AU2006201228B2 - Pyrazole Compounds Useful as Protein Kinase Inhibitors - Google Patents

Description

- 1 AUSTRALIA Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Vertex Pharmaceuticals Incorporated Address for Service: CULLEN & CO Patent & Trade Mark Attorneys, 239 George Street Brisbane Qld 4000 Australia Invention Title: 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: -la FIELD OF THE INVENTION The present- invention is in the field of medicinal chemistry and relates to compounds that are protein kinase inhibitors, compositions containing such compounds and methods of use. More particularly, this 5 invention relates to compounds that are inhibitors of Aurora-2 protein kinase. The invention also relates to methods of treating diseases associated with protein kinases, especially diseases associated with Aurora-2, such as cancer. 10 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 15 associated with target diseases. One important class of enzymes that has been the subject of extensive study is the protein kinases. . Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl 20 transfer from a nucleoside triphosphate to a protein acceptor that is involved in a signaling pathway. There are a number of kinases and pathways through which -2 extracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals (e.g. osmotic shock, heat shock, ultraviolet 5 radiation, bacterial endotoxin, H 2 0 2 ), cytokines (e.g. interleukin-1 (IL-1) and tumor necrosis.factor a (TNF a)), and growth factors (e.g. granulocyte macrophage colony-stimulating factor (GM-CSF), and fibroblast growth factor .(FGF). An extracellular stimulus may effect one 10 or more cellular responses related to cell growth, migration, differentiation, secretion of hormones, activation of transcription factors, muscle contraction, glucose metabolism, control of protein synthesis and regulation of cell cycle. 15 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 20 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 25 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 30 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 -3 Bischoff et al., EMBO J., 1998, 17, 3052-3065; Schumacher et al., J. Cell Biol., 1998, 143,' 1635-1646; Kimura et al., J. Biol. Chem., 1997, 272, 13766-13771. Glycogen synthase kinase-3 (GSK-3) is a 5 serine/threonine protein kinase comprised of a and f 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 10 diabetes, Alzheimer's disease, CNS disorders such as manic depressive disorder and neurodegenerative diseases, and cardiomyocete hypertrophy [WO 99/65897; WO 00/38675; and Haq et al., J. Cell Biol. (2000) 151, 117].. These diseases may be caused by, or result in, the abnormal 15 operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for 20 glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor 0-catenin, the translation initiation factor e1F2B, as well as ATP citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBX. These diverse protein targets 25 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 30 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 -4 phosphorylation and deactivation of glycogen synthase. The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. J., 303, 21-26 5 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)]. However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood 10 levels of insulin. This leads .to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It 15 has also been reported that in. patients with type II diabetes, GSK-3 is overexpressed [WO 00/386751. Therapeutic inhibitors of GSK-3 therefore are considered to be useful for treating diabetic patients suffering from -an impaired response to insulin. 20 GSK-3 activity has also been associated with Alzheimer's disease. This disease is characterized by the well-known J-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau 25 protein where Tau is phosphorylated on abnornial 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, 30 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.

-5 Another substrate of GSK-3 is J-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 5 diseases related to increase in neuron'al cell death (Zhong et al., Nature, 395, 698-702 (1998); Takashima et al., PNAS, 90, 7789-93 (1993); Pei et al., J. Neuropathol. Exp, 56, 70-78 (1997)]. As a result of the biological importance of 10 GSK-3, there is current interest in therapeutically effective GSK-3 inhbitors. Small molecules that inhibit GSK-3 have recently been reported [WO 99/65897 (Chiron) and WO 00/38675 (SmithKline Beecham)]. For many of the aforementioned diseases 15 associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating the same diseases. However, the various protein kinases often act through different biological pathways. For example, certain quinazoline derivatives have been reported 20 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-a activity and/or enhanced TGF- activity. While p38 activity has been implicated in a wide variety of 25 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 30 uptake. There is a continued need to find new therapeutic agents to treat human diseases. The protein -6 kinases Aurora-2 and GSK-3 are especially attractive targets for the discovery of new therapeutics due to their important roles in cancer and diabetes, . respectively. 5 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 10 inhibitors of Aurora-2. These compounds have the general formula I:

R

2 NH HN N R Z A RY .I Q-R or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Z" is -nitrogen or C-R and Z 2 is nitrogen or CH, wherein 15 at least one of Z' and Z2 is nitrogen; RX and RY are independently selected from T-R 3 or L-Z-R3 or RX and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsAturated, 5-7 membered ring having 0-3 ring 20 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R' and RY is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring -7 nitrogen of said ring formed by RX and Ry is independently substituted by R'; Q is selected from -N(R)-, --, -S-, -C(R 6

')

2 -, 1,2 cyclopropanediyl, 1, 2-cyclobutanediyl, or 1,3 5 cyclobutanediy;

R

1 is T- (Ring D); Ring D is a 5-7 membered monocyclic ring -or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or 10 heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-Rs, or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently 15 substituted by -R 4 ; T is a valence bond or a C2..4 alkylidene chain, wherein when Q is -C(R"') 2 -, a methylene unit of said C 1

.

4 alkylidene chain is optionally replaced by -0-, -S-, -N(R')-, -CO-, -CONH-, -NHCO-, -S02-, -SO 2 NH-, -NHSO 2 -, -20 -Ca 2 -, -OC(O)-, -OC(0)NH-, or --NHC0 2 -; Z is a C 1

..

4 alkylidene chain; L is -0-, -S-, -SO-, -SO2-, -N(R')S0 2 -, -SO 2

N(R

6 )-,

-N(R

6 ) -, -CO-, -CO 2 -, -N(R')CO-, -N(R 6 )C(0)0-,

-N(R

6 )CON(R') -, -N(R5)SO 2

N(R

6 )-, -N(R 6 )N(R')-, 25 -C(O)N(R)-, -OC(O)N(R 6 )-, -C(R) 2 0-; -C(R') 2 S-, -C(R6) 2 SO-, -C(R 6

)

2

SO

2 -, -C(R 6

)

2

SO

2 N(R)-, -C(R()2N(R6) . -C(R') 2 N(R)C(O)-, -C(R 6

)

2 N(R)C(0)o-, -C(R 6 )=NN(R')-,

-C(R

6 )=N-0-, -C(Rt) 2

N(R

6

)N(R

6 )-, -C(R) 2

N(R

6

)SO

2

N(R

6 )-, or -C (R 6 ) 2 N (R 6 ) CON (R 6 ); 30 R 2 and R 2 are independently selected from -R, -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 -8 selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R, or -V-R 6 , and each substitutable ring 5 nitrogen of said-ring -formed by-R 2 and R2, is independently substituted by R 4 ;

R

3 is selected from -R, -halo, -OR, -C(=o)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR,

-N(R

4

)

2 , -CON(R 7

)

2 , -SO 2 N(R7) 2 , -OC(=o)R, -N(R")COR, 10 -N(R 7 ) CO 2

(C

6 s aliphatic),

-N(R

4

)N(R

4

)

2 , -C=NN(R 4

)

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

)CON(R

7

)

2 , -N(R 7 )S0 2

N(R)

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 Ces 15 aliphatic, C 6

..

1 0 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 -R7, -COR,

-CO

2 (optionally substituted C3,_ 6 aliphatic), -CON(R 7

)

2 ; 20 or -S0 2 R; each R5 is independently selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR,

-N(R

4

)

2 , -CON(R 4

)

2 , -SO 2 N (R 4 ) 2 , -OC(=O)R, -N(R 4 ) COR,

-N(R

4 ) C0 2 (optionally substituted Ci 1 6 aliphatic), 25 -N(R4)N(R 4 ) 2 , -C=NN(R4) 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 -OC(=O)N(R4 ) 2 V is -0-, -S-, -SO-, -SO2-, -N(Rt)SO 2 -, -SO 2 N(R)-, -N(R6)-, -CO-, -C0 2 -, -N(R')CO-, -N(R 6 )C(0)0-, -N (R5) CON (R') -, -N (R)SO2N (R 6)-_, -N (R") N(R')- , 30 -C(O)N(R')-, -OC(O)N(R')-, -C(R6) 2 0-, -C(R') 2 S-, -C(R 6)2SO-, -C(R6) 2 S0 2 -, -C(R') 2

SO

2 N(R')-, -C(R6) 2 N (R')-,

-C(R')

2 N(R')C(O)-, -C( R') 2 N(R)C(o)0-,

-C(R')=NN(R')-,

-9-. -C(R')=N-O-,

-C(R')

2 N(RS)N(R6)-,

-C(R

6

)

2

N(R

6 )S0'N(R 6 )-, or -C(R6) 2 N(R')CON(R6) -; W is -C(R)20-,

-C(R

6

)

2 S-, -C(R 6

)

2 SO-, -C(R 6

)

2

SO

2 -,

-C(R

6

)

2

SO

2 N(R')-,

-C(R

6

)

2 N(R')-, -CO-, -CO 2 -, 5 -C (R 6 ) OC (O) - -C-(R 6 ) OC (o) N (R 6 ) -, -C (R 6 ) 2 N (R 6 ) CO-,

-C(R'

)

2

N(R

6 ) C (0)0-, -C (R')=NN(R 6 ) -, -C(R 6 )=N-O-,

-C(R')

2

N(R')N(R

6 ) -, -C(R) 2

N(R)SO

2 N(R6) -,

-C(R')

2 N(R')CON(R')-, or -CON(R')-; each R 6 is independently selected from hydrogen or an 10 optionally substituted

CI-

4 aliphatic group, or two R' groups on the same nitrogen atom may be taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or a CI.4 15 aliphatic group, or two R' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring; each R 7 is independently selected from hydrogen or an optionally substituted

C

1

..

6 aliphatic group, or two R on the same nitrogen are taken together with the 20 nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and

R

8 is selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR,

-NO

2 , -CN, -S(O)R, -S02R, -SR, -N(R 4

)

2 , -CONC (R 4

)

2 ,

-SO

2

N(R

4 )f 2 , -OC(=O)R, -N (R 4 ) COR, -N(R 4 ) CO 2 (optionally 25 substituted C., aliphatic),

-N(R

4

)N(R

4

)

2 , -C=NNCR 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 -OC(=0)N(R 4

)

2 As used herein, the following definitions shall apply-unless otherwise indicated. The phrase "optionally 30 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 -10 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 C 1

-C

12 hydrocarbons 5 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 10 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 15 carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both straight and branched chains containing two to twelve carbon atoms. The term "cycloalkyl" used alone or as part of a larger moiety shall include cyclic C 3 -Q 20 hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic. The terms "haloalkyl", "haloalkenyl" and "haloalkoxy" means alkyl, alkenyl or alkoxy, as the case 25 may be, substituted with one or more halogen atoms. The term "halogen" means F, Cl, Br, or I. The term "heteroatom" means nitrogen, oxygen, or sulfur and includes any oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen. 30 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 -11 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", - 5 -"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. 10 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. 15 The term "aryl" used alone or as part of a larger moiety-as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to aromatic ring groups having - five to fourteen members, such as phenyl, benzyl, phenethyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2 20 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 25 include 1-naphthyl, 2-naphthyl, 1-anthracyl and 2 anthracyl. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or 30 tetrahydronaphthyl, where the radical or point of attachment is on the Aromatic ring. The term "heterocycle", "heterocyclyl", or "heterocyclic" as used herein includes non-aromatic ring -12 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, 0, or S. Examples of heterocyclic rings include 3-lH 5 benzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3 yl, 2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2 tetrahydropyranyl, 3-tetrahydropyranyl, 4 .tetrahydropyranyl, [1,3]-dioxalanyl, [1,33-dithiolanyl, [1,3]-dioxanyl, 2-tetrahydrothiophenyl, 3 10 tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4 morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 4 thiomorpholinyl, 1-pyrrolidinyl, 2-pyrrolidinyl, 3 -pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1 piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 15 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1 phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also included within the scope of the term "heterocyclyl" or "heterocyclic", as it is used herein, 20 is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic .rings, such as in an indolinyl, chromanyl, - phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic 25 heteroatom-containing ring. The term "heterocycle", "heterocyclyl", or "heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted. The term "heteroaryl", used alone or as part of 30 a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl, 3-furazanyl, N- -13 imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3 isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, 5 oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, l pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 1-pyrazolyl, 2 5 pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyli 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2 thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2 triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, benzimidazolyl, benzothienyl, benzofuranyl, indolyl, 10 quinolinyl, benzotriazolyl, benzothiazolyl, benzooxazolyl, benzimidazolyl, isoquinolinyl-, indazolyl, isoindolyl, acridinyl, or benzoisoxazolyl. Also included within the scope of the term "heteroaryl", as it is used herein, is a group in which a heteroatomic ring is fused 15 to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoguinolinyl, and pyrido[3,4-dlpyrimidinyl. The term "heteroaryl" also refers to rings that are 20 optionally substituted. The term "heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic". An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including 25 heteroaralkyl and heteroarylalkoxy and the like) group may contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl, or heteroaralkyl group include a halogen, -R*, -OR", -SR", 1,2-methylene-dioxy, 30 1,2-ethylenedioxy, protected OH (such as acyloxy), phenyl (Ph), substituted Ph, -O(Ph), substituted -O(Ph),

-CH

2 (Ph), substituted -CHt(Ph), -CH 2

CH

2 (Ph), substituted

-CH

2

CH

2 (Ph) , -NO 2 , -CN, -N(R") 2 , -NRC(o)R, -NRoC (o) N (R*) 2

,

-14

-NR*CO

2 R*, -NR"NR*C (0) R*, -NR"NR*C (0) N (R*) 2 , -NR*NR*C0 2 R*, -C(O)C(O)R", -C(0)CH 2 C(O)R*, -C0 2 R*, -C(O)R*, -C(O)N(R*) 2 ,

-OC(O)N(R*)

2 , -S(0) 2 R*, -SO 2

N(R*)

2 , -S(O)R*, -NR*S0 2 N(R*)2,

-NR"SO

2 R*, -C(=S)N(R*) 2 , -C(=NH)-N(R*) 2 , -(CH 2 ) yNHC(O)R*, 5 - (CH 2 ) yNHC (0) CH (V-R*) (R*) ; wherein each R* is independently selected from hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or heterocyclic ring, phenyl (Ph), substituted Ph, -O(Ph), substituted -0 (Ph) , -CH 2 (Ph) , or substituted -CH 2 (Ph) ; y 10 is 0-6; and V is a linker group. Examples of substituents on the aliphatic group or the phenyl ring of R* include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, 15 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 20 of an aliphatic group or of a non-aromatic -heterocyclic ring include those listed above for the unsaturated carbon of an aryl or heteroaryl group and the following: =0, =S, =NNHR*, =NN(R*) 2 , =N-, =NNHC(0)R*,

=NNHCO

2 (alkyl),

=NNHSO

2 (alkyl), or =NR*, where each R* is independently 25 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, 30 alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

-15 Suitable substituents on the nitrogen of a non aromatic heterocyclic ring include -Re, -N(R*) 2 , -C(O)R*, -C0 2 R*, -C(O)C(O)R*, -C(O)CH 2 C(O)R*, -SO 2 R*, -SO 2

N(R*)

2 ,

-C(=S)N(R*)

2 , -C(=NH)-N(R*) 2 , and -NR t

SO

2 R*; wherein each R* 5 is independently selected from hydrogen, an aliphatic group, a substituted aliphatic group, phenyl (Ph), substituted Ph, -O(Ph), substituted -O(Ph), CH 2 (Ph), substituted CH 2 (Ph), or an unsubstituted heteroaryl or heterocyclic ring. Examples-of substituents on the 10 aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, 15 hydroxy, haloalkoxy, or haloalkyl. The term "linker group" or "linker" means an organic moiety that connects two parts of a compound. Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -NH-, -CH 2 -, -C(O)-, -C(O)NH-, 20 or a chain of atoms, such as an alkylidene chain. The molecular mass of a linker is typically in the range of about 14 to 200, preferably in the range of 14 to 96 with a length of up to about six atoms. Examples of linkers include a saturated or unsaturated C1.6 alkylidene chain 25 which is optionally substituted, and wherein one or- two saturated carbons of the chain are optionally replaced by -C(O)-, -C-(O)C(O)-, -CONH-, -CONrHNH-, -CO2-, -OC(O.)-,

-NHCO

2 -, -0-, -NHCONH-, -oC(o)NH-, -NHNH-, -NHCO-, -S-, -SO-, -SO 2 -, -NH-, -SO 2 NH-, or -NHSO 2 -. 30 The term "alkylidene chain" refers to an optionally substituted, straight or branched carbon chain that may be fully saturated or have one or more units of -16 unsaturation. The optional substituents are as described above for an aliphatic group. A combination of substituents or variables is permissible only if such a combination results in a S 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 10 least a week. Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; i.e., the R and S configurations for each asymmetric center. Therefore, single stereochemical 15 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 20 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 13 C- or 14C-enriched carbon are within the scope of this invention. 25 Compounds of formula I or salts thereof may be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein 30 kinase, particularly Aurora-2, in a biological sample or in a patient. Compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat -17 or prevent an Aurora-2-mediated condition and a pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient. 5 Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a 10 compound of formula I or a pharmaceutical composition thereof. The term "Aurora-2-mediated disease" or "Aurora-2-mediated condition", as used herein, means any disease or other deleterious condition in which Aurora is 15 known to play a role.. The terms "Aurora-2-mediated disease" or "Aurora-2-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, colon, breast, stomach, and ovarian 20 cancer. Another aspect of the invention relates to inhibiting Aurora-2 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 inhibitor of formula I, or a 25 composition thereof.. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said 30 compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises -18 administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. The terms "GSK-3-mediated disease" or "GSK-3 5 mediated condition", as used herein, mean any disease or other deleterious condition or state in which GSK-3 is known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDS 10 associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, rpe.rfusion/ischemia, and baldness. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering 15 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 20 method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates.to inhibiting the phosphorylation of P-catenin, which is useful for 25 treating schizophrenia. Another aspect of the invention relates to inhibiting GSK-3 activity in a biological sample*, which method comprises contacting the biological sample with a GSK-3 inhibitor of formula I. 30 Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.

-19 Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated disease with a CDK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a 5 therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. . The terms "CDK-2-mediated disease" or "CDK-2 mediated condition", as used herein, mean any disease or other deleterious condition in which CDK-2 is known to 10 play a role. The terms "CDK-2-mediated disease" or "CDX 2-mediated condition" also mean those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such conditions include, without limitation,. cancer, Alzheimer's disease, restenosis, angiogenesis, 15 glomerulonephritis, cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such.as rheumatoid arthritis. See Fischer, P.M. and Lane, D.P., Current Medicinal Chemistry, 7, 1213-1245 (2000); Mani,'S., Wang, C., Wu, K., Francis, R. and 20 Pestell, R., Exp. Opin. Invest. Drugs, 9, 1849 (2000); Fry, D.W. and Garrett,. M.D., Current Opinion in Oncologic, Endocrine & Metabolic Investigational Drugs, 2, 40-59 (2000) Another aspect of the invention relates to 25 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 30 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 -20 therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. The terms "ERK-mediated disease" or "ERK mediated condition", as used herein mean any disease or 5 other deleterious condition in- which ERK is known to play a role. The terms "ERK-2-mediated disease" or "ERK-2 mediated condition" also mean those diseases or conditions that are alleviated by treatment with a ERK-2 inhibitor'. Such conditions include, without limitation, 10 cancer, stroke, diabetes, hepatomegaly, cardiovascular disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological 15 disorders and hormone-related diseases. The term "cancer" includes, but is not limited to the following cancers: breast, ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach, skin, keratoacanthoma, lung, 20 epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver 25 carcinoma and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip, tongue, mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, andleukemia. 30 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 -21 al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, Cell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol. 16, 1247; Raingeaud et al. 1996; Chen et al., 1993 Proc. Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, 5 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, Am. J. Respir. Cell Mol. Biol. 16, 589]. 10 Another aspect of the invention relates to inhibiting ERK-2 activity in a biological sample or 'a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound. 15 Another aspect of this invention relates to a method of treating or preventing an AKT-mediated diseases with an AKT inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically.effective amount of a compound of formula 20 I or a pharmaceutical composition thereof. The terms "AKT-mediated disease" or "AKT mediated condition", as used herein, mean any disease or other deleterious condition in which AKT is known to play a role. The terms "AKT-mediated disease" or "AKT 25 mediated condition" also mean those diseases or conditions that are alleviated-by treatment with a AKT inhibitor. AKT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT, 30 also known as protein kinase B, with various diseases has been described [Khwaja, A., Nature, pp. 33-34, 1990; Zang; Q. Y., et al, Oncogene, 19.2000; Kazuhiko, N., et al, The Journal of Neuroscience, 20 2000].

-22 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 5 comprising said- compound. Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a 10 therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. The terms "Src-mediated disease" or "Src mediated condition", as used herein mean any disease or other deleterious condition in which Src is known to play 15 a role. The terms "Src-mediated disease" or "Src mediated condition" also mean those diseases or conditions that are alleviated by treatment with a Src inhibitor. Such conditions include, without limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, 20 symptomatic treatment of bone metastasis, and.Paget's disease. Src protein kinase and its implication in various diseases has been described (Soriano, Cell, 69, 551 (1992); Soriano'et al., Cell, 64, 693 (1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, 25 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, 30 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)].

-23 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 5 comprising said compound. Another aspect of this invention relates to a method of treating or preventing an Lck-mediated diseases with an Lck inhibitor, which method comprises administering to a patient in need of such a treatment a 10. therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof. The terms "Lck-mediated disease" or "Lck mediated condition", as used herein, mean any disease state or other deleterious condition in which Lck is 15 known to play a role. The terms "Lck-mediated disease" or "Lck-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an Lck inhibitor. Lck-mediated diseases or conditions include, but are not limited to, autoimmune diseases such as 20 transplant rejection, allergies, rheumatoid arthritis, and leukemia. The association of Lck with various diseases has been described [Molina et al., Nature, 357, 161 (1992)]. Another aspect of the invention relates to 25 inhibiting Lck activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound. The term pharmaceuticallyy acceptable carrier, 30 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 -24 which does not destroy the pharmacological activity thereof. The term "patient" includes human and veterinary subjects. 5 The term-"biolog-ical sample", as used herein, includes, without limitation, cell cultures or extracts thereof; preparations of an enzyme suitable for in vitro assay; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, 10 tears, or other'body fluids or extracts thereof. An amount effective to inhibit protein kinase, for example, Aurora-2 and GSK-3, is an amount that causes measurable inhibition of the kinase activity when compared to the activity of the enzyme in the absence of 15 an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below. Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions are 20 generally known in the art. They include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of 25 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 30 substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

-25 The compositions of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as 5 used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, 10 intraperitoneally or intravenously. Sterile injectable forms of the compositions of this invention may be aqueous or oleaginous suspension. These suspensions may be formulated according to techniques known in the art using suitable dispersing or 15 wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in.1,3-butanediol. Among the acceptable vehicles and 20 solvents-that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono 25 or di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions. These oil 30 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 -26 dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans and other emulsifying agents or bioavailability enhancers which are commonly used in the manufacture of 5 pharmaceutically acceptable solid, liquid, or-other dosage forms may also be used for the purposes of formulation. The pharmaceutical compositions of this invention may be orally administered in any orally 10 acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. 15 For oral administration in a capsule form, useful diluents include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or 20 coloring agents may also beadded. Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non 25 irritating excipient which is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols. The pharmaceutical compositions of this 30 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- -27 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 5 (see above) or in- a suitable enema formulation. Topically-transdermal patches may also be used. For topical applications, the pharmaceutical compositions may be formulated in a suitable ointment containing the active componentsuspended or dissolved in 10 one or, more carriers. Carriers for topical administration of the compounds of this invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying 15 wax and water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited 20 to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water. For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions 25 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 30 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 -28 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, 5 fluorocarbons 1 -and/or other -conventional solubilizing or dispersing agents. In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of the compounds of this invention may also be employed in 10 compositions to treat or prevent the above-identified disease or disorders. A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt of an ester or other derivative of a compound 15 of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof. Particularly favored derivatives or prodrugs are those 20 that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient (e.g., by allowing an orally administered compound:to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a 25 biological compartment (e.g., the brain or lymphatic system) relative to the parent species. Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, the following derivatives of the present compounds: 30 esters, amino acid- esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides. Pharmaceutically acceptable salts of the compounds of this invention include those derived from -29 pharmaceutically acceptable inorganic and organic acids and bases. Examples of suitable acid salts include acetate, adipate, alginate, aspartate, benzoate,. benzenesulfonate, bisulfate, butyrate, citrate, 5 camphorate,- camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptanoate, glycerophosphate, glycolate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxyethanesulfonate, 10 lactate, maleate, malonate, methanesulfonate, 2 naphthalenesulfonate, nicotinate, nitrate,.oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate, tartrate, thiocyanate, tosylate and 15 undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may be-employed in the preparation of salts useful as intermediates in obtaining the compounds of the.invention and their pharmaceutically acceptable acid addition salts. 20 Salts derived from appropriate bases include alkali metal (e.g., sodium and potassium), alkaline earth metalj(e.g., magnesium), ammonium and N* (CI 4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of the compounds 25 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 30 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 -30 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 5 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 the judgment of the treating physician and the severity 10 of the particular disease being treated. The amount of the inhibitor will also depend upon the particular compound in the composition. Depending upon the particular protein kinase mediated condition to be treated or prevented, additional 15 therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative 20 agents may be combined with the present compounds to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives. 25 other examples of agents the -inhibitors of this invention may also be combined with include, without limitation, agents for treating diabetes such as insulin or insulin analogues,.in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, 30 insulin sensitizers, and sulfonyl ureas; anti inflammatory agents such as corticosteroids, TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine;- immunomodulatory and immunosuppressive -31 agents such as cyclosporin, tacrolimus, rapamycin, mycophenolate mofetil, interferons, corticosteroids, cyclophophamide, azathioprine, and sulfasalazine; neurotrophic factors-such as acetylcholinesterase 5 inhibitors,--MAO inhibitors, interferons, anti convulsants, ion channel blockers, riluzole, and anti Parkinsonian agents; agents for treating cardiovascular disease such as beta-blockers, ACE inhibitors, diuretics, nitrates, calcium channel blockers, and stating; agents 10 for treating liver disease such as corticosteroids, cholestyramine, interferons, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency 15 disorders such as gamma globulin. Those additional agents may be administered separately from the protein kinase inhibitor-containing composition, as part of a multiple dosage regimen. Alternatively, those agents may be part of a single 20 dosage form, mixed together with the protein kinase inhibitor of this invention in a. single composition. Compounds of this invention may exist in alternative tautomeric forms, as in tautomers i and iI shown below. Unless otherwise indicated, the 25 representation of either tautomer is meant to include the other.

-32 R2' R2 N NH RF Z2H e Rx Z2 j A A I Z* R Q-Ri - R 1Zi Q-R' RX and RY may be taken together to form a fused 5 ring, providing a bicyclic ring system containing Ring A. Preferred RX/RY rings include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/RY ring is optionally substituted. Examples of bicyclic systems, containing 10 Ring A are shown below by compounds I-A through I-BB, wherein Z' is nitrogen or C(R) and Z 2 is nitrogen or C(H).

R

2 -R2 I-A I-B -I-C HHNNN HN>? R,4 N Ry Z I-D I-B

I-F

-33

R

4 HN HNt HN I-G I-H - I HN H N z2 N Z , Z2 I-J -G HNIZ HN'1 HN31 NN I-M I-N I-L HN- HN- HN 3 ? N... IN A (-N LZ<k I-P I-N 1-0 HN HN? HN? I-P I-Q I-U I-B - I-ti -34 HN HN3Z' HN>% R R Z I-V I-W I-X HNA HN>H -zN2 NN z2 Z' N N 1 I-Y I-Z I-AA HNN ( I Z '25 I-BB Preferred bicyclic Ring A systems include I-A, I-B, I-C, I-D, Z-E, I-F, I-I, I-J, I-K, I-P, I-Q, I-V, and I-U, more preferably I-A, I-B, I-D, I-E, I-J, I-P, 5 and I-V, and most preferably I-A, I-B, I-D, I-E and I-J. In the monocyclic Ring A system, preferred RX groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl. Preferred RY 10 groups, when present, include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, -C(R 6

)

2 0-, -CO- or -N(R 4 )-, and R 3 is -R, -N(R 4

)

2 , or -OR. Preferred RY groups include 5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl, pyrrolidinyl, 15 piperidinyl, morpholinyl, or piperazinyl; C- aliphatic, such as methyl, ethyl, cyclopropyl, isopropyl, or -35 t-butyl; alkoxyalkylamino such as methoxyethylamino;, alkoxyalkyl such as methoxymethyl or methoxyethyl; alkyl or dialkylamino such as ethylamino or dimethylamino; alkyl- or dialkylaminoalkoxy such as 5 dimethylaminopropyloxy; acetamido; and optionally substituted phenyl such as phenyl or halo-substituted phenyl. In the bicyclic Ring A system, the ring formed when RX and RY are taken together may be substituted or 10 unsubstituted. Suitable substituents include -R, halo, -O (CH 2 ) 2- 4 -N (R 4

)

2 , -0 (CH 2

)

2 -4-R, -OR, -N (R 4 ) - (CH 2 ) 2-4-N (R 4 ) 2 ,

-N(R

4 )-(CH2)2-4-R, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , '-CN, -S(O)R, -SO 2 R, -SR, -N(R 4

)

2 , -CON(R4) 2 , -SO 2

N(R

4

)

2 , -OC(=O)R, -N(R 4 )COR, -N(R 4 ) C0 2 (optionally substituted CI-g 15 aliphatic), -N(R 4 )N(R4) 2 , -C=NN(R 4

)

2 , -C=N-OR, -N (R4) CON (R) 2 , -N (R 4 ) SO 2 N (R4) 2 , -N(R 4 ) SO 2 R, or

-OC(=O)N(R

4

)

2 , wherein R and R 4 are as defined above. Preferred RX/RY ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON(R 4

)

2 , -CN, -O(CH 2 )2- 4

-N(R

4

)

2 , -o (CH 2

)

2 4 -R, 20 -NO 2 -N (R 4 ) 2 ,.-NRCOR, -NRSO 2 R, -SO 2 N(R4)2 wherein'R is hydrogen or an optionally substituted C 1

..

6 aliphatic group.

R

2 and R 2 ' may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, 25 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: -36 NIH H N N N \ N'% Z2RNH NH H NH N I-- - N-N RY Zi Q-RI, , ,, ad Preferred substituents on the R 2

/R

2 ' fused ring include one or more of the following: -halo, -N(R4) 2 , -C 1

-.

3 5 alkyl, -C 1

..

3 haloalkyl, -NO 2 , -O(C-3 alkyl) , -C0 2

.(C

1

..

3 alkyl) , - CN, -SO 2 (C--3 alkyl) , -SO 2

NH

2 , -OC (O) NH 2 ,

-NHSO

2 (CI_3 alkyl) , -NHC (0) (C 1

..

3 alkyl) , -C (O) NH 2 , and -CO(C-..3 alkyl), wherein the (CI-3 alkyl) is most preferably methyl. 10 When the pyrazole ring system is monocyclic, preferred R 2 groups include hydrogen, C1.4 aliphatic, alkoxycarbonyl, (un)substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbonyl, aminoalkyl, alkylaminoalkyl, 15 dialkylaminoalkyl, phenylaminocarbonyl, and (N heterocyclyl)carbonyl. Examples of such preferred R 2 substituents include methyl, cyclopropyl, ethyl, isopropyl, propyl, t-butyl, cyclopentyl, phenyl, C02H, CO2CH31 CH20H, CH 2 0CH 3 , CH 2

CH

2

CH

2 OH, CH2CH2CH20CH3, 20 CH2CH2CH20CH2Ph,

CH

2

CH

2

CH

2

NH

2 , CH 2

CH

2

CH

2 NHCOOC (CH 3

)

3 , CONHCH (CH3) 2 , CONHCH 2

CH=CH

2 , CONHCH 2

CH

2 0CH 3 , CONHCH 2 Ph, CONH (cyclohexyl) , CON,(Et) 2 , CON (CH 3 ) CH 2 Ph, CONH (n-C3H 7 ) , CON (Et) CH2CH2CH3, CONHCH 2 CH (CH3)2, CON (n-C 3

H,)

2 , CO(3 methoxymethylpyrrolidin-1-yl), CONH(3-tolyl), CONH(4 25 tolyl), CONHCH 3 , CO(morpholin-1-yl), CO(4-methylpiperazin l-yl), CONHCH 2

CH

2 OH, CONH 2 , and CO(piperidin-1-yl). A preferred R 2 ' group is hydrogen.

-37 An embodiment that is particularly useful for treating Aurora-2-mediated diseases relates to compounds of formula Ila: R2 NH HN N RR Ry N*"S-R' Ila or a pharmaceutically acceptable derivative or prodrug 5 thereof, wherein; RX and R are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each 10 substitutable ring carbon of said fused ring formed by RX and Ry is independently substituted by oxo, T-R 3 , or 3 L-Z-R , and each substitutable ring nitrogen of said ring formed by RX and Ry is independently substituted by R4; 15 R 1 is T- (Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected 20 from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each. substitutable ring nitrogen of Ring D is independently substituted by -R 25 T is a valence bond or a C 1

-

4 alkylidene chain; -38 Z is a C 1

-

4 alkylidene chain; L is -0-, -S-, -SO-, -S02-, -N(RG)SO 2 -, -SO 2 N(R5)-,

-N(R

6 ) -, -CO-, -C0 2 -, -N(R 6 )CO-, -N(R')C(0)O-,

-N(R

6

)CON(R

6 )-, -N(R 6

)SO

2 N(Rr)-, -N(R)N(R)-, 5 -C(O)N(R 6 )-, -OC(O)N(R)-,- -C(R 6

)

2 0-, -C(R) 2 S-, -C (R) 2SO- , -C (R 6 ) 2SO2-, -C(R 6 ) 2

SO

2 N (R 6 ) -, -C(R 6 ) 2

N(R

6 ) -, -C (R 6 ) 2

N(R

6 )C(O) -, -C(R 6

)

2

N(R

6 ) C(0)O-, -C(R 6 )=NN(R') -,

-C(R

6 )=N-O-, -C(R 6

)

2

N(R

6 )N(R)-, -C(R6) 2

N(R

6

)SO

2 N(R) -, or -C (R 6

)

2

N(R

6 ) CON(R 6 ) -; 10 R 2 and R 2 ' are independently selected from -R, -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 is substitutable ring carbon of said fused ring formed by

R

2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R7, or -V-R; and each substitutable ring nitrogen of said ring formed by R2 and R 2 ' is independently substituted by R 4 ; 20 R 3 is selected from -R, -halo, -OR, -C(=O)R, -C0 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(0) 2 R, -SR,

-N(R

4

)

2 , -CON(R 7

)

2 , -SO2N(R)2, -OC(=O)R, -N(R )COR,

-N(R

7 ) CO 2 (CI- aliphatic), -N(R 4

)N(R

4

)

2 , -C=NN.(R4) 2 , -C=N-OR, -N (R) CON(R ) 2 , -N (R 7 ) SO 2 N (R 7 ) 2 , -N (R 4 ) SO 2 R, or 25 -OC(=0)N(R7) 2; each R is independently selected from hydrogen or an optionally substituted group selected from 'Cl. aliphatic, Cg-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring 30 atoms; each R 4 .is independently selected from -- R 7 , -COR, -C02 (optionally substituted CI- 6 aliphatic), -CON(R 7

)

2 , or -S0 2

R;

-39 each R 5 is independently selected from -R, halo, -OR, -C(=O)R, -C0 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R4) 2 , -CON(R 4

)

2 , -S02N(R 4

)

2 , -OC(=O)R; -N(R4)COR, -N (R4) C02 (optionally substituted C- aliphatic), 5 -N(R 4

)-N(R

4

)

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(R4)SO 2 R, or -OC(=0)N(R4)2; V is -0-, -S-, -SO-, -SO2-, -N(R')S0 2 -, -SO 2

N(R

6 )-, -N(R)-, -CO-, -CO2-, -N(R 6 )CO-, -N(R')C (0)0-, -N(R')CON(R)-, -N(R6)SO 2 N(R6)-, -N(R6)N(R)-, 10 -C(O)N(R')-, -OC(O)N(R4)-, -C(R6) 2 0-, -C(R') 2 S-,

-C(R')

2 SO-, -C(R') 2

SO

2 -, -C(Rt) 2

SO

2 N(R)-, -C(R) 2 N(R)-, -C (R6) 2

N(R

6 ) C(O) -, -C (R') 2 N(R) C(o)o-, -C(R6)=NN(R6)-, -C(R')=N-O-, -C(R') 2 N(R6)N(R 6 )-, -C(R') 2

N(R')SO

2 N(R)-, or -C (R 6 ) 2 N (R') CON (R') -; 15 W is -C(Rr) 2 0-, -C(R') 2 s-, -C(R) 2 SO-, -C(R) 2

SO

2 -, -C(R6)2

S

o 2 N(R)-, -C(RG) 2 N(RG)~-, -Co-, -C02-, -C(R6)OC(O)-, -C(R)OC(O)N(R6) -, -C (R6) 2 N(R')CO-,

-C(R')

2 N(R') C(O)O-, -C(R')=NN(R6) -, -C(R 6 )=N-O-, -C(R6) 2 N(R6)N(R)-,. -C (R) 2 N(R) So 2 N(R6)-, 20 -C(R') 2

N(R

6

)CON(R

6 )-, or' -CON(Rt)-; each R 6 is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R, groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered 25 heterocyclyl or heteroaryl ring; and . each R7 is independently selected from hydrogen or an optionally substituted CI-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 30 heteroaryl ring. Preferred rings formed by Rx and Ry include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said -40 Re/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula Ila are shown below. R - R 2 NHHNN SN HN Iha-A Ia-B I1a-C HN' HN> HNAI < N R %N tN R4,Nq N-N N N IIa-D Ia-B Ia-F HNO HN HN0 N N 0 N N Ila-J Ila-K Ila-L HN HN -1 HN N hla-P hla-a ha-V -41 R IIa-W More preferred pyrimidine ring systems of formula Ila include Ifa-A, Ila-B, IIa-D, Ila-E, IIa-J, XIa-P, and Ia-V, most preferably Ila-A, Iha-B, Ia-D, 5 Ia-E, and Ia-J. The ring formed when R7 and R are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH 2

)

2 4

-N(R

4

)

2 ,

-O(CH

2 )2- 4 -R, -OR, -N(R 4 ) - (C 2 ) 2 .4 -N (R) 2 , -N (R 4 ) - (CH 2 ) 2-4-R, 10 -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR,

-N(R

4

)

2 , -CON(R 4

)

2 , -SO 2 N(R4) 2 , -OC(=O)R, -N(R4)COR,

-N(R

4 )C0 2 (optionally substituted C..5 aliphatic), -N(R4)N(R 4 ) 2 ,- -C=NN(R 4 ) 2 , -C=N-OR, -N(R 4

)CON(R

4

)

2 , -N (R4) SO 2 N(R4)2, -N(R 4 ) SO 2 R, or -OC(=O)N(R 4 ) 2 , wherein R and 15 R 4 are as defined above. Preferred RX/RY ring substituents include -halo, -R, -OR, -COR, -CO 2 R,

-CON(R

4

)

2 , -CN, -O(CH 2

)

2

.

4

-N(R

4 )2, -O(CH2)2 4 -R, , -NO 2

-N(R

4

)

2 , -NR 4 COR, -NR'SO 2 R, -S0 2

N(R

4 ) 2 wherein R is hydrogen or an optionally substituted C 1 .. aliphatic group. 20 The R 2 and Ra' groups of formula Ila 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. 25 These are exemplified in the following formula Ia compounds having a pyrazole-containing bicyclic ring system: -42 N[N NN N N \N-kN HN N N Rx'

.

--

..--

N RX< N kNH NH NH N N N ''NN R~ N S-R 1 , , , ,and Preferred substituents on the~ R 2

/R

2 ' fused ring of formula lIa include one or more of the following: -halo, -N(R 4 ) 2 , -C 1

..

4 alkyl, -C3-4 haloalkyl, -N0 2 , -O(C 1

.

4 alkyl), -C02 (C 1

.

4 alkyl), -CN, -S02 (CI- 4 alkyl), -SO 2

NH

2 , 5 -OC(O)NH 2 , -NH 2

SO

2

(CI-

4 alkyl), -NHC(O) (C 1

-

4 alkyl), -C (0) NH 2 , and - CO (C 1 -4 alkyl) , wherein the (C 1

.

4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the -(C 1 .4 alkyl) group is methyl or ethyl. When the pyrazole ring system of formula Ila is 10 monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1

-

6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, 15 methoxypropyl, and benzyloxypropyl. A preferred R 2 ' group is hydrogen. When Ring D of formula IIa is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. 20 When Ring D of formula Ila is bicyclic, preferred bicyclic Ring D groups include -naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, -43 cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula Ila, preferred T-Rs or

V-Z-R

5 substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , 5 optionally substituted C1.. aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH (R4) , -N(R 4 ) COR, -N(R 4 ) C0 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N(R') COCH 2 N (R 4

)

2 , -N(R 6 ) COCH 2

CH

2 N (R 4 ) 2, and -N (R 6 ) COCH 2

CH

2

CH

2 N (R 4

)

2 , wherein R is selected from hydrogen, C 1

-

6 aliphatic, phenyl, a 5-6 membered 10 heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N (CO 2 t-Bu) CH3, -NHCOCH 2 N (CH3)2, 15 -NHCOCH2CH 2 N (CH3) 2, -NHCOCH 2

CH

2

CH

2 N (CH 3 ) 2, -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl), -NHCOCH 2

CH

2

CH

2 (morpholin 4-yl) , -NHCO 2 (t-butyl), -NH(C 1

-

4 aliphatic) such as -NHMe,

-N((C

1

-

4 aliphatic) 2 such as -NMe 2 , OH, -O(C 1

-.

4 aliphatic) 20 such as -OMe, C1..4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(C 1 -4' aliphatic). Preferred formula Ila compounds have one or more, and more preferably all, of the features selected 25 fromthe group consisting of: (a) Rx and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, 30 sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by Rx and RY is independently substituted by oxo, T-R , or L-Z-R, and each substitutable ring nitrogen of -44 said ring formed by R" and Ry is independently substituted by R 4 ; (b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit; 5 (c) Ring-D is-a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R Vare taken together to form an optionally 10 substituted benzo ring; and (e) R 3 is selected from -R, -halo, -OR, or -N(R4) 2 . More preferred compounds of formula Ila have one or more, and more preferably all, of the features selected from the group consisting of: 15 (a) RX and RY are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring; (b) R' is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 20 8-10 membered bicyclic-ring selected from an aryl or heteroaryl ring; (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1

..

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered 25 heterocyclic ring; and (d) R 3 is selected from -R, -halo, -OR, or -N(R4) wherein R is selected from hydrogen, C 6 s aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; and L is -0-, -S-, 30 or -N(R")-. Even more preferred compounds of formula Ila have one or more, and more preferably all, of the features selected from the group consisting of: -45 (a) R' and Ry are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring; (b) R' is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl 5 ring; (c) R 2 is hydrogen or CL.

4 aliphatic .and R 2 ' is hydrogen; (d) R 3 is selected from'-R, -OR, or -N(R4) 2 , wherein R is selected from hydrogen, C1-6 aliphatic, 5-6 10 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 ,

-N(R

4

)

2 , optionally substituted C-6 aliphatic 15 group, -OR, -C(O)R, -CO 2 R, -CONH(R 4 ) , -N (R4) COR, -N(R4) CO 2 R, -SO 2 N (R 4

)

2 , -N (Rt) SOR, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R6) COCH 2

CH

2 N (R 4 ) 2 , or

-N(R

6

)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is selected from hydrogen, C 1 -. aliphatic, phenyl, a 5-6 20 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. Representative compounds of formula Ila are shown below in Table 1. 25 Table 1. Me Me Me HN PH HNiP HNZH S S S C C1 I1a-1 IIa-2 IIa-3 -46 Me Me Me HNPH H N H HNP CF OMe HNS CF3 Et IIa-4 Ia-5 Ila-6 Me Me Me HN H HNp H HNt H NS' SC CIN S CI CI CI IIa-7 Ila-S hIa-9 Me Me Me HN J H HN H HN p CNS N4SQ Ce F OH F IIa-10 Ia-11 Ila-12 Me Me Me

HN

4 H HN 4 p HN H S OMe S e OMe IIa-13 - IIa-14 Ia-15 Me Me Me HNN HNt$ Cl IIa-16 Ila-17 Ila-18 -47 Me Me

HN

4 P HN HN r S N S) S, H

NH

2 IIa-19 IIa-20 IIa-21 HN H HN H HNH IZX>S A COOMe t Me S Me IIa-22 IIa-23 IIa-24 HN JH HN H HN H . xN jO

M

e S OOH IIa-25 IIa-26 IIa-27 HN HN HN HNJ F CI IIa-21 IIa-29 IIa-30 H H H HNJX HNJX HN )"Sj::CI Ila-31 IIa-32 IIa-33 -48 H d HH HNYq HN HNJ H O tN2MeNHAc H IIa-34 IIa-35 IIa-36 Me Me H HNZ HN HN,* H, HNJNH HN XH S N'SMeNHAc Ila-37 IIa-38 Ita-39 Me Me Me

HN

4 H HN p HN H N S JNHAc NHAc cCO2Me. OMe cO,.

N (0) IIa-40 IIa-41 IIa-42 Me Me Me H HH HNI HN-4 . HN S H S NHAc COOHO S N IIa-43 IIa-44 IIa-45 -49 Me Me Me HN<P H H c Br S Br N N'SO2Pr IIa-46 IIa-47 IIa-48 Me Me Me HNP HHN H HN H c C -S c N H tP r N H E t O N rN H 1 A IIa-49 IIa-50 IIa-51 Me Me Me HN

HN

4 P HN H yj; y S yN HAc iN S PNHAcr OH N IIa-52 IIa-53 IIa-54 Me Me Me HN H HkH H H HNJt H HNXP

HN

4 H Si JO c H.NJt NHAc IIa-58 ha-59 Iha-60 Ct ,

C:)C

-50 OF Me HN H H HN H HN A H HN~ HN<VHJdlN~ a ,rrI.Me kN NH 2 N lIa-61 IIa-62 IIa-63 Me 0 Me Me HN H H N 0 O HN H H 0Hf Qtkflp M NSNjo N -a %Me g, OMe Ila-64 IIa-65 IIa-66 Me Me Me

HN

4 H 0 HN*iH Me4 e HNP H O % H SN

M

e NHt .

M

e Me OH IIa-67 IIa-68 IIa-69 Me Me

HN

4 p 0 HN H H HN H N Mee N -e NHAc ~ % ~y 4 Nfl..0 N-Me ~A OMe IIa-70 IIa-71 Iha-72 Me Me Me HNHHN tH HN S Y N.HO N S NHAc NHAo NMe Me IIa-73 IIa-74 IIa-75 -51 Me Me HN H H HH H N HN H HNJX N -N S N evN eYNHAc 0 S3oc . OI F Ia-76 IIa-77 IIa-78 H HN IIa-79 In another embodiment, this' invention. provides a composition comprising a compound of formula Ila and a pharmaceutically acceptable carrier. 5 Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of- a 10 compound of formula Ila or a pharmaceutical composition thereof. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a. 15 compound of formula Ila or a composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises 20 administering to a patient in need of such a treatment a -52 therapeutically effective amount of a compound of formula Ila or a pharmaceutical composition thereof. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering 5 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 Ila or a pharmaceutical composition thereof. This method is especially useful for diabetic patients.. Another 10 method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for 15 treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula Ila or a composition comprising said compound. 20 Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated disease with a CDK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula 25 Ia or a pharmaceutical composition thereof. - Another aspect of the invention relates to inhibiting CDK-2 activity in a patient, which method comprises administering to the patient a compound of formula Ila or a composition comprising said compound. 30 Another aspect of this invention relates to a -method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a -53 therapeutically effective amount of a compound of formula Ila or a pharmaceutical composition thereof. Another aspect of the invention relates to inhibiting Src activity in a patient, which method 5 comprises administering to the patient a -compound of formula Ila or a composition comprising said compound. Another method relates to inhibiting Aurora-2, GSK-3, CDK2, or Src activity in a biological sample, which method comprises -contacting the biological sample 10 with the Aurora-2, GSK-3, CDK2, or Src inhibitor of formula Ia, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2, GSK-3, CDK2, or Src. Each of the aforementioned methods directed to 15 -the inhibition of Aurora-2, GSK-3, CDK2, or Src, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula Ila, as described above. Another embodiment of this invention relates to 20 compounds of formula Ib: NH HNN R N R) N'10-R1 Ilb 25 or a pharmaceutically acceptable derivative or prodrug thereof, wherein; RX and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected -54 from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and Ry is independently substituted by oxo, T-R3, or

L-Z-R

3 , and each substitutable ring nitrogen of said 5 ring formed by RX and Ry is independently substituted by R 4 ;

R

1 is T-(Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, 10 heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R 5 , and each 15 substitutable ring nitrogen of, Ring D is independently substituted by -R'; T is. a valence bond or a C 1

.

4 alkylidene chain; Z is a C1.4 alkylidene chain; L is -0-, -S-, -SO-, -S02-, -N(R6)S0 2 -, -SO2N(R 6 )-, 20 -N(R')-, -CO-, -C0 2 -, -N(R)CO-, -N(R')C(O)O-,

-N(R

6 ) CON (R 6 ) -, -N(R)SO 2

N(R

6 ) -, -N(R 6

)N(R

6 ) -, -C(0)N(R 6 )-, -OC(O)N(R 6 ) -, -C(R4) 2 0-, -C(R) 2 S-, -C (R 6 ) 2 SO-, -C(R')2SO2-, -C(R') 2

SO

2

N(R

6 )-, -C(R 6

)

2 N(R')-,

-C(R

6

)

2

N(R

6 )C(O)-, -C(R') 2 N(R')C(0)0-,

-C(R')=NN(R

6 )-, 25 -C(R 6 )=N-O-, -C(R 6

)

2

N(R')N(R

6 )-, -C(R 6

)

2

N(R')SO

2 N(R)-, or

-C(R')

2 N(Rs)CON(R) -;

R

2 and R 2 ' are independently selected from -R, -T-W-R4, or

R

2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or 30 partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R 2 ' is independently substituted by halo, oxo, -55 -CN, -NO 2 , -R, or --V-R, and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ; Ra is selected from -R, -halo, -OR, -C(=o)R, -CO 2 R, 5 -COCOR, -COCH 2 COR, -N O2 ,---CN, -S(O)R, -S(O) 2 R, -SR, -N (R4) 2 , -CON(R) 2 , -SQ 2 N(R7) 2 , -OC (=O) R, -N (RI) COR,

-N(R

7 ) CO2 (C-- aliphatic),

-N(R

4

)N(R

4

)

2 , -C=NN(R 4

)

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

)CON(R

7

)

2 , -N(R 7

)SO

2

N(R

7

)

2 , -N(Rt)SO 2 R, or

-OC(=O)N(R

7 ) 2; 10 each R is independently selected from hydrogen or an optionally substituted group selected from C1-6 aliphatic, C-2.0 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; 15 each R 4 is -independently selected from -R7, -COR, -C02 (optionally substituted C1-6 aliphatic), -CON () 2 , or -SO 2 R'; each R 5 is independently selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, 20 -N(R 4

)

2 , -CON(R 4 ) 2 , -SO 2 N (R 4

)

2 , -OC (=O) R, -N (R 4 ) COR,

-N(R

4 ) C02 (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 4

)

2 ,

-N(R

4 ) SO 2 N (R4) 2 , -N(R4) S0 2 R, or -OC(=0)N(R4)2; V is -0-, -s-, -SO-, -SO 2 -, -N(R')S0 2 -, -S02N(R)-, 25 -N(R)-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O-, -N (R6)CON (R6) -, -N (R') S2N (R") -, -N (R') N(R6) -,

-C(O)N(R

6 )-, -OC(0)N(R)-,

-C(R')

2 0-, -C(R 6

)

2 S-, -C (R 6 ) 2SO-, -C(R) 2SO2-, -C (R) 2SO 2 N (R')-, -C C(R 6 ) 2 N (R 6 )-,

-C(R

6

)

2 N(R)C(0) -, -C(R) 2

N(R{

6 )C(O)O-, -C(R)=NN(R 6 ) _ 30 -C(R')=N-O-, -C(R 6 ) 2 N (R') N (R 6 )-, -C (R 6 ) 2 N (R 6 ) SO 2 N (R 6 )-, or

-C(R

6

)

2

N(R

6 ) CON(R') -; W is -C(R') 2 0-, -C(R 6

)

2 S-, -C(R 6

)

2 SO-, -C(R') 2

SO

2 -, -C(Rt)2SO 2 N(R) -, -C(R 6

)

2 N(R6) -, -CO-, -C02-, -56 -C(R')OC(0)-,

-C(R

6 )OC(0)N(R 6 )-, -C(R 6

)

2

N(R

6 )CO-,

-C(R

6 )2

N

(R

6 )C(0)0-, -C(R 6 )=NN(R')-, -C(R 6 )=N-O-,

-C(R

6

)

2

N(R

6

)N(R

6 ) -, -C (R) 2 N(R')So 2 N(R) -,

-C(R

6

)

2

N(R')CON(R

6 )-, or -CON(R 6 )-; 5 each R 6 is independently selected from hydrogen or an optionally substituted C4 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; and 10 each R7 is independently selected from hydrogen or an optionally substituted C-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. 15 Preferred rings formed by RX and RI include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. 20 Examples of preferred pyrimidine ring systems of formula IIb are shown below. R2 R2 NH HN HN>9 Ib-A Ib-B Ilb-C HN HN HN R4, R4 N N Ib IbJ IIb-D Ilb-E Ilb-F -57 HN HN3 HNZ N N IIb-J IIb-K I~b-L. N HtN H, N N4N H . R IIb-W More preferred pyrimnidine ring systems of formula Ib include IIb-A, Ilb-B, IIb-D, IIb-E, IIb-J, Inb-P, and Inb-V, most preferably Inb-A, IIb-B, IIb-D, 5 IIb-E, and IIb-J. The ring formed when RX and RF are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH 2

)

2 24-N(R 4

)

2 , -o (Ca 2 ) 2

..

4 -R , -OR, -N (Rz4) - (CH 2 ) 2- 4 -N (R 4 ) 2, -N (R 4 ) - (CH 2 ) 2

-

4 -R, 10 -CC(=O) R, -CO 2 R, -COCOR,- -NO 2 , -CN, -S (O) R, -SO 2 R, -SR,

-NC(R

4 ) 2 , -- CoN(R 4 ) 2 , -SO 2 N (R 4 ) 2 , -QOC(=0o) R, -N (R 4 ) COR , -N (R 4 ) CO 2 (optionally substituted -C 1

.

6 aliphatic) , -N (R 4 ) N(R 4 ) 2 , -C=NN (R 4 ) 2 , -C=N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R 4 ) SO 2 N(R4) 2 , -N (R 4 ) SO 2 R , or -OC(=o) N(R 4 ) 2 , R and R 4 are -5S8as defined above. Preferred RX/RY ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON(R) 2 , -CN,

-O(CH

2

)

2

-

4

-N(R)

2 , -O(CH 2

)

2

.

4 -R, , -NO 2 -N(R4) 2 , -NR 4 COR,

-NR

4

SO

2 R, -SO 2

N(R

4

)

2 wherein R is hydrogen or an optionally 5 substituted C- 6 aliphatic group. The R 2 and R 2 ' groups of formula 1Ib 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, 10 and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIb compounds having a pyrazole--containing bicyclic ring system: ONH N N \N N HN N R N NH NH NH NH R- N 0-R , ,anN Preferred substituents on the R2 /R 2 ' fused ring 15 of formula IIb include one or more of the following: -halo, -N(R 4

)

2 , -C 1

..

4 alkyl, -C 1

-

4 haloalkyl, -NO 2 , -O(C 1

...

4 alkyl) , -CO2 (CI-4 alkyl) , -CN, -SO2 (CI-4 alkyl) , -SO2NH2, -OC (O) NH 2 , -NH 2 SO2 (C 1

-

4 alkyl) , -NHC (0) (C 1

.-

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

..

4 alkyl) , wherein the (C 1

-

4 alkyl) is a 20 straight, branched, or cyclic alkyl group. Preferably, the (C 1

..

4 alkyl) group is methyl or ethyl. When the pyrazole ring system of formula IIb is monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, 25. heteroaryl, or a C 1

..

6 aliphatic group. Examples of such -59 preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R 2 ' group is hydrogen. 5 When Ring.D -of formula I1b is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. When Ring D of formula 1Ib is bicyclic, preferred bicyclic Ring D groups include naphthyl, 10 tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl. 15 On Ring D of formula 1Ib, preferred T-R 5 or V-Z R. substituents include -halo, -CN, -NO 2 , -N(R4') 2 , optionally substituted Ci.-6 aliphatic group, -OR, -C(O)R,

-CO

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

-N(R

4 ) SO 2 R, -N(R 6 ) COCH 2

N(R')

2 , -N(R) COCH 2

CH

2

N(R

4

)

2 , and 20 -N(R 6

)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is selected from hydrogen, CI- 6 aliphatic, phenyl, a 5-6 niembered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred Rs substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, 25 -NHSO 2 Et, -NHSO 2 (n-propyl), -NHSO2(isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3

)

2 ,

-NHCOCH

2

CH

2 N (CH3) 2, -NHCOCH 2

CH

2

CH

2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4 -yl), -NHCOCH 2

CH

2

CH

2 (morpholin 30 4 -yl) , -NHCO 2 (t-butyl) , -NH (C 1

.

4 aliphatic) such as -NHMe,

-N(C

1

.

4 aliphatic) 2 such as -NMe 2 , OH, -0(C 1

.

4 aliphatic) such as -OMe, C 1

..

4 aliphatic such as methyl, ethyl, -60 cyclopropyl, isopropyl, or t-butyl, and -C0 2

(C..

4 aliphatic). Preferred formula IIb compounds have one or more, and more preferably all, of the features selected 5 from the group consisting of: (a) RX and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, 10 sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and

R

7 is independently substituted by oxo, T-R, or 3 L-Z-R , and each substitutable ring nitrogen of said ring formed by R and Ry is independently 15 substituted by R'; (b) R- -is T- (Ring D), wherein T is a valence bond or a methylene unit; (c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an 20 aryl or heteroaryl ring; (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R' are taken together to form an optionally substituted benzo ring; and (e) R 3 is selected from -R, -halo, -OR, or -N(R4) 2 . 25 More preferred compounds of formula Ib have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX and R are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, 30 thieno, piperidino, or imidazo ring; (b) R' is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an -61 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1 6 aliphatic, phenyl, a 5 5-6 membered heteroaryl- ring, or a 5-6 membered heterocyclic ring;. and (d) R 3 is selected from -R, -halo, -OR, or -N(R 4

)

2 , wherein R is selected from hydrogen, C..

6 aliphatic, or 5-6 membered heterocyclyl, phenyl, 10 or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4) Even more preferred compounds of formula 1Ib have one or more, and more preferably all, of the features selected from the group consisting of: 15 (a) RX and Ry are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring; (b) R' is T-Ring D, wherein T is a valence bond and ~ Ring D is a 5-6 membered aryl or heteroaryl ring; 20 (c) R 2 is hydrogen or'C1.

4 aliphatic and R 2 ' is hydrogen; (d) R 3 is selected from -R, -OR, or -N(R 4

)

2 , wherein R is selected from hydrogen, C1- 6 aliphatic, 5-6. membered heterocyclyl, phenyl, or 5-6 membered 25 - heteroaryl, and L is -0-, -S-, or -NH-; and. (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 ,

-N(R

4

)

2 , optionally substituted C..

