method of inhibiting the production of hyperphoaphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a dompound of formula -124- V. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

oN Another aspect relates to a method of inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula V. This method is CA especially useful for treating schizophrenia.

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, Ci comprising administering to the patient a therapeutically o effective "amount of a composition comprising a compound of formula V.

o Another aspect relates to a method of treating I a disease that is alleviated by treatment with 'an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

one aspect of this in-vention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patien t a therapeutically effective amount of a composition comprising a compound of formula V.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDIC-2 inhibitor, said method comprising Ache step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula V. This method is especially useful for treating cance r, Alzheimer's disease, restenosis, angiogenesis; glomerulonephritis, -125cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid o arthritis.

C Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity in a biological sample, which Smethod comprises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula V, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

O 10 Each of the aforementioned methods directed to

VO

the inhibition of GSK-3, Aurora or CDK-2, or the O treatment of a disease alleviated thereby, is preferably r \s carried out with a preferred compound of formula V, as Sdescribed above.

(N 15 Another embodiment of this invention relates to compounds of formula VI: N H HN N

N-N

RNR

VI

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their -126intervening atoms to form a fused, unsaturated or DO partially unsaturated, 5-6 membered ring having 0-3 O heteroatoms selected from oxygen, sulfur or nitrogen, C said fused ring being optionally substituted by halo, oxo, or -R 8 SRing 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 0 10 from nitrogen, oxygen or sulfur, wherein Ring D is C substituted at any substitutable ring carbon by oxo or o

-R

5 and at any substitutable ring nitrogen by -R 4 C\ provided that when Ring D is a six-membered aryl or o heteroaryl ring, -R 5 is -hydrogen at each ortho carbon Ci 15 position of Ring D;

R

1 is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or -R 8 said C1i- aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; RY is T-R 3 T is a valence bond or a C 14 alkylidene chain;

R

2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 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 carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or -127-

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R" 2 is substituted by R'; o R' is an optionally substituted group selected from C 1 -6 0 aliphatic, C3-3.

0 carbocyclyl, Cs-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -6 aliphatic, Cs 61 o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; o each R' is independently selected from -COR, IN -CO2(optionally substituted C 1 6 aliphatic), -CON(R') 2 o7 4 5 or -SQ 2 R or two R on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 2

-CON(R')

2

-SO

2 -N(Rt)COR, -N C02 (optionally substituted C1-.

6 aliphatic), -C=NN(R4), -C-N-OR, -N(R')CON(R

-N(R

4

SO

2

N(R')

2

-N(R')SO

2 R, or -OC(=O)N(R) 2 or Rs -and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; V is -S0O-, -N(R 6 )S0 2

-SO

2

-N(R

6 -con-, -N(R 6

N(R')CON(R

6

-N(R

6

)SON(R

6 2

-C(R

6 2

S-,

2 SO-, -C(R) 2

SO

2 2 S0 2

N(R

6 -C(R')hN( 6 2 2

-C(R')=NN(R

6 -c(R 6

-C(R

6 2

N(R

6 )N(R C(R)N(R 6 C 6

)SO

2 or 2 N(R)COi W is -C(R 6 2

C(R)

2

-C(R

6 2 SO-, 2 SO0 2 2

SO

2

-C(R)

2

-CO-,

-128-

-C(R

S

-C(R' OC(O)N(R 6 -C (R 6

CO-,

2

N(R

6

-C(R

6 o

-(R

6 2

N(R

6 N (R -C 2 N (R 6

SO

2 N (R 6 S-C 2 N (R CON (R 6 or -CON (R 6 each R 6 is independently selected from hydrogen, an Soptionally substituted Ci-4.aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; ci 10 each R' is independently selected from hydrogen or an optionally substituted C3-6 aliphatic group, or two R 7 O on the same nitrogen are taken together with the I\ nitrogen to form a 5-8 membered heterocyclyl or Sheteroaryl ring; and Ci 15 each R e is independently selected from an optionally substituted CI-4 aliphatic group, -SR 6

-COR

6

-SO

2

R

6 -N(R6) 2 -N(R6)N(R6) 2 -CN, -NO2, -CON(R6)2, or

-CO

2

R

6 Preferred R Y groups of formula VI include T-R 3 wherein T is a valence bond or a methylene, and R 3 is an optionally substituted group selected from Ci-s aliphatic, C3- 0 carbocyclyl, Cs-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms. A preferred R 3 group is an optionally substituted group selected from C3-6 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred R y include 2-pyridyl, 4-pyridyl, piperidinyl, morpholinyl, cyclopropyl, cyclohexyl, and optionally substituted phenyl such as phenyl or halo-substituted phenyl.

The R 2 and R 2 groups of formula VI 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 -129unsaturated 6-meinbered carbocyclo ring. These are IND exemplified in the-following formula VI compounds having o a pyrazole-containing bicyclic ring system: ct riN :1 1 Preferred substituents on the R 2 /R2' fused ring o include one or more of the following: -halo, -N(Rt) 2 -Ci-4 o alkyl, -C2__ 4 haloalkyl, -NO 2 -0O(C..

4 alkyl) -00 2

(C

14 alkyl) -CN, -S0 2

(C

1 4 alkyl) -SO 2

NH

2 -oc N 2

-NH

2 S0 2 (0 1

L

4 alkyl) -iiiC alkyl),, -C N 2 and

-CO(C

1 4 alkyl), wherein'the (CL- alkyl.) is a straight, b ranched, or cyclic alkyl group. Preferably, the 4 alkyl) group is methyl.

when the pyrazole ring systenf is monocyclic, 'pref erred R 2 groups of formula V7 include hydrogen, C1_4 aliphatic, alkoxycarbonyl, (tin) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylatninoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl,.t-butyl, cyclopentyl, phenyl, 00 2

H,

0303, CH 2 OH, CH30CH3, CH 2

CH

2

CH

2 OH, Oi 2

CH

2 CHaOOIH 3

CR

2

CH

2

CH

2 00H 2 Ph, CH 2

CH

2

CH

2

NH

2

CI

2

CH

2

CH-

2 NHCOOC (CH3)3, CONECH (053)2, CONRCH 2

O{=CH

2

CONHCH

2

CII

2 0CH 3

CONHCH

2 Ph, CONH (cylohexyl) CON (Et) 2 CON (CH 3

CH

2 ph, CONH (n-C 3

H

7 CON(Et)CH23053053, CONHCR 2 CH (CH3)2, 'CON (n-C 3 2 CO (3methoxymethylpyrrolidin-l-yl), CONS (3 -tolyl), CONS (4- -130tolyl), CONHCH, CO(morpholin-l-yl), CO(4-methylpiperazin- Nl1-yl), CONHCH 2 CH20H, CONH2, and CO(piperidin--yl). A S preferred R 2 group is hydrogen.

C When G is Ring C, preferred formula VI Ring C S groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta O 10 positions of Ring C. Examples of preferred bicyclic Ring C -C systems include naphthyl and isoquinolinyl. Preferred o R' groups include -halo, an optionally substituted C 1 2.

C aliphatic group, phenyl, -COR, -OR 6 -CN, -SO 2 -S02N2{ 2 0 2

-CO

2

R

6

-CONH

2

-NHCOR

6

-OC(O)NH

2 or -NHSO 2

R

6 C 15 When R' is an optionally substituted C 16 aliphatic group, the most preferred optional substituents are halogen..

Examples of preferred R' groups include -CF 3 -Cl, -F, -CN, -COCH 3 -OCH3, -OH, -CHhI3, -OCH 2

CH

3 -CH3, -CF2CH 3 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CeCH, -mC-CH 3

-SO

2

CH

3 -S02NH 2

-N(CH

3 2

-CO

2

CH

2

-CONH

2

-NHCOCH

3

-OC(O)NH

2

-NHSO

2

CH

3 and -OCF 3 On Ring C preferred Rs substituents, when present, include -halo, -CN, -NO 2 2 optionally substituted C 1 6 aliphatic group, -OR, -CO2R, -CONH(R'), -N (R 4 )COR, -SOaN(R') 2 and -N(R')SO 2 R. More preferred R5 substituents include -C1, -CF, -NH2, -NH(C2-4 aliphatic), -N(C1.4 aliphatic)2, -0(Cl.4 aliphatic), C 1 4 aliphatic, and -CO 2 4 aliphatic) Examples of such preferred Rs substituents include -Cl, -CN, -CF3, -NH 2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 3 Et.

When G is Ring D, preferred formula VI Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, -131pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

NO When two adjacent substituents on Ring D are taken O together to form a fused ring, the Ring D system is bicyclic.. Preferred formula VI Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1IH-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

IN 10 Preferred substituents on formula VI Ring D include one or more of the following: halo, oxo, CN, -NO 2

S-N(R

4 2

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -SO 2 N(R4) 2

-N(R')SO

2

R,

O0 -SR, -OR, or substituted or unsubstituted group o selected from 5-6 membered heterocyclyl, C6-30 aryl, or Ci-6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from.5-6 membered heterocyclyl, C 6 -o 0 aryl, or C1-6 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH0OH,.CHCH2OH, pyrrolidinyl, OPh, CF 3 C-CH, Cl, Br, F, I, NH 2 C(O)CH3, i-propyl, tert-butyl, SEt, OMe, N(Me)2, methylene dioxy, and ethylene dioxy.

Preferred formula VI compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is selected from a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl-or isoquinolinyl ring, and R .is -halo, an optionally substituted C1-6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

-SO

2

NH

2 2 -COaR 6

-CONH

2

-NHCOR

6

-OC(O).NH

2 or -NHSO 2 or Ring D is-an optionally substituted ring selected from a -132phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, .1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, C- .2,3-dihydro-1H-isoindolyl, 2,3-dihydro- H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; S(b) R Y is T-R 3 wherein T is a valence bond or a methylene; and

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, \O 10 heteroaryl, or a C 16 aliphatic group, or R 2 and R' are Ci taken together with their intervening atoms to form a o substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.

SMore preferred compounds of formula VI have one C' 15 or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a C1_6 haloaliphatic group, a CI6. aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1, 2 ,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl;

R

Y is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from C.-6 aliphatic, C3-6 carbocyclyl, C6d0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -133-

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, or N2 Sa CI-6 aliphatic group, or R 2 and R 2 are taken together 0 with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially C unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein Ci each R 5 is independently selected from -halo, -CN, -NO 2 -N(R4)2, optionally substituted C,-6 aliphatic group, -OR, 1 2 10 -C0 2 R, -CONH(R), -N(R')COR, -SO 2

N{R

4 2 or Ci -N (R S0 2

R.

O Even more preferred compounds of formula VI have one or more, and more preferably all, of the features selected from the group consisting of: ci 15 R Y is T-R 3 wherein T is a valence bond or a methylene and R' is an optionally substituted group selected from C1-4 aliphatic, C3-6 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R' is -halo, a CI-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or naphthyl;.

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R' 2 -C1-4 alkyl, -Ci-4 haloalkyl, -NO 2 -0 (C14 alkyl) -C02 (C.4 alkyl) -CN, -134-

-SO

2 (C-4 alkyl) -SO 2 NH2, -OC (O)NH, -NH 2 SO2 (C 1 -4 alkyl) -NHC(O) (C.4 alkyl), -C(O)NHa, or -CO(C-.

4 alkyl), wherein

VO

O the (Ci-4 alkyl) is a straight, branched, or cyclic alkyl Cl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -cl, -CN, -CF 3

-NH

2 -NH(CI-4 aliphatic), -N(Ci.4 aliphatic) 2 -0(C.

4 r C aliphatic), Ci-4 aliphatic, and -C0 2 (CI-4 aliphatic).

Another embodiment of this invention relates to C' 10 compounds of formula'VIa:

VO

CR2

HN

VIa or a pharmaceutically acceptable derivative or prodrug thereof, wherein: G is Ring C or Ring D; Ring C is selected from a phenyl, pyridinyl, pyrimidihyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, Oxo, or -RO; -135- Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl,

IO

o heterocyclyl or carbocyclyl, said heteroaryl or 0 heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein Ring D is .substituted at any substitutable ring carbon by oxo or

-R

s and at any substitutable ring nitrogen by -R 4 CI. provided that when Ring D is a six-membered aryl or heteroaryl ring, -Rs is hydrogen at each ortho carbon position of Ring D; ^C R 1 is selected from -halo, -CN, -N02, phenyl, 5-6 o membered heteroaryl ring, 5-6 membered heterocyclyl LO ring, or CI-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by 0C 15 up to three groups independently selected from halo, oxo, or said CI-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; T is a valence bond or a Ci-, alkylidene. chain;

R

2 and R 2 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 carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4 each R is independently selected from hydrogen or an optionally substituted group.selected from Ci-6 Saliphatic, C6-ao aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -136each R' is independently selected from -COR', -CO2 (optionally substituted C 1 -e aliphatic), or -SO 2 R7, or two R on the same nitrogen are taken 0 together to form a 5-8 membered heterocyclyl or heteroaryl ring; S each R 5 is independently selected from halo, -OR, -C(0O)R, -C02R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, Cl 2

-CON(R')

2 -S0 2

N(R')

2 -N(R )COR, COa (optionally substituted OI-r aliphatic), 2

-C=NN(R)

2 -C=N-OR, -N(R 4 )CON(R')2, c -N(R 4

)SO

2

N(R)

2

-N(R

4

)SO

2 R, or 2 or R5 and an adjacent substituent taken together with their IDintervening atoms form said ring fused to Ring C; V is -SO2-, -N(R')S0 2

-SO

3 -N(R')S0 2 -N(R6)N -CRW) 2S-, -C(R)2SO-, -C(R6)2SO3-, -C(R),S0 2 N(R) 2 N(R) 2 2 2 N(R')SO2N(R6')-, or -C(Rr),2N(R)CON(R 6 W is 2 2 -C(R6)2SO-, -C(Rt) 2

SO

2 -C 2SO2N 2 -002-, -C(R6) OC OC(O)N(R6)-, 2N(R6)CO-, 2

N(R

6

-C(R

6 2 N 2 N So02N (R6)- -C 1aN CON (R6) or -CON(R) each R6 is independently selected from hydrogen, 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 CI-s aliphatic group, or two R7 -137on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or

VO

o heteroaryl ring; and C each R B is independently selected from an optionally substituted C1-4 aliphatic group, -OR 6

-SR

6

-COR

6

S-SO

2

R

6

-NCR)

2

-N(.R

6

)N(R

6 2 -CN, -NOs, -CON(R 6 2 or S-C0 2

R

6 Preferred rings formed by the R 2 and R 2 groups of formula Via include benzo, pyrido, pyrimido, and a \0 10 partially unsaturated 6-membered carbocyclo ring. These C are exemplified in the. following formula VIa compounds o having a pyrazole-containing bicyclic ring system: o

NNH

N N N-kN

HNH

Nk NH NH NH NH S, and Preferred substituents on the R 2

/R

2 fused ring include one or more of the following: -halo, -N(R 4 2 -C-.4 alkyl, haloalkyl, -NO2, -0(C-4 alkyl) -CO2(C.-4 alkyl), -CN, -S0 2

(C-

4 alkyl), -S0 2

NH

2

-OC(O)NH

2

-NH

2

SO

2

(C

1 alkyl), -NHC(O) (C 1 -4 alkyl) -C(O)NH 2 and

-CO(C-.

4 alkyl), wherein the (Ci- 4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the 4 alkyl) group is methyl.

When G is Ring C, preferred formula VIa Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta -138positions of Ring Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl.. Preferred INDR groups include -halo, an optionally substituted C1.-6 aliphatic group, phenyl, -COR', -CN, -SO 2

-SO

2

NH

2 2

-CO

2

-CONH

2 -NHCOR', -OC(o)NH 3 or -NHSO 2

R'.

When R' is an.optionally substituted C1_. aliphatic group, the most preferred optional substituents are halogen.

SExamples of preferred R groups include -CF 3 -C1, -F, -CN, -COCH 3

-OCH

3 -OR, -CH 2

CR

3 -OCH2CHS 3

-C

3

-CF

2

CH

3 C 10 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -CaOCH, Va C1 -CeC-CH3, -S0 2 CH0 3 -S0 2

NH

2

-N(C

3 2

-COH

3

-CONH

a o -NRCOCH 3

-OC(O)N

2

-NHSO

3

CH

3 and -OCP 3 \O On Ring C preferred R 5 substituents, when 0 present, include -halo, -CN, -NO 2 2 optionally Cl 15 substituted Ca.. aliphatic group, -OR, -CO 2

R,

-CONH -N(R)COR, -SO s

N(R')

2 and -N(R 4

)SO

2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3 -NH(C,-r aliphatic), -N(C1_4 aliphatic)2,- -0(CI..

aliphatic), CI-..4 aliphatic, and -CO2(C3-.

4 aliphatic).

Examples of such preferred R 5 substituents include -C1,

-CF

3

-NH

2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -COgEt When G is Ring D, preferred formula VIa Ring D monocyclic rings include substituted and unsubstituted phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

When two adjacent substituents on Ring D -are taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula VIa Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

-139- Preferred substituents on the formula Via Ring D include one or more of the following: halo, oxo, CN,

\O

-N0 2 2

-CO

2 R, -CONH(R), -N(R')COR, -S0 2

N(R')

2 0 -N(Rf)SO 2 R, -SR, -OR, or substituted or.

unsubstituted group selected from 5-6 membered heterocyclyl, C 6 1 o aryl, or C 1 6 aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, or a substituted-or unsubstituted group selected from 5-6 membered heterocyclyl, C6_ 10 aryl, or C.

6 i 10 aliphatic. Examples of-Ring D substituents include -OH, phenyl, methyl, CH 2 OH, CH 2

CH

2 OH, pyrrolidinyl, OPh, CF 3 C£CH, C1, Br, F, I, NH 2

C(O)CH

3 i-propyl, tert-butyl, IO SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

0 Preferred formula VIa compounds have one or c 15 more, and more preferably all, of the features selected from the group consisting of: Ring.C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is -halo, an optionally substituted C:-6 aliphatic group, phenyl, -COR', -OR 6 -CN, -SO 2 -0 2

NH

2 -N(R6) 2

-CO

2

R',

-CONH2, -NHCOR', -OC(O)NH 2 or -NHSO 2 or Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; and

R

2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6membered carbocyclo ring.

-140- More preferred compounds of formula VIa have one or more, and more preferably all, of the features

VO

0 selected from the group consisting of: C Ring C is a phenyl or pyridinyl ring, optionally substituted by -R s wherein when Ring C and two Sadjacent substituents.thereon.form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and cl R is -halo, a C1-6 haloaliphatic group, a C1-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally C 10 substituted ring selected from phenyl, pyridinyl, C piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, o 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- \O tetrahydroquinolinyl, 2,3-dihydro-iH-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or C( 15 naphthyl;

R

2 and R 2 are taken together with their intervening atoms to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring optionally substituted with -halo, -N(R 4 2 -C1-4 alkyl, -CI-4 haloalkyl, NO2, -0(C_4 alkyl), -C02 (C.4 alkyl) -CN, -SO2 (C-4 alkyl), -SO 2 NH,, -OC(O)NH2, -NH 2 SO2(CI- 4 alkyl), -NHC(O) alkyl), -C()NH 2 and -CO(Cx.4 alkyl), wherein the (CI-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted CI-, aliphatic group, -OR,

-CO

2 R, -CONH(R 4 -N(R')COR, -SO 2

N(R

4 2 or -N (R 4

SO

2

R.

Even more preferred compounds of formula VIa have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two -141adjacent substituents thereon form a bicyclic ring D system, the bicyclic ring system is a'naphthyl ring, and o R 1 is -halo, a CI-. aliphatic group optionally substituted 0 Cl with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, Spiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydrbisoquinolinyl, 1,2,3,4- Stetrahydroguinolinyl, isoquinolinyl, quinolinyl, or naphthyl; 10 R' and R 2 1 are taken together with their l intervening atoms to form a benzo, pyrido, or partially o unsaturated 6-membered carbocyclo ring optionally CN I\ substituted with -halo, -N(R 4 2 -Cz-4 alkyl, -C-_4 o haloalkyl, -NO 2 alkyl) -CO2 (C-4 alkyl), -CN, Cl 15 -S2 (Ci-4 alkyl), -S02NHa, -OC(0)NH 2

-NH

2 SO (CI-4 alkyl), -NHC(O) alkyl), -C(0)NH 2 or -CO(Ci-, alkyl), wherein the (Ci-4 alkyl)- is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R 5 wherein each R s is independently selected from -Cl, -CN, -CF 3 -NKH, -NH(Ci-4 aliphatic), aliphatic)2, -O(CI-4 aliphatic), C~-4 aliphatic, and -CO2(Ci-4 aliphatic).

Representative compounds of formula VI and Iva are set forth in Table 5 below.

Table 5.

CHO

HN-*N HN HNN NN N'N NN NI o^ o VI-1 VI-2 VI-3 -142-

CH

3

HN

4

P&

N

4

N

VI -4

HN

N '1%N N 4-0

CH

3

HN*H

N VT-s

OH

3 HNJ t

N

4

N

VI -6 VI -7

HN

4 NkN

NN

VI- 8 Pr HNr*t

NN

V& -1 e HNf-J4tH NI Et N -t N VI 9 Bu HNI -i VI -12

HN

4 VI OMe HNiH N 'N VI -13 VI -14 -143oNN lo F 3

C

VI -16

F

3

C

VI-19

NN

VI -22 N J N VI-3-7

F

N )-N VI -20 H 4H

ON

VI -23

HNZ

A

VI -26 0 NN

F

3 VI -21 HN

J:P

N 'L'N

FS

3

C

VI-24

HN

NC~

VI -27 -144-

HN~

H tN'YtrfN

F

3

C

VI-28

YNN

(DA

N

VI -34 Hg

A

N

VI -37 VI -29 F

,H

N HN%2)C)O VI-32 N kN Nq

F

3

C

VI -35

N

VI -38 VI

HNYNN

NF

3 0 VI -33

HN&

N

NF

3

C

VI-33

HNX

N

4

F

8

C

VI -39 -145- H IN J-H

NN

VI -40 VI -41 HN2 N-k

NH

2 VI -42

?NN

N 4-N -FaG VI

N-.

k ,F 3 0C VI -43 HN2P N -I-N K VI-44

N)'N

N

VIa-i HNt N'kN ON

HNJ-X

N-

N

HN

N

A

VI a-2 VIa -3 F'

H

H-N

N'N Me Via-S

N

N IN OF 3 Vla -6 Vla- 4 -14 6- HN H HN HN N IAN CN IN Me NN NHMe VIa-7 VIa-8 VIa-9 0 )H H H HN HN HN N-N N N NAN INDN $MeN o ONH2 NHMe 1 5 VIa-10 VIa-11 VIa-12 In another embodiment, this invention provides a composition comprising a compound of formula VI or Via and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VI or Via.

Another aspect relates .to a method of treating a disease that is alleviated by treatment with a GSK-3 .inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising.a compound of formula VI or Via.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective -147amount of a composition comprising a compound of formula VI or VIa. This method is especia~lly'useful for diabetic o patients.

Another aspect relates to a method of S' inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula VI or VIa. This method is especially useful in halting or slowing the progr-ession of Alzheimer's disease.

Ci Another aspect relates to a method of o inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient o a therapeutically effective amount of a composition comprising a compound of formula VI or Via. This methodis especially useful for treating schizophrenia.

one aspect of this invention relates to a method of inhibiting Aurora activity in a patient, comprising administering to the patient a therapeutically .effective amount of a composition comprising a compound of formula VI or VIa.

Another aspect relates to a method of treating a disease tha t is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula VI or Via. This method is especially useful for treating cancer, such as colon, ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2 activity mna patient, comprising administering to the patient a therapeutically effective amount of a composition comprising'a compound of formula VI or Via..

-148- Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 0 inhibitor, said method comprising the step of Cl administering to a patient in need of such a treatment a therapeutically effective amount of a composition Scomprising a compound of formula VI or Via. This method is especially useful for treating cancer, Alzheimer's Cl disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis,

C

N

10 alopecia, and autoimmune diseases such as rheumatoid Cl arthritis.

o Another method relates to inhibiting GSK-3, Cl 0Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with C 15 the GSK-3 or Aurora inhibitor of formula VI or Via, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora or CDK-2, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula VI or Via, as described above.

Another embodiment of this invention relates to compounds of formula VII: HN N N N

VII

-149or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

VO

oG is Ring C or Ring D; 0 Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, Swherein said Ring C has one or two ortho substituents 5 independently selected from -R 1 any substitutable non- C ortho carbon position on Ring C is independently substituted-by -R 5 and two adjacent substituents on .D Ring C are optionally taken together with their <C .intervening atoms to form a fused, unsaturated or o 10 partially unsaturated, 5-6 membered ring having 0-3 LO heteroatoms selected from oxygen, sulfur or nitrogen, Ssaid fused ring being optionally substituted by halo, C1 oxo, or -Re; 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 Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by provided that when Ring D is a six-membered aryl or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D;

R

I is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or CI-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by Sup to three groups independently selected from halo, oxo, or -R 8 said C 1 -6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; -150-

R

Y is hydrogen or T-R3"; T is a valence bond, hydrogen, or a alkylidene chain;

\O

SR

2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or Spartially unsaturated, ring having 0-3 ring heteroatoms 5 selected from nitrogen, oxygen, or sulfur, wherein each substitutable carbon on said fused ring formed by R 2 and R 2 is substituted by halo, oxo, -CN, -NO 2 or C'

-V-R

6 and any substitutable nitrogen on said ring .formed by R 2 and R 2 is substituted by R 4

R

3 is selected from an optionally substituted group selected from C3-o0 carbocyclyl, CG-io aryl, a heteroaryl Sring having 5-10 ring atoms, or a heterocyclyl ring CR' having 5-10 ring atoms; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, C-Io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7

-COR',

-CO2(optionally substituted Ci-6 aliphatic), -CON(R 7 2 or -SOa 2 R, or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R')

2

-N(R

4

)COR,

-N(R')CO

2 (optionally substituted Ci-6 aliphatic)

-N(R

4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR, -N(R 4

)CON(R)

2

-N(R')SO

2

N(R

4 2 -N(R4)SO 2 R, or -OC(=O)N(R 4 2 or R 5 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; -151v is -502-, -N(R 15O 2

-SO

2

-NCR

6 f-CO-, -C0 2

-N(R'

6

-N(R

6 C(O)o 7 o -N(R 6

-N(R

6

)SO

2

N(R

6

-N(R

6

)N(R

6 0 -cCO)N(R6) -0C(0)N(R 6 -cCR) 2

-C(R)

2

S-,

-C(R

6 2 So-, -C(R 6 2 so 2

-C(R

6 2 S0 2

N(R

6

'-C(R

6 2 ,N(a 6

-C(R

6 2

N(R

6 2

N(R

6 -C(R 6 NN(R5) 2

-C(R

6 2

N(R')SO

2 or (NC WCR) 2 N (R 6 )CON W is -cCR 6 -C 2 -C (26.)2SO -C (R 6 2SO2-, 2 So 2

N(R

6

-C(R

6 2

N(R

6 -co 2 22 -C(R 6

)OC(O)N(R

6

-C(R

6 2

N(R

6

)CO-,

O 2 N4(R 6

-C(R)=NN(R

6 -C(n 6 2

Z.C(R')

2 N2 6

)S

2 o 2 ,N(R6)coN(2 6 or -CON(Rs)-; each R6 is independently selected from hydrogen, an optionally substituted c 1 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 R27 is independently selected from hydrogen or an optionally substituted c 1 6 aliphatic group, or two R27 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; each Ro is independently selected from an optionally substituted C 1 _6 aliphatic group, -O6, -SR, -COR6, -S0 2

R

6

-N(R

6 2 6) 2 -cit -140,, -cON(R') 2 or -C0 2 2 6 and 29 is selected from halo, -OR, -CO 2 R, -COCOR,

-NO

2 -CN, -SO 2 R, -SR, 2 -CiI(R)2,

-SO

2 N(Rt 2 -OC8=O)R, -N(R')COR, C0 2 (optionally substituted C±- 6 aliphatic), -N(R 4 )N(2 4 2

-C=NN(R')

2 -C=N-OR, -N (R4) CON(R') 2

-N(R

4

)SO

2 -N (R 4 SOR, or

C

4 2 -152- Preferred R Y groups of formula VII include T-R 3 ND wherein T is a valence bond or a methylene. Preferred R 3 O groups include an optionally substituted group selected C from C 3 -6 carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. Examples of preferred Rf Sinclude 2-pyridyl, 4-pyridyl, piperidinyl, cyclopropyl, and an optionally substituted phenyl such as phenyl or halo-substituted phenyl.

The R 2 and R 2 groups of formula VII may be 10 taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.

o Preferred fused rings include benzo, pyrido, pyrimido, I\ and a partially unsaturated 6-membered carbocyclo ring.

SThese are exemplified in the following formula VII C' 15 compounds having a pyrazole-containing bicyclic ring system:

NH

HN N N r N .N RyS p

N

H NNH NH NH N1NH and Preferred substituents on the R 2 fused ring include one or.more of the following: -halo, -N(R 4 2

-C

1 4 alkyl, -CI-4 haloalkyl, -NO 2 -0(Ci- 4 alkyl) -C2 (C 1 -4 alkyl), -CN, -S02 (C 1 -4 alkyl), -S0 2

NH

2 -OC(0)NHa, -NHSO2 (Ci-4 alkyl) -NHC (C1- 4 alkyl) NH 2 and

-CO(C

1 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (CI.4 alkyl) group is methyl.

When the pyrazole ring system of formula VII is monocyclic, preferred R 2 groups include hydrogen., Ci-4 -153aliphatic, alkoxycarbonyl,,(tan) subs'tituted phenyl, IND hydroxyaikyl, alkoxyalkyl, aminocarbonyl, mono- or o dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbonyl. Examples of sucb'preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, CO3Ii, CA C0 2 0H 3

CH

2 OH, CII 2

OCH

3

CH

2

CH

2

CH

2 OH, CH 2

CH

2

CH

2

OCH

3

CH

2 CH2CH 2 00H 2 Ph, CH 2

CH

2

CH

2

NH

2

CH

2

CH

2

CH

2 NRCOOC (CH 3 3 v.010 CONHCH (CH 3 2 CONI4CN 2

CH=CH

2

CONHCH

2

CH

2

OCH

3

CONRCH

2 Ph, Ci CONE(cyclohexyl), CON(EL) 2 CON(cH 3

)CH

2 Ph, CONH(n-C 3

H

7 O CON(Et)CH 2

CH

2

CH

3 COI'mCH 2 CH(cH 3 2 CON(n-C 3

IH

7 2 C0(3- IND methoxymethylpyrrolidin-l-yl), CONH(3-tolyl), CONH(4o tolyl), CONHCH 3 CO (morpholin-1-yl), CO (4-methylpiperazin- 1-yl), CONHCH 2

CH

2 OH, CONE 2 and CO(piperidin-l-yl). A preferred R 2 group is hydrogen.

when G is Ring C, preferred formula VII Ring C groups are phenyl and pyridinyl. When two adjacent substituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions of Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred groups include -halo, an optionally substituted Ca1aliphatic group, phenyl, -OR 6

-OR

6 -CN, -SO 2 R6, -SO 3

NH,

-N(R

6 2 -00 2

R

6

-CONH

2

-NHCOR

6

-OO(O)NH

2 or. -NHSO 2

R

6 Then R' is an optionally substituted CI-6 aliphatic group, the most preferred optional substituents are halogen.

Examples of preferred R' groups include -CF3, -Cl, -F, -ON, -CMC 3 -0CH 3 -OH, -011tH 3

-OO{

2

CH

2

-CH

3 -CF2C113, cyclohexyl, t-butyl, isopropyl, cyclopropyl, -C~s0Hq,

-CEC-OM

3 '-SO2CH3, -S0 2

NH

2

-N(CH

3 2 -0020113, -CONE 2

-NHCOCM

3 -00()NH12, -NHSO 2

CH

3 and 0OCF 3 -154- On Ring C preferred R5 substituents, when present, include -halo, -CN, -NO 2 2 optionally o substituted C 1 6 aliphatic group, -OR, -CO 2

R,

S-CONH(R

4 -N (R 4 COR, -SO 2

N(R')

2 and SO 2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3

-NI

2

-NS(C..

4 aliphatic), 4 aliphatic) 2

-O(C

1 -4 aliphatic), C 1 4 aliphatic, and -C0 2

(C.

4 aliphatic).

cl Examples of such preferred R 5 substituents include -Cl, -CN, -CF3, -N 2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et.

ClWhen G is Ring D, preferred formula VII Ring D omonocyclic rings include substituted and unsubstituted iC phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

C 15 When two adjacent substituents on Ring D are taken' together to form a fused ring, the Ring D system is bicyclic. Preferred formula VII Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred substituents on Ring D include one or more of the following: halo, oxo, CN, -NO 2

-CO

2

R,

-CONH(R'), -N(R 4 )COR, -SO 2

N(R')

2

-N(R')SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-1o aryl, or C1.-s aliphatic. More preferred Ring D substituents include -halo, -CN, -oxo, -SR, -OR, 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-o 0 aryl, or C 1 6 aliphatic.

Examples of Ring D substituents include -OH, phenyl, methyl, CH20H, CH 2

H

2 0H, pyrrolidinyl, OPh, CF 3 COm, Cl, -155- Br, F, I, NH 2 C(O)CH3, i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

\O

o Preferred formula VII compounds have one or C more, and more preferably all, of the features selected from the group consisting of: S(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two <C adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a C 10 naphthyl, quinolinyl or isoquinolinyl ring, and R is

VO

Ci -halo, an optionally substituted Ci-6 aliphatic group, o phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6

-SONH

2

-N(R

6 -CO2R 6 Ci -CONH 2

-NHCOR

6

-OC(O)NH

2 or -NHSO 2

R

6 or Ring D is an Soptionally substituted ring selected from a phenyl, C 15 pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

Y is T-R 3 wherein T is a valence bond or a methylene; and

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl-, heteroaryl, or a CI-6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VII have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -156x- is -nalo, a Ci-. haloaliphatic group, a C 1 -6 aliphatic group, phenyl, or -CN; or Ring D is an optionally O substituted ring selected from phenyl, pyridinyl, Spiperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1 ,2,3,4-tetrahydroisoquinolinyl," 1,2,3,4t tetrahydroquinolinyl, 2,3-dihydro-H- isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or (C naphthyl;

R

Y is wherein T is a valence bond or Ci 10 a methylene and R 3 is an optionally substituted group

\O

IN selected from C3-. carbocyclyl, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; C'

R

2 is hydrogen and R 2 is hydrogen or a o substituted or unsubstituted group selected from aryl, or 15 a C 1 -6 aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and Ring D is substituted by oxo or R 5 wherein each R 5 is independently selected from -halo, -CN, -NO 2 2 optionally substituted C.-6 aliphatic group, -OR,

-CO

2 R, -CONH(R'), -N(R 4 )COR, -SO 2

N(R

4 2 or

-N(R

4 S0 2

R.

Even more preferred compounds of formula VII have one or more,.and more preferably all, of the features selected from the group consisting of:

R

Y is T-R 3 wherein T is a valence bond or a methylene and R 3 is an optionally substituted group selected from phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -157is -nalo, a C.

4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally Va substituted ring selected from phenyl, pyridinyl, o piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, isoquinolinyl, quinoliyl, or naphthyl; C R' and are taken together with their intervening atoms to form.a benzo, pyrido, pyrimido or C 10 partially unsaturated 6-membered carbocyclo ring

O

C- optionally substituted with -halo, -N(R 4 2 -C.1- 4 alkyl,

-C

1 4 haloalkyl, -NO2, -O(C 1 4 .alkyl), -CO, 2

(C

1 4 alkyl), -CN,

~-SO

2

(C

1 4 aliyl), -SO 2

NH

2 -OC(O)NH2, -NH 2

SO

2

(C

1 4 alkyl) o -NHC(0) (C1.4 alkyl), -C(O)NH 2 or -CO(C-4 alkyl), wherein 0 s the (CI-4 alkyl) is a straight, branched, or cyclic alkyl group; and Ring D is substituted by oxo or R5, wherein each R 5 is independently selected from -Cl, -CN, -CF3, -NH2, -NH(C 1 4 aliphatic)-, -N(C 1 -4 aliphatic) 2 -O(C-4 aliphatic), C1-4 aliphatic, and -C02(Cl.

4 aliphatic).

Representative compounds of formula VII are set forth in Table 6 below.

Table 6.

F

H F HN H HN H NN N N NIN o^ o o VII-1 VII-2 VII-3 -158- VII-4 VII-5 N 'N"

QNI

VII -7

F

t4 N 'LN N 'N VII-13

HZH

'N

VII -8 N A.

HN

VII-14

HN

VII -6

HN

N

4

N

VII -9

HN

N A.'N VII -12 H N~ N lN VII 9-

F

3 VII -16 N '-N

F

3 0 VII -17' N N VII -20

N

4

N

F

3 0C VII -18

NN

VII -21

N

4

N

HN

UN N k

N

4 -N CF 3 1 -CHS VII -24 VII -22 VII -23

HN

A,

HN

I,)

NNC

VII -26 1 0 HN

_X

N'N CI

N

VII -27 -160-

CH

3 HN u

H

N

4

N

VII-28 CHs HNN H N IN VII-29 HN f N -N

CH

3

HNN

N'JN

VII-33 VII-31 VII-32 CH3

HN<

H

N -N VII-34 CHs HN-

H

N N VII-35 Et HN H

N

4

-N

NVII-6 VII-36 In another embodiment, this invention provides a composition comprising a compound of formula VII and a pharmaceutically acceptable carrier.

One aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a -161therapeutically effective amount of a composition comprising a compound of formula VII.

o Another aspect relates to a method of enhancing C glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising G administering to said patient a therapeutically effective amount of a composition comprising a compound of formula ^C VII. This method is especially useful for diabetic patients.

Another aspect relates to a method of Ci inhibiting the production of hyperphosphorylated Tau o protein in a patient in need thereof, comprising \O administering to said patient a therapeutically effective O amount of a composition comprising a compound of formula VII. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

Another aspect relates to a method of inhibiting the phosphorylation of P-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula VII. This method is especially useful for treating schizophrenia.

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII.

Another aspect relates to a method of treating a disease. that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula VII. This method is -162especially useful for treating cancer, such as colon, ovarian, and breast cancer.

o One aspect of this invention relates to a 0 method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VII.

Clq Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2 inhibitor, said method comprising the step of (N administering to a patient in need of such a treatment a otherapeutically effective amount of a composition Cl comprising a compound of formula VII. This method is oespecially useful for treating cancer, Alzheimer's (N 15 disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis.

Another method relates to inhibiting GSK-3, Aurora, or CDK-2 activity in a biological sample, which method comprises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula VII, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora or CDK-2, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula VII, as described above.

Another embodiment of this invention relates to compounds of formula VIII: -163-

R

2 R 2 NH HN HN C< VIII (N or a pharmaceutically acceptable derivative or prodrug

O

CI thereof, wherein:

SZ

1 is N or CR 9

Z

2 is N or CH, and Z 3 is N or CRx, provided (C that one of Z 1 and Z 3 is nitrogen; G is Ring C or Ring D; Cl 5 Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said.Ring C has one or two ortho substituents independently selected from any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R e 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 Ring D is substituted at any substitutable ring carbon by halo, oxo, or -R 5 and at any substitutable ring .nitrogen by

-R

4 provided that when Ring D is a six-membered aryl -164or heteroaryl ring, -R 5 is hydrogen at each ortho carbon position of Ring D;

VO

0 R 1 is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl, Sand heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, CN oxo, or -R 8 said Ci-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R

I

and an adjacent substituent taken together with their (N intervening atoms form said ring fused to Ring C; SR is T-R3; \c T is a valence bond- or a C 1 4 alkylidene chain; 0

R

2 and R 2 are independently selected from -T-W-R 6 or

R

2 and R 2 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 carbon on said fused ring formed by R' and R 2 is substituted by halo, oxo, -CN, -NO 2

-R

7 or

-V-R

6 and any substitutable nitrogen on said ring formed by R 2 and R 2 is substituted by R 4

R

3 is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR, -N(R4) -CON(R')2, -S02N(R 7

-N(R')COR,

-N (R C02(optionally substituted Ci-6 aliphatic),

-N(R')N

R 4 2

-C=NN(R')

2 -C=N-OR, -N(R 7

)CON(R

7 2

-N(R

7

)SO

2

N(R

7 2

-N(R')SO

2 R, or -OC(=O)N(R 7 2 each R is independently selected from hydrogen or an optionally substituted group selected from Ci-6.

aliphatic, Cs-lo aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -165each R' is independently selected from -COR, -002 (optionally substituted C1-6 aliphatic), -CON(R') 2

O

or -SOR7', or two R' on the same nitrogen are taken 0 together to form a 5-8 membered heterocyclyl or heteroaryi ring;..

each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, cl -CON(R') 2

-SO

2

N(R

4 2

-N(R')COR,

CO2 (optionally substituted CI-6 aliphatic), 2 -C=NN 2 -C=N-OR, -N(R')CON(R') 2 Va -N SON 2 SOR, or 2 or R 5 and an adjacent substituent taken together with their O .ntervening atoms form said ring fused to Ring C; o V is -S02-, -N(R')S0 2

-SO

2 -CO2-, -N CON(R') -N(R )SO 2 2 2

S-,

2 SO-, 20S-, 2 S0 2 12N 2 2

-C(R(R

2 N 0SO 2 or 2 N CON W is -C(R6)20-, -C(R6)2SO-, -C(R6)2SO2-, 2

CO-,

2 -C(R 2 2 SOaN-(R6')-, 2 or each R' is independently selected from hydrogen, an optionally substituted Ca-4 aliphatic group, or two R' groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each i7 is independently selected from hydrogen or an optionally substituted C1-( aliphatic group, or two R7 -166on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocycly1 or

\O

heteroaryl ring; each R8 is independently selected from an optionally substituted C1..4 aliphatic group, -oR, -SR 6

-COR',

-SOR', -N(R 6 2 2 -NO, -CON(R') 2 or -C0 2 R; and cl R 9 is selected from halo, -OR, -CO 2 R, -COCOR,

NO

2 -CN, -SO 2 R, -SR, 2

-CON(R')

2

-SO

2

N(R

4 2 -N(R)COR, -N(R 4 C0 2 (optionally ci substituted C-6 aliphatic), -N(R')N(R 4 2

-C=NN(R)

2

-N(RRCON(R

4 2

-N(R

4 )SON(R4 2 N(R')S0 2 R, or O -OC 2 Accordingly, the present invention relates to compounds of formula VIIIa, VIZIb, VIII and VIZId as shown below: R 2 R2 F? R Rr NH NH RE NH Rr NH HN N HN 6N HN N HN N N N N N

GG

N AB N G and VIIIa VIIIb VIIc VIIId Preferred RX groups of formula VIII include T-R 3 wherein T is a valence bond or a methylene and R 3 is CN, or -OR. When R' is preferred R 3 .groups include an optionally substituted group selected from C-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring. When R' is -OR, preferred R groups include an optionally substituted group CI-6 aliphatic group such as alkyl- or dialkylaminoalkyl and aminoalkyl. Examples of -167preferred R include acetamido,- CN, piperidinyl, piperazinyl, phenyl, pyridinyl, imidazol-i-yl, imidazol-

IO

2-yl, cyclohexyl, cyclopropyl, methyl, ethyl, isopropyl, 0 t-butyl, NH 2

CH

2 CHNH, and NH 2

CH

2 Preferred R 9 groups of formula VIII, when present, include R, OR, and N(R Examples of preferred

R

9 include methyl, ethyl, NH 2

NX

2

H

2

C

2 NH, N( 3 2

OH

2

CH

2

NH,

SN(CHa)2H 2

CH

2 0, (piperidin-1-yl)CH 2

CH

2 0, and NH 2

CH

2

CH

2 0.

The R 2 and R 2 groups of formula VIII may be C 10 taken together to form a fused ring, thus providing a c bicyclic ring system containing a pyrazole ring.

Preferred fused rings include benzo, pyrido, pyrimido, \Oand a partially unsaturated 6-membered carbocyclo ring.

These are exemplified in the following formula VIII c 15 compounds having a pyrazole-containing bicyclic ring system:

'NH

HN

NN

Z2 NH NH tNH NH -CN SNN fN NH and Preferred substituents on the formula VIII

R

2

/R

2 fused ring include one or more of the following: -halo, -N(R alkyl, -C2-4 haloalkyl, -No2, -0 (C3alkyl), -C02(1-4 alkyl), -CN, -SO 2 04-4 alkyl), -SO 2

NH

2 -OC NH 2

-NH

2 S02 (C 1 4 alkyl) NHC(O) alkyl)

-C(O)NH

2 and -CO(Ca.4 alkyl), wherein the (Cj.4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C3_4 alkyl) group is methyl.

