AU2006201229B2 - Pyrazole Compounds Useful as Protein Kinase Inhibitors - Google Patents

Description

-1-

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT Name of Applicant: Address for Service: Invention Title: Vertex Pharmaceuticals Incorporated CULLEN CO Patent Trade Mark Attorneys, 239 George Street Brisbane QId 4000 Australia Pyrazole Compounds Useful as Protein Kinase Inhibitors The following statement is a full description of this invention, including the best method of performing it, known to us: (N Vaa E PYRAZOLE COMPOUNDS USEFUL AS PROTEIN KINASE INHIBITORS 0

V\

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 invention relates to compounds that are inhibitors of Aurora-2 protein kinase. The invention also relates to methods of treating diseases associated with protein kinases, especially diseases associated with:Aurora-2, such as cancer.

BACKGROUND OF THE INVENTION The search for new therapeutic agents has been greatly aided in recent years by better understanding of the structure of enzymes and other biomolecules associated with target diseases. One important class of.

enzymes that has been the subject of extensive study is the protein kinases.

Protein kinases mediate intracellular signal transduction. They do this by effecting a phosphoryl transfer from a nucleoside triphosphate to.a protein acceptor that is involved in a signaling pathway There Sare a number of kinases and pathways through which NO -2- Sextracellular and other stimuli cause a variety of cellular responses to occur inside the cell. Examples of such stimuli include environmental and chemical stress signals osmotic shock, heat shock, ultraviolet .radiation, bacterial endotoxin, H202), cytokines (e.g.

interleukin-1 (IL-1) and tumor necrosis -factor-a

(TNF-

a and growth factors granulocyte macrophagec.olony-stimulating-factor (GM-CSF), and fibroblast growth cO factor An extracellular stimulus may effect one 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.

any diseases are associated with abnormal cellular responses triggered by protein kinase-mediated events. These diseases include autoimmune diseases, inflammatory diseases, neurological and neurodegenerative diseases, cancer, cardiovascular diseases, allergies and asthma, Alzheimer's disease or hormone-related diseases.

Accordingly, there has-been a substantial effort-in medicinal chemistry to find protein kinase.inhibitors that are effective as therapeutic agents.

Aurora-2 is a serine/threonine protein kinase that has been implicated.in human cancer, such as colon, breast and other solid tumors. This kinase is believed to be involved in protein phosphorylation events that regulate the cell cycle. Specifically, Aurora-2 may play a role in controlling the accurate segregation of chromosomes during mitosis. Misregulation of the cell cycle can lead to cellular proliferation and other abnormalities. In human colon cancer tissue,'the aurora- 2 protein has been found to. be overexpressed. See

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D -3- CA Bischoff et al., EMBO.J., 1998, 17, 3052-3065; Schumacher Set al., J. Cell Biol., 1998, 143, 1 635 -1646; Kimura et Sal., J. Biol. Chem., 1997, 272, 13766-13771.

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

ND GSK-3 has been implicated in various diseases including o 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 operation of certain cell signaling pathways in which GSK-3 plays a role. GSK-3 has been found to phosphorylate and modulate the activity of a number of regulatory proteins. These proteins include glycogen synthase which is the rate limiting enzyme necessary for glycogen synthesis, the microtubule associated protein Tau, the gene transcription factor p-catenin, the translation initiation factor elF2B, as well as ATP.

citrate lyase, axin, heat shock factor-1, c-Jun, c-Myc, c-Myb, CREB, and CEPBa. These diverse protein targets implicate GSK-3 in many aspects of cellular metabolism, proliferation, differentiation and development.

In a GSK-3 mediated pathway that is relevant for the treatment of type II diabetes, insulin-induced signaling leads to cellular glucose uptake and glycogen synthesis. Along this pathway, GSK-3 is a negative regulator of the insulin-induced signal. Normally, the presence of insulin causes inhibition of GSK-3 mediated -4phosphorylation and deactivation of glycogen synthase.

The inhibition of GSK-3 leads to increased glycogen synthesis and glucose uptake [Klein et al., PNAS, 93, 8455-9 (1996); Cross et al., Biochem. 303, 21-26 (1994); Cohen, Biochem. Soc. Trans., 21, 555-567 (1993); Massillon et al., Biochem J. 299, 123-128 (1994)].

However, in a diabetic patient where the insulin response is impaired, glycogen synthesis and glucose uptake fail to increase despite the presence of relatively high blood levels of insulin. This leads to abnormally high blood levels of glucose with acute and long term effects that may ultimately result in cardiovascular disease, renal .failure and blindness. In such patients, the normal insulin-induced inhibition of GSK-3 fails to occur. It has also been reported that in patients with type II diabetes, GSK-3 is overexpressed [WO 00/38675].

Therapeutic inhibitors of GSK-3 therefore are considered to be useful for treating diabetic patients suffering from an impaired response to insulin.

GSK-3 activity has also been associated with Alzheimer's disease. This disease is characterized by the well-known P-amyloid peptide and the formation of intracellular neurofibrillary tangles. The neurofibrillary tangles contain hyperphosphorylated Tau protein where Tau is phosphorylated on abnormal sites.