6 aliphatic group, -oR, -C(O)R, -C0 2 R, -CONH(R4), -N(R 4 )COR, 30 -N (R4) CO 2 R, -SO 2 N(R4) 2 , --N(R 4

)SO

2 R, -N (R") COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2, or -N (R') COCH 2

CH

2

CH

2 N (R 4 ) 2 , wherein R is selected from hydrogen, C1_ 6 aliphatic, phenyl, a 5-6 -62 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. Representative compounds of formula Ib are shown below in Table 2. 5.

Table 2. Me Me HN H HN 4 H - HN H IIb-1- IIb-2 IIb-3 Me HNJXH HAH - HP HN HN .IN OQ( O Me 0$ O OMe IIb-4 IIb-5 IIb-6 Me Me Me -HNAI HP HN H HNp KNNt WN-tO Me 1) 'N O > OZ CO 2 Me IIb-7 lIb-8 IIb-9 In another embodiment, this -invention provides a composition comprising a compound of formula Ilb and a pharmaceutically acceptable carrier. 10 Another aspect of this invention relates to a method of- treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of sucha -63 treatment a therapeutically effective amount of a compound of formula I1b or a pharmaceutical composition thereof. Another aspect of this invention relates to a 5 method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula 1Ib or a composition comprising said compound. Another aspect of this invention relates to a 10 method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a. therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition thereof. 15 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 20 Ilb 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 hilting or slowing the progression of Alzheimer's 25 disease. Another method relates to inhibiting the phosphorylation of -catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which 30 method comprises administering to the patient a compound of formula Ilb or a composition comprising said compound. Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample,' which method -64 comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula Ilb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. 5 Each of the-aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula Ib, as described above. 10 Another embodiment of this invention relates to compounds of formula lic: R 2 HN N Rx R) N N-R H IIc 15 or a pharmaceutically acceptable derivative or prodrug thereof, wherein; RX and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 20 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and RY is independently substituted by oxo, T-R 3 , or

L-Z-R

3 , and each substitutable ring nitrogen of said 25 ring formed by RX and RY is independently substituted by R 4 ;

R

1 is T- (Ring D); -65 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 5 from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R5, or V-Z-R5, and each substitutable ring nitrogen of Ring D is independently substituted by 7 R4; 10 T is a valence bond or a C1.4 alkylidene chain; Z is a C14 alkylidene chain; L is -0-, -S-, -SO-, -SO 2 -, -N(R')SO 2 -, -SO 2 N(R )-, -N(R6)-, -CO-, -C02-, -N(R') CO-, -N(R6) C (0)0-, -N(R')CON(R')-, -N(R")SO 2 N(R')-, -N(R)N(R)-, 15 -C(O)N(R6)-, -OC(O)N(R 6 )-, -C(R6) 2 0-, -C(R') 2 S-,

-C(R')

2 SO-, -C(R')2So 2 -, -C(R') 2 So 2 N(R6)-, -cks) 2 N(R)-, -C(R6) 2 N (R')C(O)-, -C(R 6

)

2 N(R')C(0)0-, -C(R')=NN(R')-, -C(R')=N-O-, -C(R6) 2 N(R)N(R')-, -C(R') 2

N(R)SO

2 N(-R6)-, or -C(Rs) 2 N (R') CON (R') -; 20 R 2 and R 2 ' are independently selected from -R, -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 25 substitutable ring carbon of said fused ring formed by R2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R, or -V-R', and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ; 30 R 3 is selected from -R, -halo, -OR, -C(=0)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(0) 2 R, -SR, -N (R 4 ) 2 , -CON (R7) 2 , -S0 2

NX(R

7

)

2 , -OC(=O)R, -N(R)COR,

-N(R

7 )C0 2

(CI-

6 aliphatic), -N(R 4

)N(R

4

)

2 , -C=NN(R4) 2

,

-C=N-OR, -N(R 7 ) CON (R 7

)

2 , -N (R) SO 2 N (R) 2 , -N(R 4

)SO

2 R, or -OC (=O) N(R )2; each R is independently selected from hydrogen or an optionally substituted group selected from C0..6 5 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 -R 7 , -COR, -Co 2 (optionally substituted C1-6 aliphatic), -CON(R 7 )2, 10 or -SO 2 R'; each R 5 is independently selected from -R, halo, -OR, -C(=Q)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(0)R, -SO 2 R, -SR,.

-N(R

4

)

2 , -CON(R 4

)

2 , -SO 2 N(R4) 2 , -OC(=O)R, -N(R 4 )COR, -N (R4) C02 (optionally substituted CI-. aliphatic), 15 -N(R4)N(R 4

)

2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R4)CON(R 4

)

2 ,

-N(R

4 ) SO 2 N(R) 2 , -N(R 4

)SO

2 R, or -OC(=:)N(Rd)2; V is -0-, -S-, -SO-, -SO 2 -, -N(R')S0 2 -, -SO 2 N(R)-, -N(R')-,--CO-, -C02-, -N(R 6 )CO-, -N(R 6 )C(0)0-,

-N(R

6 )CON(R)-, -N(R5)SO 2 N(R)-, -N(R 6 )N(R)-, 20 -C(O)N(R') -, -OC(O)N(R 6 ) -, -C(R6) 2 0-, -C(R 6 ) 2S-, -C (Rt) 2 SO-, -C(R) 2

SO

2 -- , -C(R 6 )2SO 2

N(R

6 )-, -C(R) 2 N(R)-,

-C(R')

2

N(R

6 )C(O)-, -C(R) 2

N(R

6 )C(O)O-, -C(R)=NN(R 6 )-, -C(R) =N-0-, -C(R 6

)

2

N(R

6 )N(R)-, -C(R 6

)

2

N(R')SO

2 N (R)-, or - C (R 6 ) 2 N (R) CON (R 6 ) -; 25 Wis -C(R 6

)

2 0-, -C(R 6 )2S-, -C(R 6

)

2 SO-, -C(R 6

)

2 S0 2 -,

-C(R

6

)

2

SO

2

N(R

6 ) -, -C(R 6

)

2 N(R) -, -co-, -CO2-, -C(Rd)OC(O)-, -C(R 6 )OC(O)N(R)-, -C(R 6 ) 2 N (R 6 ) CO-, -C (R 6

)

2 N(Rf) C(0)0-, -C(R)=NN(R') -, -C(R)=N-O-, -C (R 6

)

2

N(R

6 )N(R) -, -C(R 6 )2N (R)So 2 N(R6)-, 30 -C(R") 2 N(R4)CON(R 6 )-, or -CON(R4)-; each R 6 is independently selected from hydrogen or an optionally substituted C1.4 aliphatic group, or two R' groups on the same nitrogen atom are taken together -67 with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R7 is independently selected from hydrogen or an optionally substituted CI- 6 aliphatic group, or two R 7 5 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring. Preferred rings formed .by RX and R' include a 5-, 6-, or 7-membered unsaturated or partially 10 unsaturated ring having 0-2 heteroatoms, wherein said Re/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula Ile are shown below. R2 H HNt HN' CaN.N-R H IIc-A IIc-B Ic-C HNHNN HN'? R 'N R4%N N Nt IIC-D IIc-E IIC-F -68- HN HN HN N N NN II- Ie-K IIc-L - HN~ N I(XZ-W IIc-I- II- IIc HNN RR lN More preferred pyrimidine ring systems of formula 11c include Ic-A, IIc-E, ho-, Ile-E, Ilc-J, Ile-P, and ie-V, most preferably Ic-A, ie-B, IIc-D, hoc-S 1 and hle-J. 5 The ring formed when R' and Ry of formula 1Ic are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH 2 )2- 4

-N(R

4

)

2 , -O (CH 2 ) 2 4 -R, -OR, -N (R 4 ) - (CH 2 ) 2

-

4 -N (R 4 ) 2, -N (R 4 ) - (CH 2 ) 2

..

4 -R, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, 10 -N (R 4

)

2 , -CON(R 4 ) 2 , -SO 2 N (R4) 2 , -OC (=o) R, -N (R 4 ) COR, -N (R 4 ) CO 2 (optionally substituted C 1 .. aliphatic), -N (R 4 ) N (R 4

)

2 , -C=NN(R 4

)

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

)CON(R

4 ) 2 , -N R 4 ) S0 2 N (R 4 ) 2 , -N (R4) SO 2 R, or -OC (=O) N (R 4 ) 2 , R and R 4 are as defined above. Preferred Re/RY ring substituents -69 include -halo, -R, -OR, -COR, -CO 2 R, -CON(R4) 2 , -CN, -O (CH 2 ) 2- 4 -N (R 4

)

2 , -O(CH 2 )2-4-R, , -NO 2 -N(R4) 2 , -NR 4 COR,

-NR

4

SO

2 R, -SO 2 N(R4) 2 wherein R is hydrogen or an optionally substituted C1..6 aliphatic group. 5 The R 2 and R 2 ' groups of formula Ic 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. 10 These are exemplified in the following formula Ilc compounds having a pyrazole-containing bicyclic ring system: NH HN N N-k R2,NH NH

-

NH NH . R N N-RI N N N N H , , , ,and Preferred substituents on the R 2

/R

2 ' fused ring. of formula IIc include one or more of the following: 15 -halo, -N(R 4

)

2 , -C 1

..

4 alkyl, -C 1

.

4 haloalkyl, -NO 2 , -O(C.4 alkyl) , -CO2 (Cl.4 alkyl) , -CN, -S02.(C- 1

.

4 alkyl) , -SO 2

NH

2 , -OC (0) NH 2 , -NH 2

SO

2 (Ci- 4 alkyl) , -NHC (0) (C1..4 alkyl) ,

-C(O)NH

2 , and -CO(C 1 .4 alkyl), wherein the (CI-4 alkyl ) is a straight, branched, or cyclic alkyl group. Preferably, 20 the (C1.4 alkyl) group is methyl. When the pyrazole ring system of formula I1c is monocyclic, preferred R 2 groups include hydrogen or-a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci-s aliphatic group. Examples of such 25 preferred R 2 groups include H, methyl, ethyl, propyl, -70 cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R' group is hydrogen. When Ring D of formula lic is monocyclic, 5 preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. When Ring D of formula 1Ic is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, 10 indolyl, isoindolyl, indolinyl, benzo[b~furyl, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula iIc, preferred T-R 5 or 15 V-Z-R 5 substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , optionally substituted C.. aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH(R4), -N(R 4 )COR, -N(R4) CO 2 R, -SO 2 N (R4) 2 , -N (R 4 ) S0 2 R, -N (R 6 ) COCHN (R 4 ) 2 , -N (R5) COCH2CH 2 N (R 4 ) 2 , and

-N(R

6 )COCH2CH2CH 2

N(R

4

)

2 , wherein R is selected from 20 hydrogen, Clr aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R 5 substituents include' -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO 2 (n-propyl),

-NHSO

2 (isopropyl), -NHCOEt, 25 -NHCOCH 2

NHCH

3 , -NHCOCH 2

N(CO

2 t-Bu)CH 3 , -NHCOCH 2

N(CH

3

)

2 ,

-NHCOCH

2

CH

2 N (CH 3 ) 2 , -NHCOCH 2

CH

2

CH

2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 y1)j, -NHCOCH 2

CH

2 (morpholin-4 -yl), -NHCOCH 2

CH

2

CH

2 (morpholin-. 4-yl), -NHCO 2 (t-butyl), -NH(C 1

.

4 aliphatic) such as -NHMe, 30 -N(C.

4 aliphatic) 2 .such as -NMe 2 , OH, -O(C.4 aliphatic) such as -OMe, C-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02 (C.-4. aliphatic).

-71 Preferred formula 1Ic compounds have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX and RY are taken together with their 5. -- intervening-atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by a and 10 R is independently substituted by oxo, T-R 3 , or L-Z-Ra, and each substitutable ring nitrogen of said ring formed by Rx and RY is independently substituted by R 4 ; (b) R' is T- (Ring D), wherein T is a valence bond or 15 a methylene unit; (c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and 20 R 2 ' are taken together to form an optionally substituted benzo ring; and (e) R 3 is selected from -R, -halo, -OR, or -N(R4) 2 . More preferred compounds of formula I1c have one or more, and more preferably all, of the features 25 selected from the group consisting of: (a) RX and Ry are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring; (b) R' is T-(Ring D), wherein T is a valence bond and 30 Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; -72 (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C..

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and 5 (d) R 3 is-selected from -R, -halo, -OR, or -N(R4)2, wherein R is selected from hydrogen, C..

6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4) 10 Even.more preferred compounds of formula IIc have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX and RY are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring; 15 (b) R 1 is T-Ring D, wherein T is a valence bond and Ring D is -a 5-6 membered aryl or heteroaryl ring; (c) R 2 is hydrogen or C 1

.

4 aliphatic and R 2 is hydrogen; 20 (d) R 3 is selected from -R, -OR, or -N(R 4

)

2 , wherein R is selected from hydrogen, C.

6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and (e) Ring D is substituted by up to three 25 substituents selected from -halo, -CN, -NO 2 ,

-N(R

4

)

2 , optionally substituted Cl-6 aliphatic group, -OR, -C(O)R, -CO 2 R, -CONH(R"), -N(RT)COR, -N (R) CO 2 R, -SO 2 N (R 4 ) 2, -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R4) 2 , -N (R) COCH 2

CH

2 N (R 4 ) 2 , or 30 -N(R 6

)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is .selected from hydrogen, CI- aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

-73 Preferred compounds of formula I1c include compounds of formula II':

F

2 HN R N R )N 1N-R H IIc' or a pharmaceutically acceptable derivative or prodrug thereof, wherein; 5 R and Ry are taken together with their intervening atoms to form a fused benzo ring, wherein each substitutable ring carbon of said fused ring formed by R and Ry is independently substituted by T-R 3 , or L-Z-R 3 ;

R

1 is T-(Ring D); 10 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 heterbatoms selected from nitrogen, oxygen or sulfur, wherein each 15 substitutable ring carbon of Rinc D is independently substituted by oxo, T-R 5 , or V-Z-R, and each substitutable ring nitrogen of Ring D is independently substituted by -R'; T is a valence bond or a C1..4 alkylidene chain; 20 Z is a C1..

4 alkylidene chain; L is -O-, -S-, -SO-, -SO2-, -N(R6)S0 2 -, -SO 2

N(R

6 )-,

-N(R

6 )-, -CO-, -CO 2 -, -N(R')CO-, -N(R 6 )C(O)O-, -N(R")CON(R)-, -N(R 6

)SO

2 N(R)-, -N(R)N(R 6 )-, -C(0)N(R6)-, '-OC(O)N(RG)-, -C(R 6 )20-, -C(R) 2

S-,

-74 -C(R)2SO-, -C(R 6

)

2 S0 2 -, -C(R 6

)

2

SO

2 N(R')-, -C(R') 2

N(R

6 )-,

-C(R

6 ) 2 N(R)C(O)-,

-C(R

6

)

2

N(R

6 )C(0)O-, -C(R 6

)=NN(R

6 )-,

-C(R

6 )=N-0-, -C(R 6

)

2 N(R)N(R6)-, -C(R4) 2

N(R')SO

2 N(R)-, or

-C(R)

2 N(R6)CON(R6) -; 5 R 2 and R 2 ' are independently selected from -R, -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 10 substitutable ring carbon of said fused ring formed by

R

2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R', or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R2' is independently substituted by R 4 ; 15 R 3 is selected from -R, -halo, -OR, -C(=O)R, -C0 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR,

-N(R

4 ) 2, -CON(R 7

)

2 , -SO2N(R7)2, -OC(=0) R, -N(R)COR, -N(R ) C02 (Ca.6 aliphatic) , -N (R 4 ) N (R4 ) 2 , -C=NN(R4) 2 , -C=N-OR, -N(R') CON(R 7 ) 2,' -N (R7) SO2N(R 7 ) 2, -N (R 4 ) SO 2 R, or 20 -OC(=O)N(R7)2; each R is independently selected from hydrogen or an optionally substituted group selected from C,.6 aliphatic, C6-.20 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring 25 atoms; each R 4 is independently selected from -R7, -COR, -C02(optionally substituted C.6 aliphatic), -CON(R 7

)

2 , or -S0 2

R

7 ; each R 5 is independently selected from -R, halo, -OR, 30 -C(=O)R, -C02R, -COCOR, -NO2, -CN, -S(O)R, -SO2R, -SR, -N (R 4 )2, -CON(R 4 ) 2, -SO2N (R)2, -OC(=o)R, -N(R 4 )COR,

-N(R

4 ) C02 (optionally substituted CI- aliphatic), -75 -N (R 4 ) N (R 4 ) 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(R4)SO 2 R, or -OC(=0)N(R4)2; V is -0-, -S-- -SO-, -SO 2 -, -N(R 6

)SO

2 -, -SQ 2 N(R') -,

-N(R

6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)0-, 5 -N (R 6 ) CON (R') -,-N (R 6 ) SO 2 N (R) -, -N (R) N (R 6

)

-C(O)N(R

6 )-, -OC(O)N(R)-,

-C(R)

2 0-, -C(R) 2 S-,

-C(R

6 )2So-, -C(R 6 )2SO2-, -C(R 6 )2SO 2

N(R

6 )-, -C(R) 2

N(R

6 )-,

-C(R)

2 N(R)C(0)-, -C(R 6 )2N(R)C(o)O-, -C(R 6

)=NN(R

6 )-,

-C(R

6 )=N-O-, -C(R 6

)

2 N(R)N(R) -, -C(R') 2

N(R)SO

2 N(R) -, or 10 -C (R 6

)

2

N(R)CON(R

6 ) -; W is -C(R6)20-, -C(R 6 )2S-, -C(R) 2 SO-, -C(R 6

)

2

SO

2 -,

-C(R

6

)

2 S0 2

N(R

6 )-, -C(R 6

)

2 N(R)-, -CO-, -C02-, -C(R')OC(O)-, -C(R)OC(O)N(R6)-,

-C(R

6

)

2 N(R)Co-,

-C(R

6 ) 2

N(R

6 ) C(0)0-, -C(R')=NN(R 6 )-, -C(R 6 )=N-O-, 15 -C(R 6

)

2

N(R

6 )N(R6)-, -C(R') 2 N(Rs.)SO 2 N(R6)-,

-C(R)

2

N(R

6 )CON(R6) -, or -CON(R6)-; each R6 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 20 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 CI.6 aliphatic group, or two R' on the same nitrogen are taken together with the 25 nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring. The ring formed when Rx and Ry of formula IIc' are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH 2

)

2

-

4

-N(R)

2 , 30 -0 (CH 2 ) 2- 4 -R, -OR, .- N(R 4 ) - (CH 2 ) 2- 4 -N (R 4 ) 2 , -N (R4) - (CH2) 2-4-R, -C(=0)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(0)R, -SO 2 R, -SR, -N(R4) 2 , -CON(R 4

)

2 , -S0 2

N(R

4

)

2 , -OC(=0)R, -N(R 4 )COR, -N (R 4 ) C0 2 (optionally substituted C1..6 aliphatic), -76 -N (R 4

)N(R)

2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R 4 ) CON (R 4 ) 2 , -N(R4)SO 2

N(R)

2 , -N(R 4

)SO

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

)

2 , wherein R and R are as defined above. Preferred RX/RY ring substituents include -halo, -R, -OR, -COR, -CO 2 R, 5 -CON(R 4

)

2 , -CN, -O(CH 2 )2- 4

-N(R

4

)

2 , -O(CH 2 )2-4-R, , -NO 2 -N (R 4 ) 2 , -NR 4 COR, -NR 4

SQ

2 R, -SO 2 N (R 4

)

2 , wherein R is hydrogen or an optionally substituted C 1

.

6 aliphatic group. The R2 and R 2 groups of formula IIc' may be taken together to form a fused ring, thus providing a 10 bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified -in the following formula IIc' compounds having a pyrazole-containing bicyclic ring 15 system: NH HN NN -N \N N R NN .NH NH NH NH RY N" N-R1 l N'N H ,,-,' , and. Preferred substituents on the R 2

/R

2 ' fused ring 20 of formula Ile' include one or more of the following: -halo, -N(R 4

)

2 , -C 1

.-

4 alkyl, -C 1

..

4 haloalkyl, -NO 2 , -O(CI-4 alkyl), -C0 2

(C

1

-

4 alkyl), -CN, -S0 2

(C-

4 alkyl), -SO 2

NH

2 , -OC (O) NH 2 , -NH 2

SO

2

(CI

4 alkyl) , -NHC (Q) (Cj..4 alkyl) , - C (0) NH 2 , and -CO (Ci 4 alkyl) , wherein the (CI 4 alkyl) is a 25 straight, branched, or cyclic alkyl group. Preferably, the (Ci.

4 alkyl) group is methyl. When the pyrazole ring system of formula Ile' is monocyclic, preferred R2 groups include hydrogen or a -77 substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1

..

6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, 5 methoxypropyl, and-benzyloxypropyl. A preferred R 2 ' group is hydrogen. When Ring D of formula Ihc' is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and-pyrazinyl. 10 When Ring D of formula lic' is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, is'oindolyl, indolinyl, benzo[b]furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, 15 cinnolinyl,. phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula Ic', preferred T-R 5 or V-Z-Rs substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , optionally substituted C16- aliphatic group, -OR, -C(O)R, 20 -C0 2 R, -CONH(R 4 ), -N(R 4 )COR, -N(R 4 )C0 2 R, -SO 2 N(R4) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4

)

2 , -N (R) COCH 2

CH

2 N (R4 ) 2 , and

-N(R

6

)COCH

2

CH

2

CH

2

N(R

4

)

2 , wherein R is selected from hydrogen, C 1

-

6 aliphatic, phenyl, a 5-6 -membered heteroaryl ring, or a 5-6 membered heterocyclic ring. 25 More preferred R9 substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, -NHS0Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3

)

2 ,

-NHCOCH

2

CH

2 N (CH 3 ) 2 , -NHCOCH 2

CH

2

CH

2 N (CHA) 2 , 30 -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl), -NHCOCH 2

CH

2

CH

2 (morpholin 4 -yl) , -NHCO 2 (t -butyl) , -NH (C- 4 aliphatic) such as -NHMe,

-N(C

1

-

4 aliphatic) 2 such as -NMe 2 , OH, -O(C 1

..

4 aliphatic) -78 such as -OMe, C 1

-

4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO 2 (C1-4 aliphatic). Preferred formula Ic' compounds have one or 5 more, -and more preferably all, of the features selected from the group consisting of: (a) Rt is T-(Ring D), wherein T is a valence bond or a methylene unit; (b) Ring D is a 5-7 membered monocyclic ring or an 10 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; (c) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R2 are taken together to form an optionally. substituted benzo ring; and is (d) R 3 is selected from -R, -halo, -OR, or -N(R 4

)

2 . More preferred compounds of formula I1c' have one or more, and more preferably all, of the features selected from the group consisting of: (a) R' is T-(Ring D), wherein T is a valence bond and 20 Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; (b) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1

.

6 aliphatic, phenyl, a 25 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (c) R 3 is selected from -R, -halo, -OR, or -N(R 4

)

2 , wherein R is selected from hydrogen, C 1

._

6 aliphatic, or-5-6 -membered heterocyclyl, phenyl, 30 or 5-6 membered heteroaryl, and L is.-O-, -S-, or -N(R 4

)-.

-79 Even more preferred compounds of formula I1c' have one or more, -and more preferably all, of the features selected from the group consisting of: (a) R3 is T-Ring D, wherein T is a valence bond and 5 Ring D is-a 5-6 membered ary-1 or heteroaryl ring; (b) R 2 is hydrogen or C1.

4 aliphatic and R 2 ' is hydrogen; (c) R 3 is selected from -R, -OR, or -N(R4) 2 , wherein 10 R is selected from hydrogen, C1.

6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -O--, -S-, or -NH-; and. (d) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 , 15 -N(R 4

)

2 , optionally substituted CI. aliphatic group, -OR, -C(O)R, -CO 2 R, -CONH(R4), -N(R4)COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R') 2 , , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2 , or

-N(R)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is selected 20 from hydrogen, CI. aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. other preferred compounds of formula IIc include compounds of formula Ioc":

R

2 NH HNN RxN RY N 'N-R' H Ixc" -8 0 or a pharmaceutically acceptable derivative or prodrug thereof, wherein; RX and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5 -5-7 membe-red -ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and Ry is optionally substituted by oxo, T-R, or L

Z-R

3 , and each substitutable ring nitrogen of said ring 10 formed by RE and RY is optionally substituted by R 4 ; provided that said fused ring formed by Re and Ry is other than benzo;

R

1 is T-(Ring D); Ring D is a 5-7 membered monocyclic ring or 8-20 membered 15 bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl,. said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently 20' substituted by oxo, T-R, or V-Z-R 5 , and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ; T is a valence bond or a C 1

-

4 alkylidene chain; Z is a C1.4 alkylidene chain; 25 L is -0-, -S-, -SO-, -SO2-, -N(RG)SO 2 -, -SQ 2 N(R)-, -N (R 6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O-,

-N(R

6 )CON(R)-, -N(RG)SO 2 N(R)-, -N(R')N(R 6 )-, -C(O)N(R") -, -OC(O)N(R) -, -C(R 6 )20-, -C(R 6

)

2 S-,

-C(R')

2 SO-, -C(R 6

)

2

SO

2 -, -C(R) 2 SO2N(R)-, -C(R 6

)

2

N(R

6 )-, 30 -C(R 6

)

2 N(R6)C(O)-, -C(R 6 )2N(Rn)C(0)o-, -C(RS)=NN(R6)-,

-C(R

6 )=N-O-, -C(R 6

)

2

N(R

6

)N(R

6 )-, -C(R 6

)

2

N(R

6

)SO

2 N(R), or

-C(R

6

)

2

N(R

6 )CON(R) -; -- 81- R2 and R 2 ' are independently selected from -R, -. T-W-R6, 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 5 selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by - 2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R', or -V-R, and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is 10 independently substituted by R 4 ; R3 is selected. from -R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR, -- N(R) 2 , -CON(R 7

)

2 , -SO 2 N (R7) 2 , -OC(=O)R, -N(R 7 ) COR,

-N(R

7 ) C02 (CI..

6 aliphatic) , -N (R 4

)N(R

4 ) 2 , -C=NN(R4) 2 , 15 -C=N-OR, -N(R 7 ) CON (R) 2 , -N (R 7 ) SO 2 N (R 7

)

2 , -N(R4) SO 2 R, or -OC(=0)N(R7)2 each R is independently selected from hydrogen or an optionally substituted group selected from C1.6 aliphatic, C6..10 aryl, a heteroaryl ring having 5-10 20 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R7, -COR 7 , -CO2 (optionally substituted C,. aliphatic), -CON(R) 2 , or -SO 2 R 7 25 each R 5 is independently selected from -R, halo, -OR, -C(=O)R, -C0 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R 4

)

2 , -CON(R 4 ) 2 , -SO 2

N(R

4 ) 2 , -OC(=o)R, -N(R 4 )COR,

-N(R

4 )C02(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

4

)

2 , 30 -N(R4) So 2 N (R 4 ) 2 , -N(R 4

)SO

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

)

2 ; V is -0-, -S-, -so-, -S02-, -N(R 6 )S0 2 -, -SO 2

N(R

6 )-,

-N(R

6 ) -, -CO-, -C02-, -N(R 6 ) Co-, -N(R') C(0)0-, -N (R 6 ) CON (R 6 )-, -N (R 6 ) SO 2 N (R) -, -N (R 6 ) N (R 6 ) -, -82

-C(O)N(R

6 )-, -OC(O)N(R 6 )-, -C(R 6 )20-, -C(R 6

)

2 S-,

-C(R

6

)

2 SO-, -C(R 6

)

2 S0 2 -, -C(R 6

)

2

SO

2

N(R

6 )-, -C(RG) 2

N(R

6 )-,

-C(R

6

)

2

N(R

6 )C(O)-, -C(Rt) 2

N(R

6 )C(o)o-, -C(R 6 )=NN(R)-, .

-C(R

6 )=N-0-, -C(R 6

)

2

N(R

6 ) N(R 6 )-, -C(R 6

)

2

N(R)SO

2

N(R

6 )-, or 5 -C(R') 2

N(R

6

)CON(R

6

)-;.

W is -C(R') 2 0-, -C(R 6

)

2 S-, -C(R 6

)

2 SO-, -C(R 6

)

2

SO

2 -, -C (R") 2

SO

2

N(R

6 )-, -C(R 6 ) N(R)-, -CO-, -CO2-, -C(R)OC(O)-, -C(R 6 )OC(O)N(R) -, -C(R 6

)

2 N(R)CO-, -C (R 6 ) 2

N(R

6 ) C (0) 0-, -C(R 6 ) =NN (R 6 ) -, -C (R') =N-O-, 10 -C (R 6 ) 2 N (R 6 )N(R)-, -C(R) 2

N(R

6

)SO

2 N(R)A , -C (R') 2

N(R')CON(R

6 ) -, -or -CON(R) -t. each R6 is independently selected from hydrogen or an optionally substituted C..4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together is with the nitrogen atom to form a 5-6 membered heterocyclyl or heter6aryl ring; and each R is independently selected from hydrogen or an optionally substituted C.

6 aliphatic group, or two R 7 on the same nitrogen are taken together with the 20 nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring. Preferred rings formed by RX and RY of formula hIc" include a S-, 6-, or 7-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms, or a 25 partially unsaturated carbocyclo ring, wherein said RI/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred pyrimidine ring systems of formula I1c" are shown below.

-83 HN HN HN>f I1c"-B Ic"-C -1Ic"-D HN HN HN N N IIc"-E III-F I "-J HNR < HtN HN NJ N IIc"-K IIc"-L IIc"-P HNHN HN3% NR R SIIc"-V IIc" More preferred pyrimidine ring systems of formula Ia" include IIc"-B, IIc-D, IIc-E, IIc-J, IIc-P, and lIc-V, most preferably IIc-B, IIc-D, IIc-E, and Ic J. 5 The ring formed when RX and RY of formula lIc are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH 2 )2- 4

-N(R

4

)

2 ,

-O(CH

2 ) 2-4-R, -OR, -N(R 4 ) - (CH 2 ) 2- 4

-N(R

4

)

2 , -N(R 4 ) - (CH 2 ) 2-4-R, -84 -C(=0)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR,

-N(R

4

)

2 , -CON (R 4

)

2 , -SO 2 N(R4) 2 , -OC(=0).R, -N(R 4 ) COR, -N (R 4 ) C0 2 (optionally substituted C.. aliphatic), -N (R 4

)N(R

4 ) 2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R4)CON(R 4

)

2 , 5 -N(R 4

)SO

2

N(R

4 )2,---N(RI)SO 2 R,.or.-OC(=O)N(R4) 2 , wherein R and R 4 are as defined above. Preferred R/RY ring substituents include -halo, -R, -OR, -COR, -CO 2 R,

-CON(R

4

)

2 , -CN, -Q(CH 2 )2- 4 -N(R4) 2 , -O(CH 2

)

2

.

4 -R, , -NO 2 -N (R 4 ) 2 , -NR 4 CO', -NR 4

SO

2 R, -SO 2 N (R) 2 wherein R is hydrogen 10 or an optionally substituted C1..6 aliphatic group. The R 2 and R 2 ' groups of formula IIc" may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, 15 and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIc" compounds having a pyrazole-containing bicyclic ring system: HN N N N N N Rx,, 'N ,NH NH NH NH R . N-RINNN- N H ,and Preferred substituents on the R 2 /R fused ring 20 of formula IIc" include one or more of the following: -halo, -N(R 4

)

2 , -C-4 alkyl, -C1.4 haloalkyl, -NO 2 , -0(C1-4 alkyl), -C02(C-4 alkyl), -CN, -S0 2

(C

1

-

4 alkyl), -SO 2

NH

2 ,

-OC(O)NH

2 , -NH 2

SO

2

(C

1

.

4 alkyl), -NHC(O) (C 1

.

4 alkyl), -C (0) NH 2 , and -CO (C.4 alkyl) , wherein the (C1.4 alkyl) is a -85 straight, branched, or cyclic alkyl group. Preferably, the (C 1

-

4 alkyl) group is methyl. When the pyrazole ring system of formula lic" is monocyclic, preferred R2 groups include hydrogen or a 5 substituted or unsubstituted. group selected from aryl, heteroaryl, or a C.6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R 2 ' group 10 is hydrogen. When Ring D of formula Ic" is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. When Ring D of formula 1Ic" is bicyclic, 15 preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 20 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula lIc", preferred T-R 5 'or

V-Z-R

5 substituents include -halo-, -CN, -NO 2 , -N(R 4

)

2 , optionally substituted C2-6 aliphatic group, -OR, -C(Q)R,

-CO

2 R, -CONE(R'); -N(R4)COR, -N(R 4 ) C0 2 R, -SO 2 N (R4) 2 , 25 -N (R 4 ) SO 2 R, .-N (R6) COCH 2 N (R 4 ) 2 , -N(R6) COCH 2

CH

2 N (R) 2 , and -N(R6)COCH 2

CH

2

CH

2

N(R

4

)

2 , wherein R is selected from hydrogen, C1.6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred Rs substituents include -Cl, -Br, -F, -CN, 30 -CFa, - -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N (C0 2 t-Bu) CH, -NHCOCH 2 N (CH 3

)

2 ,

-NHCOCH

2

CH

2 N(CH43)2, -NHCOCH 2

CH

2

CH

2 N(CH3)2, -86 -NHCO(cyclopropyl), -NHCO(isobutyl), -NHCOCH 2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin 4-yl), -NHCO 2 (t-butyl), -NH(C 1

..

4 aliphatic) such as -NHMe,

-N(C

1

..

4 aliphatic) 2 such as -NMe 2 , OH, -O(Cs..4 aliphatic) .5 such as -OMer-Cj.4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C-4 aliphatic). Preferred formula IIc" compounds have one or more, and more preferably-all, of the features selected 10 from the group consisting of: (a) Re and RY are taken together with their interening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 1-2 heteroatoms selected from oxygen,. 15 - sulfur, or nitrogen, or a partially unsaturated 6-membered carbocyclo ring; wherein each substitutable ring carbon of said fused ring formed by RE and Ry is independently substituted by oxo, T-R 3 or L-Z-R, and each substitutable 20 ring nitrogen of said ring formed by RE and RF 'is independently substituted by R4; (b) R" is T- (Ring D), wherein T is a valence bond or a methylene unit, and Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or 25 heteroaryl ring; (c) R 2 is -R or -T-W-R' and R 2 ' is hydrogen; or R 2 and R2' are taken together to form an optionally substituted benzo ring; and (d) R 3 is selected from -R, -halo,- -OR, or -N(R 4

)

2 . 30 More preferred compounds of formula IIc" have one or more, and more preferably all, of the features selected from the group consisting of: -87 (a) RX and RY are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, - thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused S ring formed by-R' and RF is independently substituted by oxo, T-R3, or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by RX and Ry is independently substituted by R.; (b) R' is T-(Ring D)., wherein T is a valence bond and 10 Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an .aryl'or heteroaryl ring; (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, C.

6 aliphatic, phenyl, a 15 5-6 membered heteroaryl ring, or a S-6 membered heterocyclic ring; and (d) R 3 is selected from -R, -halo, -OR, or -N(R4)2, wherein R is selected from hydrogen, C 1

_

6 aliphatic, or-5-6 membered heterocyclyl,. phenyl; 20 or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4)~. - Even more preferred compounds of formUla IIc" have one or more,'and more preferably all, of the features selected.from the group consisting of: 25 (a) R' and R are taken together to form a pyrido, piperidino, or cyclohexo ring, wherein each substitutable ring carbon of said fused ring formed by R' and Rr is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable 30 ring nitrogen of said ring formed by R and R! is independently substituted by R'; -88 (b) R' is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 mnembered aryl or heteroaryl ring; (c) R 2 is hydrogen or C1.4 aliphatic and R 2 ' is 5 hydrogen; (d) R 3 is selected from -R, -OR, or -N(R) 2 , wherein R is selected from hydrogen, C 1

.

6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and 10 (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 ,

-N(R

4

)

2 , optionally substituted C 1 .- aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH(R 4 ), -N(R4)COR, -N (R 4 ) CO 2 R, -- SO 2

N.(R

4

)-

2 , -N(R4)SO 2 R, 15 -N (R') COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2 , or -N (R") COCH 2 CH2CH 2 N (R 4 ) 2 , wherein R i.s selected from hydrogen, CIa- 6 aliphatic, phenyl, a 5 -6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. 20 Representative compounds of formula I1c are shown below in Table 3. Table 3. Me Me H H* H

HN

4 HN- HN N 1o N N N ? Me C1IJ OH' IIc-1 IIc-2 IIc-3 -89 Me Me Me

HNH

4 HNH HNXH r$N, 0 N N O H HQ H IIc-4 IIc-5 IIc-6 Me Me Me HN H HNAH HN H CNI N O N Cr NNJO H H H H IIc-7 IIc-8 IIc-9 Me Me Me - H IH IH

HN

4 P HNf-$ HNN NNl'N kt AANaC( ZN1J HH H IIc-lo IIc-l IIc-12 Me Me . Me HNt H H N H HN H HN<NA F H H . OH IIc-13 IIc-14 lIc-15 Me Me H H_ H HNNH HN Q& NJZQOH c NcOH ' N H H *H Ilc-16 IIc-17 IIc-18 -90 H H H HN HN HN N aMe CN O Nj H H H IIC-19 IIc-20 IIc-21 HN&H HN H HN H N N J NHAc N e H H .'i ~Me C NN-Me, H H IIc-22 IIc-23 IIc-24 HN HN 4

HN

4 N CE t zONJQ r 0$N OHP - H H H IIc-25 IIc-26 IIc-27 HN 4 HN 4 HN 4 NN N N Ow-COIOH H H H IIc-28 Ilc-29 IIc-30 -91

HN

4 HN H HN XH N C N N N Me CtN- N(CAIN-N C r NL- N'JMe H H H IIc-31 IIc-32 IIc-33 HN HN HN(~ N O N N OOH IIc-34 IIc-35 IIc-36 HN H HNX- HNrP H COOHe H H H IIc-37 Ilc-38 IIc-39 HN HN HN Oi$N COOH 0 N&Et 0$N

M

e H H H Me IIc-40 IIc-41 IIc-42 -92 Me HH *H

HN

4 - HNHN N M N OMe NN H H H IIc-43 IIc-44 I Ic-45 Me pH H.H HN HN HN NO N Q I $' N C N H A c IIc-46 IIc-47 IIc-48 Me Me HN H HN H HN XMe N N MN Wo (C0$N'0%N~ Me ') H H H Cl IIc-49 lIc-50 IIc-51 Me Me H '' H - '' H HN 4 Co HNe 4 HN OKNN S N Me H H H IIc-52 IIc-53 IIc-54 -93 Me Me Me

HN

4 1H HN-$ HN 4 P N EN yN NHAc alN%4J~aEt (lN'Na~%e C N' NaCN H H H IIc-55 IIc-56 IIc-57 Me Me Me

HN

4 P- Hi H , N 'N a NHAc NHBoc H H IIc-58 IIc-59 IIc-60 Me Me Me HN HN H HN H r~ N CN rT'N )'X Ot$'N Q H O IIc-61 IIc-62 IIc-63 Me Me Me HN H HN H HN H N COOMe N COOH $ NH2 H H H IIc-64 IIc-65 IIc-66 Me Me Et H H H IIc-67 IIc-68 IIc-69 -94 H H H HN HN HN QNC~ rNNaCF3 IIc-70 IIc-71 IIc-72 HH Y H &ZHN HN NO N Noa F N H Me HCI IIc-73 IIc-74 Ilc-75 9 0- Me H H - H. HN HN HN N CN C) If-I' NNrN C# N H CFM e H IIc-76 IIc-77 IIc-78 Me Me Me HN HN 4 H HN H NQ B.N -N BnN - Q H . H H IIc-79 IIc-80 IIc-81 -95 Me Me Me N H HN H B HN H BnjjN N Cl Bn'Nj N N{Q' HN<1 NA QQ NQ H H H H IIc-82 IIc-83 IIc-84 MeN HN H HpH HN HN $N N NcCN N HH H CN IIc-85 IIc-86 IIc-87 H HN2H H N C N . N CNN H H HXIaCN IIc-88 IIc-89 lIc-90 In-another embodiment, this invention provides a composition comprising a compound of formula. Ilc, lIc', or IIc", and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula lIc, Ic', or' IIc, or a 10 pharmaceutical composition thereof. Another aspect of this invention relates to a method of inhibiting'Aurora-2 activity in a patient, -96 which method comprises administering to the patient a compound of formula Ilc, Ihc', or Ic", or a composition comprising said compound. Another aspect of this invention relates to a 5 method of treating-or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment, a' therapeutically effective amount of a compound of formula Io, Ile', or Ilo", or a pharmaceutical composition 10 thereof. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises -administering to the patient a 15 therapeutically effective amount of a compound of formula 11c, Ic', or Ic", 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 20 useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of 0-catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a 25 method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IIc, Ilo', or Io", or a composition comprising said compound. Another aspect of this invention relates to a 30 method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula -97 Ila, 'Il', or IIc", or a pharmaceutical composition thereof. . . Another aspect of the invention relates to inhibiting Src activity in a patient, which method 5 comprises administering to the-patient a compound of formula Ila, Ile', or Ilc", or a composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated 10 diseases with an ERK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a. compound of formula IIc, IIc', or Irc", or a pharmaceutical composition thereof. 15 -Another aspect of the invention relates to inhibiting ERK-2 activity in a patient, which method comprises administering to the patient a compound of formula IIc, IIc', or IIc", or a composition comprising said compound.. 20 Another aspect of this invention relates to a method of treating or preventing an AKT-mediated diseases with an AKT inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula 25 Ia, Ia', or IIc", or a pharmaceutical composition thereof. Another aspect of the invention relates to inhibiting AKT activity in a patient, which method comprises administering to the patient a compound of 30 formula Ilo, Ilo', or Ilo", or a composition comprising said compound. Another method relates to inhibiting Aurora-2, GSK-3, Src, ERK-2, or AKT activity in a biological -98 sample, which method comprises contacting the biological sample with the Aurora-2, GSK-3, Src, ERK-2, or AKT inhibitor of formula Ilo, lie', or Ihc", or a pharmaceutical composition thereof, in an amount 5 effective to inhibit Aurora-2, GSK-3, Src, ERK-2, or AKT. Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, Src, ERK-2, or AKT, or the treatment of a disease alleviated thereby,-is preferably carried out with a preferred compound of 10 formula I1c, Ilo', or Ie", as described above. Another embodiment that is particularly useful for treating Aurora-2-mediated diseases relates to compounds of formula lId: R 2') ,NH HN N . RXX Ry N Q'-R' IId . or a pharmaceutically acceptable derivative or prodrug 15 thereof, wherein; Q' is selected from -C(R 6t

)

2 -, 1,2-cyclopropanediyl, 1,2 cyclobutanediyl, or 1,3-cyclobutanediyl; RX and RY are taken together with their intervening atoms . to form a fused, unsaturated or partially unsaturated, 20 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and RY is independently substituted by oxo, T-R 3 , or

L-Z-R

3 , and each substitutable ring nitrogen of said -99 ring formed by RX and RY is independently substituted by R'; R' is T-(Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered 5 bicyclic ring selected from aryl, -heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently 10 substituted by oxo, T-R 5 , or V-Z-R, and each substitutable ring nitrogen of Ring D is independently substituted by -R'; T is a valence bond or a CI.4 alkylidene chain, wherein when Q' is -C(R') 2 - a methylene group of said C1_4 15 alkylidene chain is optionally replaced by -0-, -S-, -N(R')-, -CO-, -CONH-, -NHCO-, -SO 2 -, -SO 2 NH-, -NHSO 2 -, -C02-, -OC(0)-, -OC(O)NH-, or -NHCO 2 -; Z is a C1.4 alkylidene chain; L is -0-, -S-, -SO-, -SO2-, -N(R 6

)SO

2 -, -SO 2 N(R')-, 20 -N(R)-, 00, _C0-, -N(R 6 )CO-, -N(R)C(O)O-,

-N(R

6 )CON(R') -, -N(R 6 )S0 2 N(R6) -, -N(R 6

)N(R

6 )-, -C(0)N(R)-,

-OC(O)N(R

6 )-, -C(R 6

)

2 0-, -C(R') 2 S-,

-C(R

6

)

2 SO-, -C(R 6

)

2

SO

2 -, -C(R') 2

SO

2 N(R'.)-', -C(R') 2

N(R

6 )-, C (R) 2 N (R) C(O)-, - C (R') 2 N(R')C(o)0-, -C(R')=NN(R6)-, 25 -C(R')=N--, -C(R)2N(RS)N(R4)-,

-C(R')

2

N(R

6

)SO

2

N(R

6 )-, or -C (R) 2

N(R

6 ) CON (R 6 )-;

R

2 and R 2 ' are independently selected from -R, -T-W-R', or

R

2 and R 2 ' are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or 30 partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R 2 ' is independently substituted by halo, oxo, -100 -CN, -NO 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 is independently substituted by R 4 ;

R

3 is selected from -R, -halo, -OR, -C(=O)R, -CO 2 R, 5 -COCOR, -COCH 2 COR, -N0 2 , -CN, -S(O)R, -S(O)- 2 R, -SR, -N(R4); - CON (R 1 ) 2 , -SO 2 N (R 7

)

2 , -OC(=O)R, -N(R 7 ) COR,

-N(R

7 ) UO2(CI-6 aliphatic),

-N(R

4

)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 4 ) SO 2 R, or -OC (=0)N(R7) 2 ; 10 each R is independently selected from hydrogen or an optionally substituted group selected from C..

6 aliphatic, C5- 1 3 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; 15 each R 4 is independently selected from -R', -COR,

-CO

2 (optionally substituted C2.. aliphatic),

-CON(R

7

)

2 , or -S0 2 R; each R 5 is independently selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, 20 -N(R4) 2 , -CON(R 4

)

2 , -S0 2

N(R

4

)

2 , -OC(=O)R, -N(R4)COR, -N (R4) CO2 (optionally substituted

C

1

..

6 aliphatic) ,

-N(R

4 )N(R4) 2 , -C=NN(R 4

)

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

)CON(R)

2 ,

-N(R

4

)SO

2

N(R

4

)

2 , -N(R 4

)SO

2 R, or --OC(=b)N(R4)2 V is_-O-, -S-, -SO-, -SO2-, -N(R)S0 2 -, -S0 2 N(R)-, 25 -N(R)--, '-CO-, -C0 2 -, -N(R 6 )CO-, -N(R 6 )C(O)O-,

-N(R

6 )CON(R)-, -N(R)So2N(R)-,

-N(R)N(R

6 )-, -C (0) N (R 6 ) -, -OC (0) N (R 6 )-, -C (R) 20-, -C (R) 2s

-C(R

6

)

2 SO-, -C(R 6

)

2

SO

2 -, -C(R 6

)

2

SO

2 N(R)-, -C(R 6

)

2

N(R

6 )-,

-C(R

6

)

2

N(R

6 )C(0).-, -C(R 6

)

2

N(R

6 )C(0)0-, -C C(R 6

)=NN(R

6 )-, 30 -C(R)=N-O-, -C(R) 2 N(R6)N(R)-, -C(R 6

)

2

N(R

6

)SO

2 N(R)-, or -C(R6) 2 N(R6) CON(R 6 )-; W is -C(R6) 2 0-, -C(R') 2 S-, -C(R)2SO-, -C(R6) 2

SO

2 -, -C(R6) 2

SO

2 N(R)-, -C(R') 2 N(R6)-, -cO-, -C0 2

-,

-101 -C (R')OC(0) -, -C(R') OC(0)N (R')-, -C (R6)2,N(R4) CO-,

-C(R

6

)

2

N(R

6 )C(0)0-, -C(R 6

)=NN(R

6 )-, -C(R 6 )=N-0-,

-C(R

6

)

2

N(R

6 )N(R)-, -C(R 6

)

2

N(R')SO

2 N(R6)-,

-C(RS)

2 N(RE)CON(R)-, or -CON(R 6 )-; 5 each R5 is independently selected f-rom hydrogen or an optionally- substituted C01.4 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; 10 each R6' is independently selected from hydrogen or a C..4 aliphatic group, or two R 6 ' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring; and each R is independently selected from hydrogen or an 15 optionally substituted C.6 aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring. Preferred rings formed by RX and RY include a 20 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said

R

1 /RY ring is optionally substituted. This provides a bicyclic ringsystem containing a pyrimidiie ring. Examples of preferred pyrimidine ring systems of formula 25 Ild are shown below. R2 RF R 'NH HN HN'? Ild-A Ild-B Ild-C -102 HNNHN HN R4., N Ild-D IId-E IlId-F HN HN HN H N NN IId-J Ild-K IId-L HN HN'HN <N R Ild-P IId-R IId-V - . HN R IId-W More preferred pyrimidine ring systems of formula lid include lid-A, Ild-B, IId-D, Ild-E, IId-J, IId-P, and.IId-V, most preferably Ild-A, Ild-B, lId-D, IId-E, and Ild-J. 5 The ring formed when RX and Ry of formula lid are taken together may be substituted or unsubstituted. Suitable substituents include -R, halo, -O(CH 2

)

2

-

4

-N(R

4

)

2 , -O (CH 2 ) 2-4-R, -OR, -N (R 4 ) - (CH 2 ) 2

-

4 -N (R 4 ) 2, -N (R 4 ) - (CH 2 ) 2

-

4

-R,

-103 -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR,

-N(R

4

)

2 , -CON(R) 2 , -SO 2

N(R

4

)

2 , -OC(=O)R, -N(R 4 )COR, -N (R 4 ) C0 2 (optionally substituted C1- aliphatic),

-N(R

4

)N(R

4

)

2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R4)CON(R 4 ) 2 , 5 -N (R 4 ) SO 2 N (R'-) 2 , -N (R 4 ) SO 2 R, or -OC (=O) N (R 4 ) 2 , R -and R 4 are as defined above. Preferred RX/RY ring substituents include -halo, -R, -OR, -COR, -CO 2 R, -CON(R 4

)

2 , -CN, -O (CH2) 2-4 -N (R 4 ) 2 , -O(CH 2

)

2

..

4 -R; , -NO 2

-N(R

4 ) 2 , -NR 4 COR,

-NR

4

SO

2 R, -SO 2

N(R

4

)

2 wherein R is hydrogen or an optionally 10 substituted C1-6 aliphatic group. The R2 -and R 2 ' groups of formula IId may be taken together to form a fused ring, -thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, 15 and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IId compounds having a pyrazole-containing bicyclic .ring system:. 9 NH i- l f HN N N N Rx N .$NH NH NH -NH -N N'Pi 20 R N Q-R' , and Preferred substituents on the R 2

/R

2 ' fused ring of formula I1d include one or more of the following: -halo, -N(R 4)2, -CI-4 alkyl, -C1i4 haloalkyl, -NO2, -0(Ci-4 25 alkyl), -C02(C1-4 alkyl), -CN, -SO 2

(C.-

4 alkyl), -SO 2

NH

2 , -OC (O) NH 2 , -NH 2

SO

2

(C.

4 alkyl) , -NHC (O) (C..4 alkyl), - -C(O)NH 2 , and -CO(CI-4 alkyl), wherein the (Ca..4 alkyl) is a -104 straight, branched, or cyclic alkyl group. Preferably, the (CI.4 alkyl) group is methyl. When the pyrazole ring system of formula lid is monocyclic, preferred

R

2 groups include hydrogen or.a 5 substituted or uns substituted' group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred

R

2 . group 10 is' hydrogen. - When Ring. D of formula lid is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. When Ring D of formula lid is bicyclic, 15 preferred bicyclic Ring D groups 'include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 20 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula lid, preferred T-RS or V-Z- R 5 substituents include -halo, -CN, -NO 2 , -N(Rt) 2 , optionally substituted Cjs aliphatic group, -OR, -C(O)R,

-CO

2 R, - CONH(R), -N(R4) COR, -N (RO4)CO 2 R, - SO 2 N (R4) 2 , 25 -N (R 4 ) So 2 R, -N (R 6 ) COCH 2 N (R4) 2 , -N (R) COCH 2

CH

2 N (R) 2 , and -N(R6)COCH 2

CH

2 CH2N(R ) 2 , wherein R'is selected from hydrogen, CI-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred Rs substituents include -Cl, -Br, -F, -CN, 30 -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me,

-NHSQ

2 Et, -NHSO 2 (n-propyl),

-NHSO

2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N(C02t-Bu)CH 3 , -NHCOCH 2

N(CH

3 )2,

-NHCOCH

2

CH

2 N (CH 3 ) 2 , -NHCOCH2CH 2

CH

2 N (CH) 2

,

-105 -NHCO (cyclopropyl), -NHCO (isobutyl),

-NHCOCH

2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin 4-yl),

-NHCO

2 (t-butyl),

-NH(C

1

..

4 aliphatic) such as -NHMe,

-N(C

1

-

4 aliphatic) 2 such as -NMe 2 , OH, -O(C- 4 aliphatic) 5 such as -OMe, C..-4 aliphatic such as methyl, -ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO 2

(C

1

..

4 aliphatic).

Preferred Q'. groups of formula Ild include -C(R'')2- or 1

,

2 -cyclopropanediyl, wherein each R' is 10 independently selected from hydrogen or methyl. A more preferred Q' group is -CH 2

-

Preferred formula Ic compounds have one or more, and more preferably all, of the features selected from the group consisting of: 15. (a) R7 and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6- membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable 20 ring carbon of said fused ring formed by RX and 33 Ry is independently substituted by oxo, T-R , or L-Z-R , and each substitutable ring nitrogen of said ring formed by RX and RY is, independently substituted by R 4 ; 25 (b) R- is T- (Ring D) , wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by -0-, -NH-, or -S-; (c) Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an 30 aryl or heteroaryl ring; (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen; or R 2 and R2' are taken together to form an optionally substituted benzo ring; and -106 (e) R 3 is selected from -R, -halo, -OR, or -N(R4) 2 . More preferred compounds of formula IIc have one or more, and more preferably all, of the features selected from the group consisting of: 5 (a) RX and Ry -are. taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring; (b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit and wherein said methylene unit 10 is optionally replaced by.-O-, and Ring D is .a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl.ring; (c) R 2 is- R and R 2 ' is hydrogen, wherein R is 15 selected from hydrogen, C 1

..

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; (d). R 3 is selected from -R, -halo, -OR, or -N(R4) wherein R is selected from hydrogen, C 1

:

6 20 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 )-; and (e) Q' is -C(R" t

)

2 - or 1,2-cyclopropanediyl, wherein -each Rs' is independently selected from hydrogen 25 or methyl. Even more preferred compounds of formula lie have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX and Ry are taken together to form a benzo, 30 pyrido, piperidino, or cyclohexo ring; (b) R' is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; -107 (C) R 2 is hydrogen or C1.4 aliphatic and R" is hydrogen; (d) R' is selected from -R, -OR, or -N(R4) 2 , wherein R is selected from hydrogen, C1.s aliphatic, 5-6 5 membered -heterocyclyl-, phenyl, or 5-6- membered heteroaryl, and L is -0-, -S-, or -NH-; (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 ,

-N(R

4

)

2 , optionally substituted Ci-P aliphatic 10 group, -OR, -C (0) R, -CO 2 R, -CONH(R 4 ), -N(R4) COR, -N (R) CO 2 R, -S0 2 N (Rt) 2 , -N (R 4 ) SO 2 R, -N (R4) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2

CH

2 N (R4) 2 , or

-N(R

6

)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is selected from hydrogen, C1.6 aliphatic, phenyl, a 5-6 15 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (f) Q' is -CH 2 -. Representative compounds.of formula lid are shown below in Table 4. Table 4. HN HN HNJ{ IId-1 I-Id-2 IId-3 -108 Me Me Me HN H N HHN JtH 9>jC 9a,, 0% -L IId-4 Ild-5 Ild-6 Me Me Me

HN

4 H HN H HN<* SNN Me IId-7 IId-8 IId-9 Me Me- Me .N A H HN H ON CI Id-10 -l Id-il I1d-12 Me HN H Me Me HN $tHNJZ HN IId-13 IId-14 lid-15 -109 F (rF F H . H H HN HN HN IId-16 IId-17 IId-18 Me HN IId-19 In another embodiment, this invention provides a composition comprising a compound of formula lid and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula lId or a pharmaceutical composition 10 thereof~. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula lid or a composition comprising said 15 compound. - Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprised administering to a patient in need of such a' .treatment a -110 therapeutically effective amount of a compound of formula Ild or a pharmaceutical composition thereof. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering 5 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 Ild or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another 10 method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the' phosphorylation of P-catenin, which is useful for 15 treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula lid or a composition comprising said compound. 20 Another method relates to inhibiting Aurora-2 or GSK-3 activity in a'biological sample, which method comprises cofitacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula Ild, or a pharmaceutical composition thereof, in an amount 25 effective to inhibit Aurora-2 or GSK-3. Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula Ild, as described 30 above. Another embodiment of this invention relates to compounds of formula ilia: -111 R2 R2 NH HN N Ry N WS-R ' Mia or a pharmaceutically acceptable derivative or prodrug 5 thereof, wherein:' RX and Ry are independently selected from T-R' or L-Z-R 3 R' is T- (Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, 10 heterocyclyl or carbocyclyl, said .heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms'selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-R, and each is substitutable ring nitrogen of Ring D is independently substituted by -R 4 ; T is a valence bond or a C 1

..

4 alkylidene chain; Z is a C 1

.

4 alkylidene chain; L is -0-, -S-, -SO-, -SO2-, -N(R 6

)SO

2 -, -SO 2 N(R)-, 20 -N(R 6 )-, -CO- , -C0 2 -, -N(R6)CO-, -N(R)C(O)O-,

-N(R

6

)CON(R

6 ) -, -N(R 6

)SO

2 N(R')-, -bl(R 6

)N(R

6 )-I -C(O)N(R) -, -OC(O)N(R6) -, -C(R 6

)

2 0-, -C(R 6 ) 2-,

-C(R

6 )2SO-, -C(R 6 )2SO 2 -, -C(R 6

)

2

SO

2

N(R

6 )-, -C(R 6

)

2

N(R

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

N(R

6 )C(o)O-, -C(RE)=NN(R6)-, 25 -C(R 6 )=N-O-, -C(Rt) 3 2N(R)N(R)-,

-C(R

6

)

2

N(R

6

)SO

2

N(R

6 )-, or -C (R')2N (R 6 ) CON (R) -;

R

2 and R 2 ' are independently selected from -R, -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 -112 partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of -said fused ring formed by R2 and R2' is independently substituted by halo, oxo, 5 -CN, '-NO 2 , -R, or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ;

R

3 is selected from -R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR, 10 -N (R) 2 , - CON (R 7

)

2 , -SO 2 N(R7) 2 , -OC(=O)R, -N(R')COR, -N (R 7 ) CO 2

(C

1

.