When the pyrazole ring system of formula VIII is monocyclic, preferred R 2 groups include hydrogen, CI-.4 -168aliphatic, alkoxycarbonyl, (ian) substituted phenyl, IND hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or o dialkylamninocarbonyl, aminoalkyl, alkylaminoalkyl, 0 dialkylaminoalkyl, phenylaminocarbonyl, and (N-

C']

Bubstituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, b -butyl, cyclopentyl, phenyl., C02H,

C']COPCH

3

OH

2 OH, 0H 2 00H 3

CH

2

CH

2

OH

2 OH, CH 2

CH

2

OH

2 0CH 3

CH

2

OH

2

CHOCH

2 Ph, CH2OH 2 CHaNH 2

CH

2

CH

2 CHZNHOOOC (OH 3 3 -CONHCH (CH 3 2

CONHCH

2 CH=0H 2

CONHCH

2

CH

2

OCH

3

CONHCR

2 Ph,

IND

CONH~cyclohexyl), CON(Et) 2 CON(0H 3

)CH

2 Ph, CONB(n-C 3

H

7 o ~CON (Et) CH 2

CH

2 0H 3

COIU{CH

2 CH (OH 3 2 CON (n-C 3 2 7 2 CO (3methoxymethylpyrrolidin-aL-yx), CONH(3-tolyl), OONH(4-

IN

CONHCH

3 CO (morpholin-1-yl), Co (4-methylpiperazin- 1-yl), CONHCH 2

CH

2 OH, CONH 2 and CO(piperidin-l-yl)

A

preferred R 2 group is hydrogen.

Then G is Ring C, preferred formula VIII Ring C groups are phenyl and pyridinyl. When two adjacent suibstituents on Ring C are taken together to form a fused ring, Ring C is contained in a bicyclic ring system.

Preferred fused rings include a benzo or pyrido ring.

Such rings preferably are fused at ortho and meta positions of 'Ring C. Examples of preferred bicyclic Ring C systems include naphthyl and isoquinolinyl. Preferred R' groups include -halo, an optionally substituted C3_6 aliphatic group, phenyl, -OR, -OR 6 -ON, -SO21I, -SO 2

NI{,

-NR

6 2 ,-C0 2

R

6

-CN

2

NCR,-OC(O)NH

2 or -NHSO 2

R

6 When R 1 is an optionally substituted.o 1 6 aliphatic group, the most preferred optional substituents are halogen.

Examples of preferred R3' groups include -CF, -Cl, -F, -ON, -000W 3 -OCH3, -OH, -CH 3

CH

3

-OOH

2

CH

3

-OH

3

-CF

2

CI

3 cyclohexyl, t-butyl, isopropyl, cyclopropyl, -Ce M, CeO-OCH 3

-SO

2

CH

3

-SO

2

NH

2

-N(CH

3 2 -C0 2 0H 3 ,1 -CONH 2

-NECOCH

3 -00(0)NH 2 -NHS0 2

CH

3 and -00F 3 -169- On Ring C preferred R 5 substituents, when present, include -halo, -CN, -NO 2 2 optionally

VO

substituted C1.6 aliphatic group, -OR, -CO 2

R,

-CONH(R 4 -N(R')COR, -SO 2 and -N(R')so 2 R. More preferred R 5 substituents include -Cl, -CN, -CF 3 -NH2, -NH(C-.14 aliphatic)., -N(C3.-4 aliphatic)2, -0(C1-4 aliphatic), C14 aliphatic, and -C02(CI-.4 aliphatic).

Examples of such preferred R 5 substituents include -C1, -CN, -CF 3 2 -NHMe, -NMe 2 -OEt, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, and -CO 2 Et.

C When 0 is Ring D, preferred formula VIII Ring D monocyclic rings include substituted and unsubstituted cO phenyl, pyridinyl, piperidinyl, piperazinyl, Spyrrolidinyl, thienyl, azepanyl, and morpholinyl rings.

When two adjacent substituents on Ring D are taken together to form a fused ring, the Ring D system is bicyclic. Preferred formula VIII Ring D bicyclic rings include 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-1H-indolyl, isoquinolinyl, quinolinyl, and naphthyl. Examples of more preferred bicyclic Ring D systems include naphthyl and isoquinolinyl.

Preferred R substituents on Ring D of formula VIII.include halo, oxo, CN, -NO 2 2

-CO

2

R,

-CONH(R'), -N(R 4 )COR, -SO 2

N(R')

2

-N(R

4

)SO

2 R, -SR, -OR, or substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C5_ 10 aryl, or 'C.-6 aliphatic. LMore preferred Rs 5 substittients include -halo, -CN, -oxo, -SR, -OR, 3 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, 0s6., aryl, or C1..6 aliphatic. Examples of Ring D substituents include -OH, phenyl, methyl, CH0OH, CH2CH20H, pyrrolidinyl, OPh, CF 3 CNCH, Cl, Br, F, I, NH 2 -170-

C(O)CH

3 i-propyl, tert-butyl, SEt, OMe, N(Me) 2 methylene dioxy, and ethylene dioxy.

VO

o Preferred formula VIII compounds have one or 0 more, and.more preferably all, of the features selected from the group consisting of: S(a) Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two Cl adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a 10 naphthyl, quinolinyl or isoquinolinyl ring, and R' is Cl -halo, an optionally substituted C1-e aliphatic group, o phenyl, -COR 6 -CN, -SO 2 -SO0NH 2 2 -COaR 6 \0 -CONH,, -NHCOR 6

-OC(O)NH

2 or -NHSO 2 or Ring D is an Soptionally substituted ring selected from a phenyl, C< 15 pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3',4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; Rx is T-R 3 wherein T is a valence bond or a methylene; and

R

2 is hydrogen and R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1 -e aliphatic group, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring.

More preferred compounds of formula VIII have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and -171- R' is -halo, a C2- 6 haloaliphatic group, a Ci-6 aliphatic group, phenyl, or -CN; or Ring D is an optionally

VO

o substituted ring selected from phenyl, pyridinyl, 0 piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- Stetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or <C naphthyl; Rx is T-R 3 wherein T is a valence bond or a C 10 methylene and R 3 is CN, -R or -OR; C i R 2 is hydrogen and R 2 is hydrogen or a o substituted or unsubstituted group selected from aryl, or \c a C.-6 aliphatic group, or R 2 and R 2 are taken together 1 with their intervening atoms to form a substituted or Cl 15 unsubstituted benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring; and each R 5 is independently selected from -halo, -CN, -NO 2 2 optionally substituted Ci-6 aliphatic group, -OR, CO 2 R, -CONH(R 4

-N(R

4

)COR,

-SO

2

N(R

4 2 or -N(R 4

)SO

2

R.

Even more preferred compounds of formula VIII have one or more, and more preferably all, of the features selected from the group consisting of: Rx is T-R 3 wherein T is a valence bond or a methylene and R 3 is -R or -OR wherein R is an optionally substituted group selected from CI-6 aliphatic, phenyl, or a 5-6 membered heteroaryl or heterocyclyl ring; Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and R is -halo, a Ci-4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, -172piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-

IO

tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or 0 naphthyl;

R

2 and R 2 are taken together with their intervening atoms. to form a benzo, pyrido, pyrimido or partially unsaturated 6-membered carbocyclo ring Cl optionally substituted with -halo, -N(R 4 2

-C

1 4 alkyl,

-C

1 4 haloalkyl, -N02, -O(C.4 alkyl), -C0 2

(C

1 4 alkyl), -CN, -S0 2

(C

1 4 alkyl), -S0 2

NH

2

-OC(O)NH

3

-NH

2

SO

2

(C

1 4 alkyl), C -NHC(O) (C 1 4 alkyl) NH, or -CO (C 1 -4 alkyl) wherein the (C- 4 alkyl) is a straight, branched, or byclic alkyl C group; o each R 5 is independently selected from -Cl, N 15 -CN, -CF3, -NH 2 -NH(C1- 4 aliphatic), -N(C 1 4 aliphatic) 2

-O(C

1 -4 aliphatic), C 1 -4 aliphatic, and -CO2(C 1 4 aliphatic); and

R

9 is R, OR, or N(R') 2 Representative compounds of formula VIII are set forth in Table 7 below.

Table 7.

Me Me HH IH

HN

4

P

VIII-1 VIII-2 VIII-3 -173- Et NtQ VIII-4 Bu

N,

VI 11-7 Nt~ Nt VIII -5 Pr M4NAI

HNJH

N-

VIII-6 viII -9

I

Me HNIg-H VII -1

C

3

INH

VIII-13 N "*N Viii-il 4Z VIII-14 OMe VIII -12 HN9NNH Vill-is -174- N c M~e VIII -16 Me.

VIII -17 HN HNt N NN CF 3

N

4 N CF 3

H

2 NNiH MAN.

Ae

HNRV

N

4 N CF 3

H

2

NSO

VII0 aHg CI1 VIII-21 ViII -19

NN

N "L N C F 3 VIII -22 Hg N)ZN CN VIII -25 VIII HgH N' N CI VIII-23 NON CI VIII-26

F

HN

H

N N CI VIII -27 -175- VIII-28 VIII-29 VIII-31

N

Me VIII -34 PNJ

H

N CF 3 VIII -32 N F 3 VIII- 35 VIII VIII -33 VIII -36 HN9X

N

4 N CF 3 Me VIII -38 _Xg N' N CI Me VIII1-39 VIII-37 -176- No H HNP

HN

2 o4 CF 3 A-N CI Me..A VIII-41 VIII-42 No N.0HN H N' IN OYAk 1 N CF 3 I >rN CF 3 N'I>CNI CF 3 N-N1

HN

SVIII-43 VIII-44 Hl 9H C N 2 H HNLIj N CFS C N N VIII-46 VIII-47 VIII-48

HN

2 P N% K

CF

3

CF

3 I IN CF 3 VIII-49 VIII-50 ViII-Si -177- H H H K HNc HNN I HNC HNy I F ,T N C1 I* l CF3 N N SVIII-52 VIII-53 VIII-54 i Me q .nH anohe emoiet ti netinpoie o HN c rn HN HNN r 1IN CFc H 2

N"-

0 CFa IND 5 VI-55 VIII-56 VTII-57 0 cil In another embodiment, this invention provides a composition comprising a compound of formula VIII and a pharmaceutically acceptable carrier.

One aspect of this invention relates to. a method of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VIii.

Another aspect relates to a method of treating a disease that is alleviated by treatment with a GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a compound of formula VIII.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula -178- VIII. This method is especially useful for diabetic patients.

0 Another aspect relates to a method of 0 inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising Sadministering to said patient a therapeutically effective amount of a composition comprising a compound of formula C l VIII. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

Cl 10 Another aspect relates to a method of Cl inhibiting the phosphorylation of P-catenin in a patient o in need thereof, comprising administering to said patient IN a therapeutically effective amount of a composition Scomprising a compound of formula VIII. This method is C' 15 especially useful for treating schizophrenia.

One aspect of this invention relates to a method of inhibiting Aurora activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VIII.

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of administering to a patient in need' of such a treatment a therapeutically effective amount of a composition comprising a compound of formula VIII. This method is especially useful for treating cancer, such as colon; ovarian, and breast cancer.

One aspect of this invention relates to a method of inhibiting CDK-2 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula VIII.

-179- Another aspect relates to a method of treating a disease that is alleviated by treatment with a CDK-2

\O

o inhibitor, said method comprising the step of 0 administering to a patient in need of such a treatment a therapeutically effective amount of a composition Scomprising a compound of formula VIII. This method is especially useful for treating cancer, Alzheimer's C'l disease, restenosis, angiogenesis, glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, 10 alopecia, and autoimmune diseases such as rheumatoid C1 arthritis.

o Another method relates to inhibiting GSK-3, lO Aurora, or CDK-2 activity in a biological sample, which Smethod comprises contacting the biological sample with C 15 the GSK-3 or Aurora inhibitor of formula VIII, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3, Aurora or CDK-2.

Each of the aforementioned methods directed to the inhibition of GSK-3, Aurora or CDK-2, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula VIII, as described above.

The above formula I compounds contain a pyrazole ring bearing the R 2 and R 2 substituents. In their search for further inhibitors of the protein kinases GSK and Aurora, applicants sought to replace the pyrazole moiety of formula I with other heteroaromatic rings. One of the more effective pyrazole ring replacements was found to be a triazole ring. Inhibitors having this triazole ring are otherwise structurally similar to the formula I compounds and are represented by the general formula IX: -180- ID0 A NH o HN"N RY 1

G

Ix

N.

or a pharmaceutically acceptable derivative or prodrug D 5 thereof, wherein:

Z

1 is nitrogen or CRO and Z 2 is nitrogen or CH, provided 0 that at least one of Z 1 and Z 2 is nitrogen; G is Ring C or Ring D; SRing C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together'with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or 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 Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring.nitrogen by -R 4 provided that when Ring D is a six-membered aryl or -181- 1 heteroaryl ring, -R s is hydrogen at each ortho carbon position of Ring D;

\O

o R 1 is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 0 membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C-6 aliphatic group, said phenyl, heteroaryl, and heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said C- aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1

N

10 and an adjacent substituent taken together with their 1 intervening atoms form said ring fused to Ring C; o Rx and R Y are independently selected from T-R 3 or Rx and \Q R Y are taken together with their intervening atoms to Sform a fused, unsaturated or partially unsaturated, 5-8 Ci membered ring having 0-3 ring heteroatoms selected from.

oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by Rx and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by Rx and R Y is substituted by R 4 T is a valence bond or a CI-. alkylidene chain;

R

2 is -R or -T-W-R6;

R

3 is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCH2COR, -NO 2 -CN, -S(0) 2 R, -SR,

-N(R

4 2

-CON(R

7 2 -SOaN(R) 2

-N(R

7

)COR,

C02(optionally substituted CI- 6 aliphatic),

-N(R

4 2

-C=NN(R

4 2 -C=N-OR, CON(R 7 2 -N(R SO 2 N (R 7 2

-N(R

4

)SO

2 R, or -OC(=O)N(R 7 each R is independently selected from hydrogen or an optionally substituted group selected from Ci-6 aliphatic, C-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -182each R 4 is independently selected from -COR, -C02 (optionally substituted C1-6 aliphatic), -CON

IR

or -SOR2, or two R 4 on the same nitrogen are taken 0~ together to form a 5-8 membered heterocyclyl or S heteroaryl ring; eachR' is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 3 -ON, -S03, -SR, C7l *N(R 4 2

-CON(R')

2

-SO

2 N(R4) 2

-N(R

4

)COR,

-N(R 4

CO

2 (optionally substituted C1_6 aliphatic), -N(3 4 )N(3 4 2 -C=NN(3 4 2 -C=N-OR, 4 )CON(Rf 2 cl -N(R 4

)S

2

N(R

4 2

-N(R

4 )S0 2 3, or -Og=O)N(R') 2 or R5 and an adjacent substituent taken together with their Cl intervening atoms form said ring fused to Ring C; V is 0, -S02-, -N(R6)S0-, '-SON(RP.-, is -N (R6) CO-, -C02-, -N(R6)CO-,

-N(R

6

)SO

2 2 -C(R)3S-, -C(R6)SO-, -C(R6)2S0-, -C(R 6) 2S02N(R6 2 2 2 N(R6)N(R6) 2 N(R 6)S0 2 N(R6) or -C(R6)3 2 N(R6)CON(R6) W is -C(R6)3O-, -C(R 6 2

-C(R

6 2 So 2 2 S0 2 -C(R6) 2 -COr, -C(R6) 0 -CRg) 2 N(R6)CO-, -C(R6)=NN(a) -C RP) 2 -C(R6) 2 N1 (R6) S0 2 N 2 N(6)coNcR)-, or -CON(R96)_ each R6 is independently selected from hydrogen, 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-if membered heterocyclyl or heteroaryl ring; each R 7 is. independently selected from hydrogen or an optionally sulstieutedCl0- aliphatic group, or two R7 -183on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or o heteroaryl ring; 0 each R B is independently selected from an optionally substituted CI-4 aliphatic group, -OR 6

-SR

6

-COR

6 -S0 2

R

6

-N(R

6 2

-N(R'

N

(R

6 2 -CN, -NO 2

-CON(R

6 2 or -C0 2 R6; and c]

R

9 is selected from halo, -OR, -CO 2 R, -COCOR,

-NO

2 -CN, -SO 2 R, -SR, -N(R 4 2 -CON(R4) 2 C 10 -SO 2

N(R

4 2 -N(R COR, -N(R CO2 (optionally c' substituted CI-s aliphatic), 2

-C=NN(R

4 2 o -C=N-OR, -N(R 4

)CON(R

4 -N(R')S0 2

N(R

4 2

-N(R

4 )S0 2 R, or -Q 2 SCompounds of formula IX may exist in '1 15 alternative tautomeric forms, as in tautomers 1-3 shown below. Unless otherwise indicated, the representation of any of these tautomers is meant to include the other two.

R

2

FR

2

R

2 NN HN 4 HN H HN HN RX H z RY R Z

R

Z

1 2 3 The RX and R y groups of formula IX may be taken together to form a fused ring, providing a bicyclic ring system containing Ring A. Preferred RX/RY rings include a or 8-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said Rx/RY ring is optionally substituted. Examples of Ring A systems are shown below by compounds IX-A through IX-DD, .wherein z' is nitrogen or C(R 9 and Z 2 is nitrogen or

C(H).

-184- HNN Z IX-E B IX-A

IX-C

HN3'

SX-D

Ht HN3Q Ix-J IX-! fl-F IX-E ix- I HN31

NKZX>

IX-K

N

Z

IX-L

HN3Z -x- IS-N :tx-o -185- S Zial-2, tX-P IX-Q IX-R HN ?HN Z HN>2Z

NON

tx-s XX-T IX-U 0H?' HNN

HA

0N S'-v flW l HAHNY?

HNA

NN

IX-y IX-Z IX-AA HNA HN< HA fl-SB Il-CC IX-DD Preferred bicyclic Ring A systems of formula IX include IS-A, IS-B, IS-C, Il-D, fl-B, IS-F, IS-S. fl-H, IS-If-Xj, IS-K, fl-L, and fl-M, more preferably Il-A, -186- IX-B, IX-C, IX-F, and IX-H, and most preferably IX-A, IX- B, and IX-H.

O In the monocyclic Ring A system of formula IX, 0 preferred RX groups include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 4 aliphatic group such as methyl, ethyl, cyclopropyl, isopropyl or t-butyl.

Preferred RY groups, when present, include T-R 3 wherein T is a valence bond or a methylene, and R 3 is -N(R 4 )2, or -OR. Examples of preferred RY include 2-pyridyl, 4- 10 pyridyl, piperidinyl, methyl, ethyl, cyclopropyl,

\O

C isopropyl, t-butyl, alkyl- or dialkylamino, acetamido, optionally substituted phenyl such as phenyl or halosubstituted phenyl, and methoxymethyl.

In the bicyclic Ring A system of formula-IX, Ci 15 the ring formed by RX and RY taken together may be substituted or unsubstituted. suitable substituents include halo, -OR, -CO 2 R, -COCOR, -NO 2

-CN,

-SO2R, -SR, -SON(R -N(R')COR, -N(R')CO 2 (optionally substituted C.

6 aliphatic), 2

-C=NNR)

2

-C=N-OR,

-N(R)CON(R%)

2

-N(R')SON(R

4 2 -N(Rt)SO 2 R, or -OC(=O)N(R 2 a, wherein R and R' are as defined above.

Preferred RX/RY ring pubstituents include -halo, -OR, -COR, -CO 2 R, -CON(R')2, -CN, or -N(R)2 wherein R is an optionally substituted C1- aliphatic group.

Preferred R 2 groups of formula Ix include hydrogen, C.4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, monoor dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, phenylaminocarbonyl, and (Nheterocyclyl)carbony1. Examples of such preferred R' substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, COaH, C023r 20, 0,COCHa, CHCH12CO, CH2C1_CHCH3, -187-

CH

2 CH2 CH 2 0CH 2 Ph, CH 2

CHCH

2

NH

2

CH

2

CH

2

CR

2 NHCOOC (C 3 3 CONH (CR 3 2 CONmCHC=CR 2 CONCHCH2oC 2

CH

3

CONHCH

2 Ph, Va oN CONH(cyclohexyl), CON(Et) 2

CON(CH

3

)CH

2 Ph, CONH(n-C3H 7 o~ CON(Et)CH2M 2 CH3, CONHCHRCH(CH 3 2 CON(n-C3H) 2 CO(3methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4- E tolyl), CONHCH 3 CO(morpholin--yl), CO(4-methylpiperazin- 1l-yl), CONHCH 2 CO20H, CONH2, and CO(piperidin-1-yl). A C] more preferred R2 group for formula IX compounds is hydrogen.

An embodiment that is particularly useful for Va C] treating GS3-mediated diseases relates to compounds of formula x wherein ring A is a pyrimidine ring:

IN]

0 R22 Na HN

NNH

RY

S

or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Ring C is selected from a phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R1, any substitutable nonortho carbon position on Ring C is independently substituted by -R5, and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, -188said fused ring being optionally substituted by halo, oxo, or -Ra; \0 o R is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 C membered heteroaryl ring, 5-6 membered heterocyclyl ring, or C1- aliphatic group, said phenyl, heteroaryl, Sand heterocyclyl rings.each optionally substituted by up to three groups independently selected from halo, C1 oxo, or -R 8 said Ci-6 aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R' q 10 and an adjacent substituent taken together with their C intervening atoms form said ring fused to Ring C; o R x and R y are independently selected from T-R 3 or R x and Cq R Y are taken together with their intervening atoms to o form a fused, unsaturated or partially unsaturated, 5-8 Cl membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R x and R Y is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by R x and RY is substituted by R4; T is a valence bond or a Ci-4 alkylidene chain;

R

2 is -R or -T-W-R6;

R

3 is selected from halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0)2R, -SR, -N (R 4 2 -CON (R 7 2 -S0 2 N (R 7 2

-N(R

7

)COR,

-N(R

7 CO2 (optionally substituted CI.

6 aliphatic)

-N(R')N(R

4 2

-C=NN(R

4 2 -C=N-OR, -N(R 7

)CON(R

7 2 -N (R)SO0 2

N(R

7 2

-N(R

4

)SO

2 R, or -OC(=0)N(R 7 2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-s aliphatic, C6-i0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -189each R' is independently selected from -COR', -C02 (optionally substituted CI-6 aliphatic), -CON (R) 2 or -S0 2

R

7 or two R 4 on the same nitrogen are taken o~ together to form a 5-8 membered heterocyclyl or heteroary. ring; each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -ON, -SO 2 R, -SR,

-N(R

4 2

-CON(R

4 2 -50 2

N(R')

2 -OCC=o)R, -N(R'4)COR, -N(R4)CO 2 (optionally substituted C3_6 aliphatic), 2

-C=NN(R

4 2 -C=N-OR, -N(R 4

)CON(R

4 2 IND

-N(R

4

)SO

2

N(R)

2

-N(R

4

)SO

2 R, or -OC(=O)N(R 4 2 or R 5 and an adjacent substituent taken together with their Cleintervening atoms form said ring fused to Ring C; o V is -N(Rr')S0 2

-SO

2

N(R

6 0 2 -N(RG)CO-,

-N(R

6 -N(R6)SO 2

-N(R')N(R

6

-OC(O)N(R

6 2

-C(R

6 2

-C(R

6 SO-, 2 S0 2

-C(R

6 2 0 2 NR') 2 N(R) -C(R 6 2 -0(R 6 -CCR6)=NN(R6)-, -C(R6) 2 N(R6)N(R) 2 N(R6)so 2 or -C R) 2 N CON (R 6 W is -C(R6) 2 -C(R6) 2 -CCR6) 2 S0-, -C(R")so0 2 -C (R6) 2S0N (R C(R6)2N(R6)-, _C02-, 2

N(R")CO-,

-C(R

6 2 -C(R6) NO_, 2 -C(R6) 2 N(R6)So 2 N(R6)-, -C(Rr')2N(Rr')CON(Rr'-, or -CONR6)-; each R6 is independently selected from hydrogen, an optionally substitted Cl-, aliphatic group, or two R6 groups on the same nitrogen atom are taken together with thb nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R7 is. independently selected from hydrogen or an optionally substituted aliphatic group, or two R7 -190on the same nitrogen are taken together with the IND nitrogen to form a 5-8 membered heterocyclyl or O heteroaryl ring; and C-i each R B is independently selected from an optionally substituted C 1 -4 aliphatic group, -OR 6

-SR

6

-COR

6

S-SO

2

R

6

-N(R

6 2

-N(R

6

)N(R

6 2 -CN, -N02, CON(R 6 2 or

-COR

6 Compounds of formula X are structurally similar to compounds of formula II except for the replacement of 10 the pyrazole ring moiety by the triazole ring moiety.

Preferred R 2 Rx, R Y and Ring C groups of formula X are as o described above for the formula II compounds. Preferred I\ formula X compounds have one or more, and more preferably o all, of the features selected from'the group consisting C' 15 of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring; Rx is hydrogen or Ci-4 aliphatic and R Y is T-

R

3 or R x and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens;

R

1 is -halo, an optionally substituted Ci-6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6

-SO

2

NH

2

-N(R

6 2 -CO0R, -CONH 2

-NHCOR

6

-OC(O)NH

2 or -NHSO 2

R

6 and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a CI-6 aliphatic group.

-191- More preferred compounds of formula X have one or more, and more preferably all, of the features o selected from the group consisting of: C-i Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two Sadjacent substituents .thereon form a bicyclic. ring system, the bicyclic ring system is a naphthyl ring; Rx is hydrogen or methyl and R y is -R,

N(R

4 2 or -OR, or R x and R Y are taken together with their C\ 10 intervening atoms to form a benzo ring or a 5-7 membered c carbocyclo ring, wherein said ring formed by R x and R Y is o optionally substituted with halo, -OR, -CO 2

R,

Cl O -COCOR, -N02, -CN, -SO 2 R, -SR, 2

-CON(R)

2 8 -SON(R 4 -N (R' COR, -N(R 4 C0 2 (optionally C 15 substituted C 1 -6 aliphatic), -N(R 4

-C=NN(R')

2 -C=N-OR,

SO

2 N 2 -N (R S0 2 R, or -OC

(R

4 2;

R

1 is -halo, a CI-6 haloaliphatic group, a Cz- 6 aliphatic group, phenyl, or -CN;

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl or a CI-6 aliphatic group; .and each R 5 is independently selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted CI-6 aliphatic group, -OR, -COR, -CONH(R 4

-N(R

4

)COR,

-S0 2

N(R

4 2 or -N (R SO 2

R.

Even more preferred compounds of formula X have one or more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring; -192-

R

x is hydrogen or methyl and R Y is methyl, DO methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, O alkyl- or an optionally substituted group selected from C< 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R X and RY are taken together with their intervening atoms to form San optionally substituted benzo ring or a 6-membered carbocyclo ring;

R

1 is -halo, a C1-4 aliphatic group optionally substituted with halogen, or -CN; 10 R 2 is hydrogen or a C,-6 aliphatic group; and each R 5 is independently selected from -Cl, o -CN, -CF 3

-NH

2

-NH(C-

1 aliphatic) -N(C 1 .4 Cl IN aliphatic) 2 -0(Ci-4 aliphatic), CI.4 aliphatic, and S-C02(Ci-4 aliphatic).

Cl 15 Another embodiment of this invention relates to.

compounds of formula XI:

HN.N

NRY N

XI

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: 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 Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 -193provided that when Ring D is a six-membered aryl or IO I heteroaryl ring, -R 5 is hydrogen at each ortho carbon o position of Ring D; 0 N RX and Ry are taken together with their intervening atoms to form a fused benzo ring or 5-8 membered carbocyclo .ring, wherein any substitutable carbon on said fused ring formed by RX and Ry is substituted by oxo or T-R T is a valence bond or a CI-4 alkylidene chain;

R

2 is -R or -T-W-R6; IND 5 R 3 is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR,

-N(R)

2

-CON(R')

2

-SO

2

-N(R')COR,

IND -N (R 4

CO

2 (optionally substituted C 1 aliphatic),

-C=NN(R)

2 -C=N-OR, -N(R')CON(R') 2

SO

2

N(R')

2

-N(R')SO

2 R, or -OC(=O)N(R)2; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 -6 aliphatic, C-o aryl, a beteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7

-COR

7 -CO2(optionally substituted C-6 aliphatic), -CON(R 7 or -SOR, or two R 4 on the same nitrogen are takeh together to form a 5-8. membered heterocyclyl or heteroaryl ring; 0 each R5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, 2

-CON(R')

2

-SON(R')

2

-N(R')COR,

-N(R)C0 2 (optionally substituted C3.

6 aliphatic),

-C=NN(R')

2 -C=N-OR, -N(R')CON(R') 2

-N(R)SO

2

N(R)

2 -N(R4)S02R,, or 2 V is -S02-, -N(R 6 )S0 2 -SO2N(R')-,

-N(R

6 -C0 2 -N CON -N(R 6

)SO

2 N -194-

-C(PR)

2

S.,

-C(R

6 2 SO-, -C(R 6 2 So 2

-C(R)

2

SO

2

-C(R

6 2

N(R

6 -C(R')2N(R 6

-C(R

6 )2N(R 6

-C(R

6 2

N(R

6 2 SN or -C 2N CON W is -C(R 6 2 -C(R6) 2 SO-, -C(R 6 2 s0 2

-C(R

6 2 SoN(R)-, -C(R 6 2 -C0 2 CO-, I

-C(R

6

)OC(O)N(R

6

-C(R

6 3

N(R')CO-,

2 -C(R 6

)=NN(R

6 -C 2N -C (R) 2

N(R

6 S0 2 N

-C(R

6 2 or each R 6 is independently selected from hydrogen or an optionally substituted C 1 4 aliphatic group, or two R 6 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 R' is independently selected from hydrogen or an optionally substituted C 1 6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring.

Compounds of formula XI are structurally similar to compounds of formula III except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R2, RX, and Ring D groups of formula XI are as described above for the formula III compounds. Preferred formula XI compounds have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- -195dihydro-iH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; o Rx and R Y are taken together with their C intervening atoms to form an optionally substituted benzo ring or 5-7 membered carbocyclo ring; and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a

CI-

6 aliphatic group.

More preferred compounds of formula XI have one

C]

D 10 or more, and more preferably all, of the features C selected from the group consisting of: Ring D is an optionally substituted ring \O selected from phenyl, pyridinyl, piperidinyl, C o piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- C 15 tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3-dihydro-iH-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx and R Y are taken together with their intervening atoms to form a benzo ring or 5-7 membered carbocyclo ring, wherein said ring formed by R x and R Y is optionally substituted with oxo, halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 2

-CON(R

4 2

-SO

2 N (R) 2

-N(R

4

)COR,

-N(R

4 C0 2 (optionally substituted Ci.- aliphatic), -N(R')N(R4) 2

-C=NN(R

4 2 -C=N-OR, -N(R 4

)CON(R

4 2

-N(R

4

SO

2

N(R

4 2

-N(R

4

)SO

2 R, or N 2

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl or a Ci-6 aliphatic group; and each R 5 is independently selected from halo, oxo, CN, NO 2

-N(R

4 2 -COR, CONH(R 4

-N(R

4

COR,

-SO

2 N(R4) 2 -N(Rf)S02R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-.o aryl, or Ci.- aliphatic.

-196- Even more preferred compounds of formula XI have one or more, and more preferably-all, of the

\O

o features selected from the group consisting of: 0 RX and R Y are taken together with their intervening atoms to form a benzo ring or 6-membered Scarbocyclo ring, wherein said ring formed by Rx and R Y is optionally substituted with halo, CN, oxo, Ci-6 alkyl, Ci-s Ci alkoxy, (CI-6 alkyl) carbonyl, (C-e6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or C 10 dialkylaminocarbonyloxy, or 5-6 membered heteroaryl;

VO

C each R 5 is independently selected from o -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a Va substituted or unsubstituted group selected from 5-6 0 membered heterocyclyl, C6-.o aryl, or C1i- aliphatic; and Ci 15 R 2 is hydrogen or a Ci-6 aliphatic group.

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

R

2 HN N

H

R

N

XII

or a pharmaceutically acceptable derivative or prodrug thereof, wherein: 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 Ring D is substituted at any substitutable ring carbon by oxo or -197-

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or O heteroaryl ring, -R 5 is hydrogen.at each ortho carbon 0 C position of Ring D;

R

x and R Y are independently selected from- T-R 3 or Rx and

SR

Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-8 membered ring having 1-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable *C carbon on said fused ring is optionally and Ci independently substituted by T-R 3 and any o substitutable nitrogen on said ring is substituted by O

R.

O T is a valence bond or a C1-4 alkylidene chain; C 5 R 2 is -R or -T-W-R6;

R

3 is.selected from -halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0)2R, -SR, -N (R 4 2 -CON (R 4 2 -SbaN(R 4 2 -N(R' COR,

-N(R

4

CO

2 (optionally substituted CI-e aliphatic),

-N(R

4 N -C=NN(R 4 2 -C=N-OR, CON(R 2

-N(R

4

)SO

2

N(R

4 2 -N(R4)SO 2 R, or -OC(=O)N(R)a; each R is independently selected from hydrogen or an optionally substituted group selected from C1.aliphatic, C 6 -io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -COR 7

-CO

2 (optionally substituted CI-6 aliphatic), -CON(R) 2 or -SO 2

R

7 or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R 5 is independently selected from halo, -OR, -CO2R, -COCOR, -NO 2 -CN, -SO 2 R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R

4 2

-N(R')COR,

-198- -N(RW) CO 2 (Optionall1Y substituted C1_.6 aliphatic), IND -N(R 4 2

-C=NN(R

4 2 -C=N-OR, -N(Rt)CON(R') 2

S-N(R

4 )S0 2

U(R

4 2 -N(Rt)SOR, or O=C)R)2 ClV is -S02-, -N(R 6 )80 2

-SO

2

N(R

6 -C02-, 47(R6)C(O)O.,

-N(R')CON(R.

6 -N(R6)S0 2 -N(RG)N(R 6)- -OC(O)N(R6) 2 -cC(R 6 2

S-,

Cl 2 s0-, 2 S0 2 2 S0 2 -C(R'6) 2 N(Rr) C(R6) AN(R6) C(R6) 2 N(R -C (R 6 =NN (R -C(R 6) 2

N(R')N(R

6 -C(R 6)AN(R 6

SO

2 or ClC WCR) 2 CON oW is -C(R 6 2 -c'(R 6 2 2 So-, -C(R 6 2 S0 2 Cl -C(R 6 2

S

2 -C(R6)bN(R 6 -CO-f _CO2-t -C(R')OC(O)N4(R 6 -C(R6)AN(RO) CO-, Cl 15 2

N(R

6 -CR) -0(R 6 tN-O-, -C(R6) 2 N(R6)N(R6)-, 2 N(R')80 2 N(R6)-, 2 or -CON(R)- 1 each R' is independently selected from hydrogen or an optionally substituted C_ 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 R 7 is independently selected from hydrogen or anoptionally substituted C1_6 aliphatic group, or two R7 on the same nitrogen are taken together with the nitrogen to font a 5-8 membered heterocyclyl ring or heteroaryl.

Compounds 6t formula XII'are structurally similar to compounds of formula IV except for the 'replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R2, R 2 RY, and Ring D groups of formula XII are as described above for the formula IV compounds. Preferred formula XII compounds have one or -199more, and more preferably all, of the features selected from the group consisting of:

\O

0 Ring D is an optionally substituted ring C selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, Smorpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4tetrahydroquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- Ci dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

C

10 Rx is hydrogen or C1-4 aliphatic and R Y is T- C R 3 or Rx and R Y are taken together with their intervening o atoms to form an optionally substituted 5-7 membered CO unsaturated or partially unsaturated ring having 1-2 ring Sheteroatoms; and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci-6 aliphatic group.

More preferred compounds of formula XII have one or more, and more preferably all, of the features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; Rx is hydrogen or methyl and R y is -R, or -OR, or R x and R y are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, wherein said ring is optionally substituted with -R, hal6, oxo, -OR, -COaR, -COCOR, -NO 2 -CN, -S(0)R,

-SO

2 R, -SR, -N(R 4 2

-CON'R)

2

-SO

2

N(R)

2 -OC(=0)R,

-N(R

4 COR, CO2 (opt.i nally substituted CI-6 aliphatic), -200-

-N(R

4 2

-C=NN(R')

2 -C=N-OR, -N(R 4

)CON(R

4 2 -N(R')SO2N(R') 2

-N(R

4

)SO

2 R, or -OC(=O)N(R) 2 o R 2 is hydrogen or a substituted or 0 unsubstituted group selected from aryl or a Ci.- aliphatic group; and S(d) each R 5 is independently selected from halo, oxo, CN, NO2, -N(R 4 2

-CO

2 R, -CONH(R 4 -N(R4)COR, Cl

-SO

2 N(Ra, -N(R 4

)SO

2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered Cl 10 heterocyclyl, C 6 1 o aryl, or C.6 aliphatic.

C Even more preferred compounds of formula XII o have one or more, and more preferably all, of the Cl \s features selected from the group consisting of: 0 R x and R Y are taken together with their Cl 15 intervening atoms to form a 6-membered unsaturated or partially unsaturated ring having 1-2 ring nitrogens, optionally substituted with halo, CN, oxo, CI- 1 alkyl, Ci-6 alkoxy, (CBs alkyl) carbonyl, (C 1 6 alkyl) sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 2 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, Cs-io aryl, or C 1 -6 aliphatic; and

R

2 is hydrogen or a C.-6 aliphatic group.

Another embodiment of this invention relates to compounds of formula XIII: -201-

R

2 IDN A NH Ryx

SXIIX

ci or a pharmaceutically acceptable derivative or prodrug 0 thereof, wherein: C] Z' is nitrogen, CR', or CH, and Z 2 is nitrogen or CH; O provided that one of Z 1 and Z 2 is nitrogen; \s G is Ring C or Ring D; SRing C is selected from a phenyl, pyridinyl, pyrimidinyl, C' 5 pyridazinyl, pyrazinyl, or 1,2,4-triazinyl ring, wherein said Ring C has one or two ortho substituents independently selected from -R 1 any substitutable nonortho carbon position on Ring C is independently substituted by -R 5 and two adjacent substituents on Ring C are optionally taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, said fused ring being optionally substituted by halo, oxo, or -R 8 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 Ring D is substituted at any substitutable ring carbon by oxo or

-R

5 and at any substitutable ring nitrogen by -R 4 provided that when Ring D is a six-membered aryl or -202heteroaryl ring, -R 5 is hydrogen at each ortho carbon D position of Ring D; o R 1 is selected from -halo, -CN, -NO 2

T-V-R

6 phenyl, 5-6 rC membered heteroaryl ring, 5-6 membered heterocyclyl ring, or Ci-6 aliphatic group, said phenyl, heteroaryl', Sand heterocyclyl rings each optionally substituted by up to three groups independently selected from halo, oxo, or said CI-. aliphatic group optionally substituted with halo, cyano, nitro, or oxygen, or R 1 \0 10 and an adjacent substituent taken together with their intervening atoms form said ring fused to Ring C; o Rx and R y are independently selected from T-R 3 or R x and CO R Y are taken together with their intervening atoms to Sform a fused, unsaturated or partially unsaturated, 5-8 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein any substitutable carbon on said fused ring formed by R x and R .is substituted by oxo or T-R 3 and any substitutable nitrogen on said ring formed by Rx and R Y is substituted by R'; T is a valence bond or a C-.

4 alkylidene chain;

R

2 is -R or -T-W-R6;

R

3 is selected from -halo, -OR, -CO 2

R,

-COCOR, -COCH 2 COR, -NO 2 -CN, -S(0) 2 R, -SR,

-N(R

4 2

-CON(R

7 2

-SO

2

N(R

7

-N(R')COR,

-N(R

7

CO

2 (optionally substituted Ci-6 aliphatic),

-N(R

4

N(R

4

-C=NN(R

4 2 -C=N-OR, -N(R')CON(R 7 2 -N(R S0 2 N (R 2

-N(R

4 )S0 2 R, or -OC(=0)N(R 7 each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, Cs-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -203each R 4 is independently selected from -R7, -COR', -C02 (optionally substituted C-6 aliphatic), CON(R7) 2 or -S0 2

R

7 or two R' on the same nitrogen are taken together to form a 5-8 membered-heterocyclyl or S heteroaryl ring; each 5 A.is independently selected from halo, -OR, -C0 2 R, -COCCR, -NO 2 -CN, -SO 2 R, -SR,

-N(R

4 2 -CON(Rt) 2

-SO

2 N(Rt 2

-N(R

4

)COR,

-N (R4) C 2 (optionally substituted C 1 6 aliphatic), -N(R4t (R4) 2

-C=NN(R

4 2 -C=N-OR, -N(R 4 )CON(R4) 2

-N(R

4 )80 2 N(R) 2

-N(R'YSO

2 R, or -OC(=O)N(R 4 2 or R 5 and an adjacent substituent taken tcgether with their IND intervening atoms form said ring fused to Ring C; o is -0-1 -S-1 -SO 2

-N(R

6 )S0 2

-SO

2 N(R 6 -N(Rt)CO-, -N(R 6

-N(R

6

)CON(R

6

-N(R

6

)SO

2

-N(R

6

)N(R

6 -C(R 0 -C(R 6 )3S-,

-C(R

6 2 so-, -C(R 6 2 So 2

-C(R

6 2 0 2 2

N(R

6 -0(R 6 2

N(R

6

-C(R

6 2

N(R

6

-C(R

6 )=NN(R6) -C(R"flN-O-, -C(R 6

Y-

2 -C(R6) 2

N(R

6

)SON(R

6 or -C (R 6 2 N (R 6 CON (R 6 w is 2 2 SO-, -C(R6) 2 S0 2

-C(R)

2 SoN(R6)_, 2

-CO

2

-P

-C(R6)OC(O)N(R 6 -C(R6) 2

N(R

6

)CO-,

-C(R

6 2

N(R

6 -0(R 6

-C(R

6 2

N(R

6

)N(R

6 -C(R6) 2

N(R

6

)SO

2 N(R')6, 2 N(R)CON(R6)-, or -CON(R 6 each R 6 is independetly selected from hydrogen, 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 R is independently selected from hydrogen or an optionally substituted C3;s aliphatic group, or two R' -204on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or o •heteroaryl ring; C- each R 8 is independently selected from an optionally substituted C 1 -4 aliphatic group, -OR 6

-SR

6

-COR

6

-SO

2

R

6 2

-N(R

6

N(R

6 2 -CN, -NO 2 -CON(R) 2, or

-CO

2 R6; and Ra is selected from halo, -OR, -C02R, -COCOR,

-NO

2 -CN, -SO 2 R, -SR, -N(R 2

-CON(R

4 2 2 10 -S 2

N(R

4 2

-N(R

4 )COR, -N(R 4

CO

2 (optionally C" substituted C 1 -s aliphatic) -N(R 4 )N(R4) 2

-C=NN(R)

2 S-C=N-OR, -N(R)CON(R 4

-N(R

4

S

2

N(R

4 2

-N(R

4

)SO

2

R,

Cl \O -OC(=O)N(Rt)2, or an optionally substituted group Sselected from CI- 1 aliphatic, C 6 -i 0 aryl, a heteroaryl CN 15 ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms.

Compounds of formula XIII may be represented by specifying Z I and Z 2 as shown below:

R

2 R R N-H NH N NH HN N HN HN AN Rx Fix NR x R N y

RY

G G G and XIIIa XIIIb XIIIc Compounds of formula XIII are structurally similar to compounds of formula V except for the replacement of the pyrazole ring moiety by the triazole ring moiety. Preferred R 2

R

x

R

Y

Ra, and Ring G groups of formula XIII are as described above for the formula. V compounds; Preferred formula XIII compounds have one or -205more, and more preferably all, of the features selected from the group consisting of: Ring C is a phenyl or pyridinyl ring, o optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring Ssystem, the bicyclic ring system is selected from a naphthyl, quinolinyl or isoquinolinyl ring, and R 1 is C- -halo, an optionally substituted Ci- 6 aliphatic group, phenyl, -COR 6

-OR

6 -CN, -SO 2

R

6 -SO2NH 2

-N(R)

2 -C0 2

R

6 Ci 10 -CONH2, -NHCOR 6

-OC(O)NH

2 or -NHS0 2

R

6 or Ring D is an

VO

C optionally substituted ring selected from a phenyl, Spyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, \C thienyl, azepanyl, morpholinyl, 1,2,3,4- 1 tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, C 15 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-iH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring;

R

x is hydrogen or Ci-. aliphatic and R Y is T-

R

3 or R" and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring having 0-2 ring nitrogens; and

R

2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a

C

1 -6 aliphatic group.

More preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the group consisting of: (a).Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two adjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a Ci- 6 haloaliphatic group, a C 1 -6 aliphatic group, phenyl, or -CN; or Ring D is an optionally substituted ring selected from phenyl, pyridinyl, -206piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-

NO

tetrahydrloquinolinyl, 2,3-dihydro-lH-isoindolyl, 2,3- 0g dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; RX is hydrogen or methyl and RY is -R,

N(R)

2 or -OR, or RX and RY are taken together with their intervening atoms to form a benzo ring or a 5-7 membered carbocyclo ring, wherein said ring formed by RX and RY is O 10 -optionally substitutd with halo, -OR, -CO 2

R,

Va C -COCOR, -NO 2 -CN, -S02R, -SR, 2

-CON(R

4 2

-SO

2

N(R

4 2

-N(R

4 COR, -N(R')C02 (optionally substituted aliphatic), -N(R 4 )N(Rt) 2

-C=NN(R

4 2 S-C=N-OR, -N(R' 4

)CON(R

4 2

-N(R)SO

2

N(R)

2

-N(R'

4

SO

2 R, or -oc(=o)N(R )2; R' is hydrogen or a substituted or unsubstituted group selected from aryl, or a C,; aliphatic group; and each R5 is independently selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted Cz-_ aliphatic group, -OR, -CO21R, -CONH(R'), -N(R 4

')COR,

-SO

2

N(R')

2 or -N(Rt)SO 2 R, and, when Ring G is Ring D, Ring D is substituted by oxo or Even more preferred compounds of formula XIII have one or more, and more preferably all, of the features selected from the group consisting of: RX is hydrogen or methyl and Ry is methyl, methoxymethyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkyl- or an.optionally substituted group selected from 2-pyridyl, 4-pyridyl, piperidinyl, or phenyl, or R' and RY are taken together with their intervening atoms to form a benzo ring or a 6-membered carbocyclo ring wherein said ring formed by RI and RY is optionally substituted with halo, CN, oxo, C1.-6 alkyl, C,-6 alkoxy, alkyl)carbQnyl, 207alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, o or 5-6 membered heteroaryl; eC Ring C is a phenyl or pyridinyl ring, optionally substituted by -R 5 wherein when Ring C and two Sadjacent substituents thereon form a bicyclic ring system, the bicyclic ring system is a naphthyl ring, and

R

1 is -halo, a C1- 4 aliphatic group optionally substituted with halogen, or -CN; or Ring D is an optionally 10 substituted ring selected from phenyl, pyridinyl, C piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, o 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- ND tetrahydroquinolinyl, isoquinolinyl, quinolinyl, or o naphthyl;

R

2 is hydrogen or a C-6 aliphatic group; and.

each R 5 is independently selected from -Cl, -CN, -CF3, -NH 2

-NH(C

1 4 aliphatic), -N(Ci 4 aliphatic) 2 -O(Cl-4 aliphatic), Ci-4 aliphatic, and

-CO

2 (CI-4 aliphatic), and when Ring G is Ring D,.Ring D is.

substituted by oxo or R 5 Representative compounds of formula IX are shown below in Table B.

Table 8.

CHs HN H HN HNH*-- H3C IN'X H IN' IX-1 IX-2 IX-3 -208-

OH

3 ;N A Q N r

K

3 C CR-

NI

IX-5

HNS

IX-4 Ix-6 HN4 IX- 7 IS-B IX- 9 KN4 IX- 10

CH

3

N.

HNZ HP CKd ij N

CF

3 15-14 CRs

HN

4

P

0"-NC ,-NCF3 IX-12

OH

3

HNI

c4@--N H IS-13 -209- IX-l1E IX-17IXl ix-is IX -19

OH

3 N CF 8

H

IX-22 H 30yCHa3

N

H

3

CN

OH

3 HN4 IX-20

OH

8 N A HN

LP

IX-23 Hft CHa HN 9t

H

3 C

NC

1130 N 41b IX-26 IX-21.

IX-24 tNC

I-

3 C N- IX -27 -2 IX- 28 OH3

;N

HN

IX- 31

OH

3

HAP

~N OCH34 IX-34

OH

3

HN

IX-37

CM

3

NA

HN

IX -40 MCtN

CI

IX-29 0H3 N A OH3 N A

HN

H

3

C

IX-35

OH

3

NA

H4dtI' IX

NAH

HNAJ

NCI

IX -33

OH

3

NA

HNA

IX-36

HNP

Nl IX- 39 0113

N

N.

IX -42 OH3

HN*

0 1 N OF3

N

3 IX-38

OH

3

NA

HN&

l NOH IX -41 -211- HNh'

N

4

HNAIPX

~N CF 3

N%

IX-46

HN

N CIS IX-49

HN?

Oc N CF 3

NGY

IX -44 HN 1- 0iN CF 3 IX-47

ON

*NT

HN

V-

NCF

8

OH

3 HN

PH

IX-53 HNI H CTN CF 3

NNS

OH

HN '4 N F IX-48

CH

3

HN

4

NCI

N:

IX-51.

OH

3

NA-

0-6

,I

IX-54 -212-

CH

3 t N Br Ix-

OH

3

NH

qItN CF 3 OCH

O,

IX-58

OH

3

NH

ItN IX- 61

NOCF

3

OH

3 t IX -64

CH

3

N-A

HN IX-67

H

3

INCF

3 IX- 56

OH

3 HNJd IX-59

OH

3

N

HN ClJJ

NI

NO

2 IX-62

OH

3

INA

N C IX-57

OH

3

HAPH

CF

3

NA

IX -63 00OF 3

OH

3 k- IX- 65

OH

3 HN4P IX-66

INCF

3 IX-69 IX- 68 -213- IX- 71

OH

3

QN

HNN

FC

IX-73

OH

3

HNA_,_OH

N

2 N

OH

3

HNJV

F

3

C

IX-74

OH

3 HNtNN

HC

AcNHCrF HNI H IX-72 OHs

HN

FaGb IX-75

OH

3

N-(

*H

3 0) 'N

MBSO

2 NH c 1 Ad IX-78 C H 3 HN4 H4 Hf.C N

F:

3 k IX-? 6 IX-77

OH

3 HN-t IX-79 IX -214-

OH

3

NN

IX -82

OH

3 HN rX N INX-as

OH

3 ~N CF 3

(N)

IX-83

OH

3 HN.-r NK, jhN C F, IX- 86

OK

3 IX-84

OH

3

N

4

H

INCF3

N

IX-87 IX-88

OH

3 0-40 HN H3

CF

IX -89

OH

3 HN

),NNH

NOF

3 IX- 92

INA

C Z.

IX-S

OH

3

H

3 I -yr 3

HNN

IX -93

OH

3 N -CF 3 N I IX-93

OH

3 .0KH 3 INH N-.

j* ~HN ,tN IX- 94 IX- -2 MeO2S.N#%QtNY

CI

IX-97

CH

3

INA

HNA

SCI

IX-100 IX-98 IX-99

OH

3

NA

HN JtN H CIF IX- 102 IX-101 IX- 103 05-13 HN; :4N IN

IN

IX-104

HNA&C

IX-.07 H3C CH 3 HN %P IX-105 HSCtCHS Z 3 HN LrIN IX-108 083

NA

IX-los -216-

CH

3

HNP

~N CF 3 IX-109 IX-112 HN4 ~N C(O)NH 2 IX-115

OH

3

N

4 HlNa

CH

3 Nc

HNAI

0

NCF

3

OH

3

N

4 IX-113

OH

3 N

H

HN 4 N:)N -CFS

OH

3

HN

'N

IX-114 N A

HNP

Me IX-117

OH

3

N

4

OH

3

NAH

Me IX-116 IX-19 IX- 12 0 -217-

OH

3 HN ,d NOMe IX-121

OH

3 IX-122

OH

3

NHA

H

3 C OH IX -123

OH

3 N A

HN&

NH

2 IX-126

OH

3

NAH

O~N C(O)NH 2 Nt IX-124

H

3

NA

HN'

IX -125 t*

HN

4 C N 80 2 N(Me) 2 IX- 128 IX-127 IX-129

OH

3

NA

IX- 13 0

OH

3

HN

IX-131.

N 1 t.

IX-134 IX-132 IX-133 IX -135 -218- IND 3 r1 HNJfl3N~P HN HANN i A HNN Cl C~tH r H (jH

OCH

3 IX-136 IX-137 IX-138 CHS C3

OH

3 Cl HNXNN HNXNN'. 4 HN K-kN Ht OOt G) &kNH t V.0

OH

3 \o 5 f IX-139 IX-140 NIX-141

OH

3

OH

3 HN HNAN HN 14N H NN H H

N

%CH

IX-142 IX-143 IX-144 O. CH3 NP ol s Xa14 IIX1 IX-145 IX-146 I X-147 -219- IX-148

H

Ni HNANNr IX-154

NP

Hx -iso

HNA"

atr--- IX-149 o ,-0H 3 HNf ON

_H

3 HN4 IX- 155 Ix-iso Nth H 3 HN Ao IX -156

NW

.0 IX- 159

CH

3 I CO 2

CH

3 No IX-158 MN rJJH IX-161 IX-160 IX- 162 -220-

OH

3 4-NH ci r -Zr :rX-1ss IX-163 IX-164

N~N

F

3 C IX-166 IX-167 IX-168

N-IP

HN

F

3 Co IX -169

OH

3

NA

HN NCJH3 IX -172

OH

3 HN

)_-NH

C-N N HN2, IX -170 C113 N A

HN

N'-J'

F SC IX-171

OH

3 H2N N

N

IX -174 IX-173 HNAX_4N HN P-d C'N Fa S'o IX-175 IX-176 IX -177 -221- IND In another embodiment, this invention provides O a composition comprising a compound of formula IX and a C- pharmaceutically acceptable carrier.

One aspect of this invention relates to a Smethod of inhibiting GSK-3 activity in a patient, comprising administering to the patient a therapeutically effective amount of a composition comprising a compound of formula Ix.

10 Another aspect relates to a method of treating C_ a disease that is alleviated by treatment with a GSK-3 Sinhibitor, said method comprising the step of IND administering to a patient in need of such a treatment a o therapeutically effective amount of a composition C 15 comprising a compound of formula IX.

Another aspect relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula IX. This method is especially useful for diabetic patients.

Another aspect relates to a method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition comprising a compound of formula IX. This method is especially useful in halting or slowing the progression of Alzheimer's disease.

Another aspect relates to a method of inhibiting the phosphorylation of A-catenin in a patient in need thereof, comprising administering to said patient a therapeutically effective amount of a composition -222comprising a compound of formula IX. This method is especially useful for treating schizophrenia.

o One aspect of this invention relates to a 0 method of inhibiting Aurora activity in a patient, comprising administering to the patient a therapeutically G effective amount of a composition comprising a compound of formula IX.

Another aspect relates to a method of treating a disease that is alleviated by treatment with an Aurora inhibitor, said method comprising the step of <c administering to a patient in need of such a treatment a o therapeutically effective amount of a composition V Cl k\ comprising a compound of formula IX. This method is Sespecially useful for treating cancer, such as colon, Cq 15 ovarian, and breast cancer.

Another method relates to inhibiting GSK-3 or Aurora activity in a biological sample, which method comprises contacting the biological sample with the GSK-3 or Aurora inhibitor of formula IX, or a pharmaceutical composition thereof, in an amount effective to inhibit GSK-3 or Aurora.

Each of the aforementioned compositions and methods directed to the inhibition of GSK-3 or Aurora, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IX, as described-above.

The compounds of this invention may be prepared as illustrated by the Synthetic Methods below, by the Synthetic Examples described herein and by general methods known to those skilled in the art.

General Synthetic Methods The general synthetic methods below provide a series of general reaction routes that were used to -223prepare compounds of this invention. Methods A-F below are particularly useful for preparing formula.II O compounds. In most cases, Ring C is drawn as a phenyl C ring bearing an ortho R I substituent. However, it will be apparent to one skilled in the art that compounds having Sother Ring C groups may be obtained in a similar manner.

Methods analogous to methods A-F are also useful for preparing other compounds of this invention. Methods F-I below are particulary useful for preparing compounds of \O 10 formula III or IV.

o Method A 0 -R R 2

R

2

(HO)

2 1

S

H H HN RY N'C PdRt

RX

N R 1 Ry N~ RYNS 2 g Method A is a general route for the preparation of compounds wherein ring C is an aryl or heteroaryl ring. Preparation of the starting dichloropyrimidine 1 may be achieved in a manner similar to that described in Chem. Pharm. Bull., 30, 9, 1982, 3121-3124; The chlorine in position 4 of intermediate 1 may be replaced by an aminopyrazole or aminoindazole to provide intermediate 2 _j in a manner similar to 'that described in J. Med. Chem., 38, 3547-3557 (1995). Ring C is then introduced using a boronic ester under palladium catalysis (see Tetrahedron, 48, 37, 1992, 8117-8126). This method is illustrated by the following procedure.

A suspension of 1H-quinazoline-2,4-dione (10.0 g, 61.7 mmol) in POC13 (60 mL, 644 mmol) and N,Ndimethylaniline (8mL, 63.1 mmol) is heated under reflux -224for 2 h. Excess POC13 is evaporated under vacuum, the residue is poured into ice, and the precipitate is

VO

o collected by filtration. The crude solid 2,4- C dichloroquinazoline product may be used without further S purification.

To a solution of 2,4-dichloro-quinazoline (3.3 g, 16.6 mmol) in anhydrous ethanol (150 mL) is added methyl-1H-pyrazol-3-yl amine (3.2 g, 32.9 mmol). The mixture is stirred at room temperature for 4 h, and the \C 10 resulting precipitate is collected by filtration, washed C< with ethanol, and dried under vacuum to afford (2-chloroo quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine.

Cl N To a solution of (2-chloro-quinazolin-4-yl)-(5methyl-1H-pyrazol-3-yl)-amine (50 mg, 0.19 mmol) in DMF (1.0 mL) is added the desired arylboronic acid (0.38 mmol), 2M.Na2C03 (0.96 mmol), and tri-t-butylphosphine (0.19 mmol). Under nitrogen, PdCla(dppf) (0.011 mmol) is added in one portion. The reaction mixture is then heated at 80°C for 5 to 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate is collected by filtration, washed with water, and purified by HPLC.

Method B R R 2 0 Cl N'IH Rt" NH R POC 1 3 N Hr H

N

N -RN N N- n 3 4 NH R 1 0 N _NH 2 0

NH

HN 5 6NH -225- CONH2 S0 R 1 o O R o 6 0

NH

2 (iii) 7 Methods B through F describe routes where the c 5 pyrazole ring system is introduced after Ring C and the pyrimidine ring portion are first constructed. -A versatile intermediate is the 4-chloropyrimidine 4, which Cl is readily obtained from pyrimidinone 3 as shown in O Method This reaction sequence is generally Cl \C 10 applicable for a variety of Ring C groups including Saliphatic, aryl, heteroaryl, or heterocyclyl. See J.

C Med. Chem., 38, 3547-3557 (1995).

For quinazoline ring systems (where R* and RY are taken together to form a benzo ring), the useful intermediate 6 may be obtained by condensing an anthranilic acid or its derivative with a benzamidine as shown in Method B(ii) or by condensing a benzoylchloride with an anthranilamide as shown in Method B(iii). Many substituted anthranilic acid, anthranilamide, benzamidine and benzoylchloride starting materials may be obtained by known methods. See Aust. J. Chem., 38, 467-474 and J.

Med. Chem., 38, 3547-3557 (1995). Method B(iii) is -illustrated by.the following procedure..

To a solution-oof anthranilamide (33 mmol) in THF and CH 2 C12 70 mL) is added the.desired benzoylchloride (33 mmol), and triethylamine (99 mmol) at room temperature. The mixture is stirred for about 14 hours.. The resulting precipitate is collected by filtration, washed with CH 2 C1 2 and water, and dried under vacuum. The crude 2-benzoylaminobenzamide may be used directly for the next step without further purification.

-226- To a solution of the above crude product (13 mmol) in ethanol (50 mL) is added NaOEt (26 mmol) at room

\O

o temperature. The mixture is heated under reflux for 48 0 to 96 h. The solvent is evaporated and the residue is neutralized using concentrated HC1 to pH 7. The product Sis then collected by filtration and dried under vacuum to provide 2-phenyl-3H-quinazolin-4-one that may be used C without further purification.

To a suspension of the above product (12 mmol) in POC1 3 (120 mmol) is added tri-n-propylamine (24 mmol).

C The mixture is heated under reflux for lh. After removal Sof the excess POC1 3 by evaporation, the residue is c0 dissolved in ethyl acetate, and washed with IN NaOH S(twice) and water (twice). The organic layer is dried C1 15 over.MgSO 4 the solvent is evaporated under vacuum, and the crude product is purified by flash chromatography (eluting with 10% of ethyl actetate in hexanes) to give 4-chloro-2-aryl quinazoline.

To a solution of 4-chloro-2-aryl quinazoline (0.16 mmol) in DMF (or THF, ethanol) (1 mL) is added the desired aminopyrazole or aminoindazole (0.32 mmol). The mixture is heated in DMF (or THP under reflux.) at 100 to 110OC for 16 h (or in ethanol at 130-1600C for 16 hours) and then poured into water (2 mL). The precipitate is collected by filtration and purified by HPLC.

Method C NH R

I

H2N RXN N 08 .9 R'

R

Y

N

8 .9 -227-' Method D(i) NNH R 1 oO C1 H2NAT 0" P013 C1 H2N Rx 2Et POCIrRx CO2Et 11 Cl Methods C and D(i) above employ P-ketoesters 8 and 10, respectively, as pyrimidinone precursors. The Cl substitution pattern of the R x and R Y groups on the

VO

Cl pyrimidinone ring will be reversed if a chlorocrotonate S11 (Synth. Comm, (1986), 997-1002), instead of the \Q corresponding P-ketoester 10, is condensed with the desired benzamidine. These methods are illustrated by C the following general procedure.

To a solution of a P-ketoester (5.2 mmol) and amidinium chloride (5.7 mmol) in ethanol (5 mL) is added sodium ethoxide (7.8 mmol). The mixture is heated under reflux for 7-14 hours. After evaporation the resulting residue is dissolved in water, acidified with concentrated HC1 to pH 6, and then filtered to obtain a solid product 2-aryl-3H-pyrimidin-4-one (yield 75-87%), which may be purified by flash column chromatography if needed. To this pyrimidinone (3.7 mmol) is added POC13 (4 mL) and n-Pr 3 N (1.4 mL). The mixture is heated under reflux for 1 hour. After evaporation of the excess POC1 3 the residue is dissolved in ethyl acetate, washed with IN NaOH solution (three times) and NaHC03 (once), and dried over MgSO 4 The solvent is removed under vacuum and the residue is purified by flash column chromatography eluting with 10% of ethyl acetate in hexanes to give 2aryl-4-chloro-pyrimidine as a pale yellow syrup. This crude product may be treated'with a 3-aminopyrazole or 3aminoindazole as described above.

-228- Method D(ii) SNH R H2N O POC, CI EtO CO Rx NH R1 nPrN N R 0 reflux C N 36 37 38 Fir R

R

2 H

HH

NO morphoilne, C H MeOH NR N R' reO 6 R' R' 38 o. W) 6o A 3 -CN N refix 4 Srefl r e fl ux O 39 C 5 Method D(ii) above shows a general route for the preparation of the present compounds, such as compound 40, wherein R Y is N(R 4 2 See II Farmaco, 52(1) 61-65 (1997). Displacement of the 6-chloro group is exemplified here using morpholine. This method is illustrated by the following procedure.

To a solution of 2-methylmalonic acid diethyl ester (5 mmol) and sodium ethoxide (15 mmol) is added the appropriate amidine salt (5 mmol) in ethanol (10 mL) and the reaction heated at reflux for 2-24 hours. The residue is dissolved in water and acidified with 2N HC1.

The resulting precipitate is filtered off and further purified by flash chromatography (yield 5-35%) to afford the pyrimidinedione 37. To 37 (1.6 mmol) is added POC13 (32 mmol) and tri-n-propylamine (6.4 mmol) and the reaction refluxed is for Ih. After evaporation of excess POC1 3 the residue is dissolved in ethyl acetate, basified with IN NaOH, -separated and the aqueous phase twice more extracted with ethyl acetate. The combined organics are dried (sodium sulfate) and evaporated. Purification by -229flash chromatography provides the dichloropyrimidine (38) as a yellow oil in 23% yield.

\O

o A solution of 38 (0.33 mmol) in methanol (5 mL) Sis treated with an amine, exemplified here using morpholine (0.64 mmol) and refluxed 1 hour. After Sevaporation of solvent, the residue is purified by flash chromatography to provide the mono-chloropyrimidine 39 as Cl a colorless oil in 75% yield.

The mono-chloropyrimidine, 39, (0.19 mmol) may

C

N 10 be treated with a 3-aminopyrazole or 3-aminoindazole Cl compound in a manner substantially similar those O described above in Methods A and.B.

0 R .NR 0, Method.E CR

R

N

R

R

1 O OH R N=C=O RY H H NH R

NH

4 OAc, RYN 12 AcOH, reflux 9 H) As shown.by Method E, an acyl isocyanate 12 may be condensed with an enamine to provide-pyrimidinone 9 Org. Chem (1993), 58, 414-418; J.Med.Chem., (1992), 35, 1515-1520; J.Org.Chem., 91967, 32, 313-214). This method is illustrated by the following general procedure.

The enamine is prepared according to W. White, et al, J. Org Chem. (1967), 32, 213-214. The acyl isocyanate is prepared according.to G Bradley,. et al, J.

Med. Chem. (1992), 35, 1515-1520. The coupling reaction then follows the procedure of S Kawamura, et al, J. Org.

Chem, (1993), 58, 414-418. To .the enamine (10 mmol) in tetrahydrofuran (30 mL) at OOC under nitrogen is added dropwise over 5 min a solution of acyl isocyanate .mmol) in tetrahydrofuran mL). After stirring for h, acetic acid (30 mL) is added, followed by ammonium -230acetate (50 mmol). The mixture is refluxed for 2 h with continuous removal of tetrahydrofuran. The reaction is 0 cooled to room temperature and is poured into water (100 C( mL). The precipitate is filtered, washed with water and ether and dried to provide the 2-aryl-3H-pyrimidin-4-one.

Method F NOH 7 R NH4H NH 2 Heat N NH 16 N NH 2 0) 2 13 14 15 RX

O

10 Method F shows a general route for the 0 Spreparation of the present compounds wherein R x and R Y are C N taken together to form a 5-8' membered partially unsaturated saturated or unsaturated ring having 1-3 heteroatoms. The condensation of a 2-amino-carboxylic acid, such as 2-amino-nicotinic acid 13, and an acid chloride 7 provides an oxazinone 14. Treatment of 14 with ammonium hydroxide will furnish the benzamide which-may be cyclized to a 2-(substituted)-pyrido[2,3d] [l,3pyrimidin-4-one 16. This method is illustrated by the following procedure.

2-(Trifluoromethyl)benzoyl chloride (4.2 ml, 29.2 mnol) is added dropwise to a,solution of 2- Saminonicotinic acid (2.04g, 14.76 mmol) in 20 ml of pyridine. The reaction mixture is heated-at 158 C for min then cooled to room temperature.- The reaction is poured into 200 ml of water and an oil forms which solidifies upon stirring. The solid is collected by vacuum filtration and washed with water and diethyl ether. The product is dried to give 2-(2trifluoromethyl-phenyl)-pyrido[2,3-d] [1,3]oxazin-4-one -231- (2.56 g, 60% yield) which may be used in the next step ID without further purification.

O 2-(2-Trifluoromethyl-phenyl)-pyrido [2,3- Cl d ][l,3]oxazin-4-one (2.51g) is stirred in 30% ammonium hydroxide (25 ml) at room temperature overnight. The Sresulting precipitate is filtered and rinsed with water and diethyl ether. The precipitate is dried under vacuum Cl at 50 C overnight to give 2-(2-trifluoromethylbenzoylamino)-nicotinamide (850 mg, 33% yield) O 10 2-(2-Trifluoromethyl-benzoylamino)-nicotinamide (800mg, 2.6mmol) is dissolved in 10ml of ethanol.

SPotassium etboxide (435mg, 5.2mmol) is added to the IN solution which is heated to reflux for 16 h. The 0 o reaction mixture is evaporated in vacuo to afford a gummy residue that is dissolved in water and acidified with sodium hydrogen sulfate to pH 7. The resulting precipitate is filtered and dried under vacuum at 50 C to give 2-(2-trifluoromethyl-phenyl)-3H-pyrido[2,3d]pyrimidin-4-one Method G Method G is analogous to Method B(i) above.

This method is illustrated by the following general procedure.

2-(3,4-Dichloro-phenyl)-3H-quinazolin-4-one (Ig, 3.43 mmol) is suspended in'phosphorus oxychloride (4 mL) and the reaction mixture was stirred at 110 0 C for 3 hours. The solvents are then evaporated and the residue is treated carefully with an ice cold aqueous saturated solution of NaHC0 3 The solid is collected by filtration and washed with ether to give 4-chloro-2-(3,5-dichlorophenyl)-quinazoline as a white solid (993 mg, 93%).

To 4-chloro-2-(3,5-dichloro-phenyl)-quinazoline (400mg, 1.29 mmol) in THF (30 mL) is added -232methyl pyrazole (396 mg, 2.58 mmol) and the reaction mixture is heated at 65°C overnight. The solvents are

NO

O then evaporated and the residue triturated with ethyl C acetate, filtered and washed with a minimum amount of ethanol.to give [2-(3,4-dichlorophenyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine as a white solid (311 mg e- mp 274°C; 1~ NMR (DMSO) 8 2.34 (3H, 6.69 (1H, 7.60 (1H, 7.84 (1H, 7.96 (2H, 8.39 (1H, dd), 8.60 (1H, 8.65 (1H, 10.51 (1H, 12.30 ci I\ 10 (1H, IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 (M+H) o The THF solvent used in the previous step may IO be replaced by other organic solvents such as ethanol, o N,N-dimethylformamide, or dioxane.

<c Method H R H(HO) 2 B

R

Y

WN N 17 18 ,z R 2 HN H (CH 3 3 Si1- H HN NH RIX Cu l RixI (ii) 17 .19 Method H shows routes in which a Ring D aryl group bearing a halogen (X is Br or I).may be converted to other formula III compounds.. Method H(i) shows a phenylboronic acid coupling to Ring D to provide compound -18 and Method H(ii) shows an acetylene coupling to provide compound 19. Substituent X in compound 17 may be -233bromine or iodine. These methods are illustrated by the following procedures.

I Method To a mixture of [2-(4-bromoo phenyl) -quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (196 mg, 0.51 mmol) and phenylboronic acid (75 mg, 0.62 mmol) in THF/water 4 mL) is added Na 2

CO

3 (219 mg, 2.06 mmol), triphenylphosphine (9mg,. 1/15 mol%) and Ci palladium acetate (1 mg, 1/135 mol%). The mixture is heated at 80 0 C overnight, the solvents are evaporated and Ci 10 the residue is purified by flash chromatography (gradient

NO

C' of CHa 2 C2/MeOH) to give (2-biphenyl-4-yl-quinazolin-4-yl)- S(5-methyl-2H-pyrazol-3-yl)-amine as a yellow solid (99 I mg, H NMR (DMSO) 5 2.37 (3H, 6.82 (IH, 7.39- S7.57 (4H, 7.73-7.87 (6H, 8.57 (2H, 8.67 (1H, 1 15 10.42 (1H, 12.27 (1H, MS 378.2 (M+H) Method H(ii). To a mixture of [2-(4-bromophenyl)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (114 mg, 0.3 mmol), and trimethylsilylacetylene (147 mg, mmol)in DMF (2 mL) is added CuI (1.1 mg, 1/50 mol%), Pd(PPh,) C1, (4.2 mg, 1/50 mol%) and triethylamine (121 mg, 0.36 mmol). The mixture is heated at 120 0 C overnight and the solvent is evaporated. The residue is triturated in ethyl acetate and the precipitate is collected by filtration.

To the above precipitate suspended in THF (3 mL) is added tetrabutylammonium fluoride (1M in THF, l.leq). The reaction mixture is stirred at room temperature for two hours and the solvent is evaporated.

The residue is purified by flash chromatography (gradient of CH 2 Cl 2 /MeOH) to give [2-(4-ethynylphenyl)-quinazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine as a white solid (68 mg, 'H NMR (DMSO) 8 2.34 (3H, 4.36 (1H, 6.74 (IH, 7.55 (1H, 7.65 (2H, 7.84 (2H, 8.47 -234- (2H, 8.65 (1H, 10.43 (1H, 12.24 (1H, MS 326.1 (M+H)

VO

Cq Method I R R 2 HN 4N RY N-Cl 2 H NQ I0 HN

N

Method I above shows a general route for the preparation of the present compounds wherein ring D.is a heteroaryl or heterocyclyl ring directly attached to the pyrimidine 2-position via a nitrogen atom. Displacement of the 2-chloro group, exemplified here using piperidine, may be carried out in a manner similar to that described in J. Med. Chem., 38, 2763-2773 (1995) and J. Chem. Soc., 1766-1771 (1948). This method is illustrated by the following procedure.

To a solution of (2-chloro-quinazolin-4-yl)- (1H-indazol-3-yl)-amine (1 equivalent, 0.1-0.2 mmol) in N, N-dimethylacetamide (1 ml) is added the desired amine (3 equivalents). The resulting mixture is maintained at 100OC for 6 h and then purified by reverse-phase HPLC.

Method J C1 R'y-

R

2 H2NXH 21 -235-

R

2

H

2 o H2N R J e r l H

H

SR R

H•

23 24 Method J above shows the preparation of compounds of formula V via the displacement of a chloro Cl group from an appropriately substituted pyridyl ring.

-C Method J(i) is a route for preparing compounds of formula O Va (see Indian J. Chem. Sect.B, 35, 8, 1996, 871-873).

IN Method J(ii) is a route for preparing compounds of 0 formula Vb (see Bioorg. Med. Chem.,6, 12, 1998, 2449- S2458). For convenience, the chloropyridines 21 and 23 are shown with a phenyl substituent corresponding to Ring D of formula V. It would be apparent to one skilled in the art that Method J is also useful for preparing compounds of formula V wherein Ring D is heteroaryl, heterocyclyl, carbocyclyl or other aryl rings. Method J is illustrated by the following procedures.

Method (5-Methyl-2H-pyrazol-3-yl)-(2phenyl-quinolin-4-yl)-amine. To 4-chloro-2phenylquinoline Het. Chem., 20, 1983, 121-128)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the mixture was heated at 200 0 C overnight with stirring. To the cooled mixture was added petroleum ether (20 mL) and the resulting crude precipitate was filtered and further washed with petroleum ether. The crude solid was purified by flash chromatography (SiO 2 gradient DCM-MeOH) to give the title compound as a white solid: mp 242-244oC; 1 H NMR (DMSO) 8 2.27(3H, 6.02(1H, 7.47(2H, 7.53- 7.40(2H, br 7.67(1H, 7.92(1H, 8.09(2H, d), -236- 8.48(2H, 9.20(1H, 12.17(1H, br IR (solid) .1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 O Method J(ii). (5-Methyl-2H-pyrazol-3-yl)-(3- C- phenyl-isoquinolin-l-yl)-amine. To l-chloro-3phenylisoquinoline Het. Chem., 20, 1983, 121- S128)(0.33g, 1.37 mmol) in dry DMF (5 mL) was added 3- (0.27g, 2.74 mmol) and potassium carbonate (0.57g, 4.13 mmol)and the mixture was heated under reflux for 6 hours. The mixture was cooled and the bulk of DMF was evaporated. The residue was extracted I twice with ethyl acetate and the combined organic layers o were washed with brine, dried (MgSO 4 filtered and IN concentrated. The crude was purified by flash Schromatography (SiO 2 gradient DCM-MeOH) to give the title compound as a colourless oil; 1H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (IH, 7.52(2H, 7.62(1H, m), 7.81(1H, 8.07(1H, 8.19(2H, 8.29(1H, 8.54 (1H, MS 301.2 Method K

R,

A R 2 Cl Cl C R RIN H N'N N N N N H 2N CINcI CIA N-Q 1RYN V I 26 27 Method K shows a route for the preparation of compounds of formula VI. A versatile starting material is 2,4,6-trichloro-[l,3,5]triazine 25 in which the chlorine substituents may'be sequentially displaced. The displacement of one of the chlorines by an aryl Grignard reagent or an aryl boronic acid is described in PCT patent application WO 01/25220 and Helv. Chim. Acta, 33, 1365 (1950). The displacement of one of the chlorines by a heteroaryl ring is described in WO 01/25220; J. Het.

-237- Chem., 11, 417 (1974); and Tetrahedron 31, 1879 (1975).

These reactions provide a 2,4-dichloro-(6substituted) [1,3,5]triazine 26 that is a useful intermediate for the preparation of compounds of formula VI. Alternatively, intermediate 26 may be obtained by constructing the triazine ring by known methods. See US patent 2,832,779; and US patent 2,691020 together with J.

Am. Chem. Soc. 60, 1656 (1938). In turn, one of the chlorines of 26 may be displaced as described above to IND 10 provide 2-chloro-(4,6-disubstituted)[1,3,5]triazine 27.

The treatment of 27 with an appropriate aminopyrazole provides the desired compound of formula VI.

ID

o Method L (N 15 urea 0 N NH N N 0 CI 28 29

R

2 R 2 Ha 2 N N HNr N N 31 Method L shows a route for preparing compounds of formula VII. For illustration purposes the trifluoromethylchalcone 28 is used as a starting material; however, it would be apparent to one skilled in the art that other rings may be used in place of the -238trifluoromethylphenyl and phenyl rings of compound 28.

NO Substituted chalcones may be prepared by known methods, O for example as described in the Indian J. Chemistry, 32B, 449 (1993). Condensation of a chalcone with urea provides the pyrimidinone 29, which may be treated with C POC1 3 to give the chloropyrimidine 30. See J. Chem. Eng.

Data, 30(4) 512 (1985) and Egypt. J. Chem., 37(3), 283 (1994). In an alternative approach to compound 30, one of the aryl rings attached to the pyrimidine is .10 introduced by displacement of of the 4-chloro group of C 2,4-dichloro-(6-aryl)-pyrimidine by an aryl boronic acid o using a palladium catalyst such as (Ph 3

P)

4 Pd in the \C presence of a base such as sodium carbonate as described 0 in Bioorg. Med. Lett., 1057 (1999). Displacement C 15 of the chlorine of compound 30 by an appropriate aminopyrazole provides compounds of this invention, such as 31. The last step of this method is illustrated by the following procedure.

[4-(4-Methylpiperidin-1-yl)-pyrimidin-2-yl]-(5methyl-2H-pyrazol-3-yl)-amine. To a solution of 2chloro-4-(4-methylpiperidin-l-yl)-pyrimidine (prepared using a procedure similar to the one reported in Eur. J.

Med. Chem., 26(7) 729(1991) (222 mg, 1.05 mmol) in BuOH mL)was added 3-amino-5-methyl-2H-pyrazole (305mg, 3.15 mmol) and the reaction mixture was then heated under reflux overnight. The solvent was evaporated and the residue dissolved in a mixture ethanol/water 4 mL).

Potassium carbonate (57mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water twice and rinsed with ether twice to give the title compound as a white solid (143mg, mp 193-195°C; IH NMR (DMSO) 8 0.91 (3H, 1.04 (2H, 1.67 (3H, m), 2.16 (3H, 2.83 (2H, 4.31 (2H, 6.19 (2H, m), -239- 7.87 (1H, 8.80 (1H, br 11.71 (1H, IR (solid) 1627, 1579, 1541, 1498, 1417, 1388, 1322, .1246; MS 273.3(M+H) Method M Ci R2 H2N VIIIa

CI

N

G

VIIIb Cl

N

N 0 VIIzc Cl N N 0 VIlId Method M provides routes for obtaining compounds of formula VIII. A general procedure for displacing the chlorine of a 4-chloro-6-substitutedpyridazine, 32, with an appropriately substituted -240pyrazole to provide vIIIa is described in J. Het. Chem., 1473 (1983). Analogous reactions may be carried out 0 as follows: with C 33, to provide VIIIb is described in J. Med. Chem., 41(3), 311 (1998); with 5-chloro-3-substituted- S[l,2,4]triazine, 34, to provide VIlc is described-in SHeterocycles, 26(12), 3259 (1987); and with 3-chloro- C 5-substituted-[1,2,4]triazine, 35, to provide VIIId is described in Pol. J. Chem., 57, 7, (1983); Indian J.

Chem. Sect. B, 26, 496 (1987); and Agric. Biol. Chem., C 54(12), 3367 (1990). An alternative procedure to Scompounds of formula VIIIc is described in Indian J.

C\ Chem. Sect. B, 29(5), 435 (1990).

Compounds of formula IX are prepared by methods Cl 15 substantially similar to those described above for the pyrazole-containing compounds of formula I. Methods A-J may be used to prepare the triazole-containing compounds of formula IX by replacing the amino-pyrazole compound with an amino-triazole compound. Such methods are specifically exemplified by Synthetic Examples 415-422 set forth below. The amino-triazole intermediate may be obtained by methods described in J. Org. Chem.-USSR, 27, 952-957 (1991).

Certain synthetic intermediates that are useful for preparing the protein kinase inhibitors of this invention are new. Accordingly, another aspect of this invention relates to a 3-aminoindazole compound of formula A:

H

N14 NH2

A

where R 10 is one to three substituents that are each independently selected from fluoro, bromo, C 1 6 haloalkyl, -241nitro, or 1-pyrrolyl. Examples of such compounds include the following: SH H F H F H FF F F .H

NH

2

NH

2

NH

2

NH

2 Al A2 A3 A4 F F H H H H FKB1 ,.NBr IN NH 2

NH

2 F NH 2

NH

2 2_ A5 A6 A7 AS SH

H

NH N NH 2 A9 Another aspect of this invention relates to a 4-chloropyrimidine compound of formula B: Cl N R

I

RY

N

B

wherein R x and R Y are as defined above; R 1 is selected from Cl, F, CF 3 CN, or NO 2 and is one to three substituents that are each independently selected from H, Cl, F, CF 3

NO

2 or CN; provided that R 1 and R s are not simultaneously Cl. Examples of compounds of formula B are shown below: Cl CI CI Me N CF3 Me N CI CFs Me N MeN Me B1 B2 B3 -242- MeftN

CI

Me N>-~y B4

NNF

N311bj

NCIF

N

F

B12 cI N a CFs CI

#YNC

N0 2 NCI3 B14 315 N IF 316 MeO 39

I-

B17 yjN CN 820

CI

C N

NF

)1 -243- Another aspect of this invention relates to compounds of formula C:

RZR

2

R

x

XN

C

wherein Rx, R y

R

2 and R 2 are as defined above.

of compounds of formula C are shown below: Examples Cl

HNHN

Ci HNJ4 H C4

F

H

HN

HN ^I C7

HN

(C^V^N

C2 H N

NH

CS

HN

CS

CH

3

HN

H

C3

HN

H

HaC NCI C6 HNC9 C9 -244-

IN

0 HN Jt N Ci

CIO

HNZ

C l C13

F

HN

cri C11 HNH r N N C14 N N N N .,C1 C12 Me

HNH

N N C1 ci 015 Yet another aspect of this invention relates to compounds of formula D:

O

RxNH CF3 RyN where Rs, R 1 and RY are as defined above. Examples of formula D compounds and other useful pyrimidinone intermediates are shown below: O0 HC NH CF 3

H

3 C N D1 0 NH CF 3 D4 0

H

3 C NH C1

H

3 C N D2

H

3

C

H

3 C N N 0 NH

CF

3

H

3

C

D3 -245- 0 0 0 o o o SCl NH C.F NNH NH CF 3 D7 D8 D9 0 0 0 N it NH CI NHNH Br NH Br CF0 D10 D11 D12 0 ir NH CI ilNH CF N NH Cl N F

NO

2 D13 D14 c<NH CF 8 NHCF3 NH CF 8 F

N

F

D16 D17 D18 W NH CFs 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.

-246-

VO

o SYNTHETIC EXAMPLES Cq 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.

ci C HPLC-Method A: Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones c Chromatography.

o Gradient: 100% water (containing 1% acetonitrile, C- 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 min. Flow rate: 0.8 mL/min.

HPLC-Method

B:

Column: C18, 5 um, 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 um, 4.6 X 150 mm "Microsorb" by Varian.

Gradient: 99% water TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water TEA), 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.

-247- HPLC-Method D: Va Column: Waters (YMC) ODS-AQ 2.0xSOmm, S5, 120A.

0 Gradient: 90% water Formic acid), acetonitrile (containing 0.1% Formic acid) to water 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.

C HPLC-Method E: Column: 50x2.0mm Hypersil C18 BDS;5 pm Gradient: elution 100% water TFA), to 5% water 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 [2-(2-Clorophenyl)-5,6-dimethylpyrimidin-4-yll- (5-Methyl-2H-pyrazol-3-yl)-amnine HNEMER (500 MHz, DMSO-d6) 810.4 br, 1H), 7.74 2H), 7.68 1), 7.60 11), 6.39 2.52 3H), 2.30 3H), 2.22 3 MS 314;1 Example 2 [2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-SHcycloheptapyrimidin-4-yl]-(1H-indazol-3-yl)-amine (11-2): Prepared in 30% yield. 1 HNMR (500MHz, DMSO-d6) 8 1.72 (m, 4H), 1.91 2H), 3.02 4H), 7.05 1H), 7.33 (t, IH), 7.39 1H), 7.47 1H), 7.55 3H), 7.59 (d, 1H), 10.4 1H), 13.11 (br. a, 1H); EI-MS 390.2 HPLC-Method A, Rt 2.99 min.

Example 3 (5-Fluoro-1-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido(3,4- -248dlpyrimidin-4-yl]-amine Compound II-18 (90 mg, 0.17 mmol) was treated with an equal weight of Pd/C Sin 4.4% formic acid in MeOH at room temperature for 14 h.

The mixture was filtered through celite, the filtrate was evaporated, and crude product was purified by HPLC to provide 18 mg of the desired product as pale yellow solid. 1 HNMR (500 MHz, DMSO-dS) 612.9 11), 9.51 (s, 11), 9.26 2H), 7.72 1H), 7.63 IH), 7.58 (t, IH), 7.49 2H), 7.21 (td, 7.15 (dd, 1H), 4.24 (s, 211), 3.56 2H), 2.95 2H) ppm. MS m/e= 429.22 HPLC-Method A, Rt 2.88 min.

ciExample 4 2 -chloro-phenyl)-6,7, 8,9-tetrahydro-SHcycloheptapyrimidin-4-yll-(7-fluoro-1H-indazol-3-yl)amine (Irl-4): Prepared in 52% yield to afford a white solid. 1%HNMR (0S0MHI4z, DMSO-d6) 6 1.72 4H), 1.92 Cm, 2H), 3.00 4H), 7.02(td, 1H), 7.20 (dd, 1H), 7.40 (m, 111), 7.42 11), 7.52 3H), 10.5 1H), 13.50 (br.

a, 1H); EI-MS 408.2 HPLC-Method A, Rt 3.00 min.

Example 5 [2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-SH.cycloheptapyrimidin-4-yl] (5-fluoro-1H-indazol-3-yl) amine Prepared in 51% yield. 'HNMR (500MHz, DMSOdE) 6 1.71 4H), 1.91 2H), 3.01 4H), 7.24 (td, 1H11), 7.41 2H), 7.54 4H), 10.5 IH), 13.1 (br.

s, 1i); EI-MS 408.2 HPLC-Method A, Re 3.05 min.

Exaple s6 [2-(2-Chloro-phenyl)-6,7,8,9-tetrahydro-5Rcycloheptapyrimidin-4 -yl 5 ,7-difluoro-15-indazol-3-yl)amine Prepared according to Method C in 72% yield. 1 HNMER (500MHz, DMSO-d6) 8 1.72 4H), 1.91 (m, 2H), 3.01 4H), 7.31 2H), 7.41 11), 7.54 (m, 3H), 10.5 1H), i3.6 (br. a, 1H); EI-MS 426.2 HPLC-Method A, Rt 3.21 min.