6 aliphatic),

-N(R

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

)CON(R

7

)

2 , -N(R 7

)SO

2 N(R7) 2 , -N(R4)SO 2 R, or -OC (=0) N (R )2; each R is independently selected from hydrogen or an 15 optionally substituted group selected from C1.6 aliphatic, C6-io aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -- R7, -COR 7 , 20 -C0 2 (optionally substituted C1_6 aliphatic),

-CON(R

7

)

2 , or -SO 2 R ; each R 5 is independently selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N(k 4

)

2 , -CON(R 4

)

2 , -SO 2

N(R)

2 , -OC(=O)R, -N(R4)COR, 25 -N(R)C02 (optionally substituted C-6 aliphatic), -N (R4)N(R 4 )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 -OC(=0)N(R*)2; V is -0-, -S-, -SO-, -SO2-, -N(R 6

)SO

2 -, -SO 2

N(R

6 )-,

-N(R

6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 ) C(0)0-, 30 -N(R 6 )CON(R)-, -N(R 6

)SO

2 N(R")-, -N(R 6 )N(R6) -C(O)N(R6)-,

-OC(O)N(R

6 )-, -C(R 6

)

2 0-, -C(R)2S-,

-C(R')

2 SO-, -C(R 6

)

2

SO

2 -, -C(R 6

)

2

SO

2 N(R')-, -C(R) 2

N(R

6 )-,

-C(R)

2 N(R')C(0)-,

-C(R)

2

N(R

6 )C(0)0-, -C(R 6

)=NN(R

6

)-,

-113 -C(R) =N-O-, -C(R 6

)

2

N(R

6

)N(R

6 )-, -C(R 6

)

2

N(R

6

)SO

2

N(R

6 )-, or - C (R 6 ) 2 N (R 6 ) CON (R 6 ) -; W is -C(R) 2 0-, -C(R 6

)

2 9-, -C(R) 2 SO-, -C(R 6

)

2

SO

2 -,

-C(R)

2

SO

2 N(R)-, -C(R 6

)

2

N(R

6 )-, ~Co-, -C02-, 5 -C(R 6 ) OC(O) -, -C (R') OC(O) N(R 6 ) -, -C(Rq) 2 N (R 6 ) CO-,

-C(R

6

)

2

N(R

6 )C(0)0-, -C(R 6

)=NN(R

6 )-, -C(R 6 )=N-O-,

-C(R')

2

N(R

6 )N(R)-, -C(R) 2

N(R

6

)SO

2

N(R

6 )-, -C (R 6

)

2 N (R') CON (R 6 ) -, or -CON(R 6 ) -; each R6 is independently selected from hydrogen or an 10 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; and each R7 is independently selected from hydrogen or an 15 optionally substituted CI..

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. Preferred RX groups of formula IIIa- include 20 hydrogen, alkyl- or dialkylamino, acetamido, or a C.4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl. Preferred Ry groups of formula -1I1a include T-R , or L-Z-R 3 wherein T is a valence bond or a methylene, L is 25 -0-, -S-, or -N(R 4 )-, -C(R 6

)

2 0-, -CO- and R' is -R,

-N(R

4

)

2 , or -OR. Examples of preferred Ry groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as 30 methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as -114 dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl. The R 2 and R 2 ' groups of formula ilia may be taken together to form a fused ring, thus providing a -5 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 Ilia compounds having a pyrazole-containing bicyclic ring 10 system: NH HN N /N N Noo.

R, N'NH NH NH NH NN N N R NS-R,- , , , and Preferred substituents on the R2 /R' fused ring 15. of formula Ilia include one or -more of the following: .- halo, -N(R 4)2, -CI-4 alkyl, -C3.-4 haloalkyl, -NO2, -O(CI..4 alkyl), -CO 2

(C

1

.

4 alkyl), -CN, -SO 2

(C

1

.

4 alkyl), -SO 2

NH

2 , -OC (O)NH 2 , -NH 2

SO

2

(C

1

..

4 alkyl), -NHC(O) (C 1

..

4 alkyl),

-C()NH

2 , and -CO(C- 4 alkyl) , wherein the (C 1

..

4 alkyl) is a 20 straight, branched, or cyclic alkyl group. Preferably, the (C 1

.

4 alkyl) group is methyl. When the pyrazole ring system of formula Ilia is monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, 25 heteroaryl, or a' C..

6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, -115 methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen. When Ring D of formula Ilia is monocyclic, preferred Ring D groups include phenyl, pyridyl, 5 pyridazinyl, pyrimidinyl, and pyrazinyl. When Ring D of formula IIXa is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, 10 benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl', 1,8 -naphthyridinyl and isoquinolinyl. On Ring D of formula lia, preferred T-R 5 or V

Z-R

5 substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , 15 optionally substituted C 1

.

6 aliphatic group, -OR, -C(O)R, -CO2R, -CONH(R 4 ), -N(Rt)COR, -N (R 4 ) CO2R, -SO 2

N(R

4 ) 2 , -N (R 4 ) SQ 2 R, -N (R6) COCH 2 N (R 4 ) 2, -N (R 6 ) COCH2CH 2 N (R 4

)

2 , and -N (R 6 ) COCH 2 CH2CH 2 N (R 4 ) 2 , wherein R is selected f rom hydrogen, C 1 6 aliphatic, phenyl, a.'5-6 membered 20 heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, -CF3, -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHS0Me,

-NHSO

2 Et, -NHSO 2 (n-propyl), -NHSO 2 (isopropyl), -NHCOEt,

-NHCOCH

2 NHCH3, -NHCOCH 2 N (CO2t -Bu) CH3, -NHCOCH2N (CH) 2, 25 -NHCOCH 2

CH

2 N (CH3) 2 , -NHCOCH 2 CH2CH 2 N (CH3) 2, -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl), -NHCOCH2CH 2 CH2 (morpholin 4-yl), -NHCO 2 (t-butyl), -NH(CC.- 4 aliphatic) such as -NHMe,

-N(C.-

4 aliphatic) 2 such as -NMe 2 , OH, -O(C1.4 aliphatic) 30 such as -OMe, C1-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl., and -C02(C-4 aliphatic).

-116 Preferred formula ilia compounds have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX is hydrogen, alkyl- or dialkylamino, 5 acetamido, or -a C.4 aliphatic group; (b) Ry is T-R 3 or L-Z-R3, wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4

)

2 , or -OR; (c) R 1 is T-(Ring D), wherein T is a valence bond or a methylene unit; 10 (d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (e) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and R 2 are taken together to form an optionally substituted benzo ring. 15 More preferred compounds of formula IIa have one or more, and more preferably all, of the features selected from th'e group consisting of: (a) RY is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, 20 or -N(R4) 2 , wherein R is selected from hydrogen, Ce 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; (b) R' is T- (Ring D), wherein T is a valence bond; (c) Ring D is a 5-6 membered monocyclic or an 8-.10 25 membered bicyclic aryl or heteroaryl ring; (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen, CI-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and 30 (e) L is -0-, -S-, or -N(R4) Even more preferred compounds of formula ilia have one or more, and more preferably all, of the features selected from the group consisting of: -117 (a) RK is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido; (b) RY is selected from 2-pyridyl, 4-pyridyl, 5 pyrrolidinyl., piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamind, alkyl- or dialkylaminoalkoxy, acetamido, optionally 10 substituted phenyl, or methoxymethyl; (c) R' is T- (Ring D), wherein T is a valence bond and Ring D is a 5-6 membered.aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, -CN, 15

-NO

2 , -N(R 4

)

2 , optionally substituted

C

1 6 aliphatic group, -OR, -CO 2 R, -CONH(R 4 ), -N(R4)COR,

-N(R

4

)SO

2 R, -N(R 6

)COCH

2

CH

2 N(R4) 2 , or. -N (R 6 ) COCH 2

CH

2

CH

2 N R) 2 ; and (d) R 2 is hydrogen or a substituted or unsubstituted 20

C

16 aliphatic, and L is -0-, -S-, or -NH-. Representative compounds of formula 1I1a are, shown below in Table S. Table 5.

HN

4

HN

4

HN

4 NSN

S

0 f'S CO 2

M

e N1S IIIa-1 IIIa-2 IIIa-3 -118 HN 4

HN#

4 Me S

M

etS Me N IIIa-4 IIIa-5 IIIa-6 Me HN HN HN 4 P NNS Me N CN' N SI CNAz tKNS)*tA6J Me.N& Me IIIa-7 IIIa-8 IIIa-9 Me Me Me HN H HN*H . HNP H %. N ~yNHAc IIIa-10 IIIa-11 IIIa-12 Me Me Me -N H HNH H N H HN<P H HN<Vft HN 4 Px , N N ,iPr N S ,MN NH Et MeNa-3Ia1I a IIIa-13 IIIa-14 IIIa-15 -119 Me Me Me ,H 'H e HN H HN<Vp H HNP H N N N PN N NE t IIla-16 IIIa-17 IIIa-18 Me Me Me HN-fI H HN *H H H N f:tpH N NHAc Me Ng a NHAc ,e . NtrIBu NH- 0 IIIa-19 IIIa-20 IIIa-21 Me Me Me gp H JH JPH HN HN4 H HN H M6 NNHAcHN NHAc NSN. MeO IIIa-22 IIIa-23 IIIa-24 Me Me Me HNNH H NMe 2 HN H HN H NON So . HN&S Sy MeOQ CI CI IIIa-25 IIIa-26 IIIa-27 Me Me Me HNAH HN H HN H N I CI IIIa-28 IIIa-29 IIIa-30 -120 Me Me HN CPH HN HH N H N H H M&Q 'XZ~ t 'u f ljrMe I/ cr r t N N-S t, OS O e 02 IIIa-34 IIa-32 IIIa-33 Me Me Me HN H -- HN H HN<V H N S Ne EtCNM MeN 02N eOMeO IIIa-34 IIIa-35 IIIa-36 Me Me Me JtJ'J HN<P H <I> NS Oe N scO>Ef N 'S O-e O2 MeO MeO IIIa-37 IIIa-38 IIIa-39 Me Me Me CN$5 H"* HNeH OMe OMl IIIa-40 IIIa-41 IIIa-42 -121 Me Me Me H -PHH HNHN HNH crNHAC CN&S% OH N S cS" 'S NHAc - N Et O H NMe 2 IIIa-43 IIIa-44 IIIa-45 Me Me Me Hk H '. H HN H HN 0 p H HNt H N N Me Bu N S 1 NyEt M NeON Et NS N 0 BUits2 o Mer1 0 0 0 IIIa-46 IIIa-47 IIIa-48 Me Me Me HN HN t H H HN H H N HAc -Me -N N N M t N Meg ttci Sj HcIN Sa N -N-'N)tl 0 0 MO IIIa-49 IIIa-so IIIa-51 Me Me Me Me HN HN' H HN H Me N/yNHAc N'Me N / N Et MeO N /N MIe - M Me IIIa-52 IIIa-53 IIIa-54 Me Me Me

HN

4 PH HMe HN H H HN HH Me 2 N JN N N$S N Et N N NMe Me.N Me IIIa-55 IIIa-56 IIIa-57 -122 H :NH ' Jr H H-' t H H HN HN HHNH Me2N t Sa NHAc N E N NMe MerN0 MMe Ila-58 IIIa-59 IIIa-60 H H HN H HN HN H N Nf^NMe, MeNHifH N EtO N S O 2 Me 2 N 0 NMe 2 IlIa-61 IIIa-62 IIIa-63 In another embodiment, this invention provides a composition comprising a compound of formula Ila and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which. method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula Ilia or a pharmaceutical composition 10 thereof. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula ilia or a composition comprising said 15 compound.

-123 Another aspect of this invention relates to a method of treating or, preventing a GSK-3-mediated disease with a.GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a 5 therapeutically effective-amount of a compound of formula Iila or a pharmaceutical composition thereof. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a'patient in need thereof, '10 which method comprises administering to the patient a therapeutically effective amount of a compound of formula ilia or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of 15 hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the . phosphorylation of. J-catenin, which is useful for - treating schizophrenia-. 20 . Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula 1I1a or a composition comprising said. compound. 25 Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula 30 Ilia ora pharmaceutical composition thereof. Another aspect of the invention relates to inhibiting Src activity in a patient, which method -124 comprises administering to the patient a compound of formula IIIa or a composition comprising said compound. Another method relates to inhibiting Aurora-2, GSK-3, or Src activity in a biological sample, which 5 method comprises- contacting the biological sample with the Aurora-2, GSK-3, or Src inhibitor of formula IlIa, or a pharmaceutical composition thereof, in an. amount effective to inhibit Aurora-2, GSK-3, or Src. Each of the aforementioned methods directed to 10 the inhibition of Aurora-2, GSK-3, or Src, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IIa, as described above. Another embodiment of this invention relates to 15 compounds of formula IIb: R2 RaNH HN N RY NI0-Ri II lb 20 or a pharmaceutically acceptable derivative or prodrug thereof, wherein: RX and Ry are independently selected from T-R or L-Z-R 3 ; R' is T- (Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered 25 bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl-ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently -125 substituted by oxo, T-R 5 , or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently substituted by -R4; T is a valence bond or a C1-4 alkylidene chain; 5 z is a C.4 alkylidene chain; L is -0-, -S-, -SO-, -SO 2 -, -N(R6)S0 2 -, -SO 2 N(R6)-,

-N(R

6 )-, -CO-, -CO2-, -N(R')CO-, -N(R)C(0)0-,. -N(R")CON(R')-,

-N(R')SO

2 N(R6)-, -N(R')N(R 6 )-, -C(O)N(R") -, -OC(O)N(R) -, -C(R') 2 0-, -C(R6)2S-, 10 -C(R') 2 SO-, -C(R) 2 SO2-, -C(R6) 2

SO

2 N(R)-, -C(R')2N(R 6 )-, -C (R')2

N

(R')C(O)-, -C(R') 2 N(R' )C(O)O-, -C(R')=NN(R6) -,

-C(R

6 )=N-O-, -C(R) 2 N(RG)N(R)-, -C(R 6 ) 2 N(R) SO 2 N(R() -, or

-C(R

6

)

2 N(R6)CON(R 6 ) -; R2 and R 2 ' are independently selected from -R, -T-W-R5, or 15 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 ring carbon of said fused ring formed by 20. R2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R7, or -V-R6, and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R4;

R

3 is selected from -R, -.halo, -OR, -C(=O)R, -CO 2 R, 25 -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR,

-N(R)

2 , .- CON(R) 2 , --SO 2

N(R

7

)

2 , -OC(=O)R, -N(R 7 )COR,

-N(R

7 )C0 2

(C.

6 aliphatic), -N(R4)N(R4) 2 , -C=NN(R 4

)

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

)CON(R

7

)

2 , -N(R')SO 2

N(R)

2 , -N(R4)S0 2 R, or -OC (=0) N (R ) 2; 30 each R is independently selected from hydrogen or an optionally substituted group selected from Ces aliphatic, Cs..o aryl, a heteroaryl ring having 5-10 -126 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7 , -COR', -C0 2 (optionally substituted C.6 aliphatic), -CON(R) 2 , 5 or -S0 2 R; each R 5 is independently selected from -R, halo, -OR, -C(=o)R, -C0 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -S0 2 R, -SR,

-N(R

4

)

2 , -CON(R 4

)

2 , -SO 2 N(R4) 2 , -OC(=O)R, -N (R4) COR, -N(R 4)CO 2 (optionally substituted C01 aliphatic), 10. -N (R4 N (R4)2, -C=NN(R') 2 , -C=N-OR, -N(R 4 ) CON (R4) 2 , -N(R4)SO 2

N(R

4

)

2 , -NCR 4 )S0 2 R, or -OC(=0)N(R4) 2 ; V is -a-, -S-, -SO-, -SO2-, -N(R').SO 2 -, -SO 2 N(R")-,

-N(R

6 )-, -CO-, -CO2-, -N()CO-, -N(R 6 )C(o)-0-,

-N(R

6 )CON(R)-, -N(R6)SO 2 N(R)-, -N(R)N(R 6 )-, is -C(o)N (R 6 )-, -OC(0)N(R 6 )-, 'C(R 6

)

2 0-, .C(R 6

)

2 S-,

-C(R')

2 SO-, -C(R 6

)

2

SO

2 -, -C(R 6 )2SO 2

N(R

6 )-, -C(R4) 2 N(R6)-,

-C(R

6

)

2

N(R

6 )C(O)-, -C(R 6

)

2

N(R

6 )C(0)O-, -C(R)=NN(R) -, -C(R)=N-O-, -C(R 6

)

2

N'(R

6

)N(R:

6 )-,. -C(R) 2

N(R)SO

2 N(R6)-, or -C (R 6

)

2 N(R") CON (R 6 ) -; 20. W is -C(R 6

)

2 0-, -C(R 6

)

2 S-, -C(R 6

)

2 So-, -C(R 6

)

2 SO2-,

-C(R

6

)

2

SO

2 N(R)-, -C(R 6

)

2 N(R)-, -Co-, -C02-,

-C(R

6 )Od(O) -, -C(R 6 )OC(O) N(R 6 ) -, -C (R) 2

N(R

6 ) CO-, -C (R) 2 N (R 6 )C (0)0-, -C(R 6 )=NN (R 6 ) -, -C(R') N-O-,

-C(R')

2 N(R6)N(R)-, -C(R) 2

N(R")SO

2 N(R) -, 25. -C (R") 2 N(-R6)CON(R6) -, or -CON (R) -; each R6 is independently selected from hydrogen or an optionally substituted CI.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 30 heterocyclyl or heteroaryl ring; and each R7 is independently selected from hydrogen or an optionally substituted C1es aliphatic group, or two R 7 on the same nitrogen are taken together with the.

-127 nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring. Preferred RX groups of formula IIIb include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1

..

4 5 aliphatic -3roup -such as methyl, ethyl, cyclopropyl, or isopropyl. Preferred RY groups of formula 11b include T-R 3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R5) 2 0-, -CO- and R 3 is -R, 10 -N(R4) 2 , or -OR. Examples of preferred Ry groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl,. piperidinyl, morpholinyl,' piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl' such as methoxymethyl or 15 methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl. The R2 and R 2 ' groups of formula IlIb may be 20 taken together to form a fused ring; thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIIb 25 compounds having a pyrazole-containing bicyclic ring system: NH HNN N R N ,NH NH NH $''YH R N 0-R , N ,and -128 Preferred substituents on the R 2

/R

2 ' fused ring of formula IIIb include one or more of the following: -halo, -N (R") 2, -CI-4 alkyl, -CI-4 haloalkyl, -NO2, -O (CI..4 5 alkyl) , -C02 (Cl-4 alkyl) , -CN, -SO 2 (C1--4 alkyl) ,- -SO 2

NH

2 , -OC (O) NH 2 , -NH 2

SO

2

(C

1 4 alkyl), -NHC (0) (C.4 alkyl), -C (0) NH2, and -CO (C 1 .4 alkyl), wherein the (CI.4 alkyl) -is a straight, branched, or cyclic alkyl group. Preferably, the (C- 4 alkyl) group is methyl. 10 When the pyrazole ring system of. formula IIIb is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-5 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, 15 cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R 2 ' group is hydrogen. When Ring D of formula~IIIb is monocyclic, -preferred Ring D groups include phenyl, pyridyl, 20 pyridazinyl, pyrimidinyl, and pyrazinyl. When Ring D of formula IlIb is bicyclic, preferred bicyclic Ring D 'groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b) furyl, 25 benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula IIIb, preferred T-R 5 or V-Z-R substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , 30 optionally substituted C1-6 aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH(R4), -N(R 4 ) COR, -N (R4) CO 2 R, -SO 2 N (R4) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R4) 2 , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2 , and

-N(R

6 )COCiH 2

CH

2 N(R) 2 , wherein R is selected from -129 hydrogen, C-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, 5 -NHSO 2 Et, -NHSO 2 (n-propyl),- -NHSO2.(isopropyl), -- NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH3) 2,

-NHCOCH

2

CH

2 N (CH) 2, -NHCOCH 2

CH

2

CH

2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 -(morpholin-4 yl), -NHCOCH 2 CH2(morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin 10 4-yl), -NHC0 2 (t-butyl), -NH(C 1 4 aliphatic) such as -NHMe,

-N(C.

4 aliphatic) 2 such as -NMe 2 , OH, -O(C.4 aliphatic) such as -OMe, C1-4 aliphatic such as methyl, ethyl, cyclopropyl,. isopropyl, or t-butyl, and -C02(C4 aliphatic). 15 Preferred formula IIIb compounds have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX is hydrogen, alkyl- or dialkylamino, acetamido, or a C 1

.

4 aliphatic group; 20 (b) Ry is T-R 3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R4) 2 , or -OR; (c) R3 is T-(Ring D), wherein T is a valence bond or a methylene unit; (d) Ring D is a 5-7 membered monocyclic or an 8-10 25 membered bicyclic aryl or heteroaryl ring; and (e) R 2 is -R or -T-W-R 6 and R' is hydrogen, or R 2 and . 2' are taken together to form an optionally substituted benzo ring. More preferred compounds of formula II1b have 30 one or more, and more preferably all, of the features selected from the group consisting of: (a) RI is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, -130 or -N(R 4

)

2 , wherein R is selected from hydrogen, C1-.. aliphatic, or 5-6 membered heterocyclyl,. phenyl, or 5-6 membered heteroaryl; (b) R' is T- (Ring D) , wherein T is a valence bond; 5 (c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; (d) R 2 is -R.and R 2 ' is hydrogen, wherein R is selected from hydrogen, C 1

.

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered 10 heterocyclic ring; and (e) L is -0-, -S-, or -N.(R 4 )-. Even more preferred compounds of formula 'IIb have one or more, and more preferably all, of the features selected from the group consisting of: 15 (a) R is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido; (b) RE is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, 20 piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; 25 (c) RI is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, -CN,

-NO

2 , -N(R 4

)

2 , optionally substituted

C

1

..

6 , 30 aliphatic group, -OR, -CO 2 Ri -CONE (R4), -N (R') COR, -N (R") SO 2 R, -N (R 6 ) COCH 2 CH2N (R 4

)

2 , or -N (R5) COCH 2

CH

2

CH

2 N (R 4 ) 2; and -131 (d) R 2 is hydrogen or a substituted or unsubstituted

C

1

-

6 aliphatic, and L is -0-, -S-, or -NH-. Representative compounds of formula IIb are shown below in Table 6. Table 6. HNV HH Q~$OSOCOaMe IITb-1 IIIb-2 IIIb-3 HN HN HN NO , e O (: Me 0 IIIb-4 IIIb-5 IIIb-6

HN

4 H HN 4 HN 4 P e N MeN M OI MeN ) -j5--Tb IIIb-7 IIIb-8 tIb-9 -132 Me Me Me HN<H HN<H HN 4 P O O NHAC Me Ne N H HN HN Ht~ IIIb-13 IIIb-14 IIlb-15 Me Me Me H He HN i-- H HNA H HN H N'N N OPr NH Et N0 vdr).bO cN Yne 0 IIIb-13 IIIb-14 IITb-18 Me Me Me

HN

4 P H A HN H HN H NN ,'N - .Pr NNE, Me O1 NHNV O Qiu H% N NaN N 0 IIIb-19 IIIb-17 IIIb-21 Me Me Me

HN

4 HP HNJ$ H HNH ONHH NHAc N. Me IIbN INl2INIUb-24 IIIb-19 IIIb-20 -IIIb-21 Me Me Me MOr NcNHAO NHAc _N N 02 IIlb-22 IIIb-23 Ib2 -133 Me Me Me H~ HH HN < H NMe 2 HN HN<p NO ( N OHNO % f MeO&$ C CI IIIb-25 IIIb-26 IIIb-27 Me- Me Me HHNH HN H N Hl HN PH 'N IN4T (N 4 O N 0 N ON Me.N 2 O Me C1 IIIb-28 IIIb-29 IIIb-30 In another embodiment, this invention provides a composition comprising a compound of formula IlIb and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5. method of treating or preventing an -Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises. administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula I1b or a pharmaceutical composition 10. thereof. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula11b or a composition comprising said 15 compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises -134 administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIb or a pharmaceutical composition thereof. One aspect of this invention relates to a 5 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 11b or a pharmaceutical composition thereof. This 10 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 15 phosphorylation of -catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a: method'of inhibiting GSK-3 activity in a patient, which, method comprises administering to the patient a compound 20 of formula IIb or a composition comprising said compound.. Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological.sample with the 25 Aurora-2 or GSK-3 inhibitor of formula IIIb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of 30 a disease alleviated thereby, is preferably carried out with a preferred compound of formula IIIb, as described above.

-135 Another embodiment of this invention relates to compounds of formula IlIc: HN N H 5 Ilc or a pharmaceutically acceptable derivative or prodrug - thereof, wherein: RX and RY are independently selected from T.-R 3 or L-Z-R 3 ; 10 R' is T- (Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl -or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected 15 from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of .Ring D is independently substituted by oxo, T-R 5 , or V-Z-R, and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ; 20 T is a valence bond or a C 1

-

4 alkylidene chain; Z is a C 1

.

4 alkylidene chain; L is -0-, -S-, -SO-, -S02-, -N(R)S0 2 -, -SO 2

N(R

6

)-,

-N(R

6 )-, -CO-, -C0 2 -, -N(R 6 )CO-, -N(R 6 )C(O)O-, -N(R')CON(R)-, -N(Rt)So 2

N(R

6 )-, -N(R 6 )N(R) -, 25 -C(Q)N(R)-,

-OC(O)N(R

6 )-, -C(R 6

)

2 0-,--C(R")2S-,

-C(R)

2 SO-, -C(R') 2 So 2 -, -C(R 6

)

2 S0 2 N(R)-, -C(R6) 2

N(R

6 )-,

-C(R)

2

N(R

6 )C(O)-, -C(R 6

)

2

N(R

6 )C(0)0-, -C(R 6

)=NN(R

6

)-,

-136

-C(R

6 )=N-O-, -C(R 6

)

2

N(R')N(R

6 )-, -C(RE)2N(RE)SO 2 N(R)-, or - C (R 6 ) 2 N (R 6 ) CON (R') - ; R2 and R 2 ' are independently selected from -R, -T-W-R , or

R

2 and R 2 ' are taken together with their intervening 5 atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring .having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R 2 ' is independently substituted by halo, oxo, 10 -CN, -NO 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ;

R

3 is selected from -R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR, 15 -N (R 4

)

2 , -CON(R') 2 , -SO 2 N(RT ) 2 , -OC(=O)R, -N(R 7 ) COR, -N(R C0 2 (Cj- 6 aliphatic), -N(R) N (R) 2 , -C=NN(R) 2 , -C=N-OR, -N(R')CON(R 7

)

2 , -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 20 optionally substituted group selected from C3 aliphatic, C6-1o 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 , -COR, 25 -CO2 (optionally substituted C.-- aliphatic), -CON(Rb) 2 , or -S0 2 R ; each R 5 is independently selected from -R, halo, -OR, -C(=o)R, -C0 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N (R 4

)

2 , -CON(R 4

)

2 , -SO2N(R4) 2 , -OC(=O)R, -N(Rt)COR, 30 -N(R 4 )C02 (optionally substituted C..r aliphatic),

-N(R

4 ) N (R 4 ) 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 ) SQ 2 R, or -OC (=0) N (R4)2; -137 V is -0-, -S-, -SO-, -S02-, -N(R 6

)SO

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

-N(R

6 )-, -CO-, -C02-, -N(R 6 )CO-, -N(R 6 )C(0)0-,

-N(R

6

)CON(R

6 ) -, -N(R 6 )S02N(R 6 )-, -N(R 6

)N(R

6 )-,

-C(O)N(R

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

)

2 0-, -C(R 6 )2S-, 5 -C(R) 2 SO-,. -C(R 6 )2SO 2 -, -C(R 6

)

2

SO

2 N(R ) -, -C(,R')2N(R')-,

-C(R

6

)

2 N(R')C(O)-,

-C(R

6

)

2

N(R

6 )C(0)0-, -C(R)=NN(R 6 ) -,

-C(R

6 )=N-O-, -C(R 6

)

2 N(R6)N(R 6 )._-, -C(R) 2 N (R 6 ) S0 2

N(R

6 ) - or -C (R 6 ) 2 N (R 6 ) CON (RS) -; W is -C(R)20-, -C(Rt) 2 s-, -C(R') 2 SO-, -C(R 6 )2SO 2 -, 10 -C(R4)2SO2N(R6)-, -C(R6)2N(R4)-, -CO-, -CO2-, -C(R')OC(O) -, -C(R)OC(0)N (R) -, -C(R 6

)

2

N(R

6 )oO-,

-C(R

6

)

2

N(R

6 )C(0)0-, -C(R)=NN(R)-, -C(R)=N-O-,

-C(R)

2

N(R

6 )N.(R) -~, -C(R') 2

N(R')SO

2

N(R

6 ) -, -C (R) 2 N(R') CON(R) -, or -CON(R5) -; 15 each R 6 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; and 20 each R* is independently selected from hydrogen or an optionally substituted Ci-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. 25 Preferred RX groups of formula IlIc include hydrogen, alkyl- or dialkylamino, acetamido, or a CI4 aliphatic group such as methyl, ethyl, cyclopropyl,. or isopropyl. Preferred Ry groups of formula IIIc include T-R 3 30 or L-Z-R wherein T is a valence bond or a methylene, L is -0-, -S-, or -N (R) -, -C(R) 2 0-., -CO- and R -R,

-N(R

4

)

2 , or -OR. Examples of preferred RY groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, -138 morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino 5 or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl. The R 2 and R 2 ' groups of formula I1a may be taken together to form a fused ring, thus providing a 10 bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIIc compounds having a pyrazole-containing bicyclic ring 15 system: NH HN 'N N N \N -O\N Rxt NH NH NH ' NH FF N 'N-R' 'N''N'NN H , , , ,and Preferred substituents on the R 2

/R

2 - fused ring 20 of formula IIc include one or more of the following: -halo, -N (R 4 ) 2 , -Cl-4 alkyl, -C 1

.

4 haloalkyl, -N02, -0 (C 1

..

4 alkyl) , -CO 2

(C

1

.

4 alkyl) , -CNi -S0 2

(C

1

-

4 alkyl) , -SO 2

NH

2 , -OC (O) NH 2 , -NH 2 SO2 (C 1

.

4 alkyl) , -NHC (O) (C 1

.

4 alkyl), -C(0)NH 2 , and -CO(C 1

..

4 alkyl), wherein the (C 1

..

4 alkyl) is a 25 straight, branched, or cyclic alkyl group. Preferably, the (C..

4 alkyl) group is methyl. When the pyrazole ring system of formula IIIc is monocyclic, preferred R 2 groups include hydrogen or a -139 substituted or unsubstituted group selected from aryl, heteroaryl, or a C1_6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, 5 methoxypropyl, and benzyloxypropyl. - A preferred R 2 ' group is hydrogen. When Ring D of formula IIc is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. 10 When Ring D of formula IIc is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo [b] thiophenyl, indazolyl, benzothiazolyl, 15 cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl. On Ring D of formula IlIc, preferred T-R 5 or V-Z-R substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , optionally substituted C 1 L- aliphatic group, -OR, -C(O)R, 20 -CO 2 R, -CONH(R 4 )-, -N(R 4 )COR, -N(Rf)CO 2 R, -SO 2 N (R 4

)

2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4

)

2 , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2 , and

-N(R

6

)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is selected from hydrogen, C 1

_

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. 25 More preferred R substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHSO 2 Me,

-NHSO

2 Et , -NHSO 2 (n-propyl) , -NHSO 2 (isopropyl) , -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N ( CH 3 ) 2 ,

-NHCOCH

2

CH

2 N (CH 3 ) 2 , -NHCOCH 2

CH

2

CH

2 N (CH 3 ) 2 , 30 -NHcO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl), -NHCOCH 2

CH

2

CH

2 (morpholin 4-yl), -NHCO 2 (t-butyl), -NH(C 4 aliphatic) such-as -NHMe,

-N(C

4 aliphatic) 2 such as -NMe 2 , OH, -O(C-4 aliphatic) -140 such as -OMe, CI..4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C 1 .- 4 aliphatic). Preferred formula IlIc compounds have one or 5 more, and more- pre-ferably all, of the features selected from the group consisting of: (a) R is hydrogen, alkyl- or dialkylamino, acetamido, or.a C1.4 aliphatic group; (b) R is T-R 3 or L-Z-R 3 , wherein T is a VMlence bond 10 or a methylene and R 3 is -- R, -N(R4) 2 , or -OR; (c) R' is T- (Ring -D), wherein T is a valence bond or a methylene unit; (d) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and 15 (e) R 2 is -R or -T-W-R' 6 and R 2 ' is hydrogen, or R 2 and R 2 are taken together to form an optionally substituted benzo ring. More preferred compounds of formula IIIc have one or more, and more preferably all, of the features 20 selected from the group consisting of: (a) Ry is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, or -N(Rt) 2 , wherein R is selected from C 1

..

6 aliphatic, or 5-6 membered heterocyclyl, phenyl, 25 or 5-6 membered heteroaryl; (b) R 1 is T-(Ring D), wherein T is a valence bond; (c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; (d) R2 is -R and R 2 ' is hydrogen, wherein R is 30 selected from hydrogen, C1_6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is -0-, -S-, or -N(R 4

)-.

-141 Even more preferred compounds of formula IIc have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX is hydrogen methyl, ethyl, propyl, 5 - -cyclopropyl, isopropyl, methylamino or acetimido; (b) RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,. cyclopropyl, 10 isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; (c) R' is T-(Ring D), wherein T is a valence bond and 15 Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, -CN,

-NO

2 ,. -N(R 4

)

2 , optionally substituted

C.

6 aliphatic group, -OR, -CO 2 R, -CONH(R'), 20 -N (R 4 ) COR, -N(R 4 ) SO 2 R, -N(R 6 ) COCH 2

CH

2 N (R) 2 , or -N (R) COCH 2

CH

2

CH

2

N(R

4 ) 2; and (d) R 2 is hydrogen or a substituted or unsubstituted C,...s aliphatic, and L is -0-, -S-, or -NH-. Representative compounds of formula I1c are 25 shown below in Table 7.

-142 Table 7. Me N H HNH HN

HN

4 P HN 4 HN~ NN Me H H H IIIc-1 IIIc-2 IIIc-3 Me HN H HN HN H

-

I N N N -C H H H

NO

2 IIIc-4 IIIc-5 IIIc-6 Me Me 0

HN

4 P HN'HH' MeO - N L '- MeO N SONHj2 C l qlirN NaC MeNoNp-MeN N MeO Meo H OMe *OMe IIIc-7. IIIc-8 IlIc-9 Me Ph Mei N H HNp H HN 4 H Et NNNH Me NN C Et NC H H H IIIc-10 II~c-11 IIIc-12 -143 tBu Ph H H H HN HN HN N CN C N NO2

NO

2 IIIc-13 IIIc-14 IiIc-is - Ph Me Me Me H H H HN HN fHN N N N N _N Me N'ANN Me N NNH- Me N N > H H H II[c-16 IIIc-17 IIIc-18 Me Me Me HN PH HN H HN 4 H MeJ N 9 l M AN -C Me NN Me N Me N H H H IIIc-19 IIIc-20 IIIc-21 Me Me Me -N H -N HH.er H HIN -p HN HN MO NNMeOeO - -Meo" No H H H IIIc-22 IIIc-23 IIIc-24 -144 H - H HN H HN Me N J ' MeANLN S H H IIIc-25 IIIc-26 In another embodiment, this invention provides a composition comprising- a compound of formula IIe and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIlc or a pharmaceutical composition 10 thereof. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula Ilic or a composition comprising said 15 compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a 20 therapeutically effective amount of a compound of formula 11c or a pharmaceutical composition thereof. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, 25 which method comprises administering to the patient a therapeutically effective amount of a compound of formula -145 IIe 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 5 halting or slowing the -progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of 0-catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a 10 method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IIIc or a composition comprising said compound. Another aspect of this invention relates to a 15 method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula II1c or a pharmaceutical composition thereof. 20 Another aspect of the invention relates to inhibiting Src activity in a patient, which method comprises administering to the patient a compound of formula IlIc or a composition comprising said compound. Another method relates to inhibiting Aurora-2, 25 GSK-3, or Src activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2, GSK-3, or Src inhibitor of formula Ilc, or a pharmaceutical composition thereof, in an amount effective to Aurora-2, GSK-3, or Src. 30 Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, or Src, or the treatment of a disease alleviated thereby, is preferably -146 carried out with a preferred compound of formula IIIc, as described above. Another embodiment of this invention relates to compounds of formula Id: R 2 R 2 NH HNN RX N .R) N;'-Q'-Rl IId 5- or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Q' is selected from -C(R") 2 -, 1, 2 -cyclopropanediyl, 1,2 cyclobutanediyl, 'or 1,3-cyclobutanediyl; RX and RY are independently selected from-T-R 3 or L-Z-R 3 ; 10 Ri is T-(Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered' bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected 15 from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently' substituted by 6xo, T-R, or V-Z-R, and each substitutable ring nitrogen of Ring D is independently substituted by -R' 20 T is a valence bond or a C 1

..

4 alkylidene chain, wherein when Q' is. -C(R5') 2 - a methylene group of said C..4 alkylidene chain is optionally replaced by -0-, -S-,

-N(R

4 )-, -CO-, -CONH-, -NHCO-, -So 2 -, -SO 2 NH-, -NHSO 2 -, -C02-, -OC(O)-, -OC(O)NH-, or -NHCO 2 -; 25 Z is a CI.4 alkylidene chain; -147 L is -0-, -S-, -SO-, -SO2-, -N(R6)SO 2 -, -SO 2 N(R6)-, -N(R)-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(0)0-, -N(R)CON(R)-, -N(R 6

)SO

2

N(R

6 )-, -N(R)N(R 6 )-, -C(O)N(R)-, -OC(O)N(R4)-,

-C(R

6

)

2 0-, -C(R 6

)

2 S-, 5 -C(R)2SO-,

-C(R')

2

SO

2 -, -C(R 6

)

2

SO

2

N(R

6 )-, -C(R 6

)

2

N(R

6 )-,

-C(R

6

)

2 N(R)C(O) -, -C(R 6

)

2

N(R

6 ) C(0)0-, -C(R)=NN(R 6 ) -,

-C(R

6 )=N-0-, -C(R 6 ) 2 N(Rs)N(R 6 ) -, -0(R 6

)

2

N(R

6 ) SO 2

N(R

6 ) -, or -C (R 6 ) 2 N (R) CON (Rr) -;

R

2 and R 2 ' are independently selected from -R, -T-W-R 6 , or 10 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 ring carbon of said fused ring formed by 15 R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R, or -V-R6, and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R4;

R

3 is selected from -R, -halo, -OR, -C(=O)R, -C0 2 R, 20 -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR,

-N(R

4

)

2 , -CON(R 7

)

2 , -SO2N(R 7 ):, -OC (=0) R, -N (R') COR, -N(R7) C02 (C.

6 aliphatic) , -N (R4) N (R 4

)

2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R 7 )CON(R7) 2 , -N(R 7

)SO

2

N(R

7

)

2 , -N(R 4

)SO

2 R, or -OC(=0)N(R 7)2; 25 each R is independently selected from hydrogen or an optionally substituted group selected from CI.. aliphatic, C3.10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; 30 each R 4 is independently selected from -- R7, -COR 7 , -C02 (optionally substituted Ci-g aliphatic), -CON(R 7

)

2 , or -S0 2

R

7

;

-148 each R5 is independently selected from -R, halo, -OR, -C(=o)R, -CO 2 R, -COCOR, -NO2, -CN, -S(O)R, -SO 2 R, -SR,

-N(R

4

)

2 , -CON(R 4

)

2 , -S0 2

N(R

4

)

2 , -OC(=o)R, -N(R 4 ) COR, -N (R 4 ) C02 (optionally substituted C..6 aliphatic) , 5 -N(R 4

)N(R

4

)

2 , -C=NN (R4 2 , -C=N-OR, -N (R 4 ) CON (R 4

)

2 , -N(R4) SO 2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, or -OC (=0) N (R4) 2; V is -0-, -S-, -SO-, -SO2-, -N(R)S0 2 -, -SO 2

N(R

6 ) -,

-N(R

6 ) -, -CO-, -CO2-, -N(R') CO-, -N(R') C (0)0-, -N (R') CON (R') -, -N (R') SO 2 N (R') -, -N (R 6 ) N (R') -, 10 -C(O)N(R') -, -OC(O)N(R') -, -C(R')20-, -C(R') 2 S-,

-C(R')

2 SO-, -C(R') 2 S0 2 -, -C(R6) 2

SO

2 N(R6)-, -C(R') 2 N(R)-, - C(R') 2N (R,') C(O) -, - C(R) 2N (R') C (O)0-,- -C (R') =NN (R) - , -C(R')=N-O-, -C(R') 2 N(R')N(R')-, -C(R') 2

N(R')SO

2 N(R6)-, or -C (R') 2 N (R') CON (R') - ; 15 W is -C(R') 2 o-, -C(R') 2 s-, -C(R') 2 SO-, -C(R') 2 So 2 -, -C(R')2SO 2 N(R')-, -C(R') 2 N(R)-, -CO-, -CO2-, -C(R') OC(O)-, -C (R') OC (O)N(R') -, -C(R') 2 N (R4) CO-,

-C(R')

2 N(R')C(O)O-, -C(R6)=NN(R')-,

-C(R

6 )=N-O-,

-C(R')

2 N(R6)N(R')-, -C (R) 2 N(R) So 2 N(R')-, 20 -C (R6) 2 N(R') CON(R')-, or -CON(R6) -; each R 6 is independently selected from hydrogen or an. optionally substituted C1..4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered 25 heterocyclyl or heteroaryl ring; each R' is independently selected from hydrogen or a C1-4 aliphatic group, or two R' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring; and 30 each R7 is independently selected from hydrogen or an optionally substituted CI-6 aliphatic group, or two R 7 on the same nitrogen are taken together with the -149 nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring. Preferred RX groups of formula IIId include hydrogen, alkyl- or dialkylamino, acetamido, or a C1.4 5 aliphatic group -such-as methyl, ethyl, cyclopropyl, or isopropyl. Preferred RY groups of formula IId include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R) 2 0-, -CO- and R 3 is -R, 10 -N(R 4 )2, or -OR. Examples of preferred Ry groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl,. cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or 15 methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl. The R 2 and R 2 ' groups .of formula IIId may be 20 -taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IIId 25 compounds having a pyrazole-containing bicyclic ring system: ? NH N NN HN NN N ,NH NH NH NH Ry N CH 2 R ,and -150 Preferred substituents on the R 2

/R

2 ' fused ring of formula IIId include one or more of the following: -halo, -N(R 4

)

2 , -C1-4 alkyl, -CI4 haloalkyl, -NO 2 , -O(C..4 5 alkyl) ,. -C02 (C.4 alkyl) , --CN, --SO 2

(C.

4 alkyl) ,- -SO 2

NH

2 , -OC (0) NH2, -NH 2

SO

2

(C..

4 alkyl) , -NHC (O) (C14 alkyl) , -C(0)NH 2 , and -CO(Cl4 alkyl), wherein the (C1..4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C.

4 alkyl) group is methyl. 10 When the pyrazole ring system of formula IIId is monocyclic, preferred R2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Cls aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, 15 cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R2' group is hydrogen. When Ring D of formula IIId is monocyclic, preferred Ring D groups include phenyl, pyridyl, 20 pyridazinyl, pyrimidinyl, and pyrazinyl. When Ring D of formula Id is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzolbfuryl, 25 benzo[b)thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula IIId, preferred T-R 5 or

V-Z-R

5 substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , 30 optionally substituted Cz.6 aliphatic group,'-OR, -C(O)R,

-CO

2 R, -CONH (R4), -N(R4)COR, -N(R 4

)CO

2 R, -SO 2

N(R

4

)

2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R') 2 , -N (R 6 ) COCH 2

CH

2

N(R

4

)

2 , and

-N(R)COCH

2

CH

2

CH

2

N(R

4 ), wherein R is selected from -151 hydrogen, Cz-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred

R

5 substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me, 5 -NHSO 2 Et, -NHSO 2 (n-propyl),

-NHSO

2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N (CO 2 t-Bu) CH 3 , -NHCOCH 2 N (CH 3

)

2 ,

-NHCOCH

2

CH

2 N (CH 3 ) 2 , -NHCOCH 2

CH

2

CH

2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl),

-NHCOCH

2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4 -yl), -NHCOCH 2

CH

2

CH

2 (morpholin 10 4-yl) , -NHCO 2 (t-butyl) , -NH(C 1

.-

4 aliphatic) such as -NHMe,

-N(C

1

..

4 aliphatic) 2 such as -NMe 2 , OH, -O(C..4 aliphatic) such as -OMe, C1-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(Cl-4 aliphatic). 15 Preferred Q' groups of formula 1I1d include

-C(R

6

')

2 - or 1, 2 -cyclopropanediyl, wherein each R'' -is independently selected from hydrogen or methyl. A more preferred Q' group is -CH 2 -. Preferred formula 1I1d compounds have one or 20 more, and more preferably all, of the features-selected from the group consisting of: (a) RX is hydrogen, alkyl- or dialkylamino, acetamido, or a CO..4 aliphatic group; (b) Ry is T-R 3 or L-Z-R, wherein T is a valence bond 25 or a methylene. and R 3 is -R, -N(R4) 2 , or -OR; (c) R 1 is T- (Ring D), wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by -0-, -NH-, or -S-; (d) Ring D is a 5-7 membered monocyclic or an 8-10 30 membered bicyclic aryl or heteroaryl ring; and (e) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and R2' are taken together to form an optionally substituted benzo ring.

-152 More preferred compounds of formula 1I1d have one or more, and more preferably all, of the features selected from the group consisting of: (a) RY is T-R or L-Z-R 3 wherein T is.a valence bond 5 or a methylene and R 3 is selected -from -R, -OR, or -N(R4) 2 , wherein R is selected from hydrogen,

C.

6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; (b) R 1 is T-(Ring D), wherein T is a valence bond; 10 (c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; (d) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen,

C...

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered 15 heterocyclic ring; (e) L is -0-, -S-, or -N(R 4 )-; and (f) Q' is -C(R 6

')

2 - or 1,2-cyclopropanediyl, wherein each R"' is independently selected from hydrogen or methyl. 20 Even more preferred compounds of formula IIId have one or more, and more preferably all, of the features selected from the group consisting of: (a) R 1 is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or 25 acetimido; (b) R. is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, 30 alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; -153 (c) R' is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optiohally substituted with one to two groups selected from -halo, -CN, 5 -NO 2 , -N-(R4) 2 > optionally subs-tituted-C 1

.

6 aliphatic group, -OR, -CO 2 R, ~-CONH(R 4 ), -N (R') COR, -N (R') SO 2 R, -N (R 6 ) COCH 2

CH

2 N (R4) 2 , or -N (R 6 ) COCH 2

CH

2

CH

2 N (R4) 2; (d) R 2 is hydrogen or a substituted or unsubstituted 10 C1.3 aliphatic; and L is -0-, -S-, or -NH-; and (e) Q' is -CH 2 -. Representative compounds of formula 1I1d are shown below in Table 8. Table 8. Ph Ph ,H H 'H HN t N HN .N CI 'N CI 'N Me N Me NAQ 5 Oe IIId-1 IIId-2 IIId-3 Ph H HH MMe Me MedMe IIId-4 IIId-5 IIId-6 -154 0 0 Ph0 HNC JrNH HN AN _Nil MeN Me M MeN&o %CF IIld-7 IIId-8 IId-9 Me Me Me HNtp H HN NNH H N H HN pN E t E t E t O F IIld--10 IId--1 IIId-12 Me Ph Me gNH' EtYt M e M e N & OCl MC IIId-13 IIId-14 IIId-15 Me 7? Me H H'H HNHN HN .Me C Me I IId-16 IIld-17 IIId-18 -155 Me H Me Me HN41 H H Me N C1 HN HN Me N E IIId-19 IIId-20 IIId-21 Me Me Me HNP H HNP HN H Me- Et % Et IIId-22 IIId-23 IIId-24 In another embodiment, this invention provides a composition comprising a compound of formula 1I1d and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula 1I1d or a pharmaceutical composition 10 thereof. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IId or a composition comprising said 15 compound. Another aspect of this .invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a -156 therapeutically effective amount of a compound of formula -Id or a pharmaceutical composition thereof. One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering 5 blood levels of-glucose-in a patient-in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIId or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. 10 Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of $-catenin, which is useful for 15 treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises.administering to the patient a compound of formula IIld or a composition comprising said 20 compound. Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IId, or a 25 pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out 30 with a preferred compound of formula 1I1d, as described above. Another embodiment of this invention relates to compounds of formula IVa: -157 R2 N RIZ1 S-R' IVa 5 or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is nitrogen or C-R and Z 2 is nitrogen or CH, wherein one of Z' or Z 2 is nitrogen; R" and Ry are independently selected from T-R 3 or L-Z-R, 10 or R" and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused 15 ring formed by R" and Ry is independently substituted by oxo, T-R 3 , or L-Z-R, and each substitutable ring nitrogen of said ring formed by R" and RY is independently substituted by R 4 ; R' is T-(Ring D); 20 Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each 25 substitutable ring carbon of Ring-D is independently substituted by oxo, T-RS, or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently substituted by -R4; -158 T is a valence bond or a C.

4 alkylidene chain; Z is a C 1

.

4 alkylidene chain; L is -0-, -S-, -SO-, -SO2-, -N(R)SO 2 -, -SO 2

N(R

6 )-,

-N(R

6 )-, -CO-, -CO 2 -, -N(R 6 )CO-, -N(R 6 )C(0)0-, 5 -N (R') CON,(R 6 ) -, -N(R§)SO 2

N-(R

6 ).-, -N(R 6

)N(R

6

)-,

-C(O)N(R)-, -OC(0)N(R 6 )-, -C(R 6

)

2 0-, -C(R 6

)

2 S-,

-C(R

6

)

2 SO-, -C(R 6

)

2 SO2-, -C(R 6

)

2 S.0 2

N(R

6 )-, -C(R 6

)

2 N(R)-,

-C(R

6 )2N(R 6 )C(O)-, -C(R 6

)

2

N(R

6 )C(o)o-, -C(R 6

)=NN(R

6 )-, -C(R4)=N-O-, -C(RE) 2

N(R

6 )N(R) -, -C(R6)2N(R 6 )So 2 N (R') -, or 10 -C(R 6

)

2

N(R

6 )CON(R) -; R2 and R 2 ' are independently selected from -R, -T-W-R6, or R2 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 15 selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R2' is independently substituted by halo, oxo, -CN, -NO 2 , -R7, or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is 20 independently substituted by R 4 ;

R

3 is selected from -R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO2, -CN, -S(O)R, -S(O) 2 R, -SR,

-N(R

4

)

2 , -CON(R 7

)

2 , -SO 2

N(R

7

)

2 , -OC (=O) R, -N (R 7 )COR,

-N(R

7 )C02(C15 aliphatic), -N(R')N(R') 2 , -C=NN(R 4 )2, 25 -C=N-OR, -N(R 7 ) CON'(R 7

)

2 , -N(R7) 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 C.6 aliphatic, C-.io aryl, a heteroaryl ring having 5-10 30 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; -159 each R 4 is independently selected from -R7, -COR', -CO2 (optionally substituted C2.. aliphatic),

-CON(R

7

)

2 , or -S0 2 R; each Rs is independently selected from -R, halo, -OR, 5 -C(=0)R,

-C

2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N (R 4 ) 2 , -CON(R 4 ) 2 , -SO 2 N (R4) 2 , -OC(=o)R,

-N(R

4 ) COR,

-N(R

4 )C0 2 (optionally substituted C1-6 aliphatic), -N(R4)N(R 4

)

2 , -C=NN(R 4

)

2 , -0=N-OR, -N(R4)CON(R4) 2 ,

-N(R

4

)SO

2 N(R4) 2 , -N(R4)SO 2 R, or -OC(=0)N(R 4

)

2 ; 10 V is -0-, -S-, -SO-, -S02-, -N(R6)S0 2 -, -SO 2 N(R)-, -N(R')-, -CO-, -C02-, -N(R')CO-, -N(R')C(0)0-, -N(R')CON(R)-,

-N(R")SO

2 N(R')-, -N(R6)N(R6)-, -C(O)N(R')-, -OC(0)N(R)-, -C(R)20-, -C(R)2S-,

-C(R)

2 SO-, -C(R6) 2

SO

2 -, -C(R') 2

SO

2 N(R6)-, -C(R') 2 N (R)-, 15 -C(R') 2 N(R')C(O)-, -C(R6) 2 N(R')C(0)O-, -C(R)=NN(R)-, -C(R')=N-O-,

-C(R')

2 N(R)N(R)-,

-C(R)

2 N(R6)SO 2 N(R) -, or -C(R) 2 N (R6) CON (R)-; W is -C(R5) 2 0-, -C(R6) 2 S-, -C(R6) 2 SO-, -C(R') 2 so 2 -, -C(R6) 2

SO

2 N(R)-,

-C(R')

2 N(R)-, -CO-, -Co 2 -, 20 -C(R6)OC(o)-, -C(Rt)OC(O)N(R)-,

-C(R)

2 N(R)CO-, -C (R6) 2 N(R6) C(0)0-, -C(R 6 ) =NN(R4)-, -C(R')=N-O-, -C(Rt)2N(R')N(R')-,

-C(R')

2 N(R6)So2N (R)-,

-C(R)

2 N(R)CON(R6)-, or -CON(R)-; each R is independently selected from hydrogen or an 25 optionally substituted CI..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 30 optionally substituted C- aliphatic group, or two R' on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and -160 R' is selected from -R, halo, -OR, -C(=O)R,

-CO

2 R, -COCOR,

-NO

2 , -CN, -S(O)R,. -SO 2 R, -SR, -N(R4)2, -CON(R 4

)

2 ,

-SO

2

N(R

4

)

2 , -OC(=O)R,. -N(R4)COR, -N(R4) CO 2 (optionally substituted

C..

6 aliphatic),

-N(R

4

)N(R

4 ) 2 , -C=NN (R4) 2 , 5 -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 -OC (=O)N(R 4 ) 2 Preferred rings formed by RX and RY of formula IVa include a 5-, 6-, or- 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, 10 wherein said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVa are shown below. 2 RH Nt HN AHN 2 IVa-A IV'a-B IVa-C HNH HN HN HN"N R4, RksNct IVa-D IVa-E -IVa-F HN HN HN N N I - JaI IVa-J IVa-K IVa-L -161 HN> HN HN S z 2 (X: 2N z IVa-P IVa-R IVa-V HNA R . IVa-W More preferred pyridine ring systems of formula Iva include IVa-A, IVa-B, IVa-D, IVa-E, IVa-J, IVa-P, and IVa-V, most preferably IVa-A, IVa-B, IVa-D, IVa-E, and Iva-J. Even more preferred pyridine ring systems of 5 formula IVa are those described above, wherein Z' is nitrogen and Z 2 is CH. Preferred

R

1 groups of formula IVa include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1

.

4 aliphatic group such as methyl, ethyl, cyclopropyl, or 10 isopropyl. Preferred Ry groups of formula IVa include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 ) -, -C(R 6

)

2 o-, -CO- and R 3 is -R, -N (R4) 2, or -OR. Examples of preferred RY groups include 15 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino 20 or dimethylamino, alkyl- or dialkylaminoalkoxy such as -162 dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl. The ring formed when the RX and RY groups of formula IVa are taken together may be substituted or 5 unsubstituted. Suitable--sub~stituents -include.-R, halo, -O (CH 2 ) 2 -4-N (R 4 ) 2, -O (CH 2 ) 2

-

4 -R, -OR, -N (R4) - (CH 2 ) 2

-

4 -N (R 4 ) 2, -N (R 4 ) - (CH 2 ) 2

.

4 -R, -C (=0) R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(o)R,

-SO

2 R, -SR, -N(R 4

)

2 , -CON(R 4 ) 2 , -SO 2

N(R

4

)

2 , -OC(=o)R, -N (R 4 ) COR, -N(R 4 ) CO 2 (optionally substituted

C

1

.

6 10 aliphatic), -N(R4)N(R 4

)

2 , -C=NN(R 4

)

2 , -C=N-OR, -N (R4) CON (R 4

)

2 , -N(R 4 ) S0 2 N (R 4 ) 2 , -N (R4) SO 2 R, or

-OC(=O)N(R

4

)

2 , R and R 4 are as defined above. Preferred

R

1 /Ry ring substituents include -halo, -R, -OR, -COR,

-CO

2 R, -CON(R 4 ) 2, -CN, -O(CH 2

)

2

.

4

-N(R

4 ) 2, -O(CH 2 )2- 4 -R, , -NO 2 15 -N(R 4

)

2 , -NR4 COR, -NR 4

SO

2 R, -SO 2

N(R

4

)

2 wherein R is hydrogen or an optionally substituted C1- aliphatic group. The R 2 and R 2 ' groups of formula Iva may be taken together to form a fused ring, thus providing a bicyclic ring system containing-a pyrazole ring. 20 Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following. formula Iva compounds having a pyrazole-containing bicyclic ring system: NH I) II > N NNHN N N N N N N RV Z S-R', and -163 Preferred substituents on the R 2

/R

2 fused ring of formula Iva include one or more of the following: -halo, -N(R 4)2, -Cl-4 alkyl, -Cl-4 haloalkyl, -NO2, -O(Cl-4 alkyl) , -C02 (Ca.4 alkyl) , -CN, -S0 2

.(C-

4 alkyl) , -S0 2

NH

2 , 5 -OC (0) NH 2 , -NH 2

SO

2 (C4 alkyl) , -NHC (0) (C1-4 a-lkyl) , -C(o)NH 2 , and -CO(C 1 4 alkyl), wherein the (C.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 IVa is .10 monocyclic, preferred

R

2 groups include hydrogen or a substituted or unsubstituted-group selected from aryl, heteroaryl, or a Cls aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, 15 methoxypropyl., and benzyloxypropyl. A preferred

R

2 ' group is hydrogen. When Ring D of formula Iva is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. 20 When Ring D of formula IVa is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, 'benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[bifuryl, benzo[blthiophenyl, indazolyl, benzothiazolyl, 25 cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl. On Ring D of formula IVa, preferred T-Rs or V-Z

R

5 substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , optionally substituted Ces aliphatic group, -OR, -C(O)R, 30 -CO 2 R,. -CONH(R 4 ), -N(R 4 ) COR, -N(R 4 )C0 2 R, -SO 2

N(R

4

)

2 , -N(R4) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N(R6) COCH 2

CH

2 N (R4) 2 , and -N(R ) COCH 2

CH

2

CH

2 N (R4) 2 , wherein R is selected from hydrogen, Ce aliphatic, phenyl, a 5-6 membered -164 heteroaryl ring, or a 5-6 membered-heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO2 (n-propyl) , -NHSO 2 isopropyll) , -NHCOEt, 5 -NHCOCH 2

NHCH

3 ,- -NHCOCH 2 N (CO 2 t-Bu) CH3,- -NHCOCHzN (CH 3

)

2 ,

-NHCOCH

2

CH

2 N (CH 3 ) 2 , -NHCOCH 2

CH

2

CH

2 N (CH 3 ) 2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 y1), -NHCOCH 2

CH

2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin 4-yl), -NHCO 2 (t-butyl), -NH(C 1

-

4 aliphatic) such as -NHMe, 10 -N(C 1

..

4 aliphatic) 2 such as -NMe 2 , OH, -O(C1-4 aliphatic) such as -OMe, C-1-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO2(CI-4 aliphatic). Preferred Re groups of formula IVa, when 15 present, include R, OR, and N(R4) 2 . Examples of preferred Re include methyl, ethyl, NH 2 , NH 2

CH

2

CH

2 NH, N(CH 3

)

2

CH

2

CH

2 NH,

N(CH

3

)

2

CH

2

CH

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

CH

2 0, and NH 2

CH

2

CH

2 0. Preferred formula IVa compounds have one or more, and more preferably all, of the features selected 20 from the group consisting of: (a) RX is hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group and RY is 3 3 T-R3 or L-Z-R , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 )2, or -OR; or RX and 25 RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon 30 of said fused ring formed by RX and RY is independently substituted by oxo, T-R 3 , or L-Z

R

3 , and each substitutable ring nitrogen of said -165 ring formed by R and R -is independently substituted by R 4 ; (b) R" is T- (Ring D), wherein T is a valence bond or a methylene unit; 5 (c) Ring D--is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and R are taken together t-o form an optionally substituted benzo ring. 10 More preferred compounds of formula IVa have one or more, and more preferably all, of the features selected from the group consisting of: (a) -R is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, 15 or -N(Rt) 2 , wherein R is selected from hydrogen, Ci-s aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or RX and Ry are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, 20 cyclohepto, thieno, piperidino; or imidazo ring., wherein each substitutable ring carbon of said fused ring formed by RX and Ry is independently substituted by oxo, T-R 3 , or L-Z-R, and each substitutable ring nitrogen of said ring formed 25 by RX and Ry is independently substituted by.R 4 ; (b) R 1 is T-(Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8 10 membered bicyclic aryl or heteroaryl ring; (c) R 2 is -R and R 2 ' is hydrogen,- wherein R is 30 selected from hydrogen, C 1

_

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and -166 (d) R 3 is selected from -R, -halo, -OR, or -N(R4)2, wherein R is selected from hydrogen, C13. aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, 5 or -N(R4-.- Even more preferred compounds of formula IVa have one or more, and more preferably all, of the features selected from the group consisting of: (a) Rx is hydrogen methyl, ethyl, propyl, 10 cyclopropyl, isopropyl, methylamino or acetamido and RI is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, 15 alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or R and R are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or 20 cyclohexo ring, wherein said ring is optionally substituted with -halo, -R, -OR, -COR, -CO 2 R, -CON(R4) 2 , -CN, -O(CH 2

)

2

-

4

-N(R

4

)

2 , -O(CH 2

)

2

-

4 -R, -NO 2

-N(R*)

2 , -NR 4 COR, -NR'SO 2 R, or -S0 2

N(R

4

)

2 , wherein R is hydrogen or an optionally substituted C1..s 25 aliphatic group; (b) R 1 is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO 2 , -N(R 4

)

2 , 30 optionally substituted C3 aliphatic, -OR, -C(O)R, -CO 2 R, -CONH(R 4 ) -N (R 4 ) COR, -N (R 4 ) C 2 R,

-SO

2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N (R) COCH 2 N (R) 2 , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2 , or -N (R 6 ) COCH 2 CH2CH 2 N (R 4 ) 2

;

-167 (c) R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 1

-

6 aliphatic group, and R 2 ' is hydrogen; and (d) R 3 is selected from -R, -OR, or -N(R 4

)

2 , wherein 5 R is -selected from hydrogen, C 1

..