-249oN Example 7 (7-Fluoro-1E-indazol-3-yl)-£2-(2o trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4yl]-amine Prepared in 62% yield. 1EMR (500 MHz, DMSO-d6) 813.5 br, 10.1 br, 1H), 7.75 (m, 4H), 7.33 IH), 7.17 (dd, 1H), 7.00 (td, 1iR), 2.80 (m, 2H), 2.71 2H), 1.89 (br, 4H) ppm; LC-MS 428.44 Cg 426.43 HPLC-Method A, Rt 3.02 min.

Va Example 8 (5-Fluoro-1H-indazol-3-yl)-[2-(2trifluoramethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4yll-amine Prepared in 53% yield. 'HNMR (500 MHz, DMSO-d6) 513.1 10.2 br, 1iH), 7.75 4H), 7.50 (dd, 1H), 7.27 (dd, 1H), 7.21 (td, 1H), 2.80 (m, 2H), 2.72 2H), 1.88 4H) ppm; MS 428.43 426.43 HPLC-Method A, Rt 3.01 min.

Example 9 (5,7-Difluoro-1H-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4yll-amine Prepared in 37% yield. IHNMR (500 MHz, DMSO-d6) 813.7 1H), 10.2 br, 1H), 7.80 1H), 7.76 IH), 7.69 2H), 7.31 1H), 7.18 1H), 2.81 br, 2H), 2.72 br, 2H), 1.90 4H) ppm; MS 446.42 444.37 (M-H);-HPLC-Method A, Rt 3.09 min.

Example 10 (5-Trifluoromethyl-1H-indazol-3-yl) trifluoromethyl-phenyl)-5,6,7,8-tetrahydroquinazolin-4yl]-amine (11-10): Prepared by Method C in ethanol in 35% yield. :HNMR (500 MHz, DMSO-d6) 613.2 1H), 10.1 br, 1H), 8.01 1H), 7.76 1H), 7.66 4H), 7.57 1H), 2.79 2H), 2.73 2H), 1.89 4H) ppm. MS 478.45 476.42 HPLC- Method A, Rt 3.21 min.

-250- Va o Example 11 (5 1 7-difluoro-aH-daol3.y)..r2.( 2 0 trif luoromethyl -phenyi) 6, 7, 8, 9 Crcloheptapyrimidin-4-ylJ.amine (11-11): Prepared in yield. White solid. 'HINMR (500Hz, DMSO-d6) 6 1.72 (m, 4H), 1.91 2H), 3.01 4H), 7.15 (dd, III), 7.30 (td, 11), 7.66 2H), 7.72 11), 7.78 11), 10.2 (m, ci111), 13.5 (br. s, 1H); El-MS 460.2 HPLC-Metbod

A,

Rt 3.13 min.

IND gEcample 12 (6-Benzyl-2-(2-trifluoromethy phenyl)- 5,6,7,8-tetrahydro-pyrido4,3-dlpyrimidin-4 yl).( 5 ioro- iH- ndazol-3 -yl)-amine~ Prepared in 49% yield. 1 HNMR (500 MHz, DMSO-d) 812.8 11), 9.11 (s, 1H), 7.68 1H), 7.58 iH), 7.53 t, 1H), 7.44 Cm, 411), 7.37 2H), 7.29 114), 7.19 2H), 3.78 Cs, 2H), 3.61 Cs, 2H), 2.81 Cs, br, 4H) ppm; LC-MS (ES+) 519.24 HPLC-Method A, Rt 3.11 'in.

Examnple 13 (1H-Indazol-3-yl) (2-ttifluoromethylphenyl) 9 -tetrahydro- SH- cyc1ohePtapyrimidin- 4-ylI amine (11-13):_Prepared in 40% yield. 'HNMR (500MHz, DMSO-d) 6 1.70 Cm, 4H), 1.90. 2H), 3.00 Cm, 4H), 7.01 t, 11), 7.30 (td, 1H), 7.44 1H); 7.49 11), 7.68 3H), 7.77 11), 10.01 11), 12.83 111); EI- MS 424.2 HPLO-Method A, Rt 3.17 min.

Example 14 C 7 -Fluoro-IH-incazol-3.yl)-[2-(2trifluoromethyl-penyl)-6,7,8,9-tetrahydro-scrcloheptayrimidin-4-yl3-amin e (11-14): Prepared in 78% yield. 1 11NMR (500MHz, DMSO-d) 5 1.71 (in, 1.91 (m, 2H), 3.00 41), 6.98 (td, 11), 7.16 Cdd, 1H), 7.31 (d, IH), 7.68'(m, 3H), 7.77 Cd, II), 10.25. Cm, 13.40 Cbr. a, El-MS 442.2 HPLC-Method A, Rt 3'12 -251min.

Va 0 Example 15 (5-Fluoro-1H-indazol-3-yl)- trifluoromethyl-phenyl)-6,7,8,9-tetrahydro-SHcycloheptapyrimidin-4-yll-amine (II-15): Prepared in 63% yield. 1 HNMR (500MHz, DMSO-d6).b 1.71 4H), 1.91 (m, 2H), 3.00 4H), 7.20 (td, 1H), 7.25 (dd, 1H), 7.49 C- (dd, 1H), 7.69 (br. t, 2H), 7.74 1H), 7.79 1H), Va C- 10.35 1H), 13.00 (br. s, 1H); EI-MS 442.2 HPLC-Method A, Rt 3.21 min.

o Example 16 (5-Fluoro-lH-indazol-3-yl) -12-(2trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-pyrido (4,3d]pyrimidin-4-yl]-amine (11-16): A solution of compound 11-12 (45mg, 0.087 mmol) in methanol HCOOH) was treated with an equal weight of Pd/C at room temperature for 14 h. The mixture was filtered through celite, the filtrate evaporated, and the crude product was purified by preparative HPLC to provide 15 mg (41%) of the desired product as yellow solid.. 1 HNMR (500 MHz, DMSO-d6) 812.9 1H), 9.52 1H), 9.32 2H,.TFA- OH), 7.72 IH), 7.59 2H), 7.49 2H), 7.21 (m, 1H), 7.15 4.31 2H), 3.55 2H), 3.00 (m, 2H) ppm; LC-MS 429.20 HPLC-Method A, Rt 2.79 min.

Example 17 (1H-indazol-3-yl)-[2-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine (11-17): Prepared in 58% yield. 1 HNMR (500 MHz, DMSO-dG) 813.0 10.3 br, 1H), 7.74 4H), 7.51 1H), 7.47 1H), 7.32 1H), 7.03 1H), 2.82 2H), 2.73-(m, 2H), 1.90 4H) ppm; LC-MS 410.21 HPLC-Method A, Rt 2.99 min.

-252- Va Example 18 7 -enzYl-2-(2-trifluoromethyl-phayl)- 5,6,7,8-tetrahydro-pyrido4,,3-d]pyrimidin-4.-yy.).( fluoro-1H-indazol-3y1)-amine Prepared from compound E11 in 92% yield. 1 HNIR (500 MHz, DMSO-d6) 812.9. 1H), 10.5. br, 11), 9.58 11,TFA-OH), 7.71 Cd, 7.52 9H), 7.19 Cm, 2H), 4.57 2H), ci 4.20 21), 3.70 2H), 3.00 2K) ppm; LC-MS (ES+) Ci 519.23 HPLC-Method A, Rt 3.23 min.

IN Example 19 (lE-Indazol-3-yl)- [6-methyl-2-(2o trifluoromethyl-pheny) -pyrimidin-4-yl]-amine (11-19): Prepared in 42% yield. Melting point 235-237 0 C; 1

HNMR

(500 MHz, DMSO) 8 2.44 (3H, 7.09 (1K, J=7.5 Hz, t), 7.40 (1H, J=7.1 Hz, 7.49 (1K, J=8.3 Hz, 7.70 C3H, 7.79' (1K, J=7.3 Hz, 7.87 (11, J=8.3 Hz, 8.03 (1H, J=7.7 Hz, 10.3 (111, 12.6 (1K, s) ppm; HPLC- Method A, Rt 2.958 min; MS (FIA) 370.2 (M+H)t.

-Example 20 (lH-Indazol-3-yl)- [6-phenyl-2-.(2trifluoromethy phenyl) -pyrimidin-,4-yl -amine (11-20); Prepared in 32* yield. 'HNMR (5001 MHz, DMSC) 8 6.94 (1H, L=7.4 Hz, 7.24 (1K, J-7.4 Hz, 7.33 (1H, J=8.4 Hz, 7.42 (3H, 7.57 (1H, J=7.3 Hz, 7.68 m), 7.75 (1H, J=7.9 Hz, 7.93 (3H, 8.18 (11, br a), 10.45 (1H, br 12.5 (1H, br a) ppm; HPLC-Metbod A, Rt min; MS (FIA) "432.2 Example 21 (1H-Indazol-3-yl)-(6-(pyridin-4-yl)-2-(2trifluoromethyl-phenyl) -pyrimidin-4-ylJ -amine (11-21): Prepared in 12% yield. 'HNMR (500 14Hz, DMSO) 8 7.16 (1H, J=7.4 Hz,* 7.46 J=7.6 Hz, 7.56. (11, J=8.3 Hz, 7.80 (lB, J=7.2 Hz, 7.90 (21, 7.97 (11, J=7.8 -253- Hz, 8.09 (1H, br), 8.22 (2H, J=4.9 Hz, 8.45 (1H, Va o br 8.93 (2H, J=4..8 Hz, 10.9 (1H, br 12.8 (1H, 0g br a) ppm; HPLC-Method A, Rt 3.307 min; MS (FIA) 433.2 l ~Example 22 (1H-Indazol-3-yl).-[ 6-(pyridin-2-yl)-2-(2trifluoromethyl-phenyl)-pyrimidin-4-ylJ-amine (11-22): Cl Prepared in 42% yield. 1 HNMR (500 MHz, DMSO) 8 7.07 (1H, Va C J=7.4 Hz, 7.36 (1H, J=7.4 Hz, 7.46 (1H, J=7.4 Hz, o 10 7.53 (1H, J=5.0 Hz, 7.70 (1H, J=7.4 Hz, 7.79 ID (1H, J=7.1 Hz, 7.83 (IH, J=7.4 Hz, 7.88 (1H, o J=7.8 Hz, 7.97 (IH, J=7.7 Hz, 8.02 (1W, J=5.5 Hz, br 8.36 (12, J=7.8 Hz, 8.75 (2W, J=4.1 Hz, d), 10.5 (1H, br 12.7 (1H, br s) ppm; HPLC-Method A, Rt 3.677 min; MS (FIA) 433.2 Example 23 6-(2-Chlorophenyl)-2-(2-trifluoromethylphenyl)-pyrimidin-4-yl-(1E-indazol-3-yl)-amine (11-23): Prepared in 44% yield; 1 H&MR (500 MHz, DMSO) S 7.08 (12, J=7.5 Hz, 7.37 (12, J=7.5 Hz, 7.45 (11, J=8.4 Hz, 7.51 (2H, 7.61 (1H, J=7.4, 1.9 Hz, dd), 7.69 (2H, 7.79 (2H, J=4.0 Hz, 7.86 (SH, J=7.8 Hz, 8.04 (2H, J=6.2 Hz, br 10.7 (1H, br 12.6 (1H, br a) ppm; HPLC-Method A, Rt 3.552 min; MS (FIA) 466.2 Example 24 [5,6-Dimethyl-2-(2-trifluoromethyl-phenyl)pyrimidin-4-yl]-(H-indazol-3-yl)-amine (11-24): Prepared in 35% yield; mp 183-1860C; IHNMR (500 MHz, DMSO) 2.14 (3H, 2.27 (3H, 6.85 (1H, J=7.5 Hz, 7.15 (1H, J=7.6 Hz, 7.32 7.38 (1W, J=7.5 Hz, 7.42 (12, J=7.4 Hz, 7.53 (1H, J=7.6 Hz, 8.88 (1H, a), 12.5 (1H, a) ppm; HPLC-Method A, Rt 2.889-min.; MS (FIA) 384.2 -254- Va O Example 25 [5,6-Dimethyl-2- 2 -trifluoromethy.-phenyl) C- -pyrimidin-4-yl uorolH-indazol 3-yl) amine (11-25): Prepared in 44 yield. Melting point 160-1630C; HNMR S (500 MHz, DMSO) 8 2.27 (3H, 2.40 (3H, 7.16 (2H, C-i 7.44 (21, 7.,52 (iH, J=7.4 Hz, 7.57 (11, J=7.4 Hz, 7.67 J=7.8 Hz, 9.03 (IH, 12.75 (11!, a) ppm; HPLC-Metbod A, Rt 2.790 min; MS (FIA) 402.2 cIN (M+H)f INDExample 26 (2-(2-Chiorophenyl) -5,6-dimethyi-pyriatidin-4- Yl]-(1E-indazo1-3-yl)-anine (11-26): Prepared in yield. 1 HNMR (500 MHz, DMSO) 5 2.14 (3H, 2.33 (an, 6.84 (in, J=7.4 Hz, 7.13 (iB, J=7.4 Hz, 7.19 (11, J=6.9 Hz, br 7.27 (1R, J=7.4 Hz, 7.32 (3H, br 7.37 (1H, J=7.1 Hz, 10.0 (1H, br), 12.8 (in, br a) ppm; 5 2.919. in; MS (FIA) 350.1 Example 27 (5,6-Dimethyl-2-(2-trifluoromethyl-phenya)pyrimidin-4-yl (7-fluoro1.±ndazoa..yl)amine (11-27): Prepared in 92% yield. 'NMR (500 MHz, DMSO) 6 2.33 3H, 2.50 (3H, 6.97 (lE, 7.15 (lH, 7.30 (in, J=8.1 Hz, 7.76 (1H, J=7.5-Hz, d), 10.0 (11, 13.4 (an, s) ppm; HPLC-Metbod A, Et 3.053 min; MS (FIA) 402.2 Example 28 (5,7-Difluoro-1H-inazol-3-yl)-(5,6-Dimethyl- 2-(2-trifluoromethyl-phenyl)-pyrimidin-4-yl]-amine (11- 28): Prepared in 50% yield. ImNM (500 MHz, DMSO) S 2.42 (3M, 2.63 (3H, 7.22 (1H, J7.6 Hz, 7.38 (1H, J=9.3, 1.7 Hz, dt), 7.71 (1H, 7.75 (iB, J=7.0 Hz, d), 7.79 (1H, J=6.7 Hz, 7.86 (in, J=8.0 Hz, 10.0 (1H, -255- 13.2 (11, s) ppm; HPLC-Method A, Rt 3.111 min; MS D (FIA) 420.2 Example 29 E2-(2-Chlorophenyl) -5,6-dimethyl-pyrimidin-4.

yl]-(5, 7 -difuoro-1K-indazol-3-y1)-amine. (II-29): Prepared in 58% yield. HNM (500 MHz, DMSO) .8 2.47 (3H, 2.66 (3H1, 7.44 (2H, 7.53 (IH, 7.64 (3H, Ci in), 10.4 (1H, br), 13.8 br a) ppm; HPLC-Method A, Rt Va Ci 2.921 min; MS (FIA) 386.1 Example 30 [2-(2-Chorophenyl) -S,6-dimethyl-pyrimidin-4- 1) yl]-(7-fluoro-IH-±ndazol-3-yl).amine (11-30): Prepared in yield. 1 HNMR (500 MHz, DMSO) 8 2.35 (3H, 2.51 (3H, 7.03 (11, 5=7.8, 4.4 Hz, dt), 7.22 (iN, 7.33 (1H, J=7.4 Hz, 7.42 (1H, 9.19 (11, 13.3 (iH, s) ppm; HPLC-Method A, Rt 2.859 min; MS (FIAY 368.2 Example 31 (2-(2-Chiorophenyl) -5,E-diiethyl-pyriidin-4yl-(5-fluoro-iE-indazol-3-yl)-alnine (11-31): Prepared in 86% yield. 'HNMR (500 MHz, DMSO) 8 2.49 (3H, 2.68 (3H, 7.38 (11, J=9.0 Hz, 7.54 (2H, 7.67 (4H, 10.5 (11, br), 13.2 (1H, br s) ppm; HPLC-Method A, Rt 2.850 iin;.MS (FIA) 368.1 Example 32 [2-(2,4-Dichiorophenyl)-5,6-dimethylpyrimidin-4-yl]- (1H-indazol-3-yl) -anine (11-32): Prepared in 52% yield. 'HNMR (500 MHz, DMSO) 8 2.46 (3H, 2.64 (3H, 7.16 (1K, 5=7.5 Hz, 7.46 (IH, J=7.6 Hz, t), 7.61 (2H, 7.68 (2H, 5=8.2 Hz, 7.82 (1W, 10.2 (1W, br), 13.0 (1W, br a) ppm; EPLO-Method A, Rt 2.983 min; MS (FIA) 384.1 -256- Exammple 33 (S-Methyl-2H-pyrazol-3-yl)- E2- (2methyiphenyl) -quinazolin-4-yl] -amine (11-33): 1 HNMR (DMSO) 8 1.21 2.25 (3H, 6.53 (iH, 7.38 (4H, m), 7.62 (11, 7.73 (in, 7.81 (IH, 7.89 ClH, t), 8.70 (in, MS 316.3 Example 34 (2-(2 1 4-Difluorophenyl)-quinazolin-4-yl]-(5methy.2H-pyrazol-3.yl)-amine- (11-34): 'HNMR (500 MIz, DMSO-dE) 812.4 (br s, IH), 10.8 (br a, 111), 8.58 Cd, iH), 7.97 IH), 8.36 in), 7.85 11), 7.60 in), '6.62 Cs, in), 2.30 MS 338.07 (MiH).

Example 35 [2-(2,5-Dimethoxyphenyl)-quinazolin-4-ylJ Tethyi-2H-pyrazol--y1) -amine (11-35): 1 NMR (500 Mliz, DMSO-d) 812.5 (br a, IH), 8.68 (br, 1H), 7.92 Ct, J Hz, iN), 7.86 Cd, J Hz, in), 7.65 Ct, J Hz, 1H), 7.45 Cs, in), 7.14 2H), 6.51 Cs, 1H), 3.79 3H), 3.67 3H), 2.14 Cs, 3H); MS 362.2 Example 36 [2-(2-Chorophenyl) -quinazolin-4-yi] iethyl-2H-pyrazo1-3-yl)-amine (11-36): 'lNMR (500 MHz, DMSO-d6) 811.8 Cbr, 1H), 8.80 J= 8.3 Hz, 1H), 8.00 J 7.6 Hz, 11), 7.82 J 8.3 Hz, 1N), 7.78 (m, 2H), 7.67 Cd, J 7.8 Hz, iH), 7.61 Ct, J Hz, 1H), 7.55 Ct, J 7.4 Hz, 1H), 6.56 Cs, 1i), 2.18 3H); MS 336.1 (M+H) Example 37 (2-(2-Methoxyphenyl)-quinazolin-4-yl-5 methyl-2-pyrazol-3yl).amine (11-37): 'HMI (500 MHz, DMSO-d) 88.78 br, iH), 8.00 Ct, J 7.4 Hz, 111), 7.90 Cm, 2H), 7.74- Ct, J 7.5 Hz, 1H), 7,A63 Ct, J 7.3 Hz, 1H), 7.30 Cd,. J 8.4.Hz, In), 7.18 Ct, J 7.5 Hz, -257- 11), 6.58 br, 11), 3.90 3M), 2.21 3H); MS Va N 332.1 Example 38 [2-(2,6-Dimethylphenyl)-quinazolin-4-yll-( methyl-2H-pyrazol-3-yl)-amine (II-38): 'HNMR (500 MHz, DMSO-d6) 812.2 br, 2H), 8.88 J 7.7 Hz, 1), 8.05 J 7.7 Hz, 1H), 7.80 (mn, 2H), 7.37 J 7.6 Hz, 7.21 J 7.7 Hz, 2H), 6.36.(s, 1H), 2.16 (s, IN 3H), 2.15 6H); MS 330.1 Example 39 [2-(2-Acetylphenyl)-quinazolin-4-yll-(5methy-2-pyrazol-3-yl)-amine (11-39): 1 HNMR (500 MHz, DMSO-d6) 812.35 br, 1H), 8.93 J 8.4 Hz, 1H), 8.37 J 8.6 Hz, 8.20 J 7.6 Hz, H1), 8.11 J 8.0 Hz, 2H), 7.89 2H), 7.77 2H), 6.93 (s, 2.33 2.04 3H) MS 344.1 Example 40 [2-(2,3-Dimethyiphenyl)-quinazolin-4-yl]-(5methyl-2H-pyrazol-3-yl-amine (II-40): 'HNMR (500 MHz, DMSO-d6) 812.6 br, 1H), 12.1 br, 1H), 8.91 J 7.7 Hz, 1H), 8.14 J 7.2 Hz, 1H), 7.95 J 8.4 Hz, 1H), 7.89 J 7.7 Hz, 1H), 7.58 J 7.6 Hz, 1H), 7.53 J 7.0 Hz, 1iH), 7.42'(t, J 7.6 Hz, 1H), 6.60 1i), 2.43 3H1), 2.35 2.32 3H); MS 330.1 Example 41 (5-Methyl-2H-pyrazol-3-yl)- 2-(2trifluoromethylphenyl)-quinazolin-4-ylJ-amine (11-41); 1HNMR (500 MHz, DMSO-d6) 812.3 1H), 10.5 IH), 8.77 J 8.2 Hz, 1i), 7.92 2H), 7.85 3H), 7.56 J 8.1 Hz, 1H), 7.67 J 7.4 Hz, 1H), 6.63 1H), 2.27 3H); MS 370.1 -258- Va Example 42 (2-Ethyiphenyl) -quinazolin-4-ylJ- ri 2 H-pyrazol-3-yl)-amine (11-42): LHMM4 (500 MHz, DMSO-d6) 88.80 Cm, 1K), 8.02 1H),'7.82 J 8.4 Hz, iH), 7.77 Cm, 1K), 7.62 Cd, J =7.6 Hz, 1H), 7.54 (n ri 7..41 2H), 6.40 1H), 2.75 J 7.1 Hz, 2H), 2.17 Cs, 3H), 0.99 7.5 Hz, 3H); MS 330.1 Va ci Example 43 2 -Biphenyl-2-yl-quinazolin-4.yl)- IND 2H-pyrazol-3-yl)-amine (11-43): 'INMR (500 MHz, DMSO-d6) o 8.76 J 7.6 Hz, 1H) 8.04 7 .75 6H), 7.30 Cm, 5H), 5.34 1H), 2.14 Cs, 3H); MS 378.2 Example 44 (2-Hydroyphenyl) Methyi-2H-pyrazol-3-yl)-amine (11-44): 1 HNMI (Boo MHz, DMSO-d6i) 610.9 br, 1H), 8.62 J 8.2 Hz, 1H), 8.28 Cd, J 7.9 Hz, iH), 7.87 Cm, 2H), 7.60 J 7.9 Hz, 1H), 7.37 J 7.8 Hz, iH), 6.92 6.45 Cs, in), 2.27 (s,J3H); MS 318.1 Example 45 [2-(2-Ethoxypbenyl) Methy1-2-pyrazol-3-y) .mine (11-45): IHNMR (500 MHz, DMSO-dE) 8.12.1 br, 1H), 8.75 Cd, J 8.3 Hz, 1K), 7.97 J 7.8 Hz, iN), 7.82 8.3 Hz, IN), 7.78 J 7.5 Hz, IH), 7.70 Ct, J 7.8 Hz, 1H), 7.56 J 7.8 Hz, 1K), 7.22 Cd, J 8.4 Hz, 1K), 7.12 Ct, J 7.6 Hz,'lH), 6.55 Cs, 1H), 4.11 J 6.9 Hz, 2H), 2.16 Cs, 3H), 1.22 Ct, J 6.9 Hz, 3H); MS 346.1 CM+H).

Example 46 [5-(Thiophen-2-yl) -2H-pyrazol-3-y13- trifluoromethylphenyl) -quinazolin-4-ylJ-amine (11-46): 1HNR (500 MHz, DMSO-d) 68.04 J 8.3 Hz, 1K), 8. -259- (dd, J 7.3, 8.2 Hz, 1H), 7.93 J 6.5 Hz, 1H), 7.81 S(m, 5H), 7.34 J 5.0 Hz, 1H), 7.25 7.00 (m, 1K), 6.87 1H); MS 438.1 Example 47 [4-(Thiophen-2-yl)-2H-pyrazol-3-yll-[2-(2trifluoromethylphenyl)-quinazolin-4-yl] -amine (11-47): Prepared according to Method B. IHNMR (500MHz, DMSO-dG) 8 6.97 1H), 7.08 1H), 7.27 7.36 i), IND7.66 2H), 7.77 3H), 7.83 1K), 8.00 .lH), 8.18 1K), 8.62 J 8.2 Hz, 1H), 10.7 (br. s, 1H); EI-MS 438.1 HPLC-Method A, Rt 2.97 min.

Example 48 (4-Phenyl-2H-pyrazol-3-yl)-[2-(2trifluoromethylphenyl)-quinazolin-4-ylJ -amine (11-48): Prepared according to Method B. 1'UNMR (500MHz, DMSO-d6) 7.05 (br. a, 1H), 7.14 J 7.8 Hz, 1H), 7.25 3H), 7.43 2H), 7.60 2H), 7.73 2H), 7.80 1H), 7.95 1H), 8.12 (br. a, iH), 8.60 1H), 10.6 Cbr.

a, 1H); EI-MS 432.2 HPLC-Method A, Rt 3.04 min.

Example 49 (5-tert-Butyl-25-pyrazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-49): 'NNMR (500 MHz, DMSO-d6) 8 8.76 J= 8.3 Hz, 1H),..7.94 2H), 7.79 4H), 7.70 J 7.6 Hz, 1H), 6.51 (s, 1K), 1.16 9H); MS 412.2 Example 50 (5-Phenyl-2H-pyrazol-3-yl) trifluoromethylphenyl)-quinazolin-4-yl]-amine (11-50): 2HRMR (500MHz, DMSO-d6) 5 7.09 1K), 7.36 (td, J 7.8, 1.1 Hz, 1H), 7.46 J 7.8 Hz, 2H), 7.65 (br. d, J 8.1 Hz, 2H), 7.78 2H), 7.90 4H), 7.95 J 7.7 Hz, 1H), 8.00 J 7.8 Hz, 1H), 8.81 J 8.6 Hz, 1H), 11.29 (br. s, 1H); EI-MS 432.1 HPLC-Method A, Rt 3.24 min.

-260- Va Example 51 4 ,5-Diphenyl-2-pyrazol-3. C- trifluoromethylphenyl) -quinazolin-4-yl -amine (11-51): 1 t HNMR (500MHz, DMSO-dE) 7.13 in, 11), 7.IS 51), 7.36 5H), 7.62 3H), 7.73 Cm, 2H), 7.85 Cm, 1H), 8.48 C( Cd, J 8.7 Hz, 1H), 10.02 s, 1H1), 13.19 Cs, 1H); El-MS 508.2 HPLC-Method A, Rt 3.39 min.

ci Example 52 (4-Carbamoyl-2H-pyrazol3-yl) trifluoromethyiphenyl)-quinazolin-4-yl]-amine (11-S2): Prepared in 40% yield. 'HNMR (OOMHz, DMSO-d): 8 12.85 1H1), 12.77.Cs, 1H), 11.80 11), 10.80 1H), 8.35-7.42 9H); MS 399.13 CM+H) HPLC-Me~hod A, Rt 2.782 min.

Example 53 (20-Pyrazoi-3-yl)-[2-(2trifluoromeehylphenyl) -quinazolin-4-yl -amine (11-53): Prepared in 38% yield. 'HNMR (500 MHz, DMSO-d) 8 12.52 Cs, 1H), 10.65 1H), 8.75 iH), 7.91-7.68 Cm, 8H), 6.87 MS: CM+H) 356.17. HPLC-Method A, Rt 2.798 min.

Example 54 (5-Hydroxy-2-pyrazol-3-yl)--(2-(2trifluoromethylphenyl)-quinazolin-4-ylJ-amine (11-54): Prepared in 36% yield; 'HNMR (500 MHz, DMSO-d) 5 10.61 IH), 8.75 Cs, 1H), 8.03-7.75 91), 5.97 1H); MS 372.18 HPLC-Method A, Rt 2.766 min.

Example 55 (S-Cyclopropy1-2z-pyrazol-3-yl)- trifluoromethyl-phenyl) -quinazolin-4-yl -amine Prepared in 30% yield. 1 HNMR (500 MHz, DMSO-d) 812.21 in),'10.45 11), 8.68 1H), 7.89-7.45 8H), -2'61- 6.48 1H), 0.89 2H), 0.62 2H). MS 396.18 Va HPLC-Method A, Rt 3.069 min.

Example 56 (5-Methorymethyl-2-pyrazol-3-yl) trifluoromethyl-phenyl -quinazolin-4-yl]-amine (11-56): Prepared in 33% yield; 1HNMR (500 MHz, DMSO-d) 8 12.51 10.48 1H), 8.60 s(8, 1H), 7.81-7.55 7H), Ci 6.71 1H), 4.28 2H), 3.18 3H). MS 400.19 Va Ci HPLC-Method A, Rt 2.881 min.

o IN Example 57 (1iH-indazol-3-yl)-.[2-(2-trifluoromethylo phenyl)-quinazolin-4-yl]-amine (11-57): Prepared to afford 51 mg (78% yield) as pale yellow solid. 1 MR (500 MHz, DMSO-d6) 812.7 1H), 10.4 1H), 8.55 1H), 7.81 1H), 7.71 1H), 7.61 1H), 7.58 1H), 7.46 4H), 7.36 1H), 7.22 1H),-6.91 1H) ppm; LC-MS 406.16 404.19 HPLC- Method A, Rt 3.00 min.

Example 58 (4-Chloro-1EH-indazol-3-y1)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-58): Prepared in DMF (70% yield) as pale yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.3 br, XH),-10.9 br, 1H), 8.60 iN), 7.97 7.81.(Ad,,1H), 7.75 1H), 7.67 1H),'-7.63 (dd, 1i), 7.57 2H), 7.43 1H), 7.28 (dd, 1H), 7.08 1N) ppm; LC-MS 440.10 438.12 HPLC-Method A, Rt 3.08 min.

Example 59 (5-Fluoro-1E-indazol-3-yl)-[2-(2trifluoromethyl-phenyl) -quinazolin-4-yl -amine (11-59) Prepared in DMF (34% yield) as pale yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.0 1H), 10.6 1H), 8.72 (d, 1H), 7.99 1H), 7.89 1H), 7.79 1H), 7.75 (t, IH), 7.68 3H), 7.56 (dd, 1H), 7.39 1H), 7.28 (t, -262- 1H) ppm; LC-MS 424.12 m/e= 422.13 (M- Va o HPLC-Method A, Rt 3.05 min.

Example 60 (7-Fluoro-1H-indazol-3-yl) (2trifluoramethyl-phenyl) -quinazolin-4-yl] -amine (11-60): Cl Prepared in DMF (51% yield) as yellow solid. HNMR (500 MHz, DMSO-d6) 813.4 1H), 10.6 1H), 8.68 1H), 7.95 N1), 7.85 IH), 7.72 2H), 7.63 2H), C 7.58 1H), 7.43 1, 7.18 (dd, 1H), 7.00 1H) o 10 ppm; LC-MS 424.11 422.15 HPLC- ND Method A, Rt 3.06 min.

Example 61 (5-Methyl-1H-indazol-3-yl)-12-(2trifluoromethyl-phenyl)-quinazolin-4-yl] -amine (11-61): Prepared in DMF (81% yield) as yellow solid. 1HMR (500 MHz, DMSO-d6) 813.0 br, IH), 8.79 (br, IH), 8.11 (br, 1H), 7.96,(d, iH), 7.82 5H), 7.46 1H), 7.41 (d, 1H), 7.20 1i), 2.33 3H) ppm; MS 420.15 418.17 HPLC-Method A, Rt 3.07 min.

Example 62 [2-(2,6-Dichloro-phenyl)-quinazolin-4-yll]-(5fluoro-1H-indazol-3-yl)-amine 11-62): Prepared in DMF (37% yield) as yellow solid. 1 HNMR -(500 MHz, DMSO-dS) 513.0 IH), 10.8 11), 8.72 1H), 7.97 1H), 7.90 1H), 7.75 1H), 7.53 3H), 7.43 1H), 7.35 1H), 7.23 1H) ppm; LCMS 424.08 422.10 HPLC-Method A, Rt 3.06 min.

Example 63 [2-(2-Chloro-phenyl)-quinazolin-4-yl] (1Hindazol-3-yl)-amine (II-63): Prepared in 91% yield. HINMR (500MHz, DMSO-d6) 8 7.06 IH), 7.3.6 1H), 7.39 (t, 1H), 7.52 3H), 7.62 1H), 7.72 1H), 7.82 (m, 1i), 7.90 1H), 8.05 1H), 8.76 1H), 11.5 (m, 1i), 13.02. iN); EI-MS 372.1 HPLC-Method A, Rt.

-263- 2.93 min.

Va 0~ Example 64 (5-Trifluoromethyl-1H-indazol-3-yl)- trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (I1-64): Prepared in DMF (57% yield) as yellow solid. 'HNMR (o500 MHz, DMSO-d6) 813.4-(s, br, 11), 11.4 (br, 1H), 8.72 (d, IH), 8.12 1H), 7.98 1H), 7.83 1H), 7.76 (d, Ig 1i), 7.73 (dd, 1H), 7.60 4H), 7.52 ppm; LC-MS Cg 474.12 472.17 HPLC-Method A, Rt o 10 3.25 min.

ci Example 65 (4-Trifluoromethyl-1B-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine Prepared in DMF yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.7 br, 1W), 11.2 (br, 1H), 8.70 (d, IH), 8.05 1H), 7.85 3H), 7.65 4H), 7.51 (m, 2H) ppm; LC-MS 474.13 472.17 HPLC-Method A, Rt 3.15 min.

Example 66 [2-(2,6-Dichloro-phenyl)-quinazolin-4-yl]- (1Hindazol-3-yl)-anine (11-66): Prepared in -DMF (30% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 812.9 1H), 11.1 1H), 8.69 1H), 7.95 7.82 7.73 1H), 7.56 15), 7.47 7.45 H), 7.39 2H), 7.26 IH), 6.92 1H) ppm; LC-MS (ES+) 406.11 404.12 HPLC-Method A, Rt 3.00 min.

Example 67 (1H-indazol-3-yl)-[2-(2-methyl-phenyl)quinazolin-4-yll -amine (11-67): Prepared in 55% yield.

1 HNMR (500MHz, DMSO-d6) 8 2.15 3H), 7.09 1H), 7.26 IH), 7.31 1iN), 7.39 IH), 7.42 1H), 7.55 (d 15), 7.64 15), 7.74 1K), 7.89 1H), 7.96 -264- ND 1iH), 8.10 1H), 8.81 12.0 18), 13.18 o 1H); EI-MS 352.2 HPLC-Method A, Rt 2.93 min.

Example 68 (7-Trifluoramethyl-1E-indazol-3-yl) -12-(2trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11-68) C- Prepared in DMF (75% yield) as yellow solid. HNMR (500 MHz, DMSO-dG) 813.5 br, lN), 11.2 br, 1H), 8.68 1H), 7.97 1H), 7.92 1H), 7.82 1iH), 7.74 1iH), 7.70 IH), 7.68 1H), 7.64 2H), 7.57 11), 7.14 IH) ppm; LC-MS 474.11 472.14 HPLC-Method A, Rt 3.24 min.

Example.69 (6-Trifluoromethyl-1a-indazol-3-yl)-12-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine (II-69): Prepared by Method B in DMF (78$ yield) as yellow solid.

nNMR (500 MHz, DMSO-d) 8 13.4 br, 1H), 11.1 br, 1H), 8.67 1H), 7.95 1H), 7.82 3H), 7.72 (m, 2H), 7.63 2H), 7.57 1R), 7.23 1H) ppm; LC-MS 474.12 472.15 HPLC-Method A, Rt 3.28 min.

Example 70 (5-Nitro-1H-indazol-3-yl)'-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yl] -amine (11-70): Prepared in DMF (82% yield) as yellow solid. 'HNMR.(500.

MHz, DMSO-d6) 813.6 br, 1H), 11.4 br, 1H), 8.75 1H), 8.72 8.09 (dd, 1H), 7.98 iH), 7.83 1H), 7.75 1H), 7.70 2H), 7.61 3H) ppm; LC-MS 451.14 449.12 HPLC-Method A, Rt 3.02 min.

Example 71 (5,7-Difluoro-3s-indazol-3-yl)- 12-(2trifluoromethyl-phenyl)-quinazolin-4-yll-amine (11-71): Prepared in DMF (60% yield) as yellow solid. 'fNMR (500 MHz, DMSO-d6) 813.7 br, 1H), 11.2 br, IH), 8.73 -265- 1H), 8.03 1H), 7.88 1H), 7.80 2H), 7.70 Va oND 3H), 7.32 2H) ppm; LC-MS 442.14 (ES- 0) 440.14 HPLC-Method A, Rt 3.11 min.

Example 72 (4-Pyrrol-1-yl-1H-indazol-3-yl) trifluoramethyl-phenyl)-quinazolin-4-yll -amine (11-72): Prepared in DMF (33% yield) as yellow solid. 'HMR (500 Ci MHz, DMSO-d6) 613.4 br, 1H), 11.0 br, 1H), 8.53 Va Ci 1H), 7.98 1H), 7.75 4H), 7.62 2H), 7.52 o 10 1H), 7.43 1H), 7.05 1H), 6.80 2H), 5.61 2K) ppm; LC-MS 471.18 469.18 HPLC-Method A, Rt 3.12 min.

Example 73 (5-Amino-1H-indazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yi] -amine (11-73): A solution of compound II-70 (70 mg, 0.16 mmol) in MeOH (2 mL) was treated with Raney Ni until solution was colorless (about 1.5 g Raney Ni was added). After stirring at room temperature for-40 min, the mixture was filtered through celite, the resulting celite was washed with MeOH (5 times), and the solvent was evaporated in vacuo to provide a crude.product that was then purified by HPLC to give the title compound as.a yellow solid mg, m.p. 221-223C; 1 IHINR (500 MHz, DMSO-d6) 813.2 br, 12), 10.7 br, 1H), 9.80 (br, 2H), 8.68 11), 7.97 1H), 7.87 1H), 7.75 2H), 7.65 5H), 7.30 1H) ppm; MS 421.16 (ES-) 419.17 HPLC-Method A, Re 2.41 min.

Example 74 [2-(2-Chloro-phenyl)-quinazolin-4-ylJl-(7fluoro-1H-indazol-3-yl)-amine (11-74): Prepared in DMF yield) as yellow solid. 1 HNMR (500 MHz, DMSO-d6) 613.7 1H), 11.7 br, 1H) 8.80 1H), 8.15 (t, 1H), 7.99 IH), 7.88 1H), 7.68 1H), 7.60. (m, -266- 2H), 7.53 1H), 7.46 1H), 7.25 (dd, lH), 7.04 (m, 1H) ppm; LC-MS 390.16 HPLC-Method A, Rt 3.00 min.

Example 75[ (2-(2-Chloro-phenyl) fluoro-1H-indazol-3-yl)-amine (11-75): Prepared in DMF.

'1HNMR (500 MHz, DMSO-d) 813.2 1H), 11.7(s, br, 1W), IND 8.80 1H), 8.10 1H), 7.91 2H), 7.70 1i), 7.58, 4H), 7.50 1H), 7.29 1H) ppm; LC-MS (ES+) 390.17 HPLC-Method A, Rt 3.00 min.

Ci o Example 76 [2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5,7difluoro-1-'indazol-3-yl)-amine (11-76): Prepared in DMF yield) as yellow solid. IHNMR (500 MHz, DMSO-d6) 813.8 1H), 11.5 br, 1iH), 8.76 1H), 8.08 (t, 1H), 7.93 1W), 7.84 7.64 7.55 (d, IH), 7.50 1H), 7.44 2H),.7.36 1I) ppm; LC-MS 408.15 406.17 HPLC-Method A, Rt 3.08 min.

Example 77 [2-(2-Chloro-phenyl)-quinazolin-4-yl]-(5trifluoromethyl-1H-indazol-3-yl)-amine (11-77): Prepared in DMF (66% yield) as yellow solid.' MHNMR (500 MHz, DMSOd6) 613.5 1H), 11.4 br, 1H), 8.79 11), 8.29.

1H), 8.07 1H), 7.93 1H), 7.84 1W), 7.72 iH), 7.63 2H), 7.53 1H), 7.48 1H), 7.36 IH) ppm; LC-MS m/e= 440.16 m/e= 438.18 HPLC-Method A, Rt 3.22 min.

Example 78 -[2-(2-yano-phenyl)-q uinazolin-4-yll-(1Hindazol-3-yl)-amine (11-78): Prepared in 13% yield. NMR (500MHz, DMSO) 6 12.9 (br, 10.8 (br, 1H), 8.73 (br s, 1)Hj, 7.97 4H), 7.74 7.5 4H), 7.42 -267- 1W), 7.08 1H) ppm; MS (FIA) 363.2 HPLC- Va SMethod A, Rt 2.971 min.

Example 79 (5-Bromo-1H-indazol-3-yl)- trifluoromethyl-phenyl)-quinazolin-4-yl -anine (11-79): Prepared in DMF (64% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 613.4 1H), 11.6 br, 1H), 8.93 (d, Ci 1H), 8.21 1H), 8.14 1H), 8.05 7.95 (m, Va Ci 4H), 7.86 1H), 7.65 7.59 1H) ppm; MS o 10 486.10 484.09 HPLC-Method A, Rt ID 3.22 min.

Example 80 (6-Chloro-1R-indazol-3-yl)- trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-80): Prepared in DMF (94% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 613.1 IH), 11.2 br, 1H), 8.73 (d, 1H), 8.03 11), 7.87 7.79 2H), 7.73 (m, 2H), 7.67 2H), 7.58 IH), 7.04 (dd, 1H) ppm. LC-MS 440.14 438.16 HPLC-Method A, Rt 3.25 min.

II Example 81 7 -Fluoro-6-trifluoromethyl-1H-indazol-3-yl)- [2-(2-trifluoromethyl-phenyl)-quinazolin-4-yl]-amine

(II-

81): Prepared in DMF (30% yield) as yellow solid. 'HNMR (500 MHz, DMSO-d6) 813.9 IH), 11.0 br, 11), 8.64 1H), 7.94 1H), 7.81 1H), 7.71 2H), 7.60 4H), 7.20 (dd, IH) ppm. LC-MS 492.18 490.18 HPLC-Method A, Rt 3.44 min.

Example 82 (6-Bromo-1H-indazol-3-yl)-2-(2trifluoromethyl-penyl)-quinazolin-4-yl-amine (11-82): Prepared in DMF (40% yield) as yellow solid. 1 UHNMR (500 MHz, DMSO-d6) 613.1 IH), 11.2 br, 1H), 8.73 (d, 1H), 8.03 1W), 7.87 1H), 7.80 2H), 7.73 (m, -268- IND3H1), 7.67 (in, 1H1), 7.61 11) 7.15 (dd, 1H1) ppm; MS 486.07 (14+1) HPLC-Method A, Rt 3.28 min.

Examle 823 2 4 -Bie-trifluoromethy..pheny1) S qainazolin-4-yl (S,7-difluoro-Ef-indazo.3.y1) -amine Prepa red in DMF in .28% yield. 1 ffl?4R (50014Hz, MeOt{-d4) 8 8.81 Jrn8.4HZ, 1H1), 8.35-8.20 (mn, 3H1), ci 8.19-7.96 (mn, 3H1), 7.40-7.34 (in, 111), 7.29-7.14 (in, 1H);.

Ci LC-MS (ES+i) 510.14 HPLC-Method C, Rt 8.29 min.

o INDExample 84 (5,7-Diflnoro-13-ndazol-3.yly. (4-f luoro-2o trifluoromethyl-paenyl) -quinazolin-4-y1] -amine (11-84): Prepared in 48% yield. 'HNMR (50?Oflz,MeoH-d4) 68.74-.

8.63 8.23-8.10 (in, 1H1), 7.99-7.90 (mn, 211), 7.89iS 7.80 7.71-7.61 (i,flH), 7.61-7.50 (in,11), 7.24- 7.15 7.14-7.02 (mn, 111); LaO-MS 460.14 HPLC-Method C, IIt 7.59 min.

(2-Bromo-phentyl) -qninnzoiin-4-ylJ difluoro-1HZ-inaazo1-3..ylv..nine (11-85): Prepared in THF (21% yield) "HM (500MHz, MeOH-d4) 58.81 J=8.4Hz, 111), 8.35-8.20 (mn, 3H1), 8.19-7.96 (mn, 311), 7.40-7.34 (in, 114), 7.29-7.14 (mn, 1H); LaO-MS (ES+):510.14

HPLC-

Method C, Rt 8.29 min..

Example 86 (5,7-Diflnoro-a-ndazo.3.y).[2- (5-fluoro-2trifluoromethy1-phny1) -quinazolin-4-y1J.-amine (11-86).

Prepared in THF (26% yield).. lgHNMgR '(SO'Mz, MeOH-d4) 88.62 J=8.411z, 111), 8.16-8.02 (in, 1H1), 7.96-7.73 (in, 3H1), 7.59-7.48 (in, 1H1), 7.48-7.35 (mn, 111), 7.21-7.09 (in, 111), 7.09-6.89 (mn, 1H1); LaO-MS 460.16

HPLC-

Method C, Rt 7.28 min.

-269- Example 87 (2-(2,4-Dichioro-phenyl) -quinazolin-4-ylJ- Va N (5,7-Difluoro-1E-±ndazol-3-yl)-anine (11-87): Prepared in THF (16% yield). 'HNMR (500MHz, MeOH-d4) 58.81 (d, J=8.41z, 11), 8.35-8.20.(m, 3H), 8.19-7.96 3H), 7.40- 7.34 11), 7.29-7.14 1H); LC-MS 510.14 HPLC-Method C, Rt 8.29 min.

ri Example 88 (2-(2-Chloro-5-trifluoromethyl-phenyl) Va C-i qninazolin-4-yl (5 1 7-fifluoro-1Ef-indazol-3-yl) -amine Prepared inTHF (33% yield). 'LHNMR (5001Hz, IN DMSO-d) 5 10.76 IH), 8.66 Cd, J=8.3Hz,, 11), 8.06o 7.84 3H), 7.81-7.63 3H), 7.48-7.16 2H); LC-MS.

476.16 HPLC-Method C, Rt 19.28 min.

Example 89 (4-Flnoro-1H-indazol-3-yl)- trifluorcmethyl-phenyl)-quinazolin-4-yl-amine (11-89): Prepared in NNP (79% yield) as yeloi, solid. '2IMR (500 MHz, DMSO-d6) 513.2 1H), 10.8 br, 1H), 8.63 (d, 11), 7.97 Ct, 1H), 7.85 Cd, 1H), 7.74 2H), 7.64 (t, 11), 7.57 7.32 2H), 6.82 1H) ppm; LC-MS 424.17 UPLO-Method A, RL3.14 min.

Example 90 (1B-Indazol-3-yl)- [B-methoxy-2-(2trifluoromethyl-phenyl)-quinazolin-4-ylJ-amine (11-90):.

Prepared using THF as solvent to affbrd the title compound as a TWA salt (23% yield). HPLC-Method A, Rt 2.97 min 1 HNMP (DMSO-d, 500 MHz) 8 12.9. (1N, 1s), 11.0 10.7(11, be), 8.25 7.75-7.50 (81, 7.30 (1H, 6.90 (11, 4.0 (3H, MS (m/z)'436.2 Example 91 C5-Fluoro-1Hf-indazol-3-yl)-8-methosy-2- (2trifluoromethyl-phenyl)-quinazolin-4-ylJ-amine (11-91): Prepared using TFA as solyent to afford the title compound as a TWA salt (23% yield). HPLC-Method Rt -270- ND 3.10 min. 1 HWMR (DMSO-d6, 500 MHz): 13.0 (11, ba), 11.0 10.7(1H, be), 8.25 (1M, 7.75-7.50 i), 7.35 7.25 1, 4.0 (3H, MS 454.2 C Example 92 (7-Fluoro- 1-indazol-3yj) -E8-nmethoxy-2- (2tritluoromethyl -phenyl)-quinazolin-4-yl]-amine (N Prepared using TIF as solvent to afford the title

IN

(N compound as a TFA salt (98 mg, 58% yield). HPLC-Method A, Rt 3.20 min 'HNR (DMSO-dE, 500 MHz) 8 13.45 IN(1D11 be), 11.0 -10.7(11, bs), 8.25 (1H, 7.75-7.60 7.50 U1H, 7.40 (IH, m) 7.15 m),6.95 (1H, m)4.0 MS 454.2 Example 93 (5,7-Difluoro-IH-indazol-3yl) t8-methosy-2- (2-trifluoromethyl-phenyl)-quinazolin-4-ylJ-amine

(II-

93): Prepared using THF as solvent to afford the title compound as a TFA salt (36% yield). EPLO-Method A, Rt 3.27 mmi. 'HNM (DMSO-d6, 500 MHz): 13.65 (1H, be), 11.0 10.7(11, be), .8.22 (11, 7.75-7.60 (51, m), 7.40 (1H, 7.35 (1li, 7.19 (11, 4.0 (3H, MS 472.2 Example 94 (2-Chloro-pyridin-a-yl)-quinazolin-4-yl)- (S,7-fifluoro-1f-indazol-3-yl)-amine (11-94): Prepared in DMF. 1 HflMR (500MHz, DMSO-d6) 8 13.62 (br s, 11, 11.06- 10.71 1H), 8.16-7.70 4H), 7.60-7.09

LC-

MS 409.14 HPLC-Method A, Rt 2.89 min.

Example 95 (2-Chloro-4-nitto-phenyl) -quinazolin-4-yl]- 5 7-difluoro-1H-indazol-3-yl)-amine (11-95): Prepared in THF. 1 HNMR (500MHz, DMSO-d6y6 13.35 1H), 10.74 (s, 1H), 8.67'(d, J=8.4Hz, 1H) 8.29 .=2.05Hz, 1H), 8.18- -271- 8.08 1H), 8.07-7.60 4H), 7.53-7.10 2H). LC- Va S MS 453.15 HPLC-Method D, Rt 3.63 min.

Example 96 (4-Amino-2-chloro-phenyl)-quinazolin-4-yl] (5,7-Difluoro-lH-indazol-3-yl)-amine (11-96): A solution of compound 11-95 (8mg, 0.018mmol) and tin chloride dihydrate (22mg, 0.lmmol) in ethanol (2mL) was C- heated at 1000C for 24h. The reaction was diluted with Va C- EtOAc (10mL), washed with IN NaOH solution (2x10mL), o 10 brine, and dried over anhydrous sodium sulfate to afford the crude product. Purification was achieved by flash chromatography on silica gel (eluting with 1-3% MeOH in

CH

2 C1 2 The title compound was isolated as pale yellow solid (1.2mg, 16% yield). LC-MS 423.12 .HPLC-Method C, Rt 13.78 min.

Example 97 (4,5,6,7-Tetrahydro-1H-indazol-3-yl) -12-(2-trifluoromnethyl-phenyl)-quinazolin-4-yll-amine (11-97): Prepared in 34% yield. 1'HNMR (500MHz, DMSO-d6) 8 1.58 2H), 1.66 2H), 2.24 2H), 2.54 (m 2H), 7.63 3H), 7.71 1H), 7.75 1H), 7.78 1H), 7.85 1H), 8.53.(d, 1H), 9.99 1H), 12.09 1H); EI-MS 410.2 HPLC-Method A, Rt 3.05 min.

Example 98 (1H-Pyrazolof4,3-bjpyridin-3-yl)-[2-(2trifluoromethyl-phenyl)-quinazolin-4-yl]-amine (11-98): Prepared in DMF (37% yield) as yellow solid. 'NMR (500 MHz, DMSO-d6) 613.1 br, 1H), 11.2 br, 1H), 8.73 11), 8.54 (dd, lH), 8.12 1H), 8.06 13), 7.90 1H), 7.84 11), 7.75 1H), 7.69 2H), 7.65 1H), 7.47 (dd, 11) ppm; LC-MS 407.18 HPLC-Method A, Rt 2.77 min.

-272- INDExample 99 (lH-Pyrazolo[3,4-blpyridt.3-yl) trifluoromethyl-pheny.) -qninazolin-4'-ylJ -amine (11-99): Prepared in DMF (45% yield). 'HIM (500 Mliz, DMS0-dc) 8 13. 5 br, 13) 11. 3. br, Ifl, 8.78 Cd, 13), 8.49 13), 8.17 13), 8.03 Ct, 13), 7.89 Cd, 13), 7.80 Cm, 2H), 7.74 23), 7.68 111), 7.08 Cdd, 13) ppm.

MS 407.16 405.16 HPLC-Method

A,

ci Itt 2.80 min.

Example 100 (E-MetbYl-1H-pyrazolo[3,4bpyrdn3.y1) IND(2-trifluoromethyl-phenyl) -quinazolin-4-yl] -amine (11o100): Prepared in DMF (11* yield). 1 3Hfi '(50.0 MHz, dG) 613.2 br, 10. 8 br, 13) 8. 57 13) 7..95 Ct, 1H), 7.82 1N), 7.72 Ct,'13), 7.65 22), 7.58 Cm, 2H), 2.44 3H, buried by DM50), 2.20 Cs, 3H) ppm. LC-MS 435.22 CES-)'433.25

HPLC-

Method A, Rt 2.94 min.

Example 101 (S-Oxo-5-phenyI-5,6-dihydro-.JM.pyrazolo[4,3-.

cjpyridazin-3-yl) (2-trifluoromethyl-phenyl) qulinazolin-4-ylJ-anine 11-101: Prepared in DMF C6% yield). aHNMR (500 MHz, DMSO-dE) 512.6 Cs, 12), 11. 0 Cs, br, 13), 8.60 13), 7.95 Ct, 1H);,7.88 1H), 7.80 13), 7.68 Cm, 4H), 7.40 Cs, 3H), 7.22 2H), 6.61 1H) ppm. LC-.MS 500.21 498.16 CM- II); HPLC-Method A, Rt 3.00 tnin.

Example 103 [6-Methyl-2- 2 -trifluorcimethoxcy-jphenyl) pyrimidin-4-yl (5-phenyl-2n-pyrazoa-'3-yl) -amine (11- 1.03) MS 412.13 IPLC-Metbod E Itt 1.248 min.

Example 104 (S-Furan-2-yl-2f-pyrazol.3yl) -[6-methyl-2trifluoromethoxy-phenyi) -pyrimidin-4-yl.]-amine (11- 104) MS 402.1:2 HPLC-Method E, Rt 1. 188 mini.

-2 73oxml 105j (6 -Ethyl 2- 2 -trif luorome'thosy-phenyl.)- 0 ~pyrimidin-4-yl (5-msthyl-2H-pyrazol.3.yl) -amine (II:- 105) MS 364.14 HPLC-Method E, Rt 1. 112 min.

Example 106 (2-Chloro-phenyl) -pyrido(2,3-.dpyrimidin.

4 -YlJ-(5-methy1-2H-pyrazo1-3-ya)-amine (11-106):

'HNMR

ci (500 NHz, DM50) 612.23 1H1), 10.78 111), 7.73-7.47 ci 7H1), 6.72 2.21 (as, 3H1). MS: (14+1) 337.02.

HPLC-Method A, Rt 2.783 min.

oExample 107 (-looI-nal3y)[2(2trifluoromethyl-phe'nyl) -6,7 cyclopentapyrimidn.4..yl]..amine (11-107): Prepared in 68% yield. 1 }NMp (500MHz, DMSO-ds)V62.16 2H1), 2.88 (in, 2H1), 2.98 7.21 (td, 1H), 7.29 (dd, 111), 7.50 (dd, 1I1), 7.65 111), 7.67 1I1), 7.73 111), 7.79 1H1), 10.22 (br. s, iH), 12.99 (br. a, 1H1); El-MS 414.2 HPLC-Method A, Rt 2.92 min.

Example 108 (lH-Indlazol-3-y1)- t2- (2-trifluoromethyl- Pheny1)-pyrido[2,3..dlpyrimidin-4-y1] -amiine (11-108): HPLC-Method A, Rt 2.78 min. 'HNNR (DMS0-dG, 500 MHz):132.9S (1IN, be), 11:45 611.15(11, be), 9.20 (2H1, mn), 7.85-7.70 (2H1, in), 7.70-7.55 (41, in), 7.50 (1IN; mn), 7.35 (111, mn), 7.05 (1H1, in); MS (mhz) 407.03 (14+1).

Example 109 5 ,7-Difluoro-1H-inazol.3yl) trifluoroinethyl-phenyl) -pyrido (2,3 -dl pyrimidin-4-ylJ amine (11-109): Yellow, d±-TFA salt (25% yield). HPLC (Method A) 3. 10 min. 'HNMR, (DMSO-dE, 500 MHz) 13.8,-13.6 (111, be), 11.4 11.2(111, be), 9.15 (2H1, m), 7.85-7.75 (2H1, 7.75-7.62 (3H1, mn), .7.32 (2H1, in); MS (in/z) 442.98 -274- Va Example 110 [2-(2-Chloro-phenyl) -pyrido2,3-dlpyrimidin- 4-yl3- (l-indazol-3-yI -amine (II-110) Prepared from 2aminonicotinic acid and.2-chlorobenzoyl chloride afforded the title compound as a di-TFA salt (28%-yield). HPLC- C- Method A, Rt 2.85 min. '-HNMR (DMSO-d, 500 MHz) 12.90 (1H, 11.10 10.90 (1H, bs), 9.05 (21, i), 7.75-7.60 (21, 7.51 (1H, 7.45-7.25 (51, 6.95 cl (1H1, MS (m/z).372.99(M+H)..

IND Example 111 (5-Fluoro-1H-indazol-3-yx)-[2-(2trifluoromethyl-phenyl) 8,9,10-hesahydrocycloc tapyrimidin-4Tyl -amne (11-111). Prepared in 43% yield. 'HNNR (500MHz, DMSO-dE) 5 1.46 2H), 1.53 (m, 21), 1.77 4H), 2.95 2H), 3.04 Cm, 2H), 7.22 (m, 2H), 7.50 (dd, 11), 7.72 31), 7.80 11), 10.5 (m, IH), 13.05 (br s, 11); EI-MS-456.2 HPLC-Method C, Rt 11.93 min.

Example 112 [2-(2-Chioro-phenyl) -6-,7-dihydro-5Hcyclopentapyrimidin-4-yl] 5-fluoro-H-indazol-3-yl) amine (11-112): Prepared in 67% yield. 1 1-NMR (500MHz,.

DMSO-dE) 82.18 2H), 2.89 21), 3.02 2H), 7.24 (td, 111), 7.42 2H), 7.49 (td, 1H), 7.52 Cdd, 1H), 7.54 11), 7.57 Cdd, 11), 10.50 (br. s, 11), 13.06 Cbr. s, 1H); El-MS 380.1 EPLO-Method C, Rt 9.68 min.

Example 113 (1H-Indazol-3-yl)-[2-(2-trifluoromethylphenyl)-6,7 -dihydro-5H-cycopentapyrimdin.4-yl]-amine (11-113): Prepared in 37% yield. '1*NMR (500MHz, DMSO-d) 62.65 21), 2.85 21), 2.99 Ct, 2H), 7.02 1H), 7.32 1H), 7.47 Cd, 1H), 7.55 1H), 7.68 11), -275- 7.74 Ct, 1H), 7.80 11), 10.37 (br. a, 11), 12.91 (br.

Va o 1H); El-MS 396.1 HPLC-Metbod B, Rt 9.88 min.

Examiple 114 (7-Fluoro-1H-indazol-3-yl)-[2-(2trifluoromethyl-phenyl) 7-dihydro cyclopentapyrimidin-4-yl) -amine (11-114): Prepared in yield. 1 'HNMR (SOOMHz, DMSO-d) 8 2.15 2H), 2.87 Cm, (N 2H), 2.97 2H), 6.99 (td, 111), 7.17 (dd, 11), 7.38 (d, Va Ci 11), 7.65 Cm, 2H), 7.71 11), 7.78 1H), 10.21 Cbr.

a, 11), 13.40 (br. s, IH); El-MS 414.1 HPLC-Nethod C, Rt 9.99 min. Example 115 (5,7-Difluoro-1E-indazol-3-yl)-(2-(2trifluoromethyl-phenyl)-6,7-dihydro-SHcyclopentapyrimidin-4-yl]-amine (11-115): Prepared according to Method C in 52% yield. 1HNMR (500MHz, DMSOdE) 8 2.16 211), 2.89 Cm, 2H), 2.97 Ct, 2H), 7.19 (dd, 1H), 7.29 (td, 11), 7.63 IH), 7.66 11), 7.71 Ct, 1H), 7.78 Cd, 1H), 10.16 Cbr. s, 1H), 13.55 Cbr. s, 1H).; El-MS 432.1 HPLC-Nethod C, Rt 10;09 min.

Example 116 [2-(2-Chloro-phenyl)-6,7-dihydro-5Hcyclopentapyrimidin-4-ylJ -(1H-indazol-3-yl) -amine (II- 116): Prepared in 56% yield. 'HNMR (500MHz, DMSO-d6) 8 2.16 2H), 2.85 Cm, 2H), 3.01 2H), 7.06 1H), 7.34 Ct, 11), 7.40 Ct, 1H), 7.48 Cm, 2H), 7.53 1H), 7.56 11), 7.63 1H), 10.39 Cbr. 1H), 12.91 (s, 11); EI-MS 362.1 (MiH); kPLC-Method A, Rt 3.09 rin.

Example 117 (2-Clloro-phenyl) cyclopentapyrmidin-4-yl-(7-f luoro-1H-indazol-3-yl)amine (11-117): Prepared in 63% yield. 1 HNIR (500MHz, DMso-dC) 82.15 Cm, 2-1U 2.87 Cm, 2H), 3.00 2H), 7.01 Ctd,mlH), 7.19 Cdd, 1M), 7.39 C(t, 1H), 7.45 2H), 7.51 -276- 1H), 7.55 10.35 Cbr. a, 11), 13.45 (br. a, Va o El-MS 380.1 HPLC-Method A, Rt Rt 3.15 min.

Example 118 [2-(2-Chloro-phenyl)-6,7-dihydro-53cyclopentapyrimidin-4-yl -(5,7-difluoro--1-indaw1-3-yl)amine (11-118): Prepared in 60% yield. '-HNMR (500MHZ, DMSO-dE) 52.18 2H), 2.91 21), 3.01 Ct, 2H), 7.32 Ci 11), 7.33 (td, 1H), 7.41 Ct, IH), 7.48 1K), 7.53 Va Ci 1H), 7.55 (ad, 1H), 10.35 (br. a, 1M), 13.45 (br. s, 1H); El-MS 398.1 EPLO-Method A, Rt Rt 3.24 min.

Example 119 (1E-Indazol-3-yl)-[2-(2-trifluoromethylphenyl)-5,6,7,8,9,l0-hexahydro-cyclooctaprimian-4.y13amine (11-119): Prepared in 36% yield. '1NMR (500MHz, DMSO-d) 8 1.47 2H), 1.53 211), 1.78 411), 2.96 Cm, 21i), 3.06 2H), 7.03 t, 11), 7.47 11), 7.72 7.73 1H), 7.72 31), 7.81 IH), 10.52 1H), 12.97 Cbr. s, 11); El-MS 438.2 HPLC- Method A, Ri, 3.37 min.

Example 120 (7-Fluoro-1H-indazol-3-yl) trifluoromethyl-phenyl)-5,6,7,8,9,10-hexahydrocyclooctapyrimidn-4-yll-amine (11-120): Prepared in yield. 'HNMR (500MHz, DMSO-d) 8 1.46 21), 1.52 (m, 2H), 1.77 4H), 2.94 Cm, 21), 3.04 Cm, 2H), 7.00 (td, 11), 7.17 (dd, 11), 7.30 Cd, 11), 7.70 31), 7.79 (d; 11), 10.5 1K), 13.49 Cbr s, El-MS 456.1 HPLC-Method A, Rt 3.43-min.

Example 121 (5,7-Difluoro-1H-indazol-3-yx)- C2trifluoromethyl-phenyl)-5,6,7,8,9,10-hesahydro- Cyclooctapyrimidin-4-yl]-amine (11-121): Prepared in 48t yield. 1 11NMR (5001Hz, DMSO-AG) 5 1.46 (ni, 2H), 1.52 (m, 2H), 1.77 41), 2.95 Cm, 214), 3.03 21), 7.14 (d, -277- 1H), 7.30 11), 7.73 3H), 7.80 1H1), 10.5 Cm, 1H) 13.62 (br. s, 1H); El-MS 475.1 kPLc-Method A, 0 Rt 3.52 min.

Example 122 [6-Cyclohexyl-2- (2-trifluoromethyl-phenyl)pyrimidin-4-ylJ- (1H-indazol-3-yl)-amine (11-122): Prepared in 45% yield. 1HNMR (500 MHz, CDC13) 8 1.30 (21, C-I im), 1.46 (2H, 1.65 (2H, 1.76 (2H, 1.91 (2H,

IN

C- 2.61 (1H, br 7.08 t, J=7.4 Hz), 7.27 (1H, d, J=n8.0 Hz), 7.35 t, J= 7.1 Hz), 7.50 (11, t, INDHz), 7.58 (1H, t, J=7.4 Hz), 7.66 (3H, 7.72 (1H, d, o J7.8 Hz), 8.0 (11, br), 9.87 (11, br) ppm; EPLO-Method D, Rt 3.57 min; LC-MS 438.17 (M+H) 4 Example 123 [6-(2-Fluoro-phenyl) -2-(2-trifluoromethylphenyl)-pyrimidin-4-yll-(IH-indazol-3-yl)-amine (11-123): Prepared in 8% yield. 'HNNR (500 MHz, CDC1 3 8 7.18 (3H, 7.37 (11, 7.43 (1R, t, J=7.9 Hz), 7.51 (11, d, J=7.9 Hz), 7.55 (11, t, J=7.6 Hz), 7.65 (11, t, J=7.4 Hz), 7.79 (1H, d, J=7.9 Hz), 7.85 (IH, J= 7.6 Hz), 8.19 (2H, 8.70 (11, d, J= 8.S 1 Hz) ppm; HPLC-Method D, Rt 4.93 min; LC-MS 450.13 CM+HVL Example 124 (6-Fluoro-1H-indazol-3-yl)-[2-(2trifluoromethyl-phenyl) -quinazolin-4-yl -amine (11-124).

Prepared in DMF (87% yield) as yellow solid. alMR (500 MHz, DMSO-d) 513.0 Cs, 11), 11.1 Cs, br, 1H), 8.66 (d, 11), 7.95 1H), 7.80 Cd, 11), 7.72 2H), 7.62 Cm, 4H), 7.21 1H), 6.84 (td, 11) ppm. LC-MS; 424.15 IPLC-Method A, Rt 3.05 min.

Example 125 3-[2-(2-Trifluoromethyl-phenyl)-quinazolin-4acid methyl ester (II- 125): To a solution of compound 11-79 (100 mg 0.21 mmol) -278- INDin DMF (2 nt) was added MeOH (1 mL), DIEA (54 uL, 0.31 mmol). and PdC1 2 (dppf) (4 mg, 0.005 mmdl). The flask was flushed with CO three times and then charged with a CO balloon. The reaction mixture was heated at 80 0 C for 14 h then poured into water. The resulting precipitate was C collected and washed with water. The crude product was then purified first by flash column (silica gel, ciethyl acetate in hexanes) then by preparative HPLC to to afford 1-125 as yellow solid. 1NMMR (500 MHz, DMSO-d6) 613.3 1H), 11.3 br, 1H), 8.70 1H), 8.36 1H), 7.97 1H), 7.82 2H), T.71 3H), o 7.58 2H), 7.51 1H), 3.75 3H) ppm; LC-MS (ES+) 464.13 HPLC-Method A, Rt 3.12 min.

Example 208 (5-Methyl-2H-pyrazol-3-yl)-[2-(2-naphthyl-1yl)-quinazolin-4-yl] -amine (11-208) 'HNMR (500 MHz, DMSOd6) 88.92 1H), 8.73 1H), 8.39 1iH), 8.09 (m, 211), 7.95 3H), 7.62 3H), 6.78 1H), 2.32 (s, 3H); MS 352.2 Example 209 (2-Chloro-phenyl)-pyrido[2,3-djpyrimidin- 4 -yl]-(7-fluoro-1H-indazol-3-yl)-amine (11-214): Prepared from 4-Chloro-2-(2-chloro-phenyl)-pyrido[2,3-dlpyrimidine (100 mg, 0.36mmol) and 7 -Fluoro-1H-indazol-3-ylamine (108mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (93 mg, 46% yield). HPLC-Method A, R 3.04 min; ZH NMR (DMSO, 500 MHz): 8 13.67 (1H, 11.40-11.25 (1H, be), 9.35- 9.25 (2H, 7.95 (11, 7.80-7.47 (5H, 7.35(111, 7.15 (1H, MS MW 391.1.

Example 210 [2-(2-Chloro-phenyl)-pyrido(2,3-d]pyrimidin- 4 -yl]-(5-fluoro-1H-indazol-3-yl)-amine (11-215): Prepared from 4-Chloro-2-'(2-chloro-phenyl) -pyrido[2,3-dI -279pyrimidine (100 mg, 0.36mmol) and 5-Fluoro-1H-indazol-3- Va ylamine (108mg, 0.72mmol). Purification by preparative 0~ HPC afforded the title compound as a yellow, di-TFA salt mg, 22% yield). HPLC-Method A, Rt 3.00 min; 'H NMR (DMso, 500 MHz): 13.0 (1H, 10.90(1, be), 9.15-9.05 (211,- 7.70 (1H, 7.60-7.30 (6 H, m) 7.20 (1H, m); MS MH+ 391.1.

ci Ci Example 211 (2-Chioro-phenyl) -pyrido [2,3-dipyrimidin- 4-ylJ (S,7-difluoro-lH-indazol-3-yl) -amine. (IX-216): Prepared from 4-Chloro-2-(2-chioro-phenyl) -pyrido[2,3dlpyriiidine (100 mg, 0.36mmol) and 7-Difluoro-1Hindazol.-3-ylamine (112mg, 0.66mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (130 mg, 62% yield). HPLC-Method A, Rt 3.12 min; 1H NMR (DMSO, 500 MHz): 13.80-13.60 bs), 11.30- 11.10 (1H, be), 9.20-9.10 (2H, 7.80 (1H, 7.-60- 7.30 (6H, MS MH- 409.1.

Example 212 (2-Chioro-phenyl) -pyrido [3,4-dipyrimidin- 4-ylJ-(1H-indazol-3-yl)-amine (11-217): Prepared from 4- Chloro-2-(2-chioro-phenyl) -pyrido [3,4-dlpyrimidine (100 mg, 0.3Gmmol) and 1H-indazol-3-ylamine (88mg, 0.66mmol) Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt ,(72 mg, 33% yield).

HPLC-Method A, Rt 3.21 min; %H NMR (DMSO, 500 MHz): S 12.95 (11, 10.90 (11, be), 9.25 (1H, 8.75 (1H, 8.55 (1S, 7.65. 7.55 7.50-7.30 (51, 7.00(11, MS MH 373.1.

Example 213 (2-Chioro-phenyl) -pyrido [3,4-dipyrimidin- 4-yl.1- (7-fluoro-IH-±ndazol-3-y1) -amine (11-218): Prepared from 4-Chloro-2- (2-chioro-phenyl) -pyrido [3,4-djpyrimidine (100 mg, 0.36mmol) and 7-Fluoro-1H-indazol-3-ylamine -280- (108mg, 0.72mmol). Purification by preparative HPLC afforded the title compound as a yellow, di-TFA salt (48.7 mg, 22% yield). HPLC-Method A, Rt 3.35 min; 'H NMR (DMSO, 500 MHz): 6 12.95 (1i, 10.90 bs), 9.25 (i 8.75 (1H, 8.55 (1i, 7.70-7.35 (5H, m), c 7.25(1H,im), 6.95 (iN, MS NMH 391.08.

Example 214 [2-(2-Chloro-phenyl) -pyrido[3,4-d pyrimidin- C 4 -ylJ-(5-fluoro-lH-indazol-3-yl)-amine (II-219): Prepared from 4-chloro-2-( 2 -chloro-5-fluoro-1H-indazol-3-y1amine (108mg, 0.72mmol). Purification by preparative HPLC o afforded the title compound as a yellow, di-TFA salt (57.2 mg,' 26% yield). HPLC-Method.A, Pt 3.27 min; 1 H NMR (DMSO, 500 MHz): 8 13.05 (1H, 10.95 (IH, 9.25 8.75 8.55 (1i, 7.60 (1i, 7.55 (1H, 7.50-7.30 (5H, 7.25(1H, MS MTh 391.1.

Example 215 [2-(2-Chloro-phenyl)-pyrido13,4-d]pyrimidin- 4 -yl]-(5,7-difluoro-1-indazol-3-yl)-amine (11-220): Prepared from 4-chloro-2-(2-chloro-7-difluoro-1H-indazol- 3-ylamine (112mg, 0.66mmol). Purification by preparative HPLC afforded the title compound as a.yellow, di-TFA salt (57.2 mg, 26% yield). HPLC-Metod A, Rt 3.45 min; 1' NMR (DMSO, 500 MHz): 8 13.65 (1H, 11.0 (1H, 9.25 (1H, 8.80 8.50 (1i, 7.60 (1H, 7.55 (1H, 7.50-7.30 (5n, MS MH 409.1.

Example 216 6-Fluoro-1H-indazol-3-ylamine 1HNEMR (500 MHz, DMSO-d6) 611.4 1H), 7.68 (dd, 1H), 6.95 (dd, 1H), 6.75 (td, 1H), 5.45 2H) ppm; LC-MS (ES+) 152.03 HPLC-Method A, Rt 2.00 min.

-281- Example 217 5-Fluoro-1H-indazol-3-ylamine

'HNMR

Va S(500 MHz, DMSO-d) 811.3 Cs, 1H), 7.43 Cd, 1H), 7.22 Cm, Cl J.H) 7.08 1H), 5.29 2H) ppm; LC-MS 152.01 HPLC-Method A, Rt 1.93 min.

Example .218 *5,-7-Difluoro-lE-indazol-3-yl-aine

'HNMR

(500 MHz, CD 3 OD) 67.22 (dd, 8.45Hz, 1H), 7.04-6.87 Cl IH); LC-MS 169.95 HPLC-Method C, Rt 2.94 cl min o Example 219 7-Fluoro-IH-indazol-3-ylamine 'HNMR (500 o MHz, DMSO-dG) .11.8 1H), 7.42 1H), 6.97 1H), 6.78 1H), 5.40 Cs, 2H) ppm; LCMS 152.01 HPLC-Method A, Rt 2.00 min.

Example 220 7-Fluoro-6-trifluoromethyl-1H-indazol-3ylamine 'H-DMR (500 MHz, DMSO) 8 12.5 1H), 7.75 Cd, 1H), 7.25 in), 5.85 Cm, 12) ppm; MS (FIA) 220.0 CM+H); HPLC-Method A, Rt 2.899 min.

Example 221 6-Bromo-IZB-indazol-3-ylamine e -'3H-NMR (500 MHz, DMSQ) 8 11.5 1H), 7.65 Cd, 1H), 7.40 11)., 7.00 Cd, 12), 5.45 (br s, iH) ppm; MS (FIA) 213.8 HPLC-Method A, Rt 2.441.min.

Example 222 4-Fiuoro-1E-indazoi-3-ylamine 1

H-NMR

(500 MHz, DMSO) 8 11.7 Cs, IH), 7.17 Cm, 1H), 7.05- d, 12), 6.7 Cbr, 12), 6.60 (dd, 1H), 5.20 (br s, 22) ppm; MS (FIA) 152.0 Method A, Rt 2.256 min.

Example 223 5-Bromo-1H-indazol-3-ylamine 'H-NMR (500 MHz, DMSO) 8 11.55 (br s, 12), 7.95 Cs, 1H), 7.30 (d, -282- IN1H), 7.20 1H), 5.45 (br s, 2H) ppm; MS (FIA) 213.8 Method A, Rt 2.451 min.

Example 224 5-Nitro-1E-indazol-3-ylamine 'H-NMR (500 MHz, DMSO-d) S 9.00 IR), 8.20 IH), 7.45 1H), c 6.15 -(br s, 1i) ppm-; Method A, Rt 2.184 min CA Example 225 4 -Pyrrol-1-yl-1H-indazol-3-ylamine (A10): 'H- NMR (500 MHz, DMSO) 8 7.20 2H), 7.00 2H), 6.75 0 10 1H), 6.25 2H), 4.30 1H) ppm; Method A, Rt

CA

o 2.625 min.

Example 226 4-Chloro-5,6-dimethyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a colorless oil in 75% yield. 1 H-NMR (500S MHz, CDC13) 5 7.70 (d, J=7.8 Hz, 11), 7.64 J=7.6 Hz, 1H), 7.55 J5=7.6 Hz, 1H), 7.48 5=7.5 Hz, 1H), 2.54 3H), 2.36 3H) ppm; MS (FIA) 287.0 HPLC-Method A, Rt 3.891 min.

Example 227 4-Chloro-2-(2-chloro-phenyl)-5,6-dimethylpyrimidine Prepared to afford 'a yellow-orange oil in 71% yield. 'H-NMR (560 MHz, CDC13) 8 7.73 1H), 7.52 1H), 7.39 2H), 2.66 3H), 2.45 311H) ppm; MS (FIA) 253.0 HPLC-Method A, Rt Rt 4.156 min.

Example 228 4-Chloro-6-methyl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a pale.yellow oil in 68% yield. 'H-NMR (500 MHz, CDC13) 8 7.72 (d, 5=7.8 Hz, 1H), 7.65 J=7.9 Hz, 1H), 7.57 J=7.5 Hz, 1H), 7.52 J5=7.8 Hz, 1H), 7.16 1H), 2.54 3H) ppm; MS (FIA) 273.0 HPLC-Method A, Rt 3.746 min.

-283- Example 229 4-Chloro-6-cyclohecyl-2-(2-trifluoromethyl- Va IN phenyl)-pyrimidine Prepared to afford a yellow oil C in 22% yield. 1 H-NMR (500 MHz, CDC13) 8 7.70 2H), 7.57 J=7.5 Hz, 1H), 7.50 J=7.5 Hz, 1H), 7.19 (s, 1H), 2.65 1H), 1.9 2H), 1.8 2H), 1.5 2H), 1.3 2H), ppm; MS (FIA) 341.0 (M+H) C- Example 230 4-Chloro-6-phenyl-2-(2-trifluoromethyl- INDphenyl)-pyrimidine Prepared to afford a yellow oil in 53% yield. 'H-NMR (500 MHz, CDC13) 8 8.08 (dd, J=7.9, ID 1.6 Hz, 2H), 7.80 J=7.6'Hz, 1H), 7.77 J=7.8 Hz, o 1H), 7.67 1H), 7.61 J=7.5 Hz, 1H), 7.54 J=7.6 Hz, 1H), 7.47 3H) ppm; MS (FIA) 335.0 HPLC- Method A, Rt 4.393 min.

Example 231 4-Chloro-2-(2,4-dichloro-phenyl)-5,6dimethyl-pyrimidine Prepared to afford a white solid in 91% yield. 'H-NMR (500 MHz, CDC13) 8 7.62 (d, J=8.3 Hz, 1H), 7.43 J=7.0 Hz, 1H), 7.27 (dd, J=8.3, 2.0 Hz, iN), 2.55 3H), 2.35 3H) ppm; MS (FIA) 287, 289 HPLC-Method A, Rt 4.140 min.

Example 232 4-Chloro-6-(2-chloro-phenyl)-2-c(2trifluoromethyl-phenyl)-pyrimidine Prepared to affod a yellow oil in 52% yield. 1 H-NMR (500 MHz, CDC13) 8 7.75 3H), 7.65 2H), 7.53 1I), 7.44 1H), 7.36 ppm; MS (FIA) 369.1 HPLC-Method A, Rt 4.426 min.

Example 233 4-Chloro-6-(2-fluoro-phenyl)-2-(2trifluoromethyl-phenyl)-pyrimidine Prepared to afford a yellow oil in 95% yield. 'H-NMR. (500 MHz, CDC13) 8 8.24 J=7.9 Hz, 1H), 7.84 1H), 7.78 J=7.7 -284- Hz, 7.76 J=8.0 Hz, IH), 7.60 J=7.5 Hz, 1H), Va o 7.53 Jc7.6 Hz, 1H), 7.43 1H), 7.23 J=7.6 Hz, Cl 1H), 7.13 1H) ppm; MS (FIA) 353.0 Example 234 4-Chloro-6-pyridin-2-yl-2-(2-trifluoromethylphenyl)-pyrimidine Prepared to afford a pale yellow solid in 50% yield. 'H-NMR (500 MHz, CDC13) 8.68 (m, C IH), 8.48 (dd, J=7.9, 0.8 Hz, 1H), 8.38 J=2.3 Hz, Cl 1K), 7.84 3H), 7.62 J=7.6 Hz, 11), 7.55 J=7.6 o 10 Hz, 1H), 7.38 1H) ppm; MS (FIA) 336.0 HPLC- \O Method A, Rt 4.575 min.

Example 235 6-Benzyl-4-chloro-2-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-pyrido[4,3-d]lpyrimidine 'ENMR (500 MHz, CDC1 3 87.70 1H), 7.62 1H); 7.55 1H), 7.48 1H), 7.32 4H), 7.25 1H), 3.74 2H), 3.66 2H), 2.99 2H), 2.80 2H) ppm; LCMS 404.17 HPLC-Method A, Rt 3.18 min.

Example 236 7-Benzyl-4-chloro-2-(2-trifluoromethyl-, phenyl)-5,6,7,8-tetrahydro-pyridol3,4-djpyrimidine (l11): IHNEMR (500 MHz, CDC1 3 57.69 1H), 7.60 1H), 7.54

'I

IH), 7.47 1H), 7.28 4K), 7.20 1H), 3.68 2H), 3.67 2H), 2.86 2K),.2.79 2H) ppm. MS 404.18 HPLC-Method A, Rt 3.12 min.

Example 237 4-Chloro-2-(4-fluoro-2-trifluoromethylphenyl)-quinazoline (812): 1 INMR (500MHz, CD30D) 8 8.43 J=8.1Hz, 1H), 8.20-8.05 2H), 8.05-7.82 2H), 7.71-7.51 2H). LC-MS 327.09 HPLC-Method D, Rt 4.56 min.

-285- Example 238 4-Chloro-2-(2-chloro-5-trifluoromethylphenyl)-quinazoline (313): LC-MS (ESi) 342.97 HPLC-Method D, Rt 4.91 min.

Ct Example 239 4-Chloro-2- (2-chloro-4-nitro-phenyl) quinazoline (314): LC-MS 319.98 CM+W).-HPLC-Method D, Rt 4.45 min.

Example 240 4-Chloro-2-(2-trifluoromethyl-phenyl)quinazoline (315): Prepared in 57% yield. White solid.

lHNMqR (500MHz, DM50-d6) 8 7.79 Ct, 1H), 7.86 1H), 7.94 o Cm, 3H), 8.15 (dd, iN), 8.20 (td, 1H), 8.37 1K); El- MS 308.9 M).

Example 241 4-Chloro-2-(2-trifluoromeehyl-phenyl)-6,7- (216): Prepared in 22% yield. 'HNMR (5001Hz, DMSO-d) 8 2.19 3.01 Ct, 2H), 3.08 2H), 7.49 Ct, 11), 7.55 1H), 7.62 (d, 1H), 7.71 1H). El-MS 299.0 CM+H)..

Example 242 4-Chloro-2- (2-chloro-phlnyl)-6,7,8,9tetrahydro-SH-cycloheptapyrinidine (B17): Prepared according to Method C in 82% yield to-afford a white solid. 'HNMR. (500MHz, CDC1 3 8 1.67, (m 41), 1.87 (m 2H1L 3.02 Cm 4H), 7.28 2H), 7.40 (m,11H), 7.65 1H)i EI-MS 293.0' Example 243 4-Chloro-2-(2-trifluoromethyl-phenyl)- 5,S,7,8,9,1O-hexahydro-cyclooctapyrimidine (318): Prepared in 38% yield to afford a brown oil. 'HNMR (5004Hz, CDC1 3 8 1.35 (m 2H), 1.41'(m 21), 1.76 (m 4H), 2.96- Cm, AK), 7.48 Ct, 1H), 7.56 Ct, 1H), 7.66 Cd, 1H), 7.70 Cd, 1H); El-MS 341.0 -286- ND Example 244 4-Chloro-8-mthoxy-2-(2-trifluoromethylphenyl)-quinazoline (319): Prepared from 8-methoxy-2-(2- (N trifluoromethyl-phenyl)-3H-quinazolin-4-one Og, 3.12mmol), triethylamine hydrochloride.(472mg, 3.43mmol), and POC13. Purification by flash chromiatography afforded Ci a white solid (89% yield). HPLC-Method A, Rt 4.10 min, MS 258.08 ci C( Example 245 2-(4-Chloro-quinazolin-2-yl)-benzonitrile o 10 (B20): Prepared to afford a yellow solid in 1.5% yield.

O 1 H-NMR (500 MHz, CDC13) 8 8.47 8.24 1H), 8.16 o 1H), 8.07 (impurity), 7.941(t, IH), 7.92 (impurity), 7.86 1H) 7.68 2H), 7.65 (impurity), '7.54 (impurity), 7.49 1H), 4.2 (impurity), 1.05 (impurity) ppm; MS (LC/MS) 266.05 HPLC-Method A, Rt 3.88 min.

Example 246 6-Methyl-2-(2-trifluoromethyl-phenyl)-3Hpyrimidin-4-one Prepared to afford a yellow solid in 50% yield. 1 H-NMR (500 MHz, DMSO-d6) 6 12.7 (br s, 1K), 7.9 1H), 7.8 2K), 7.7. IH), 6.3 1H), 2.21 3H) ppm; MS (FIA) 255.0 HPLC-Method A, Re 2.578 min.

Example 247 6-Cyclohexyl-2-(2-trifluoromethyl-phenyl)-3Hpyrimidin-4-one Prepared to afford an off-white solid in 54% yield. 1'H-NMR (500 MHz, DMSO-dG) 8 12.9 (br a, 1H), 7.9 4H), 6.3 1H), 2.5 1H), 1.9 (m, BH), 1.4 5H) ppm; MS (FIA) 323.1 HPLC-Method A, Rt 3.842 min.

Example 248 2-(2-Chloro-5-trifluoromethyl-phenyl)-3Hquinazoli-4-one (D10): 'NR (500SMHz, CD 3 OD) 8 8.32-8.25 1H), 8.01 1H), 7.91-7.72 1H), 7.66-7.55 (m, -287- IH). LC-MS 325.01 HPLC-Method D, Rt 3.29 min.

Example 249 2-( 4 -Fluoro-2-trifluoromethyl-phnyl) -3H- S quinazolin-4-one (D14): '!NMR (500MHz, Cb 3 OD) 8 8.28 (d, 8.OHz, 1H)) 7.94-7.84 IH), 7.84-7.77 lB), 7.76- 7.67 2H), 7.65-7.53 2H). LC-MS 309.06 HPLC-Method"D, Rt 2.28 min.

Example 250 2-( 4 -Nitro-2-chloro-pbenyl) -3H-quinazolin-4one (D15): LC-MS 302.03 HPLC-Method D, Rt 2.81 rin.

Example 251 2-(S-Fluoro-2-trifluorometyl-phenyl)-3Hquinazolin-4-one (D17): 'HNMR (500MHz, Cfl30D) 3 8.28 (d, Rt J=8.05Hz, 1K), 7.96 (dd, J=5.05, 8.55Hz, 1K), 7.89 (t,i J=7.SHz, 1H), 7..78-7.69 7.66-7.46

LC-MS

309.14 HPLC-Method D, Rt 2.90 rnin.

Example 252 (lH-Indazol-3-yl)- (2-phenyl-quinazolin-4-y)amine (111-1): Prepared by Method A in DMF to afford mg (50% yield) as pale yellow solid. 'H NNR (500 MHz, DMSO-d) 813.1 br, 1H), 8.48 lW), 7.91 2H), 7.76 (br, 2H), 7.45 2H), 7.36 1H), 7.20 4H) 6.86 1W) ppm. MS 338.07 (M4H); 336.11 (M- HPLC-Method A, Rt 2.88 min.

Example 253 (5-Methyl-2s-pyrazoJ-3-yl).(2.phenyls,6,7,8 tetrahydroquinazolin-4-yl)-amine Prepared according to Method A. 1H NMR (500 MHz, DMSO-d6) 512.1 br, 1H), 8.70 br, lW), 8.37 J 6.7 Hz, 2H), .7.54 3H), 6.67 2.82 Cm, 2H), 2.68 Cm, 2H), 2.37 3H), 1.90 Cs, br, 4H); MS 306.1 CM+H).