6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 , 10

-N(R

4

)

2 , optionally substituted C_ aliphatic group, -OR, -C(O)R, -CO 2 R, -CONH(R 4 ), -N(R4)COR, -- N(R)CO 2 R, -SO 2

N(R

4 ) 2 , -N (R4) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2

CH

2 N (R4) 2 , or

-N(R

6

)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is selected 15 from hydrogen, C 1

.

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. Representative compounds of formula IVa are shown below in Table 9. Table 9. Me HH HCrpH H NJ H HN ., NN Na N S IVa-1 IVa-2 IVa-3 -168 Me HN<

HN

4 r H X

H

4 H HN (~fl~.Ac & AS. N HN HN S N'cNS IVa-7 IVa-8 IVa-9 Me HN H H HN H HN H HN & St 0 S OMS IVa-10 IVa-ll IVa-12 In another embodiment 1 this invention provides a composition comprising a compound of formula IVa and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition 10 thereof . Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a -169 compound of formula Iva or a composition comprising said compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease 5 with a GSK-3 inhibitor, which method comprises administering to a patient in-need of such a treatment a therapeutically effective amount of a compound of formula Iva or a pharmaceutical composition thereof. One aspect of this invention relates to a 10 method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IVa or a pharmaceutical composition thereof. This method 15 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 20 phosphorylation of f-catenih, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound 25 of formula Iva or a composition comprising said compound. Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IVa, or a 30 pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of -170 a disease alleviated thereby, is preferably carried out with a preferred compound of formula IVa, as described above. Another embodiment of this invention relates to 5 compounds of formula-IVb: R12 R2NH HN N I ~Z2 Ryi Z O-OR' IVb 10 or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is nitrogen or C-Ra and Z 2 is nitrogen or CH, wherein one of Z 1 or Z 2 is nitrogen;

R

1 and RY are independently selected from T-R 3 or L-Z-R, 15' or RX and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused 20 ring formed by R' and Ry is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by RX and RF is independently substituted by R 4 ; R' is T-(Ring D); 25 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 -171 from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 , or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently 5 substituted by -- R 4 ; T is a valence bond or a C1.4 alkylidene chain; Z is a CI-4 alkylidene chain; L is -O-, -S-, -SO-, -S02-, -N(R 6 )S0 2 -, -SO 2

N(R

6 )-,

-N(R

6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(0)0-, 10 -N(R 6

)CON(R

6 )-, -N(R 6

)SO

2 N(R)-, -N(R')N(R 6 )-,

-C(O)N(R

6 )-, -OC(O)N(RG)-,

-C(R

6

)

2 o-, -C(R 6

)

2 S-,

-C(R)

2 SO-, -C(R 6

)

2

SO

2 -, -C(R4) 2

SO

2 N(R)-, -C(R') 2 N(R)-,

-C(R

6

)

2

N(R

6 )C(O)-, -C(R) 2 N(R)C(o)o-, -C(Rt)=NN(R)-,

-C(R

6 )=N-O-, -C(R') 2

N(R

6 )N(R)-, -C(R 6

)

2

N(R

6

)SO

2

N(R

6 )-, or 15 -C (R) N(R6) CON (R 6 ) -;

R

2 and R 2 ' are independently selected from -R, -T-W-R, or

R

2 and R2' are taken together with- their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms 20 selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R, or -V-R, and each substitutable ring nitrogen of said ring formed by Ra and R is 25 independently substituted' by R

R

3 is selected from -R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -COCH2COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -Sit,

-N(R

4

)

2 , -CON(R7)2, -S0 2

N(R

7

)

2 , -OC(=O)R, -N(R 7 )COR,

-N(R

7 )C0 2

(C..

6 aliphatic), -N(R 4

)N(R

4

)

2 , -C=NN(R 4

)

2 , 30 -C=N-OR, -N(R")CON(R') 2 , -N(R 7 ) SO 2 N (R 7

)

2 , -N(R')SO 2 R, or -OC(=0)N(R 7)2; each R is independently selected from hydrogen or an optionally substituted group selected from C1..6 -172 aliphatic, C6-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, -COR7, 5 -0O2 (optionally -substituted C1-6 aliphatic),

-CON(R)

2 , or -SO2R7; each R 5 is independently selected from -R, halo, -OR, -C(=o)R,

-CO

2 R, -COCOR,

-NO

2 , -CN, -S(O)R,

-SO

2 R, -S, -N (R 4 ) 2 , -CON(R ) 2 , -SO 2

N(R

4

)

2 , -OC(=o)R, -N(R)COR, 10 -N (R) CO 2 (optionally substituted C1-6 aliphatic), -N(R4)N(R4) 2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R 4 )CON(R4) 2 ,

-N(R

4

)SO

2

N(R

4

)

2 , -N(R 4

)SO

2 R, or -OC(=0)N(R)2; V is -0-, -S-, -SO-, -SO 2 -, -N(Rt)SO 2 -, -SO 2

N(R

6 )-,

-N(R

6 ) -, -CO-, -C02-, -N(R 6 )CO-, -N(R)C(O)0-, 15 .- N(R 6

)CON(R

6 )-, -N(R 6

)SO

2 N(R) -, -N(R 6 )N(R) -, -C(O)N(R)-,

-OC(O)N(R

6 )-, -C(R 6

)

2 0-, -C(R) 2 S-,

-C(R

6

)

2 SO-, -C(R6)2SO2-, -C(R) 2

SO

2

N(R

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

-C(RG)

2

N(R

6 )C(O)-, -C(R) 2

N(R

6 ) C(0)0-, -C(R6) =NN (RE)-, -C(R6)=N-O-, -C(R6) 2 N(RE)N(R6)-, -C(R') 2

N(R

6

)SO

2 N(R)-, or 20 -C(R) 2

N(R

6 )CON(Rs 6

)

W is -C(R6)20-,

-C(R

6

)

2 S-, -C(R6)2SO-, -C(R6)2SO2-,

-C(R)

2

SO

2

N(R

6 )-, -C(R 6

)

2

N(R

6 )-, -CO-, -C02-, -C(R 6 )OC(O)-, -C (R 6 ) OC(O)N(R)-, -C(R 6

)

2 N(R')CO-,

-C(R

6

)

2

N(R

6 )C(0)0-, -C(R5)=NN(R 6 ) -, -C(R) =N-O-, 25 -C(R4) 2

N(R

6 )N(R)-, -C(R6) 2

N(R

6 )S0 2 N(R) -,

-C(R

6

)

2

N(R

6 )CON(RY) -, or -CON(R 6 ) -; each R' is independently selected from hydrogen or an optionally substituted C.-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together 30 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 -173 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and Ra is selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR, 5 -NO 2 , -CN, -S(O)R, --SO 2 R, -SR, -N(R 4

)'

2 , -CON(R4) 2, -S0 2

N(R

4

),

2 , -OC(=O)R, -N(R 4 )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

4

)

2 , -N(R 4 )S0 2

N(R

4

)

2 , -N(R4)SO 2 R, or -OC(=)N(R) 2 . 10 Preferred rings formed by RX and R of formula IVb include a 5-, 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine 15 ring. Preferred pyrimidine ring systems of formula IVb are shown below. R2 QtR2 R2 NH HN-1 HN-? HHN IVb-A IVb-B IVb-C HNI3b HNL HNZb RRN N Z 2Z IM-D IVb-E IVb-F -174 HN HN? HN N Z IVb- IVb-K IVb-L HNN HN HN I -P IZb- IAb R IVb-P IVb-R ivb-V HN R IVb-W More preferred pyrimidine ring systems of formula IVb include IVb-A, IMb-B, IVb-D, IVb-E, IVb-J, IVb-P, and IVb-V, most preferably IVb-A, IVb-B, IVb-D, IVb-E, and IVb-J. Even more preferred pyridine' ring 5 systems of formula IVb are those described above, wherein Z' is nitrogen and Z 2 is CH. Preferred R? groups of formula IVb include hydrogen, alkyl- or dialkylamino, acetamido, or a C1.4 aliphatic group such as methyl, ethyl, cyclopropyl, or 10 isopropyl. Preferred Ry groups of formula IVb include T-R ~ or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6

)

2 0-, -CO- and R 3 is -R, -N{R4)2, or -OR. Examples of preferred R groups include -175 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or 5 methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted. phenyl. The ring formed when the RX and R groups of 10 formula Iba are taken together may be substituted or unsubstituted. -Suitable substituents include -R, halo, -O (CH 2 ) 2-4-N (R4 )2, -O(CH 2 )2- 4 -R, -OR, -N(R 4 ) - (CH 2 ) 2- 4

-N(R

4 )2,

-N(R

4

)-(CH

2

)

2

-

4 -R, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R 4

)

2 , -CON(R 4

)

2 , -SO 2

N(R

4

)

2 , 15 -OC (=O) R, -N (R 4 ) COR, -N(R 4 ) C02 (optionally substituted C1 aliphatic), -N(R 4

)N(R

4

)

2 , -C=NN(R4) 2 , -C=N-OR, -N (R 4 ) CON (R 4 ) 2 , -N (R4) SO 2 N (R) 2 , -N (R 4 ) SO 2 R, or -OC(=O)N(R4) 2 , R and R 4 areas defined above. Preferred

R

1 /RY ring substituents include -halo, -R, -OR, -COR, 20 -CO 2 R, -CON(R4) 2 , -CN, -O(CH 2

)

2

-

4

-N(R

4

)

2 , -O(CH 2

)

2

-

4 -R, , -NO 2 -N(R4 ) 2 , -NR 4 COR, -NR4S0 2 R, -SO 2

N(R

4

)

2 wherein R is hydrogen or an optionally substituted C1-6 aliphatic group. The R 2 and R 2 ' groups of formula IVb may be taken together to form a fused ring, thus providing a 25 bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IVb compounds having a pyrazole-containing bicyclic ring 30 system: -176 HN N, N R tK2NH NH NH NH RY ZtO-R ,and. Preferred substituents on the R 2

/R

2 ' fused ring of formula ZM include one or more of the following: -halo, -N(R 4

)

2 , -C 1

-

4 alkyl, -C.- 4 haloalkyl,

-NO

2 , -0(C 1

.

4 alkyl) , -C02 (C 1

.-

4 alkyl) , -CN, -S02 (C 1

.

4 alkyl) , -SO 2

NH

2 , 5 -OC (O) NH 2 , -NH 2 SO2 (C 1

..

4 alkyl) , -NHC (0) (C 1

.

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

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

4 alkyl) group is methyl. When the pyrazole ring system of formula IVb is 10 monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C-s aliphatic group. Examples of such preferred R 2 groups include hydrogen, methyl, ethyl, propyl, , cyclopropyl, i-propyl, cyclopentyl, 15 hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R 2 ' group is hydrogen. When Ring D of formula IM is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. 20 When Ring D of formula Ivh is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo[blthiophenyl, indazolyl, benzothiazolyl, 25 cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.

-177 On Ring D of formula IVb, preferred T-R 5 or

V-Z-R

5 substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , optionally substituted Cj-G aliphatic group, -OR, -C(O)R, -C0 2 R, -CONH(R 4 ), -N(R 4 ) COR, -N(R4) CO 2 R, -SO 2 N (R 4 ) 2 , 5 -N (R 4 ) SO 2 R, -N (R4) COC1 2 N (R4 ) 2 , -N (R 6 ) COCH 2

CH

2 N (R4) 2 , and -N(Rs)COCH 2

CH

2

CH

2 N(R4) 2 , wherein R is selected from hydrogen, C-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN, 10 -CF 3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAC, -NHSO 2 Me,

-NHSO

2 Et, -NHSO 2 (n-propyl) , -NHS0 2 (isopropyl) , -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2 N(C0 2 t-Bu) CH3, -NHCOCH 2 N(CH3)2,

-NHCOCH

2

CH

2 N (CH3) 2, -NHCOCH 2

CH

2

CH

2 N (CH3) 2, ?NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH2 (morpholin-4 15 yl), -NHCOCH2CH 2 (morpholin-4 -yl), -NHCOCH2C 2 0H 2 (morpholin 4-yl), -NHCO 2 (t-butyl) , -NH (C 1

-

4 aliphatic) such as -NHMe, -N(OCl-4 aliphatic) 2 such as -NMe 2 , OH, -O(C-4 aliphatic) such as -OMe, C1..4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(CI..

4 20 aliphatic). Preferred Re groups of formula IVb, when present, include R, OR, and N(R 4

)

2 . Examples of preferred Re include methyl, ethyl, NH 2 , NH2CH2CH 2 NH, N(CH 3 )2CH 2

CH

2 NH,

N(CH

3 ) 2CH2CH20, (piperidin-1-yl) CH2CH20, and NH 2 CH2CH200. 25 Preferred formula IVb compounds have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX is hydrogen, alkyl- or dialkylamino, acetamido, or a C1..4 aliphatic group and Ry is 30

T-R

3 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N (R 4 ) 2 , or -OR; or RX and R are taken together with their intervening atoms to form a fused, unsaturated or partially -178 unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RE and RY is 5 - independently substituted by oxo, T-R, or L-Z

R

3 , and each substitutable ring nitrogen of said ring formed by RE and Ry is independently substituted by R 4 ; (b) R2 is T- (Ring D), wherein T is a valence bond or 10 a methylene unit; (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and R2' are taken together to form an optionally 15 substituted benzo ring. More preferred compounds of formula IVb have one or more, and more preferably all, of the features selected from the group consisting of: (a) R 7 is T-R 3 or L-Z-R 3 wherein T is a valence bond 20 or a methylene and R 3 is selected from -R, -OR, or -N(R 4

)

2 , wherein R is selected from hydrogen, C3.-. aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or RE and RY are taken together with their intervening atoms 25 to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R 1 and RY is independently substituted by oxo, T-R 3 , or L-Z-R3, and each 30 substitutable ring nitrogen of said ring formed by RE and RY is independently substituted by R 4

;

-179 (b) R 1 is T- (Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an B 10 membered bicyclic aryl or heteroaryl ring; (c) R 2 is -R and R 2 ' is hydrogen, wherein R is 5 selected from hydrogen,.c- 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and (d) R 3 is selected from -R, -halo, -OR, or -N(R4)2, wherein R is selected from hydrogen, C.1- 6 10 aliphatic, or 5-6 membered heterocyclyl, phenyle or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R4) Even more preferred compounds of formula ib have one or more, and more preferably all, of the 15 features selected from the group consisting of: (a) RX is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl,.methylamino or acetamido and RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, 20 - piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or RX and 25 RY are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclohexo ring, wherein said ring is optionally substituted with -halo, -R, -OR, -COR, -CO 2 R,

-CON(R

4 ) 2, -CN, -O(CH 2 )2- 4

-N(R

4 )2, -O(CH 2

)

2

.

4 -R, -NO 2 30 -N(R 4 )2, -NR 4 COR, -NR'SO 2 R, or -SO 2 N(R4 ) 2 , wherein R is hydrogen or an optionally substituted C,.. aliphatic group; -180 (b) R 1 is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO 2 , -N(R 4

)

2 , 5 optionally substituted C1.6 aliphatic,. -OR, -C(O)R, -CO 2 R, -CONH(R 4 ), -N(Rt)COR, -N(R')C 2 R,

-SO

2 N (R 4 ) 2 , -N (R 4 ) SO 2 R, -N(R')COCH 2

N(R)

2 , . -N (R 6 ) COCH 2

CH

2 N (R4 ) 2 , or -N(R4)COCH 2

CH

2

CH

2 N(R4)2; (c) R 2 is hydrogen or a substituted or unsubstituted 10 group selected from aryl, heteroaryl, or a C1.. aliphatic group, and R 2 ' is hydrogen; and (d) R 3 is selected from -R, -OR, or -N(R4) 2 , wherein R is selected from hydrogen, CI-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered 15 heteroaryl, and L is.-O-, -S-, or -NH-; and (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 ,

-N(R

4

)

2 , optionally substituted C1. aliphatic group, -OR, -C(O)R, -CO 2 R, -CONH(R 4 ), -N(R 4 ) COR, 20 -N(R 4

)CO

2 R, -SO 2

N(R

4

)

2 , -N (R 4 ) S0 2 R, -N (R 6 ) COCH 2 N (R 4

)

2 , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2 , or -N(R6)COCH 2

CH

2

CH

2 N(R4) 2 , wherein R is selected from hydrogen, C1-6 aliphatic, phenyl,. a 5-6 membered heteroaryl ring, or a 5-6 membered 25 heterocyclic ring. Representative compounds of formula IVb are shown below in Table 10.

-181 Table 10. Me

HN

4 H H HN jO NAc CO N 0 IVb-1 IVb-2 IVb-3 Me HN HHN 4 H HH QNflrNAc ObNQ OMe -IVb-4 IVb-5 IVb-6 Me H HN H HN Ot tYNAc 'N IVb-7 IVb-8 IVb-9 Me HN HNSH H HN &NVN' &O OMe IVb-10 IVb-11 IVb-12 -182 Me HN HNItpH HNZ: Z tYO Z CN tN CN O CN IVb-13 IVb-14 IVb-15 Me HNPH N . J9CN IVb-16 In another embodiment, this invention provides a composition comprising a compound of formula IVb and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition 10 thereof-. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IVb or a composition comprising said 15 compound. Another aspect 'of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a 20 therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition thereof.

-183 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 5 therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in 10 halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of $-catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a 15 method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IVb or a composition comprising said compound. Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method' 20 comprises contacting the biological sample with the Aurora-2 or GSK-3 inhibitor of formula IMb, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. Each of the aforementioned methods directed to 25 the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IVb, as described above. Another embodiment of this invention relates to 30 compounds of formula IVc: -184 R22 N H HN N R Z' N-RI H IVC or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is nitrogen or C-Ra and Z 2 is nitrogen -or CH, wherein one of Z' or Z 2 is nitrogen; 5 R and R 7 are independently selected from T-R 3 or L-Z-R 3 , or Rx and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, 10 wherein each substitutable ring carbon of said fused ring formed by RX and Ry is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each- substitutable ring nitrogen of said ring formed by ax and Ry is independently substituted by R 4 ; 15 R' is T- (Ring D); Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected 20 from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R, or V-Z-R, and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 ; 25 T is a valence bond or a C1-4 alkylidene chain; -185 2 is a C1..4 alkylidene chain; L is -0-, -S-, -SO-, -SO2-, -N(RG)So 2 -, -SO 2

N(R

6 )-,

-N(R

6 )-, -CO-, -CO2-, -N(R 6 )CO-, -N(R 6 )C(O)O-,

-N(R

6 )CON(R)-, -N(R 6

)SO

2

N(R

6 )-, -N(R 6

)N(R

6 )-, 5 -C(O)N(R 6 )-, -OC(O)N(R 6 )-, -C(R) 2 0-, -C(R) 2 S-, -C(R) 2 SO-, -C(R 6

)

2 So 2 -, -C(R 6

)

2

SO

2

N(R

6 )-, -C(R 6 )2N(Ri)-,

-C(R')

2 N(R)C(0)-, -C(R) 2 N(R)C(0)o-, -C(RG)=NN(R)-,

-C(R

6 )=N-O-, -C(RE)2N(RG)N(R)-, -C(Rt) 2

N(R

6

)SO

2 N(R)-, or -C(RG)2N (R') CON (R") 10 R 2 and R 2 ' are independently selected from -R, -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 15 substitutable ring carbon of said fused ring formed by R 2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R 7 , or -V-R 6 , and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by R 4 ; 20 R 3 is selected from -R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S (O) R, -S(0)2R, -SR,

-N(R

4

)

2 , -CON(R 7 ) 2 , -S02N (R 7

)

2 , -OC(=Q)R, -N(R 7 ) COR,

-N(R

7 ) C02 (C1--S aliphatic), -N(R4)N(R 4

)

2 , -C=NN(R4) 2 , -C=N-OR, -N(R 7 ) CON (R') 2 , -N (R7) SO 2 N (R7) 2 , -N (R 4 ) S0 2 R, or 25 -OC(=0)N(R7)2; each R is independently selected from hydrogen or an optionally substituted group selected from C1..6 aliphatic, C 6

..

10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring 30 atoms; each R 4 is independently selected from -R, -COR, -C02 (optionally substituted C1-6 aliphatic), -CON(R 7

)

2 , or -S0 2

R;

-186 each R 5 is independently selected from -R, halo, -OR, -C(=o)R, -CO2R, -COCOR, -NO2, -CN, -S(o)R, -SO 2 R, -SR, -N (R 4 ) 2, - CON (R4) 2 , -SO 2 N(R4) 2 , -OC(=O)R, -N(R4) COR,

-N(R

4 ) C02 (optionally substituted C1.3 aliphatic), 5 -N (R 4

)N(R

4 ) 2, -C=NN (R 4

)

2 , -C=N-OR, -N(R 4 ) CON-(R 4 )2, -N(R4)SO 2

N(R)

2 , -N(R 4

)SO

2 R, or -OC(=O)N(R V is -0-, -S- 1 -SO-, -802-, -N(R')S0 2 -, -SO 2 N(R)-, -N(RG)-, -CO-, -C 0 2-, -N(R')CO-, -N(R6)C(O)O-, . -N(R6)CON(R6)-, -N(R6)SO 2 N(R6)-, -N(R)N(R6)-, 10 -C(O)N(R6)-, -OC(O)N(R')-, -C(R6) 2 0-, -C(R') 2 S-,

-C(R')

2 SO-, -C(R') 2

SO

2 -, -C(R') 2 S0 2 N(R')-, -C(R) 2 N(R6)-,

-C(R

6

)

2 N(R')C(O)-, -C(R) 6)2N(R)C(0)0-, -C(R)=NN(R6)-, -C(R')=N-O-, -C(R 6

)

2

N(R

6 )N(R')-, -C(R')2

N

(R')SO

2 N(R')-, or -C (R6) 2N (R") CON (R)-; 15 W is -C(R') 2 0-, -C(R) 2 S-, -C(R6) 2 SO-, -C(R6) 2

SO

2 -, -C(R4)2SO2N(R') -, -C(R6)2N(R6) -, -CO -, -C02-, -C(R')OC(O)-, -C(R6)OC(O)N(R)-, -- C(R') 2 N(R6)CO-,

-C(R

6

)

2 N(R')C(O)0-, -C(R6)=NN(R')-, -C(Rg)=N-O-, -C(R4) 2 N(R)N(R)-, -C(R) 2 N(R6)SO 2 N(R)-, 20 -C(R') 2 N(R')CON(R)-, or -CON(R)-; each R6 is independently selected from hydrogen or an optionally substituted C2.4 aliphatic group, or two R6 groups on the same nitrogen atom .are taken together with the nitrogen atom to form a 5-6 membered 25 heterocyclyl or heteroaryl ring; each R 7 is independently selected from hydrogen or an optionally substituted C,.. aliphatic group, or two R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclyl or 30 heteroaryl ring; and R8 is selected from -R, halo, -OR, -C(=0)R, -C0 2 R, -COCOR,

-NO

2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R 4

)

2 , -CON(R 4

).

2 , -S0 2

NM(R

4

)

2 , -OC(=0)R, -N(R 4 )COR, -N(R 4 )CO2 (optionally -187 substituted C 1

.

6 aliphatic), -N(R)N(R 4 ) 2 , -C=NN (R 4

)

2 , -C=N-OR, -N(R4)CON(R) 2 , -N(R 4 )SO2N(R 4

)

2 , -N(R4) SO 2 R, or

-OC(=O)N(R

4

)

2 . Preferred rings formed by RX and RY of formula 5 IVc-include a 5-, *E-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RetRY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVc are 10 shown below. z 2 NHHNH -R IVc-A ZVc-B IVc-C HN HN HN>7 R4'N2 R N z2 HN IVc-D IVC-E IVC-F HN.? HN3 HN3Z N Z2 N Z z I' -%2 J I, -KZ - Iz-L IVc-J IVc-K IVc-L -188 HNA H N HN S _Z20 N zi IVc-P IVc-R IVc-V HN? R IVc-W More preferred pyridine ring systems of formula IVc include IVc-A, IVc-B, IVc-D, IVc-E, IVc-J, IVc-P, and IVc-V, most preferably IVc-A, IVc-B, -IVc-D, IVc-E, and IVc-J. Even more preferred pyridine ring systems of 5 formula IVc are those described above, wherein Z- is nitrogen and Z 2 is CH Preferred RX groups of formula IVc include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1

..

4 aliphatic group such as methyl, ethyl, cyclopropyl, or 10 isopropyl. Preferred RY groups of formula IVc include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 )-, -C(R 6

)

2 0-, -CO- and R 3 is -R, -N(R4)2, or -OR. Examples of preferred Ry groups include 15 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino 20 or dimethylamino, alkyl- or dialkylaminoalkoxy such as' -189 dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl. The ring formed when the RX and Ry groups of formula Ivo are taken together may be substituted or 5 unsubstituted. -Suitable substituents include -R, halo, -O (CH 2 ) 2 -4 -N (R 4 ) 2, -O (CH 2 ) 2 -4-R, -OR, -N (R 4 ) - (CH 2 ) 2 -4 -N (R 4 ) 2,

-N(R

4

)-(CH

2

)

2

..

4 -R, -C(=O)R, -C0 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R 4

)

2 , -CON(R 4

)

2 , -SO 2

N(R

4

)

2 , -OC(=O)R, -N(R 4 )COR, -N(R 4 ) C02 (optionally stibstituted Cl.g 10 aliphatic), -N(R 4

)N(R

4

)

2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R4) CON(R 4 ) 2 , -N (R) SO 2 N (R 4

)

2 , -N (R 4 ) SO 2 R, or

-OC(=O)N(R

4

)

2 , R and R 4 are as defined above. Preferred Re/RY ring substituents include -halo, -R, -OR, -COR,

-CO

2 R, -CON(R4) 2 , -CN, -O(CH 2

)

2

.

4

-N(R

4

)

2 , -O(CH 2

)

2

-

4 -R, , -NO 2 15 -N (R4) 2 , -NR*COR, -NR 4

SO

2 R, -SO 2 N (R 4

)

2 wherein R is hydrogen or an optionally substituted C1..6 aliphatic group. The R 2 and R 2 ' groups of formula IVc may be taken 'together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. 20 Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IVc conipounds having a pyrazole-containing bicyclic ring system: NH HN N \N IN R tNH NH NH NH R) Z' N-R1 N N N' H , , , ,and -190 Preferred substituents on the R 2

/R

2 ' fused ring of formula IVc include one or more of the following: -halo, -N(R )2, -C1..4 alkyl, -CI-4 hal'oalkyl, -NO2, -O(C3 4 alkyl), -C0 2

(CI-

4 alkyl), -CN, -SO2(CI.

4 alkyl), -S0 2

NH

2 , 5 -OC (O) NH 2 , -NH 2

SO

2

(C,._

4 alkyl) , -NHC (O) (C1-4 alkyl) ,

-C(O)NH

2 ,- and -CO(C3.

4 alkyl), wherein the (C.4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (C 1

.

4 alkyl) group is methyl. When the pyrazole ring system of formula IVc is 10 monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1.. aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, 15 methoxypropyl, and benzyloxypropyl. A preferred R 2 ' group is hydrogen. When Ring D of formula IVo is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. 20 When Ring D of formula IVa is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzo(b]thiophenyl, indazolyl, benzothiazolyl, 25 cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl. On Ring D of formula IVo, preferred T-R 5 or V-Z-Rs substituents include -halo, -CN, -NO 2 , -N(R') 2 , optionally substituted C- 6 aliphatic group, -OR, -C(o)R, 30 -CO 2 R, -CONH(R 4 ), -N(R 4 ) COR, -N(R4)CO 2 R, -SO 2 N(R4) 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R 4 ) 2 , -N (R') COCH 2

CH

2 N (R 4 ) 2 , and -N (R 6 ) COCH 2

CH

2

CH

2 N(R4) 2 , wherein R is selected from hydrogen, C-s_ aliphatic, phenyl, a 5-6 membered -191 heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , '-NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO 2 (n-propyl), -NHSO 2 isopropyll), -NHCOEt, 5 -NHCOCH 2

NHCH

3 , -NHCOCH 2

N(CO

2 t-Bu)CH 3 , -NHCOCH 2

N(CH

3

)

2 ,

-NHCOCH

2

CH

2 N (CH 3

)

2 , -NHCOCH 2 CH2CH 2 N (CH 3

)

2 , -NHCO (cyclopropyl), -NHCO (isobutyl), -NHCOCH 2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl), -NHCOCH 2

CH

2

CH

2 (morpholin 4-yl), -NHCO 2 (t-butyl), -NH(C 1

-

4 aliphatic) such as -NHMe, 10 -N(Ci.- 4 aliphatic) 2 such as -NMe 2 , OH, -O(CI- 4 aliphatic) such as -OMe, C1-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -CO 2

(C

1

.

4 aliphatic). Preferred R 8 groups of formula IVc, when 15 present, include R, OR, and N(R4) 2 . Examples of preferred Re include methyl, ethyl, NH 2 , NH 2

CH

2

CH

2 NH, N(CH 3

)

2

CH

2

CH

2 NH, N(CH3) 2

CH

2

CH

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

CH

2 0, and NH 2

CH

2

CH

2 O. Preferred formula IVc compounds have one or more,-and more preferably all, of the features selected 20 from the group consisting of: (a) RX is hydrogen, alkyl- or dialkylamino, acetamido, or a CI-4 aliphatic group and RY is T-R' or L-Z-R, wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4

)

2 , or -OR; or RX and 25 Ry are -taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon 30 of said fused ring formed by R and Ry is independently substituted by oxo, T-R 3 , or L-Z

R

3 , and each substitutable ring nitrogen of said -192 ring formed by RX and RY is independently substituted by R; (b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit; 5 (c) Ring D is a-5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and R2' are taken together to form an optionally substituted benzo ring. 10 More preferred compounds of formula IVc have one or more, and more preferably all, of the features selected from the group consisting of: (a) RY is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -R, -OR, 15 or -N(R 4

)

2 , wherein R is selected from hydrogen,

C

1 -, aliphatic, or 5-6 membered heterocyclyl,. phenyl, or 5-6 membered heteroaryl; or RX and RY are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, 20 cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by RX and RY is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed 25 by RX and RY is independently substituted by R4; (b) R' is T-(Ring D), wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic.or an 8 10 membered bicyclic aryl or heteroaryl ring; (c) R 2 is -R and R 2 - is hydrogen, wherein R is 30 selected from hydrogen, Cj..

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and -193 (d) R 3 is selected from -R, -halo, -OR, or -N(R4)2, wherein R is selected from hydrogen, Ce6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, 5 or -N (R) Even more preferred compounds of formula IMe have one or more, and more preferably all, of the features selected from the group consisting of: (a) RX is hydrogen methyl, ethyl, propyl,. 10 cyclopropyl, isopropyl, methylamino or acetamido and RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, 15 alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or RX and Ry are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or 20 cyclohexo ring, wherein said ring is optionally substituted with -halo, -R, .-OR, -COR, -CO 2 R,

-CON(R)

2 , -CN, -O(CH 2 )2-4-N(R 4

)

2 , -O(CH 2

)

2

.

4 -R, -NO 2 -N(R4) 2 , -NR4doR, -NR 4

SO

2 R, or -SO 2

N(R

4

)

2 , wherein R is hydrogen or an optionally substituted Cl-6 25 aliphatic group; (b) R" is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO 2 , -N(R 4

)

2 , 30 optionally -substituted CIs aliphatic, .- OR, -C(O)R, -CO 2 R, -CONH(R 4 ), -N (R 4 ) COR, -N (R 4 ) CO 2 R,

-SO

2

N(R

4

)

2 , -N(R 4

)SO

2 R, -N(R 6

)COCH

2

N(R

4

)

2 , -N (R 6 ) COCH 2

CH

2 N (R 4

)

2 , or -N (R 6 ) COCH 2

CH

2

CH

2 N (R 4 ) 2

;

-194 (c) R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1.6 aliphatic group, and R 2 ' is hydrogen; and (d) R 3 is selected from -R, ~-OR, or -N(R) 2 , wherein 5 R is se-lected from hydrogen, C 1

-

6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; and (e) Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 , 10 -N(R 4

)

2 , optionally substituted C 16 .. aliphatic group, -OR, -C(O)R, -CO 2 R, -CONH(R4), .- N(R)COR,

-N(R

4 ) CO 2 R, -SO 2 N (R 4 ) 2, -N (R 4 ) SO 2 R, -N (R) COCH 2 N (R 4 ) 2 , -N (R 6 ) COCH 2

CH

2 N (R 4 ) 2 , or -N (R 6 ) COCH 2

CH

2

CH

2 N (R4) 2 , wherein R is selected 15 from hydrogen, C 1

..

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring. Representative compounds of formula IVc are shown below in Table 11. Table 11. Me HN-eH HN H HN911H H H NQN H IVc-1 IVc-2 IVc-3 -195 Me HN H HN H HN " HNH HN CIN N N N'ae IVc -7 IVc -8 IVc -9 HNS H H H H IVc-10 IVc-11 IVc-12 In another embodiment, this invention provides a composition comprising a compound of formula ZVc and a pharmaceutically acceptable carrier.. 5 Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a 10 compound of formula IVc or a pharmaceutical composition thereof . Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, -196 which method comprises administering to the patient a compound of formula IVa or a composition comprising said compound. Another aspect of this invention relates to a 5 method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVc or a pharmaceutical composition thereof. 10 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 15 IVc or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's 20 disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which 25 method comprises administering to the patient a compound of formula IVc or a composition comprising said compound. Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the 30 Aurora-2 or GSK-3 inhibitor of formula IVc, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.

-197 Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IVc, as described 5 above. Another embodiment of this invention relates to compounds of formula IVd: R 2 NH HNN NZ2 RY Z1 '-R1 IVd or a pharmaceutically acceptable derivative or prodrug thereof, wherein: 10 Z 1 is nitrogen or C-Ra and Z 2 is nitrogen or CH, wherein one of Z3 or Z 2 is nitrogen; Q' is selected from -C(R6') 2 -, 1,2-cyclopropanediyl, 1,2 cyclobutanediyl, or 1,3-cyclobutanediyl; RX and RY are, independently selected from T-R 2 or L-Z-Ra, 15 or RX and R are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused 20 ring formed by R and RY is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each substitutable ring nitrogen of said ring formed by R' and RY is independently substituted by R'; R2 is T-(Ring D); -198 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 5 from nitrogen, -oxygen or sulfur, wherein each substitutable ring carbon of Ring .D is independently substituted by oxo, T-R 5 , or V-Z-R, and each substitutable ring nitrogen of Ring D is independently substituted by -R'; 10 T is a valence bond or a C1.4 alkylidene chain, wherein when Q' is -C(R 6

')

2 - a methylene group of said C1.4 alkylidene chain is optionally replaced by -0-, -S-,

-N(R

4 )-, -CO-, -CONH-, -NHCO-, -SO 2 -, -SO 2 NH-, -NHSO 2 -, -Co 2

-

1 -OC(O)-, -OC(O)NH-, or -NHCO 2 -; 15 Z is a C1.4 alkylidene chain; L is -0-, -S-, -SO-, -SO2-, -N(R)SO 2 -, -S0 2 N(R6)-,

-N(R

6 ) -, -CO-, -C02-, -N(R') CO-, -N(R') C (0)0-, -N(R')CON (R') -, -N(R')SO 2 N(R') -, -N(R6)N(R 6 ) -, -C(O)N(R')-, -OC(O)N(R')-,

-C(R')

2 0-, -C(R') 2 S-, 20 -C(R6) 2 SO-, -C(R') 2

SO

2 -, -C(R') 2

SO

2 N(R')-, -C(R')2N(R')-,

-C(R')

2 N(R6)C(O)-, -C(R') 2 N(R)C(O)O-, -C(R')=NN(R')-, -C(R")=N-O-, -C(RS) 2 N(R')N(R)-, -C(R6) 2

N(R')SO

2 N(R)-, or -C (R') 2 N (R') CON(R') -;

R

2 and R 2 ' are independently selected from -R, -T-W-R6, or 25 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 ring carbon of said fused ring formed by 30 R2 and R 2 ' is independently substituted by halo, oxo, -CN, -NO 2 , -R7, or -V-R', and each substitutable ring nitrogen of said ring formed by R 2 and R 2 ' is independently substituted by RI; -199

R

3 is selected from -R, -halo, -OR, -C(=O)R, -C0 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(0) 2 R, -SR,

-N(R

4

)

2 , -CON(R 7

)

2 , -SO 2

N(R

7

)

2 , -OC(=O)R, -N(R 7 )COR, -N(R7) C02(C16 aliphatic),

-N(R

4

)N(R

4

)

2 , -C=NN(R4) 2 , 5 -C=N-OR, -N(R 7

)CON-(RZ)

2 , -N(R')S0 2

N(R

7

)

2 , -N(R 4

)SO

2 R, or -OC (=0) N(R7)2'; each R is independently selected from hydrogen or an optionally substituted group selected from C1.6 aliphatic, C-io aryl, a heteroaryl ring having 5-10 10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7 , -COR', -C02 (optionally substituted C1-6 aliphatic), -CON(R7) 2 , or -SO 2 R'; 15 each R9 is independently selected from -R, halo, -OR, -C(=O)R, -C0 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR,

-N(R

4

)

2 , -CON(R 4

)

2 , -SO 2

N(R

4

)

2 , -OC(=O)R, -N(R4)COR,

-N(R

4 ) C02 (optionally substituted Cl-15 aliphatic),

-N(R

4

)N(R

4

)

2 , -C=NN(R 4

)

2 , -C=N-OR, -N(R 4 )CON(R4) 2 , 20 -N(R 4

)SO

2

N(R

4

)

2 , -N(R 4

)SO

2 R, or -OC(=O)N(R4)2; V is -O-, ~-, -SO-, -S02-, -N(R 6 )S0 2 -, -SO 2 N(R) -,

-N(R

6 )-, -CO-, -C02-, -N(R.)CO-, -N(R 6 )C(0)0-,

-N(R

6 )CON(R)[-, -N(R 6

)SO

2 N(RD)-, -N(R 6 )N(R)-,

-C(O)N(R

6 )-, -OC(O)N(R 6 )-, .- C(R 6

)

2 0-, -C(R)2S-, 25 -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(Rt)-,

-C(R

6 ) 2

N(R

6 ) C(O) -, -C(R 6

)

2

N(R

6 )C(0)0-, -C(R 6 )=NN(R') -, -C(R')=N-O-, -C(R 6

)

2

N(R)N(R

6 )-, -C(R 6

)

2

N(R

6

)SO

2 N(R 6 )-, or -C (R.") 2 N (R 6 ) CON (R 6 ) -; W is -C(R 6

)

2 0-, -C(R 6

)

2 S-, -C(R 6

)

2 SO-, -C(R 6

)

2 S0 2 -, 30 -C(R 6

)

2

SO

2

N(R

6 ) -, -C(R 6

)

2

N(R

6 )-, -CO-, -C02-, -C(R)OC(O)-, -C(R 6

)OC(O)N(R

6 )-, -C(R) 2

N(R

6 )CO-,

-C(R

6 ) 2 N (R 6 ) C(0)0-, -C(R 6 ) =NN (R') -, -C (R') =N-O-, -200

-C(R')

2 N(R')N(R')-, -C(R 6

)

2

N(R

6

)SO

2 N(R)-,

-C(R

6

)

2 N(R')CON(R')-, or -CON(R)-; each R' is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group,-or two R 6 5 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 a C1.4 aliphatic group, or two R'' on the same carbon atom are 10 taken together to form a 3-6 membered carbocyclic ring; each R7 is independently selected from hydrogen or an optionally substituted CI-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 15 heteroaryl ring; and Re is selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR,

-NO

2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R 4

)

2 , -CON(R 4

)

2 ,

-SO

2 N (R4) 2 , -OC(=O)R, -N(R')COR, -N(R 4 ) C0 2 (optionally substituted C-6 aliphatic),

-N(R

4 )N(R4) 2 , -C=NN(R 4

)

2 , 20 -C=N-OR, -N(R 4

)CON(R

4

)

2 , -N(R 4

)SO

2

N(R

4

)

2 , -N(R 4 )S0 2 R, or

-OC(=O)N(R

4

)

2 . Preferred rings formed by RX and RI of formula IVd include a 5-', 6-, or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, 25 wherein said RE/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVa are shown below.

-201 R' R2 R2 HN>? HN3 Z2 Z2 tCH2Rt' IVd-A IVd-B IVd-C HN HN? HN>? R4 N R N Z IVd-D IVd-E IVd-P HN HN>? HN>? N Z N NN IVd-J IVd-K IVd-L HN HNN' HNdt IVd-P IVd-R IVd-V HN> '4 rs R IVd-W -202 More preferred pyridine ring systems of formula IVd include IVd-A, IVd-B, IVd-D, IVd-E, IVd-J, IVd-P, and IVd-V, most preferably IVd-A, IVd-B, IVd-D, IVd-E, and IVd-J. Even more preferred pyridine ring systems of 5 formula IVd include those described above, wherein Z' is nitrogen and Z2 is CH. Preferred RX groups of formula IVd include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1

.

4 aliphatic group such as methyl, ethyl, cyclopropyl, or 10 isopropyl. Preferred -RY groups of formula IVd include T-R3 or L-Z-R3 wherein T is a valence bond or a methylene, L is -0-, -S-, or -N(R 4 ) -, -C(R 6

)

2 0-, -CO- and R3 is -R, -N(R4)2, or -OR. Examples of preferred R groups include 15 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, mbrpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino 20 or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl. The ring formed when the RX and Ry groups of formula IVd are taken together may be substituted or 25 unsubstituted. Suitable substituents include -R, halo, -O (CH 2 ) 2- 4

-N(R

4 ) 2 , -O (CH 2 ) 2-4-R, -OR, -N(R 4 ) - (CH2) 2-4-N(R4) 2,

-N(R

4

)-(CH

2

)

2 -4-R, -C(=O)R, -C0 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R 4

)

2 , -CON(R 4

)

2 , -SO 2

N(R

4

)

2 , -OC(=O)R, -N(R 4 )COR, -N(R 4 ) C02 (optionally substituted Cj..6 30 al.iphatic), -N(R 4

)N(R

4

)

2 , -C=NN(R4) 2 , -C=N-OR, -N(R4)CON(R 4

)

2 , -N(R 4

)SO

2

N(R*)

2 , -N(R4)SO 2 R, or

-OC(=O)N(R

4

)

2 , R and R 4 are as defined above. Preferred RX/RY ring substituents include -halo, -R, -OR, -COR, -203

-CO

2 R, -CON(R 4

)

2 , -CN, -O(CH 2

)

2

-

4

-N(R

4

)

2 , -O(CH 2

)

2

-

4 -R, , -NO 2 -N (R4) 2 , -NR 4 COR, -NR 4

SO

2 R, -SO 2

N(R

4

)

2 wherein R is hydrogen or an optionally substituted C1,- aliphatic group. The R 2 and R 2 ' groups of formula IVd may be 5 taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring. Preferred fused rings include benzo, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring. These are exemplified in the following formula IVd 10 compounds having a pyrazole-containing bicyclic ring system:, N N N RX Z NH NH NH NH NN N N N' .Y Z XQ'-Rd,, and. Preferred substituents on the R 2

/R

2 - fused ring of formula IVd include one or more of the following: -halo, -N(R 4

)

2 , -C- 4 alkyl, -C- 4 haloalkyl, -NO 2 , -O(C 1 -4 15 alkyl) , -C02 (C3..4 alkyl) , -CN, -SO (C- 4 alkyl) , -S0 2

NH

2 , -OC (O) NH 2 , -NH 2

SO

2 (Cl- 4 alkyl) , -NHC (O) (C 1

-

4 alkyl) ,

-C(O)NH

2 , and -CO(C- 4 alkyl), wherein the (C 1

-

4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the (CI- 4 alkyl) group is methyl. 20 When the pyrazole ring system of formula IVd is monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1.

6 aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, 25 cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, -204 methoxypropyl, and benzyloxypropyl. A preferred R' group is hydrogen. When Ring D of formula IVd is monocyclic, preferred Ring D groups include phenyl, pyridyl, 5 pyridazinyl, -pyrimidinyl, and pytazinyl. When Ring.D of formula IVd is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo [b] furyl, 10 benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl,- quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl. On Ring D of formula IVd, preferred T-R 5 or

V-Z-R

5 substituents include -halo, -CN, -NO 2 , -N(R 4

)

2 , 15 optionally substituted CI.3 aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH(R),

-N(R

4 )COR, -N(R 4

)CO

2 R, -SO 2 N'(R4)t 2 , -N (R 4 ) SO 2 R, -N (R 6 ) COCH 2 N (R) 2 , -N (R') COCH 2

CH

2 N (R 4 ) 2 , and -N (R") COCH 2

CH

2

CH

2 N (R 4 ) 2 , wherein R is selected from hydrogen, Ci-6 aliphatic, phenyl, a 5-6 membered 20 heteroaryl ring, or a 5-6 membered heterocyclic ring. More preferred R 5 substituents include -Cl, -Br, -F, -CN,

-CF

3 , -COOH, -CONHMe, -CONHEt, -NH 2 , -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO 2 (n-propyl), -NHSc 2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 , -NHCOCH 2

N(CO

2 t-Bu)CH 3 , -NHCOCH 2

N(CH

3

)

2 , 25 -NHCOCH 2

CH

2 N (CH 3 ) 2 , -NHCOCH 2

CH

2

CH

2 N (CH2) 2, -NHCO(cyclopropyl), -NHCO(isobutyl),

-NHCOCH

2 (morpholin-4 yl), -NHCOCH 2

CH

2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin 4-yl), -NHCO 2 (t-butyl),

-NH(C

1

..

4 aliphatic) such as -NHMe,

-N(CI.

4 aliphatic) 2 such as -NMe 2 , OH, -O(C1.4 aliphatic) 30 such as -OMe, C1..4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C1.4 aliphatic).

-205 Preferred R 8 groups of formula IVd, when present, include R, OR, and N(R 4

)

2 . Examples of preferred R' include methyl, ethyl, NH 2 ; NH 2

CH

2

CH

2 NH, N(CH 3 )2CH 2

CH

2 NH, N (CH 3 ) 2

CH

2

CH

2 0, (piperidin-1-yl)

CH

2

CH

2 O, and NH 2

CH

2

CH

2 0. 5 Preferred-Q' groups-of-formula IVd -include -C(R'')2- or 1, 2 -cyclopropanediyl, wherein each R'' is independently selected from hydrogen or methyl. A more preferred Q' group is -CH 2 -. Preferred formula IVd compounds have one or 10 more, and more preferably all, of the features selected from the group consisting of: (a) RX is hydrogen, alkyl- or dialkylamino, acetamido, or a C1..4 aliphatic group and RY is T-R or L-Z-_R 3 , wherein T is a valence bond or a 15 methylene and R 3 is -R, -N(R 4

)

2 , or -OR; or RX and R are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur,'or 20 nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and Ry is independently substituted by oxo, T-R 3 , or L-Z

R

3 , and each substitutable ring nitrogen of said ring formed by RX and RY is independently 25 substituted by R4; (b) R' is T- (Ring D), wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by -O-, -NH-, or -S-; (c) Ring D is a 5-7 membered monocyclic or an 8-10 30 membered bicyclic aryl or heteroaryl ring; and (d) R 2 is -R or -T-W-R 6 and R 2 , is hydrogen, or R 2 and R2' are taken together to form an optionally substituted benzo ring.

-206 More preferred compounds of formula IVd have one or more, and more preferably all, of the features selected from the group consisting of: (a) Ry is T-R 3 or L-Z-R 3 wherein T is a valence bond 5 or a methylene and R 3 is selected from -R, -OR, or -N(R 4

)

2 , wherein R is selected from hydrogen, C1 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or R 1 and RY are taken together with their intervening atoms 10 to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by x and Ry is independently substituted by oxo, T-R 3 , or L-Z-R 3 , and each 15 substitutable ring nitrogen of said ring formed by R and Ry is independently substituted by R4; (b) R' is T- (Ring D) , wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8 10 membered bicyclic aryl or heteroaryl ring; 20 (c) R 2 is -R and R 2 ' is hydrogen, wherein R is selected from hydrogen,

C..

6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, .or a 5-6 membered heterocyclic ring; (d) R 3 is selected from -R, -halo, -OR, or -N(R4)2, 25 wherein R is selected from hydrogen,

C

1

.

6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -N(R 4 ) -; and (e) Q' is -C(R"') 2 - or 1, 2 -cyclopropanediyl, wherein 30 each R' is independently selected from hydrogen or methyl.

-207 Even more preferred compounds of formula IVd have one or more, and more preferably all, of the features selected from the group consisting of: (a) R is hydrogen methyl, ethyl, propyl, 5 cyclopropyl, -isopropyl, methylamino .or acetamido and RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, 10 alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or RX and Ry are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or 15 cyclohexo ring, wherein said ring is optionally. substituted with -halo, -R, -OR, -COR, -CO 2 R, -CON (R 4 ) 2, -CN, -O (CH 2 ) 2

-

4 -N (R4) 2, -O (CH 2 ) 24-R, -NO 2

-N(R

4

)

2 , -NR4COR, -NR 4

SO

2 R, or -SO 2

N(R

4

)

2 , wherein R is hydrogen or an optionally substituted

C

1

.

6 20 aliphatic group; (b) R3 is T- (Ring D) , wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups selected from -halo, -CN, -NO 2 , -N(Rt) 2 , 25 optionally substituted

C

1

..

6 aliphatic, -OR, -C(O)R, -CO 2 R, -CONH(R 4 ) , -N(R 4 ) COR, -N (R 4 ) CO 2 R,

-SO

2

N(R

4

)

2 , -N(R 4 ) So 2 R, -N (R) COCH 2 N (R 4

)

2 , -N (R 6 ) COCH 2 CHaN (R 4

)

2 , or -N (R 6 ) COCH 2

CH

2

CH

2 N (R4) 2 ; (c) R 2 is hydrogen or a substituted or unsubstituted 30 group selected from aryl, heteroaryl, or a CI.. aliphatic group, and R 2 ' is hydrogen; and (d) R 3 is selected from -R, -OR, or -N(R 4

)

2 , wherein R is selected from hydrogen, C._ 6 aliphatic, 5-6 -208 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is -0-, -S-, or -NH-; (e). Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 , S -N(R 4

)

2 ; optionally substituted C1_6 aliphatic group, -OR, -C(O)R, -C0 2 R, -CONH(R 4 ), -N(R 4 )COR, -N (R 4 ) CO 2 R, -SO 2 N (R 4

)

2 , -N (R 4 ) SO 2 R, -N (R) COCH 2 N (R 4 ) 2 , -N (R) COCHCH 2 N (R 4

)

2 , or

-N(R

6

)COCH

2

CH

2

CH

2 N(R4) 2 , wherein R is selected 10 from hydrogen, C- 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (f) Q' is -CH 2 -. Representative compounds of formula IVd are 15 shown below in Table 12. Table 12. ,N't HN H. 'XH HN HN HN IVd-1 IVd-2 IVd-3 Me Me Me HN H HN HHNr S C0dO IId Os IVd-4 IVd-5 IVd-6 -209 Me Me HN HNft OMe N Me IVd-7 -- IVd-8 In-another embodiment, this invention provides a composition comprising a compound of formula IVd and a pharmaceutically acceptable carrier. Another aspect of this invention relates to a 5 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition 10 thereof. Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IVd or a composition comprising said 15 compound. Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a 20 therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition thereof. One aspect of this invention relates to a method of enhancing glycogen-synthesis and/or lowering blood levels of glucose in a patient in need thereof, 25 which method comprises administering to the patient a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition thereof. This method -210 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 5 disease. 'Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia. Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which 10 method comprises administering to the patient a compound of formula IVd or a composition comprising said compound. Another method relates to inhibiting Aurora-2 or GSK-3 activity in a biological sample, which method comprises contacting the biological sample with the 15 Aurora-2 or GSK-3 inhibitor of formula IVd, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3. Each'of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of 20 a disease alleviated thereby, is preferably carried out with a preferred compound of formula IVd, as described above. The compounds of this invention may be prepared in general by methods known to those skilled in the art 25 for analogous compounds, as illustrated by the general Schemes I-VII, the general-methods that follow, and by the preparative examples below.

-211 Scheme I ,1 R2R R2 H RtH RXXN Rr - - RXH bH xH I N ' N I R N RI N1 HNN1 R NCI RY N£NQ-R 1 2 3 II Reagents: (a) EtOH, Et 3 N, room temperature; (b) R'-QH (Q = S, NH or 0) or R -CH2-M/catalyst (M is -Al or Mg or Sn, catalyst = Pd" or Ni*) Scheme I above shows a general route for the preparation of the present compounds. The dichlorinated starting material 1 may be prepared using methods similar 5 to the those reported in J. Indian. Chem. Soc., 61, 690 693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994). The reaction of 1 with aminopyrazole (or aminoindazole) 2 in a manner as described in Bioorg. Med. Chem. Lett, 10, 11, 1175-1180, (2000) or in J. Het. Chem, 21, 1161-1167, 10 (1984) provides the versatile monochloro intermediate 3. Conditions for displacing the chloro group of 3 by R 1 -Q will .depend on the nature of the Q.linker moiety and are generally known in the field. See, for example, J. Med. Chem, 38, 14, 2763-2773, (1995) (where Q-is an N-Link), 15 or Chem. Pharm. Bull., 40, 1, 227-229, (1992) (S-Link), or J. Het. Chem., 21, 1161-1167, (1984) (0-Link) or Bioorg. Med. Chem. Lett, 8, 20, 2891-2896, (1998) (C Link).

-212 Scheme II R2 R OH CR 2

R

4 H Rxa +X bR2 ~x RY NQ-R' R NkQ-Rl

H

2 N RY N Q-R 4 5 2 II Reagents: (a) POCl 3 , Pr 3 N, 110oC; (b) EtOH, Et 3 N, room temperature. Scheme II above shows an alternative route for the preparation of the present compounds. The starting material 4 may be prepared in a manner similar to that described for analogous compounds. See Chem. Heterocycl. 5 Compd., 35, 7, 818-820 (1999) (where Q is an N-Link), Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (0-Link) , J. Med. Chem., 23, 8, 913-918 (1980) (S-Link) , or Pharmazie, 43, 7, 475-476 (1988) (C-Link). The chlorination of 4 10 provides intermediate 5. See J. Med. Chem., 43, 22, 4288-4312 (2000) (Q is an N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (0-Link), J. Med. Chem., 41, 20, 3793-3803 (1998) (S-Link), or J. Med. Chem., 43, 22, 4288-4312 (2000) (C-Link). Displacement of the 4-Cl group in 15 intermediate 5 with aminopyrazole (or aminoindazole) 2 to provide compounds of this invention may be performed according to known methods for analogous compounds. See J. Med. Chem., 38, 14, 2763-2773 (1995) (where Q is an N Link), Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997) (0 20 Link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-Link), or J. Med. Chem., 41, 21, 4021-4035 (1998) (C Link).

-213 Scheme III R2 F OH C , RH H Rx N a -Rx 'N + R 2' H b R" HN it:- tNrkH INLSM RY N"S S-Me R AN% -Me H 2 N R NS-M 6 7 2 8 R F2 2R2 C HN H d H Rx~ R Fxf N RY N S*Me RN-R 9 Reagents: (a) POCl 3 ; (b) EtOH, Et 3 N, room temperature; (c) Oxone; (d) R2-QH (Q = S, NH or 0) or R--CH 2 -M/catalyst (M is Al or Mg or Sn, catalyst = Pd* or Ni*) Scheme III above shows another alternative route for preparing the present compounds. The starting material 6 may be chlorinated to provide intermediate 7. Displacement of the 4-chloro group in 7 with 5 aminopyrazole (or aminoindazole) 2 gives intermediate 8 which, upon oxidation of the methylsulfanyl group, provides the methylsulfone 9. The methylsulfonyl group of 9 may be displaced readily with R 1 -QH to give the desired product 1. See J. Ain. Chem. Soc., 81, 5997-6006 10 (1959) (where 0 is an N-Link)or in Bioorg. Med. Chem. Lett., 10, 8, 821-826 (2000) (S- Link).

-214 Scheme IV R2 OH C1 R1 2 R2:d H HQ<N - N + H b RH N HO N C N -Me H 2 N Ci N S-Me 10 11 2 12 c d H H ?V H Rx N Rx , N R RY NhS-Me RY N S Me RY R' 13 14 II Reagents: (a) POC1 3 ; (b) EtOH, Et 3 N, room temperature; (c) R-H (R = S, NH or 0) ; (d) oxone; (e) R 1 -QH (Q = S, NH or 0) or R -CH 2 -M/catalyst (M is Al or Mg or Sn, catalyst Pd* or Ni*) Scheme IV above shows a general route for the preparation of the present compounds wherein RY is a group attached to the pyrimidine core via a nitrogen, oxygen or 5 sulfur heteroatom. The starting 4,6-dihydroxy-2 methylsulfanylpyrimidine 10 may be prepared as described in J. Med. Chem., 27, 12, 1621-1629 (1984) . The chloro groups of intermediate 11 may be displaced sequentially with aminopyrazole (or aminoindazole) 2 and then with 10 another amine (or alcohol or thiol) following procedures similar to those reported in US Patent 2585906 (ICI, 1949). The methylsulfanyl group of 13 may then be oxidized to provide the methylsulfone 14. Displacement of the methylsulfonyl group of 14 gives the desired 15 product II.