-288- IND Examle 254 (5-Methyln2S-pyrazol-3-yl) (2-phenyl-6,7,8,tetrahydro-Ss-aycloheptapyrimidi4..-yl)-ami (111-8): MS 320.48 HPLC-Method E, Rt 1.124 min.

Example 255 (5-Methy1-2H-pyrazol-3-yl)- (2-pyridtn-4-ylquinnolin-4-yl) -amine. (111-9) Yellow solid, mp 286- 289 0 C, 1 NMR .(DMSO) 8 2.35 (3H, 6.76 7.61 (1W 7.89 (2H, 8.32 (2H, 8.70 8.78 (2H, 10.56 (in, br 12.30 (1H, br IR (solid) 1620, 1598, 1571, 1554, 1483, 1413, 1370, 1328; MS 303.2

IND(M+H)+

Example 256 7 -Chloro-2-'pridin-4 -yl quinazolin-4..yl) methyl-2H-pyrazol-a-yi) -&mine (111-28): 'H NMR (DMSO-d6) 8 2.35 6.75 (lH, 7.65 7.93 (1H, s), 8.30 (2H, 8.73 (iN, 8.79 (2H, 10.69 a), 12.33 (i1H, MS m/z 337.2 (MiH) 4 Example 257 6 -Chioro-2-pyrain-4-i..qinazon-4-y)-(5methy1-2H-pyrazol-3-y)-amine (111-29):' 1 H NMh (DMSO-d) S 2.31 (3H, 6.74 (1H,s) 7.89 '8.30 (2H, d), 8.80 (2H, 8.91 iN, 10.63 (1H, 12.29 (iN, 8); MS 337.2 Example 258 (2-Cyclohexyl-quinazolin.4-yl)-(5-methyl2K.

pyrazol-3-yl)-amine (11,1-30): 1IH NMR (DMSO) 2.35 (3H, 1.70 (3H, mi), 1.87 (2H, 1.99 (2H, 2.95.(iN, 6. 72 (IH, 7. 7 S (IH, d) 7. 88 (IH, s) 9 (IH, 8.83 (1H, 11.95 12.70 (1N, MS 308.4 Exain)1e 259 (5-Methyi-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine. (111-31): op 246 0 C; 'H NMR -289- 6 2.35 (3H, 6.70 (1H, br 7.51-7.57 (4H, 7.83-

VO

o 7.84 (2H, 8.47-8.50 (2H, 8.65 (1H, 10.4 (1H, C 12.2 (11, bs); IR (solid) 3696, 3680, 2972, 2922, 2865; MS 302.1 C- Example 260 [2-(4-Iodophenyl)-quinazolin-4-yl]-(5-methyl- 2H-pyrazol-3-yl)-amine (III-32): IH NMR (DMSO-d6) 8 2.34 CA (3H, 6.72 (1H, 7.56 (IH, 7.84 (2H, 7.93 Cl (2H, 8.23 (2H, 8.65 (1H, 10.44 (1H, 12.24 o 10 (1H, MS 428.5 cO

IND

o Example 261 [2-.(3,4-Dichlorophenyl)-quinazolin-4-yl]- methyl-2H-pyrazol-3-yl)-amine (III-33): A suspension of 2-(3,4-dichloro-phenyl)-3H-quinazolin-4-one (1g, 3.43 mmol) in phosphorus oxychloride (4 mL) was stirred at 1100C for 3 hours. The solvent was removed by evaporation and the residue is treated carefully with cold aqueous, saturated NaHC03. The resulting solid was collected by filtration and washed with ether to afford 4-chloro-2- (3,5-dichloro-phenyl)-quinazoline as a white solid (993 mg, To the above compound (400mg, 1.29 mmol) in THF (30 mni) was added 3-amino-5-methyl pyrazole (396 mg, 2.58 mmol) and the resulting mixture heated at.650C overnight. The solvents were evaporated and the residue triturated with ethyl acetate, filtered, and washed with the minimum amount of ethanol to afford compound III-33 as a white solid (311 mg mp 274C; 1H NMR (DMSO) 6 2.34 (3H, 6.69 (1H, 7.60 (1H, 7.84 (1H, d), 7.96 (2H, 8.39 (1H, dd), 8.60 (1H, 8.65 (1H, d), 10.51 (1H, 12.30 (1H, IR (solid) 1619, 1600, 1559, 1528, 1476, 1449, 1376, 1352, 797, 764, 738; MS 370.5 (M+H) -290- Example 262 (2-(4-Brouophenyl) -quinazolin-4-ylI-

IN

methyl-2H-pyrazol-3-yl)-amne (111-34)': mp 262-265 0 C; 111 NMR (DMSO) 8 2.34 (3S, 6.73 (1H, 7.55 (lI, m), 7.74 (2H, 7.83 (2H, 8.40 (21, 8.65 d), 10.44 12.25 (11, IR (solid) 1603, 1579, 1546, 1484, 1408,1365; MS 380.1/382.1 Example 263 (4-Chlorophenyl) -guinazolin-4-yl]- ci methyl-2H-pyrazol-3-yl)-amine (111-35) .mp >300 0 C; 'H NMR (DMSO) 8 2.34 (3H, 6.74 (1H, 7.53-7.62 (3H, m), 7.84 (2H, B.47 (2H, 8.65 (1H, 10.44 (1H, a), 12.26 (1H, XE (solid) 1628, 1608, 1584, 1546, 1489, 1408, 1369, 1169; MS 336.2 Examle 264 (3,5-Dichiorophenyl) -quinazoin-4-yl methyl-2H-pyrazol-3-yl)-amine (111-36): mp 228 0 C; 'H NMR (DMSO) 8 2.34 (3H, 6.69 (111, 7.9.6 8.21 (3H, 8.56 (1H, 8.60 (2H; 10.51 12.30 (1LH, s) ER (solid) 1546, 1331, 802, 763, 729, 658, 652;.

MS 370.5 Examle 265 (2-(4-Cyanophenyl)-quinazolin-4-ylJ-(5methyl-2H-pyraz6lI--yl)'-amine (111-37): mp 2630C; H NMR (DMSO) 8 2.34 (3H, 6.72 (111, (11, 7.88 (2H, 8.04 (21, 8.63 (2H, 8.67 (IH, 10.52 (1H, 12.27 (11, ZR (solid) 1739, 1436, 1366, 1229, 1217; MS 327.2 Example 266 (2-(3-Zodophenyl)-quinazolin-4-yll-(5-methyl- 2H-pyrazol-3-yl)-aine (111-38): mp 234-23500; 'H NMR (DMSO) 8 2.35 (3H, 6.73 (IH, 7.35 (11, 7.56 (11, 7.85 (3H, m) 8.471111, '8.65 (11, 8.86 -291- (11, 10.49 (1H, 12.28 br IR (solid) Va N 1560, 1541, 1469, 1360; MS 428.1 Example 267 [2-(4-Ethylsulfanylphenyl)-quinazolin-4-yll- (5-methyl-2H-pyrazol-3-yl)-amine (111-39): mp 229-231 0

C;

*H NMR (DMSO) 8 1.29 (3H, 2.35 (3H, 3.07 (2H, q), 6.76 (1H, 7.43 (2H, 7.51 7.81 (2H, m), 8.41- (2H, 8.64 (1H, 10.38 (11, 12.24 (1H, br IN IR (solid) 1587, 1574, 1555, 1531, 1484, 1412, 1369; MS 362.1 Example 268 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl) -amine (III-40): mp 218-219IC; '1H NMR (DMSO-d6aG) 8 0.70-0.80(2H, 0.90-1.00 (2H, 6.70 (1H, 7.45-7.55 (4H, 7.80-7.85 (2H, 8.45-8.55 (2H, 8.65 (1H, 10.40 (11, 12.27 (1H, IR (solid) 1624, 1605, 1591, 1572, 1561, 1533, 1479, 1439, 1419, 1361, 1327, 997, 82B,.803, 780, 762, 710; MS 328.2 Example 269 [2-(4-tert-Butyiphenyl)-quinazolin-4-ylJ-(5methyl-2H-pyrazol-3-yl)-amine (111-41): mp >30000; IH NMR

L

(DMSO-d6) 8 1.35 (91, 2.34 (3H, 6.79 a), 7.55 (3H, 7.85 (2H, 8.39 (2H, 8.62 (1H, d), 10.35 12.22 (1H, IR (solid) 1603, 1599, 1577, 1561, 1535, 1481, 1409, 1371, 1359, 998, 841, 825, 766, 757; MS 358.3 .Example 270 [2-(4-Chlorophenyl)-quinazolin-4-yl-(5cyclopropyl-2H-pyrazol-3-yl)-amine (III-42): 1H NMR (DMSOd6) 8 0.77 (4H, br m) ,2.05 (1H, 6.59 7.60 (1H, 7.85 (2H, 7.91 (2H, 8.22. (2H, 8.65 (1H, 10.51 12.33 MS 362.1 -292- IND Example 271 (2-Een.zotl,3]dioxol-5-yl-qunazolin-4-yl).-(s.

metyl-2Hpyrazo13-y1)-aine (111-43): '1 NMR (DM80) B 2.33 (3H, 6.13 (2H, 6.78 7.11. (11, d), 7.80 (11, 7.94 8.09 8.25 (IH, d), 10.34 (IH, 12.21 (1H, MS 346.5 Example 272 [2-(4-Dimethylaninophenyl)-quinazolin-4-ylI- (5-methyl-2H-pyrazol-3-yl) -amine (111-44): 1H NMR (DMSOd 6) 8 2.02 (6H, 2.39 6.83 (1H, 7.71 (1H, 7.98 (21, 8.04 (21, 8.33 (2H, 8.67 (11, INs), 11.82 (1H, 12.72 (11, MS 345.3 (M+HY+.

Example 273 12- (3-Methosyphenyl) -quinazoln-4-yl- methyl-2H-pyrazol-3-yl)-amine (111-45): mp 226OC; 'H NMR (DMSO) 8 2.34 3.92 (3H, 6.72 (11, 7.21 (1H, 7.57 (11, 7.79 (1H, 8.02 (31, 8.14 8.79 (11, 10.39 12.22 (11, IR (solid) 1599, 1572, 1538, 1478, 1427, 1359, 833, 761, 661; MS 332.2 Example 275 (5-Cyclopropyl-2s-pyrazol-3-yl)-[2-(3,4dichiorophenyl) -quinazolin-4-yl -amine (111-46): 'H NMR (DMSO-dE) 8 0.86 (2H, 1.02 1.69 (11, m), 6.56 (1H, 7.57 (11, 7.84 (4H, 8.40 (11, d), 8.58 (1H, s),'8.64 (1H, 10.53 (111, 12.36 (1H, s); MS 396.0 Example 276 (2-Biphenyl-4-yl-qainazolin-4-yl)-(5-methyl- 2H-pyrazol:-3-yl)-amine (111-47): To a mixture of bromo-phenyl) -quinazolin-4-yl (5-methyl-21-pyrazol-3yl)-amine (111-34) (196 mg, 0.51 mmol) and phenylboronic acid (75'mg, 0.62 mmol) in THF:water 4 mL) was added Na 2

CO

3 (219 .mg, 2.06 mmol), triphenyiphoaphine (9mg, 1/15 mol%) and palladium acetate (1 mg, 1:135 mol%)t. The -293resulting mixture was heated at 80°C overnight, the

\O

solvents were evaporated and the residue purified by C flash chromatography (gradient of dichloromethane:MeOH) cto afford III-21 as a yellow solid (99 mg, 1H NMR (DMSO) 6 2.37 (3H, 6.82 (1H, 7.39-7.57 (4H, m), 7.73-7.87 (6H, m) 8.57 8.67 (1H, 10.42 (1H, 12.27 (1H, MS 378.2 ci C Example 277 (4-Ethynylphenyl) -quinazolin-4-yl]- o 10 methyl-2H-pyrazol-3-yl)-amine (III-48): To a mixture of 2- (4-bromo-phenyl) -quinazolin-4-yl) (5-methyl-2H- Spyrazol-3-yl)-amine (111-34) (114 mg,' 0.3 mmol), and trimethylsilylacetylene (147 mg, 1.5 mmol)in DMF (2 mL) was added CuI (1.1 mg, 1:50 mol%), Pd(PPh 3 2 C1 2 (4.2 mg, 1:50 mol%) and triethylamine (121 mg, 0.36 mmol). The resulting mixture was heated at 120 0 C overnight and the solvent evaporated. The residue was triturated in ethyl acetate and the resulting precipitate collected by filtration. The collected solid was suspended in THP (3 mL) and TBAF (1M in THF, 1.leq) was added. The reaction mixture was stirred at room temperature for 2 hours and the solvent evaporated. The residue was purified by flash chromatography (silica gel, gradient of DCM:MeOH) to afford III-48 as a white solid (68 mg, IH NMR (DMSO) 8 2.34 (3H, 4.36 (1H, 6.74 (1H, 7.55 (1H, 7.65 (2H, 7.84 (2H, 8.47 (2H, 8.65 (1H, 10.43 (IH, 12.24 (1H, MS 326.1 Example 278 [2-(3-Ethynylphenyl)-quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (III-49): mp 204-207°C; 'H NMR (DMSO) 8 2.34 (3H, 4.28 (1H, 6.74 (1H, s), 7.55-7.63 (3H, 7.83-7.87 (2H, 8.49 (1H, 8.57 (1H, 8.65 (1H, 10.46 (1H, 12.27 (1H, IR -294- (solid) 1598, 1574, 1541, 1489, 1474, 1422, 1365; MS 326.1 M Example 279 [2-(3-Methylphenyl)-quinazolin-4-yl i 5 methyl-25-pyrazol-3-yl)-amine (III-50): A suspension of (C IH-quinazoline-2.,4-dione (10.0 g, 61.7 mmol) in POCl 3 mL, 644 mmol) and N,N-dimethylaniline (8mL, 63.1 mmol) Ci was heated under reflux for 2 h. The excess POCl 3 was Ci removed in vacuo, the residue poured into ice, and the o 10 resulting precipitate collected by filtration. The crude \D solid product 2,4-dichloro-quinazoline (6.5 g, 53% yield) Swas washed with water and dried under vacuum for next step use without further purification. To a solution of the 2,4-dichloro-quinazoline (3.3 g,.16.6 mmol) in anhydrous ethanol (150 mL) was added 5-methyl-1i-pyrazol- 3-yl amine (3.2 g, 32.9 mmol)and the resulting mixture was stirred at room temperature for 4 hours. The resulting precipitate was collected by filtration, washed with ethanol, and dried under-vacuum to afford 4.0 g (93% yield) of (2-chloro-quinazolin-4-yl)-(5-methyl-IHpyrazol-3-yl)-amine which was used in the next step without further purification. To a solution of the (2chloro-quinazolin-4-yl)-(5-methyl-1H-pyrazol-3-yl)-amine mg, 0.19 mmol) in DMF (1.0 mL) was added m-tolyl boronic acid (0.38 mmol), 2M Na2C0 3 (0.96 mmol), and trit-butylphosphine (0.19 mmol). The flask was flushed with nitrogen and the catalyst'PdCl 2 (dppf) (0.011 mmol) added in one portion. The reaction mixture was then heated at 800C for 10 hours, cooled to room temperature, and poured into water (2 mL). The resulting precipitate was collected by filtration, washed with water, and purified by HPLC to afford II-50 as a pale yellow solid (61mg, 1 H NMR (500 MHz, DMSO-d6) 812.3 (br s, 1H), 10.4 (br s, IH), 8.75 1H), 8.30 1H), 8.25 1H), -295- 7.78 2H), 7.55 1H), 7.45 Cm, IH), 7.35 1H), IND 6.80 1H), 2.47 2.30 MS 316.1 Example 280 [2-(3,5-Difluorophenyl)-quinazolin-4-ylJ-(5methyl-2H-pyrazol-3-yl)-amine (ZnI-51): 3N NNR (500 MHz, DMSO-d6) 612.3 (br s, 1H), 10.8 (br s, 1H), 8.63 11), 7.95 2H), 7.85 2H), 7.58 1H), 7.41 1H), 6.59 1H), 2.27 31); MS 338.1 Example 281 [2-(3-Chloro-4-fluoropbenyl) -guinazolin-4ci y1J- (5-methyl-21-pyrazol-3-y-amine (111-52): 1 H NNR (500 (7 MHz, DMSO-d) 612.4 Cbr a, iR), 10.8 (br a, 1H), 8.65 (d, 1H), 8.50 1H), 8.36 1H), 7.85 Cm, 1H), 7.60 (m, 1H), 6.62 13), 2.30 Cs, 3H); MS 354.1 Example 282 (5-Methyl-2H-pyrazol-3-yl)-[2-(3trifluoromethyphenyl) -quinazolin-4-ylJ -amine (111-53) 13 NMR (500 MHz, DMSO-d) 812.2 (br, 13), 10.45(br, 1R), 7.53 13), 7.43 J 7.2 Hz, IH), 7.06 7 8.2 Hz, H) 6.65- J 8.3 Hz, 1H), 6.57' J 7.6 Hz, 1H), 6.51 J 7.8 Hz, 13), 6.43 J 7.8 Hz, 11), 6.32 J 7.6 Hz, 1H), 5.51 13), 2.03 Ca, 3H); MS 4-_ 370.2 Example 283 [2-(3-Cyanophenyl) -quinazolin-4-ylJ methyi-2H-pyrazol-3-yl)-amine (111-54): 3 NMR (500 MHz, DMSO-dC) 89.01 IH), 8.96 Cm, 2H), 8.28 J 7.3 Hz, 1H), 8.16 br, 2H), 8.06 J 7.8 Hz, 13), 7.88 (m,1IH), 6.96 1H), 2.58 33); MS 327.1 Example 284 E2-(3-Isopropyiphenyl)-quinazolin-4-ylJ-(5methyl-2H-pyrazol-3-yl)-amine (111-55): '1H NNR (500 MHz, DMSO-d6) 68.89 J 7.5 Hz, 1H), 8. 37 11) 8.26 -296- 11), 8.08 2H), 7.81 br, 1H), 7.67 2H), 6.88 1H), 3.12 1H), 2.40 3H), 1.38 J 6.9 Hz, 6H);.MS 344.2 Example 285 (5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-3-ylquinazolin-4-yl)-amine (111-56): 'H NMR (500 MHz, DMSO-d6) 89.50 1H), 8.84 J 7.3 Hz, 1H), 8.80 J 4.4 Hz, 1H), 8.66 J 8.2 Hz, 1H), 7.87 2H), 7.77 (m, 1H), 7.60 J 7.2 Hz, 1H), 6.67 1H), 2.28 (s, 3H); MS 303.1 Example 286 (3-Acetylphenyl) -quinazolin-4-yll methyl-2H-pyrazol-3-yl)-amine (111-57): 'H NMR (500 MHz, DMSO-d6) S8.80 1H), 8.55 J 7.7 Hz, 1H), 8.42 J 7.6 Hz, 1i), 8.00 J 7.0 Hz, 11), 7.76 (m, 2H), 7.58 J 7.7 Hz, 1H), 7.48 br, 1H), 6.60 (s, IH), 2.49 3H), 2.03 Cs, 3H); MS 344.1 Example 287 [2-(3,5-Ditrifluoromethylphenyl)-quinazolin- 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (III-58): 'H NMR (500 MHz, DMSO-d6) 810.7 br, 1H), 8.95 2H), 8.63 J 8.2 Hz, 1H), 8.25 7.86 2H), 7.58 (t, J 6.9 Hz, 1H), 6.62 1H), 2.26 3H); MS 438.1 Example 288 [2-(3-Hydroxymethylphenyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (II1-59): 'H NMR (500 MHz, DMSO-d6) 8 8.74 J 7.9 Hz, 1H), 8.33 IH), 8.17 br, 1H), 7.95 br, 1H), 7.89 11), 7.62 3H), 6.72 1H), 5.53 s(8, 1H), 4.60 2H), 2.28 3H)) MS 332.1 Example 289 (5-Methyl-2H-pyrazol-3-yl)-[2-(3phenoxyphenyl)-guinazolin-4-yl]-amine (111-60): mp 231- -297- 232 0 C; 1H NMR (DMSO-d6) 8 2.21 (3H, s),-6.59 (1H, s), Va o 7.10-7.22 (4H, 7.41-7.45 (2H, 7.54-7.59 (2H, m), C 7.81 (2H, 8.09 (1i, 8.27 (1W, 8.64 (1i, m), 10.40 (1H, 12.20 (1I, IR (solid); IR (solid) 15891 1560, 1541, 1536, 1484, 1360, 1227; MS 394.7 Example 290 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3- C phenozyphenyl)-guinazolin-4-yl]-amine (111-61): mp 193- C 195 0 C; 1H NMR (DMSO-d6) 8 0.67 (2H, 0.93 (2H, m),1.87 o 10 6.56 (1I, 7.06-7.20 (4H, 7.40-7.43 (2H, ID 7.55-7.59 (2H, 7.81 (2H, 8.11 (1H, 8.27 o (1H, in), 8.63 (1H, 10.43 (11, 12.26 (1H, IR (solid); IR (solid) 1589, 1574, 1527, 1483, 1369, 1226; MS 420.7 Example. 291 (5-Methyl-2H-pyrazol-3-yl) (2-thiophen-3-ylquinazolin-4-yl)-anine (III-62): 1H NMR (500 MHz, DMSO-d6) 811.78 br, iH), 8.75 J 8.1 Hz, 1H), 8.68 (s, 1iH), 7.98 (dd, J 7.9, 7.5 Hz, 1H), 7.89 2H), 7.81 1H), 7.68 J =7.5 Hz, 1H), 6.69 1H), 2.30 (s, 3H); MS 308.1 Example 292 (2-Phenyl-quinazolin-4-yl)-(2H-pyrazol-3-yl)amine (111-63): mp 247-2490C; IH NMR (DMSO) 6 6.99 (1H, br 7.49-7.58 (5H, 7.81 (1H, br 7.83 (2H, m), 8.47-8.49 (2H, 8.66 (1H, 10.54 (1W, 12.59 IR (solid) 3145, 2922, 1622, 1597; MS 288;2 Example 293 (2H-Pyrazol-3-yl) (2-pyridin-4-yl-quinazolin- 4-yl)-amine (111-64): mp 285-286C; 1H NMR (DMSO) 6 6.99 (1H, br 7.65 (1H, 7.81-7.94 (3H, 8.3-8.35 (2H, 8.73 (1H, 8.84-8.90 (2H, 10.76 (1H, s), -298- 12.6 (1H, IR (solid) 3180, 2972, 1600, 1574; MS 289.2 Va Example 294 5-Ethyl-2H-pyrazol-3-yl) (2-phenylquinazolin-4-yl)-amine (111-65): mp 221-2220C; 1H NMR (DMSO) 6 1.31 (3H, 2.68 (2H, 6.80 (IH, 7.50- 7.60 (4H, 8.45-8.55 (2H, 8.65-8.75 (1H, 10.44 12.27 IR (solid) 3190, 1622, 1595, 1575, 1533, 1482, 1441, 1420, 1403, 1361, 758, 711; MS 316.2 o 10 Cl o Example 295 (2-Phenyl-quinazolin-4-yl).- (5-propyl-2Hpyrazol-3-yl)-amine -(II1-66): mp 204-205C; 1H NMR (DMSOd6) 6 1.02 (3H, 1.66-1.75 (2H, 2.69 (2H, 6.80 (1H, 7.45-7.60 7.80-7.88 (2H, 8.45-8.50 (2H, 8.65 (1H, 10.39 (1H, 12.25 (1H, IR (solid) 1621, 1560, 1572, 1533, 1479, 1441, 1421, 1363, 1328, 999, 827; 808, 763, 709, 697; MS 330.2 Example 296 (S-Isopropyl-2a-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-67): mp 218-219 0 C; 1H NMR (DMSO-d6) 8 1.36 (6H, 3.05 (1H, 6.86 (1H, s), 7.48-7.59 (4H, 7.80-7.88 (2H, 8.49-8.58 (2H, m), 8.66 (1H, 10.47 (1H, 12.30 (1H, IR (solid) 3173, 2968, 1619, 1593, 1573, 1533, 1478, 1438, 1413, 1398, 1363, 1329, 995, 822, 798, 761, 707, 666, 659; MS 330.2 Example 297 (5-tert-Butyl-2H-pyrazo-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-68): mp 136-137C; 'I NMR (DMSO-ds) 6 1.38 (9H, 6.87 (1H, br 7.51-7.57 (4H, in), 7.84-7.85 (2H, 8.49-8.51 (2H, 8.65 (1H, d), 10.43 (iH, 12.21 (1H, br IR (solid) 3162, 2963, 1621, 1590, 1572; MS 344.2(M+H)*+.

-299- Va Example 298 (5-tert-Butyl-2H-pyrazol-3-yl)-(2-pyridin-4- 0 yl-quinazolin-4-yl)-amine (111-69): mp >3000W; 1H NMR (DMSO) 6 1.38 (9H, 6.82 (1H, br.s), 7.63 (1H, m), 7.86-7.91 (2H, 8.32-8.33 (28, 8.69 (lH, d), 8.75-8.76 10.60 (1H, 12.31 (1H, br IR (solid) 3683, 3149, 2963, 1621; MS 345.2(M+H)*.

ci IN Example 299 (5-Cyclopentyl-2-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-70): mp 240-241 0 C; 3H NMR Ci \O (DMSO-d6) 8 1.68-1.89 (6H, 2.03-2.17 (2H, 3.14- S3.22 m),-6.80 (IH, 7.50-7.60 (4H, 7.80-7.89 (2H, 8.45-8.52 (2H, 8.67 (12, 10.52 (1H, S), 12.26 (1H, IR (solid) 2957, 1621, 1591, 1571, 1531, 1476, 1438, 1405, 1370, 1325, 999, 951, 801, 775, 761, 747, 710695, 668, 654; MS 356.2(M+H)+.

Example 300 (5-Phenyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl) -amine (III-71): mp 207-209 0 C; 1H NMR (DMSO) 6 7.38-7.40 (1H, 7.50-7.58 7.82-7.88 (4H, 8.51 (2H, 8.67 10.58 (1H, 13.11 br IR (solid) 3345, 3108, 1627, 1612; MS 364.2 Example 301 (5-Carboxy-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (II1-72): (5-Methoxycarbonyl-2Hpyrazol-3-yl)-(2-phenyl-quinazolin-4-yl)-amine (111-73) (345mg, 1 mmole in THF, 6 mL) was treated with NaOH (IM, mL), stirred at 50 0 C for 5 hours, cooled to room temperature, and neutralised with IM HC1. The mixture was concentrated in vacuo to remove THF then diluted with water and the resulting precipitate filtered. The residual solid was dried at 80 0 C under.vacuum to afford 111-72 as an off-white solid (312 mg, mp 289-2910C -300- ND iH NMR (DMSO) 8 7.45 (1H, br 7.50-7.60 O 7.80-7.88. (2H, 7.40-7.50 (2H, 8.60-8.70 (1H, C 10.70 (1H, 13.00-13.80 (2H, br IR (solid) 1699, 1624, 1607, 1570,1539, 1506, 1486, 1398, 1333, 1256, 1177, 1004, 827, 764, 705; MS 332:3(M+H)*.

Example 302 (5-Methoxycarbonyl-2H-pyrazol-3-yl)- (2phenyl-quinazolin-4-yl)-amine (III-73): mp 271-2730C; 1H NMR (DMSO) 8 3.95 (3H, 7.50-7.65 (5H, 7.80-7.98 (2H, 8.40-8.50 (2H, 8.65-8.73 (IH, 10.80 (1H, Ss), 13.80 (1H, IR (solid) 3359, 1720, 1624, 1597, 01561, 1538, 1500, 1475, 1435, 1410, 1358, 1329, 1283, 1261, 1146, 1125, 1018, 1010, 944, 827, 806, 780, 763, 703, 690, 670; MS 346.3(M+H) Example 303 (5-Hydroxymethyl-2H-pyrazol-3-yl)- (2-phenylquinazolin-4-yl)-amine (III-74): A solution of Methoxycarbonyl-2H-pyrazol-3-yl)-(2-phenyl-quinazolin-4yl)-amine (III-73) (345mg, Immol) in anhydrous THF was treated with lithium borohydride (125mg, 5.75 mmol) at 65 0 C for 5 hours. The mixture was cooled to room temperature then combined with 2M HCI' and ethyl acetate.

Solid sodium hydrogen carbonate was added to achieve pH 8 and the resulting mixture extracted with ethyl acetate..

The extracts were dried over magnesium sulphate and concentrated. Purification by flash chromatography (SiO 2 methanol-dichloromethane gradient) afforded III-74 mg, 30%) as an off-white solid: mp 238-239 0 C; IH NMR (DMSO) 8 4.58 (2H, d, CH2), 5.35 (1H, s, OH), 6.94 (1H, 7.50-7.60 (4H, 7.85-7.90 (2H, 8.48-8.54 (2H, 8.69 (IH, 1H), 10.40 (1H, 12.48 (1H, IR (solid) 1652, 1621, 1603, 1575, 1558, 1539, 1532, 1480, 1373, 1320, 1276, 1175, 1057, 1037, 1007, 951, 865, 843, 793; 780, 7124; MS 318.2(M+H) -301o Example 304 (5-Methoxymethyl-2H-pyrazol-3-yl) (2-phenyl- Squinazolin-4-yl)-amine (111-75): mp 190-1910C; "H NMR (DMSO) 8 3.34 (3H, 4.45 (2H, 7.00 (1H, 7.50- 7.62 (4H, 7.82-7.90 (2H, 8.45-8.52 (2H, 8.65 c- (1H, br. 10.50 (1 12.30 (1H, IR .(solid) 3177, 1606, 1589, 1530, 1479, 1441, 1406, 1374, 1363, 1329, 1152, 1099, 999, 954, 834, 813, 766, 707, 691; MS S 332.3(M+H) CD c0 Example 305 [5-(3-Hydroxyprop-1-yl) -2H-pyrazol-3-yll- (2o phenyl-quinazolin-4-yl)-amine (111-76): A solution of benzyloxypropyl-2H-pyrazol-3-yl) (2-phenyl-quinazolin-4yl)-amine (III-78) (200mg, 0.46mmol) in toluene (4mL) and acetonitrile (8mL) was stirred with trimethylsilyl iodide (0.64ml, 4.6mmol) at 550C for 3 hours to afford an amber coloured solution. This mixture was diluted with ethyl acetate and aqueous sodium hydrogen carbonate. The resulting layers were separated, the organic layer was dried over magnesium sulphate and concentrated in vacuo.

Purification by.flash chromatography (SiO 2 methanoldichloromethane gradient) affords a yellow oil (115mg).

Trituration with dichloromethane affords III-76 as an off-white solid dried at 750C under vacuum (83mg, mp 164-165C; IH NMR (DMSO) 8 1.80-1.90 (2H, m) 2.70-2.80 (2H, 3.50-3.60 (2H, 4.59 (1H, 6.80 (1H, s), 7.50-7.60 (4H, 7.82-7.90 (2H, 8.48-8.53 (2H, m), 8.63 (1H, 10.40 (1H, 12.25 (1H, IR (solid) 1622, 1587, 1574, 1562, 1528, 1480, 1440, 1421, 1368, 1329, 1173, 1052, 1030, 1006, 952, 833, 762, 734, 706, 690, 671, 665; MS 346.0(M+H)*.

Example 306 [5-(3-Methoxyprop-l-yl)-2H-pyrazol-3-yl] phenyl-quinazolin-4-yl)-amine (111-77): mp 169-1700C; 'H -302- ID NMR (DMSO-d6) 1.86-1.97 (2H, 2.75 (2H, 3.30 (3H, 3.45 (2H, 6.80 (1H, 7.50-7.60 (4H, 7.80- C< 7.90 (2H, 8.45-8.55 (2H, 8.67 (1H, 10.30 (1H, 12.25 (1H, IR (solid) 1620, 1591, 1572, 1532, 1476, 1425, 1408, 1373, 1326, 1117, 1003, 831, 764, 714, 695; MS 360.3(M+H) SExample 307 [5-(3-Benzyloxyprop-l-yl)-2H-pyrazol-3-yl]- Ci (2-phenyl-quinazolin-4-yl)-amine (11-78): mp 177-178oC; 1H NMR (DMSO) 8 1.92-2.03 (2H, 3.76-3.85 (2H, m), I 3.52-3.62 (2H, 4.51 (2H, 6.82 (1H, 7.28-7.40 o (5H, 7.46-7.58 (4H, 7.80-7.85 (2H, 8.47-8.52 (2H, 8.66 (1H, 10.45 (1H, IR (solid) 1621, 1591, 1562, 1532, 1479, 1454, 1426, 1408, 1374, 1101, 1006, 835, 766, 738, 712, 696; MS 436.3(M+H) Example 308 [5-(3-Aminoprop-l-yl)-2H-pyrazol-3-yl]-(2phenyl-quinazolin-4-yl)-amine (III-79): A solution of (3-tert-butoxycarbonylaminoprop-1-yl)-2H-pyrazol-3-yl] (2-phenyl-quinazolin-4-yl)-amine (III-80) (250mg, 0.56mmol), in dichloromethane (3mL) at 0 C was treated with TFA (2mL). The mixture was warmed to room temperature then concentrated in vacuo. The residue was triturated and concentrated from dichloromethane and ether, then triturated with dichloromethane to crystallize the TFA salt. The resulting solid was collected by filtration and dissolved in a mixture of ethanol (3mL) and water (3mL). Potassium carbonate was added in portions to achieve pH 8 then the mixture allowed to crystallize. The product was collected by filtration and dried at 800C under vacuum to afford III-79 as an off-white powder (122mg, mp 205-207oC; 1H NMR (DMSO) 8 1.68-1.83 (2H, 2.65-2.80(.4H, 6.80 (1H, 7.50-7.60 (4H, 7.80-7.90 (2H, 8.45-8.53, (2H, -303- 8.65 (1H, 10.45 (1H, br IR (solid) 1621, D 1598, 1568, 1533, 1484, 1414, 1364, 1327, 1169, 1030, 0 951, 830, 776, 764, 705, 677; MS 345.3(M+H) Example 309 3 -tert-Butoxycarbonylaminprorop--yl)-2Hpyrazol-3-yl] -(2-phenyl-quinazolin-4-yl)-amine (111-80): mp 199-200 0 C; IH NMR (DMSO) 8 1.37 (9H, 1.71-1.82 eC 2.67 (2H, 3.00-3.11 (2H, 7.81 (1H, s), 7.99 (1H, 7.50-7.60 (4H, 7.80-7.85 (2H, 8.48- 8.52 (2H, 8.63 (1H, 10.40 (1H, 12.26 (1H, m); \0 IR (solid) 2953, 1687, 1622, 1594, 1573, 1535, 1481, S1441, 1419, 1364, 1327, 1281, 1252, 1166, 1070, 1028, 998, 951, 848, 807, 768, 740, 728, 710,693; MS 445.3 Example 310 5-Isopropylcarbamoyl-2H-pyrazol-3-yl) phenyl-quinazolin-4-yl)-amine (III-81): 1H NMR (500MHz, DMSO-d6) 8 1.20 J .6.6 Hz, 6H), 4.13 1H), 7.42 (br. s, 1H), 7.61 (dd, J 7.0, 7.7 Hz, 2H), 7.66 J 7.1 Hz, 1H), 7.71 1H), 7.99 8.39 1H), 8.42 J 7.1 Hz, 2H), 8.74 J 8.2 Hz, 1H), 11.41 (br. s, 1H); EI-MS 373.2 HPLC-Method C, Rt 14.09 min.

Example 311 (5-Allylcarbamoyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-82) IH NMR (500MHz, DMSO-d6) 6 4.02 2H), 5.15 1H), 5.23 1H), 5.94 1H), 7.45 (br. s, 1H), 7.60 J 6.9 Hz, 2H), 7.64 1H), 7.72 1H), 7.98 2H), 8.43 (m 8.72 J 8.2 Hz, 1H), 8.84 (br. s, 1H), 11.34 (br. s, 1H); EI-MS 371.2 HPLC-Method C, Rt 13.67 min.

Example 312 [5-(2-Methoxyethylcarbamoyl) -2H-pyrazol-3yl]-( 2 -phenyl-quinazolin-4-yl)-amine (III-83): 1H NMR -304- IND(500MHz, DMSO-d6) 8 3.32 3H), 3.48 4H), 7.36 (br.

s, 1H), 7.62 2H), 7.63 1R), 7.71 1K), 7.98 Im, 2H), 8.41 (dd, J 1.4, 7.0, 2H), 8.70 2H), 11.30 (br. s, 1H); EI-MS 389.2 HPLC-Method C, Rt 12.37 min.

Example 313 (5-Benzylcarbamoyl-2H-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl)-amine (III-84): 1R NNR (500MHz, DMSO-d6) 8 4.52 J 6.0 Hz, 2H), 7.29 1H), 7.38 o 10 J 4.2 Hz, 4H), 7.58 J 7.5 Hz, 2H), 7.63 (m, 1H), 7.72 1H), 7.98 2H), 8.43 J 7.7 Hz, 2H), 8.72 J 7.5 Hz, 1H), 9.23 (br. s, 2H), 11.34 (br. s, 1H); EI-MS 421.2 HPLC-Method C, Rt 16.76 min.

Example 314 (5-Cyclohexylcarbamoyl-2H-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl)-amine (III-85): 1H NMR (500MHz, DMSO-d6) 8 1.16 1H), 1.34 1.62 2.6 Hz, IH), 1.76 2H), 1.85 2H), 3.79 1H), 7.43 1H), 7.60 iJ 7.2 Hz, 2H), 7.65 7.1 Hz, 1H), 7.71 (ddd, J= 2.2, 5.4, 8.2 Hz,i 1H), 7.98 2H), 8.35 1H), 8.43 (dd, J 1.4, 7.2 Hz, 2H), 8.72 J 8.2 Hz, 1H), 11.34 (br. s, 11); EI-MS 413.5 HPLC-Method C, Rt 17.18 min.

Example 315 (5-Diethylcarbamoyl-2H-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl)-amine (111-86): 1H NMR (500MHz, DMSO-d6) 6 1.18 (br. 3H), 1.25 (br. s, 3H), 3.49 (br.

9, 2H), 3.69 s, 2H), 7.21 1H), 7.59 J 6.9 Hz, 2H); 7..62 1H), 7.70 1H), 7.96 21) 8.39 7.1 Hz, 2H), 8.74 J 8.4 Hz, 1H), 11.37 (br.

EI-MS 387.2 HPLC-Method C, Rt 14.50 min.

-305- Example 316 [5-(Benzyl-methyl-carbamoyl)-2H-pyrazol-3- ID yl]-(2-phenyl-quinazolin-4-yl)-amine (11-87): 'H NMR (500MHz, DMSO-d6) 6 3.33 3H), 4.75 2H), 7.26 (m, 1H), 7.31 1K), 7.38 4H), 7.58 2H), 7.70 (m, 1H), 7.95 3H), 8.26 1H), 8.40 J 7.8 Hz, 2H), 8.75 1K), 11.2 (br. a, 1H); EI-MS 435.2 HPLC-Method C, Rt 16.77 min.

ci IN Example 317 (2-Phenyl-quinazolin-4-yl)-(5propylcarbamoyl-2H-pyrazol-3-yl)-amine (II1-88): 1

NMR

\O (500MHz, DMSO-d6) 8 0.94 J 7.3 Hz, 3H), 1.57 (m, S2K), 3.24 JC 6.5 Hz, 2H), 7.39 (br. a, 1H), 7.60 (t, J 7.3 Hz, 2K), 7.64 1H), 7.71 (br. t, J 6.5 Hz, 1H), 7.98 2H), 8.42 J 7.2.Hz, 2K), 8.61 Cbr. s, 1H), 8.72 J 8.5 Hz, 1H), 11.34 (br. a, 1H); EI-MS 373.3 HPLC-Method C, Rt 13.51 min.

Example 318 [5-(Etyl-isopropyl-carbamoyl)-2H-pyrazol-3yl]-( 2 -phenyl-quinazolin-4-yl)-amine (111-89): 1H NMR (500MHz, DMSO-d6) 8 0.92 J 7.4 Hz; 6H), 1.52 (m, 2H), 1.59 1H), 3.79 2H), 7.53 (br. a, 1K), 7.57 J 7.5 Hz, 2K), 7.65 J 7.2 Hz, 1H), 7.71 (m, 1H), 7.99 2H), 8.23 (br. d, J =8.8 Hz, IH), 8.46 (d, J 7.5 Hz, 2H), 8.74 J 8.4 Hz, 1K), 11.34 (br. s, 18); EI-MS 401.2 HPLC-Method C, Rt 15.51 min.

Example 319 (5-Cyclopropylcarbamoyl-2H-pyrazol-3-yl)-(2phenyl-quinazolin-4-yl)-amine (111-90): 'H NMR (500MHz, DMSO-d6) 8 0.60 2H), 0.74 2K), 2.86 1H), 7.34 (br. a, 1K), 7.62 3H), 7.70 7.97 2H), 8.41 J 7.9 Hz, 2H), 8.63 (br. s, 1H), 8.72 J 7.8 Hz, 1H), 11.35 (br. a, 11); EI-MS 371.2 (M+H);'HPLC- Method C, Rt 12.64 min.

-306- Example 320 (5-Isobutylcarbamoyl-2H-pyrazol-3-yl)-(2- Va phenyi-quinazoln-4-yl).amine (311-91): 1 M NMIR (500MHZ, Cl DMS-d6) 8 0.94 J 6.7 Hz, 6H), 1.88 (in, 1H), 3.12 J 6.4 Hz, 2H), 7.45 (br. s, 1H), 7.58 J 7.2 Hz, 3H), 7.64 J 7.1 Hz, lH), 7.71 im, IH), 7.98 (Im, 2H)i j.44 (dd, J m 1.3, 7.9 Hz, 2H), .8.62 (br. a, 1H), '8.72 J 8.3 Hz, 1H), 11.33 s, 1H); El-MS 387.2 C( HPLC-Method C, Rt 14.70 min.

Cl o 10 Exgmple 321 S-((3S)-3-Methoxymetyl-pyrrolidine-l- INDcarbonyl -2H-pyrazol-3-yl)- (2-phenyl-quinazolin-4-y) amine (111-93): 'H NMR (500MHz, DMSO-dG) 6 2.00 2H)), 2.12 1H), 3.29 3H), 3.45 J 8.7 Hz, 1H), 3.57 (dd, J 3.2, .9.3 Hz, 1H), 3.86 1H), 3.92 (m, iH), 4.36 21), 7.45 (br. s, 1M), 7.59 J 7.2 Hz, 2H), 7.63 11), 7.69 1H), 7.97 (m,y2H), 8.40 J Hz, 21H), 8.74 J 7.6 Hz, 11H), 11.38 (br. a, 11); El-MS 429.2 HPLC-Method C, Rt 13'.84 min.

Example 322 (2-Phenyl-qninazolin-4 (5 -mtolylcarbazuoyl-23-pyrazo-3.yl) -aine (111-94): 1H NMR (500MHz, DMSO-d) 8 2.33' 3H), 6.97 J 7.5 Hz, iH), 7.27 7.8 H, 1H); 7.62 7H), 7.72 Cfn, 1H), 7.98 Cm, 2H), 8.46 (dd, S 2.0, 7.9 Hz, 2H), 8.71, 11), 10.22 1H),.11.31 (br. a, 1H); El-MS 421.2 HPLC-Method C, Rt 17.11 min..

Example 323 (2-Phenyl-quinazolin-4-yl) tolylcarbanoyl-2E-pyrazol-3-yl)-amine (111-95): 1 H NMR (500MHz, DMSO-d6) 8 2.30 3H), 7.20 J 8.3 Hz, 2H), 7.62 Cm, 5H), 7.68 J 8.3 Hz, 2H), 7.72 (m, 11), 7.98 2H), 8.46 (dd, J 1.8, 7.0 Hz, 8.72 Cm, 1i), 10.31 11), 11.36 (br. s, 1H); El-MS 421.2 HPLC-Method C, Rt 16.95 min.

-307om Example 324 (5-IMethylcarbanoyl-2-pyrazol-3-yl) phenyl-quinazolin-4-yl)-amine (111-96) 'H NMR (500MHz, DMSO-dS) 8 2.82 J Hz, 3H), 7.31 (br. s, 1H), 7.62 32), 7.69 1H), 7.97 2H), 8.42 J 7.1 Hz, 2H), 8.59 (br. s, 1H), 8.71 J 8.0 Hz, 1H), 11.30 (br. s, 1H); El-MS 345.1 HPLC-Method C, Rt C~K 11.02 min.

Va 'Example 325 [5-(Morpholine-4-carbonyl)-2H-pyrazol-3-yll- IC 2 -phenyl-quinazolin-4-yl)-amine (111-97): 'H NMR (500MHz, DMSO-dE) 8 3.33 Cm, 42), 3.83 (m 4H), 7.34 Cbr. s, 12), 7.53 (mn, 4H), 7.86 (Tn, 22), 8.43 2H), 8.67 Cd, J 8.6 Hz, 1H), 10.70 Cs, 12), 13.56 1H); EI-MS,401.2 2PLC-Method A, Rt 2.68 min.

Example 326 [5-(l-Methylpiperazine-4-carbonyl)-ZEpyrazol-3-ylJ-(2-phenyl-quinazolin-4-yl)-amine (111-98) 3H NM (50OMHz, DMSO-d) 8 2.25 Cs, 3H), 2.43 4H), 3.87 (m 42), 7.33 Cbr. a, 12), 7.53 4H), 7.87 2H), 8.45 22), 8.67 J 7.6 Hz, iH), 10.70 (s, 1H), 13.30 Cs, 12); El-MS 414.2 HPLC-Method A, Rt 2.38 min.

Example 327 [5-(2-Hydroxyethylcarbamoyl-2&-pyrazol-3-ylJ- (2-phenyl-quinazolin-4-yl)-amine (111-99): 1H NM (500MHz, DMSO-dE) 8 3.36 Cm, 2H), 3.52. 2H), 4.79 12), 7.50 5H) 7.83 2H) 8.50'(m, 4H) 10.52 Cbr. a, 1H), 13.25 12); El-MS 375.1 (14tH); HPLC-Method A, Rt 2.51 min.

Example 328 (5-Carbamoyl-2H-pyrazol-3-yl)- (2-phenylquinazolin-4-yl)-amine (111-100): To a solution of 5-(2phenyl-quinazolin-4-ylamino) -H-pyr~zole-3-carboxylic -308acid 2,5-dioxo-pyrrolidin-1-yl ester (270 mg, 0.63 mmol).

Va N in DMF (20 ml) was added a solution of ammonia in 1,4- 0 dioxane (0.5 M, 10 ml). The resulting mixture was stirred at room temperature for 24 h. After concentration of the solvents, the residue was added to water (20 ml). The resulting precipitate was collected to afford III-100 (168 mg, 80%)as a yellow solid. 1H NMR C (500MHz, DMSO-d6) 6 7.77-7.51 6H), 7.86 (br s, Va CI 8.11 1K), 8.50 2H), 8.63 H1K), 10.52 1H), o 10 11.25 1H); EI-MS 331.1 HPLC-Method A, -Rt 2.52 imin.

Example. 329 (4-Bramo-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (III-101): Prepared according to Method A to afford a yellow solid, mp 189C; 'H NMR (DMSOdG) 8 7.44-7.46 (3H, 7.58 (1H, 7.87 (2H, d),.8.15 (1K, 8.31-8.34 (2H, 8.49 (1iH, 10.08 (1H, s), 13.13 (1H, IR (solid) 3286, 2969, 1738, 1632; MS 366.2/368.2(M+H) Example 330 4 -Bromo-5-methyl-2H-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-102) mp, 183-18SC; 'H NMR (DMSO) 6 2.33 (3H, br 7.44-7.46 (3H, 7.57 (1H, 7.84-7,87 (2H, 8.31-8.34 (2H, 8.48 (1H, d), 10.05 (1H, 12.91 (1i, br IR (solid) 3362, 3065, 2831, 1619, 1578; MS 380.2/382.2(M+H)+.

Example 331 (4-Cyano-20-pyrazol-3-yl)-(2-phenylquinazolin-4-yl)-amine (111-103): mp >250OC; 1H NMR (DMSO) 6 7.47-7.49 (3H, 7.64 (1H, 7.91 (2H, 8.40- 8.43 (2H, 8.53 (1H, 8.71 (1H, 10.61 (1H, s), 13.60 IR (solid) 3277, 3069, 2855, 2231, 1625; MS 313.2(M+H)+.

-309- Example 332 (5-Methyl-2H-pyrazol-3-yl)-(2-morpholin-4.yl- IND quinazolin-4-yl)-amine (111-104): mp 223-224 0 C; 1H NMR (DMSO) 5 2.26(3H, 3.65(4H, 3.75(4H, 6.44(11, 7.12(11, 7.33(1l, 7.56(lH, 8.37(11, d), 10.02(11, 12.13(12, br IR (solid) 1621, 1578, 1537, 1475, 1434, 1385; MS 311.0 Example 333 (5-Methyl-2H-pyrazol-3-yl) (2-piperazin-1-yl- Va qninazolin-4-y) -amine (111-105): mp. 179-181oC, IH NMR (DMSO) 8 2.26(32, 2.74 (4H, br 3.71(4, br s), 6.43(1, 7.08(12, 7.30(1H, 7.53(11, t), 8.34(12, 9.50(12, 12.0812, br IR (solid) 2853, 1619, 1603, 1566, 1549, 1539; MS 310.0 (M+H) Example 334 (4-M4ethylpiperidin-1-yl) -quinazolin-4-yll- (5-ietbyl-2H-pyrazol-3-yl)-amine (111-106): mp 148-150 0

C;

1 NMR (DMSO) 6 1.06(3H, .1.03(2H, 1.51-1.70(3H, 2.26(30, 2.86(2H, 4.73(2H, 6.44(11, s), 7.06(1H, 7.29(1H, 7.52(11, 8.32(11, d), 9.92(12, 12.09(1H, br IR (solid) 2917, 2840, 1629, 1593, 1562, 1546, 1486; MS 323.0 Example 335 (4-Methylpiperazin-1-yl) -quinazolin-4-ylJ (5-methyl-2-pyrazol-3-yl)-amine (111-107): mp 105-107 0

C;

I- NMR (DMSO) S 2.21(3H, 2.26(3H,' 2.34(4H, in), 3.75(4, 6.45(12, 7.09(12, 7.31(12, d), 7.54(2, 8.34(12, 9.96(11, 12.12(11, br s); IR (solid) 2934, 2844, 2804,, 1620, 1593, 1572, 1536, 1476; MS 324.0 Example 336 (5-Methyl-2H-pyrazol-3-yl)-(2-piperidin-1-ylquinazolin-4-yl) -amine (111-108) mp 294-C; NMR (DMSO) 8 1.45-1.58 (4H, 1.63 (2H, m, 2.26 (31, 3.79 -310- (4H, 6.45 (1H, br 7.06 (1H, 7.29 (1H, d), Va oN 7.52 (1H, 8.33 (1H, 9.92 (1H, 12.11 (1H, br 0 IR (solid) 2929, 2847, 1632, 1591, 1500, 1482, 1437, 1382;MS 309.3 Example 337 (2-Azepan-1-yl) 2H-pyrazol-3-yl) -amine (111-109): mp 269-C; H NMR (DMSO) C8 6 1.50 (4H, br 1.76 (4H, br 2.25 (3H, 3.78 IN (41H, 6.55 (1H, br 7.03 (1H, 7.28 (1H, d), 10 7.50 (1H, 8.33 (11, 9.92 (1H, 12.09 (lH, br IR (solid) 3427, 2963, 2927, 2909, 2872, 2850, 1623, 1595, 1586, 1568, 1504, 1486, 1468, 1386, 1427; MS 323.3 Example 338 [2-(4-(2-fHydroxyethylpiperidin-1-yl)quinazolin-4-yll (5-methyl-2H-pyrazol-3-yl)-amine

(III-

110): mp 1750C; 1H NMR (DMSO) 8 1.08 (2H, 1.38 (2H, 1.57-1.83 (3H, 2.26 (3H, 2.85 (2H, 3.47 (2H, 4.38 (11, 4.75 (2H, 6.45 (1H, br s), 7.06 (1H, t),-7.29 (1H, 7.52 (1H, 8.32 (1H, d), 9.93 (1H, 12.12 (1H, br IR (solid) 3365, 3073, 2972, 2868, 1622, 1604, 1586, 1568, 1486, 1463, 1440, 1394; MS 353.2 Example 339 (5-Cyclopropyl-2H-pyrazol-3-y)- methylpiperidin-1-yl)-quinazolin-4-ylJ-amine (111-111): To a solution of (5-cyclopropyl-11-pyrazol-3-yl)-(2chloro-quinazolin-4-yl)-amine (118 mg, 0.41 mmol) in tert-butanol (3.0 mL) was added 4-methylpiperidine (0.49 mL, 4.1 mmol) and.the reaction mixture heated at reflux overnight. The reaction mixture was concentrated in vacuo and the residue dissolved in a mixture EtOI:water 4 mL). Potassium carbonate (57mg, 0.41 mmol) was added and the mixture stirred at room temperature for 2 -311hours. The resulting suspension was filtered, washed ND with water and rinsed with Et20 (x2) to afford IIIo 111 as a white solid (123mg, mp 190 0 C; 1H NMR (DMSO) 8 0.66 (2H, 0.93 (5W, br 1.07 (2H 1.66 (3H, 1.91 (I1, 2.85 (2H, 4.72 (2H, 6.33 (1H, 7.06 (1H, 7.29 (1H, 7.52 (1W, 8.31 (1i, 9.95 12.18 (1W, br IR (solid) 2925, 2852, 1622, 1590, 1581, 1558, 1494, 1481, 1453, 1435, IND1394; MS 349.2 Example 340 2 1 4 -Diosa-8-aza-spiro[4,5]dec-8-yl)- C quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl) -amine (III- N 112): mp 191 0 C; 1 NMR (DMSO) 8 1.65 (4H, 2.26 (3H, 3.90 (4H, 3.93 (4H, 6.43 (11, br 7.09 (11, 7.32 (11, 7.54 (1H, 8.35 (1H, 9.99 (1U, br 12.13 (1H, br IR (solid) 3069, 2964, 2927, 2868, 1618, 1581, 1568, 1540, 1495, 1481, 1435, 1390; MS 367.3 Example 341 [2-(4-Cyclopentylamino-piperidin-1-yl) quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine

(III-

113): mp 191 0 C; 1H NMR (DMSO) 1.33 (2H, d) 1.65 (4H, 1.87 (2H, 2.20 (1H, 2.26 (3H, 2.49 (2H, 3.00 (2H, 3.36 (2H, 4.61 (2H, 6.45 (1H, br 7.07 (1H, 7.31 (1W, 7.52 (1H, 8.33 (1H, 9.94 (1H, bra 12.12 (1H, br IR (solid) 3371, 2943, 1622, 1600, 1581, 1545, 1509, 1463, 1440, 1390; MS 378.2 (M+H) 4 Example 342 (4-Hydroxypiperidin-1-yl)-quinazolin-4yll- (5-methyl-2H-pyrazol-3-yl)-amine (III-114): mp 123C; 'H NMR (DMSO) 8 1.34 (2H, 1.80 (2H, 2.26 (3H, s), 3.24 (2H, 3.72 (1H, br 4.39 4.70 (1H, 6.44 (1H, br 7.07 (1H, 7.30 (1H, 7.53 -312- (1H, 8.33 (1H, 9.94 (1H, br 12.11 (IH, br s); IR (solid) 3265, 3151, 2927, 2863, 1622, 1600, 1572, 1540, 1504, 1476, 1440, 1390, 1349, 1066, 1098; MS 325.3 Example 343 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4hydroxy-4-phenylpiperidin- -yl) -quinazolin-4-yl] -amine (III-115) mp 131°C; 'H NMR (DMSO) 8 0.64 (2H, 0.93 (2H, 1.68 (2H, 1.83-1.97 (3H, 3.20-3.45 (2H, 4.69 (2H, 5.11 (1H, 6.37 (1H, br 7.08 (1H, 7.20 (1H, 7.31 (3H, 7.49 (2H, 7.53 (1H, 8.33 (1H, 9.98 (IH, br 12.18 (1H, br s); IR (solid) 3362, 2952, 2934, 2911, 2870, 2825, 1618, 1584, 1570, 1559, 1536, 1481, 1459, 1431, 1372, 1336, 1213, 994; MS 427.6 Example 344 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1,3dihydro-isoindol-2-yl)-quinazolin-4-yl]-amine (III-116): Prepared according to Method E-I to afford an off-white solid, mp 237oC; 'H NMR (DMSO-d6) 5 0.79 (2H, 1.00 (2H, 1.99 (1H, 4.92 (4H, 6.72 (1H, br s), 7.13 (1H, 7.33 (2H, 7.30-7.48 (3H, 7.58 (1H, 8.40 (1H, 10.12 (1H, 12-17 (1H, s);:IR (solid) 3449, 3318, 2850, 1623, 1595, 1577, 1541, 1509, 1482, 1432, 1391, 1359, 1141, 1027, 877, 814; MS 369.4 (M+H)1.

Example 345 (2-Azepan-l-yl)-quinazolin-4-yl] cyclopropyl-25-pyrazol-3-yl)-amine (III-117): mp 199- 200°C; IH NMR (DMSO-d6) 8 0.60-0.70 (2H, 0.90-1.00 (2H, 1.45-1..57 (4H, 1.70-1.85 (4H, i.88-1.97 (1H, 3.75-3.87 (4H, 6.42 (1H, 7.02 (1H, t), 7.27 (1H, 7.49 (1H, 8.29 (1H, 9.91 (1H, s), 12.19 (1H,.br IR (solid) 2929, 1624, 1595, 1581, -313- 1563, 1542, 1498, 1482, 1440, 1426, 1397, 1356, 1305, NO 1000, 825, 754; MS 349.2 Example 346 (5-Cyclopropyl-2-pyrazol-3-yl)- dihydro-1H-isoquinolin-2-yl) -quinazolin-4-yll]-amine

(III-

118): mp 182-184CC; 1 H NMR (DMSO) 8 0.75 (2H, 1.02 (2H, 1.96 (1H, 2.89 (2H, 4.05 (2H, m),.4.94 (2H, 6.46 (1H, 7.10 (1H, 7.21 (4H, 7.37 ID(1H, 7.55 (1H, 8.36 (iH, 10.05 (1H, 12.23 (1H, br IR (solid) 1621, 1581, 1560, 1537, 1479, CA 1456, 1426, 1396, 1374, 1341, 1222; MS 383.3 (M+H) 4 Ci Example 347 (5-Cyclopropyl-2&-pyrazol-3-yl) dihydro-indol-1-yl)-quinazolin-4-yl] -amine (111-119): mp 150-153 0 C; .H NMR (DMSO) 6 0.74 (2H, 0.98 (2H, d), 1.96 (1H, 3.15 (2H, 4.25 (2H, t),'6.45 (1H, br 6.88 (1H, 7.09 (1H, 7.20 (2H, 7.53 (1H, 7.65 (1H, 8.43 (2H, br 10.09 (1ii, 12.28 (1H, br IR (solid) 1621, 1588, 1577, 1564, 1537, 1487, 1455, 1425, 1386, 1259; MS 369.3 Example 348 (5-Cyclopropyl-25-pyrazol-3-yl)-[2-(4hydroxymethylpiperidin-1-yl)-quinazolin-4-yl] -amine. (III- 120): mp 1420C; 'H NMR (DMSO) 8 0.67 (21H, 0.96 (2H, 1.10 (2H, 1.55-1.70 (3H, 1.91 (1H, 2.85 (2H, 3.28 (2H, 4.48 (1H, 4.76 (2H, 6.34 (1H, 7.06 (1H, 7.30 (1H, 7.52 t),,8.31 (1H, 9.96 (1W, 12.19 (1W, a) IR (solid) 3363, 3000, 2927, 2854, 1618, 1604, 1573, 1536, 1509, 1477, 1436, 1395, 1354, 1314, 1241, 1186, 1091, 995, 941, 823; MS 365.8 Example 349 (5-Cyclopropyl-2H-pyrazol-3-yl)-2-(3,4dihydro-2H-quinolin-1-yl)-quinazolin-4-yl]-amine

(III-

-314- 121): mp 137-145OC; 'H NMR (DMSO-d) S 0.55. (2H, 0.88 Va S(2H, 1.78 (1K, 1.92 (2H, 2.75 (2H, 4.04 0 (2H, 6.20 (1i, br 6.97 7.14 (1H, m), 7.19 (1H, 7.42 (1H, 7.61 (1H, 7.67 (12, d), 8.43 (1H, 10.04 (1H, 12.21 (1H, br IR (solid) 1622,-1572, 1539, 1493, 1454, 1420, 1373, 1249; MS 383.3 ci IN Example 350 (5-Methosycarbonyl-2s-pyrazol-3-yl)-[2- (piperidine-1-y1)-quinazolin-4-yl] -amine (III-122): 'H NMR \O (500MHz, CDCl 3 81.7-1.8(6H, 8 3.8 (4H, 3.9 (3H, o S 5.5 (lH, 6 7.15 (1H, S 7.4 (1H, 6 7.6 (1i, 8 8.0 (1H, HPLC-Method B, (starting with Rt 7.4 min; MS 353.24 Example 351 [5-(Piperidine-1-carbonyl)-23-pyrazol-3-yl- [2-(piperidine-1-yl)-quinazolin-4-yl]-amine (111-123): HPLC-Method B, (starting with 95% HO20:0.1% TFA) R, min; MS 406.30, 404.30.

Example 352 (5-Hydroxymethyl-2u-pyrazol-3-yl)-[2- (piperidin-1-yl)-quinazolin-4-ylJ-anine (111-124): To a solution of III-122 (10.0 mg, 0.028 mmol) in THF (6 mL) at ambient.temperature was slowly added a 1M solution of LiAlH 4 in THF (0.05 mL, 0.05 mmol). After 15 minutes the solution was quenched with water and 1N HC1. The product was extracted from the aqueous layer with EtOAc. The organic layer was dried over MgSO 4 filtered, and concentrated in vacuo. The residue was purified by preparatory HPLC to afford 111-124 (4.0 mg, HPLC- Method B, (starting with 95% H20:0.1% TFA) Rt 6.1 min; MS 325.13 323.13 -315- Exmple 353 (5-Carbamoyl-2H-pyrazol-3-yl)-[2-(piperidin- ND 1-yl)-quinazolin-4-yl] -amine (111-125): A solution of o 111-122 (1.5 g, 4.3 mmol) in 2.0 M NH 3 /MeOH (100 mL) was heated at 110 0 C for 2 days. The dark brown reaction mixture was concentrated in vacuo to afford a viscous oil which was.purified by column chromatography to yield 0.7 g of 111-125. 1H NMR (500MHz, CD30D-d 3 81.6 Cg- (4H, 81.7 (2H, 8 3.3 (1iN, 8 3.8 (4H, 8 Cy (1H, 8 7.15 (1N, 8 7.45 (1R, 8 7.55 (1N, 8 o 10 8.0 (IH, HPLC-Method B, (starting with 95% H20:0.1% \O TFA) Rt 5.9 min; MS 338.13, 336.15.

Example 354 (5-Carbamoyl-2E-pyrazol-3-yl)- methylpiperidin-1-yl)-quinazolin-4-yl]-amine (111-126): HPLC-Method B, (starting with 95% H 2 0:0.1% TFA) Rt 6.4 min; MS 352.19, 350.20.

Example 355 (5,7-Difluoro-lH-indazol-3-yl)-(2-phenyl- 5,6,7,8-tetrahydroquinazolin-4-yl)-amine (111-127): 1H NMR (500 MHz, DMSO-d6) 813.7 1N), 10.3 br, IH), 7.90 2H), 7.52 1H), 7.45 3H), 7.26 1H), 2.99 2H), 2.75 2H), 1.95 (br, 4H) ppm; MS 378.24 376.23 HPLC-Method A, Rt 3.04 min.

Example 356 (2-Phenyl-5,6,7,8-tetrahydroquinazolin-4-yl)- (5-trifluoromethyl-1H-indazol-3-yl)-amine (111-128): 1H NMR (500 MHz, DMSO-d6) 813.4 1H), 10.2 br, 1H), 8.13 1H), 7.86 7.78 1H), 7.69 N1H), 7.50 1H), 7.35 (dd, 2H), 2.89 2H), 2.72 2H), 1.90 br, 4H).ppm; MS 410.24 408.23 HPLC-Method A, Rt 3.19 min.

-316- Example 357 (7-Fluoro-1H-indazol-3..yl)-(2-phenyl- Squinazolin-4-yl) -amine 1111-129): 'H NMR (500 MHz, DMSOdE) 813.6 1H), 11.1 Cs, br, 1H), 8.65 1H), 8.03 2H), 7.95 Cs, 2H), 7.67 1H), 7.45 2H), 7.33 t, 2H), 7.22 (dd, 1H), 6.99 (td, 1H) ppm. MS m/e= 356;20 CM+H); HPLC-Method A Rt 3.00 min.

Example 358 (S-Fluoro-1H-indazol-3-ylp (2.phenylguinazolin-4-yl)-amine (111-130): 1H NNR (500 MHz, DMSOo 10 d6) 813-.2 1H), 11.3 hr, 1H), 8.67 1H), 8.04 IN 2H), 7.96 21), 7.70 Cm, IH), 7.58 (cd, 1H), 7.43 4H), 7.28 (td, 1) ppm. MS 356.20

HPLC-

Method A, Rt 3.00 min.

Example 359 (5 7- Difluoro-zH- indazol3 -yl) (2-phenylquinazolin-4-yl)-aaine (111-131): '1 NMR (500 MHz, DMSOd6) 513.7 1H), 8.65 Cd, 1H), 8.04 2H), 7.95 Cs, 2H), 7.68 11), 7.45 1H), 7.35 4H) ppm. MS CES+): m/e= 374.17 HPLC-Method A, Rt 3.07 min.

Example 360 (1H-Indazol-3-yl)-r2-(3-trifluoromethylphenyl) -quinazolin-4-ylJ aaine (111-132) 'H NMR (500MHz, DMSO-d6) 6 7.06 Ct, 1K), 7.42 Ct, 1W), 7.59 11), 7.63 1H), 7.66 7.71 7.80 C(d, 1H), 7.98' 2H), 8.33 aa), 8.46 1H), 8.71 11), 11.04 Cbr. a, 11), 12.97 Cs, 11); El-MS 406.1 KPLC- Method A, Rt 3.1-5 min.

Example 361 2 -Phenyl-quinazolin-4-yl)-(I1H-pyrazoioE4,3blpyridin-3-yl)-amine (111-133): 1 NMR (500 MHz, DMSO-d6) 813.3 Cs, br, 1H), 11.4 Cs, br, 11), 8.78 Cd, 1H), 8.58 Cdd, 1H), 8.24 1H), 8.10 2H), 7.95 2H), 7.86 -317- 1W), 7.56 2H), 7.44 2H) ppm. MS 339.11 S KPLC-Nethod A, Rt 2.63 min.

Examle 362 (3-lMethoxy-phenyl) -6-oxo-5, 6-dihydro-lE- S pyrazolo pyridazin-3-yl (2-phenyl-quinazolin-4yl*) -mmine (111-134): 1 H NM? (500 MHz, MeOK-d4) 88.65 (d, 1K), 8.1.7 m,3H), 8.10 1K), 7.90 1K), 7.75 Ct, 1K), 7.58 m,2H), 7.25 lW), 6.95 2H), 6.85 (d, IND 1K), 6.80 Cs, iN), 3.64 3H) ppm. MS m/e= 462.2(14+H1> 0 Example 363 (E-Oxo-5-phenyl-5,6-dihydro.1Hpyrazolo4,3.

cjpyridazin-3-yl) -(2-phenyl-qui'nazolin-4-yl) -amine (III- 135)f l 1 H NM? (500 MHz, MeOK-d4) 88.61. Cd, 111), 8.13 (m, 3H), 8.05 1K), 7.85 Ct,' 11), 7.70 Ct, 111), 7.58 Cm, 2H); 7.32 (mh, 5H), 6.79 Cs, 1K) ppm. MS m/e= 432.2 CM+K).

Example 364 (4-Methoxy-phenyl) -6-oxo-5,6-dihydro-aapyrazolo pyridazin-3-yl (2-phenyl-quinazolin-4yl)-amine (111-136): MS 462.2(M+K);, Exa-mple 365. S- (2,4-Dichloro-pheny.) -6-oso-S,6-dihydrola-pyrazolo [4,3-clpyridazin-3-yl (2-phenyl-quinazolin-4yl) -amnine (111-137): 1 H NM? (500 MHz, MeOK-d4) 88.63 (d, 1K), 8.17 4H), 7.89 (t,1IH), 7.73 1H), 7.61 Ct, 2H), 7.57 iH), 7.32 1W), 7.21 IH), 6.84 Cs, iS) ppm. MS m/e= 500.iCM+K).

Example 366 [S-Oxo-5-(3.-trifluoromethyl-phenyl)-s,6dihydro-1I-pyrazoo4,3.clpyridazn3.yl]- (2-phenylquinazolin-4-yl) -amine (111-138): -H NMR .(500 MHz, MeOWd4) 5a.55 1H1), 8.19 2H), 7.92 2H), 7.65 (m, -318- 31), 7.45 Ct, 2H), 7.25 Ct, 1H), 7.13 1H), 7.05 (t, Va ol), 6.75 Cs, 1H) ppm. MS (ESi): m/e="500.2 (M14+).

Example 367 [6-Oxo-5-(4-Phenoxy-phenyl)s-5,6-dihydro n.

S pyrazolo [4,3-c]pyridazin-3-ylJ- (2-phenyl-guinazolin-4yl)-amine (111-139).: MS 524.3(M+H).

Example 368 (4-Chioro-phenyl) -6-oxo-5,6-dihydro-1Hpyrazolo (4,3-c]pyridazin-3-yl (2-phenyl-quinazolin-4yl)-amine (111-140): MS 466.2(M+H).

INO

Example 369 (2-imidazol-1-yl-quinazolin-4-yl) -(1Hindazol-3-yl)-amine (111-141): '1H NMR (50OMHz, DMSO-d6) B 7.10 Ct, 12), 7.44 Ct, 12), 7.50 (br. s, 1H), 7.60 (d, 12), 7.72 21), 7.77 Cm, 11), 7.88 11), 7.98 (t, 1H), 8.73 1H), 8.96 Cs, 1H), 11.23 1H), 13.06 (s, 12); El-MS 328.1 HPLC-Metbod A, Rt 2.93 -min.

Example 370 (XH-Indazol-3-yl)-[2-(2-methyl-imidazol-1-ylquinazolin-4-yl]-aaine (111-142): 1H NMR (5001Hz, DMSO-d6) 2.48 Cs, 3H), 7.10 1H), 7.43 Ct, IN), 7.57 11), 7.60 12), 7.67 11), 7.76 (td, IH), 7.86 Cd, iN), 7.91 1H), 8.01 (td, 1H), 8.72 IH), 11.15 1H); 13.10 Cs, 1H); El-MS 342.1 HPLO-Method A, Rt 3.06 min.

Example 371 (1H-Indazol-3-y1)- (2-piperidin-1-ylquinazolin-4-yl)-anine (111-143): 111 NMR C50OMHz, DMSO-d6) 1.48 6H), 3.60 Cm, 41), 7.11 Ct, 12), 7.52 IH), 7.55 1H), 7.64 Cd, 1H), 7.69 IH), 7.75 Cd, 111), 7.90 Ct, 11), 8.58 12), 11.82 Cbr. s, 12), 13.25 (s, 12);'El-MS 345.1 HPLC-Method A, Rt 3.03 min.

-319- Example 372 (1H-Indazol-3-yl) -[2-(oetabydro-quinolin-1- INDyl) -quinazolin-4-yl] -amine (III-144): H NMR (500MHz, DMSO-d6) 8 0.6-1.9 13 3.15 1H), 3.25 1H), 11), 7.10 0;5H), 7.12 0.5H), 7.55 (m, 2H), 7.66 0.5 7.69 0.5 7.77 11), 7.91 1I) 8.55 Id, 0.5 8.59 0.5 11.46 11.54 0.5 11.78 0.5 11.84 0.5 H), 13.10 0.5 13.12 0.5 EI-MS 399.3 INDHPLC-Method A, Rt 3.37 min.

ci Example 373 (1E-Indazol-3-yl)-[2-(2,6-dimethyl-morpholin- 4-yl)-quinazolin-4-yl]-amine (111-145): 'H NMR (500MHz, DMSO-d6) 8 1.0 6H), 4.0 6H), 7.12 1H), 7.41 (td, 1H), 7.56 Ct, 1H), 7.58 1H), 7.68 (dd, 1H), 7.77 t, 1H), 7.93 Ct, 1H), B.60 11.69 1H), 13.16 1H); EI-MS 375.3 HPLC-Method A, Rt 2.93 min.

Example 374 (5-Methyl-2B-pyrazol-3-yl)-(2-phenylpyrimidin-4-yl)-amine mp 245-2460C; 'H NMR (DMSO) S 2.26 (3H, 6.32 (1H, br 7.07 (11, br 7.48- 7.54 (31, 8.33-8.39 (3H, 9.87 (1H, 12.03 (1H, IR (solid) 1628, 1589, 1579, 1522, 1479, 1441, 1393, 1336;MS 252.2 Example 375 [6-(4-Acetanidophenylsulfanyl)-2-phenylpyrimtdin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine (IV-3): A suspension of Fenclorim (4,6-dichloro-2phenylpyrimidine) (0.lg, 0.44 mmol), methylpyrazole .(0.045 g, 0.47 mmol), N, Ndiisopropylethylamine (0.08 ml, 0.47 mmol) and sodium iodide (0.067 g, 0.44 mmol) in n-butanol (5 ml) were heated at 117 OC for 18 hours. The solvent was removed in vacuo and the crude product purified'by flash chromatography (silica gel, 3:2 Petrol:EtOAc) to afford -320- 0.037 g (29 yield) of (6-Chloro-2-phenyl-pyrimidin-4-

VO

o yl)-(5-methyl-2H-pyrazol-3-yl)-amine as a off-white C solid. A suspension of the above pyrimidine (0.037 g, 0.13 mmol) and thioacetamidothiophenol (0.108 g, 0.64 mmol) in tert-butanol was heated at 85 °C under nitrogen for 2 days. The reaction mixture was cooled to room temperature and the. solvent removed in vacuo. The C- concentrate was dissolved in EtOAc, and washed with NaHCO,

VO

Cq (sat, The organic layer is concentrated in vacuo, and the crude product by preperative HPLC. The residual 4\ disulfide that still remained in the mixture after HPLC Smay be removed by precipitation from EtOAc and filtration. The mother liquor was concentrated to afford IV-3 (7mg, 13 yield) as an off-white solid: mp 235- 236 0 C; H NMR (DMSO) 6 2.10 (3H, 2.21 (3H, 6.33 (1H, br 7.50 (3H, 7.7-7.59 (2H, 7.76-7.78 (2H, 8.25 (2H, 9.72, 10.26 and 11.93 (3 H, 3 x br IR (solid) 1669, 1585, 1551, 1492, 1392, 1372, 1312, 1289, 1259, 1174, 1102, 1089, 1027, 1015, 984; MS 417.3

(M+H)

4 Example 376 [2-(4-Methylpiperidin-l-yl)-pyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl)-amine mp 215-216 0 C; 1H NMR (CD 3 0D) 8 0.96 (3H, 1.16 (2H, 1.66 (3H, m), 2.27 (3H, 2.86 (2H, 4.58 (2H, 4.78 (2H, exch.protons), 6.13 (2H, 7.83 (1H, IR (solid) 1593, 1550, 1489, 1436, 1331, 1246, 1231; MS 273.1 Example 377 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine mp 185- 187 0 C; 1H NMR (DMSO) 8 0.93 (3H, 1.06-1.18 (2H, m), 1.68-1.80 (3H, 2.26 (3H, 3.01-3.12 (2H, 4.63 (1H, 4.80 (1H, 6.39 (1H, 9'.00 (1H, 10.41 -321- (1H, 12.36 (1H, IR (solid) 1589, 1517,. 1479, Va 1446, 1346, 1317, 1246, 1222, 1055; MS 318.2 Example 378 [5-Amino-2-(4-Methylpiperidin-1-yl)pyrimidin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine (IV-6): To a solution of.IV-5 (48 mg, 0.151 mmol) in,ethanol mL) was added tin dichloride dihydrate (171 mg, 0.756 mmol) and the resulting mixture heated at reflux for 3 hours. The reaction was cooled to room temperature and poured onto a mixture of 1M NaOH:dichloromethane:propanol (18:8:4mL) and stirred for 15 minutes. The layers were o separated and the aqueous layer extracted twice with c dichloromethane. The combined organic layers were concentrated in vacuo and the residue purified by flash chromatography (silica gel, gradient dichloromethane:MeOH) to afford IV-6 as a grey solid (27mg, 1' NMR (DMSO) 8 0.88-1.04 (SH, 1.55-1.62 (3H, 2.21 (3H, 2.70 (2H, 3.36 (2H, 4.40 (2H, 6.37 (1H, 7.49 (1H, 8.40 (1H, 11.92 (1K, br MS 288.2 Example 379 [5-Amino-6-methyl-2-(4-methylpiperidin-1-yl)pyrimidin-4-yll (5-methyl-2H-pyrazol-3-yl)-amine (IV-7): mp 172-175CC; H NMR (DMSO) 8 0.90 (3H, 1.03 (2H, m), 1.52-1.62 (3H, 2.13 (3H, 2.20 (3H, 2.69 (2H, 3.92 (2H, br 4.44 (2H, 6.35 (1K, 8.41 (1H, 11.85 (1H, br IR (solid) 1612, 1589, 1489, 1446, 1317; MS 302.5 Example 380 6-Methyl-2-(4-methyl-phbenyl)-pyrimidin-4yl] (5-phenyl-2H-pyrazol-3-yl)-amnine (IV-10): MS 342.34 HPLC-Method E, Rt 1.334 min.

-322- Examle 381 (4-Chioro-phenyl) -6-methyl-pyrimidin-4yl] -(5-furan-2-y1-2u-pyrazo1-3-y1)-amine (IV-11): MS 352. 11 (M41) HPLC Method E, Rt 1. 194 min.

Example 382 5-Furan-2-yl-2H-pyrazol-3.yl) -(6-methyl-2phenyl-pyrimidin-4-yl) -amine (IV-12): MS 318.21 (M-iH); HPLC-Method E, 1.192 min.

Examle 3.83 [G-Methyl-2- (4-trifluoromeehyl-phenyl) pyrimidin-4-ylJ -(S-phenyl-2-yl-20-pyrazol-3-yl) -amine (IV-13): MS 396.24 FPLC-Method E, Rt 1.419 min.

Example 384 (5-Furan-2-yl-2H-pyrazol-3-yl) 6-methyl-2- (4-trifluoromethyl-phenyl) -pyrimidin-4-yl] -amine (IV-14): MS 386.08 HPLC-Method E 1.347 min.

Example 385 12-(2,3-Dihiydro-benzo[1,4ldiosin-z-yl)-6methyl-pyrimidin-4-yl (5-furan-2-yl-2H-pyrazol-3-yl) amine (Zy-is): MS 376. 18 HPLC-Method E, Rt 1. 181 min.

Example 386 [2-(2,3-Dihydro-bezo[1,4dioxin-2-yl)..s ethyl-pyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amin'e (IV-16): MS 338.17 HPLC-Method E, Rt 1.082 min.

Example 387 (6-Ethyl-2-phenyl-pyrinidin-4-yl) (-methyl- 2H-pyrazol--3-yl)-amine (IV-17): MS 280.18 HPLC- Method E, Rt 1.024 min.

Exa!mple 388 (6-Methyl-2-phenyl-pyrimidin-4-y1) 2H-pyrazol-3-yl) -a.mine (tV-iS): MS 328.51 (MI-IH); HPLC- Method E, Rt 1.192 min.

-323- Example 389 [6-Ethyl-2- (4-trifluoromethyl-phenyl) o pyrimidin-4-yl] -(5-methyl-2H-pyrazol-3-yl) -amine oMS 348. 5 HPLC-Method E, Rt 1. 224 min.

Example 390 (5-Furan-2-yl-2H-pyrazol-3-yl) -[6-methyl-2- (4-methyl-phenyl),-pyrimidin-4-yl] -amine (IV-21): MS .332.23 HPLC-Method E, Rt 1. 139 min.

NO ~Example 391 (6 -Hethoxymethyl 2-phenyl -pyrimi din -4-yl) xnethyl-2H-pyrazol-3-yl)-anine (IV-22): MS 296.31 HPLC-Method E, Rt 0. 971 min.

ci Example 392 (5,6-Dimetbyl-2-phenyl-pyrimidin-4..yl) methyl- 2H-pyrazol-3 -yl) -amine (IV-23): MS 280.2 HPLC-Method E, Rt 0. 927 mini.

Exa-mle 393 (6-Methyl-2-phenyl-pyrimidin-4-yl) 2H-pyrazol-3-yl)-amine (IV-24): MS 266.18 HPLC- Method E, Rt 0.925 min.

Example 394 C6-Ethyl-2- (4-methyl-phenyl) -pyrimidin-4-ylJ (5-methyl-2H-pyrazol-3-yl)-amine (IV-25): MS 294.46 HPLC-Method R, Rt 1.174 min.

Example 395 [2 (4 -Chioro-phenyl) -6 -ethyl -pyrimidin- 4-yl] *(5-methyl-2H-pyrazol-3-yl) -amine (IV-26): MS 314.42 HPLC-Method E Rt 1.213 min.

*-Example 396 (5-Kethyl-1H-pyrazol-3-yl) -(6-methyl-2-ptolyl-pyrimidin-4-yl)-anane (IV-27): MS 280.45 (14+1); HPLC-Method E, Rt 1.135 min.

Example 397 (1H-Indazol-3-yl) -(6-methoxymethyl-2-phenylpyrimidira-4-yl)-am~ine (IV-28): 'H NMR (500 MHz, DMSO)S -324- 3.57 (3H, 4.65 (2H, 7.23 (1H, J=7.5 Hz, 7.52 (1H, J=7.6 Hz, 7.63 (4H, 7.75 (1H, br), 8.13 (1H, Hz, br 8.44 (1H, J=5.7 Hz, br 10.6 (1H, br), 12.8 (1H, br s) ppm; HPLC-Method A, Rt 2.944 min; MS (FIA) 332.1 (M+H) 4 Example 398 (5-Methyl-2H-pyrazol-3-yl)-(2-pyridin-4-ylthieno[3,2-d]pyrimidin-4-yl)-amine (IV-29): 1H NMR (DMSO) 6 2.34 6.66 (1H, 7.53 (1H, 7.84 (1H, d), 8.32 (2H, 8.70 (2H, MS 309.6 (M+H) Example 399 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylpyrido[3,4-dpyrimidin -4-yl)-amine (IV-30): mp 225 0 C; "H NMR (DMSO) 8 2.35 (3H, 6.81 (1H, 7.50-7.63 (3H, 8.45-8.52 (2H, 8.54 (1H, 8.62 (1H, 9.20 (1H, 10.79 (1H, 12.38 (1H, br IR (solid) 2958, 2917, 2852, 1593, 1565, 1524, 1467, 1450; MS 303.2 Example 400 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylpyrido[2,3-d]pyrimidin-4-yl)-amine (IV-31): To a solution of 4-chloro-2-phenyl-pyrido[2,3d]pyrimidine Pharm. Belg., 29, 1974, 145-148) (109mg, 0.45 mmol) in THF (15 mL) was added pyrazole (48 mg, 0.5 mmol) and the resulting mixture heated at 65 OC overnight. The mixture was cooled to room temperature and the resulting suspension was filtered and washed with EtzO. The solid was dissolved in a mixture EtOH:water and the pH adjusted to pH 7. The aqueous was extracted twice with ethyl acetate and the combined organic layers were dried (MgSO 4 filtered, and concentrated in vacuo. The residue was purified by flash chromatography (SiO0, DCM-MeOH gradient) to afford IV-31 as an off-white solid (69 mg, mp 234C; IH NMR -325- (DMSO) 8 2.14 (3H, 5.99 (1H, 7.20-7.40 (3H, m),

VO

o 7.40-7.50 (3H, 8.60 (1H, 8.79 (1H, 12.82 (1H, C br IR (solid) 2957, 2921, 2857, 1644, 1560, 1459, 1427; MS 303.2 (M+H) 4 Example 401 (5-Cyclopropyl-2H-pyrazol-3-yl) (2-phenylpyrido[3,4-d]pyrimidin-4-yl)-amine (IV-32): off-white Ci solid, mp 232-233oC; 1H NMR (DMSO) 5 0.70-0.85 (2H, m),

\O

Ci 0.90-1.05 (2H, 1.05-2.07 (1H, 6.75 (1H, 7.50- 7.75 (3H, 8.40-8.70 (4H, 9.20 (1H, 10.80 (IH, ND 12.41 IR (solid) 3178, 1601, 1573, 1532, 1484, 0 1452, 1409, 1367, 1328, 802, 781, 667; MS 329.2 c( Example 402 [2-(4-Methylpiperidin-l-yl)-purin-4-yl]-(5methyl-2H-pyrazol-3-yl)-amine (IV-33): To a suspension of 2,4-dichloro-purine (2.0 g, 10.6 mmol) in anhydrous ethanol (10 mL) was added 5-methyl-1H-pyrazol-3-yl amine (2.05 g, 21.2 mmol). The resulting mixture was stirred at room temperature for 48 h. The resulting precipitate was collected by filtration, washed with ethanol, and dried under vacuum to afford 1.524 g (58% yield) of (2chloro-purin-4-yl) (5-methyl-1H-pyrazol-3-yl)-amine which was used in the next step without further purification.

To a solution of (2-chloro-purin-4-yl)-(5-methyl-1Hpyrazol-3-yl)-amine (200 mg, 0.80 mmol) was added 4methylpiperidine (4 mL, 8.01 mmol) and the reaction mixture heated at reflux overnight. The solvent was evaporated and the residue dissolved in a mixture EtOH:water 4 mL). Potassium carbonate (57mg, 0.41 mmol) was added and the mixture was stirred at room temperature for 2 hours. The resulting suspension was filtered, washed with water (x2) and rinsed with Eta2 (x2) to afford IV-33 as a white solid (225mg, mp >3000C; 1H NMR (DMSO) 8 0.91 (3H, .1.10 (2H, 1.65 (3H, m), -326- 2.24 (3H, 2.84 (2H, 4.60 (21, 6.40 (18, a), 7.87 (18, 9.37-9.59 (18, 12.03-12.39 (2H, IR 0 (solid) 1651, 1612, 1574, 1484, 1446, 1327, 1317, 1255, 1203; MS 313.3 C Example 403 (5-Cyclopropyl-2-pyrazol-3-yl)-[2-(4methylpiperidin--yl)-pyrrolo[3,2-dlpyrimidin-4-yl]-amine Ci (IV-34): white solid; 'H NMR (DMSO) 5 0.65 (2H, 0.91- C- 0.96 (5H, 1.08 (2H, 1.58-1.64 (38, 1.89 (18, cO 10 2.77 (2H, 4.57 (2H, 6.09 (1H, 6.38 (1H, \o 7.33 (18, 9.42 (1H, 10.65 (1H, 12.02 (1H, o br MS 338.3 Example 404 [6-Benzyl-2-phenyl-5,6,7,8-tetrahydropyrido[4,3-dpyrimidin-4-yl]-(5-fluoro-1H-indazol-3-yl)amine (IV-35): 'H NMR (500 MHz, DMSO-d6) 613.0 1H), 10.4 br, 11), 9.73 1H, TFA-OH), 8.00 2H), 7.64 2H), 7.59 (dd, 1H), 7.52 3H), 7.41 IH), 7.31 3H), 7.14 (dd, 1H), 4.58 4.35 (br, 28), 3.74 2H), 3.17 2H) ppm. MS m/e= 451.30 HPLC-Method A, Trot 2.96 min.

Example 405 (5-Fluoro-1-indazol-3-y1)-(2-phenyl-5,6,7,8tetrahydro-pyrido(4,3-dlpyrimidin-4-yl)-amine (IV-36): Prepared from V-35 (0.13 mmol) by treatment with an equal weight of Pd/C in 4.4% HCOOH in MeOH at room temperature for 12 h. The mixture was filtered through celite, the filtrate was evaporated, and crude product was purified by HPLC to afford IV-36 as yellow solid in 35% yield. 'H NMR (500 MHz, DMSO-d6) 612.9 1H), 9.06 7.99 2H), 7.57 (dd, 1H), 7.34 1H), 7.28 3H), 7.22 1H), 3.83 28), 3.05 28), 2.72 2H) ppm. MS m/e= 361.20 HPLC-Method A, Tret 2.68 min.