-215 Scheme V Cl H' R2 H -R C l H2 H a Cl b x RX~ ZFl a Rxk b R~ + H R5NCI H 2 N"Fl 'N CI RY N 0 15 2 16 IV C1 t3 2 H N * H 2a b R.+ R H Cl H 2 N H aNCI b Q-R 17 2 18 IV Scheme V above shows general routes for the preparation of compounds of formulae IVa, IVb, IVc., and IVd. Steps (a) and (b) are analogous to the 5 corresponding steps described in Scheme I above. See Indian J. Chem. Sect. B, 34, 9, 1995, 778-790; J. Chem. Soc., 1947, 899-905; J. Chem. Soc., 34, 9, 1948, 777-782; and Indian J. Chem., 1967, 467-470. The synthetic transformations shown in Schemes 10 I-IV above are further illustrated by the following methods. Scheme VI a~R

R

6 ' R NR'NNb -RR1>$NH2 N1 NH Me'

'NH

2 19 20 21 -216 Scheme VI above shows a general route for preparing the aryl guanidine intermediate used to prepare compounds where Q is -C(R 6

)

2 -. The mono- or bis alkylation of 19 at step (a) to prepare compound 20 can S be -achieved by using methods substantially similar to those described by Jeffery, J. E., et al, J.- Chem Soc, Perkin Trans 1, 1996 (21) 2583-2589; Gnecco, D., et al, Org Prep Proced Int, 1996, 28 (4), 478-480; Fedorynski, M. and Jonczyk, A., Org Prep Proced Int, 1995, 27 (3), 10 355-359; Suzuki, S, et al, Can J Chem, 1994,. 71 (2) 357 361; and Prasad, G., et al, J Org Chem, 1991, (25), 7188 7190. The method of step (b) to prepare compound 21 from compound 20 can be achieved by using methods substantially similar to those described by Moss, R., et 15 al, Tetrahedron Lett, 1995, (48), 8761-8764 and Garigipati, R., Tetrahedron Lett, 1990, (14), 1969-1972. The aryl guanidine intermediates prepared according -to Scheme VI may then be used to prepare the ,compounds of this invention by the methods described in 20 the above Schemes I-V and by methods known to one skilled in the art. Scheme VII NH + 0 a NH2 b + c-S A 22 23 24 0 CC ZN. 25 26 Scheme VII above shows a general method that may be used to prepare compounds of formula II wherein Q -217 is 1,2-cyclopropanediyl. Compound 26 may then be used to prepare the desired amino-pyrazole compounds using the methods described above at Scheme I step (b). Method A. To a solution of 2,4 5 dichloroquinazoline (12.69g, 63mmol) and 3-amino-5 methylpyrazole (6.18g, 63mmol) in ethanol (220mL) is added triethylamine (8.13mL, 63mmol) and the reaction mixture is stirred for 3 hours at room temperature. The pale yellow precipitate is then collected by filtration, 10 washed with cold ethanol and dried under vacuum to give (2-chloroquinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl) amine. The above-prepared (2-chloroquinazolin-4-yl) (5-methyl-2H-pyrazol-3-yl)-amine (155 mg, 0.6 mmol) and 15 3-chloroaniline (0.316 mL, 2.99 mmol) are refluxed in tert-butanol (3 mL) over 20 h. The mixture is concentrated in vacuo and the residue is suspended in EtOH/H 2 0 (lmL/3mL). K2CO3 (83 mg, 0.6 mmol) is added and the suspension is stirred for 2h at room temperature. 20 The solid that forms is collected and dried under vacuum to give the product [ 2 -(3-chlorophenylamino)-quinazolin 4-ylj-(5-methyl-2H-pyrazol-3-yl)-amine. Method B. Sodium hydride (45 mg, 1.12 mmol) in THF (2 mL) is treated with 3-methoxyphenol (0.94g, 7.6 25 mmol) and the reaction mixture is stirred until effervescence ceases. The THF is removed in vacuo and the above-prepared (2-chloroquinazolin-4-yl)-(S-methyl 2H-pyrazol-3-yl)-amine (150 mg, 0.51 mmol)) is added. The reaction mixture is stirred at 1000C for 20 h, then 30 poured into aqueous K2C03 and stirred for 2h at room temperature. The.solid that forms is collected and re crystallized from ethanol to give the product [2-(3- -218 methoxyphenoxy)-quinazolin-4-ylJ-(5-methyl-2H-pyrazol-3 yl)-amine. Method C. To a solution of 4-hydroxy-2 phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus 5 oxychloride (1OmL) -is added--tripropy1amine (3.2 mL, 15.8 mmol) and the reaction mixture is heated for 30 minutes at 1100C. The excess phosphorus oxychloride is evaporated in vacuo, the residue is poured on ice cold aqueous NaHC0 3 and extracted with ethyl acetate. The 10 organic layer is washed with brine, dried, filtered and evaporated. The resulting residue is purified on flash chromatography (SiO 2 , hexane /AcOEt gradient) to give 4 chloro-2 -phenoxymethylquinazoline. To a solution of the above 4-chloro-2 15 phenoxymethylquinazoline (0.5 g, 1.85 mmol) in THF (30 mL) is added 3-amino-5-cyclopropylpyrazole (0.47 g, 3.69 mmol) and the reaction mixture is heated at 650C for 24 hours. Solvent is evaporated and ethanol is added. A white solid forms and is collected by filtration and 20 dried under vacuum to give (5-cCyclopropyl-2H-pyrazol-3 yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine. Method D. To a solution of the above-prepared (2-chloroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3 yl)-amine (123 mg, 0.43 mmol) in THF (5 mL) is added 25 NiCl 2 (dppp) (12 mg, 2.1.10~5 mol), followed by IM benzylmagnesium chloride in THF (2.15 mL, 2.15 mmol). The solution is heated at 500C for 20 hours and the reaction mixture is then quenched with aqueous NH 4 C1 and the product extracted in ethyl acetate. The solvent is 30 evaporated and the residue purified by flash chromatography to yield the desired (2-benzyl-quinazolin 4-yl)-(S-cyclopropyl-2H-pyrazol-3-yl)-amine.

-219 Method E. A solution of (2-chloroquinazolin-4 yl)-(5-methyl-2H-pyrazol-3-yl)-amine (200 mg, 0.77 mmol) and 4-acetamidothiophenol (644 mg, 3.85 mmol) is refluxed in tert-butanol (3 mL) over a 20 hour period. 5 Diethylether (10.mL) is added to the mixture and a solid forms that is collected by, filtration. This solid is suspended in EtOH/H 2 0 1mL/3mL), then K 2 C0 3 (110 mg, 0.8 mmol) is added and the suspension is stirred for 2h at room temperature. A solid forms and is collected and 10 dried under vacuum to give the product [2-(4 acetamidophenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2H pyrazol-3-yl)-amine. Method F. To a solution of 2,4-dichloro 5,6,7,8-tetrahydroquinazoline (500 mg, 2.46 mmol) and 3 15 amino-5-cyclopropylpyrazole (303 mg, 2.46 mmol) in DMF (10mL) is added triethylamine (0.357 mL, 2.56 mmol) followed by sodium iodide (368 mg, 2.46 mmol) and the reaction mixture.is heated at 90 *C for 20 h. The reaction mixture is partitioned between ethyl'acetate and 20 aqueous saturated NaHCO 3 . The organic layer is washed with brine and evaporated in vacuo. The residue is purified by flash chromatography (SiO 2 , hexane/AcOEt gradient) to give (2-chloro-5,6,7,8-tetrahydroquinazolin 4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine. 25 The above-prepared (2-chloro-5,6,7,8 tetrahydroquinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3 yl)-amine is reacted with 2-naphthalene mercaptan as described in Method L to yield the desired (5 cyclopropyl-2H-pyrazol-3-yl)-[2-(naphthalen-2 30 ylsulfanyl)-5,6,7,8-tetrahydroquinazolin-4-yl]-amine..

Method G. A solution of (5-cyclopropyl-2H pyrazol-3-yl)-[2-(3-methoxycarbonylphenylsulfanyl) quinazolin-4-yl]-amine (110 mg, 0.26 mmol) in a mixture -220 of THF/water (1/1, 10 mL) is treated with 1M LiOH (0.75 mL, 0.75 mmol). The mixture is stirred for 20 hours at room temperature and then neutralized with IM HCl (0.75 mL, 0.75 mmol). A solid forms and is collected by 5 filtration to afford the desired [2-(3- carboxyphenylsulfanyl) -quinazolin-4-yl] - (5-cyclopropyl 2H-pyrazol-3-yl)-amine. Method H. A solution of (2-(4 acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl]-(5 10 methyl-2H-pyrazol-3-yl)-amine (23 mg, S.54.10~5 mol) in dichloroethane (3 mL) is treated with IM BBr 3 in dichloromethane (222 pL, 2.21.10- mol). The mixture os heated at 80 "C for 4 hours before IM BBr 3 in DCM (222 IL, 2.21.10~4 mol) is added. The reaction mixture is heated 15 at 80 *C for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench residual BBr 3 . The solvent is evaporated in vacuo and this operation repeated 3 times. iM HC1(2 mL) is added to the solid residue and the.suspension stirred.at room 20 temperature for 15 hours. The solid is collected by filtration and suspended in a mixture water/EtOH (3/1, 8 mL). The mixture is neutralized with NaHCO 3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl 25 ether to give the desired [2-(4-acetamidophenylsulfanyl) 7-hydroxy-quinazolin-4-yll-(5-methyl-2H-pyrazol-3-yl) amine. Method I. To a solution of [2-(4 acetamidophenylsulfanyl) -7-hydroxy-quinazolin-4-yl] - (5 30 methyl-2H-pyrazol-3-yl)-amine (32 mg, 7.87.10-5 mol) in DMF (1~mL) is added potassium carbonate (65 mg, 4.72.10-4 mol) and the reaction mixture is heated to 80 *C. N-(3- -221 chloropropyl)morpholine (39 mg, 2.36.10'4 mol) is then added, and the mixture is stirred at 80 *C for 4 hours, cooled to room temperature and the solvent is evaporated. The resulting residue is purified by flash chromatography 5 to afford the desired [2-(4-acetamidophenylsulfanyl)-7 (3-morpholin-4-yl-propoxy) -quinazolin-4-yl] - (5-methyl-2H pyrazol-3-yl)-amine. Method J. To a solution of [2-(4-acetamido phenylsulfanyl)-7-nitroquinazolin-4-yl]-(5-methyl-2H 10 pyrazol-3-yl)-amine (147.mg, 3.38.104 mol) in methanol (5 ML) is added Pd/C 10% (40 mg) and the reaction mixture is treated with hydrogen at balloon pressure at 45 *C for 20 hours. The catalyst is filtered through a pad of celite which is then washed with dilute HC1. The combined 15 yellow filtrate is evaporated and the resulting solid residue is crystallized from methanol to afford the desired [2-(4-acetamido-phenylsulfanyl)-7 hydroxyaminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl) amine. 20 Method K. [2-(4-Acetamido-phenylsulfanyl)-7 nitroquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (182 mg, 4.18.104 mol) is dissolved in a mixture EtOH/water/AcOH (25/10/1, 36 mL) and the reaction is heated at 90 *C. Iron powder (93 mg) is added and the 25 mixture is stirred at 90 *C for 4 hours, cooled to room temperature and filtered through a pad of celite. The pad is washed with methanol and- the combined filtrate is concentrated in vacuo. The residue is purified by'flash chromatography (SiO 2 , DCM/MeOH gradient) to give the 30 desired [2-(4-acetamido-phenylsulfanyl)-7 aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

-222 Method L. To a solution of 2,4-dichloro-6 phenyl-pyrimidine (300 mg, 1.33 mmol) and 3-amino-5 methylpyrazole (129 mg, 1.33 mmol) in DMF (7 mL) is added triethylamine (195 JL, 1.40 mmol) followed by sodium 5 iodide (200 mg, 1:33 mmol) and the reaction mixture is stirred for 15 hours at 90 0 C. The resulting solution is partitioned between ethyl acetate and water and the organic phase washed with brine, dried over MgSO 4 then concentrated in vacuo. The residue is triturated in 10 methanol and the resulting white solid collected by filtration to afford (2-chloro-6-phenyl-pyrimidin-4-yl) (5-methyl-2H-pyrazol-3-yl)-amine (236 mg, 62%). The above prepared (2-chloro-6-phenyl pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60'mg, 15 0.21 mmol) is combined with 4-acetamidothiophenol (176 mg, 1.05 mmol) in tert-butanol (5 mL) and the mixture heated at reflux for 20 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHC 3 . The organic layer is washed 20 with brine, dried over MgSO 4 and concentrated in vacuo. The resulting residue is purified by flash chromatography (SiO 2 , DCM/MeOH gradient) to afford [2-(4-acetamido phenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2H pyrazol-3-yl)-amine (74 mg, 85%) 25 Method M. To a suspension of 4,6 dihydroxymercaptopyrimidine (8 g, 55 mmol) in a mixture of EtOH/water (1/1, 140 mL) is added NaOH (2.33 g, 58.3 mmol) followed by 4-methoxybenzyl chloride (7.90 mL, 58.3 mmol). The solution is stirred for 1.5 hours at 60 0 C 30 and then at room temperature for a further 6 hours. The resulting white precipitate is collected by filtration to give 4,6 -dihydroxy-2- (4-methoxy-benzylsulfanyl) pyrimidine.

-223 The above-prepared 4,6-dihydroxy-2-(4-methoxy benzylsulfanyl)-pyrimidine (2.5 g, 9.46 mmol) is suspended in POCl 3 (20 mL), and tripropylamine (3.60 mL, 18.9 mmol) is added dropwise to the mixture. T he 5 reaction is then heated at 110 *C for 4 hours. The brown solution is cooled to room temperature and the solvent is evaporated. The residue is poured on ice cold NaHCO 3 and the product is then extracted with ethyl acetate. The organic phase is dried over MgSO 4 , concentrated in vacuo 10, and the residue is purified by flash chromatography (Si0 2 , hexane/AcOEt gradient) to give 4,6-dichloro-2-(4-methoxy benzylsulfanyl)-pyrimidine. To a solution of above-prepared 4,6-dichloro-2 (4-methoxy-benzylsulfanyl)-pyrimidine (915 mg, 3.04 mmol) 15 and 3-amino-S-methylpyrazole (310 mg, 3.19 mmol) in BuOH (20 mL) is added diisopropylethylamine (0.56 mL, 3.19 mmol) followed by sodium iodide (455 mg, 3.04 mmol). The reaction mixture is stirred for 15 hours at 120 *C. The solvent is removed in vacuo and the residue is purified 20 by flash chromatography (SiO 2 , hexane/AcOEt gardient) to give [6-chloro-2-(4-methoxy-benzylsulfanyl)-pyrimidin-4 yl)-(5-methyl-2H-pyrazol-3-yl)-amine. The above-prepared [6-chloro-2-(4-methoxy benzylsulfanyl)-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3 25 yl)-amine (500 mg, 1.38 mmol) in 1-methylpiperazine (10 mL) is heated at 130 OC for 15 hours. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO 2 , dichloromethane/MeOH gradient) to give the desired product [2-(4-methoxy 30 benzylsulfany1j - 6-(4-methylpiperazin-1-yl)-pyrimidin-4 yl]-(5-methyl-2H-pyrazol-3-yl)-amine. Method N. A solution of (2-(4-acetamido phenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5- -224 methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10-4 mol) in dichloroethane (5 mL) is treated with IM BBr 3 in DCM (896 gL, 8.96.10 mol). The mixture is then heated at 80 0 C for 4 hours before IM BBr 3 in DCM (896 IL, 8.96.-10-4 mol) 5 is added. The reaction mixture is then heated at 80 0 C for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual BBr 3 . The solvent is evaporated in vacuo and this evaporation step is repeated 3 times. IM HC1(8 mL) is 10 added to the solid residue and the suspension is stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture of water/EtOH' (3/1, 24 mL). The mixture is neutralized with NaHCO 3 and stirred for 2 hours at room temperature. The solid is 15 then collected by filtration, rinsed with water and with diethyl ether to give [2-(4-acetamido-phenyl-sulfanyl)-6 (4-hydroxyphenyl) -pyrimidin-4-yl] - (S-methyl-2H-pyrazol-3 yl)-amine. To a solution of the above-prepared (2-(4 20 acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (70 mg, 1.62.1074 mol) in DMF (3 mL) is added potassium carbonate (134 mg, 9.71.10~4 moi). ~The reaction mixture is heated to 80*C before 1-dimethylamino-3-chloropropane hydrochloride (77 25 mg, 4.86.10~4 mol) is added. The mixture is stirred at 80*C for 4 hours, cooled to room temperature and the solvent is evaporated.. The -residue is purified by flash chromatography to afford the desired product {2-(4 acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylamino 30 propoxy)-phenyl]-pyrimidin-4-yl}-(5-methyl-2H-pyrazol-3 yl)-amine. Method 0. To a solution of (6-methoxycarbonyl 2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl)-(5- -225 methyl-2H-pyrazol-3-yl)-amine (2g, 4.85 mmol) in THF (100 mL) is added lithium borohydride (0.32 g, 14.5 mmol). The reaction mixture is stirred at 50*C for 1.5 hours. The reaction is then quenched with dilute HCl and 5 extracted with ethyl acetate. The organic layer is successively washed with aqueous saturated NaHCO 3 and brine, dried over MgSO 4 and evaporated. The solid residue is triturated in ethyl acetate and the resulting white solid is collected by filtration to give the desired 10 product [6-hydroxymethyl-2- (4-propionylamino-phenyl sulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) amine. Method P. To a solution of 4,6-dichloro-2 methylsulfanyl-pyrimidine (5 g, 25.6 mmol) and 3-amino-5 15 methylpyrazole 2.61 g, 26.9 mmol) in BuOH (60 mL) is added diisopropylethylamine (4.69 mL', 26.9 mmol) followed by sodium iodide (3.84 g, 25.6 mmol). The reaction mixture is stirred for 15 hours at 120 0C. The solvent is then removed In vacuo and the residue is purified by 20. flash chromatography (SiO 2 , hexane/AcOEt gradient) to give [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2H pyrazol-3-yl)-amine. The above-prepared [6-chloro-2-methylsulfanyl pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine .(2.42 g, 25 9.46 mmol) is heated in morpholine (10 mL) at 130 0C for 15 hours. The solvent is then removed in vacuo and the solid residue is triturated in EtOH and collected by filtration to give [2-methylsulfanyl-6-(morpholin-4-yl) pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine. 30 To a suspension of the above-prepared [2 methylsulfanyl-6-(morpholin-4-yl)-pyrimidin-4-yl)-(5 methyl-2H-pyrazol-3-yl)-amine (500 mg, 1.63 mmol) in MeOH (10 mL) is added a solution of oxone (3.0 g) in water (10 -226 mL). The reaction mixture is stirred at room temperature for 15 hours and most of the solvent is evaporated. The residue is partitioned between DCM and aqueous saturated NaHCO 3 . The organic layer is washed with brine, dried, 5 filtered and evaporated. The residue is triturated in MeOH and the resulting white solid is collected by filtration to give [2-methylsulfonyl-6-(morpholin-4-yl) pyrimidin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine. The above-prepared [2-methylsulfonyl-6 10 (morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3 yl)-amine (178 mg, 0.52 mmol) and 4-acetamidothiophenol (176 mg, 1.05 mmol) are refluxed in tert-butanol (5 mL) over' 20 h. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and 15 aqueous NaHCO 3 . The organic layer is washed with brine, dried over MgSO 4 and concentrated in vacuo.- The residue is purified by flash chromatography to give the desired 'product [2-(4-acetamidophenylsulfanyl)-6-(morpholin-4 yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine. 20 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. 25 SYNTHETIC EXAMPLES The following HPLC methods were used in the analysis of the compounds as specified in the Synthetic Examples set forth below. As used herein, the term "Rt" 30 refers to the retention time observed for the compound using the HPLC method specified.

-227 HPLC-Method A: Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones Chromatography. Gradient: 100% water (containing 1% acetonitrile, 5 0.1% TFA).to 100% acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100% acetonitrile for 1.4 min and return to initial conditions. Total run time 7.0 min. Flow rate: 0.8 mL/min. 10 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 15 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 20 Varian. Gradient: 99% water (0.1% TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water (0.1% TFA), 50% acetonitrile (containing 0.1% TFA) over 20 min, hold for 8.0 min and return to initial conditions. Total 25 run time 30 min. Flow rate: 1.0 mL/min. HPLC-Method D: Column: Waters (YMC) ODS-AQ 2.Ox5Omm, S5, 120A. Gradient: 90% water (0.2% Formic acid), 10% 30 acetonitrile (containing 0.1% Formic acid) to 10% water (0.1% formic acid), 90% acetonitrile (containing 0.1% formic acid) over 5.0 min, hold for -228 0.8 min and return to initial conditions. Total run time 7.0 min. Flow rate: 1.0 mL/min. 5 HPLC-Method E: Column: 50x2.Omm Hypersil C18 BDS;5 gm Gradient: elution 100% water (0.1% TFA), to 5% water (0.1% TFA), 95% acetonitrile (containing 0.1* TFA) over 2.1 min, returning to initial conditions after 10 2.3 min. Flow rate: 1 mL/min. Example 1 (5-Methyl-2E-pyrazol-3-yl)-(2-phenylsulfanyl quinazolin-4-yl)-amine (Ila-1): Prepared in a manner 15 similar to the above described Method E to afford a pale yellow solid, mp >300 0 C (dec.); 'H NMR (DMSO) 8 2.07(3H, s), 5.54(1H, s), 7.38(1H, m), 7.56-7.45(4H, m), 7.65(2H, m),- 7.73 (1H, m), 8.55(1H, d), 10.43(1H, s), 12.05(1H, br s); IR (solid) 3259, 3170, 3109, 1618, 1594, 1565, 1525, 20 1476; MS 334.0 (M+H)* Example 2 [2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-2): Prepared in a manner similar to the above described Method E to afford 25 a pale yellow solid, mp 259-260*C; 'H NMR (DMSO) 8 2.12 (3H, s), 5.40 (1H, s), 7.60 (1H, t),.7.64 (2H, d), 7.76 (3H, d), 7.92 (1H, t), 8.70 (1H, d) 11.50. (1H, br s); IR (solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339, 1286, 1219; MS 368.0 (M+H)* 30 Example 3 [2-(2, 4 -Dichlorophenysulfanyl)-quinazolin-4 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-3): Prepared in -229 a manner similar to the above described Method E to afford a pale yellow solid, mp 258-259OC; 1H NMR (DMSO) S 2.12 (3H, s), 5.40 (1H, s), 7.54 (1H, t), 7.63 (1H, m), 7.68 (iH, d), 7.86 (iH, t), 7.92 (1H, d), 7.96 (i , d), 5 8.66 (iH, d) 11.20 (1Hi- br s); IR (solid) 1623, 1610, 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0 (M+H)* Example 4 (2- (4-Methoxyphenylsulfanyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-4): Prepared in a 10 manner similar to the above described Method E to afford a pale yellow solid, mp 264-268oC; 1H NMR (DMSO) S 2.04 (3H, s), 3.85 (3H, s), 5.43 (iH, s), 7.12 (2H, d), 7.53 (1H, t), 7.61 (3H, d), 7.84 (3H, t), 8.63 (1H, d), 11.09 (iH, br s), 12.30 (iH, br s); IR (solid) 1622, 1598, 15 1552, 1492, 1404, 1340, 1292, 1249, 1219, 1171, 1161; MS 364.1 (M+H) 4 Example 5 [2- (2-Ethylphenylsulfanyl) -quinazolin-4-yl -(5 methyl-2H-pyrazol-3-yl)-amine (IIa-5): Prepared in a 20 manner similar to the above described Method E to afford a pale yellow solid, mp 205-208*C; 'H NMR (DMSO) 8 2.05 (3H, s), 5.19 (1H, S), 7.38 (1H, t), 7.52-7.64 (3H, m), 7.68 (2H, d), 7.90 (1H, t), 8.68 (1H, d); IR (solid) 3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403, 1344, 25 1294, 1224, 1162; MS 362.1 (M+H)* Example 6 {2-[ 2

,

4 -Bis(trifluoromethyl)phenylsulfanyl] quinazolin-4-yl}-(5-methyl-25-pyrazol-3-yl)-amine (IIa-6): Prepared in a manner similar to the above 30 described Method E to afford a pale yellow solid, mp >300 0 C; 1H NMR (DMSO) 8 1.98 (3H, s), 5.37 (iH, S), 7.50 (iH, t), 7.59 (2H, d), 7.84 (iH, d), 8.32 (iH, s), 8.40 -230' (2H, s), 8.66 (1H, d), .10.73 (1H, br s); IR (solid) 1628, 1603, 1577, 1548, 1512, 1493, 1448, 1417, 1354, 1275, 1196, 1124; MS 470.1 (M+H)* 5 Example 7 (2- (2-Chlorophenylsulfanyl)-quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (IIa-7): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 262-263*C; 1 H NMR (DMSO) 6 2.05 (3H, s), 5.35 (1H, s), 7.52 (2H, t), 7.65 (2H, m), 7.74 10 (1H, d), 7.83 (1H, t), 7.88 (1H, d), 8.62 (1H, d), 10.97 (1H, br s); IR (solid) 1621, 1603, 1569, 1544, 1491, 1448, 1400, 1376, 1336, 1288, 1208; MS 368.0 (M+H)* Example 8 [2-(2, 3 -Dichlorophenylsulfanyl) -quinazolin-4 15 yl]-(S-methyl-2H-pyrazol-3-yl)-amine (IIa-8): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp >300*C; 'H NMR (DMSO) S 2.05 (3H, s), 5.34 (1H, s), 7.50 (2H, m), 7.60 (1H, d), 7.75 (1H, t), 7.88 (2H, m), 8.62 (1H, d), 10.72 (iH, br 20 s); IR (solid) 1632, 1609, 1561, 1532, 1492, 1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125; MS 402.0 (M+H)* Example 9 [2-( 3 -Chlorophenylulfanyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-9): Prepared in a 25 manner similar to the above described Method E to afford a pale yellow solid, mp 248-249 0 C; 'H NMR (DMSO) 8 2.05 (3H, s), 5.42 (1Hi s), 7.55 (2H, m), 7.66 (3H, m), 7.81 (1H, s), 7.85 (1H, t), 8.62 (1H, d), 11.10 (1H, br s); IR (solid) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292, 30 1217, 1165; MS 368.0 (M+H)* -231 Example 10 [2-(1-Methylimidazol-2-ylsulfanyl)-quinazolin 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (Ila-10): Prepared in a manner similar to the above described Method E to afford an off white solid, mp 255-256OC; "H NMR (DMSO) & 5 2.19 (3H, s), 3.59 (1H, s)/~5.S1 (1H, s), 7.18 (1H, s), 7.45 (1H, t), 7.57 (iH, s), 7.59 (1H, d), 7.77 (1H, t), 8.57 (1H, d), 10.57 (1H, s), 12-.13 (1H, br s); IR (solid) 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292, 1278, 1211; MS 338.2 (M+H)* 10 Example 11 [2- (2-Hydroxyphenylsulfanyl) -quinazolin-4-yl] (5-methyl-21-pyrazol-3-yl)-amine (Ia-11): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 273-275"C; !H NMR (DMSO) 8 2.06 15 (3H, s), 5.41 (1H, s), 6.99 (1H, t), 7.07 (1H, d), 7.50 (1H, t), 7.57-7.62 (2H,.m), 7.73 (1H, d), 7.94 (iH, t), 8.71 (1H, d), 10.29 (1H, br s), 11.66 (1H, br s); IR (solid) 1623; 1597, 1552, 1485, 1442, 1404, 1354, 1341, 1289, 1221, 1165; MS 350.1 (M+H)* 20 Example 12 [2-(2,4-Difluorophenylsulfanyl)-quinazolin-4 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-12): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 256-258*C; 1 H NMR (DMSO) 25 2.10 (3H, s), 5.41 (1H, s), 7.33 (iH, t), 7.51-7.58 (2H, m), 7.65 (1H, d), 7.82-7.91 (2H, m), 8.63 (iH, d), 11.06 (1H, br s); IR (solid) 1626, 1608, 1556, 1482, 1409, 1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 (M+H)* 30 Example 13 [2- (3,4-Dimethoxyphenylaulfanyl) -quinazolin-4 yl]-(5-methyil-2H-pyrazol-3-yl)-amine (Ia-13): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 229-232oC; 'H NMR (DMSO) 8 -232 2.05 (3H, s), 3.70 (3H, S), 3.85 (3:H, a), 5.39 (1H, s), 6.95 (1H, d), 7.30 (2H, d), 7.60 (1:H, t), 7.77 (1H, d), 7.94 (1H, t), 8.72 (1H, d), 11.66 (1H, br s); IR (solid) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254, 5 1237, 1218,--1161-, 1137- -MS--394.1 -(M+H)* Example 14 [2-(3-Methylphenylsulfanyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-14): Prepared in a manner similar to the above described Method E to afford 10 a pale yellow solid, mp 249-250*C; 1H NMR (DMSO) 8 2.06 (3H, s), 2.36 (3H, s), 5.31 (1H, s), 7.45 (2H, d), 7.48-, 7.58 (3H, m), 7.61 (111, d), 7.88 (1:H, t), 8.68 (1H, d), 11.66 (1H, br s); IR (solid) 1617, 1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 (M+H)* 15 Example 15 [2- (2-Methoxyphenylsulfanyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (Ila-15): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 237-239 0 C; 'H NMR (DMSO) 8 2.07 20 (3H, s), 3.71 (3H, s), 5.35 (1H, s), 7.12 (1H, t), 7.23 (1H, d), 7.55 (1H, t), 7.60-7.67 (3H, m), 7.87 (1H, t), 8.66 (1H, d), 11.20 (1H, br s); IR (solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251, 1224; MS 364.1 (M+H)* 25 Example 16 [2-(2-Naphthalenylsulfanyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (Ila-16): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 267-270CC; 'H NMR (DMSO) 8 2.05 30 (3H, s), 5.09 (1H, s), 7.57 (1H, t), 7.62-7.75 (4H, m), 7.90 (1H, t), 8.07 (3H, t), 8.40 (1H, s), 8.66 (1H, d), -233 11.28 (1H, br s); IR (solid) 1624, 1606, 1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 (M+H)* Example 17 [2-(2,6-Dichlorophenylsulfanyl)-quinazolin-4 5 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-17): Prepared in a manner similar to the above described Method E to afford a pale brown solid, mp >300*C; 'H NMR (DMSO) 6 2.11 (3H, s), 5.49 (1H, s), 7.49 (1H, t), 7.59-7.67 (2H, m), 7.76 (2H, d), 7.81 (111, d), 8.60 (1H, d), 10.60 (1H, s); 10 IR (solid) 1618, 1599, 1565, 1533, 1486, 1424, 1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 (M+H)* Example 18 [2-(3,4-Dichlorophenylsulfanyl)-quinazolin-4 yl]-(5-mathyl-2H-pyrazol-3-yl)-amine (Ia-18): Prepared 15 in a manner similar to the above described Method E to afford a pale yellow solid, mp 268-272 0 C; 'H NMR (DMSO) S 2.11 (3H, s), 5.47 (1H, s), 7.56 (1H, t), 7.68-7.72 (2H, m), 7.83 (2H, d), 7.88 (1H, t), 8.05 (1H, d), 8.66 (1H, d); IR (solid) 1628, 1607, 1556, 1488, 1436, 14412, 1399, 20 1367, 1341, 1288, 1216, 1166; MS 402.0 (M+H)* Example 19.[2.-(Benzimidazol-2-ylsulfanyl)-quinazolin-4 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (Ila-19): Prepared in a manner similar to the above described Method E to 25 afford a pale grey solid, mp 192-196OC; 'H NMR (DMSO) 5 1.60 (3H, s), 5.48 (1H, s), 7.44 (2H, m), 7.53 (1H, t), 7.69 (2H, d), 7.76 (2H, m), 7.85 (1H, t), 8.64 (IH, d), 10.79 (1H, s); IR (solid) 1618, 1606, 1569, 1537, 1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374.1 (M+H)* 30 Example 20 [2- (2-Aminophenylsulfanyl) -quinazolin-4-yl] (5-methyl-2E-pyrazol-3-yl) -amine (IIa-20): Prepared in a -234 manner similar to the above described Method E to afford a bright yellow solid, mp 257-259*C; 1H NMR (DMSO) 8 2.11 2.30 (3H, 2xbr s), 6.10 (iH, br s), 7.10-7.80 (7H, m), 8.60 (1H, br s), 9.80 (1H, br s), 10.80 (iH, br s); IR 5 (solid) 1623, 1591, 1567, -1538, '1496, 1483, -1410, 1351 Example 21 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2 phenylsulfanyl-quinazolin-4-y1)-amine (IIa-21): Prepared in a manner similar to the above described Method E to 10 afford a yellow solid, mp 233-236*C; 1H NMR (DMSO) 8 0.89 (2H, d), 0.98 (2H, d), 1.67 (1H, m), 5.48 (iH, s), 7.54 7.73 (7H, m), 7.89 (iH, t), 8.68 (i, d), 11.60 (iH, br s); IR (solid) 1629, 1606, 1577, 1546, 1509, 1484, 1438, 1413, 1370, 1291, 1219; MS 360.3 (M+H)* 15 Example 22 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3 methoxycarbonylphenylsulfanyl) -quinazolin-4 -ylJ -amine (IIa-22): Prepared in a manner similar to the above described Method E to afford a white solid, mp 224-225oC; 20 1H NMR (DMSO) 8 0.52 (2H, m), 0.86 (2H, m), 1.67 (i 1 H, m), 3.86 (3H, s), 5.60 (iH, s), 7.45 (1H, t), 7.56 (iH, d), 7.66 (1H, ,t), 7.76 (iH, t), 7.93 (1H, d), 8.10 (iH, d), 8.18 (iH, a), 8.57 (IH, d), 10.48 (1H, br s), 12.07 (iH, br s); IR (solid) 1724, 1617, 1593, 1567, 1526, 1478, 25 1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169, 1128; MS 418.3 (M+H)* Example 23 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (3 methylphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-23): 30 Prepared in a manner similar to the above described Method E to afford a white solid, mp 241-243CC; IH NMR (DMSO) 8 0.55-0.63 (2H, m), 1.87-1.97 (1H, m), 1.67-1.79 -235 (1H, m), 2.35 (3H, S), 5.72 (1H, S), 7.30-7.60 (6H, m), 7.68-7.78 (1H,m), 8.50-8.60 (1H, d), 10.38 (1H, s), 12.02 (1H, S); IR (solid) 1617, 1594, 1568, 1529, 1480, 1401, 1344, 1287, 1176, 758, 665,656; MS (M+H)* Example 24 (5-Cyclopropyl-2H-pyrazol-3-y1) - [2- (3 methoxyphenylsulfanyl) -quinazolin-4-yl -amine (IIa-24): Prepared in a manner similar to the above described Method E to afford a white solid, mp 232-234*C; 1H NMR 10 (DMSO) 8 0.55-0.62 (2H, m), 0.88-0.97 (2H, m), 1.70-1.80 (1H, m),' 3.79 (3H, s), 5.79 (1H, s), 7.08 (1H, d), 7.22 7.29 (2H, m), 7.40-7.50 (2H, m), 7.60 (1H, d), 7.79 (1H, t), 8.57 (1H, d), 10.40 (1H, s), 12.04 (1H, s); IR (solid) 3100, 1618, 1592, 1567, 1527, 1477, 1402, 1345, 15 1284, 1246, 1231, 1171, 1041, 1001, 969, 826, 761, 692, 667; MS (M+H)* Example 25 (5-Cyclopropy-2-pyrazol-3-yl) -[2- (3,44 dimethoxyphenylsulfanyl) -quinazolin-4-y1]- 0 amine (IIa-25): 20 Prepared in 'a manner similar to the above described Method E to afford a white solid, mp 250-252OC; 1H NMR (DMSO) 8 0.54-0.60- (2H, m),-0.83-0.91 (2H, m), 1.68-1.77 (1H, m), 3.79 (3H, S), 3.85 (3H, s), 5.79 (1H, s), 7.10. (1H, d), 7.20-7.26 (2H, m), 7.45 (1H, t), 7.57 (iH, d), 25 7.77 (1H, t), 8.55 (1H, d), 10.45 (1H, s), 12.04 (1H, m); IR (solid) 1617, 1593, 1567, 1530, 1504, 1479, 1457, 1439, 1398, 1364, 1347, 1288, 1269, 1250, 1232, 1181, 1169, 1138, 1037, 1020, 997, 972, 882, 846, 804, 764, 750; MS- (M+H)* 30 Example 26 [2- (3-Carboxyphenylsulfanyl) -quinazolin-4-ylj (5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-26): Prepared from IIa-22 according to Method G to afford a yellow -236 solid, mp >300 0 C; 1 H NMR (DMSO) 8 0.53 (2H, d), 0.86 (2H, d), 1.65 (1H, m), 5.3-7 (1H, S), 7.55 (1H, t), 7.68 (1H, t), 7.81 (1H, d), 7.88 (1H, t), 7.95 (1H, d), 8.15 (1H, d), 8.15 (1H, a), 8.71 (1H, d), 11.32 (1H, br s); IR 5 (solid) 1702, 1626,' 1609,- 1559, 1490, 1412, 1355, 1293, 1222, 1170; MS 404.7(M+H)* Example 27 (5-Cyclopropyl-2-pyrazol-3-y1)-[2-(naphtalen 2-ylsulfanyl)-quinazolin-4-yll-amine (IIa-27): Prepared 10 in a manner similar to the above described Method E to afford an off-white solid, mp 285-288*C; 1H NMR (DMSO) S 0.25 (2H, br s), 0.52 (2H, br s), 0.87 (1H, m), 5.54 (1H, br s), 7.42 - 7.77 (4H, m), 8.00 (3H, m), 8.30 (1H, br s), 8.56 (1H, br d), 10.42 and 11.88 (1H, 2 x br s); IR 15 (solid) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287, 1240, 1216, 1167, 1158, 1142, 1128, 996, 965; MS 410.7(M+H)+ Example 28 (S-Cyclopropyl-2H-pyrazol-3-yl)-[2-(2,4 20 difluorophenylaulfanyl)-quinazolin-4-y1]-amine (IIa-28): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 250-253"C; 'H NMR (DMSO) 8 0.61 (2H, m), 0.91 (2Hi m), 1.74 (1H, m), 5.67 (H,' m), 7.24-7.28 (1H, m), 7.44-7.48 (3H, m), 7.53 25 7.81 (2H, brm), 8.55 (1H, m), 10.47 and 12.10 (1H, 2 x br s); IR (solid) 1614, 1598, 1565, 1525, 1479, 1423, 1398, 1366, 1345, 1285, 1267, 1243, 1213, 1168, 1143, 1114, 1026, 995, 968; MS 396.6(M+H)* 30 Example 29 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2 (naphthalen-2-ylaulfanyl)-5,6,7,8-tetrahydroquinazolin-4 yl]-amine (IIa-29): Prepared in a manner similar to the -237 above described Method F to afford a white solid, mp 2440C; 1H NMR (DMSO) -. 0.13 (2H, s) , 0.45. (2H, s) , 0. 79 (1H, s), 1.73 (4H, s), 2.42 (2H, S), 2.58 (2I-, s), 5.28' (1H, a), 7.58 (2H, d), 7.61 (2H, d), 7.97 (3H,.d), 8.23 (1H, 5 s), 8.56 (1H, s), 11.63 (1H, s); IR (solid) 1594, 1561, 1514, 1477, 1423, 1333, 1279, 1251, 990, 808, 744, 657, 651; MS 414.7(M+H)* Example 30 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (2,3 10 dichlorophenylsulfanyl) -quinazolin-4-yl] -amine (IIa-30): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 250-252 0 C; 1H NMR (DMSO) 8 0.60 (2H, d) , 0.93 (2H, d), 1.70 (1H, m), 5.54 (1H, s), 7.47 (2H, m), 7.57 (1H, d), 7.76 (1H, t), 15 7.86 (2H, d), 8.57 (1H, d), 10.48 (1H, s), 12..04 (1H, s); IR (solid) 1616, 1601, 1570, 1528, 1486, 1432, 1400, 1367, 1335, 1285, 1246, 1210, 1159, 1146, 1051, 1033, 1021, 997; MS 428.6(M+H). 20 Example 31 [2- ( 3 -Chlorophenylsulfanyl) -quinazolin-4-yl] (5-cyclopropyl-2H-pyrazol-3 -yl) -amine (IIa-31): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 235-238C; 1H NMR (DMSO) S 0.58 (2H, d), 0.92 (2H, d), 1.75 (1H, m), 5.71 (1H, s), 25 7.44 (1H, t), 7.50 - 7.63 (4H, m), 7.73 (1H, s), 7.75 (1H, t), 8.57 (1H, d), 10.46 (1H, s), 12.08 (11H, s); IR (solid) 1616, 1593, 1562,.1528, 1479, 1456, 1406, 1367, 1343, 1286, 1244, 1216, 1176, 1067, 1051, 997; MS 394.7(M+H)* 30 Example 32 [2- (2-Chiorophenylsulfanyl) -quinazolin-4-yl] (5-cyclopropyl-2-pyrazol-3-yl) -amine (Iia-32): Prepared -238 in a manner similar to the above described Method E to afford an off-white solid, mp 255-257 0 C; 'H NMR (DMSO) B 0.59 (2H, d), 0.91 (2H, d), 1.71 (1H, m), 5.62 (1H, B), 7.45 (2H, m), 7.57 (1H, m), 7.69 (1H, d), 7.75 (IH, t), 5 7.85 (1H; d), 8.56- (1H,- d)-, -10.43 (1H, s-), 12.-03 (1H, s); IR (solid) 1619, 1596, 1564, 1529, 1480, 1446, 1398, 1370, 1343, 1289, 1246, 1218, 1165, 1148, 1089, 1054, 1030, 997; MS 394.7(M+H)* 10 Example 33 (5-Cyclopropyl-2h-pyrazol-3-yl) - [2- (3,4 dimethylphenylsulfanyl) -quinazolin-4-yl] -amine (IIa-33): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 255-256*C; 'H NMR (DMSO) 8 0. 56 (2H, m) , 0. 90. (2H, m) , 1. 67 (1H, m) , 15 2.26 and 2.29 (6H, 2 x s), 5.75 (iH, br s), 7.26 (1H, m), 7.35-7.55 (4H,. m), 7.74 (1H, m), 8.54 (1H, br s), 10.44 and 12.06 (2H, 2 x br s); IR (solid) 1617, 1596, 1569, 1526, 1479, 1459, 1404, 1366, 1343, 1287, 1243. .1218, 1167, 1145, 1017, 996, 966; MS 388.3(M+H)* 20 Example 34 [2-(Benzimidazol-2-ylsulfany1)-quinazolin-4 yl - (5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIa-34): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 201-203WC; 'H 25 NMR (DMSO) 8 0.44 (2H, m), 0.71 (2H, m), 1.17 (1H, m), 5.72 (1H, m), 7.23 (2H; m), 7.51-7.81 (5:H, m), 8.59 (1H, m), 10.59, 12.06 and 13.17 (3H, 3 x br s); IR (solid) 1617, 1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290, 1273, 1209, 1168, 1024, 1010, 965; MS 400.2(M+H)* 30 Example 35 (5-Cyclopropyl-2H-pyrazol-3-y1) -[2- (4 methoxycarbonylphenylsulf anyl) -quinazolin-4-ylJ -amine -239 (Ila-35): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 245 2460C; 'H NMR (DMSO) 8 0.47 (2H, br s), 0.80 (2H, br s), 1.62 (1H, m), 3.85 (3H, s), 5.69 (1H, br s), 7.46 (1H, 5 m)), 7:58 (1H, m), 7.76-7.81 (3H, m), 8.02-8.05 (2H, m), 8.57 (1H, m), 10.48 and 12.11.(2.H, 2 x br s); IR (solid) 1721, 1712, 1616, 1596, 1572, 1564, 1523, 1481, 1435, 1404, 1360, 1346, 1277, 1181, 1114, 1106, 996, 971; MS 418.2(M+H)+ 1.0 Example 36 [2- (4-Acetamido-phenylsulfanyl) -quinazolin-4 yl]-(S-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-36): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 239-241"C; 'H 15 NMR (DMSO) 8 0.57 (21, m), 0.83 (2H, m), 1.69 (1H, m), 2.02 (3H, s), 5.73 (1H, br s), 7.41 (1H, m), 7.53-7.57 (311, m)', 7.73-7.75 (3H, m), 8.54 (1H, m), 10.18, 10.39 and 11.98 (3H, 3 xbr s); IR (solid) 1665, 1618, 1607, 1586, 1572, 1564, 1529, 1482, 1387, 1343, 1320, 1287, 20 1243, 1221, 1162, 1005, 968; MS 417.2(M+H)*. Example 37 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2 (naphthalen-.1-ylsulfanyl)-quinazolin-4-yl]-amine (IIa 37): Prepared in a manner similar to the above described 25 Method E to afford. an off-white solid, mp 271-273*C; 1H NMR (DMSO) 8 0.46-0.47 (2H, m), 0.87-0.89 (2H, m), 1.57 (1H, m), 5.01 (1H, m), 7.42 (1H, m), 7.52-7.54 (3H, m), 7.64 (1H, m), 7.75 (1H, m), 7.98 (1H, m), 8.06 (1H, m), 8.17 (1H, m), 8.28 (1H, m), 8.50 (1H, m), 10.29 (1H, br 30 s), 11.84 (1H, br s); IR (solid) 1615, 1592, 1567, 1528, 1483, 1401, 1362,.1343, 1285, 1242, 1219, 1173, 998, 963; MS 410.2(M+H)* -240 Example 38 [2-( 4 -Acetamidophenylsulfanyl)-quinazolin-4 yll-(5-methyl-2K-pyrazol-3-yl)-amine (IIa-38): Prepared in a manner similar to the above described Method E to 5 afford an white solid, "np 268-271*C; 'H NMR (DMSO) 6 2.02 (3H, s), 2.09 (3H, s), 5.56 (1H, a), 7.40 (1H, t), 7.55 (3H, m), 7.75 (3H, d), 8.55 (1H, d), 10.21 (1H, s), 10.40 (1H, s), 12.03 (1H, s); IR (solid) 1662, 1620, 1599, 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312, 10 1278, 1265, 1245, 1216, 1161, 1006, 966; MS 391.2(M+H)* Example 39 (2-(4-Methanesulfonylamino-phenylsulfanyl) quinazolin-4-yl]-(S-methyl-2z-pyrazol-3-yl)-amine (I3a 39) : Prepared in a manner similar to the above described 15 Method E to afford an off-white solid, mp 219-222*C; H NMR (DMSO) 8 2.15 (314, s), 2.61 (3H, s), 5.84 (1H, s), 6.91 (2H, d), 7.22 (214, d), 7.36 (1H, s), 7.52 (1H, d), 7.69 (1H, s), 8.53 (1H, d), 10.31 (1H, s); 11.96 (1H, s); IR (solid) 1621, 1602, 15B4, 1567, 1528, 1486, 1351; 20 1287, 1253, 1207, 1179, 1102, 1091, 983; MS 427.0(M+H)* Example 40 (2-(4-Acetamidophenylsulfanyl)-7-methoxy quinazolin-4-yll-(5-methyl-2n-pyrazol-3-yl)-amine (IXa 40): Prepared in a manner similar to the above described 25 Method E to afford a white solid, mp 291-293*C; 'H NMR (DMSO) 8 2.01 (3H, s), 2.09 (3H, s), 3.87 (3H, s), 5.55 (1H, s), 6.96 (1H, s), 6.99 (1H, d), 7.55 (2H, d), 7.73 (2H, d), 8.45 (1H, d), 10.21 (1H, s), 10.23 (1H, s), 11.99 (1H, s); IR (solid) ; MS 421.2(M+H)* 30 Example 41 (2- (4-Acetamidophenylsulfanyl) -8- (3-morpholin 4 -yl-propoxy)-quinazolin-4-yl]-(5-methyl-25-pyrazol-3- -241 yl)-amine (IIa-41): Prepared in a manner similar to the above described Method E to afford a white solid, mp 262 2640C; 'H NMR (DMSO) 8 1.94 (2H, quint.), 2.03 (3H, s), 2.09 (3H, s), 2.38 (4H, s), 2.45 (2H, t), 3.58 (4:H, s), 5 4.11 (2H, t), 5.60 (1H,- s), 7.-24 (1H, d), 7.30 (1H, t), 7.57 (2H, d), 7.73 (2H, d), 8.07 (1H, d), 10.20 (H,' s), 10.24 (1H, s), 12.02 (1H, br s); IR (solid) 3245, 3045, 2954, 2918, 2845, 1663, 1609, 1586, 1527, 1468, 1391, 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823 ; MS 10 534.4(M+H)* Example 42 [2- ( 4 -Methoxycarbonylphenylsulfanyl) quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa 42): Prepared in a manner similar to the above described' 15 Method E to afford an off-white solid, mp 257-260*C; 1H NMR (DMSO) 8 1.95 (3H, s), 3.89 (3H, s), 5.51 (iH, br s), 7.39 (1H, br s), 7.51 (1H, br a), 7.70 (1:H, br s), 7.81 (2H, d), 8.04 (2H, d), 8.51 (1H1, br s), 10.48 (1H, br s), 12.03 (1H, br s); IR (solid) 1718, 1618, 1599, 1568, 20. 1531, 1481, 1434, 1395, 1362, 1342, 1286, 1247, 1216, 1156, 1116, 1018, 1003, 968 ; MS 392.2(M+H)* Example 43 [2- (4-Carboxyphenylsulfanyl) -quinazolin-4-ylJ (5-methyl-2H-pyrazol-3-yl)-amine (IIa-43): Prepared in a 25 manner similar to the above described Method E to afford an off-white solid, mp 263-265OC; 'H NMR (DMSO) 8 1.98 (3H, s), 5.50 (1H, s), 7.46 (iH, t), 7.60 (1H, d), 7.78 (3H, m), 8.02 (2H, d), 8.58 (1H, d), 10.58 (1H, s), 12.50 (1H, br s); IR (solid) 1623, 1605, 1574, 1560, 1533, 30. 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131, 1088, 1018; MS 378.2(M+H)* -242 Example 44 [2- ( 4 -Acetamidophenylsulfanyl) -8-methoxy quinazolin-4-yll-( 5 -methyl-2H-pyrazol-3-yl)-amine (Iha 44): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 247-2490C; H 5 NMR (DMSO) 1.99 (3H,-s)- 2.10 (3H, s), 3.93 (3t{, s), 5.40 (1H, s), 7.31 (1H, d), 7.38 (1H, t), 7.57 (2H, d), 7.76 (2H, d), 8.11 (1H, d), 10.28 (1H, s), 10.61 (1H, s), 12.11 (1H, br s); IR (solid) 3234, 3052, 2938, 1673, 1618, 1591, 1536, 1481, 1459, 1390, 1372, 1345, 1317, 10 1267, 1249, 1158, 1058, 985, 830; MS 421.2(M+H) 4 Example 45 [2-( 4 -Acetamidophenylsulfanyl)-7-(3-morpholin 4-yl-propoxy)-quinazolin-4-yll-(5-methyl-2E-pyrazol-3 yl)-amine (IIa-45): Prepared from IIa-74 according to 15 Method I to afford an off-white solid, mp 1530C (dec.); 'H NMR (DMSO) 8 2.02 (3H, s), 2.09,(3H, s), 2.29 (2H, quint.), 3.16 (2H, m), 3.36 (4H,m), 3.57 -(4H, m), 4.11 (2H, m), 5.58 (1H, s),' 7.22-7.29 (2H, m), 7.55 (2H, d), 7.76 (2H, d), 8.07 (1H, d), 10.26 (1H, br s), 10.35 (1H, 20 s), 12.06 (1H, br s); IR (solid) 1673; 1614, 1591, 1532, 1486, 1391, 1336, 1254, 1109, 1063, 995; MS 534.2(M+H) Example 46 [2- ( 4 -Bromophenylsulfanyl) -quinazolin-4-yl] (5-methyl-2-pyrazol-3-y1)-amine (IIa-46): Prepared in a 25 manner similar to the above described Method E to afford an off-white solid, mp >3000C; 'H NMR (DMSO) 8 2.15 (3H, s), 5.63 (1H, br s), 7.44 (1H, m), 7.55-7.62 (3H, m), 7.69-7.77 (3H, m), 8.56 (1H, in), 10.47 and 12.12 (2H, 2 x br s); IR (solid). 1615, 1597, 1565, 1525, 1478, 1396, 30 1362, 1339, 1285, 1218, 1158, 1034, 1009, 967; MS 412.1/414.1 (M+H)* -243 Example 47 [2-(3-Bromophenylsulfanyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-47): Prepared in a manner similar to the above described Method E to afford an off-white solid,. mp 280-281*C; 1H NMR (DMSO) 8 2.12 5 (3H, s), 5.54- (1H, br -s), 7.46 (1H, m); 7.55-7.68 (3H, m), 7.75-7.88 (3H, m), 8.81 (1H, m), 10.49 and 12.11 (2H, 2 x br s); IR (solid) 1617, 1600, 1567, 1530, 1483, 1399, 1362, 1342, 1282, 1200, 1168, 1054, 1034, 1005, 967; MS 412.2/414.2(M+H)* 10 Example 48 [2- (4 -Isopropanesulfonylamino-phenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIa 48): Prepared in a manner similar to the above described Method E to afford a white solid, mp 294-297*C; 'H NMR 15 (DMSO) 8 1.26 (6H, d), 2.13 (3H, s), 5.75 (1H!, s), 7.34 (2H,.d), 7.41 (1H, t),' 7.54 (1H, d), 7.59 (2H, d), 7.73 (iH; t), 8.53 (1H, d), 10.16 (1H,. s), 10.42 (1H, s), 12.07 (1H, br s); IR (solid) 1613, 1593, 1560, 1530, 1482, 1384, 1364, 1346, 1320, 1290, 1265, 1243, 1216, 20 1169, 1141, 1084, 1056, 1019, 999, 969, 916; MS 455.2(M+H)* Example 49 [2- ( 4 -Isobutyrylamino-phenylsulfanyl) quinazolin-4-yl]-(5-methyl-21-pyrazol-3-yl)-amine (IIa 25 49): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 285-287OC; 'H NMR (DMSO) 8 1.12-1.13.(6H, m), 1.9-9 (3H, s), 2.64 (1H, m), 5.52 (11H, br s), 7.41 (1, m), 7.54-7.57 (3H, m), 7.72-7.77 (3H, m), 8.54 (1H, m), 10.12, 10.41 and 12.04 30 (3H, 3 x br s); IR (solid) 1704, 1680, 1617, 1590, 1566, 1516, 1481, 1395, 1358, 1341, 1286, 1247, 1214, 1155, 1052, 1032, 1006, 969; MS 419.3(M+H)* -244 Example 50 (5-Methyl-2H-pyrazol-3-yl)-[2-(4 propionylamino-phenyleulfanyl) -quinazolin-4-yl] -amine (Ia-50): Prepared in a manner similar to the above 5 described Method E to-afford an off-white solid, mp 281 2820c; 3H NMR (DMSO) 8 1.11-1.13 (3H, m), 1.98 (3H, s), 2.33 (2H, m), 5.51 (1H, br s), 7.41 (1H, m), 7.55-7.57 (3H, m), 7.71-7.78 (3H, m), 8.54 (1H, m), 10.11, 10.41 and 12.04 (3H, 3 x br s); IR (solid) 1654, 1621, 1599, 10 1571, 1527, 1476, 1398,-1358, 1341, 1286, 1244, 1216, 1155, 1006, 969; MS 405.3(M+H)* Example 51 [2- ( 4 -cyclopropanecarbonylamino phenylsulfanyl) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3 15 yl)-amine (IIa-51): Prepared in a manner similar to the above described Method E to afford an off-white solid,, mp 300-303"C; H NMR (DMSO) 8 0.82-0.84 (4H, m), 1.83 (1H, m), 2.01 (3H, s), 5.55 (1H, br s), 7.39-7.41 (2H, m), 7.53-7.57 (2H, m), 7.72-7.77 (2H, m), 8.53-8.55 (21H, ), 20 10.40, 10.46 and 12.03 (3H, 3 x br s); IR (solid) 1664, 1614, 1591, 1560, 1526, 1480, 1432, 1390, 1344, 1288, 1240, 1194, 1177, 1152, 997; MS 417.2(M+H)* Example 52 [2--(4-Acetamido-phenylsulfanyl)-8 25 hydroxyquinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl).-amine (IIa-52)' tan solid, mp 258-259OC; 'H NMR (DMSO) 6 1.99 (3H, s), 2.09 (3H, s), 5.45 (1H, s), 7.10 (1H, d), 7.22 (11H, t), 7.57 (2H, d), 7.75 (2H, d), 7.95 (1:H, d), 9.35 (1H, s), 10.22 (1H, s), 10.26 (1H, s), 12.00 (1H, br s); 30 IR (solid) 3295, 3272, 3181, 3109, 1654, 1591, 1527, 1482, 1459, 1386, 1368, 1314, 1268, 1141, 1077, 991, 814; MS 407.2(M+H)* -245 Example 53 [2-(4-Acetamido-phenylsulfanyl)-7 nitroquinazolin-4-yll-(5-methyl-2&-pyrazol-3-yl)-amine (IIa-53): Prepared in a manner similar to the above 5 described Method- E- to -afford a yellow solid; 'R NMR (DMSO) 8 2.02 (3H, s), 2.09 (3H, s), 5.54 (1H, s.), 7.58 (2H, d), 7.75 (2H, d), 8.08 (1H, d), 8.22 (1H, s), 8.80 (1H, d), 10.24 (1H, s), 10.85 (1H, s), 12.15 (1H, s); IR (solid); MS 436.2(M+H) 10 Example 54 (5-Methyl-2H-pyrazol-3-y1)-{2-[4-(propane-i sulfonylamino)-phenylsulfanyl]-quinazolin-4-yl}-amine (IIa-54): Prepared in. a manner similar to the above described Method E to afford a white solid, mp 272-273*C; 15 -H NMR (DMSO) 8 0.95' (3H, t), 1.71 (2H, m) , 2.13 (3H,s), 3.18 (2H, t), 5.70 (1H, s), 7.31 (2H, d), 7.41 (1H, t), 7.52 (1H, d), 7.58 (1H, d), 7.73 (1H, t), 8.55 (1H, d), 10.16 (lH,.s), 10.42 (1H,. s), 12.07 (1H, s); IR (solid) 1615, '1594, 1563, 1530, 1481, 1389,.1362, 1346,-1325, 20 1291, 1245, 1147, 969; MS 455.2(M+H)* Example 55 [2- ( 4 -Ethylsulfonylanino-phenylsulfanyl) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIa-55): Prepared in a manner similar to the above 25 described Method E to afford an off-white solid, mp 279 280C; 1H NMR (DMSO) 6 1.28. (3H, t), 2.19 (3H,s), 3.25 (2H, m), 5.76 (1H, s), 7.36 (2H, d), 7.48 (1H,,t), 7.53 (1H, d), 7,65 (1H, d), 7.80 (1H, t), 8.61 (1H, d), 10.23 (1H, s), 10.49 (1H, a), 12.13 (1H, s); IR (solid) 1615, 30 1597, 1564, 1532, '1506, 1485, 1455, 1388, 1361, 1347, 1323, 1294, 1218, 1150, 1033, 1016, 998, 968, 918; MS 441.2(M+H)* -246 Example 56 [2-( 4 -Acetamido-phenyleulfanyl)-7 hydroxyaminoqainazolin-4-yl] - (S-methyl-2H-pyrazol-3 -yl) amine (XIa-56): Prepared from IIa-53 according to Method J to afford a yellow solid; 1H NMR (DMSO) 8 1.97 (3H, s), 5 2.11 (3H, s), 5.-19 (1H, s), 6.88-6.91 (2H, m), 7.65 (2H, d), 7.85 (2H, d), 8.44.(lH, d), 9.27 (1H, br s); 10.49 (1H, s), 11.38 (1H, s), 14.58 (1H, br s); IR (solid); MS 422.2(M+H)* 10 Example 57 [2-( 4 -Isobutanecarbonylamino-phenylsulfanyl).

quinazolin-4-yl]-(S-methyl-23-pyrazol-3-yl)-amine (Ila 57): Prepared in a manner similar -to the above described Method E to afford a white solid, mp 281-282*C; 'H NMR (DMSO) 8 0.95-0.97 (6H, m), 2.00 (3H, s), 2.12 (1H, m), 15 2.23-2.25 (2H, m), 5.56 (1H, s), 7.41 (1H, m), 7.54-7.57 (3H, m), 7.72-7.-78 (3H, m), 8.54 (1H, m), 10.14, 10.41 and 12.03 (3H, 3 x br s); IR (solid) 1737, 1658, 1618, 1599, 1566, 1530, 1483, 1432, 1394, 1364, 1343, 1313, 1287, 1242, 1216, 1167, 1151, 1003, 967; MS 433.2(M+H)* 20 Example 58 [2- ( 4 -tert-Butoxycarbonylamino phenylsulfanyl)-quinazolin-4-yl]-(5-methyl-2a-pyrazol-3 yl)-amine (Ila-58): Prepared in a manner similar to the above described Method E to afford a white solid, mp 243 25 246 0 C; 'H NMR (DMSO) 8 1.50 (9H, s), 1.97 (3Hs), 5.40 (1H, s), 7.07 (2H, br s), 7.36 (1H, br a), 7.47 (2:H, d), 7.58 (2H, d), 8.12 (1H, br s), 9.58 (1H, s), 11.24 (1H, br B); IR (solid) 1701, 1593, 1559, 1515, 1482, 1396, 1365, 1346, 1308, 1288, 1237, 1154, 1051, 1020, 969; MS 30 449.2(M+H)* -247 Example 59 [2-( 4 -Acetamido-phenylsulfanyl)-7 aminoquinazolin-4-yl] - (5-methyl-2s-pyrazol-3-yl) -amine (IIa-59): Prepared from IIa-53 according to Method K to afford an off-white solid, mp 264-265 "C; 1H NMR (DMSO) 5 5 1.99 (3H, s), 2.09 (1H1,'s), 5.53 (1H, s), 5.97 (2H, s), 6.47 (1H, s), 6.68 (iH, d), 7.52 (2H, d), 7.71 (2H, d), 8.15 (1H, d),'9.83 (1H, br s), 10.19 (1H, s), 10.87 (1H, br s); IR (solid); MS 406.2(M+H)* 10 Example 60 (5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin 4-yl-acetylamino) -phenylsulfanyl] -quinazolin-4-yl)-amine (IIa-60): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 266 267 0C; -H NMR (DMSO) 8 2.03 (3H, s), 2.57 (4H, m), 3.23 15 (2H,s), 3.69 (4H, m), 5.58 (1H, s), 7.40 (1H, t), 7.55 7.62 (3H, m), 7.75 (11H, t), 7.80 (21H, d ), 8.54 (1H, d), 10.02 (1H, s), 10.41 (1H, s), 12.03 (1H,s); IR (solid) 1686, 1598, 1564, 1533, 1515, 1484,,1387, 1362, 1348, 1291, 1113, 868, 801, 773; MS 476.4(M+H)* 20 Example 61 (5-Cycloprpyl-21-pyrazol-3-yl) - [2- (4 methylsulfonylamino-phenylsulfanyl) -quinazolin-4-yl] amine (IIa-61): Prepared in a manner similar to the above described Method E to afford a white solid, mp 235-238*C; 25 1H NMR (DMSO) 8 0.61 (2H, s), 0.92 (2H, d), 1.82 (1H, br s), 2.98 (3H,s), 5.90 (1H, s),' 7.23 (2H, d), 7.41 (11H, t), 7.54 (3H, m), 7.72 (1H, t), 8.55 (1H, d), 10.16 (1H, br s), 10.38 (1H, a), 11.99 (1H, s); IR (solid) 1621, 1605, 1573, 1532, 1494, 1455, 1375, 1342, 1316, 1290, 30 1232, 1143, 1113, 985, 972; MS 453.3(M+H)* -248 Example 62 [2-(4-Amino-phenyluulfanyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-62): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp >300"C; 'H NMR (DMSO) 5 .2.16 (3H, 5 s), 5.58 (IH, s), 6.78 (2H,. d), 7.36 (2H, d), -7.64 (2H, m), 7.94 (1H, t), 8.74 (1H, d), 11.82 (1H, br s); IR (solid) 1615, 1591, 1561, 1532, 1495,'1480, 1387, 1363, .1344, 1288, 1244, 1148, 966; MS 349.2(M+H)* 10 Example 63 [2-(4-Acetamido-phenylsulfanyl)-quinazolin-4 y1]-(2H-pyrazol-3-yl)-nmine.(IIa-63): Prepared in a manner similar to the above described Method E to afford a white solid, 1H NMR (DMSO) 6 2.11 (3H, s), 5.93 (1H, s), 7.31-7.68 (8H, m), 8.54 (1H, s), 10.17 (1H, s), 10.54 15 (1H, s), 12.38 (1H, s); IR (solid);- MS 377.4(M+H)* Example 64 (5-Methyl-2H-pyrazol-3-yl) -(2- [4- (4-morpholin 4-yl-butyrylamino) -phenylsulfanyl -quinazolin-4-yl}-amine (IIa-64): Prepared in a manner similar to the above 20 described Method E to afford a white solid, mp 240-243C; 1 H NMR (DMSO)- 6 1.77 (2H,rm), 2.00 (3H, a), 2.31-2.38 (8H, m), 3.57 (4H, m), 5.54 (lH, s), 7.39-7.76 (7H, m), 8.53 (1H, br m), 10.15 (1H, s), 10.41 (1H, s), 12.00 (1H, br s); IR (solid); MS 504.-3(M+H)* 25 Example 65 (5-Methyl-2H-pyrazol-3-yl)-(2-[4-(2-morpholin 4-yl-ethylcarbamoyl) -phenylsulfanyl -quinazolin-4-yl} amine (IIa-65): Prepared in a manner similar to the above described Method E to afford a white solid, mp 246-248*C; 30 "H NMR (DMSO) 6 1.97 (3H, s), 2.43 (4H, br s), 3.30 (2H, s), 3.42 (2H, m), 3.58 (4H, br s), 5.52 (1H, s), 7.43 (1H, t), 7.55 (iH, d), 7.76 (3H, m), 7.97 (2H, d), 8.56 -249 (2H, m), 10.45 (1H, s), 12.05 (lH, br s); ±R (solid) 1637, 1618, 1596, 1568, 1530, 1484, 1396, 1362, 1343, 1286, 1247, 1216, 1159, 1116, 1006, 967; MS-490.3(M+H)* 5 Example 66- [8-Methoxy-2-( 4 -methylsulfonylamino phenylsulfanyl) -quinazolin-4-yl] - (5-methyl-2H-pyrazol-3 yl)-amine (Ila-66): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 275-277 OC; 1H NMR (DMSO) 8 2.10 (3H, s), 3.07 (3H, s), 10 3.89 (3H, s), 5.58 (1H, a), 7.24 (11H, d), 7.26-7.36 (3H, m), 7.60 (2H, d) , 8.07 (1H, d), 10.13 (1H,.s), 11.26 (1H, s), 12.03 (1:H, s); IR (solid) 3379, 1622, 1595, 1531, 1481, 1467, 1344., 1326, 1271, 1248, 1143-, 1061, 993, 975, 924, 829; MS 457.2(M+H)* 15 Example 67 {2-[4-(2-Dimethylamino-ethylcarbamoyl) phenylsulfanyl] -quinazolin-4-yl}- (5-methyl-2H-pyrazol-3 yl)-amine (IIa-67): Prepared in a manner similar to the above described Method E to afford a white solid, mp 192 20 1930C; IH NMR (DMSO) 8 1.99 (3H, s), 2.20 (6H,s), 2.42 (2H, t), 3.40 (2H, q), 5.56 (1H, s), 7.43 (1H, t), 7.57 (11H, d), 7.77 (3H, m), 7.92 (2H, d), 8.56 (2H, m), 10.44 (1H, s), 12.04.(1H, br a); IR (solid) 1650, 1618, 1593, 1561, 1525, 1481, 1419, 1395,- 1361, 1337, 1287, 1247, 25' 1214, 1165, -1004, 969; MS 448.3(M+H)* Example 68 {2- [4- ( 2 -Dimethylamino-acetylamino) phenylsulfanyl]-quinazolin-4-yl}-(5-methyl-2H-pyrazol-3 yl)-amine (Ila-68): Prepared in a manner similar to the 30 above described Method E to afford a white solid, mp 241 2430C; 'H NMR (DMSO) 8 2.00 (3H, s), 2.33 (6H, s), 3.14 (2H, s), 5.60 (iH, S)-, 7.40 (1H, t), 7.58 (3H, m ), 7.77 -250 (1H, t ), 7.76 (2H, d), 8.58 (1H, d), 10.04 (1H, s), 10.42 (1H, S), 11.99 (1H, S).; IR.(solid) 1707, 1617, 1601, 1571, 1509, 1485, 1420, 1397, 1365, 1304, 1290, 1243, 1215, 1161, 970, 847, 813, 765, 716, 683, 656; MS 5 434.3(M+H)* Example 69 [8-Hydroxy-2-( 4 -methylsulfonylamino phenylsulfanyl) -quinazolin-4 -yiJ - (5-methyl-2-pyrazol-3 yl)-amine (IIa-69): pale green solid, mp 291-293 0 C; 1H NMR 10 (DMSO) 8 2.10 (3H, s), 3.09 (3H, s), 5.57 (1H, s), 7.11 (1H, d), 7.24 (1H, t), 7.31 (2H, d), 7.62 (2H, d), 7.96 (1H, d), 9.32 (1H,' s), 10.16 (1H, s), 11.28 (1H, s), 12.02 (1H, s); IR (solid) 3256, 1596, -1531, 1460, 1392, 1317, 1334, 1296, 1267, 1146, 993, 968, 931, 824; MS 15 443.2(M+H) . Example 70 {2-[4-(3-Dimethylamino-propylcarbamoy1) -, phenylsulfanyl1-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3 yl)-amine (IIa-70): Prepared in a manner similar to. the 20 above described Method E to afford a pink solid, mp 210 213"C; I NMR (DMSO) 5 1.48 (2H, m), 2.01 (3H, s), 2.24 (6H,s), 2.38 (2H, br s), 2.93 (2H, s), 5.57 (1H, s), 7.48 (11H, t), 7.62 (1H,.d), 7.80 (3H, m), 8.02 (2H, d)., 8.61. (1H, d) 8.74 (1H, s), 10.50 (1H, s), 12.15 (1H, br s); IR 25 (solid) 1682, 1618, 1595, 1567; 1528, 1484, 1400, 1361, 1344, 1285, 1247, 1219, 1172, 1084, 1006, 969; MS 462.3(M+H)* Example 71 {2- [4- ( 3 -Dimethylamino-propionylamino) 30 phenylsulfanyl]-quinazolin-4-y}-(5-methyl-2-pyrazol-3 yl)-amine (IIa-71): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 2800C (dec.); 'H NMR (DMSO) 82.09 (3 H, s), 2.60 (6H, s), -251 2.93 (2H, m), 3.10 (2H, m), 5.64 (1H, s), 7.47 (1H, t), 7.59-7.70 (3H, m), 7.80-7.87 (3H, m), 8.61 (1H, d), 10.47 (iH, s), 10.48 (1H, S), 12.15 (iN, s).; IR (solid) 1670, 1619, 1598, 1586, 1571, 1534, 1515, 1481, 1397, 1364, 5 1 3 4 8 -,-1286i 1178,- 1162, 764; MS 448.4(M+H)* Example 72 {2-(4-Acetamido-phenylsulfanyl)-8-methoxy quinazolin-4-yl]-(5-cyclopropyl.-2H-pyrazol-3-yl)-amine (IIa-72): Prepared in a manner similar to the above 10 described Method E to, afford an off-white solid, mp 265 268"C; H NMR (DMSO) b 0.49-0.56 (2H, m), 0.79-0.83 (2H, m), 1.55-1.70 (1H, m), 2.06 (3H, s), 3.89 (3H, s), 5.61 (iN, s), 7.25 (1H, d), 7.33 (1H, t), 7.56 (2H, d), 7.74 (2H, d), 8.07 (1H, d), 10.17 (1H, S), 10.26 (1H, S), 15 11.94 (1H, br s); IR (solid) 3250, 1671, 1617, 1595, 1536, 1480, 1460, 1396, 1373, 1335, 1254, 1160, 1131, 1071, 1011, 984, 869,_815; MS 447.4(M+H)+ Example 73 [2- (4-Acetamidophenylsulfanyl) -8- (3 20 dimethylamino-propoxy) -quinazolin-4-yl] - (5-methyl-2& pyrazol-3-yl)-amine (IIa-73): Prepared in a manner similar to the above described Method E to afford an off white solid, mp 170-172*C; 1 H NMR (DMSO) .8 1.91 (2H, quint.), 2.0,3 (3H, s), 2.09 (3H, s), 2.17 (6H, a), 2.40 25 (2H, t), 4.10 (2H, t), 5.59 (IN, s), 7.23 (1H, d), 7.30' (1H, t), 7.57 (2H, d), 7.73 (2H, d), 8.06 (1H, d),.10.20 (1H, s), 10.24 (1H, s), 12.02 (1H, br s); IR (solid) 3234, 3108, 1675, 1614, 1592, 1531, 1484, 1395, 1371, 1338, 1316, 1253, 1161, 1137, 1062, 1038,-994, 958, 823; 30 MS 492.4(M+H)* Example 74 [2-(4-Acetamidophenylsulfanyl)-7-hydroxy quinazolin-4-yll - (5-methyl-2R-pyrazol-3-yl) -amine -252 (IIa-74): Prepared from IIa-40 according to Method H to afford an off-white solid, mp 246-248*C; 'H NMR (DMSO) & 2.00 (3H, 5), 2.08 (3H, S), 5.52 (1H, s),- 6.78 (1H, s), 6.87 (1H, d), 7.54 (2H, d), 7.72 (2H, d), 8.37 (1H, d), 5 10.06 (1H, s)'' 10.17 (1H, s), 10.37 (H, s),-11.95 (1H, br a); IR (solid) 1661, 1633, 1594, 1572, 1539, 1492, 1420, 1389, 1359, 1298, 1223, 1176, 1148, 1087, 1026, 1010, 965; MS 407.4(M+H)* 10 Example 75 (2-(4-Acetamidophenylsulfanyl)-7-(3 dimethylamino-propoxy) -quinazolin-4-yl] - (5 -methyl-25 pyrazol-3-yl)-amine (IIa-75): Prepared in a- manner similar to the above described.Method I to afford an off white solid, mp 249-2500C 1 'H NMR (DMSO) 8 1.90 (2H, 15 quint.), 2.01 (3H, s), 2.09 (3H, s), 2.19 (6H, s), 2.42 (2H, m), 4.12 (2H, t), 5.55 (1H, a), 6.93 (1H1, s), 6.98 (iH, d), 7.55 (2H, d), 7.73 (2H, d), 8.43 (1H, d), 10.21 (1H, s), 10.23 (iH, s), 11.98 (1H, br s); IR (solid) 3272, 1677, 1615, 1571, 1558, 1530, 1501, 1434, 1420, 20 1394, 1344, 1320, 1292, 1263, 1222, 1168, 1048, 1034, 1005,. 967, 864, 844; MS 492.4(M+H)* Example 76 (2-{4- [2- (tert-Butoxycarbonyl-methyl-amino) acetylamino-phenylsulfanyl}-quinazolin-4-yl)-(5-methyl 25 2H-pyrazol-3-yl)-amine (IIa-76): Prepared in a manner similar to the above described Method E to afford a white solid, mp 228-229 0 C (dec.); 3'H NMR (DMSO) 6 1.37 (3H, s)., 1.40 (3H, s), 2.02 + 2.03 (3H, 2xs), 2.88 + 2.90 (3H, 2xs), 4.01 +4.02 (2H, 2xs), 5.52 + 5.57 (1H, 2xs), 7.47 30 (1H, t), 7.55-7.63 (3H, m), 7.75-7.80 (3H, m), 8.60 (1H,d), 10.28 + 10.30 (1H, 2xs), 10.45 (1H, s), 12.08 (1H, s).; IR (solid) 1698, 1683, 1653, 1617, 1594, 1559, -253 1538, 1532, 1507, 1488, 1457, 1418, 1397, 1364, 1346, 1307, 1287, 1246, 1151, 842, 827, 759; MS 520.4 (M+H)* Example 77 (2-[4-( 2 -Methylamino-acetylamino) 5 phenylsultanyl]-quinazoli-n-4-yl}-(5-methyl-2H-pyrazol-3 yl)-amine (IIa-77): Prepared in a manner similar to the above described Method E to afford a white solid, mp 242 244 0 C; H NMR (DMSO) 82.01 (3H, s), 2.34 (3H, s), 3.32 (2H, s), 5.58 (1H, s), 7.45 (1H, t), 7.50-7.60 (3H, m), 10 7.75 (1H, t), 7.80 (2H, d), 8.55 (1H, d), 10.10 (1H, br S), 10.42 (1H, s), 12.02 (1H, s); IR (solid) 1674, 1619, 1598, 1570, 1525, 1483, 1417, 1363, 1345, 1298, 1285, 1247, 1160, 966, 827, 804, 784, 763, 712, 670, 653; MS 420.4 (M+H)* 15 Example 78 [2-(4-Acetamidophenylsulfanyl) -8-fluoro quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Ila 78): Prepared in a manner similar to the above described Method E to afford a white solid, mp 257-259"C; 'H NMR 20 (DMSO) 82.01 (3H, s), 2.09 (3H, a), 5.49. (1H, s), 7.42 (1H, t), -7.57-7.68 (3H, m), 7.75 (2H, d), 8.40 (1H, d), 10.28 (1H, s), 10.75 (1H, s); "F NMR (DMSo) 8-127.3 ; IR (solid) 1690, 1670, 1637, 1609, 1588, 1543, 1519, 1493, 1456, 1434, 1395, 1366, 1332, 1315, 1289, 1254, 1242, 25 1032, 838, 829, 808, 744; MS 409.4(M+H)* Example 79- (1H-Indazol-3-yl)-(2-phenylsulfanyl quinazolin-4-yl)-amine (IIaT79): Prepared in a manner similar to the above described Method E to afford a white 30 solid. 1H NMR (DMSO) 8 7.07 (m, 3H), 7.19 (t, 1H), 7.37 (d, 2H), 7.39 (t, 1H), 7.52 (dd; 1H), 7.54 (t, 1H),. 7.55 -254 (d, 1H), 7.56 (t, 1H), 7.83 (t, 1H), 8.53 (d, 1H), 10.71 (s, 1H), 12.85 (s, 1H); MS 370.1 (M+H4)* Example 80 (2- [(2-Hydroxyethyl)phenylamino -quinazolin-4 5 yl}-(5-methyl-2H-pyrazol-3-yl)-amine (I-Ic-1):--Prepared in a manner similar to the above described Method A to afford a brown solid, mp 2170C; 1H NMR (DMSO) 8 1.99 (3H, s), 3.69 (2H, t), 4.05 (2H, t), 5.00 (1H, br s), 5.53 (1H, br s), 7.09 (1H, m), 7.25-7.40 (4H, m), 7.40-7.48 10 (2H, m), 7.54 (1H, m), 8.34 (1H, m), 10.07 (1H, S), 11.67 (1H, br s); IR (solid) 3395, 3155, 3052, 2934, 1623, 1598, 1577, 1475, 1434, 1393; MS 361.2 (M+H)* Example 81 [2-(Methylphenylamino)-quinazolin-4-yl]-(5 15 methyl-2H-pyrazol-3-yl)-amine (IIc-2): Prepared in a manner similar to the above described Method A to afford a white solid, mp 154-156*C; "H NMR (DMSO) S 2.03(3H, s), 3.51(3H, s), 5.70(1H, s), 7.13(1H, m), 7.36-7.25(3H, m), 7.48-7.37 (3H, m),_.7.58 (1H, m),.8.38 (1H, d), 9.98(1H, 20 s), 11.91 (1H s); IR (solid) 1621, 1598, 1578, 1540, 1494, 1473, 1398, 1374; MS 331.0 (M+H)* Example 82- (5-methyl-2H-pyrazol-3-yl)-{2-[N-methyl-N (pyridin-3-ylmethyl)amino]-quinazolin-4-yl}-amine 25 (IIc-3): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 1770C; 1H NMR(DMSO) 8 0.45.(2H, s), 0.84 (2H, s), 1.80 (1H, s), 3.16 (3H, s), 4.93 (2H, s), 6.18 (1H, br s), 7.10 (1H, t), 7.34 (2H, a), 7.55 (1H, t), 7.64 (1H, s), 8.36 (1H, 30 d), 8.45 (1H, s), 8.52 (1H, a), 10.03 (1H, s), 12.17 (11H, s); IR (solid) 3104, 2995,.2936, 1618, 1591, 1559, 1541, 1518, 1477, 1409, 1386, 1350, 1300, 1018, 991, 873, 827; MS 372.3 (M+H)*, -255 Example 83 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino quinazolin-4-yl)-amine (IIc-4): Prepared in a manner similar to the above described Method A to afford a white 5. solid; 'H NMR (DMSO @60*C) 8 2.27(3H, s); 6.47(1H, br s), 6.92(1H, m), 7.31(3H, m), 7.53(1H, m), 7.70 (1H, m), 7.91 (2H, m), 8.37 (2H, d), 9.16 (1H, br s), 10.05 (1H,- br s), 12.15 (1H, br s); IR (solid) 1623, 1601, 1573, 1541, 1478; MS 317.0 (M+H) t 10 Example.84 ( 2 -Benzylamino-quinazolin-4-y1)-(5-methyl-2H pyrazol-3-yl)-amine (IIc-5): Prepared -in a manner similar to the above described Method A to afford a white solid, mp 225-227*C; 11 NMR (DMSO) & 2.20 (3H, s), 4.62(2H, d), 15 7.18 (1H, s), 7.43-7.60(8H, m), 8.22 (1H, s), 9.99 (1H, br s), 12.05 (1H, br s); IR (solid) 1630, 1609, 1578, 1538, 1511; MS 331.0 (M+H)' Example 85 .(2-Cyclohexylamino-quinazolin-4 -yl) - (5-methyl 20 2H-pyrazol-3-yl)-amine (IIc-6) Prepared in a manner similar to the above' described Method A to'afford an of f white solid, mp 280 0 C (dec.); IH NMR (DMSO)- 1.11 1.44(5H, m), 1.56 (1H, m), 1.71(2H, m), 1.92 (2H, m), 2.26(3H, s), 3.75(1H, s), 6.63 (1H, br s), 7.04 (1H, s), 25 7.28 (1H, s), 7.51(1H, m), 8.26(1H, s), 9.97(1H, br s), 12.08(1H, br s), 12.75(1H, br s); IR (solid) 2927, -2853, 1619, 1596, 1569, 1522, 1482; MS 323.0 (M+H) 4 Example 86 [2-(2,3-Dihydrobenzo[1,4]dioxin-6-ylamino) 30 quinazolin-4-yl]-(5-methyl-2R-pyrazol-3-yl)-amine (11c-7): Prepared in a manner similar to the above described Method A to afford an off-green solid, mp -256 >250*C; 1H NMR (DMSO) 8 2.23 (3H, S), 4.15 (4H, m), 6.32 (1H, br a), 6.76 (1H, d), 7.16 (1H, t), 7.22 (1H, dd), 7.39 (1H, d), 7.57 (1H, t), 7.66 (1H, a), 8.34 (iH, d), 9.07 (1H, br a), 10.20 (1H, br s), 12.15 (iH, br s); IR S (solid) 3445, 3045, 2968, 2927, 2868, 1618, -1595, 1577, 1559, 1509, 1441, 1377, 1073; MS 375.1 (M+H)* Example 87 (2-Cyclohexylmethylamino-quinazolin-4-yl) - (5 methyl-2H-pyrazol-3-yl)-amine (I1c-8): Prepared'in a 10 manner similar to the above described Method A to afford a white solid, mp 2110c; 'H NMR (DMSO) 8 0.85-1.30 (5H, m), 1.50-1.85 (6H, m), 2.22 (3H, s), 3.19 (2H, s), 6.50 7.00 (1H, br s), 7.06 (iH, br s), 7.29 (1H, br s), 7.51 (1H, tY, 8.26 (1H, br s), 9.97 (1:H, br a), 12.04 (1H, br 15 s), 12.75. (1H, br s); IR (solid) 3333, 2927, 2850, 2831, 1627, 1609, 1577, 1540, 1508, 1449, 1422, 1340, 98B; MS 337.4 (M+H)* Example 88 -[2- (1K-Indazol-6-ylamino) -quinazolin-4-yl] -(5 20 methyl-2H-pyrazol-3-yl)-mine -(IIc-9): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >250*C; 'H NMR (DMSO) 8 2.24 (3H, s), 5.93 and 6.89 (1H, 2xbr s), 7.05-8.15 (6H, m), 8.25 8.90 (2H, m), +9.25 and 9.97 (1H, 2xbr s), 10.11 and 10.57 25 (1:H,~2xbrs), 12.15 and 12.80 (2H, 2xbr s); IR (solid) 3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467; MS 357.1 .(M+H)* Example89 (5-Methyl-2H;pyrazol-3-yl)-[2-(pyridin-3 30 ylmethylamino) -quinazolin-4-ylJ -amine (lIc-10):. Prepared in a manner similar to the above described Method A to afford an off-white solid,- mp 2180C; 'H NMR (DMSO) 6 2.20 -257 (3H, s), 4.59 (2H, S), .6.30 (iH, br a), 7.10 (1H, s), 7.33 (2H, s), 7.54 (iH, a), 7.78 (1H, s), 8.31 (iH, s), 8.43 (1H, s), 8.61 (1H, S), 10.0 (1:H, br s), 12.15 (1H, br s); IR (solid) 3368, 2945, 2919, 2858, 1623, 1593, 5 1577, 1552, 1501,-1475i- 144-9-, 1383; MS 332.1- (M+H)* Example 90 [2-(3-Chlorophenylamino)-quinazolin-4-yll-(5 methyl-2H-pyrazol-3-yl)-amine (Ilc-11): Prepared in a manner similar to the above described Method A to afford 10 an off-white solid, mp >2500C, 'H NMR (DMSO) a 2.29 (3H, s), 5.30-6'.98 (1H, m), 6.96 (iH, a), 7.28 (2H, s), 7.51 (1H, s), 7.67 (1H, s), 7.77 (iH, s), 8.23 (1H, s), 8.46 .(lH, a), 9.35 and 10.00 (1H, 2xbr s), 10.14 and 10.64 (iH, 2xbr s), 12.20 and 12.82 ~(1H, 2xbr s); IR (solid) 15 3447, 3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549, -1472, 1440, 1403, 1372; MS 351.1 (M+H)* Example 91 [2-(4-Chlorophenylamino)-quinazolin-4-yl3-(5 methyl-2H-pyrazol-3-yl)-amine (IIc-12): Prepared in a 20 manner similar to the above described Method A to afford an off-white solid, mp >250*C; 'H-NMR (DMSO) 8 2.27 (3H, . s), 5.20-6.80 (1H, m), 7.26 (iH, s), 7.33 (2.H, s), 7.51 (1H, s), 7.66 (iH, s), 7.99 (2H, d), 8.42 (1H, s), 9.29 and 9.93 (iH, 2xbr S), 10.13 and 10.55 (1H, 2xbr s), ..25 12.19 and 12.81 (1H, 2xbr a); IR (solid) 3439, 3057, . 2957, 1618, 1600, 1586, 1572, 1550, 1504, 1486, 1431, 1413, 1367; MS 351.1 (M+H)* Example 92 [2- (4-Fluorobenzylamino) -quinazolin-4-yl -(5 30 methyl-2H-pyrazol-3-yl)-anine (Ic-13): Prepared in a manner similar to the above described Method A to afford a white solid, mp 216"C; 'H NMR (DMSO) 8 2.20 (3H, b), -258 4.56 (2H, d), 6.30 (1H, br S), 7.05-7.20 (3H, m), 7.31 (iH, d), 7.42 (2H, s), 7.54 (1H, t), 8.32 (iH, s), 10.01 and 10.34 (1H, 2xbr s), 12.09 and 12.'75 (1H, 2xbr s); IR (solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508, 1367; 5 MS 349.3 .(M+H)* Example 93 (2- [2- (2 -Hydroxyethyl) phenylamino] -quinazolin 4-yl}-(5-methyl-2a-pyrazol-3-yl),-amine (IIc-14): Prepared in a manner similar-to the above described Method A to 10 afford a white solid, mp 2220C; 1 H NMR (DMSO) 8 2.09 (3H, s), 2.80 (2H, t), 3.61 (2H, t), 4.87 (1H, br a), 5.85 (i, br s), 7.30-7.53 (SH, m), 7.63 (1H, d), 7.86 (1H, t), 8.68 (1H, d), 10.11 (1H, br s), 11.55 (1H, br s), 12.49 (iH, br s), 13.50 (1H, br s); IR (solid) 3193, 15 3171, 3111, 3084, 1636, 1577, 1559, 1509, 1486, 1413, 1340, 1058; MS 361.3 (M+H)* Eaple 9 4 [2- ( 4 -Cyanomethylphenylamino) -quinazolin-4 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (lIc-15): Prepared 20 in a manner similar to the above described Method A to afford an off-white solid, mp >25000; 'H NMR (DMSO) 2.23 (3H, s), 4.09 (2H, s), 6.28 (iH, br s), 7.41 (2H, d), 7.48 (1H, t), 7.57-7.63 (3H, m), 7.87 (1H, t), 10.70 (1H, s), 11.56 (1H, a), 12.63 (1H, br s), 13.25 (1H, br s); IR 25 (solid) 3294, 3271, 3093, 1641, 1586, 1568, 1550, 1513, 1481, 1413, 1336, 1158, 999; MS 356.2 (M+H) Example 95 [2- ( 3 -Hydroxymethylphenylamino) -quinazolin-4 yll-(5-methyl-2H-pyrazol-3-yl)-amine (Ilc-16): Prepared 30 in a manner similar to the above described Method A to afford an off-white solid, mp >250"C; 'H NMR (DMSO) 8 2.20 (3H, s), 4.53 (2H, s), 5.22 (1H, br s), 6.31 (iH, br s), 7.24 (iH, d), 7.33-7.53 (4H, m), 7.61 (1H, d), 7.86 (iH, -259 t), 8.67 (1H, d), 10.61 (1H, br s), 11.52 (1H, br s), 12.59 (1H, br s), 13.10 (1H, br s); IR (solid)'3401, 3209, 3108, 3071, 2975, 2916, 1632, 1609, 1595, 1554, 1485, 1421, 1371, 1348, 1046, 1005, 813; MS 347.3 (M+H)* 5. - .