-327- IO Example 406 (5-Methyl-2H-pyrazol-3-yl) (3-phenyl- O isoquinolin-l-yl)-amine To a solution of l-chloro- 3-phenylisoquinoline Het. Chem., 20, 1983, 121- 128)(0.33g, 1.37 mmol) in DMF (anhydrous, 5 mL) was added (0.27g, 2.74 mmol) and potassium carbonate (0.-57g, 4.13 mmol)and the resulting mixture was heated at reflux for 6 hours. The reaction mixture was 0D then cooled and solvent removed in vacuo. The residue was extracted twice with ethyl acetate and the combined Ci organic layers washed with brine, dried (MgSO 4 filtered

VO

o and concentrated in vacuo. The crude product was C purified by flash chromatography (SiO 2 gradient DCM-MeOH) to afford V-1 as a colourless oil; 1H NMR (MeOD) 8 2.23 (3H, 5.61 (1H, 7.41 (1H, 7.52(2H, m), 7.62(1H, 7.81(1H, 8.07(1H, 8.19(2H, m), 8.29(1H, 8.54 (1H, MS 301.2 Example 407 (1H-Indazol-3-yl)- [3-(2-trifluoromethylphenyl)-isoquinoline-1-yl -amine A solution of 1chloro-3-(2-trifluoromethyl-phenyl)-isoquinoline (100 mg, 0.326 mmol) and 1H-indazol-3-ylamine (86 mg, 0.651 mmol) in ethanol (3 mL) was heated at 160-C and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 C for 18 hours under nitrogen.

The resulting melt was dissolved in methanol:dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1 x 25 mL) then dried over magnesium sulfate. Purification by silica gel.

chromatography (25% to 50% hexane:ethyl acetate) afforded V-2 as a yellow solid (35 mg, 1H NMR (500 MHz, dr- DMSO) 6 9.78 (br s, 1H), 8.62- 1H), 7.9-7.85 1H), 7.78-7.72 1H), 7.70-7.68 1H), 7.65-7.62

IH),

7.60-7.55 1H), 7.52-7.45 3H), 7.41-7.38 1H), -328- 7.28-7.25 1H), 7.18 1H), 6.95-6.92 1H), 5:76 Va S 1H); LC-MS m/e= 405.18 HPLC-Method D Rt 2.74 min.

Example 408 (5,7-Difluoro-1H-indazol-3-yl)-[3-(2trifluoromethyl-phenyl)-isoquinolin-1-yl] -amine Prepared from 5, 7 -difluoro-1H-indazol-3-ylamineto afford compound V-3 as a yellow solid (90 mg, 'H NMR (500 Va C MHz, d 6 -DMSO) 8 13.25 1H); 9.92 (br s, 1H), 8.61 (d, o 10 1H), 7.9 1H), 7.81-7.49 6H), 7.26-7.2 2H), 7.12-7.10 1H); LC-MS m/e= 441.16 HPLCo Method D, Rt 3.58 min.

Example 409 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylquinolin-4-yl)-amine. To a mixture of 4-chloro-2phenylquinoline Het. Chem., 20, 1983, 121-128)(0.53g, 2.21 mmol) in diphenylether (5 mL) was added methylpyrazole (0.43g, 4.42 mmol) and the resulting mixture heated at 200 0 C overnight with stirring. The reaction mixture was cooled to ambient temperature then petroleum ether (20 mtL) was added and the resulting precipitate was isolated by filtration. The crude solid was purified by flash chromatography (Sio2, gradient DCM- MeOH) to afford V-4 as a white solid: mp 242-244oC; 1H NMR (DMSO) 8 2.27(3H, 6.02(1H, 7.47(2H, 7.53- 7.40(2H, br 7.67(11, 7.92(11, 8.09(2H, d), 8.48(2H, 9.20(1H, 12.17(1H, br IR (solid) 1584, 1559, 1554, 1483, 1447, 1430, 1389; MS 301.2 Example 410 (1H-Indazo1-3-yl)-(2-phenyl-quinolin-4-yl)amine 1H NMR (500 MHz, d 6 -DMSO) 6 12.78 11), 9.50 1H), 8.65 1H), 8.15 8.04-7.98 (m, 3H), 7.94 7.78-7.75 1H), 7.60-7.40 6H), -329- 7.15-7.10 1H). LC-MS m/e= 337.11 HPLC- IN Method D, Rt 2.10 min.

Example 411 (2-Phenyl-quinolin-4-yl) -C1E-pyrazolo[4,3b] pyridin-3-yl)-amine '1 NI4R (500 MHz, DMSO-d6) 813.6 11), 11.4 s, 8.94 1H), 8.61 (dd, 1H), 8.23 11), 8.16.Cdd, 1H), 7.89 1H), 7.86 Cd, 1H), 7.65 4H), 7.54 1H), 7.52 Cdd, 1H) IN ppm. MS m/e= 338.11 HPLC-Method A, HPLC- Method D, Rt 2.91 min.

Example 412 (1H-Indazol-3-yl) (2-trifluoromethylphenyl) -quinolin-4-yl -amine 1H NNR (500 14Hz, d6- DMSO) 8 12.68 IH), 9.51 1H). 8.7 1H), 7.95- 7.89 2H), 7.83-7.70.Cm, 311), 7.68-7.62 21), 7.60 Cs, 1H), 7.55-7.52 Cm, 21), 7.49-7.45 (muiR), 7.40-7.37 Cm, 1H), 7.12-7.09 11); LC-MS 'AES+) m/e= 405.15 HPLC-Method D Rt 2.25 min.

Example 413 (5,7-Difluoro-1H-indazol-3-yl)- trifluoromethyl-phenyl) -quinolin-4-yl] -amine 1H NMR (500 MHz, dsrDMSO) 8 13.31 Cs, IH), 9.49 IH), 8.70- 8.67 Cm, 1H), 7.96-7.92 11), 7.85-7.66 Cm, 7H), 7.63- 7.60 IH), 7.42-7.40 Cm, 1H). LC-MS m/e= 441.18 HPLC-Method D Rt 2.39 min.

Example 414 [2-(2-trifluoromethyl-phenyl) -quinolin-4-yl- (1H-pyrazolo[4,3-blpyridin-3-yl)-amine 'H NMR (500 MHz, DMSO-d) 513.6 Cs, 1H), 11.'6 Cs, br, 8.98 (d, 1H), 8.57 (dd, 1H), 8.12 3H), 7.97 Cm, 2H), 7.86 (m, 3H), 7.49 (dd, IH), 7.23 Cs, 11) ppm. MS m/e= 406.20 HPLC-Method A Rt. 2.91 min.

-330- Example 415 2 -Phenyl-qi4nazoln-.yl)-(2-* IN 1,2,4Jtriazol-3-yl)-amne (IX-154): off-white solid, mp 266-267 0 C; 1H NMR CDMSO) 8 7.50-7.70 (4H, 7.85-8.00 (2H, 8.15-8.25 (2H, 8.37-8.45 (2H, 8.58 (lH, 13.90 (11, br IR (solid) 3344, 3659, 1630, 1609, 1570, 1557, 1543, 1501, 1495, 1445, 1411, 1355, 1326, 1267, 1182, 1053, 1038, 760, 676, 667, 654; MS 289.2 o 10 Example 416 (5-Methyl-2H-[1,2,4).triazol-3Jyl)p(2phenylquinazolin-4-yl) -amine (IX-155): 'H NM? (500 MHz, DMSOo dE) 68.59 1H), 8.42 J 6.7 Hz, 2H), 7.79 (m, 4H), 8.03 2H), 7.74 4H), 2.51 3H) ppm. MS i/e= 303.08 CM+H); HPLC-Method Re 2.64 min.

BKaaple 417 (2k-11,2,43 -Triazol-3-yl)- 12-(2trifluoromethylphenyl)-quunazolin-4-yl-amine (IX-47): Pale yellow solid (52% yield) 1H NM? (500 MHz, DMSO-d) 58.54 11), 8.15 br, IH), 7.91 Ct, 1H), 7.85 (m, 21), 7.76 7.66 1H) ppm. MS (ESi): m/e= 357.13 m/e= 355.15 HPLC-Method A, Rt 2.81 min.

Example 418 (5-Methyl-2H-[1,2,4trazol3-yl).[2 (2.

trifluoronethylphenyl) -guinazolin-4-ylJ -amine (IX-38): Pale yellow solid (54% yield) 3I NM? (5'00 MHz, DMSO-d) 58.44 br, 11), 7.92 Cm, 3H), 7.84 1H), 7.77 (m, 2H), 7.68 Ct, 11), 2.28 Cs, 3H) ppm. MS m/e= 371.14 i/e= 369.18 HPLCrMethod A, Rt 2.89 min.

Example 419 (5-Methy~lsulfanyl-2'- E1,2,4jtriazol-3-yl) (2-trifluoromethylphenyl)-quinazolin-4-yl]-amine

(IX-

156): Pale yellow solid (65% yield). 'H NMR (500 14Hz, -331- DMSO-d6) 68.56 (br, 1H), 7.90 1H), 7.84 2H), 7.78 2H), 7.67 2H), 2.51 3H, buried by DMSO) ppm.

MS m/e= 403.12 m/e= 401.16 HPLC-Method A, Rt 3.20 min.

Example 420.. (1H-[1,2,4]Triazol-3-yl)- trifluoramethyl-phenyl)-isoquinolin-1-yl]-amine (IX-175): A solution of 1-chloro-3-(2-trifluoromethyl-phenyl)isoquinoline (0.326 mmol) and 1H-11,2,4]triazol-3-ylamine (0.651 mmol) in ethanol (3 mL) was heated at 1600C and the solvent evaporated with a stream of nitrogen. The remaining oil was then heated at 160 0 C for 18 hours under Ci nitrogen. The resulting melt was dissolved in methanol/dichloromethane (50 mL), washed with saturated aqueous sodium bicarbonate (1 x 25 mL) then dried over magnesium sulfate. Purification by silica gel chromatography afforded IX-175 as a colorless oil (4% yield). aH NMR (500 MHz, CDC1 3 9.18 11), 8.82 (s, 11), 7.90 1H), 7.85-7.75 3H), 7.71-7.62 3H), 7.60-7.55 2H), 4.42-4.35 IH). LC-MS 356.16 HPLC-Method D, Rt 3.55 min.

Example 421 (2-Phenyl-quinolin-4-yl)-(lf-[1,2,4]triazol- 3-yl)-amine (IX-176): Pale yellow solid (30% yield). 'H- NMR (500 MHz, d-DMSO) 13.82 IH), -9.91 1H), 8.80 1H), 8.70-8.65 1H), 8.55 1H), 8.15-8.12 2H), 8.03-7.98 1H), 7.75-7.72 1H), 7.57-7.49 3H). LC-MS m/e= 288.11 HPLC-Method D, Rt .1.55 min.

Example 422 (1H-1,2,4]triazol-3-yl)-[2-(2trifluoromethyl-phenyl)-quinolin-4-yl]-amine (IX-177): Pale yellow solid (46% yield). H NMR (500 MHz, d6-DMSO) 6 13.70 1I), 9.98 1H), 8.70 1H), 8.49 (s, -332- 1H), 8.30 1H), 7.94-7.88 2H), 7.80-7.68 3H),

VO

o 7.64-7.56 2H). LC-MS m/e= 356.18 HPLC- C Method D, Rt 1.68 min.

Example 423 (l-H-Indazol-3-yl)- [5-methyl-6-morpholin-4yl-2- (2-trifluoromethyl-phenyl) -pyrimidin-4-yll -amine (11-251): Colorless film; 2 yield; 1 H-NMR (500 MHz, CA CD 3 OD) 8 7.84 2H), 7.71 3H), 7.41 2H), 7.14

VO

Ci 1H), 3.74 4H), 3.69 4H), 1.24 3H) ppm; o 10 HPLC-Method A Rt 3.26 min; MS (FIA) 455.1

ND

o BIOLOGICAL TESTING The activity of the compounds as protein kinase inhibitors may be assayed in vitro, in vivo or in a cell line. In vitro assays include assays that determine inhibition of either the phosphorylation activity or ATPase activity of the activated protein kinase.

Alternate in vitro assays quantitate the ability of the inhibitor to bind to the protein kinase. Inhibitor binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound.

Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands.

BIOLOGICAL TESTING EXAMPLE 1 Ki DETERMINATION FOR THE INHIBITION OF GSK-3 Compounds were screened for their ability to inhibit GSK-3P (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998) Protein Sci. 7, 2249). Reactions were carried out in a solution containing 100 mM HEPES (pH 10 mM MgC12, 25 mM NaC1, -333- 300 4M NADH, 1 mM DTT and 1.5% DMSO. Final substrate s ~concentrations in the assay were 20 uM ATP (Sigma o Chemicals, St Louis, MO) and 300 pM peptide c (HSSPHQS (PO 3 H) EDEEE, American Peptide, Sunnyvale, CA).

ct Reactions were carried out at 30 °C and 20 nM Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 pM NADH, 30 pg/ml pyruvate kinase and 10 ug/ml lactate IN0 dehydrogenase.

ci An assay stock buffer solution was prepared Cq^ containing all of the reagents listed above with the-7

INO

0exception of ATP and the test compound of interest. The C assay stock buffer solution (175 pl) was incubated in a 96 well plate with 5 41 of the test compound of interest at final concentrations spanning 0.002 uM to 30 pM at °C for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated by the addition of 20 jl of ATP-(final concentration 20 pM).

Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, 'CA) over 10 min at C. The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM for GSK-3: compounds II-l, II- 105, 11-33, 11-34, 11-36, 11-39, 11-38, 11-39> 11-40, II- 41, 11-42, 11-46, 11-57, 11-59, 11-60, 11-61, 11-62, II- 63, 11-64, 11-66, 11-67, 11-69, 11-70, 11-53, 11-71, II- 99, 11-73, 11-74, 11-75, 11-76, 11-77, .11-7, 11-B, 11-9, 11-10, 11-24, 11-19, 11-78, 11-54, 11-79, 11-80, 11-81, 11-82, 11-83, 11-84, 11-56, 11-86, 11-20, 11-25, 11-26, 11-85, 11-21, 11-27, 11-28, 11-87, 11-88, 11-29, 11-11, 11-12, 11-30, 11-31, 11-13, 11-14, I-15, 11-16, 11-17, -334- 11-18, 11-79, 11-23, 11-2, lI-SO, I1-91, 11-92, 11-93, o 11-4, 11-5, 11-6, 11-94, 11-95 1-6 1-07, 11- 01086, 11-109, 11-110, 11-124, 11-125, 1I-1ll, 11-112, 11- 113, 11-114, 11-115, 11-116, 11-117, 11-118,' 11-119, 11- 120, 11-121, 11-208&, 111-8, 111-7, 111-9, 111-37, 111-38, 111-3.9, 111-40, 1.11-42,.111-45, 111-46, 111-47, 111-48, 111-49, 111-51, 111-52, 111-53, 111-54, 111-55, 111-56, 111-57, 111-58, 111-59, 111-60, 111-6l, 111-62, 111-63, IND 111-30, 111-65, I11-66, 111-67, 111-70, 111-73, 111-31, -111-75, 111-76, 111-77, 111-3 3, 111-34, 111-106, 111-108, 111-109, Ill-1ll, 111-35, 111-116, 111-117, 111-118, 111o 119, 111-120, 111-121, 111-127, 111-128, 111-141, 111ci 130, 111-131, TV-iS, IV-16, IV-17, IV-20, IV-25, IV-26, IV-34, V-3, and IX-47.

The following compounds were shown to have Kj values between 0.1 and 1.0 p14 for GSK-3: compounds II- 103, 11-104, 11-35, 11-44, 11-45, 11-49, 11-SO, 11-97, 11-1011 11-22, 11-32, 111-41, 111-43, 111-44, 111-28, 111-29, 111-64, 111-71, 111-74, 111-78, 111-82, 111-88, 111-90, 111-102, 111-105, 111-107, 111-110, 111- 112, 111-114, 111-115, 111-122, 111-124, 111-124, IV-1, I11-i, 111-138, 111-140, 111-142, 111-129, 111-132, 11I- 134, 111-135, 111-136, IV-1, IV-10, .IV-11, IV-12, IV-.13, IV-14, IV-19, IV-21, IV-22, IV-23, IV-24, IV-3, IV-4, IV- 6, IV-7., IV-8, IV-29, IV-31, IV-32, IV-33, IV-36, V-2, V- 7, IX-38, IX-154, and IX-177.

The following compounds were shown to have Kj values between 1.0 and 20 J11 for GSK-3: compounds 11-43, 11-65, 11-48, 11-47, Il-5i, 11-68, 11-52, 11-72, 11-100, 11-98, 11-89, 111-68, Il1-81,.111-83, 111-91, 111-94, 111-951 111-96, 111-97, 111-98, 111-99, 111-100, 111-101, 111-103, 111-123, 111-137, 11-1-139, 111-143, 111-145, 111-146, V-4, V-B, IX-ISE, and IX-176.

-335- BIOLOGICAL TESTING EXAMPLE 2 \0 KI DETERMINATION FOR THE INHIBITION OF AURORA-2 o ,Compounds were screened in the following manner for their ability to inhibit Aurora-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

C To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgC1 2 1 mM DTT, 25 mM NaC1, 2.5 mM ci \D phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate 10 kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and C 800 uM peptide (LRRASLG; American Peptide, Sunnyvale, CA) iI o was added a DMSO solution of a compound of the present C invention to a final concentration of 30 uM. The resulting mixture was incubated at 30 'C for 10 min. The reaction was initiated by the addition of 10 PL of Aurora-2 stock solution to give a final concentration of nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5 minute read time at 30 OC using a BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 pM for Aurora-2: compounds 11-33, II-34, II-36, 11-37, 11-40, 11-41, 11-55, III-7, III-9, III-37, III-38, 111-39, III-40, III-41, III-42, III-44, III-46, 111-47, III-48, III-49, III-50, III-51, III-52, III-53, III-54, III-55, III-56, III-57, 111-59, III-61, III-63, III30, III-65, III-66, III-67, 111-70, III-31, III-76, III-77, III-78, III-80, III-32, III-33, III-34, III-106, III-108, III-109, III-110, III- 111, III-112, III-114, III-35, III-115, III-116, III-117, III-118, III-119, III-120, III-121, IV-7, IV-30, IV-32, and IV-34.

-336- The following compounds were shown to have Ki \0 O values between 0.1 and 1.0 WM for Aurora-2: compounds II- C 1, 11-105, 11-35, II-38, 11-39, 11-42, II-64, 11-70, II- C53, 11-99, 11-77, II-79, I1-86, II-20, II-93, 11-94, III- S 5 28, III-58, III-64, III-71, III-73, II1-74, III-75, III- 102, III-105, III-107, III-113, III-124, III-1, 111-130, IV-1, IV-3, IV-4, IV-6, IV-29, IV-33, and V-4.

C The following compounds were shown to have Ki

VO

C values between 1.0 and 20 pM for Aurora-2: compounds II- O 10 103, 11-104, 11-57, 11-59, 11-61, 11-63, 11-67, 11-69, 0 11-75, 11-76, II-10, 11-19, 11-78, 11-54, 11-80, 11-82, o 11-21, II-90, 11-91, 11-96, 11-107, III-68, III-79, III- 82, III-101, III-103, III-127, III-141, III-129, III-132, IV-31, V-2, IX-47, IX-154, and IX-177.

BIOLOGICAL TESTING EXAMPLE 3 CDK-2 INHIBITION ASSAY Compounds were screened in the following manner for their ability to inhibit CDK-2 using a standard coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249).

To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgC12, 1 mM DTT, 25 mM NaC1, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 100 uM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 pM.

The resulting mixture was incubated at 30 OC for 10 min.

The reaction was initiated by the addition of UL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5-minute read time at 30 OC using a BioRad -337- Ultramark plate reader (Hercules, CA). The Ki values were IND determined from the rate data as a function of inhibitor o concentration.

ci S BIOLOGICAL TESTING EXAMPLE 4 ERK .INHIBITION ASSAY Compounds were assayed for the inhibition of ERK2 by a spectrophotometric coupled-enzyme assay (Fox et sD al (1998) Protein Sci 7, 2249). In this assay, a fixed concentration of activated ERK2 (10 nM) was incubated 0g with various concentrations of the compound in DMSO (2.5 a-i cO o for 10 min. at 30 0 C in 0.1 M HEPES buffer, pH Ci containing 10 mM MgC1 2 2.5 mM phosphoenolpyruvate, 200 pM NADH, 150 pg/mL pyruvate kinase, 50 pg/mL lactate dehydrogenase, and 200 pM erktide peptide. The reaction was initiated by the addition of 65 pM ATP. The rate of decrease of absorbance at 340 nM was monitored. The ICso was evaluated from the rate data as a function of inhibitor concentration.

The following compounds were shown to have a Ki value of <ipM for ERK-2: III-109, III-ll, III-115, III- 117, 111-118, III-120, and IV-4.

The following compounds were shown to have a Ki value of between 1pM and 12pM for ERK-2: III-63, and III-108.

BIOLOGICAL TESTING EXAMPLE AKT INHIBITION ASSAY Compounds were screened for their ability to inhibit AKT using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249). Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM MgC12, 25 mM NaCl 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 pM ATP (Sigma -338- Chemicals) and 200 pM peptide (RPRAATF, American Peptide,

\O

0 Sunnyvale, CA). Assays were carried out at 30 'C and C nM AKT. Final concentrations of the components of the Scoupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 pM NADH, 30 pg/ML pyruvate kinase and 10 pg/ml lactate dehydrogenase.

An assay stock buffer solution was prepared (C containing all of the reagents listed above, with the

VO

(C exception of AKT, DTT, and the test compound of interest.

10 56 pl.of the stock solution was placed in a 384 well c0 plate followed by addition of 1 il of 2 mM DMSO stock containing the.test compound (final compound concentration 30 The plate was preincubated for about 10 minutes at 30'C and the reaction initiated by addition of 10 1l of enzyme (final concentration 45 nM) and 1 mM DTT. Rates of reaction were obtained using a BioRad Ultramark plate.reader (Hercules, CA) over a minute read time at 30'C. Compounds showing greater than inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine ICo 0 values.

BIOLOGICAL TESTING.EXAMPLE 6 SRC INHIBITION ASSAY The compounds were evaluated as inhibitors of human Src kinase using either a radioactivity-based assay or spectrophotometric assay.

Src Inhibition Assay A: Radioactivity-based Assay The compounds were assayed as inhibitors of full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified from baculo viral cells. Src kinase activity was monitored by following the incorporation of 33 P from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu:Tyr 4:1 (Sigma, cat. no.

-339- P-0275). The following were the final concentrations of sO the assay components: 0.05 M HEPES, pH 7.6, 10 mM MgC12, 2 O mM DTT, 0.25 mg/ml BSA, 10 M ATP (1-2 PCi 3P-ATP per Sreaction), 5 mg/ml poly.Glu-Tyr, and 1-2 units of recombinant human Src kinase. In a typical assay, all the reaction components with the exception of ATP were pre-mixed and aliquoted into assay plate wells.

Inhibitors dissolved in DMSO were added to the wells to ci DO give a final DMSO concentration of The assay plate 10 was incubated' at 30 OC for 10 min before initiating the Ci reaction with 3 P-ATP. After 20 min of reaction, the

VO

o reactions were quenched with 150 pl of Ci trichloroacetic acid (TCA) containing 20 mM Na 3

PO

4 The quenched samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filter, cat no. 7700-3310) installed on a filter plate vacuum manifold. Filter plates were washed four times .with 10% TCA containing 20 mM Na 3

PO

4 and then 4 times with methanol. 2 0 0pl of scintillation fluid was then added to each well. The plates were sealed and the amount of radioactivity associated with the filters was quantified on a TopCount scintillation counter.. The radioactivity incorporated was plotted as a function of the inhibitor concentration. The data was fitted to a competitive inhibition kinetics model to get the Ki for the compound.

Src Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate was quanitified using a coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay one molecule of NADH is oxidised to NAD for every molecule of ADP produced in the kinase reaction. The -340disappearance of NADH can be conveniently followed at 340 Va ID nm.

0 C The following were the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgCl2, 2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nM of recombinant human Src kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM Sphosphoenolpyruvate, 200 pM NADH, 30 jg/ml pyruvate IN kinase and 10 pg/ml lactate dehydrogenase.

In a typical assay, all the reaction components -cQ with the exception of ATP were pre-mixed and aliquoted Sinto assay plate wells. Inhibitors dissolved in DMSO Ci were added to the wells to give a final DMSO concentration of The assay plate was incubated at 30'C for 10 min before initiating the reaction with 100 pM ATP. The absorbance change at 340 rnm with time, the rate of the reaction, was monitored on a molecular devices plate reader. The data of rate as a function of the inhibitor concentration was fitted to compettive inhibition kinetics model to get the Ki for the, compound.

The following compounds were shown to have a Ki *value of <100nN on SRC: III-31, III-32, III-33, III-34, 11III-35, III-47, III-65, III-66, III-37, III-38, 111-39, III-42, III-44, III-48, III-49, III-70, III-78, 111-76, and IV- 32.

The following compounds were shown to have a Ki value of between 100nm and lpM for SRC: III-63, III-71, III-73, III-72, III-74, III-80, III-50, The following compounds were shown to have a Ki value of between IpM and 6pM for SRC: III-79, IV-1, and IV-31.

While we have hereinbefore presented a number of embodiments of this invention, it is apparent that our basic construction can be altered to provide other -341- 00 embodiments which utilize the compounds and methods of this invention. Therefore, it will be appreciated that the scope of this invention is to be defined by the appended claims rather than by the specific embodiments 5 which have been represented by way of example.

NO The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the inclusion of a stated integer or stated integers but not to exclude any other integer or any other integers, C- unless in the context or usage an exclusive interpretation of the term is required.

Any reference to publications cited in this specification is not an admission that the disclosures constitute common general knowledge in Australia.

-342-

Claims (3)

1. 5-8 membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by R x and R y is substituted by oxo or T-R 3 T is a valence bond or a C1-4 alkylidene chain; R 2 and R 2 are independently selected from -T-W-R 6 or R 2 and R 2 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 carbon on said fused ring formed by R 2 -343- 00 and R 2 'is substituted by halo, oxo, -ON, -NO 2 -R7, or -V- R 6, and any substitutable nitrogen on said ring formed by R 2and R 2'is substituted by R4 R 3 is selected from -halo, -OR, -C R, -CO 2 R, CI-COCOR, -OH 2 COR, -NO 2 -ON, R, -S 2 R, -SR, -N(R 4 2, -CON(R 4 2, -SO 2 N (R 4 2, -OCC=O)R, -N(R 4 )OCOR, -NCR 4)0C0 2 (optionally substituted C1- aliphatic), )N(R 4) 2, -O=NN(R 4) 2, -O=N-OR, -N(R)CON (R 4 2, -N(R 4) S0 2 N(R 4) 2, -N(R 4)SO 2 R, or -OC (=O)NC(R 4) 2 IND 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 R 4 is independently selected from -00R, -C0 2 (optionally substituted C 1 6 aliphatic) -OON(R 7) 2, or -S0 2 R or two R 4 on the same nitrogen are taken together to form a 5-8 membered heterocyclyl or heteroaryl ring; each R' is independently selected from halo, -OR, -C R, -00 2 R, -COCOR, -NO 2 -ON, -S -SO 2 R, -SR, -NC(R) -CON(R') -SO 2 N (R 4 2, -00C=O)R, -N(R 4 )OCOR, -NCR 4)0 2 optionally substituted 01-6 aliphatic), -NCR 4 )NCR 4 2, -C=NNC(R) -O=N-OR, -N(R')OCON(R 4 2 -N(R 4 )S0 2 NC(R') 2 -N(R 4 )SO 2 R, or -OC N R 4 2 V is -SO 2 -N (R 6 SO 2 -SO 2 N (R 6 -002- -NCR 6 )COO-, N( 6)CO)O_, -NCR 6) CONC(R)- -NCR) S0 2 N -NC(R) )N(R -OCO)NCR -OCO)N(R) -OCR 6)20-, -OCR 6) 2S-, -CR 6) 2 S0-, -CR 6)2S02-, 2 SO 2 NC(R -CR 6) 2 N(R 6)- 2 N(R -CR 6) 2 NC(R6 CO) O_ -CR 6)=NN(R 6)- -CR -CR 6) 2 N(R 6)NCR -CR 6) 2 NC(R 6)S0 2 N(R or -CR 6) 2 NCR 6)CON(R) -34 4- 00 W is -C (R 6
2. 20-, -C (R 6 2 -C (R 6 2 SO-, -C (R 6 2 S0 2 S-C (R 6 2 S 2 N (R 6 -C (R 6 2 N(R 6 -CO 2 -C (R 6 -C (R 6 )OC (0)N -C (R 6 2 N (R 6 CO-, S-C (R 6 2 N(R 6 C -C (R 6 =NN (R 6 -C (R S-C (R 6 2 N (R 6 N (R 6 -C (R 6 2 N(R 6 )SO 2 N(R 6 -C(R 6 2 N(R 6 CON(R 6 or -CON(R 6 Sleach R 6 is independently selected from hydrogen or an _optionally substituted C1- 4 aliphatic group, or two R 6 C-i groups on the same nitrogen atom are taken together \O Swith the nitrogen atom to form a 5-6 membered C- heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted C 1 -6 aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring. 2. The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of: Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, thienyl, azepanyl, morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-lH-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; R x and R Y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring; and R 2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is -C (R 6 20-, -C (R 6 2 N(R 6 -CO 2 -C(R6) 2 N(R6) CO-, -C(R6) 2 N(R6)C(0)O-, or -CON(R6)-, and R is an optionally substituted group -345- 00 selected from C1-6 aliphatic or phenyl, or R 2 and R 2 are O taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring. 3. The compound according to claim 2, wherein: 4\ Ring D is an optionally substituted ring selected from a phenyl, pyridinyl, piperidinyl, N- piperazinyl, pyrrolidinyl, thienyl, azepanyl, \O morpholinyl, 1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4- Ce tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3- dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl ring; Rx and R y are taken together with their intervening atoms to form an optionally substituted 5-7 membered unsaturated or partially unsaturated ring; and R 2 is hydrogen or methyl and R 2 is T-W-R 6 or R, wherein W is -C(R 6 20-, -C (R 6 2 N (R 6 -CO2-, -C 2 N(R) CO-, 2 N(R6) C or -CON(R and R is an optionally substituted group selected from C 1 -6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, pyrimido, or partially unsaturated 6-membered carbocyclo ring. 4. The compound according to claim 2, wherein said compound has one or more features selected from the group consisting of: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; -346- 00 RX and RY are taken together with their 0 intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with oxo, halo, -OR, -CO 2 R, (1 -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 -CON(R 4 )2r -SO 2 N (R 4 -N(R 4 )COR, -N(R 4 )CO0 2 (optionally substituted C16 aliphatic), -N(R )N(R -C=NN(R )2, -C=N-OR, -N (R CON (R -N SO 2 N 2, -NR SO 2 R, or c- -OC(=0)N(R and \O (N CN, NO 2 -N (R 4 -CO 2 R, -CONH (R 4 -N (R 4 )COR, -SO 2 N (R 4 )2, -N(R 4 )S0 2 R, -SR, -OR, or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-10 aryl, or C1-6 aliphatic. The compound according to claim 4, wherein: Ring D is an optionally substituted ring selected from phenyl, pyridinyl, piperidinyl, piperazinyl, pyrrolidinyl, morpholinyl, 1,2,3,4- tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroquinolinyl, 2,3-dihydro-1H-isoindolyl, 2,3-dihydro-1H-indolyl, isoquinolinyl, quinolinyl, or naphthyl; RX and Ry are taken together with their intervening atoms to form a 5-7 membered unsaturated or partially unsaturated carbocyclic ring optionally substituted with oxo, halo, -OR, -C02R, -COCOR, -NO 2 -CN, -SO 2 R, -SR, -N(R 4 -CON(R 4 )2r -SO 2 N (R 4 2 -N(R )COR, -N(R 4 CO2 (optionally substituted C1-6 aliphatic), -N(R 4 )N(R 4 2 -C=NN(R 4 2 -C=N-OR, -N (R 4 )CON(R -N (R 4 SO 2 N (R 4 2 -N (R SO 2 R, or -OC(=0)N(R 4 and each R 5 is independently selected from halo, oxo, CN, NO 2 -N (R 4 2, -CO 2 R, -CONH (R 4 -N (R 4 COR, -SO 2 N (R 4 2, -N(R 4 )S0 2 R, -SR, -OR, or a substituted or -347- 00 unsubstituted group selected from 5-6 membered 0 0 heterocyclyl, C6-10 aryl, or C1-6 aliphatic. 6. The compound according to claim 4, wherein said CI compound has one or more features selected from the group consisting of: \0 RX and R y are taken together with their intervening atoms to form a 6-membered unsaturated or C- partially unsaturated carbocyclic ring optionally Ssubstituted with halo, CN, oxo, C1-6 alkyl, C1-6 alkoxy, c( (C0-6 alkyl)carbonyl, (Ci-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, -CN, -oxo, -SR, -OR, -N(R 4 or a substituted or unsubstituted group selected from 5-6 membered heterocyclyl, C6-io aryl, or C1-6 aliphatic; and R 2 is hydrogen and R 2 is T-W-R 6 or R, wherein W is -C(R6)20-, 2 N -CO2-, -C (R6) OC(O)-, -C(R 6 2 N(R 6 CO-, or -CON(R 6 and R is an optionally substituted group selected from C1-6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R 4 -C1-4 alkyl, -C1-4 haloalkyl, -NO 2 -O(C-4 alkyl), -C02 (C1-4 alkyl), -CN, -S0 2 (C 1 -4 alkyl), -SO 2 NH 2 -OC(0)NH 2 -NH 2 SO 2 (C1- 4 alkyl), -NHC(O) (C1-4 alkyl), -C(O)NH 2 or -CO(Ci- 4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. 7. The compound according to claim 6, wherein: -348- 00 Rx and R Y are taken together with their Sintervening atoms to form a 6-membered unsaturated or partially unsaturated carbocyclic ring optionally c, substituted with halo, CN, oxo, C1-6 alkyl, C1-6 alkoxy, 1 (Ci-6 alkyl)carbonyl, (Ci-6 alkyl)sulfonyl, mono- or dialkylamino, mono- or dialkylaminocarbonyl, mono- or dialkylaminocarbonyloxy, or 5-6 membered heteroaryl; each R 5 is independently selected from -halo, S-CN, -oxo, -SR, -OR, -N(R 4 or a substituted or I unsubstituted group selected from 5-6 membered C( heterocyclyl, C6-10 aryl, or Ci-6 aliphatic; and R 2 is hydrogen and R 2 is T-W-R 6 or R, wherein W is -C (R 6 20-, -C (R 6 2N (R 6 -C (R 6 OC -C(R 6 2 N(R 6 CO-, or -CON(R 6 and R is an optionally substituted group selected from C1-6 aliphatic or phenyl, or R 2 and R 2 are taken together with their intervening atoms to form a substituted or unsubstituted benzo, pyrido, or partially unsaturated 6-membered carbocyclic ring optionally substituted with -halo, -N(R 4 2, -C1-4 alkyl, -C1-4 haloalkyl, -NO 2 -O(C1-4 alkyl) -C02(C-4 alkyl), -CN, -S2 (C 1 4 alkyl), -SO 2 NH 2 -OC (0)NH 2 -NH 2 S0 2 (C1-4 alkyl), -NHC(0) (C1-4 alkyl), -C(0)NH 2 or -CO(CI- 4 alkyl), wherein the (C1-4 alkyl) is a straight, branched, or cyclic alkyl group. 8. The compound according to claim 1, wherein said compound is selected from the following Table 2 compounds: Table 2 SCH 3 HN HN C C HN HN H N HNH N N 4 CI I CI -349- III-1 111-2 111-3 HNNNr QJ2N H 0 CH 3 HN<*l AcNH'
3. 111-4 111-5 111-6 <H 3 HN')I H N "-N 111-9 111-7 111-8 OH 3 HN< H 3 C N- ''I-ic HN 111-11 CH 3 HN<* ENN H E1NHNN 111-12 OH 3 HN'* 'e ,N H CH 3 HN4*I 111-13 111-14 OH 3 H N 11 N1 111-16 OH 3 HN<* 111-17 111-18 -350- OH 3 HN<N H NC" N OH 3 111-19 CH 3 HIN CH 3 NH OH 3 111-22 CH 3 HN& H 3 C D, 3 N 111-25 OH 3 HN4* H 3 N H OH 3 111-20 CH 3 HN' CH 3 SO 2 N 111-23 CH 3 HN<* 111-21 OH 3 H N N H 111-24 OH 3 50 H N ITT-27 111-26 111-28 111-29 111-30 CH 3 HN< 111-31 111-32 111-33 -351- CH 3 HN< N7 1VN HZ 111-34 111-35 CH 3 HN 111-38 111-36 111-37 111-39 111-40 CH 3 H2f N Jl IH N c O 111-43 H 111-46 CH 3 HOH 3 OH 3 111-41 OH 3 5;e NN H 1-NMe2 111-42 111-44 111-45 OH 3 HN<* 111-47 111-48 -352- CH 3 I N H CH N CH 3 H 111-49 111-50 CH 3 HN<l N ZN~QCF3 111-53 111-52 CH 3 HN<* ~I N H CH3 N H 3 111-55 CH 3 H CF 3 CF 3 111-58 111-51 CH 3 H N N 111-54 CH 3 N H 111-57 OH 3 HN<N oj NH 111-60 111-56 111-59 CH 3 HN<* H 1 111-62 I, IH 111-63 111-61 -353- HN'Q' 111-64 H 3 C C 1 x HNIP 111-67 CH2 CH 3 H N CH 3 HN Itjr H N 111-65 111-66 111-68 111-69 C0 2 H HN 111-72 111-70 111-71 C0 2 CH 3 HNH N2N 111-73 OH HN'P N 111-76 CH 2 0H NN H HN< 111-74 1 OCH 3 HNH 111-77 CH 2 OCH 3 HN* H 'Il 111-75 OCH 2 Ph N 111-78 -354- NH 2 HN't'N N H 111-79 111-80 111-81 CH 2 NH N H 111-82 o 1 -CI N '-C Hf N HNN/' 111-86 OCH 3 N H HN 111-83 rN -NH 111-84 r-Q? -N 'OH 3 N N 111-87 CH 3 o NH HNrP H N 111-88 NH HNI r:: 111-90 111-89 -355- CH 3 NH H 3 0 ,N 0 CH 2 OCH 3 H 111-93 111-91 111-92 o ,CH 3 N H HN' H 111-96 N 0 H N'NN NH 111-97 0 \N CH HN I' 111-98 OH -NH 111-99 6- NH 2 111-100 CH 3 0N> K~o 111-104 CH 3 it HN 111-108 CH 3 H NN KNH 111-105 CH 3 HN< 111-107 OH 3 HN* NH 111-109 HN<* NH 111-112 HN' OH 111-115 OH 3 HN4* NH OH 3 111-110 OH 3 HN4* 111-113 HNr I~N 111-116 111-114 111-117 -357- 111-118 HN N 111-121 CH 2 0H HN<)[ ~N H 111-124 F F N~ H H NI f 111-127 HN N Nq 111-119 C0 2 CH 3 HN4N 111-122 CONH 2 HN*Z1 111-125 HNI OH 111-120 HN'r N H 111-123 CONH 2 HN* 111-126 Qi F H 111-129 111-128 HN N 3 1111CF3 111-132 111-130 111-131 -358- N HN H HNNNHN 2 H HR N lN 111-133 111-141 HN 111-142 HN2 H'I NN 111-143 HN% 1 CtN j'N 111-144 HN2' r4 H Me 111-145 HN dH HN P-N Me0D 111-146. 9. A compound selected from the following: Q 0 Na 3/H20CH3 HN 0 H 111-93 111-85 111-94 -359- Br OH 3 HN H N 111-102 111-95 III-101 NC HNX24N H N1-1 N0 111-103 111-106 111-134 HNAFt4 ~7N N~l NZ 111-135 F 3 C N HN r4N H N N 111-138 MeO O IH H NN 111-136 PhO0-, O HN 1 It" 111-139 111-137 0 N~FT -NI H NN 111-140. -360- 00 A composition comprising a compound according to any one of claims 1-9 and a pharmaceutically acceptable carrier. 11. The composition according to claim 10, further comprising a second therapeutic agent. IND S12. A method of inhibiting GSK-3, Aurora, or Src Iactivity in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. 13. The method according to claim 12, wherein said method inhibits GSK-3 activity in said patient. 14. A method of inhibiting GSK-3, Aurora, or Src activity in a biological sample comprising contacting said biological sample with the compound according to any one of claims 1-9. A method of treating a disease that is alleviated by treatment with an GSK-3 inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. 16. The method according to claim 15, further comprising the step of administering to said patient a second therapeutic agent. -361- 00 17. The method according to claim 15, wherein said disease is diabetes. S18. The method according to claim 15, wherein said (Ni disease is Alzheimer's disease. S19. The method according to claim 15, wherein said disease is schizophrenia. \O A method of enhancing glycogen synthesis in a C-i patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. 21. A method of lowering blood levels of glucose in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or 11. 22. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. 23. A method of inhibiting the phosphorylation of -catenin in a patient in need thereof, which method comprises the step of administering to said patient a therapeutically effective amount of the compound -362- 00 according to any one of claims 1-9 or the composition according to claim 10 or 11. S24. A method of treating a disease that is (1 alleviated by treatment with an aurora inhibitor, which method comprises the step of administering to a patient O in need of such a treatment a therapeutically effective amount of the compound according to any one of claims 1-9 C- or the composition according to claim 10 or 11. \O IND The method according to claim 24, further comprising the step of administering to said patient a second therapeutic agent. 26. The method according to claim 24, wherein said disease is cancer. 27. A method of treating a disease that is alleviated by treatment with a Src inhibitor, which method comprises the step of administering to a patient in need of such a treatment a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. 28. The method according to claim 27, further comprising the step of administering to said patient a second therapeutic agent. 29. The method according to claim 28, wherein said disease is selected from hypercalcemia, osteoporosis, osteoarthritis, or symptomatic treatment of bone metastasis. -363- 00 30. The method according to claim 27, wherein said disease is cancer. S31. A method of inhibiting ERK activity in a Ci patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and the compound according to claim 1 wherein R 2 is hydrogen and R" and R Y are taken together Iwith their intervening atoms to form a benzo ring. 32. A method of inhibiting ERK activity in a biological sample comprising contacting said biological sample with the compound according to claim 1 wherein R 2 is hydrogen and RX and R Y are taken together with their intervening atoms to form a benzo ring. 33. A method of treating a disease that is alleviated by treatment with an ERK inhibitor, said method comprising the step of administering to a patient in need of such a treatment a therapeutically effective amount of a composition comprising a pharmaceutically acceptable carrier and the compound according to claim 1 wherein R 2 is hydrogen and R' and R y are taken together with their intervening atoms to form a benzo ring. 34. The method according to claim 33, further comprising the step of administering to said patient a second therapeutic agent. The method according to claim 33, wherein said disease is selected from cancer, stroke, diabetes, hepatomegaly, cardiovascular disease, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune -364- 00 diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, and neurological disorders. Ci 36. The method according to claim 35, wherein said disease is cancer. \O 37. The method according to claim 35, wherein said disease is restenosis. \O IND S38. A method of treating diabetes in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or 11. 39. A method of treating Alzheimer's disease in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. A method of treating schizophrenia in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or 11. 41. A method of treating cancer in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. -365- 00 42. A method of treating hypercalcemia, Sosteoporosis, osteoarthritis, or symptomatic treatment of bone metastasis in a patient in need thereof, comprising the step of administering to said patient a CI therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. IND S43. A method of treating cancer, stroke, diabetes, IND hepatomegaly, cardiovascular disease, Alzheimer's (Ni disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders, inflammation, and neurological disorders in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of the compound according to any one of claims 1-9 or the composition according to claim 10 or claim 11. 44. A compound of formula III as defined in claim 1 and substantially as described in at least one of the accompanying examples. A pharmaceutical composition comprising the compound of claim 44 and a pharmaceutically acceptable carrier. 46. A method of inhibiting GSK-3, Aurora, or Src activity in a patient in need thereof, comprising the step of administering to said patient a therapeutically effective amount of the compound according to claim 44 or the composition according to claim -366- 00 Dated this day of 21 July 2008 SVertex Pharmaceuticals Incorporated By their Patent Attorneys CULLEN Co. IN (O -367-