Example 96 [2- (3-Hydroxyphenylamino) -quinazolin-4-yl -(5 methyl-20-pyrazol-3-yl)-amine (Ilo-17): Prepared in a manner similar to.the above described Method A to afford a white solid, mp >250 0 C; 'H NMR (DMSO) 8 2.22 (3H, s), 10 6.42 (1H, br s), 6.72 (1H, d), 6.97 (2H, s), 7.21 (1H, t), 7.47 (1H, t), 7.60 (1H, d), 7.85 (1H, t), 8.67 (1H, d), 9.76 (iH, S), 10.53 (iH, s), 11.53 (1H, s), 12.58 (1H, br s), 12.99 (i, br s); IR (solid) 3354, 3027, 2893, 2817, 1654, 1588, 1541, 1490, 1436, 1418, 1332, 15 1154, 1004; MS 333.2 (M+H)* Example 97 (5-Cyclopropyl-2E-pyrazol-3-yl)-(2 phenylamino-quinazolin-4-yl)-amine.(IIc-18): Prepared in a manner similar to the above described Method A to 20 afford an off-white solid, mp 234 0 C; 'H NMR (DMSO) 8 0.74 (2H, s), 0.92 (2Hf s), 1.91 (1H, s), 5.83 and 6.54 (1H, 2xbr s), 6.94 (1H, t), 7.30 (3H, m), 7.50 (iH, s), 7.65 (1H, s), -7.91 (2H, d), 8.27 (1H, s), 9.13 and 9.77 (1H, 2xbr s), 10.07 and 10.52 (H, -2xbr s), 12.19 and 12.82 25 (iH, 2xbr s); IR (solid) 3443, 1622, 1595, 1577, 1554, 1486, 1449, 1413, 1376, 1340, 1235, 1171, 988, 806; MS 343.2 (M+H)* Example 98 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3 30 methylphenylamino) -quinazolin-4-yl -amine (Io-19): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 117"C; 'H NMR (DMSO) 8 0.72 (2H, s), 0.92 (2H, s), 1.90 (1H, m), 2.32 -260 (3H, s), 6.20 (1H, br s), 6.80 (1H, d), 7.20 (1H, t), 7.27 (1H, br s), 7.51 (1H, br s), 7.55-7.85 (3H, m), 8.43 (1H, br s), 9.50 (1H, br s), 10.44 (1H, s), 12.55 (1H, br s);'IR-(solid) 3303, 1618, 1581, 1554, 1536, 1495, 1472., 5 1436, 1413, 1372, 1336, 1240, 990; MS 357.4 (M+H)* Example 99 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (6 methoxypyridin-3-ylamino)-quinazolin-4-yl]-amine (Ic-20): Prepared in a manner similar to the above 10 described Method A to afford a pink solid, mp 120 0 C; IH NMR (DMSO) 6 0.-72 (2H, s) , 0. 91 (2H, s) , 1. 89 (1H, m) , 3.85 (3H, s), 6.20 (1U1, br s), 6.82 (1H, d), 7.25 (1H, s),. 7.48 (1H, m), 7.66 (1H, t), 8.13 (1H, br s), 8.42 (1H, br s), 8.61 (iH, br s), 9.50 (1H, br s), 10.48(1H, 15 br s), 12.55 (1H, br s); IR (solid) 3457, 3439, 1622, 1604, 1577, 1554, 1481, 1422, 1386, 1363, 1272, 1235, 1035, 985, 821; MS 374.2 (M+H)* Example 100 (5-Cyclopropyl-2a-pyrazol-3-y1)-[2-(indan-5 20 ylamino)-quinazolin-4-yl]-amine (IIc-21): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 199-204*C; 1H NMR (DMSO) 8 0.69 (2H, br s),, 0.91 (2H, br s), 1.90. (1H, m), 2.02 (2:H, m)., 2.68 (1H, m), 2.83 (3H, m), 6.46 (1H, br s),. 7.18 (1H, 25 d), 7.26 (1H, br s), 7.50 (1H, d),'7.67 (1H, t), 7.75 (1H, br s), 8.45 (1H, br s),.. 9.70 (1H, br s), 10.60 (lH, br s), 12.30 and 12.80 (1H, 2xbr s); IR (solid) 1621, 1601, 1572, 1552, 1495, 1474, 1439, 1425, 1408, 1382, 1363, 1319, 1267; MS 383.3 (M+H)* t 30 Example 101 (5-Cyclopropyl-2H-pyrazol-3-yl) - [2- (lE-indol 6-ylamino)-quinazolin-4-yl]-amine (IIc-22): Prepared in a manner similar to the above described Method A to afford -261 a dark brown solid, mp >3000C; 'H NMR (DMSO) 8 0.69 (2H, br s), 0.89 (2H, br s), 1.88 (1H, M), 5.77 and 6.74 (1H, 2xbr s), 6.35 (1H, s), 7.22 (3H, br S), 7.45 (2H, d), 7.65 (1H, s), 8.35 (2H, br s), 8.86, 9.70 and 10.01 (IH, 5 3xbr s)', 10:49, 12.12 'and 12:84 '(iH, 3xbr s), '10.94 (s, 1H); IR (solid) 1623, 1603, 1571, 1549, 1495, 1477, 1460, 1419, 1383, 1336, 1264, 1250, 1238; MS 382.4 (M+H) 4 Example 102 [2-(4-Acetamido-3-methylphenylmino) 10 quinazolin-4-yl]-(S-cyclopropyl-2-pyrazol-3-yl)-amine (IIc-23): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >1881C (dec.); 'H NMR (DMSO) 6 0.72 (2H, br s), 0.94. (2H, br s), 1.92 (1H, m), 2.03 (3H, s), 2.19 (3H, s), 5.80 and 15 6.69 ,(1H, 2xbr s), 7.22 (2H, br s), 7.49 (1H, br s), 7.70 (3H, m), 8.35.(1H, br S), 9.01, 9.59 and 10.01 (1H, 3xbr s), 9.19 (1H, s), 10.53, 12.16 and 12.81 (1H, 3xbr s); IR (solid) 1637, 1624, 1578, 1542, 1502, 1474, 1428, 1403, 1343, 1320, 1307, 1250;. MS 414.4 (M+H)* 20 Example 103 [2-(4-Chloro-3-methylphenylamino)-quinazolin 4-yl]-(S-cyclopropyl-2-pyrazol-3-y1)-amine (IIc-24):. Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 244-246*C; 'H 25 NMR (DMSO) 5 0.69 (2H, br s), 0.94 (2H,,br s), 1.91 (1H, m), 2.32 (3H, s), 5.89 and 6.63 (1H, 2xbr s), 7.28 (2H, m), 7.49 (1H, m), 7.65 (i, m), 7.80 (1H, br s), 7.86 (1H, s), 8.40 (1H, br s), 9.17, 9.81 and 10.06 (1H, 3xbr s), 10.58, 12.19 and 12.78 (iH, 3xbr s); IR (solid) 1615, 30 1578, 1549, 1475, 1419, 1397, 1365, 1331, 1296, 1261, .1238, 1187, 1139; MS 391.4 (M+H)* -262 Example. 104 (5-Cyclopropyl-2-pyrazol-3 -yl) - [2- (4 ethylphenylamino) -quinazolin-4-ylJ -amine (IIc-25): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 250-251*C; aH 5 NMR (DMSO) 8 0.72 (2H,- br s), 0.91 (2H, br-S), 1.19 (3H, t), 1.91 (1H, m), 2.58 (2H, q), 5.81 and 6.64 (1H, .2xbr s), 7.15 (2H, d), 7.22 (1H, S), 7.47 (1H, s), 7.64 (1H, a), 7.78 (2H, s), 8.36 (1H, br s), 9.03, 9.66 and 10.05 (1H, 3xbr s), 10.49, 12.20 and 12.80 (iH, 3xbr s); IR 10 (solid) 1603, 1574, 1546, 1509, 1497, 1474, 1439, 1417, 1386; MS 371.5 (M+H)* Example 105 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4 pi-opylphenylamino) -quinazolin-4-yl] -amine (Ilc-26): 15 Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 255-256 0 C; 11H NMR (DMSO) 6 0.72 (2H, br s), 0.91 (SH, t), 1.60 (2H, m), 1.90 (1H, m), 2.58 ,(2H, q), 5.81 and 6.63 (1H, 2xbr s), 7.12 (2H, d), 7.21 (1H, s), 7.47 (1H, s), 7.63 (1H, s), 20 7.77 (2H, s), 8.36 (iH, br s), 9.01, 9.70 and 10.11 (1H, 3x br s), 10.51, 12.17 and 12.80 (1H, 3xbr s); IR (solid) 1595, 1571, 1545, 1499, 1477, 1442, 1413, 1388; MS 385.6 (M+H)* 25 Example 106 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2-[4-(2 hydrcxyethyl) phenylamino] -quinazolin-4-yl}-amine (IIc-27): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 255 256 C; IH NMR (DMSO) 8 0.73 (2H, br s), 0.91 (5H, t), 1.90 30 (1H, m), 2.69 (2H, t),~3.60 (2H, q), 4.62..(1H, t), 5.81 and 6.65 (1H, 2xbr s), 7.15 (2H, d), 7.22 (1H, s), 7.46 (1H, s), 7.63 (1H, s), 7.77 (2H, s), 8.36 (iH, br s), -263 9.05, 9.69 and 10.02 (1H, 3xbr s), 10.52, 12.17 and 12.79 (1H, 3xbr s) ; IR (solid) 1632, 1569, 1546, 1483, 1452, 1434, 1402, 1371, 1267, 1231; MS 387.4 (M+H)* 5 Example 107 ( 5 -Cyclopropyl-2H-pyrazol-3-yl) -(2 phenetylamino-quinazolin-4-yl)-amine (IIc-28): Prepared in a manner similar to the above described Method A to afford a white solid, mp >2500C; 'H NMR (DMSO) 5 0.66 (2H, m), 0.84 (2H, m), 1.83 (1H, m), 2.90 (2H, t), 3.56 (2H, 10 m), 6.29 (1H, br s), 7.01 (11H, t), 7.12-7.38 (6H, m), 7.48 (1H, t), 8.42 (1H, s), 10.91 (1H, br s), 13.11 (1H, br s); IR (solid) 2922, 1650, 1627, 1577, 1550, 1500, 1482, 1395, 1368, 1004, 832; MS 371.3 (M+H)* 15 Example 108 [2-( 2 -Cyclohexylethylamino)-quinazolin-4-yl] (5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIc-29): Prepared in a manner similar to the above described Method A to afford a white solid, mp >2500C; IH NMR (DMSO) 5 0.70 (2H, s), 0.80-1.00 (4H, m), 1.05-1.30 (4H, m), 1.30-1.50 (3H, 20 m), 1.55-1.80 (5H, m), 1.87 (1H, s), 5.40-6.70 (2H, br s), 7.04 (1H, s), 7.25 (1H, s), 7.49 (1H, s), 8.25 (1H, s), 10.06 (1H, br s), 11.93 (1H, br s); IR (solid) 3448, 2920, 2852, 1618, 1600, 1568, 1550, 1486, ~1418, 1395, 1367, 1258, 1008, 985; MS 377.4 (M+H)* 25~ Example 109 [2-( 4 -Carboxymethoxyphenylamino)-quinazolin 4-yl]-(S-cyclopropyl-2B-pyrazol-3-yl)-amine (IIc-30): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp >250"C; 'H NMR 30 (DMSO) 0.72 (2H, m), 0.91 (2H, m), 1.90 (1H, m), 4.62 (2H, s), 6.24 (1H, s), 6.88 (21H, s), 7.21 (1:H, m), 7.45 (1H, m), 7.62 (111, m), 7.78 (2H, m), 8.35 (1H, m), 9.31 (1H, s), 10.25 (1H, s), 11.70 (1H, br s);JIR (solid) -264 1663, 1595, 1563, 1509, 1422, 1331, 1240, 1176, 1053, 999; MS 417.3 (M+H)* Example 110 [2- (4-Cyanomethylphenylamino) -quinazolin-4 5 yl]-(5-cyclopropyl-2H-pyra-zol-3-yl).-amine- (Ioa-31): Prepared in a manner similar to the above described Method A to afford a white solid, mp 222 0 C; 'H NMR (DMSO) 8 0.74 (2H, m), 0.93 (2H, m), 1.92 (1H, m), 3.97 (2H, s), 5.82 and 6.65 (1H, 2xbr s), 7.29 (3H, m), 7.50 (1H, m), 10 7.66 (1H, m), 7.92 (2H, m), 8.39 (1H, m), 9.21 and 9.85 (1H, 2xbr s), 9.90 and 10.56 (1H, 2xs), 12.19 and 12.80 (1H, 2xbr s); IR (solid) 1641, 1622; 1595, 1581, 1554, 1513, 1486, 1463,.1408, 1372, 985, 821;.MS 382.3 (M+H) 4 15 Example 111 (2-(Benzothiazol-6-ylamino)-quinazolin-4-yl] (5-cyclopropyl-2-pyrazol-3-yl)-amine (IIc-32): Prepared in a manner similar to -the above described Method A to afford an off-white solid, mp 255-256OC; 'H NMR (DMSO) 8 0.73 (2H, m), 0.92 (2H, m), 1.92 (1H, m), 5.83 and 6.63 20 (1H, 2xbr -s), 7.27 (1H, br s), 7.59 (1H, br s), 7.68 (1H, br s), 7.79 (1H, br-s),.7.98 (1H, br s), 8.41 (1H, br s), 8.97 (1H, br s), 9.19 (1H, s), 9.58 and 10.10 (1H, 2xbr s), 10.57, 12.21 and 12.85 (1H, 3xbr s); IR (solid) 1624, 1592, 1575, 1512, 1472, 1411, 1377, 1333, 1244; MS -400.3 25 (M+H)+ Example 112 (5-Cyclopropyl-2Hapyrazol-3-yl)-[2-(3,4 dimethylphenylamino)-quinazolin-4-yl]-amine (IIc-33): Prepared in a manner similar to the above described 30 Method A to afford a-white solid, mp 245-246*c; I NMR (DMSO) 8 0.72 (2H, br s), 0.90 (2H, br s), 1.90 (1H, m), 2.18 (3H, a), 2.23 (3H, s), 5.77 and 6.63 (1H, 2xbr s), -265 7.09 (1H, d), 7.23 (1H, br s), 7.47. (1H, br S), 7.59 (1H, br s), 7.64 (1H, br s), 8.36. (1H, br s), 9.02, 9.55 and 10.07 (1H, 3xbr s), 10.49, 12.31 and 12.80 (1H, 3xbr s); IR (solid) 1620, 1600, 1574, 1552, 1497, 1474, 1436, 5 1416, 1 3 8 5,- 1262; MS 371.5 (M+H)* Example 113 -( 5 -Cyclopropyl-2H-pyrazol-3-yl)-[2-(2 phenoxyethylamino) -quinazolin-4-yl] -amine (IIc-34): Prepared in -a manner similar to the above described 10 Method A to afford a white solid, mp 203 0 C; 1 H NMR (DMSO) - 0.70 (2H, m), 0.88 (2H, M), 1.87 (1H, m), 3.73 (2H, d), 4.16 (2H, s), 5.75 and 6.70 (1H, 2xbr s), 6.93 (1H, t), 6.90-7.20 (3H, m), 7.20-7.45 (3H, m), 7.55 (1H, s), 7.76 (1H, br s), 8.32 (1H, s), 9.95 and 10.35 (1H, 2xs), 12.13 15 and 12.75 (1H, 2xbr s); IR (solid) 3434,. 1622, 1600, 1572, 1554, 1499, 1476, 1422, 1399, 1385, 1303, 1267, 1226, 1212, 1052, 829; MS 387.4 (M+H)* Example 114 (5-Cyclopropyl-2H-pyrazol-3 -yl) - [2- (thi.ophen 20 2-methylamino)-quinazolin-4-yl]-amine (IIc-35): Prepared in a manner similar to the above described Method A to afford a white solid, mp 212 0 C; 'H NMR (DMSO) S 0.67 (2H, m), 0.90 (2H, m), 1.86 (1H, m), 4.74 (2H, d), 5.76 and 6.66 (1H, 2xbr s), 6.95 (1H, a), 6.90-7.20 (2H, m), 25 7.20-8.45 (5H, m), 9.94 and 10.40 (1H, 2xs), 12.13 and 12.71 (1H, 2xbr s); IR (solid) 3444, 2948, 2847, 1622, 1600, 1559, 1500, 1481, 1418, 1390, 13.58, 1336, 1313, 1263, 1217, 1185, 1149, 990, 821; MS 363.4 (M+IH)* 30 Example 115 [2- (4-Carboxymethylphenylamino) -quinazolin-4 yl]-(S-cyclopropyl-2H-pyrazol-3-yl)-amine (IIc-36): Prepared in a manner similar to the above described Method A to afford a brown solid, mp >2100C (dec.); 'H NMR -266 (DMSO) 8 0.64 (2H, br s)., 0.92 (2H,' m), 1.92 (1H, m-) 3.50 (2H, s), 5.76 and 6.54 (1H, 2xs), 7.19 (1H, s), 7.24 (1H, m), 7.49 (1H, d), 7.64 (iH, t), 7.84 (2H, d), 8.37 (1H, m) , 10.27 and 12.25 (1H, 2xbr s) ; IR (solid) 1648, 5 1591,- 1555;' 1512, 1489, 1428, 1411, 1374; MS 401.4 (M+H)* Example 116 (5-Cyclopropyl-2H-pyrazol-3-y1)-[2-(1H indazol-5-ylamino)-quinazolin-4.-yl]-amine (IIc-37):* Prepared in a -manner similar to the above described 10 Method A to afford, a purple solid, mp 268-271*C; 'H NR (DMSO) 8 0.69 (2H, br s), 0.90 (2H, m), 1.88 (1H. m), 5.86 and 6.58 (1H, 2xs), 7.22 (iH, s),- 7.61 (1H, s), 7.71 (2H, m), 8.01 (1H, s), 8.37 (2H, s), 8.58, 9.05 and 9.58 (1H, 3xbr s), 10.01, 10.68 and 12.38 (1H, 3xbr-s), 12.90 15 (1H, s); IR (solid) 1626, 1605, 1576, 1546, 1512, 1495, 1476, 1447, 1431, 1416, '1393, 1261, 1224; MS 383.3 (M+H)* Example 117 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(pyridin 3 -ylmethylamino)-quinazolin-4-yl]-amine (IIc-38): 20 Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 193*C; 'H NMR (DMSO) 8 0.69 (2H, m), 0.89 (2H, m); 1.86 (1H, m), 4.60 (2H, s), 5.76, 6.22-and 6.66 (1H, 3xbr-s), 7.10 (1H, s), 7.33 (2H, s), 7.54 (1H, s), 7.78 (1H, s), 8.31 (1H, s), 8.44 25 (1H, s), 8.61 (1H, s); 10.00 and 10.32 (1H, 2xs), 12.15 and 12.63 (1H, 2xbr s); IR (solid) 2927, 2850, -1623, 1600, 1577, -1536, 1477, 1418, 1332, 1254, 814; MS 358.3 (M+H)+ 30 Example 118 (5-Cyclopropy1-2a-pyrazol-3-y1)-[2-(3 methoxycarbonylphenylamino) -quinazolin-4-y1] -amine (I1c-39): Prepared in a manner similar to the above -267 described Method A to afford a white solid, mp 228-231 0 C; 'H NMR (DMSO) 8 0.73 (2H, br s), 0.91 (2H, m), 1.92 (1H, m), 3.88 (3H, s), 5.99 and 6.79 (1H, 2xs), 7.27 (1H, s), 7.46 (3H, m), 7.68 (1H, s), 8.36 (I , d), 8.48 (2H, s), 5 9.36, 9.84 and 10.00 (iH, 3xbr s), 10.63, 12.17 and 12.79 (1H, 3xbr s); IR (solid) 1716, 1615, 1591, 1579, 1557, 1473, 1432, 1416,-1379, 1334, 1298, 1276,.1226, 1191, 1142, 1110, 1020, 985; MS 401.3 (M+H)* 10 Example 119 [2-(3-Carboxyphenylamino)-quinazolin-4-y1] (5-cyclopropyl-25-pyrazol-3-yl)-amine (XIc-40): Prepared' in a manner similar to the above described Method A to afford an off-white solid, mp 298-302*C; 'H NMR (DMSO) S 0.73 (2H, br s), 0.91 (2H, m), 1.90 (1H, m), 7.26 (1H, 15 s), 7.35 (IH, t), 7.50 (2H, d), 7.66 (11, t), 8.31 (2H, m), 8.41 (1H, d);.IR (solid) 1661, 1597, 1578, 1558, 1517, 1486, 1424, 1385; MS 387.3 (M+H)* Example 12-0 (5-Cyclopropyl-2H-pyrazol-3-y1)-[2-(3 20 ethylphenylamino)-quinazolin-4-yl]-amine (Ic-41): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 186-188"C; 1H NMR (DMSO) 6 0.73 -(2H, br s), 0.91 (2H, br s), 1.22 (3H1, t), 1.90 (1H, m), 2.62 (2H, d), 5.81 and 6.70 (1H,,2 x br. 25 a), 6.78 (1H,d), 7.20 (2H, s), 7.48 (1H, s), 7.65 (1H, s), 7.69 (1H, s), 7.81 (1H, s), 8.38 (1H, bras), 9.03, 9.74 and 10.03 (1H, 3 x br S), 10.55, 12.16 and 12.82 (iH, 3 x br s); IR (solid) 1614, 1580, 1549, 1534, 1493, 1471, 1433, 1409, 1374, 1340, 1240, 1182, 1165, 1138; MS 30 371.3 (M+H)* -268 Example 121 (5-Cyclopropyl-2z-pyrazol-3-yl)-[2-(2,3 dimethylphenylamino)-quinazolin-4-yl]-amine (IIc-42): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 241-242C; 1H 5 NNR (DMSO) 8 0.58 (2H,-br s),-0.86 (2H, d), 1-.-77 (1H, br s), 2.11 (3H, br s), 2.28 (3H, s), 5.77 and 6.14 (1H, 2 x br s;), 7.01 (1H, s), 7.11 (1H, t), 7.22 (1H, br s), 7.29 (1H, d), 7.56 (1H, s), 8.36 (1H, br s), 8.49, 8.98 and 9.98 (1H, 3 x br S), 10.48, 12.04 and 12.68 (1H, 3 x br 10 S); IR (solid) 1622, 1603, 1573, 1552, 1495, 1471; 1440, 1428, 1412, 1384, 1268; MS 371.4 (M+H)* Example 122 (5-Cyclopropyl-2a-pyrazol-3-yl)-[2-(3,4 dimethoxyphenylamino) -quinazolin-4-yl] -amine (IIc-43): 15 Prepared in a manner similar to the above described Method A to afford a grey solid, mp 1440C; 'H NMR (DMSO) B 0.69 (2H, s), 0.86 (2H, d), 1.89 (1H, m), 3.61 (3H,.5), 3.67 (3H, -s), 5.76 (1H, br B), 6.12 (1H, d), 6.31 (1H, s), 6.66 (11H, d), 6.94 (1H, d), 7.27 (1H, t), 7.50. (11H, 20 d), 7.68 (1H, t), 8.45 and 9.36- (1H, br s,.rotamers), 9.42 and 10.54 (1H, s, rotamers), 12.29 and 12.82 (1H, br s, rotamers); IR (solid) 3331, 3000, 2959, 2931, 2836, 1627, 1604, 1577, 1536, 1509, 1463, 1441, 1418, 1336, 1259, 1232, 1200, 1027; MS 403.8 (M+H)+ 25 Example 123 (5-Cyclopropyl-2a-pyrazol-3-y1)-[2-(3 methoxyphenylamino)-quinazolin-4-yl]-amine (IIc-44): Prepared in a manner similar to the above described Method A to afford a grey solid, mp 207-211*C; 'H NMR 30 (DMSO) 6 0.73 (2H, br s), 0.91 (2H, br S), 1.91 (1H, m), 3.77 (3H, s), 5.81 and 6.71 (1H, 2 x br a), 6.53 (1H, d), 7.19 - 7.85 (7H, m), 8.34 (i, s), 9.08, 9.79 and 10.06 ~269 (1H, 3 x br s), 10.56, 12.16 and 12.82 (1H, 3 x br s); IR (solid) 1611, 1580, 1549, 1533, 1498, 1477, 1430, 1409, 1374, 1337, 1253, 1204, 1180, 1157, 1141, 1041,.1030,. 992; MS 373.7 (M+H)* S Example- 124 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino 5,6,7,8-tetrahydroquinazolinin-4-yl)-amine (Ic-45): -Prepared in a manner similar to the above described Method C. 10 Example 125 [2-(Biphenyl-3-ylamino)-quinazolin-4-yl]-(5 cyclopropyl-2H-pyrazol-3-yl)-amine (IIc-46): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 1530C; 1H NMR (DMSO) 5 0.73 15 (2H, s), 0.90 (2H, d), 1.89 (1H, m), 5.83 and 6.70 (1H, br s, rotamers), 7.25 (2H, d), 7.32 (2H, m), 7.50 (3H, t), 7.68 (3H, m), 8.00 (1H, d), 8.22 (1:H br s), 8.40 (1H, br s), 9.20 and 9.89 (1H, br s, rotamers), 10.06 and 10.46 (1H, s, rotamers), 12.17 and 12.84 (1H, br s, 20 rotamers); IR (solid) 3333, 1627, 1609, 1581, 1540, 1504, 1472, 1449, 1426, 1335, 1248, 1216, 1102, 988, 819;-MS .419.3 (M+H)* Example 126 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3 25 phenylprop-1-ylamino)-quinazolin-4-yl]-amine (IIc-47): Prepared in a manner similar.to the above described Method A to afford a white solid,-mp 189*C; 'H NMR (DMSO) 6 0.71 (2H, s), 0.91 (2H, s), 1.89 (3H, S), 2.69 (2H, s), 3.37 (2H, s), 5.76 and 6.66 (1H, br s, rotamers), 6.95 30 7.60 (8H, m), 8.10-8.40 (1H, m), 9.89 and 10.30 (1H, br s, rotamers), 12.10 and 12.75 (1H, br s, rotamers); IR (solid) 1622, 1595, 1572, 1545, 1499, 1481, 1417, 1390, 1367, 1048, 997, 829; MS 385.4 (M+H)* -270 Example 127 [2- ( 4 -acetamido-3-methylphenylamino) quinazolin-4-yl]-(S-methyl-21-pyrazol-3-yl)-amine (IIc-48): Prepared in a manner similar to the above 5 described Method:A to-afford-a-pale brown solid, mp, 251 0 C; 1H NMR (DMSO) 8 2.04 (3H,- s), 2.19 (3H, s), 2.56 (3H, s), 5.92 and 6.80 (1H, br s, rotamers), 7.22 (2H, s), 7.48 (111, s), 7.64 (1H, s), 7.73 (2H, s), 8.40 (1H, s), 9.05 and 9.74 (1H, br s, rotamers), 9.20 (1H, s), 10 10.05 and 10.54 (1H, br s, rotamers),. 12.15 and 12.82 (1H, br s, rotamers); IR (solid) 3309,.2972, 2936, 1641, 1604, 1577, 1536, 1504, 1468, 1423, 1409, 1377, 1341, 1304, 1259, 1223, 1100, 1009, 864;.MS 388.2 (M+H)* 15 Example 128 (5-Cyclopropyl-2a-pyrazol-3-y1)-[2-(indan-2 ylamino)-quinazolin-4-ylJ-amine (IIc-49): Prepared-in a manner similar to the above described Method A to afford a brown solid, mp 233-234"C ; 1H NMR (DMSO) 8 0.65 (2H, a), 0.84 (2H, s), 1.83 (1H, s), 2.91 (2H, m), 3.33 (2H, s), 20 4.72 (1H, s), 6.07 (1H,ybr a), 7.00-7.60 (8H, m), 8.29 (1H, s), 10.30 (1H, br s), 12.24 (1H, br a); IR (solid) 3425, 2941, 2836, 1622, 1595, 1572, 1540, 1495, 1476, 1426, 1394, 1248, 1025, 1007, 870, 833; MS 383.3 (M+H)* 25 Example 129 [2-( 3 -Methylphenylamino)-quinazolin-4-yl]-(5 methyl-2H-pyrazol-3-yl) -amine (Iac-50): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 240-242 0 c; 'H NMR (DMSO) 8 2.25 (3H, s), 2.30 (3H, s), 5.95 (1H, br s), 6.76 (1H, d), 30 7.10-7.35 (2H, m), 7.48 (1H, a), 7.55-7.85 (3H,- m), 8.40 (1H, s), 9.05 and 9.74 (1H, br s, rotamers), 10.07 and, 10.55 (1H, br S, rotamers), 12.14 and 12.81 (1H, br s, -271 rotamers); IR (solid) 3443, 2914, 2859, 1622, 1586, 1549, 1536, 1481, 1445, 1408, 1372, 1330, 1267, 1239, 1184, 1166, 1139, 993, 838, 806; MS 331.3 (M+H)" 5 Example 130 (2-( 2 -Chloro-5-methylphenylamino)-quinazolin 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (Ic-51): Prepared in a manner similar to the above described Method A to afford a grey solid, mp 246-247*C; 'H NMR (DMSO) 8 2.19 (3H, s), 2.31 (3H, s), 6.37 (1H, br s), 6.94 (1H4, d), 10 7.23 (1H, s), 7.37 (1H, d), 7.43 (1H, d), 7.64 (1H, t), 7.97 (IH, s), 8.19 (iH, s), 8.42 (14, br s), 10.17 (1H, br s), 12.19 (1H, br s); IR (solid) 3409, 2918, 2850, 1627, 1591, 1573, 1545, 1513, 1486, 1463, 1418, 1386, 1332, 1291, 1259, 1182, 1000, 827; MS 365.2 (M+H)* 15 Example 131 (5-cyclopropyl-2H-pyrazol-3-yl) -42- [4 (morpholin-1-yl)phenyl amino] -quinazolin-4-yl}-amine (IIc-52): Prepared in a manner similar to the above described Method A to afford a grey -solid, mp 275-276*C; 20 'H NMR (DMSO) B 0.71, (2H, s)-' 0.90 (2H, s), 1.89.(1H, s), 3.05 (4H, s), 3.75 (4H, s), 5.78 and 6.61 (1H, br s, rotamers), 6.93 (2H, s), 7.20 (iH, s), 7.43 (1H, s), 7.50-7.90- (3H, m), 8.39 (1H, s),- 8.95 and 9.58 (iH, br s, rotamers), 10.07 and 10.47 (1H, br s, rotamers), -12.16 25 and 12.81 (iH, br s, rotamers); IR (solid) 3245, 2990, 2972, 2959, 2936, 2918, 1618, 1577, 1559, 1509, .1477, 1445, 1413, 1382, 1264, 1223, 1150, 1109, 1050, 923, 882, 823; MS 428.3 (M+H)* - 30 Example 132 [ 2 -(Benzothiazol-6-ylamino)-guinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (Ilc-53): Prepared in a. manner similar to the above described Method A to afford an off-white solid, mp 236-239*C; 'H NMR (DMSO) 8 2.25 -272 (3H, S), 6.35 (1H, br S), 7.22 (1H, t), 7.53 (1H, d), 7.62 (1H, t), 7.76 (1H, d), 7.98 (1H, d), 8.39 (1H, d), 9.05 (1H, s), 9.17 (1H, s), 9.59 (1H, br s), 10.30 (1H, br s), 12.35 (1H, br s); IR (solid) 1622, 1605, 1567, 5 1546, 1505, 1473,-1441-, -1417; 1385, 1341, 1297, 1273, 1253, 1192, 1130; MS 374.1 (M+H)* Example 133 [2-(3,4-Dimethylphenylamino) -quinazolin-4 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-54): Prepared 10 in a manner similar to the above described Method A to afford an off-white solid, mp 249-251*C; 'H NMR (DMSO) S 2.18 (3H, br s), 2.21 (3H, br s), 2.24 (3H, br s), 5.92 and 6.80 (1H, 2.x br s), 7.05 (1H, br B), 7.21 (1H, br s), 7.46 (1H, br s), 7.64 (3H, br s),, 8.37 (1H, br s), 15 9.00, 9.51.and 9.73 (1H, 3 x br s), 10.-12, 10.54 and 12.17 (1H, 3 x br s); IR (solid) 1616, 1582, 1547, 1505, 1473, 1452, 1413, 1368, 1334, 1294, 1246, 1210, 1188, 1170, 1139; MS 345.3 (M+H)* 20 Example 134 [2-(3-Ethylphenylamino)-quinazolin-4-yl]-(5 methyl-.2H-pyrazol-3-yl)-amine (IIc-55): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 238-239 0 c; 'H NMR (DMSO) 8 1.21 (3H, t), 2.25 (3H, br S), 2.61 (2H, q), 5.92 and 6.80 25 (1H, 2 x br s), 6.78 (IH, d), 7.21 (2H, br s), 7.48 (1H, br s), 7.65 (IH, s), 7.72 (1H, s), 7.80 (1H, s), 8.40 (1H, br's), 9.09, 9.58 and 10.10 (1H, 3 x br s), 10.54, 12.26 and 12.81 (1H, 3 x br s); IR (solid) 1619, 1556, 1535, 1471, 1441, 1407, 1377, 1341, 1274, 1246, 1185, 30 1167, 1139, 995; MS 345.5 (M+H)* Example 135 [2- (3-Methoxyphenylamino) -quinazolin-4-yl ( 5 -methyl-2H-pyrazol-3-y1)-amine (lIc-56): Prepared in a -273 manner similar to the above described Method A to afford an off-white solid, mp 212-215"C; 'H NMR (DMSO) 8 2.25 (3H, br s), 3.77 (3H, s), 5.92 and 6.84 (1H, 2 x br s), 6.55 (111, d), 7.13 (2H, m), 7.41-7.50 (-2H, m), 7.65 (1H, 5 s), 7.77 (1H, s), 8.41 (1H, br s), 9.10, 9.79 and .10.10 (1H, 3 x br s), 10.55, 12.13 and 12.82 (1H, 3 x br s); IR (solid)- 1610, 1576, 1532, 1494, 1468, 1425, 1337, 1277, 1256, 1201, 1159; MS 347.4 (M+H)* 10 Example 136 [2-(4-Acetamido-3-cyanophenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIc-57): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 294 296*C; :H NMR (DMSO) 8 2.08 (3H, a), 2.28 (3H, s), 6.67 15 (1H, br s), 7.27 (1H, a), 7.43 (1H, d), 7.53 (1H, s), 7.68 (1H, s), 8.04 (1H, d), 8.4.5 (2H, s), 9.41, 10.35 and 12.18 (2H, 3 x br s), 10.00 (1H, S); IR (solid) 1620, 1583, 1558, 1237, 1508, 1477, 1446, 1413, 1373, 1341, 1292, 1259, 1241, 1180, 1162, 1142, 1105, 1030, 1000; MS 20 399.2 (M+H) Example 137 [2-(2-Methoxybiphenyl-5-ylamino)-quinazolin 4-yl]-(5-methyl-2H-pyrazol-3.-yl)-amine (IIc-58): Prepared in a manner similar to the above described Method A to 25 afford a white solid, 222-223OC; IH NMR (DMSO) 8 2.22 (3H, s), 3.75 (31H, s), 6.82 (1H, br s), 7.05-7.11 (1H, m), 7.15-7.25 (1H,' m)., 7.30-7.36 (1H, m), 7.40-7.50 (3H, m.), 7.49-7.55 (2H, m), 7.55-7.70 _(1H, m), 7.70-7.82 (1H, m), 7.90-8.02 (1H, m), 8.30-8.50 (1H, m); IR (solid) 1625, 30 1604, 1574, 1556, 1496, 1473, 1444, 1403, 1384, 1258, 1234, 1182, 1018, 824, 806, 755, 698; MS 423.4 (M+H)* -274 Example 138 [2-( 4 -Acetamidophenylamino)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIc-59): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 253-256"C; 1H NMR (DMSO) 6 2.02 5 (3H, s), 2.25 (3H, br -s), 5.92 and 6.77 ~(1H, 2 x br s), 7.21 (1H, S), 7.49 (3H, s), 7.63 '(1H, s), 7.83 (2H, d), 8.38 (1H, br s), 9.03 and 10.05 (1H, 2 x br s), 9.81 (1H, s), 12.13 and 12.80 (1H, 2 x br s); IR (solid) 1669, 1635, 1617, 1574, 1535, 1512, 1486, 1422, 1394, 1366, 10 1316, 1268, 1231, 1184, 1119, 1101;. MS 374.1 (M+H)* Example 139 [2-( 4 -tert-Butoxycarbonylamino-phenylamino) quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-60): Prepared in a manner similar to the above 15 described Method A to afford an off-white solid, mp 238 242 0 C; IH NMR (DMSO) 8 1.48 (9H, s), 2.24 (3H, s) 6.23 (1H, br a), 7.12 (1H, s), 7.36 (3H, s), 7.54 (1H, s), 7.67 (2H, d), 8.30 (1H, d),.9.14 (2H, br s), 10.24 and 12.19 (1H, 2 x br s); IR (solid) 1698, 1620, 1555, 1520, 20 1475, 1443, 1405, 1371, 1310, 1241, 1167, 1055, 996; MS 432.1 (M+H)+ Example 140 [2- (4-Cyanophenylamino) -quinazolin-4-yl] - (5 methyl-2H-pyrazol-3-yl)-amine (IIc-61): Prepared in a 25 manner similar to the above described Method A to afford an off-white solid, mp 293-298"C; "H NMR (DMSO) 5 2.25 (3H, s)., 6.50 (1H,. br s), 7.27 (1H, s), 7.51 (1H, s), 7.64~ (1H, s), 7.71 (2H, d), 8.40 (1H, s), 9.76 (1H, br 5), 10.34 (1H, br S), 12.33 (1H, br s); IR (solid) 1633, 30 1605, 1571, 1517, 1505, 1469, 1418, 1337, 1255, 1174, 1000; MS 342.1 (M+H)* -275 Example 141 (5-Methyl-2H-pyrazol-3-yl)-[2-(6-oxo-6,lOb dihydro-4aH-benzoc] chromen-2-ylamino)-quinazolin-4-yl] amine (Ic-62): Prepared in a manner similar to the above described Method A to afford a pale yellow solid, mp 293 5 298*C; 'H NMR (DMSO) 8 1.72 (3H, br s), 6.23 (IH, br s), 7.50 (1H, t), 7.66 (2H, t), 7.75 (1H, t), 7.87 (1H, t), 7.77 (1H, t), 8.26 (1H, d), 8.33 (1H, d), 8.58-8.72 (2H, m), 10.55 (1H, s), 11.55 (1H,. s), 12.40 (1H, s); IR (solid) 1707, 1629, 1607, 1579, 1540, 1497, 1488, 1471, 10 1446, 1428, 1417, 1346, 1332, 1298, 1270, 1255, 1207, 1114, 998, 816., 793,- 766, 758, 710, 685; MS 435.4 (M+H)* Example 142 [2-(Biphenyl-3-ylamino)-quinazolin-4-yl]-(5 methyl-2H-pyrazol-3-yl)-amine (IIc-63): Prepared in a 15 manner similar to the above described Method A to afford a pale brown solid, mp 206-207OC; 1H NMR (DMSO) 8 2.20 (3H,s), 6.80 (1H, br S), 7.24-7.27 (2H, m), 7.36-7.40 (2H, m), 7.48-7.52 (3H, m), 7.67-7.69 (3H, m)~, 7.94 (1H, m), 8.26 (1H, m), 8.42 (1H, m), 9.30 (1H, br s), 10.16 20 (1H, br s)', 12.13 (1H, br s); IR (solid) 1593, 1578, 1544, 1498, 1479, 1414, 1384, 1251, 1209, 1003; MS 393.2 (M+H)* Example 143 [2-(4-Methoxycarbonylmethyl-3 25 methylphenylamino) -. quinazolin-4-yl] - (5-methyl-2H-pyrazol 3-yl)-amine (IIc-64): Prepared in a manner similar to the above described Method A to afford a white solid, mp 245 246*C; ;H NMR (DMSO) 8 2.23 (3H, s)', 2.26 (3:H, s), 3.63 (3H, s),.3.64 (2H, s), 5.99 (0.5H, br s), 6.80 (0.5 H, br 30 s), 7.10 (1H, m), 7.25 (1H, m), 7.50 (1H, m), 7.61-7.80 (3H, m), 8.44 (1H, m), 9.10 (0.5H, br S), 9.78 (0.5H, br S), 10.11 (0.51H, br S), 10.56 (0.51H, br s), 12.18 (0.5 H, -276 br s), 12.90 (0.5H, br s); IR (solid) 1732, 1710, 1622, 1581;. 1554, 1538, 1508, 1490, 1446, 1411, 1371, 1336, 1306, 1257, 1244, 1204, 1146, 1016, 998, 797, 754, 692; MS 403.4 (M+H)' 5 Example 144 [2- (4-Carboxymethyl-3-methylphenylamino) quinazolin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (Ic-65): A solution of [2-(4-methoxycarbonylmethyl-3 methylphenylamino) -quinazolin-4-yl] - (5-methyl-2H-pyrazol 10 3-yl)-amine (IIc-64, 200 mg, 0.5 mmol) in a mixture of methanol/water (3/1, 8 mL) was treated with IM NaOH (2 mL, 2 mmol). The mixture was heated at 700C for 2 hours and then neutralised with 1M HC1 (2mL, 2 mmol). The solid that formed was collected by filtration to afford 15 the title compound (185 mg, 95%) 'as a pale yellow solid, mp 2450C (dec.); 2H NMR (DMSO) 8 2.27 (6H, 2xs), 3.55 (2H, s), 6.49 (1H, a), 7.13 (1:H, d), 7.26 (1H, t), 7.50 (1H, d), 7.62-7.78 (3H, m), 8.42 (1H, d), 9.34 (1H,d), 10.26 (1H, s), 12.36 (1H, s)-; IR (solid) 1660, 1590, 1562, 20 1504. 1427,-1385, 810, 776, 751, 693; MS 389.4 (M+H)* Example 145 [2- (4-Aminophenylamino) -quinazolin-4-yl]J (5 methyl-2H-pyrazol-3-yl)-amine (I16-66): A solution of [2 (4-tert-Butoxycarbonylamino-phenylamino)-quinazolin-4 25 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (lIc-60, 100 mg, 0.232 mmol) in a mixture of DCM/TFA (5/1, 12 mL) was stirred for 2 hours at room temperature. The solvents were removed In vacuo and the residue triturated in aqueous K2C03. The resulting solid was collected by 30 filtration and washed with diethyl ether to -afford I1c-66 (69 ng, 90%) as an off-white solid, mp 164-167OC; 'H NMR (DMSO) 8 2.24.(3H, s), 6.33 (1H, br s), 7.12 (211, d), 7.48 (3H, m), 7.58 (1H, d), 7.86 (1H, t), 8.64 (1H, d), -277 10.86 (1H, br s), 11.46 (iH, s); IR (solid) 1681., 1512, 1496, 1433, 1415, 1187, 1129; MS 332.4 (M+H)* Example 146 [2-(4-Bromophenylamino)-quinaz'olin-4-yl]-(5 5 methyl-2-pyrazol-3-yl)--amine.--(3Ic-67): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 290-293OC; 2H NMR -(DMSO-) 8 2.27 (3H, s), 6.71 (iH, br s), 7.22 (iH, m), 7.46-7.50 (3H, m), 7.66 (1H, m), 7.92-7.94 (2H, m), 8.38 (in, m), 9.28, 10 10.11 and 12.13 (3H, 3 x br s); IR (solid) 1619, 1572, 1548, 1486, 1436, 1409, 1372, 1238, 1186, 1136, 1071, 997; MS 395.1/397.1 (M+H)* Example 147 [2- (4- Isobutyrylamino -phenylamino) 15 quinazolin-4-yl]-(5-methyl-2u-pyrazol-3-yl)-amine (lic 68): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 176-179*C; H.NNR (DMSO) 8 1.11 (6H, d), 2.15 (3H, s),, 2.62 (1H, m), 6.25 (1H, br s), 7.41 (1H, d), 7.46'(1H, t), 7.63 (iH, d), 20 7.71 (2H, d), 7.84 (iH, t), 8.64 (1H, d), 10.00 (1H, S), 10.34 (1H, br s), 11.47 (1H, br s), 12.47 (iH, br s); IR (solid) 1676, 1653, 1585, 1561, 1512, 1423, 1407, 1312, 1199, 1177, 1128; MS 402.3 (M+H)* 25 Example 148 (5-Ethyl-2H-pyrazol-3-yl)-[2-(5-ethyl-2H pyrazol-3-ylamino)-quinazolin-4-yl]-amine (IIc-69):. To a solution of 2,4-dichloroquinazoline (0.5g, 2.51mmol) and 3-amino-S-ethylpyrazole (558 mg,.5.02 mmol) in ethanol (1imL) was added triethylamine (0.35mL, 2.51mmol) and the 30 resulting mixture was stirred' for 3 hours at room temperature. The resulting pale yellow precipitate was collected by filtration, washed with cold ethanol and dried under vacuum to afford IIc-69 (306 mg, 35%) as an -278 off-white solid, mp 248-252C; H NMR (DMSO) 8 1.30 (m, 6H), 2.72 (m, 4H), 6.12 (br.s, 1H), 6.54 and 6.90 (br. s, 1H), 7.58 (t, 1H), 7.74 (d, 1H), 7.90 (t, 1H), 8.78 (d, 1H); IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2 5 (M+H) Example 149 (1H-Indazol-3-yl)-(2-phenylamino-quinazolin 4-yl)-amine (IIc-70): Prepared in a manner similar to the above described Method -A to afford a white solid; 'H NMR 10. (DMSO) 6 6.90 (m, 3H), 7.11 (t, 1H)~ 7.19 (m, 2H), 7.44 (t, 1H), 7.57 (m, 1H), 7.62 (d, 1H), 7.67 (d, 2H), 7.71 (d, 1H), 7.93 (t, 1H), 8.59 (d, 1H), 11.55 (br. s, 1H), 13.15 (s, 1H); MS 353.2 (M+H)* 15 Example 150 (1H-Indazol-3-yl)-[2-(3 tri fluoromethylphenylamino) -quinazolin-4 -yll -amine (IIc-71): Prepared in a manner similar to the above described Method A to afford a pale yellow solid. 'H NMR (DMSO) 8-7.00 (t, 1H), 7.02 (d, 1H), 7.22 (d, 1H), 7.37 20 (td, 1H), 7.56 (m, 3H), 7.61 (d, 1H), 7.66 (d, 2H), 7.92 (t, 1H), 8.60 (d, 1H), 10.61 (br. s, 1H), 11.42 (br. s, 1H), 13.12 (s, 1H.); MS 421.2 (M+H)* Example 151 (1H-Indazol-3-yl) - [2- (4 25 trifluoromethylphenylamino)-quinazolin-4-yll-amine (IIc-72): Prepared in a manner similar to the above described Method A to afford a pale yellow solid. 1H NMR (DMSO) 8 7.08 (t, 1H), 7.16 '(d, 2H), 7.44 (m, 3H), 7.58 (t, 1H), 7.6 (t, 2H), 7.69 (d, 1H), 7.95 (t, 1H), 8.62 30 (d, 1H), 10.82 (br. s, 1H), 11.50 (br. s, 1H), 12.20 (s, 1H); MS 421.2 (M+H)* -279 Example 152 [2-(Adamantan-2-ylamino)-quinazolin-4-yl] (1H-indazol-3-yl)-amine (IIc-73):.Prepared in a manner similar to the above described Method A to afford a white solid. 3H NMR (DMSO) -S 0.83 (br. s, 1H), 0.85 (br. s, 1H), 5 1.44 (m, 4H), 1.55- (m,"3H)-, -1.63 (s, 2H)'; 1.73 (s, iH), 1.82 (s, 1H), 1.84 (s, 1H), 3.56 (m, 1H), 7.10 (t, 1H), 7.41 (t, 1K), 7.51 (t,.1H), 7.54 (d, 1H), 7.57 (d, 1H), 7.69 (d, 1H), 7.90 (t, 1H), 8.45 (d, 1H), 8.58 (d, 1H), 11.60 (s, 1H), 13.10 (s, 1H); MS 411.3 (M+H)* 10 Example 153- (1H-Indazol-3-yl)-(2-methyl-phenyl-amino quinazolin-4-yl)-amine (IIc-74): Prepared in a manner similar to the above described Method A to afford a white solid; 'H NMR (DMSO) 53.27 (s, 1H), 6.88 (t, 1H), 6.93 15 (t, 2H), 7.04 (t, 1H), 7.14 (d, 2H), 7.22.(t, 1H), 7.36 (m, 2H), 7.48 (d, 1H), 7.54 (d, 1H), 7.62 (t, 1H), 8.37 (d, 1H), 10.11 (s, 1H), 12.71 (s, 1H); MS 367.2 (M+H)* Example 154 [2-(2-Chloro-phenyl)-amino-quinazolin-4-yl] 20 (1H-indazol-3-yl)-amine (IIc-75): Prepared in a manner similar to the above described Method A to afford-a white solid. 'H NMR (DMSO) 8 6.81 (t, 1H), 6.87 (td, 1H), 7.07 (t, 1H), 7.34 (dd,.lH), 7.35 (t, 1H), 7.40 (t, 1H), 7.53 (d, iH), 7.56 (d, 1H), 7.63 (d, 2H),.7.72 (t, 1H), 8.07 25 (d, 1H), 8.46 (d, 1H)-, 10.37 (s, 1H), 12.89 (s, 1H); MS 387.1 (M+H)* Example 155 (1B-Indazol-3-yl)-[2-(2 trifluoromethylphenylamino) -quinazolin-4-yl] -amine (XIc 30 76): Prepared in a manner similar to the above described Method A to afford a white solid; 'H NMR (DMSO) 8 7.01 (t, 1H), 7.20 (m, iH), 7.32 (m, 1H), 7.36 (t, 1H), 7.43 (d, -280 1H), 7.49 (d, 1H), 7.55 (d, 1H), 7.61 (t, 1H), 7.64 (d, 1H), 7.69 (d, 1H), 7.95 (t, 2H), 8.62 (d, 1H), 10.15 (m, iH), 11.62 (s, iH), 13.03 (s, iH); MS 421.2 (M+H)* 5 Example 156 [2- ( 4 -Cyanomethylphenylamino) -quinazolin-4 ylJ-(1H-indazol-3-yl)-amine (lic-77): Prepared in a manner similar to the above described Method A to afford a white solid; 1H NMR (DMSO) 8 13.16 (s, iH) , 11.49 (br. a, iH), 10.38 (br. s, iH), 8.58 (d, 1H), 7.92 (t, iH), 10 7.67 (t, 2H), 7.61 (d, 1H), 7.56 (m, iH), 7.44 (t, 1H), 7.22 (m, 2H), 7.08 (t, 1H), 6.86 (m, 2H-), 3.87 (s, 2H); MS 392.2 (M+H)*. Example 157 [2-(4-Chlorophenylamino) -5,6,7,8 15 tetrahydroquinazolinin--4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (IIc-78): Prepared in a manner similar to the above described Method C; MS 355.5 (M+H)* Example 158 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylamino 20- 6,7,8,9-t.etrahydro-5H-cycloheptapyrimidin-4-yl)-amine (IIc-79): Prepared in a manner similar to the above described Method C; MS 335.3 (M+H)* Example 159 [2-(Benzimidazol-2-ylamino)-7-benzyl-5,6,7,8 25 tetrahydro-pyrido[3,4-d]pyrimidin-4-yl]-(5-methyl-2H pyrazol-3-yl)-amine (IIc-80): Prepared in a manner similar to the above described Method C; MS 452.0.(M+H)* Example 160 (7-Benzyl- 2 -phenylamino-.5,6,7,8-tetrahydro 30 pyrido[3,4-d]pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-. amine (Ilc-81): Prepared in a manner similar to the above described Method C; MS 412.1 (M+H-) -281 Example 161 [6-Benzyl-2- (4-chlorophenylamino) -5,6,7,8 tetrahydro-pyrido [4,3-d]pyrimidin-4 -yl] - (5-methyl-2H pyrazol-3-yl)-amine (IIc-82): Prepared in a manner similar to the above described Method C; MS 446.3 (M+H)* Example 162 [2-(Benzimidazol-2-ylamino)-6-benzyl-5,6,7,8 tetrahydro-pyrido [4,3-d]pyrimidin-4-y1] - (5-methyl-2H pyrazol-3-yl)-amine (I1c-83): Prepared in a manner . similar to the above described Method C; MS 452.2 (M+H)* 10 Example 163 (6-Benzyl-2-phenylamino-5,6,7,8-tetrahydro pyrido[4,3-dlpyrimidin-4-yl) - (5-methyl-2E-pyrazol-3-yi) amine (IIc-84): Prepared in a manner similar to the above described Method C; MS 411.9 (M+H)* 15 Example 164 (5-Methyl-2H-pyrazol-3-yl) - (2-phenylamino 5,6,7, 8-tetrahydro-pyrido [3,4-d]pyrimidin-4-yl) -amine (fIc-85): Prepared in a manner similar to the above described Method C; MS 322.3 (M+H)* 20 Example 165 [2- (4-Cyanomethylphenylamino) -quinazolin-4 yl - (1H-pyrazolo[3,4-blpyridin-3-yl)-amine (IIc-86): Prepared in a manner similar to the above described Method A to afford an off-white solid; 'H NMR (DMSO) S 25 13.65 (s, 1H), 12.82 (br. s, 1H), 11.69 (br. s, 1H), 8.55 (dd, 2H), 8.12 (d, 1H), 7.88 (m, 1H), 7.66 (m, 1H), 7.50 (m, 1H), 7.30 (m, 2H), 7.09 (m, 1H), 6.94 (m, 2H), 3.89 (s, 2H); MS 393.1 (M+H)*. 30 Example 166 [2- (4-Cyanobenzylamino) -quinazolin-4-yl] - (i pyrazolo [3,4-b]pyridin-3-yl) -amine (IXc-87): Prepared in a manner similar to the above described Method A to afford an off-white solid; 1H NMR (DMSO) & 13.68 (s, 1H), -282 12.82 (br. s, 1H), 11.70 (br. s, 1H), 8.55 (m, 3H), 8.00 (d, 1H), 7.92 (t, 1H), 7.59 (m, 4H), 6.96 '(m, 2H), 6.86 (m, 1H), 4.23 (s, 2H); MS 393.1 (M+H)*. 5 Example 167 [2-( 4 -Cyanomethylphenylamino)-quinazolin-4 yl]-(4-fluoro-15-indazol-3-yl)-amine (Ilc-88): Prepared in a manner similar to the above described Method A to afford a white solid; 'H NMR (DMSO) 8 13.49 (s, 1H), 11.61 (br. s, 1H), 10.64 (br. s, 1H), 8.56 (d, 1H), 7.95 (t, 10 1H), 7.67 (d, 1H), 7.58 (t, 1H), 7.46 (t, 1H), 7.43 (dd, 1H), 7.14 (m, 2H), 6.85 (dd, 3H), 3.88 (s, 2H); MS 410.1 (M+H)*. Example 168 [2- ( 4 -Cyanophenylamino) -quinazolin-4-yl] - (1H 15 indazol-3-yl)-amine (IIc-89): Prepared in a manner similar to the above described Method A to afford a white solid; 'H NMR (DMSO) 6 13.14 (s, 1H),' 11.31 (br. s, 1H), 10.51 (br. s, 1H), 8.59 (d, 1H), 7.91 (t, 1H), 7.65 (d, 3H), 7.56 ('t, 1H), 7.50 (m, 2H), 7.45 (dd,- 1H), 7.26 (d, 20 2H), 7.08 (t, 1H); MS 378.2 (M+H)*. Example 169 [2- (4-Cyanobenzylamino) -quinazolin-4-yl] - (1H indazol-3-y1)-amine (IIc-90): Prepared in a manner similar to the above described Method A to afford a white 25 solid; 1H NMR (DMSO) 6 13.12 (s, 1H), 12.91 (br. s, 1H), 11.60 (br. s, 1H), 8.57 (d, 1H), 7.91 (t, 1H), 7.63 (d, 1H), 7.55 (m,5H), 7.38 (t, 1H), 6.89 (t, 1H), 6.84 (br. d, 2H), 4.19 (s-, 2H); MS 392.2 (M+H). 30 Example 170 (5-Cyclopropyl-2H--pyrazol-3-yl)-(2 (naphthalen-2-yloxy)-quinazolin-4-yl]-amine (Ib-1): Prepared in a manner similar to the above described -283 Method B to afford a white solid, mp 327-328*C; 1H NMR (DMSO) 5 -0.05-0.07 (2H, m), 0.50-0.68 (2H, m), 1.28-1.40 (1H, m), 5.68 (1H,s), 7.40-7.50 (2H,-.m), 7.50-7.64 (3H, m), 7.70-7.80 (2H, m), 7.82-8.08 (3H, m), 8.64 (1H,d), 5 10.58 (1H, S), 12.-07 (1H, s); IR (solid) 1621,-1595; 1575, 1554, 1508, 1480, 1410, 1385, 1320, 1254, 1240, 1212, 1166, 830, 819, 758; MS 394.4 (M+H)* Example 171 (5-Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2 10 yloxy)-quinazolin-4-yl-anine (IIb-2): Prepared in a manner similar to the above described Method B to afford a pale brown solid, mp >300 0 C; 'H NMR (DMSO) 8 1.62 (3H, a), 5.65 (1:H, s), 7.96 (2H, br s), 7.55 (3H, d), 7.76 (2H, m), 7.92 (1H, d), 8.00 (2H, m), 8.58 (11H, d), 10.56 15 (1H, S), 11.99 (1H, s); IR (solid) 1625, 1601, 1571, 1556, 1479, 1377, 1315, 1250, 1236, 1210, 1159; MS 368.7(M+H)* Example 172 (5-Hethyl-2H-pyrazol-3-yl)-(2-phenoxy 20 quinazolin-4-yl)-amine (IIb-3): Prepared in a manner similar to the above described Method B to afford a tan solid, mp 287-290oC; "H NMR (DMSO) 8 2.10 (3H, s), 5.92 (1H, s), 7.23 (2H, d), 7.29 (1H, t), 7.38 (1H, t), 7.46 7.53 (3H, m), 7.85 (1H, t), 8.58 (1H, d), 10.55. (1H, s), 25 12.11 (1H, s); IR (solid) 1622, 1602, 1572, 1556, 1542, 1477, 1454, 1402, 1373, 1316, 1249, 1200, 1172, 1158; MS 318.3(M+H)* Example 173 (5-Cyclopropyl-2a-pyrazol-3-yl)-[2-(5,6,7,8 30 tetrahydronaphthalen-2-yloxy)-quinazolin-4-y-amine (IIb-4): Prepared in a manner similar to the above described Method B to afford a solid, mp 277-279OC; 'H NMR -284 (DMSO) 8 0.40-0.50 (2H, M), 0.89-0.96 (2H, m), 1.71-1.87 (5H, m), 2.70-2.83 (4H, m), 5.88 (1H, s), 6.88-6.96 (2H, m), 7.12 (1H, d), 7.39 (1H,t), 7.58 (1H, d), 7.76 (1H, t), 8.58 (1H, d), 10.54 (1H, s), 12.20 (1H, s); IR 5 (solid) 1731, 1641, 1614, 1570, 1506, 14-95, 1464, 1424, 1362, 1340, 1240, 880, 831, 812, 776, 758; MS 398.4 (M+H)+ Example 174 (5-Cyclopropyl-2H-pyrazol-3-y1)-[2-(3 methylphenoxy)-quinazolin-4-yl]-amine (IIb-5): Prepared 10 in a manner similar to the above described Method B to afford an off-white solid, mp 283-284C; 'H NMR (DMSO) S 0.49-0.53 (2H, m), 0.89-0.96 (2H, m), 1.72-1.81 (1H, m), 2.40 (3H, s), 5.82 (1H, s), 7.03 (1H, d), 7.08 (1H, s), 7.15' (1H, d), 7.35-7.46 (2H, m), 7.58 (1H, d), 7.78 (1H, 15 t), 8.62 (1H, d), 10.58 (1H, s), 12.25 (1H, s); IR (solid) 1622, 1604, 1576, 1557, 1483, 1419, 1381, 1319, 1253, 1189, 1158, 997, 842,,789, 763; MS 358.4 (M+H)* Exap2e 175 [2-(3-Methoxyphenoxy)-quinazolin-4-ylJ -(5 20 methyl-2H-pyrazol-3-yl)-emine (IIb-6): Prepared in a manner similar to the above described Method B to afford a white solid, mp 277-278OC; 'H NMR (DMSO) 8 2.15 (3H, s), 3.78 (3H, s), 6.00 (1H, s), 6.77-6.90 (3H, m), 7.30-7.41 (2H, m), 7.52 (1H, d), 7.70 (1H, t), 8.59 (1H, d), 10.57 25 (1H, s), 12.10 (1H, s); IR- (solid) 1623, 1603, 1575, 1556, 1487, 1456, 1430, 1373, 1316, 1253, 1192, 1142, 1046, 1022, 833, 760; MS 348.4 (M+H)* Example 176 [2-(3,4-Dimethoxyphenoxy)-quinazolin-4-yl] 30 (5-methyl-2H-pyrazol-3-yl)-amine (IIb-7): Prepared in a manner similar to the above described Method B to afford an off-white solid, mp 277-278oC; 'H NMR (DMSO) -8 2.09 -285 (3H, .s), 3.70 (3H, s), 3.78 (3H, s), 5.98 (1H, S), 6..73 6.77 (1H, m), 6.90 (1H, s), 7.00 (1H, d), 7.35-7.45 (1H, m), 7.58 (1H, d), 7.70-7.78 (1H, m), 8.63 (11H,. d), 10.55 (iH, s), 12.19 (1H, S).; IR (solid) 1626, 1603, 1576, 5 1557, 1509, 1481, -1436,; 1409, 1382, 1372, 1318, 1249, 1227, 1195, 1180, 1158, 1120, 1029, 965, 835, 803, 767,753; MS 378.4 (M+H)* Example 177 [2-(Benzo[1,3]dioxol-5-yloxy)-quinazolin-4 10 yl] -(5-methyl-2H-pyrazol-3-y1) -amine (Ilb-8): Prepared in -a manner similar to the above described Method B to afford an off-white solid, mp 296-299 0 C (dec.); 'H NMR (DMSO) 6 2.13 (3H, s), 6.05 (1,, s), 6.09 (2H, s), 6.69 - (1H, d), 6.90 (1H, s), 6.98 (iH, d), 7.39 (1H, t), 7.53 15 (1H, d), 7.70 (1H,t), 8.58 (1H, d), 10.59 (1H, s); IR (solid).1602, 1577, 1538, 1508, 1499, 1481, 1455, 1401, 1377, 1323, 1251, 1241, 1169, 1121-, 1038, 1022, 951, 935, 863, 813, 752; MS 362.4 (M+H)* 20 Example 178 [2-(3-Methoxycarbonylphenoxy) -quinazolin-4 yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIb-9): Prepared in' a manner similar to the above described Method B to afford an off-white solid, mp 269-2700C; 1H NMR (DMSO) S 2.05 (3H, s), 3.90 (3H, s), 5.88 (1H, s), 7.00-7.90 (7H, 25 m), 8.50-8.65 (iH, m), 10.65 (1H, s); IR (solid) 1722, 1626, 1605, 1578, 1559, 1507, 1429, 1378, 1317, 1282, 1272, 1255, 1204, 1185', 1096, 1021, 990, 869, 841, 758; MS 362.4 (M+H)* 30 Example 179 (5-Cyclopropyl-2H-pyrazol-3-yl)-(2 phenoxymethyl-quinazolin-4-yl)-amine (lid-1): Prepared in a manner similar- to the above described Method C to afford a pale yellow solid, mp 265-267OC; 1H NMR (DMSO) S -286 0.67 (2H, m), 0.93 (2H, m), 1.87 (1H, M), 5.19 (2H, S), 6.55 (1H, br s), 6.90-7.02 (3H, m)', 7.26-7.30 (2H, m), 7.54 (1H, M), 7.74-7.83 (2H, m), 8.61 (1H, m), 10.45 (1H, br s), 12.18 (1H, br s); MS 358.4 (M+H)* Example 180 ( 2 -Benzyloxymethyl-quinazolin-4-yl)-(5 cyclopropyl-2H-pyrazol-3-yl)-amine (IId-2): Prepared in a manner similar to the above described Method C to afford a white solid, mp 211-213 0 C; 'H NMR (DMSO) 8 0.65 (2H, m), 10 0.90 (2H, m), 1.86 (1H, m), 4.63 (2H, -a), 4.68 (1H, s), 6.71 (1H, s), 7.28-7.54 (6H, m), 7.76-7.81 (2H, m), 8.61 (iH, m), 10.41 (1H, S), 12.19 (1H, s); MS 372.3 (M+H)* Example 181 ( 2 -Benzyl-quinazolin-4-yl)-(5-cyclopropyl-2H 15 pyrazol-3-yl)-amine (IId-3): Prepared in a manner similar to the above described Method D to afford a white solid, mp 219-221"C; 11 NMR (DMSO) 8 0.66 (2H, m), 0.95 (2H, m), 1.87 (1H, m), 4.11 (2H, s), 6.31 (1H, s), 7.20-7.50 (6H, m), 7.71-7.79 (2H, m), 8.55 .(iH, m), 10.27 (1H, s), 12.15 20 (1H, s); MS 342.7 (M+H)* Example 182 (5-Cyclopropyl-2H-pyrazol-3-yl) - (2-methyl quinazolin-4-yl)-amine.(IId-4): Prepared in a manner similar to the above described Method C to afford a white 25 solid, mp 289-290'C; 'H NMR (DMSO) 6 2.31 (3H, S), 2.71 (3H, s), 6.73 (1H, S), 7.75 (2H, q), 8.04 (1H, t), 8.82 (1H, s), 11.94 (1H, s), 12.65 (IH,.s); IR (solid) 3266, 1636, 1607, 1579, 1479, 1407, 769, 668; MS 240.4 (M+H)* 30 Example 183 [2-( 4 -Chlorophenoxymethyl)-6,7,8,9 tetrahydro-5E-cycloheptapyrimidin-4-ylJ - (5-methyl-2H pyrazol-3-yl)-amine (IId-5): Prepared in a manner similar -287 to the above described Method C to afford a white solid; 'H NMR (DMSO) 81.58 (2:H, m), 1.68 (2H, m), 1.85 (2H, i), 2.20 (3H, s), 2.90 (2H, m), 3.00 (2H, m), 5.26 (2H, s), 6.15 (1H, s), 7.15 (2H, d), 7.40 (2H, d), 10.25 (1H, br); 5 MS 384.3 (MUH)*. Example 184 [2-(4-Chlorophenoxymethyl)-5,6,7,8 tetrahydro-quinazolin-4-yl - (5-methyl-2H-pyrazol-3-yl) amine (iId-6): Prepared in a manner similar to -the above 10 described Method C to afford a white solid; 1H NMR (DMSO) 61.80 (4H, m), 2.15 (3H, s), 2.55 (2H, m obscured), 2.75 (2H, m), 5.25 (2H, s), 6.12 (1H, s), 7.08 (2H, d), 7.35 (21H, d), 9.80 (1H, br); MS 370.2 (M+H)*. 15 Example 185 (5-Cyclopropyl-2-pyrazol-3-yl)-[2 (naphtalen-2-ylsulfanyl)-6-phenylpyrimidin-4-yl]-amine (Ila-1): Prepared in a manner similar to the above described Method L to afford a white solid, mp 233-234 0 C; 'H NMR (DMSO) 6 0.21 (2H, br s), 0.56 (2H, br s), 1.17 20 (1H,- br m), 5.35 (1H, br s), 7.02 (1H, br s), 7.49 (3H, m),- 7.59 (2H, m), 7..73 (1H, d), 7.88 (2H, m), 8.02 (3H, m),-8.30 (i, m), 10.01 (1H, s), 11.75 (1H, br s); IR (solid); MS 436.7(M+H)+ 25 Example 186 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3 methoxycarbonyl-phenylyleulfanyl) -6 -phenylpyrimidin-4 yl] -anine (IIa-2): Prepared in a manner similar tb the above described Method L to afford a white solid, mp 126 129"C; 'H NMR (DMSO) 8 0.52 (2H, m), 0.87 (2H, M), 1.69 30 (1H, m), 3.87 (3H, s), 5.47 (1H, s), 7.03 (1H, br s), 7.49 (3H, m), 7.67 (1H, m), 7.87 (2H, m), 7.94 (1H, m), -288 8.09 (1H, m), 8.23 (1H, m), 10.07 (1H, S); 11.94 (1H, s); IR (solid); MS 444.7(M+H)* Example 187 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2 5 (naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine (IIIa-3): Prepared in a manner similar to the above described Method L to afford a white solid, mp 248-250*C; 1H NMR (DMSO) 8 0.21 (2H, br s), 0.55 (2H, br s), 0.94 (1H, br m), 5.31 (1H, br s); 6.55 (1H, br a), 7.57-7.66 (3H, m), 10 7.99-8.03 (4H, m), 8.25 '(1H, s), 9.94 (1H, s), 11.75 (1H, br s); IR (solid); MS 360.7(M+H)* Example 188 (5-Cyclopropyl-2H-pyrazol-3-yl)-[5,6 dimethyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl 15 amine (IIIa-4): Prepared in a manner similar to the above described Method L to afford a white solid, mp >270*C; IH NMR (DMSO) 6 0.14 (2H, d), 0.45 (2H, d), 0.78 (1H, s), 2.05 (3H, s), 2.27 (3H, s), 5.26 (1H, s), 7.60 (3H, d), 7.99 (3H, d), 8.21 (1H, s), 8.66 (1H., s), 11.60 (1H, s); 20 IR (solid) 1560, 1508, 1478, 1288, 1176, 1109, 994, 809, 740, 669; MS 388.7(M+H)* Example 189 (5-Cyclopropyl-2H-pyrazol-3-yl)-[S-methyl-2 (naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine (IIIa-5): 25 Prepared in a manner similar to the above described Method L to afford a white solid, mp 1970C; 1H NMR (DMSO) 8 0.21 (2H, d), 0.51 (2H, d), 0'.78 (iH, s), 2.08 (3H, s), 5.40 (iH, s), 7.57 (2H, d), 7.62 (1H, d), 7.92 (1H, S), 7.97 (3H, d), 8.22 (1H, s), 8.88 (1H, s), 11.70 (1H, s); 30 IR (solid) 1738, 1583, 1563, 1488, 1460, 1364, 1234,1216, 808, 656; MS 374.2(M+H)+ -289 Example 190 (5-Cyclopropyl-25-pyrazol-3-yl)-[6-methyl-2 (naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]-amine (IIIa-6): Prepared in a manner similar to the above described Method L to afford a white solid, mp 232*C; 'H NMR (DMSO) 5 6 0.15 (2H, S), 0.51,(2H, s-), 0.92 (1H, s), 2.20 (3H, s), 5.22 (1H, s), 7.60 (2H, s), 7.67 (1H, d), 7.98 (3H, s), 8.24 (1H, s), 9.79 (1H, s), 11.60 (1:H, s); IR (solid) 1586, 1508.7, 1485, 1282, 1180, 815, 788, 744, 674, 666; MS 374.2(M+H)* 10 Example 191 (S-Cyclopropyl-2s-pyrazol-3-yl) - [6 (morpholin-4-yl)-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4 yl]-amine (I1a-7): To a solution of 2;4,6 trichloropyrimidine (600 mg, 3.27 mmol) and 3-amino-5 15 cyclopropylpyrazole (403 mg, 3.27 mmol) in EtOH (10 mL) was added triethylamine (456 JL, 3.27 mmol) and the reaction mixture was stirred for 15 hours at room temperature. The solvent was evaporated and the residue was purified by flash chromatography (Si0 2 , Hexane/AcOEt 20 gradient) to afford (5-cyclopropyl-2H-pyrazol-3-yl)-(2,.6 dichloropyrimidin-4-yl)-amine (705 mg, 80%). To a solution of (5-cyclopropyl-2H-pyrazol-3 yl)-(2,6-dichloropyrimidin-4-yl)-amine (211 mg, 0.781 mmol) and.2-naphthalenethiol (125 mg, 0.781 mmol) in 25 tert-butanol (5 mL) was added triethylamine (174 gL, 1.25 mmol) and the resulting'mixture was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO 3 . The organic layer was washed with brine, 30 dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash chromatography (SiO 2 , Hexane/AcoEt gradient) to afford [6-chloro-2-(naphthalen-2- -290 ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3 yl)-amine.' The above formed [6-chloro-2-(naphthalen-2 ylsulfanyl)-pyrimidin-4-yl]- (5-cyclopropyl-2K-pyrazol-3 5 yl)-amine (70 mg, 1.78-.-10 mol) was dissolved.-in morpholine (3 mL) and the mixture heated at 1200C for 15 hours. The solvent was evaporated and the residue was purified by flash chromdtography to afford IIIa-7 (50 mg, 63%) as a white solid, mp 118-120OC; 'H NMR (DMSO) 8 0.34 10 0.91 (4H, 4xm), 1.28 and 1.78 (1H, 2xm), 3.32 (2H, m), 3.60 (6H, m), 5.38-6.16 (2H, br m), 7.55-7.66 (3H, m), 7.95-8.02 (3H, m), 8.19 and 8.23 (1H, 2xs), 9.28 and 9.31 (1H, 2xbr a), 11.71 and 11.84 (1H, 2xbr s); IR (solid); MS 445.2(M+H)* 15 Example 192 (5-Cyclopropy1-2n-pyrazol-3-yl)-[6- (1 methylpiperazin-4-yl)-2-(naphthalen-2-ylsulfanyl) pyrimidin-4-yl]-amine (IlIa-8): Prepared in a manner substantially similar to the method describe above for 20 compound IIIb-7 to afford a white solid, mp 113-115oC; 'H NMR (DMSO) 0 C.35-0.91 (4H, 4xm), 1.31 and 1.78 (1H, 2xm), 2.17 and 2.19 (3H,.2xs), 2.29 (4H, m), 3.35 (2H, m), 3.61 (2H, m), 5.38-6.20 (2H, br m), 7.5.5-7.66 (3H-, m), 7.95-8.02 (3H, m), 8.17 and 8.23 (1:H, 2xs), 9.26 and 25 9.32 (1H, 2xbr s), 11.71 and 11.85 (1H, 2xbr s);.IR (solid); MS 458.3(M+H)* Example 193 [6-(2,6-Dimethylphenyl)-2-(naphthalen-2 ylsulfanyl) -pyrimidin-4-yl - (5 -me thyl-2H-pyrazol-3-yl) 30 amine (IIIa-9): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 148 1520C; 'H NMR (DMSO) 8 2.10 (6H, s), 2.26 (3H, d), 5.09 and 6.31 (1H, 2x br s), 7.03 (3H, s), 7.22 (1H, a), 7.59 -291 (2H, t), 7.69 (1H, d), 7.99 (3H, d), 8.28 (IR, S), 9.93 (1H, s), 11.67. (1H, br s); IR (solid) 2970, 1739, 1436, 1365, 1229, 1217, 1205; MS 438.3(M+H)* 5 Example 194 [6- (2-Methylphenyl) -2- (naphthalen-2 ylsulfanyl) -pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) amine (Ia-10): Prepared in a manner similar to the above described Method L to afford a white solid, mp 211 214*C; 'H NMR (DMSO) 6 1.41 (3H, s), 2.30 (3H, s), 5.26. 10 and 6.55 (1H, 2x br s), 7.34 (5H, m), 7.62 (2H, t), 7.70 (1H, d), 7.99 (3H, t), 8.30.(1H, s), 9.97 (1H, s), 11.73 (1H, br s); IR (solid) 2356, 1615, 1582, 1483, 1265, 851, 822, 761; MS 424.0(M+H)* 15 Example 195 [2-(4-Acetamido-phenylsulfanyl)-6-phenyl pyrimidin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine (Ilia 11): Prepared in a manner similar to the above described Method L to afford a white solid, mp 153-155oC; 'H NMR (DMSO) 6 2.01 (3H., s), 2.08 (3H, s), 5.43 (1H, s), 6.96 20 (1H, br s), 7.49-7.88 (9H, m), 10.00 (1H, br s), 10.23 (1H, s), 11.86 (1:H, br s).; MS 417.2(M+H)* Example 196 (5-Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2 ylsulfanyl)-6-phenyl-pyrimidin-4-yl] -amine (IIIa-12): 25 Prepared in a manner similar to the above described Method L to afford a white solid, mp 237-239*C; 'H NMR (DMSO) 6 1.39 (3H, br s), 5.12 (1H, br s),. 6.98 (11H, br s), 7.50 (3H, M), 7.62-7.63 (2H, m), 7.72 (1H, d), 7.90 (2H, m), 8.03-8.05 (3H, m), 8.31 (1H, s), 10.00 (1H, s), 30 11.73 (1H, br s); IR (solid) ; MS 410.2(M+H)* Example 197 {2-( 4 -Isobutyrylylamino-phenylsulfanyl)-6 phenylpyrimidin-4-yl]-(5-methyl-25-pyrazol-3-yl)-amine -292 (IIIa-13): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 201 202*C; 1H NMR (DMSO) 8 1.05-1.13 (6H, m), 1.97 (3H, s), 2.65 (1H, m), 5.37 (iH, br s), 6.93 (1H, br s), 7.50-7.58 5 (5H, m), 7.78-7.90 (4H, m), 9.99, 10.12 and 11.84 (3H, 3 x br s); IR (solid) 1676, 1614, 1586, 1573, 1514, 1483, 1395, 1299, 1262, 1242, 1214, 1168, 1089, 988; MS 445.3(M+H) 10 Example 198 [6-( 4 -Methylpiperazin-1-yl)-2-methylaulfanyl pyrimidin-4-yl]-(S-methyl-2s-pyrazol-3-yl)-amine (IIIa 14): Prepared in a manner similar to the above described Method M to afford an off-white solid; 1H NMR (DMSO) S 2.18 (3H, s), 2.20 (3H, s), 2.36 (4H,- m), 2.41 (3H, s), 15 3.46 (4H, m), 5.91 (1H, s)., 6.41 (1H, br.s), 9.20 (1H, s), 11.87 (1H, s); IR (solid); MS 320._3(M+H)* Example 199 (5-Methyl-2H-pyrazol-3-yl)-[6-phenyl-2-(4 propionylamino -phenylsul fanyl) -pyrimidin -4-yl] - amine 20 (IIIa-15): Prepared in a manner similar to the above described Method L to afford a pale pink solid, mp 204 2060C; IH NMR (DMSO) 5 1.09-1.13 (3H, m), 2.00 (3H, s), 2.33-2.37 (2H, m), 5.40 (1H, br s), 6.95 (1H, br s), 7.50 (3H, m), 7.56-7.58 (2H, m), 7.76-7.78 (2H, m), 7.88 (2H, 25 m), 9.99, 10.15 and 11.85 (3H, 3 x br s); IR (solid) 1678, 1623, 1580, 1534, 1496, 1453, 1398, 130.7, 1245, 1203, 1119, 1049, 1030, 1004; MS 431.2(M+H)* Example 200 [2- ( 4 -Cyclopropanecarbonylamino 30 phenylsulfanyl)-6-phenylpyrimidin-4-yl -(5-methyl-2H pyrazol-3-yl)-amine (IIIa-16): Prepared in a manner similar to the above described Method L to afford an off- -293 white solid, mp 253-255*C; 'H NMR (DMSO) 8 0.82-0.83 (4H, m), 1.83 (1H, ), 2.00 (3H, s), 5.41 (1H, br s), 6.88 (1H, br s), 7.42-7.50(3H, m), 7.56-7.58 (2H, m), 7.76 7.78 (2H, m), 7.89 (2H, m), 9.99, 10.47 and 11.85 (3H, 3 5 x br s) ; IR (solid) 1672, 1621, 1591, 1581, 1573, 1537, 1495, 1448, 1405, 1390, 1312, 1254, 1246; 1202, 1192, 1179, 1119.2, 1005, 959; MS 443.2(M+H)* Example 201 (5-Methyl-2H-pyrazol-3-yl)-{6-pheny-2-[4 10 (propane-1-sulfonylamino) -phenylsulfanylj -pyrimidin-4 yl)-amine (IIIa-17): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 232-235*C; 1H NMR (DMSO) 8 0.94 (3H, t), 1.71 (2H, m), 2.12 (3H,s), 3.13 (2:H, t), 5.59 (1H, s), 7.31 (2H, d), 15 7..49 (3H, s), 7.59 (2H, d), 7.85 (2H, s), 10.00 (1H, br s), 1.0.16 (1H, s), 12.05 (1H, br s); IR (solid) 1628, 1587, 1545, 1525, 1496, 1455, 1311, 1255, 1236, 1212, 1186, 1140, 1032, 1001, 934; MS 481.2(M+H)* 20 Example 202 [2- ( 4 -Ethanesulfonylamino-phenylsulfanyl) -6 phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (Ila-18): Prepared in a manner similar to the above described Method L to afford a pale yellow solid, mp 251 254*C; 3H NMR (DMSO) 8 1.21 (3H, t), 2.12 (3H,s), 3.15 25 (2H, q), 5.59 (1H, s), 7.32 (2H, d), 7.49 (3H, s), 7.57 (2H, d), 7.85 (2H, s), 9.99 (1H, br s), 10.15 (1H, br s), 11.90 (1H, br s); IR (solid) 1621, 1585, 1542, 1523, 1495, 1455, 1315, 1257, 1208, 1142, 1049, 1033, 1002, 932; MS 467.2(M+H)* 30 Example 203 [2-(4-Acetamidophenyl-sulfanyl)-6-(2 methylphenyl) -pyrimidin-4-yl -. (5-methyl-2H-pyrazol-3 -yl) - -294 amine (IIIa-19): Prepared in a manner similar to the above described Method L to afford a white solid, mp 212 214 0 C; 1H NMR (DMSO) 6 2.01 (3H, S), 2.08 (3H, s), 2.24 (3H, s), 5.43 (1H1, s), 6.56 (1H, br s), 7.49-7.88 (9H, 5 m), 10.00 (1H, bras), 10.23 (IH- s), 11.86 (1H, br s); IR (solid1701, 1634, 1588, 1555, 1496, 1390, 1307, 1208, 1169, 823, 803; MS 431.4(M+H)+ Example 204 [2-(4-Isobutanecarbonylamino-phenyl 10 sulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2-pyrazol 3-yl)-amine (IIIa-20): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 241-243*C; 'H NMR (DMSO) 6 0. 95-0.96 '(6H, m), 2.00 (3H, s), 2.11 (1H, m), 2.23-2.25 (2H, m), 5.43 (1H, 15 br s), 6.95 (1H, br s), 7.50-7.58 (5H, m), 7.77-7.89 (4H, m), 10.00, 10.13 and 11.84 (3H, 3 x br s); IR (solid) 1660-, 1628, 1589, 1575, 1543, 1525, 1496, 1451, 1398, 1357, 1314, 1301, 1251, 12.06, 1108, 995; MS 459.2 (M+H)* 20 Example 205 [2- ( 4 -Acetamido-phenyl-sulfanyl) -5-methyl-6 phenyl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIIa-21): Prepared in a manner similar to the above described Method L to afford a pale-pink solid, mp 276 277 0 C; 'H NMR (DMSO) 8 1.98 (3H, s), 2.08 (6H, s); 5.41 25 (1H, br s), 7.47-7.55 (7H, m), 7.72-7.74 (2H, m), 8.89, 10.20 and 11.87 (3H, 3 x br s); IR (solid) 1676, 1591, 1555, 1540, 1519, 1493, 139-3, 1375, 13.03, 1260, 1230, 1176, 1148, 1045, 1011, 969; MS 431.'2 (M+H)* 30 Example 206 [2-(4-Acetamido-phenyl-sulfanyl)-6-(4 methoxyphenyl) -pyrimidin-4-yll - (5-methyl-21-pyrazol-3 yl)-amine (IIIa-22): Prepared in a manner similar to the -295 above described Method L to afford an off white solid, mp 241-245*C; 'H NMR (DMSO) 8 1.99 (3H,s), 2.06 (31H, s), 3.82 (3H, s), 5.44 (1H, s), 7.03 (2H, d), 7.53 (2H, d), 7.71 (2H, s), 7.83 (2H, s), 10.12 (1H, a), 10.23 (1H, s), 5 11.84 (1H, s); IR (solid) 1627, 1606, 1571, 1511, 1313, 1257, 1181, 830; MS 447.2 (M+H)* Example 207 [6- (3-Acetamidophenyl) - 2- (4-acetamido phenyl-sulfanyl)-pyrimidin-4-yl-(5-methyl-2H-pyrazol-3 10 yl)-amine (IIa-23): Prepared in a manner similar to the above described Method L to afford a brown solid, mp 227 230CC; 'H NMR (DMSO) 6 2.01 (3H, s), 2.11- (6H, s), 5.34 (iH, s), 6.99 (1H, br s), 7.41 (iH, t), 7.49-7.62 (3H, m), 3.71-3.76 (3H, m), 8.19 (.1H s), 10.09-10.18 (2H, br 15 s), 10.23 (1H, s), 12.20 (iH, br s); IR (solid) 1635, 1573, 1533, 1488, 1372, 1318, 1297, 827, 798; MS 474.3 (M+H)* Example 208 [2- (4-Isopropanesulfonylamino-phenyl 20 sulfanyl) -6-phenyl-pyrimidin-4-y13 - (5-methyl-2H-pyrazo1 3-yl)-amine (IlIa-24): Prepared in a manner similar to the above described Method L to afford a white solid, mp 255-257OC; 1 H NI4R (DMSO) 8 1.28 (6H, d), 2.14 (3H,s), 3.32 (1H, s), 5.60 (iH, s), 7.36 (2H, d), 7.49 (3H, s), 7.60 25 (2H, d), 7.85 (2H, s), 10.00 (iH, br s), 10.11 (1H, a), 11.92 (iH, br s); IR (solid) 1625, 1587, 1574, 1545, 1525, 1495, 1313, 1295, 1257, 1234, 1136, 1000,. 934; MS 481.2 (M+H)* 30 Example 209 {2-[4-(2-Dimethylamino-acetylamino) phenylsulfanyl] -6-phenyl-pyrimidin-4-yl}- (5-methyl-2H pyrazol-3-yl).-amine (IIIa-25): Prepared in a manner -296 similar to the above described Method L to afford an off white solid, mp 213-215*C; 'H NMR (DMSO) 82.00 -(3H, s), 2.31 (6H, s), 3.15 (2H, s), 5.45 (1H, s), 6.83 (iH, br s), 7.46-7.51 (3H, m), 7.59 (2H, d), 7.80-7.92 (SH, m), 5 9.98 (lH, S), 10.05 (lH, s); IR (solid) 1701, 1617, 1587, 1571, 1509, 1480, 1456, 1304, 1284, 1254, 1238, 1213, 1181, 1156, 987, 833, 782, 754, 695; MS 460.3(M+H)* Example 210 [2-( 3 -Chloro-benzylsulfanyl)-6-morpholin-4 10 yl-pyrimidin-4-yl]-(5-methyl-2a-pyrazol-3-yl)-amine (Ila-26): Prepared in a manner similar to the above described Method M to afford a white solid, mp 224-225*C; 2H NMR (DMSO) 6 2.17. (3H, s), 3.40-3.50 (4H, m), 3.60-3.71 (4H, m), 4.30 (2H, s), 5.95 (1H, bra), 6.41 (1H, brs), 15 7.23-7.55 (4H, m), 9.31 (iH, s), 11.89 (1H, brs); IR. (solid) 1557, 1476, 1442, 1401, 1314, 1232, 1121, 1018; MS 417.4 (M+H)* Example 211 [2-(3-Chloro-benzylsulfanyl)-6-(2-methoxy 20 ethylamino)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl) amine (IIIa-27): Prepared in -a manner similar to the above described Method M to afford a white solid, mp 101 102*C; H NMR (DMSO) 82.15 (3H, s), 3.21 (3H, s), 3.28 3.41 (4H, m), 4.29 (2H, s), 5.78 (1H, brs), 6.20 (1H, 25 brs), 7.10 (1H, brs), 7.21-7.50 (4H, m), 9.01 (1H, brs); IR (solid) 1598, 1555, 1527, 1336, 1293, 1117, 1079, 974, 783; MS 405.4 (M+H)*' Example 212 2-Eenzylsulfanyl-6- (4-methylpiperazin-1-yl) 30 pyrimidin-4-yl] - (S-methyl-2H-pyrazol-3-yl) -amine (IIIa-28): Prepared in a manner similar to the above described Method M to afford a yellow gum; 'H NMR (CDCl 3

)

-297 8 2.23 (3H, s), 2.28 (3H, s), 2.31-2.64 (4H, m),- 3.30 3.65 (4H, m), 4.38 (2H, s), 5.83 (1H, s), 6.23 (1K, br a), 7.17-7.49 (5H, m), 7.98-8.18 (1H, m); IR (solid) 1555, 1494, 1371, 1315, 1286, 1233, 999, 977, 801, 774, 5 709; MS 396.4 (M+H)* Example 213 [2-Benzylsulfanyl-6-mbrpholin-4-yl-pyrimidin 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIIa-29): Prepared in a manner similar to the above described 10 Method M to afford an off-white foam; 'H NMR (CDCl 3 ) S 2.3-1 (3H, s), 3.39-3.80 (8H, m), 4.39 (2H, s), 5.84 (.1H, s), 6.25 (1H, brs), 7.20-7.50 (5H, m), 8.10 (1H, s); IR (solid) 1557, 1486, 1442, 1314, 1229, 1213, 1121, 767, 698; MS 383.4 (M+H)* 15 Example 214 [2-(3-chloro-benzylsulfanyl)-6-(4 methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2H pyrazol-3-yl)-amine (IIXa-30): Prepared ina manner similar to the above described Method M to afford a white 20 foam; 1H NMR (CDCl 3 ) 6 2.31 (3H, s), 2.35 (3H, s), 2.40 2.51 (4H, m), 3.56-3.69 (4H, m), 4.34 (2H, s), 5.85 (1H, s), 6.29 (1H, bra), 6.89 (1H, s), 7.18-7.50 (4H, m); IR (solid) 1553, 1514, 1484, 1446, 1277, 1228, 999, 799; MS 430.4 (M+H)* 25 Example 215 [2-(4-methoxy-benzylsulfanyl)-6-(4 methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-25 pyrazol-3-yl)-amine (IIIa-31): Prepared in a manner - similar to the above described Method M to afford a 30 yellow oil; 3H NMR (CDCl 3 ) 8 2.28 (3H, S), 2.33 (3H, 6), 2.44-2.45 (4H, m), 3.62 (4H, m), 3.80 (3H, s), 4.34 (2H, S), 5.32 (1H, s), 6.28 (1H, br s)', 6.83-6.85 (2 H, m), -298 7.34-7.36 (2H, m); IR (solid) 1659, 1554, 1508, 1485, 1449, 1366, 1318, 1302, 1277, 1230, 1166, 1146, 1030, 999, 973, 948; MS 443.4 (M+H)* 5 Example 216 (2-(4-Acetamnido-phenyl-sulfanyl)-6-tert butyl-pyrimidin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine (Ila-32): Prepared in a manner similar to the above described Method L to afford'a white solid, mp 227-228*C; 1H NMR (DMSO) 6 1.10 (3H, br a), 1.20 (9H, s), 2.00 (3H, 10 s), 2.35 (2H, q), 5.35 (1:H, br s), 6.55 (1H, br s), 7.55 (2H,- d), 7.75 (2H, d), 10.1 (1H, br s), 1.15 (1H, s), 12.1 (1H, br s); IR (solid); MS (M+H)* Example 217 (5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2 15 (4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-amine (IIIa-33): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 208 .209*C; 1H NMR (DMSO) 8- 0.52 (2H, m), 0.80 (2H, m), 1.08 1.10 (3H, m), 1.65 (1H, br s), 2.33-2.37 (2H, m), 5.50 20 (1H, br s), 7.03 (1H, br s), 7.47 (3H, W), 7.50-7.58 (2H, m), 7.76-7.77 (2H, m), 7.88-7.98 (2H, m), 10.00, 10.11 and 11.86 (3H, 3 x br s); IR (solid) 1676, 1617, 1575, 1539, 1520, 1485, 1459, 1418; 1395, 1304, 1255, 1243, 1215, 1161, 1071, 990; MS 457.4 (M+H)* 25 Example 218 [2-(3-Chloro-benzylsulfanyl)-6-(piperidin-1 yl) -pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIIa-34): Prepared in a manner similar to the above described Method M to afford a white solid, mp 234-23SC; 30 "H NMR (DMSO) 8 1.40-1.64 (6H, m), 2.13 (3H, s), 3.42-3.51 (4H, m), 4.27 (2H, S), 5.85 (111, br s), 6.46 (1H, brs), 7.23-7.41 (3H, m), 7.48 (1H, s), 9.18 (1H, s), 11.83 (111, -299 8); IR (solid) 1598, 1546, 1483, 1398, 1317, 1227, 974, 798, 779; MS 415.4 (M+H)* Example 219 (5-Methyl-2H-pyrazol-3-yl)-{2-(4 5 (morpholinesulfonyl-) -benzylsulfanyl] -6-morpholin-4 -yl pyrimidin-4-yl}-amine (IIIa-35): Prepared in a manner similar to the above described Method H to afford a white solid; 2H NMR (DMSO) 8 2.24- (3H, s), 2.90-3.01 (4H, m), 3.29-3.36 (4H, m), 3.48-3.57 (4H, m), 3.67-3.75 (4H, m), 10. 4.43 (2H, s)-, 5'.82-6.10 (2H, m), 7.50-7.70 (511, m); IR (solid) 1550, 1483, 1441, 1346, 1308, 1255, 1160, 1112, 941, 726; MS 532.5 (M+H)* Example 220 {6-(2-Methoxy-ethylamino)-2-[4 15 (morpholinesulfonyl)-benzylsulfanyl]-pyrimidin-4-yl)-(5 methyl-2H-pyrazol-3-yl)-amine (IIIa-36): Prepared in a manner similar.to the above described Method M to afford. a white solid, mp 193-195*C; 'H NMR (DMSO) 8 2.15 (311, S), 2.79-2.89 (4H, m), 3.34 (3H, s), 3.40-3.51 (4H, m), 3.59 20 3.67 (4H, m), 4.41 (2H, s), 5.76-5.72 (1H, m), 6.20 (1H, brs), 7.10 (1H, brs), 7.61-7.74 (4H, m), 9.03 (1H, brs), 11.81 (1H, brs); IR (solid) 1593, 1555, 1484, 1350, 1298, 1255, 1160, 1107, 936; MS 520.5 (M+H)* 25 Example 221 {6-(4-methylpiperazin-1-yl)-2-(4 (morpholinesulfonyl)-benzylsulfanyl]-pyrimidin-4-yl)-(5 methyl-2H-pyrazol-3-yl)-amine (I-IIa-37): Prepared in a manner similar to the above described Method M to afford a white solid, mp 206-207*C; IH NMR. (DMSO) 8 2.09 (3H, s) , 30 2.20 (3H, s), 2.26-2.40 (4:H, m), 2.78-2.88 (4H, m), 3.38 3.49 (4H, m), 3.56-3.67 (4H, m), 4.41 (2H, s), 5.82 (1H, brs), 6.42 (1H, brs), 7.60-7.74 (4H, m), 9.26 (1:H, s), -300 11.89 (1H, brs); IR (solid) 1583, 1558, 1479, 1346, 1231, 1160, 1112i 998, 969, 926; MS 545.5 (M+H)* Example 222 [6-Methoxymethyl-2- (4-propionylamino-phenyl 5 sulfanyl) -pyrimidin-4-yl] --(5-methyl-2-pyrazo--3-yl) amine (IIIa-38): Prepared in a manner similar to the. above described Method L to afford a white solid; 'H NMR (DMSO) 6 1.03-1.14 (3H, m), 2.00 (3H, s), 2.29-2.40 (2H, m), OMe under DMSO, 4.22 (2H, m), 5.26 (iH, brs), 6.45 10 (iH, brs), 7.44-7.56 (2H, m), 7.68-7.80 (2H, m), 9.86 (1H, bra), 10.11 (1H, s), 11.79 (111, brs); IR (solid) 1670, 1593, 1517, 1479, 1393, 1360, 1269, 1174, 1107; MS 399.4 (M+H) - 15 Example 223 [2- ( 4 -Methoxycarbonyl-phenyl-sulfany1) -6 methoxymethyl-pyrimidin-4-y1] - (5-methyl-2H-pyrazol-3-yl) amine (IXIa-39): Prepared in a manner similar to the above described Method L to afford a white solid, mp 204 205*C; 'H NTIR (DMSO) 6 1.89 (3H, brs), 3.85 (3H, s), OMe 20 under DMSO, 4.23 (2H, a), 5.22 (iH, brs), 6.51 (1H, brs), 7.70-7.81 (2H, m), 7.96-8.06 (2H, m), 9.99 (1H, brs), 11.85 (1H,.brs); IR (solid) 1721, 1621, 1583, 1519, 1484, 1289, 1271, 1178, 1119, 1109, 997, 841; MS 386.3 (M+H)* 25 Example 224 [2-( 3 ,5-Dimethoxy-benzysulfanyl)-6 morpholin-4-y1-pyrimidin-4-y1]-(5-methyl-2H-pyrazol-3 yl)-amine (IIIa-40): Prepared in a manner similar to the above described Method M to afford a white solid; 1 H NMR (DMSO) 5 2.15 (3H, s), 3.40-3.49 (4H, m), 3.60-3.74 (10H, 30 m), 4.25 (2H, s), 5.88 (IH, brs), 6.31-6.61 (5H,,m), 9.32 -(1H, s), 11.86 (1H, s); IR (solid) 1581, 1556, 1470, 1439, 1315, 1232, 1205, 1159, 1144; MS 443.4 (M+H)* -301 Example 225 [2-(3,5-Dimethoxy-benzylsulfanyl)-6 pyrrolidin-4-yl-pyrimidin-4-yl-(5-methyl-2H-pyrazol-3 yl)-amine (IIIa-41): Prepared in a manner similar to the 5 above described Method M -to afford a white. solid; 'H NMR (DMSO) 8 1.80-1.97 (4H, m), 2.15 (3H, s), 3.43-3.45 (4H, m), 3.69 (6H, s), 4.26 (2:H, s), 5.85 (1H, bra); 6.18 (1H, brs), 6.35 (1H, brs), 6.60 (2H, a), 9.12 (1H, s), 11.88 (1H, s); IR (solid1598, 1560, 1474, 1470, 1346, 1303, 10 1207, 1136, 1050; MS 427.4 (M+H). Example 226 (5-Methyl-2H-pyrazol-3-y1)-[6-morpholin-4-yl 2-(naphthalene-2-ylmethylsulfany1)-pyrimidin-4-yl]-amine (IIIa-42): Prepared in a manner similar to.the above 15 described Method M to afford an off-white solid; 1H NMR + (DMSO) 8 2.15 (3H, s), 3.~37-3.50 (4H, m), 3.59-3.70 (4H, m), 4.48 (2H, s), 5.88 (1H, brs), 6.40 (1H, brs), 7.40 7.60 (3H, m), 7.78-7.95 (4H, m), 9.30 (1H, s), 11.89 (1H, brs); IR (solid) 1607, 1555, 1484, 1441, 1398, 1365, 20 1308, 1231, 1179, 1112; MS 433.4 (M+H)* Example 227 (2-(4-Acetamido-phenyl-sulfanyl)-6-[4-(3 dimethylamino-propoxy) -phenyl] -pyrimidin-4 -y1} - (5 -methyl 2H-pyrazol-3-yl)-amine (IIla-43): Prepared in a manner 25 similar to the above described Method N to afford a.-white solid, mp 219-222*C; 1H NMR (CDCl 3 ) 5.1.97-2.07 (2H, m), 2.14 (3H, s), 2.18 (3H, s), 2.30 (6H, s), 2.52 (2H, t), 4.09 (2H, t), 5.56 (1H, s), 6.80 (1H, br s), 6.99 (2H, d), 7.60 (2H, d), 7.68-7.78 (3H, m), 7.85 (2H, d); IR 30 (solid) 1606, 1590, 1512, 1482, 1309, 1250, 1238, 1210, 1178, 1151, 1055, 989, 824, 711, 690, 665, 656; MS 518.4

(M+H)+

-302 Example 228 [2-(4-Acetamidophenylsulfanyl)-6-(morpholin 4-yl) -pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl)'-amine (IIIa-44): Prepared in a manner similar to the above 5 described Method P to-afford a white solid;--MS 426.4 (M+H)* Example 229 [6 -Hydroxymethyl-2 - (4 -propionylamino-phenyl sulfanyl)-pyrimidin-4-yll-(5-methyl-2H-pyrazol-3-yl) 10 amine (IIIa-45): Prepared from IIIa-48 according to Method 0 to afford a white solid; "'H NMR (DMSO) 8 1.08 1.18 (3H, m), 1.96 (3H, brs)-, 2.29-2.40 (2H, m), 4.20 4.40 (3H, m), 5.20-5.46 (2H, m), 6.56 (1H, S), 7.50 (2H, d), 7.79 (2H, d), 9.90 (1H, brs), 10.13 (1H, s), 11.78 15 (1H, brs); MS 385.4 (M+H)* Example 230 [2- (4-Acetamido-phenyl-sulfanyl) -pyrimidin-4 ylj-(5-methyl-2H-pyrazol-3-yl)-amine (IIIa-46): Prepared in a manner similar to the above described Method L to 20 afford an off-white solid, mp 249-25.0oC; 'H NMR (DMSO) B 1.99 (3H, a), 2.08 (3H, s), 5.38 (111, br s), 6.45 (1H, br a), 7.50 (2H, d), 7.71 (2H, d), 7.98 (1H, d), 9.89 (1H, br a), 10.19 (1N, br a), 11.83 (1H, br a); IR (solid) 1657, 1609, 1584, 1515, 1494, 1468, 1395, 1372, 1355, 25 1330, 1316, 1201, 1175, 1157, 1027, 993; MS 341.4 (M+i-i)* Example 231 [6 - (1.-Butoxycarbonyl) -2 - (4 -propionylamino phenyl-sulfanyl) -pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3 yl)-amine (IlIa-47): Prepared in a manner similar to the 30 above described Method L to afford a yellow solid, 'H NMR (DMSO) S 0.90-0.98 (3H, m), 1.03-1.12 (3H, m), 1.31-1.45 (2H, m), 1.60-1.71 (2H, m), 1.94 (3H, brs), 2.29-2.40 -303 (2H, m), 4.20-4.30 (2H, M), 5.25 (1H, bra), 7.08 (lH, bra), 7.49-.7.55 (2H, m), 7.72-7.81 (2H, m), 10.15 (1H, bra), 10.32 (1H, bra), 11.89 (1H, bra); IR (solid) 1736, 1679, 1622, 1584, 1517, 1489, 1284, 1174; MS 455.4 (M+H)* -.5. Example 232 [6-Methoxycarbonyl-2- (4-propionylamino phenyl-sulfanyl)-pyrimidin-4-yl-(5-methyl-2H-pyrazol-3 yl)-amine (IIa-48): Prepared in a manner similar to the above described Method L to-afford a yellow solid; 1H NMR 10 (DMSO) 8 1.10 (3H, t), 1.94 (3H, bra), 2.35 (2H, q), 3.84 (3H, s), 5.22 (1H, brs), 7.05 (1H, s), 7.52 (2H, d), 7.79 (211, d), 10.18 (1H, bra), 10.38 (1H, bra), 11.89 (1H, bra).; IR (solid) 1741, 1679, 1617, 1589, 1512, 1484, 1374,,1284, 1250; MS 413.4 (M+H). 15 Example 233 (5-Methyl-2H-pyrazol-3-yl)-(6-phenyl-2 phenylamino-pyrimidin-4-yl) -amine (Ilic-1): white solid; MS 343.4 (M+H)* 20 Example 234 (5-Cyclopropyl-2a-pyrazol-3-yl)-(6-phenyl-2 phenylamino-pyrimidin-4-yl)-amine (IIIc-2): white solid-, mp 267-269 0 C; 'H NMR (DMSO) 8 0.63 (2H, m), 0.96 (2H, .m), 1.87 (1H,m), 6.07 (iH, a), 6.84 (1H, br a), 7.20 (1H, m), 7.33-8.05 (9H, m), 10..52 (1H, br a), 11.08 (1H, br a), 25 12.53 (1:H, br a); IR (solid); MS 369.7 (M+H). Example 235 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3 methylphenylamino) -6 -phenyl-pyrimidin-4 -ylJ -amine (lica 3) : white solid, mp 267-270*C; 1 H NMR (DM50) 8 0.63 (2H, 30 m), 0.94 (2H, m), 1.87 (1H,m), 2.36 (3H, a), 6.12 (1H, a), 6.81 (1H, br a), 7.03 (1H, m), 7.29-7.94 (8H, m), 10.43 (1H, br a), 11.12 (1H, br s),- 12.47 (1H, br s); IR (solid); MS 383.7 (M+H)* -304 Example 236 [2- (4-cyanomethylphenylamino) -6-phenyl pyrimidin-4-yl] - (5-cyclopropyl-2H-pyrazol-3-yl) -amine (IIIc-4): pale yellow solid, mp 294-297*C; 'H NMR (DMSO) S 5 0.64 (2H, m), 0.-97 (2H, m), 1.89 (1H, m), 4.06 (2H, s), 6.07 (1H, s), 6.87 (1H, br s), 7.40 (2H, m),' 7.63-7.90 (5H, m), 7.95 (2H, m), 10.51 (1H, br s), 11.02 (1H, br s), 12.57 (1H, br s); IR (solid); MS 408.8 (M+H)* 10 Example 237 (5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2 (pyridin-3-ylmethylamino) -pyrimidin-4-yl] -amine (IIIc-5): off-white solid, mp 191-193 0 C; 'H NMR (DMSO) S 0.65 (211, m), 0.89 (21H, m), 1.83 (1H, m), 4.59 (2:H, s), 6.04- (1H, br s), 6.76 (1H, br s), 7.32-7.56 (5H, m), 7.77 (1H, m), 15 7.88-7.97 (2H, m), 8.43 (1:H, M),. 8.61 (1H, s), 9.47 (1:H, br s), 11.93 (1:H, br s); IR (solid); MS 384.8 (M+H)* Example 238 [2- (3-Chlorophenyl) amino-6- (3-nitrophenyl) pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (lic 20 6): off-white solid; 'H NMR (CD 3 0D) 8 5.95 (1H, s), 6.65 (1H, s), 6.90 (1H, d), 7.18 (1H, t), 7.32 (1H1, d), 7.58 (1H, t), 7.82 (1:H, s), 8.18 (1:H, d), 8.25 (1H, d), 8.65 (1H, s) ; MS 422.1 (M+H)' 25 Example 239 [2-(3-Chlorophenyl)amino-6-(3,4,5 trimethoxyphenyl) -pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3 yl)-amine (IIIc-7): white solid; MS 467.7 (M+H)* Example 240 (5-Methyl-2H-pyrazol-3-yl)-[2-(4 30 sulfamoylphenylamino) -6- (3,4, 5-trimethoxyphenyl) pyrimidin-4-yl]-amine (Ilc-8): white solid; MS 512.6

(M+H)*

-305 Example 241 (2- (4-Chlorophenyl) amino-6-methyl-pyrimidin 4-yl] -[5- (furan-2-yl)-21r-pyrazol-3-yll -amine (IIIc-9): white solid; MS 367.1 (M+H)* 5 Example 242 [2-(Benzimidazol-2-ylamino-)6-ethyl pyrimidin-4-yl] - (S-methyl-2H-pyrazol-3-yl) -amine (IIIc 10): MS 335.5 (M+H)' Example 243 [2- (4-Chlorophenyl) amino-6-methyl-pyrimidin 10 4-yl] - (S-phenyl- 2 H-pyrazol-3-yl)-amine (Ilic-11): MS 377.5 (M+H)* Example 244 (2- (4-Chlorophenyl) amino-6-ethyl-pyrimidin-4 yl - (5-methyl-2H-pyrazol-3-yl) -amine (IIIc-12): MS 329.4 15 (M+H)* Example 245 (5-tert-Butyl-2-pyrazol-3-yl) - [2- (3 chlorophenyl) amino 6- (3 -nitrophenyl) -pyrimidin-4 -ylJ amine (IIIc-13): off-white solid; 1H NMR (CD 3 0D) 6 1.32 20 (9H, s), 6.18 (1H, s), 7.04 (1H, s), 7..14 (1H, d), 7.35 (1H, t), 7.58 (1H, d),' 7.82 (1H, t), 7.91 (11H, s), 8.35 (1H, d), 8.40 (1H, d), 8.90 (1H, s); MS 464.2 (M+H)* Example 246 [2- (3-Chlorophenyl)aamino-6- (3-nitrophenyl) 25 pyrimidin-4-yl] - (S-phenyl-2H-pyrazol-3-yl) -amine (IIIc-14): 8 off-white solid; 1H NMR (CD 3 0D) 8 6.66 (1Hl, s), 7.12 (1H, d), 7.30-7.45 (5H, m), 7.50 (1H, d),'7.62 (211, d), 7.78 (1H, t), 7.88 (iH, s), 8.35 (1H, d), 8.42 (1H-, d), 8.85 (1H, s); MS 484.1 (M+H)* 30 Example 247 [5-(Furan-2-yl)-2H-pyrazol-3-yl] -(6-phenyl-2 phenylamino-pyrimidin-4-yl) -amine (IIlc-15): MS 395.4 (M+n) + -306 Example 248 £2- (Benzimidazol-2-ylamino) -6-methyl pyrimidin-4-yl] - ( 5 -phenyl-2H-pyrazol-3-yl) -amine (IIIa 16): MS 383.2 (M+H)* 5 Example 249 [2- (Benzimidazol-2-ylamino) -6-methyl pyrimidin-4-yl] - [5- (Furan-2-yl) -2H-pyrazol-3-yl] -amine (IIIc-17): MS 373.4 (M+H)* 10 Example 250 [2- (4-Chlorbphenylamino) -6-methyl-pyrimidin 4-yl] -(5-methyl-2H-pyrazol-3-yl) -amine (IIc-18): MS 315.4 (M+H)* Example 251 (2- (4-Chlorophenyl) amino-5,6-dimethyl 15 pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIlc 19): MS 329.4 (M+H)* Example 252 (5,6-Dimethyl-2-phenylamino-pyrimidin-4-yl) (5-methyl-2H-pyrazol-3-yl)-amine (IIIc-20): MS 295.5 20 (M+H)* Example 253 [2- (4-Chlorophenyl) amino-6-methoxymethyl pyrimidin-4-yl] - (S-methyl-2H-pyrazol-3-yl) -amine (Ilca 21): MS 345.1 (M+H)* 25 Example 254 [2- (Benzimidazol-2-ylamino) -6-methoxymethyl pyrimidin-4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IlIc 22): MS 351.2 (M+H). 30 Example 255 (6-Methoxymethyl-2-phenylamino-pyrimidin-4 yl) - (5-methyl-2H-pyrazol-3-yl) -amine (IIIc-23): MS 311.2 (M+H) + -307 Example 256 (6-Methyl-2-phenylamino-pyrimidin-4-yl) -(5 methyl-20-pyrazol-3-yl)-amine (IZIc-24): MS 281.1 (M+H) 4 Example 257 [2- (2 -Chlorophenoxymethyl) -6 -methyl 5 pyrimidin-4-yl] - (5-phenyl-2H-pyrazo1-3-yl) -amine (Id 1): MS 392.1 (M+H) Example 258 [2- (2-Chlorophenoxymethyl) -6-methyl pyrimidin-4-yl] - [5- (furan-2-yl) -2H-pyrazol-3-yl] -amine 10 (hId-2): MS 382.1 (M+H)* Example 259 (6-methyl-2 -phenoxymethyl-pyrimidin-4-yl) - (5 phenyl-2H-pyrazol-3-yl)-amine (IIId-3): MS 358.2 (M+H)+ 15 Example 260 [5- (Furan-2-yl) -2H-pyrazol-3-yl - (6-methyl-2 phenoxymethyl-pyrimidin-4-yl)-amine (IIId-4): MS 348.2 (M+H)* Example 261 [5- (Furan-2-yl) -2H-pyrazol-3-yl] - (6-methyl-2 20 phenylsulfanylmethyl-pyrimi din-4 -yl) -amine (IId-5): MS 364.1 (M+H) t Example 262 -[6-Methyl-2- (4-methyl-phenylsulfanylmethyl) pyrimidin-4-yl - (5-phenyl-2H-pyrazol-3-yl) -amine (IId 25 6): MS 388.1 (M+H) t Example 263 [5- (Furan-2-yl) -2E-pyrazol-3-ylj - [6-Methyl-2 (4-methyl-phenyleulfanylme thyl) -pyrimidin-4 -yl] -amine (IIId-7): MS 378.1 (M+H)* 30 Example 264 [2- ( 4 -Fluoro-phenoxymethyl) -6-methyl pyrimidin-4-yl] - (5-phenyi-21-pyrazol-3-yl) -amine (IIld 8): MS 376.2 (M+H)* -308 Example 265 [2-( 4 -Fluoro-phenoxymethyl)-6-methyl pyrimidin-4-yl]-[5-(furan-2-yl)-21-pyrazol-3-yl]-amine (IIId-9): MS 366.2 (M+H)* 5 Example 266 (6 -Ethyl -2 -phenylsul fanylmethyl -pyrimidin- 4 yl)-(5-methyl-2H-pyrazol-3-yl)-amine (IIld-10): MS 326.2 (M+H)+ 10 Example 267 (6-Ethyl-2-phenoxymethyl-pyrimidin-4-y1)-(5 methyl-2-pyrazol-3-yl)-amine (IIld-11):.MS 310.2 (M+H)* Example 268 E6-Ethyl-2-(4-fluorophenoxymethyl)-pyrimidin 4-yl] - (5-methyl-2H-pyrazol-3-yl) -amine (IIld-12): MS 15 328.2 (M+H)-* Example 269 [6-Ethyl-2-(1-methyl-1-phenyl-ethyl) pyrimidin-4-yll - (5-methyl-2H-pyrazol-3-yl) -amine (IIId 13): MS 322.2 (M+H)+ 20 Example 270 [2-(4-Chlororophenoxymethyl)-6-methyl pyrimidin-4-yl]-(5-phenyl-2-pyrazol-3-yl)-amine (Id 14): MS 392.2 (M+H)* 25 Example 271 [2-(4-Chlororophenoxymethyl)-6-methyl pyrimidin-4-ylJ - (5-methyl-2H-pyrazol-3-yl) -amine (1I1d 15): MS 330.2 (M+H)* Example 272 (2-(4-Chlororophenoxymethyl)-6-methoxymethyl 30 pyrimidin-4-yl]-(5-methyl-2-pyrazol-3-yl)-amine (IIId 16): white solid; 'H NMR (DMSO) 6 2.20 (3H, s), 3.43 (3H, s) , 4.49 (2H, 's). 5.20 (2H, s), 6.05 (iH, br), 7.05 (2H, d), 7.33 (2H, d), 10.55 (iH, br); MS 360.2 (M+H)* -309 Example 273 [2- ( 4 -Chlororophenoxymethyl) -6-methyl pyrimidin-4-yl]-[5-(furan-2-yl)-2E-pyrazol-3-yl]-amine (IIId-17): MS 382.2 (M+H)* 5 Example 274 (5-Methyl-2-pyrazol-3-yl)-(2 phenylsulfanylmethyl-5,6,7,8-tetrahydro-quinazolin-4-yl) amine (Ild-7): MS 352.5 (M+H)* 10 Example 275 [2-( 4 -Methylphenylaulfanylmethyl)-6,7,8,9 tetrahydro-H-cycloheptapyrimidin-4-yl]-(5-methyl-2H pyrazol-3-yl)-amine (IId-8):MS 380.2 (M+H)* Example 276 [2-(1-Methyl-1-phenyl-ethyl)-6,7,8,9 15 tetrahydro-5H-cycloheptapyrimidin-4..y1] - (5-methyl-2H pyrazol-3-yl) -amine (Id-9) : MS 362.3 (M+H)* Example 277 [2-(2,6-Dichlorobenzyl)-5,6,7,8-tetrahydro 20 quinazolin-4-yl]-(S-methyl-2H-pyrazol-3-yl)-amine (lid 10): MS 388.1 (M+H)* Example 278 [7-Benzyl-2-(2,6-dichlorobenzyl)-5,6,7,8 tetrahydropyrido [3,4-d]pyrimidin-4-yl] - (5-methyl-2H 25 pyrazol-3-yl)-amine (Ild-11): MS 479.5 (M+H)* Example 279 [6-Benzyl-2-(4-chlorophenoxymethyl)-5,6,7,8 tetrahydro-pyrido[4,3-dlpyrimidin-4-yll-(5-methyl-2E pyrazol-3-yl)-amine (IId-12): MS 461.2 (M+H)* 30 Example 280 [2- (4-Chlorophenoxymethyl) -5,6,7,8 tetrahydro-pyrido[4,3-dlpyrimidin-4-yl]-(5-methyl-2E pyrazol-3-yl)-amine (Id-13): MS 371.3 (M+H)* -310 Example 281 [2-(2,6-Dichlorobenzyl)-6-methyl-pyrimidin-4 yll-(5-methyl-2H-pyrazol-3-yl)-amine (IIId-18): MS 348.1 (M+H) + 5 .. . Example 282 [2-(2,6-Dichlorobenzyl)-5,6-dimethyl pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (II~d 19): white solid; 1H NMR (DMSO) 0 8.50 (1H, s), 7.70 -(lH, d), 7.3-7.1 (3H, m), 5.25 (1H, s), 4.10 (1H, s), 2.30 10 (3H, s), 2.10 (3H, a), 1.80 (3H, s); MS 362.1 (M+H)* Example 283 (1H-Indazol-3-yl)-[2-(2-phenyl-cyclopropyl) quinazolin-4-yll-amine (lid-16): 'HNMR (DMSO) 13.2(1H, s), 12.0(1H, s), 8.76(1H, m), 8.10(1H, m), 7.85(2H, m), 15 7.75(1H, m), 7.61(1H, m) 7.41(1H, m), 7.30(2H, m); 7.20(2H, m), 7.12(2H, m), 2.35(2H, m), 1.60(1H, m), 1.35(1H, M); MS: m/z, 378.1 MH+; HPLC Rt=3.21 min. Example 284 (7-Fluoro-1H-indazol-3-yl)-[2-(2-phenyl 20 cyclopropyl) -quinazolin-4-yl -amine (IId-17): 'HNMR (DMSO) 13.8(1H, s), 12.05(1H, s), 8.75(1H, m), 8.10(1H, m), 7.85(2H, m), 7.60(1H, M), 7.35(3H, m) 7.25-7.10(4H, m), 2.35(2H, m), 1.60(1H, m), 1.35(1H, m); MS: m/z, 396.1 MH+; HPLC Rt=3.26 min. 25 Example 285 (5-Fluoro-1H-indazol-3-yl)-[2-(2-phenyl cyclopropyl) -quinazolin-4-yl -amine (IlId-18): 'HNMR (DMSO) 13.3(1H, s), 12.0(1H, a), 8.75(1H, m), 8.10(1H, m), 7.85(2H, m), 7.65(2H, m), 7.35(3H, m) 7.20(1H, m), 30 7.10(2H, m) 2.40 (2H, m), 1.65(1H, m), 1.35(1H, m); MS: m/z, 396.1 MH+; HPLC Rt=3.26 min.

-311 Example 286 (5-Methyl-1H-pyrazol-3-yl)-[2-(2-phenyl cyclopropyl) -quinazolin-4-yl] -amine (IId-19): 'HNMR (DMSO) 12.8 (1H, s), 11.90'(1H, s), 8.80(1H, m), 8.10(1H, m), 7.85(2H, m), 7.30-7.20(5H, m), 6.55 (1H, s) 2.80 (1H, m), 5 2.55(1H, m), 2.35 (3H,s) 2.00(2H, m); MS: m/z, 342.1 MH+.; HPLC Rt=3.13 min. BIOLOGICAL TESTING The activity of the compounds as protein kinase 10 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 15 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 20 running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands. BIOLOGICAL TESTING EXAMPLE 1 25 Ki DETERMINATION FOR THE INHIBITION OF.GSK-3 Compounds were screened for their ability to inhibit GSK-3$ (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 30 containing 100 mM HEPES (pH 7.5), 10 mM MgC2, 25 mM NaCl, 300 pM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 20 p1M ATP (Sigma Chemicals, St Louis, MO) and 300 p1M peptide -312 (HSSPHQS(PO3H 2 )EDEEE, American Peptide, Sunnyvale, CA). Reactions were carried out at 30-*C and 20 nM GSK-30. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 300 iaM 5 NADH, 30 pg/ml pyruvate kinase and 10 pg/ml lactate dehydrogenase. An assay stock buffer solution was prepared containing all of the reagents listed above with the exception of ATP and the test compound of interest. The 10 assay stock buffer solution (175 pl) was incubated in a 96 well plate with 5 y1 of the test compound of interest at final concentrations spanning 0.002 pM.to 30 M at 30 0 C for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM 15 compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated by the addition of 20 pl of ATP (final concentration 20 IxM). Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at 20 30 0 C. The Kivalues 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 JIM for GSK-3: Ila-2, a-8, IIa-9, Ila-11, IIa-12, IIa-17, Ia-18, IIa-21 to Ila-24, 25 IIa-26, IIa-28, Ila-30 through IIa-32, IIa-39, Ira-43, IIa-46, IIa-47, Ia-61, IIc-3, Ilc-6, IIc-8, IIc-10 through IIc-12, IIc-15, IIc-18, IIc-20~through IIc-22, IIc-24, Ilc-25, IIc-27, Ilc-30 through IIc-32, IIc-35 to IIc-39, IIc-42, IIc-53, Ilc-61, IIc-67, IIc-77, IIc-78, 30 IIb-1, IIb-3, IIb-5, IIb-8, Ild-1, IIIa-2, IIIa-3, IIIa 6, IIIa-17, IIIa-18, IIIa-24,.IIIa-27, IIIc-2 through IIIc-5, IIIc-9, IIIc-11, IIIc-12, IIIc-15, IIc-18, IIIc- -313 19, IIIc-21, IIIc-24, IIIb-1 through IIIb-6, IIIb-8 through IIIb-10, IIIb-13, IIIb-14, IIId-20, IIId-21, Ild 14, and Ild-19. The following compounds were shown to have Ki 5 values between-0.1 and 1;0 4M for GSK-3: Ila-1, IIa-4, Ila-5, IIa-7,-IIa-14, Ia-15, IIa-20, IIa-29, IIa-34 through IIa-36, IIa-38., IIa-41, IIa-42, IIa-48, IIa-54, IIa-55, IIa-62, IIa-63, IIa-66, IIa-69, IIa-78, IIc-1, IIc-2, IIc-4, IIc-5, IIc-7, IIc-9, IIc-13, IIc-14, IIc 10 16, IIc-17, IIc-19, IIc-23, IIc-26, IIc-28, IIc-29, IIc 33, IIc-34, IIc-40, IIc-41, IIc-43 through IIc-45, IIc-47 through IIc-52, IIc-54 through IIc-57, IIc-59, IIc-63 through IIc-66, IIc-72, IIc-75, IIc-76, IIc-79, IIc-6, IIb-7, IIb-9, IMd-2, Ild-5, IId-6, IIIa-1, 111a-4, 'IIIa 15 5, IIIa-7, IIIa-8, IIIa-10, IIIa-11, IIIa-19, IIIa-22, IIIa-23, IIIa-26, I1a-29, IIIa-30, IIIA-31, IIIa-33, 1IIa-34, IIIa-37, IIa-42, IIIc-1, IIIc-8, IIIc-20, IIIc 23, IIIb-7, IIIb-11, IIIb-12, IIIb-15, IIIb-16, IId-16, Ild-17, and IId-18. 20 The following compounds were shown to have Ki values between 1.0 and 7.0 pM for GSK-3: Ila-10, IIa-13, IIa-25, IIa-40, I1a-45, IIa-49, IIa-50 through IIa-52, IIa-64, IIa-65, IIa-67, IIa-68, IIa-71, IIa-72, IIa-74, IIa-76, Ila-77, Ila-81, IIc-58, Ilc-60, IIc-62, IIc-68 25 through IIc-71, I1c.-74, IId-3, IId-4, IIIa-15, IIIa-16, IIIa-21, IIIa-28, IIIa-35, IIIa-36, IIIa-38, IIIa-41, IIIa-43, IIIa-45, IIIa-49, IIIc-10, IIIc-16, IIIc-17, and IIIc-22. 30 BIOLOGICAL TESTING EXAMPLE ~2 Ki DETERMINATION FOR THE INHIBITION OF AURORA-2 Compounds were screened in the following manner. for their ability to inhibit Aurora-2 using a standard -314 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 MgC1 2 , 1 mM DTT, 25 mM NaCl, 2.5 mM 5 phosphoenolpyruvat-e, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and 800 pM peptide (LRRASLG, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 pM. The 10 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 70 nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5 minute read 15 time at 30 0 C using a BioRad Ultramark plate reader (Hercules, CA). The Kj 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: Ia~-1 through IIa 20 18, IIa-21 through IIa-64, IIa-66, IIa-68, IIa-69, IIa-71 through IIa-78, IIa-81, IIc-1 through IIc-13, IIc-15 through IIc-44, IIc-46 through IIc-61, -IIc-63 through lIc-65, IIc-67 through IIc-69, IIb-1 through IIb-9, IId-1 through Ild-3, IIIa-l through IIIa-8, Ilia-10 through 25 IIIa-13, IIIa-15 through IIa-32, IIIa-36 -through IIIa 41, IIIa-44 through IIIa-49, IIIc-1 through IlIc-5, IIIc 12, and IIIc-15. The following compounds were shown to have Ki values between 0.1 and 1.0 pM for Aurora-2: IIa-20, IIa 30 65, IIa-67, IIa-70, Ia-80, IIc-14, IIc-66, IId-5, hId-6, IIIa-14, IIIa-33 through IIIa-35, Ic-'9, IIIc-11, IIIb 1, Ib-2, IIIb-7, IlIb-10 through IIIb-13, IIIb-15, IIIb-16, and IIId-20.

-3 15 The following compounds were shown to have K± values between 1.0 and 10.0 gM for Aurora-2: IIa-10, IIc 71, IIc-75, IIc-76, IId-4, IIIa-42, IIIa-43, I1c-10, IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14. 5 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, 10 2249). To an assay stock buffer solution containing 0.1M HEPES 7.5, 10 mM MgCl 2 , 1 mM DTT, 25 mM NaCl, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP, and 15 100 pM peptide (MAHHHRSPRKRAKKK, American Peptide, Sunnyvale, CA) was added a DMSO solution of a compound of the present invention to a final concentration of 30 iM. The resulting mixture was incubated at 30 0 C for 10 min. The reaction was initiated by the addition -of 20 10 pL 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 "C using a BioRad Ultramark plate. reader (Hercules, CA). The Ki values were 25 determined from the rate data as a function of inhibitor concentration. The following compounds were shown to have Ki values less than 1 gM for CDK-2: IIa-14, IIa-36, IIc-15, IIc-25, IIc-27, IIc-32, IIc-53, and IIIc-4.

-316 The following compounds were shown to have Ki values between 1.0 and 20.0 pM for CDK-2: IIa-38., IIa-40, IIa-44, IIa-52, and IIa-54. 5 BIOLOGICAL TESTING EXAMPLE 4 ERK INHIBITION ASSAY Compounds were assayed for the inhibition of ERK2 by a spectrophotometric coupled-enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay, a fixed 10 concentration of activated ERK2 (10 nM) was incubated with-various concentrations of the compound in DMSO (2.5 %) for 10 min. at 304C in 0.1 M HEPES buffer, pH 7.5, containing 10 mM MgCl 2 , 2.5 mM phosphoenolpyruvate, 200 jM NADH, 150 pg/mL pyruvate kinase, 50 pg/mL lactate 15 dehydrogenase, and 200 aM 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 ICa was evaluated from the rate data as a function of inhibitor concentration. 20 The following compounds were shown to have K, values less than 1 pM for ERK-2: IIc-15, IIc-27, IIc-32, IIc-53, and IIIc-4. The following compounds were shown to have Ki values between 1.0 and 20.0 pM for ERK-2: IIc-18, IIc-25, 25 and IIa-36. BIOLOGICAL TESTING EXAMPLE 5 AKT INHIBITION ASSAY Compounds were screened for their ability to 30 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 MgCl2, 25 mM -317 NaCl , 1 mM DTT and 1.5% DMSO. -Final substrate .concentrations in the assay were 170 iM ATP (Sigma Chemicals) and 200 pM -peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 ' and 45 5 nM AKT. 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 pg/ml lactate dehydrogenase. An assay stock buffer solution was prepared 10 containing all of the reagents listed above, with the exception of AKT, DTT, and the test compound of interest. 56 pl of the stock solution was placed in a 384 well plate followed by addition of 1 pl of 2 mM DMSO stock containing the test compound (final compound 15 concentration 30 pM). The plate was preincubated for about 10 minutes at 30'C and the reaction initiated by addition of 10 pl of enzyme (final concentration 45 nM) and 1 mM D T.. Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a 5 20 minute read time at 30'C. Compounds showing greater than 50% inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine IC 50 values. The following compounds were shown to have Ki 25 values between 1.0 and 20.0 yM for AKT-3: IIc-18, IIc-22, IIc-25, IIc-27, IIc-31, IIc-32, IIc-37, IIc-39, IIc-42, and IIc-53. BIOLOGICAL TESTING EXAMPLE 6 30 SRC INHIBITION ASSAY The compounds were evaluated as inhibitors of human Src kinase using either a radioactivity-based assay or spectrophotometric assay.

-318 Src Inhibition Assay A: Radioactivity-based.Assa The compounds were assayed as inhibitors of full length recombinant human Src kinase (from Upstate Biotechnology, cat. no. 14-117) expressed and purified s from baculo-viral cells. Src kinase activity, was monitored by following the incorporation of 33P from ATP into the tyrosine of a random poly Glu-Tyr polymer substrate of composition, Glu:Tyr = 4:1 (Sigma, cat. no. P-0275). The following were the final concentrations of 10 the assay components: 0.05 M HEPES, pH 7.6, 10 mM MgCl 2 , 2 mM DTT, 0.25 mg/ml BSA, 10 pM ATP (1-2 paCi 33 P-ATP per reaction), 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 15 pre-mixed and aliquoted into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of 2.5%. The assay plate was incubated at 30 *C for 10 min before initiating the reaction with a 3 P-ATP. After 20 min of reaction, the 20 reactions were quenched with 150 pl of 10% 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 25 vacuum manifold. Filter plates were washed four times with 10% TCA containing 20 mM Na 3

PO

4 and then 4 times with methanol. 200pl of scintillation fluid was then added to each well. The plates were sealed- and the amount of radioactivity associated with the filters was quantified 30 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.

-319 Src Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly 5 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 disappearance of NADH can be conveniently followed at 340 10 nm. -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 15 components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 pM NADH, 30 ig/ml pyruvate kinase and 10 pg/ml lactate dehydrogenase. In a typical assay, -all the reaction components with the exception of ATP were pre-mixed and aliquoted 20 into assay plate wells. Inhibitors dissolved in DMSO wereadded to the wells to give a final DMSO concentration of 2.5%. The assay plate wasincubated at 30'C for 10-min before initiating the reaction with 100 pM ATP. The absorbance change at 340 nm with time, the rate of the 25 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 30 value of <100nM on SRC: IIa-8, IIa-21, IIa-23; IIa-24, IIa-27, IIa-28, IIa-30 through IIa-33, IIb-1, IIb-4, Ilb 5, IIc-3, IIc-8, IIc-10, IIC-13, IIC-15, IIC-18, IIc-19, IIc-21 through IIc-24, IIc-31.through I.Ic-,35, IIc-37 -320 through IIc-39, IIc-41 through IIc-44, IIc-51, IId-1, IId-2, IIIa-1, IIIa-6 through Ila-8, IIIa-26 through IIIa-30, and IIIc-i through IIIc-S. The following compounds were shown to have a Ki 5 value of between 100AM and 1pM for SRC: IIa-1; IIa-2, IIa-7, IIa-9, IIa-12,. IIa-14, IIa-22, IIa-25, IIa-26, IIa-29, IIa-34 through IIa-42, IIa-46, I1a-47, IIa-49 through IIa-52^, IIa-56, IIa-57, IIa-59, IIa-6, IIa-62, Iha-66, IIa-67, IIa-69, IIa-72, -IIa-73, IIa-75, IIb-6, 10 IIb-8, IIc-4 through IIc-7, IIc-9, IIc-11, IIc-12, IIc 14, lIc-16, IIc-17, IIc-20, IIc-25 through IIc-30, IIc 36, IIc-40, IIc-46 through Ilc-50, IIc-52 through IIc-61, IIc-63 throughIIc-65, IIc-67, IIc-69, IId-3, IIIa-2 through IIIa-5, IlIa-11, IIIa-14 through IlIa-18, IIIa-22 15 through IIIa-24, IIIa-31, IIIa-33, IIIa-35, IIIa-38 through IIIa-43, and IIIa-47. The following compounds were shown to.have a Ki value of between 1pM and 6M for SRC: IIa-13, IIa-20, IIa-44, Ila-45, IIa-48, IIa-54, IIa-55, IIa-E3, IIa-65,' 20 IIa-68, IIa-70, Ila-71, IIa-74, IIa-77, IIa-78, Ia-81, Ib-3, IIb-9; Ilc-1, IIc-2, Ilc-66, 1l0-68, IIIa-13, IIIa-21, IIIa-25, IIIa-34,~ IIa-36, IIIa-37, and IIIa-44. While we have presented a-number of embodiments of this invention, it is apparent that our basic 25 construction can be altered to provide other 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 which have 30 been represented by way of example.

- 321 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, unless in the 5 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.

Claims (25)

1. A compound of formula IIIc: R 2 R ,NH HN N Rx R) N N-Ri H 5 IIIc or a pharmaceutically acceptable salt or derivative thereof, wherein: R' is hydrogen; 0 Ry is independently selected from T-R 8 or L-Z-R , wherein R' is selected from a substituted C,- aliphatic, wherein at least one of the substituents on said aliphatic group is other than H; or an optionally substituted group selected from C 610 aryl, a heteroaryl ring having 5-10 ring atoms, a heterocyclyl ring 5 having 5-10 ring atoms, -OR, -C(=O)R, -CO 2 R, -COCOR, -COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR, -N(R 4 ) 2 , -CON(R 7 ) 2 , -SO 2 N(R 7 ) 2 , -OC(=O)R, -N(R 7 ) COR, -N(R 7 ) C02 (Ca aliphat ic) , -N (R 4 )N(R 4 ) 2 , -C=NN(R 4 ) 2 , -C=N-OR, -N(R 7 )CON(R 7 ) 2 , -N(R')SO 2 N(R 7 ) 2 , -N(R 4 )SO 2 R, or -OC (=O)N(R 7 ) 2; 20 R' is T- (Ring D) Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, 25 wherein Ring D is substituted at any substitutable ring carbon - 323 by oxo, T-R 5 , or V-Z-R 5 , and at any substitutable ring nitrogen by -R 4 ; T is a valence bond or a C 1 - 4 alkylidene chain; Z is a C 1 4 alkylidene chain; 5 L is -0-, -S-, -SO-, -SO 2 -, -N(R')S0 2 -, -SO 2 N(R') -, -N(R') -, -CO-, CO 2 - 1 -N(R 6 )CO-, -N(R 6 )C(0)O-, -N(R4)CON(R 6 )-, -N(R')S0 2 N(R)-, N(R")N(R 6 ) -, -C(O)N(R 6 ) -, -OC(O)N(R 6 ) -, -C(R') 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO2~, -C(R 6 ) 2 SO 2 N(R 6 )-, -C(R 6 ) 2 N(R 6 )-, -C(R') 2 N(R')C(0)-, -C (R') 2 N(R 6 ) C (0)0-, -C (R')=NN(R')-, -C(R')=N-0-, 0 -C(R') 2 N(R')N(R')-, -C(R') 2 N(R')SO 2 N(R')-, or -C(R') 2 N(R')CON(R')-; 2 622 R2 and R 2 - are independently selected from -R, -T-W-R , 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 .5 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, or -V-R , and any substitutable nitrogen on said ring formed by R 2 and R 2 - is substituted by R 4 ; R 3 is selected from -R, -halo, -OR, -C(=O)R, -CO 2 R, -COCOR, r..O COCH 2 COR, -NO 2 , -CN, -S(O)R, -S(O) 2 R, -SR, -N(R 4 ) 2 , -CON(R 7 ) 2 , -SO 2 N (R 7 ) 2 , -OC(=O)R, -N(R 7 ) COR, -N (R") CO 2 (C- aliphatic) , -N(R 4 )N(R 4 ) 2 , -C=NN(R 4 ) 2, -C=N-OR, -N(R7)CON(R 7 ) 2 , -N(R 7 )SO 2 N(R 7 ) 2 , -N(R 4 )SO 2 R, or -OC(=O)N(R') 2 ; each R is independently selected from hydrogen or an optionally 25 substituted group selected from C,_ aliphatic, C 6 . 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 2 (optionally substituted C 1 - 6 aliphatic) , -CON(R 7 ) 2 , or -S0 2 R 7 ; - 324 each R 5 is independently selected from -R, halo, -OR, -C(=O)R, -CO 2 R, -COCOR, -NO 2 , -CN, -S(O)R, -SO 2 R, -SR, -N(R 4 ) 2 , -CON(R 4 ) 2 , -SO 2 N (R 4 ) 2 , -OC(=O)R, -N(R 4 ) COR, -N(R 4 ) CO 2 (optionally substituted C 1 6 aliphatic), -N(R 4 )N(R 4 ) 2 , -C=NN(R 4 ) 2 , -C=N-OR, -N(R 4 )CON(R 4 ) 2 , 5 -N(R4 ) SO 2 N (R4 ) 2 , -N(R 4 ) SO 2 R, or -OC (=O) N (R 4 ) 2 ; V is -0-, -S-, -SO-, -SO 2 -, -N(R 6 )S0 2 -, -SO 2 N(R 6 )-, -N(R 6 )-, -CO-, CO 2 - 1 -N(R )CO-, -N(R 6 )C(O)O-, -N(R4)CON(R4)-, -N(R')SO 2 N(R')-, N(R 6 )N(R')-, -C(O)N(R 6 ) -, -OC(O)N(R')-, -C(R4) 2 0-, -C(R 6 ) 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ') 2 So 2 -, -C(R 6 ) 2 SO 2 N(R 6 )-, -C(R 6 ) 2 N(R 6 )-, O -C(R 6 ) 2 N (R 6 ) C(0)-, -C(R 6 ) 2 N(R 6 ) C (0)O-, -C(R 6 ) =NN(R 6 ) -, -C(R 6 ) =N-O-, -C(R 6 ) 2 N(R 6 )N(R 6 )-, -C(R 6 ) 2 N(R')SO 2 N(R 6 )-, or -C(R 6 ) 2 N(R 6 )CON(R 6 )-; W is -C(R 6 ) 2 0-, -C (R') 2 S-, -C(R 6 ) 2 SO-, -C(R 6 ) 2 SO 2 -, -C(R 6 ) 2 SO 2 N(R')-, C(R 6 ) 2 N(R 6 ) -, -Co-, -CC 2 -, -C(R 6 ) OC (0) -, -C(R 6 )OC (O)N(R 6 ) -, -C(R 6 ) 2 N(R 6 )CO-, -C(R 6 ) 2 N(R 6 )C(0)O-, -C(R 6 ) =NN(R 6 ) -, -C(R 6 )=N-O-, 5 -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 CR 6 ) - ; each R 6 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 0 a 5-6 membered heterocyclyl or heteroaryl ring; and each R' is independently selected from hydrogen or an optionally substituted C 16 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. 25

2. The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of: (a) Ry is T-R 8 or L-Z-R 3 , wherein T is a valence bond or a methylene and R 3 is -R, -N(R 4 ) 2 , or -OR and Ra is selected 30 from a substituted Cl 6 aliphatic, wherein at least one of - 325 the substituents on said aliphatic group is other than H; or an optionally substituted group selected from C,-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms, -N(R 4 ) 2 or -OR; (b) R' is T-(Ring D), wherein T is a valence bond or a methylene unit; (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and (d) R 2 is -R or -T-W-R 6 and R 2 ' is hydrogen, or R 2 and R 2 are taken together to form an optionally substituted benzo ring.

3. The compound according to claim 1 or claim 2, wherein: (a) Ry is T-R' or L-Z-R', wherein T is a valence bond or a 5 methylene and R 3 is -R, -N(R 4 ) 2 , or -OR and R' is selected from a substituted C 1 6 aliphatic, wherein at least one of the substituents on said aliphatic group is other than H; or an optionally substituted group selected from C,-, aryl, a heteroaryl ring having 5-10 ring atoms, or a 0 heterocyclyl ring having 5-10 ring atoms, -N(R 4 ) 2 or -OR; (b) R' is T-(Ring D), wherein T is a valence bond or a methylene unit; (c) Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and 5 (d) R 2 is -R or -T-W-R 6 and R 2 is hydrogen, or R 2 and R 2 ' are taken together to form an optionally substituted benzo ring. - 326

4. The compound according to claim 1 or claim 2, wherein said compound has one or more features selected from the group consisting of: (a) Ry is T-R' or L-Z-R 3 wherein T is a valence bond or a 5 methylene and R 3 and R 8 are selected from -R, -OR, or -N(R 4 ) 2 , wherein R is selected from C 2 - 6 aliphatic, or a 5 6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; (b) R' is T-(Ring D), wherein T is a valence bond; 0 (c) Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; (d) R 2 is -R and R 2 is hydrogen, wherein R is selected from hydrogen, C 1 - aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and 5 (e) L is -0-, -S-, or -N(R 4 )-.

5. The compound according to claim 4, wherein: (a) Ry is T-R 8 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 and R' are selected from -R, -OR, or 0 -N(R 4 ) 2 , wherein R is selected from C 2 6 aliphatic, or a 5 6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; (b) R' is T-(Ring D), wherein T is a valence bond; (c) Ring D is a 5-6 membered monocyclic or an 8-10 membered 5 bicyclic aryl or heteroaryl ring; (d) R 2 is -R and R 2 is hydrogen, wherein R is selected from hydrogen, C 1 - aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and (e) L is -0-, -S-, or -N(R 4 )-. 0 - 327

6. The compound according to claim 4, wherein said compound has one or more features selected from the group consisting of: (a) Ry is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, ethyl, 5 cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; (b) R' is T-(Ring D), wherein T is a valence bond and Ring D o is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, -CN, -NO 2 , -N(R 4 ) 2 , optionally substituted C,-, aliphatic group, -OR, -CO 2 R, -CONH(R 4 ), -N(R 4 )COR, -N(R 4 ) SO 2 R, -N(R') COCH 2 CH 2 N(R 4 ) 2, or -N(R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2; 5 and (c) R 2 is hydrogen or a substituted or unsubstituted C 1 -, aliphatic, and L is -0-, -S-, or -NH-.

7. The compound according to claim 6, wherein: 0 (a) Ry is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted 5 phenyl, or methoxymethyl; (b) R' is T-(Ring D), wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring, wherein Ring D is optionally substituted with one to two groups selected from -halo, -CN, -NO 2 , -N(R 4 ) 2 , optionally substituted C, 0 aliphatic group, -OR, -CO 2 R, -CONH(R 4 ), -N(R 4 )COR, - 328 -N (R 4 )SO 2 R, -N(R')COCH 2 CH 2 N(R 4 ) 2 , or -N(R 6 ) COCH 2 CH 2 CH 2 N (R 4 ) 2 and (c) R 2 is hydrogen or a substituted or unsubstituted C 1 aliphatic, and L is -0-, -S-, or -NH-. 5

8. A compound selected from the group consisting of: (5-Methyl-2H-pyrazol-3-yl)-(6-phenyl-2-phenylamino-pyrimidin 4 -yl)-amine; (5-Cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2- phenylamino o pyrimidin-4-yl)-amine; (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3- methylphenylamino)-6 phenyl-pyrimidin-4-yl]-amine; [2-(4-cyanomethylphenylamino)-6-phenyl-pyrimidin-4-yl]-(5 cyclopropyl-2H-pyrazol-3-yl)-amine; 5 (5-Cyclopropyl-2H-pyrazol-3-yl)-[6-phenyl-2-(pyridin-3 ylmethylamino)-pyrimidin-4-yl]-amine; [2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine; [2-(3-Chlorophenyl)amino-6-(3,4,5-trimethoxyphenyl) 0 pyrimidin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine; (5-Methyl-2H-pyrazol-3-yl)-[2-(4-sulfamoylphenylamino)-6 (3,4,5-trimethoxyphenyl)-pyrimidin-4-yl]-amine; [2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-[5-(furan 2 -yl)-2H-pyrazol-3-yl]-amine; 5 [2-(Benzimidazol-2-ylamino-)6-ethyl-pyrimidin-4-yll-(5 methyl-2H-pyrazol-3-yl)-amine; [2-(4-Chlorophenyl)amino-6-methyl-pyrimidin-4-yl]-(5-phenyl 2H-pyrazol-3-yl)-amine; [2-(4-Chlorophenyl)amino-6-ethyl-pyrimidin-4-yl]-(5-methyl 0 2H-pyrazol-3-yl)-amine; - 329 (5-tert-Butyl-2H-pyrazol-3-yl)-[2-(3- chlorophenyl)amino-6 (3-nitrophenyl)-pyrimidin-4-yl]-amine; [2-(3-Chlorophenyl)amino-6-(3-nitrophenyl)-pyrimidin-4-yll (5-phenyl-2H-pyrazol-3-yl)-amine; 5 [5-(Furan-2-yl)-2H-pyrazol-3-yl]-(6-phenyl-2-phenylamino pyrimidin-4-yl)-amine; [2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-(5 phenyl-2H-pyrazol-3-yl)-amine; [2-(Benzimidazol-2-ylamino)-6-methyl-pyrimidin-4-yl]-[5 0 (Furan-2-yl)-2H-pyrazol-3-yl]-amine; [2-(4-Chlorophenylamino)-6-methyl-pyrimidin-4-yl)-(5-methyl 2H-pyrazol-3-yl)-amine; [2-(4-Chlorophenyl)amino-5,6-dimethyl-pyrimidin-4-yl]-(5 methyl-2H-pyrazol-3-yl)-amine; 5 (5,6-Dimethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H pyrazol-3-yl)-amine; [2-(4-Chlorophenyl)amino-6-methoxymethyl-pyrimidin-4-yl]-(5 methyl-2H-pyrazol-3-yl)-amine; [2-(Benzimidazol-2-ylamino)-6-methoxymethyl-pyrimidin-4-yl) 0 (5-methyl-2H-pyrazol-3-yl)-amine; (6-Methoxymethyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H pyrazol-3-yl)-amine; (6-Methyl-2-phenylamino-pyrimidin-4-yl)-(5-methyl-2H-pyrazol 3 -yl)-amine; ?5 N4-(5-Cyclopropyl-lH-pyrazol-3-yl)-N 2 -(lH-indazol-5-yl)-6 methyl-pyrimidine-2,4-diamine; and N 2 -Benzothiazol-6-yl-N 4 - (5-cyclopropyl-lH-pyrazol-3-yl) -6 methyl-pyrimidine-2,4-diamine. - 330

9. A composition comprising a compound according to any one of claims 1-8; and a pharmaceutically acceptable carrier.

10. The composition according to claim 9, further comprising an additional therapeutic agent. 5

11. A method of inhibiting Aurora-2, GSK-3, or Src activity in a biological sample comprising the step of contacting said biological sample with a compound according to any one of claims 1-8 or a composition according to claim 9 or claim 10.

12. A method of inhibiting Aurora-2 activity in a patient 0 comprising the step of administering to said patient a compound according to any one of claims 1-8 or a composition according to claim 9 or claim 10.

13. A method of treating an Aurora-2-mediated disease, which method comprises administering to a patient in need of such a 5 treatment a therapeutically effective amount of a compound according to any one of claims 1-8 or a composition according to claim 9.

14. The method according to claim 13, wherein said disease is selected from colon, breast, stomach, or ovarian cancer. .0

15. The method according to claim 13 or claim 14, wherein said method further comprises administering an additional therapeutic agent.

16. The method according to claim 15, wherein said additional therapeutic agent is a chemotherapeutic agent. - 331

17. A method of inhibiting GSK-3 activity in a patient comprising the step of administering to said patient a compound according to any one of claims 1-8 or a composition according to claim 9 or claim 10.

18. A method of method of treating a GSK-3-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound according to any one of claims 1-8 or a composition according to claim 9 or claim 10. D

19. The method according to claim 18, wherein said GSK-3 mediated disease is selected from diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDS-associated dementia, amyotrophic lateral sclerosis (AML), multiple sclerosis (MS), schizophrenia, cardiomycete hypertrophy, 5 reperfusion/ischemia, or baldness.

20. The method according to claim 19, wherein said GSK-3 mediated disease is diabetes.

21. A method of enhancing glycogen synthesis or lowering blood levels of glucose in a patient in need thereof, which method 0 comprises administering to said patient a therapeutically effective amount of a compound according to any one of claims 1-8 or a composition according to claim 9 or claim 10.

22. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient, which method 5 comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any - 332 one of claims 1-8 or a composition according to claim 9 or claim 10.

23. A method of inhibiting the phosphorylation of 8-catenin, which method comprises administering to a patient in need thereof 5 a therapeutically effective amount of a compound according to any one of claims 1-8 or a composition according to claim 9 or claim 10.

24. A method of inhibiting Src activity in a patient comprising the step of administering to said patient a compound 0 according to any one of claims 1-8 or a composition according to claim 9 or claim 10.

25. A method of treating a Src-mediated disease, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound 5 according to any one of claims 1-8 or a composition according to claim 9 or claim 10. DATE: 24 November 2009