GSK-3 has been shown to phosphorylate these abnormal sites in cell and animal models. Furthermore, inhibition of GSK-3 has been shown to prevent hyperphosphorylation of Tau in cells [Lovestone et al., Current Biology 4, 1077-86 (1994); Brownlees et al., Neuroreport 8, 3251-55 (1997)]. Therefore, it is believed that GSK-3 activity may promote generation of the neurofibrillary tangles and the progression of Alzheimer's disease.

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0 C ,Another substrate of GSK-3 is f-catenin which Sis degradated after phosphorylation by GSK-3. Reduced •levels of 0-catenin have been reported in schizophrenic patients and have also been associated with other diseases related to increase in neuronal cell death *C [Zhong et al., Nature, 395, 698-702 (1998); .Takashima et Sal., PNAS, 90, 7789-93 (1993); Pei et al., J.

C Neuropathol. Exp, 56, 70-78 (1997)].

0D As a result of the biological importance of q 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)] S.For many of the aforementioned diseases associated with abnormal GSK-3 activity, other protein kinases have also been targeted for treating-the same diseases. However, the various protein kinases often act Sthrough different biological pathways. For example, certain quinazoline derivatives have been reported recently as inhibitors of p38 kinase (WO 00/12497 to Scios). The compounds are reported to be useful for treating conditions characterized by enhanced p38-a activity and/or enhanced TGF-P activity. While p38 activity has been implicated in a wide -variety of diseases, including diabetes, p38 kinase is not reported to be a constituent of an insulin signaling pathway that regulates glycogen synthesis or glucose uptake.

Therefore, unlike GSK-3, p38 inhibition would not be expected to enhance glycogen synthesis and/or glucose uptake.

There is-a continued need to find new therapeutic agents to treat human diseases. The protein S. -6- C-i kinases Aurora-2 and GSK-3 are especially attractive ctargets for the discovery of new therapeutics due to their important roles in cancer and diabetes, respectively.

Ch DESCRIPTION OF THE INVENTION Ce It has now been found that compounds of this o invention and pharmaceutical compositions thereof are go effective as protein kinase inhibitors, particularly as o 10 inhibitors of Aurora-2. These compounds have the general formula I: R )NH

HN$E

Fix

Z

R

y Z Q-RI

I

or a pharmaceutically acceptable derivative or prodrug .thereof, wherein: Z' is nitrogen or C-R e and Z2 is nitrogen or CH, wherein at least one of Z 1 and Z 2 is nitrogen; -Rx and RY are independently selected from T-R 3 or L-Z-R 3 or Rx and R y are taken together with their intervening atoms to'form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring hetercatoms selected from oxygen, sulfur, or nitrogen, wherein each'substitutable ring carbon of said fused ring formed by RX and R' is independently substituted by oxo, T-R3, or L-Z-R 3 and each substitutable ring Va -7nitrogen of said ring formed by -RX and Ry is C independently substituted by R 4 Q is selected from

-C(R"

6 2 1,2- C- cyclopropanediyl, 1, 2 -cyclobutanediyl, or 1,3cyclobutanediyl; R1 is T-(Ring

D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered 0 bicyclic ring selected from aryl, heteroaryl, IN heterocyclyl or carbocyclyl, said hetetoaryl or heterocyclyl ring having 1-4 ring heteroatoms.selected from nitrbgen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-Rs 5 or V-Z-Rs, and eadh substitutable ring nitrogen.of Ring D is independently substituted by -R 4 T is a valence bond or a C 1 4 alkylidene chain, wherein when Q is -C(R 6 2 a methylene unit of said C 1 -4 alkylidene chain is optionally replaced by -CONH-, -NHCO-, -SO2-, -SO2NH-, -NHSO2-, -Co 2 -OC(o)NH-, or -NHCO 2 Z is a-C-4alkylidene chain; L -SO2-, -N(R 6 )S0 2

-SO

2

-N(R

6 -CO2-, -N(R 6

-N(R

6

-N(R)SO

2

N(R

6

-N(R

6

-OC(O)N(R

6

-C(R

6 2 0- -C(R 6 2

S-,

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

SO

2

-C(R

6 2

SO

2

N(R

6

-C(R

6 2

N(R

6 2

N(R

6 )C -C(R 6 2

N(R

6

-C(R

6

=NN(R

6

-C(R

6 2

N(R

6

-C(R

6 2

N(R

6 )SON or -C 2

N(R

6 )CON(R6)

R

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

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms -8selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by SR' 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 R 2 is independently substituted by R 4 R is selected from -halo, -OR,

-CO

2

R,

-COCOR,

-COCH

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

-N(R

4 2

-CON(R')

2

-SO

2 N(R 7) 2 -N(R COR, CO02 (1-6 aliphatic),

-N(R

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

N(R')

2 S02R, or -OC N 2; each R is independently selected from hydrogen or an optionally substituted group selected from C1_, aliphatic, Cs-o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10.ring atoms; each R is independently selected from -R -COR', -C02 (optionally substituted C1.- aliphiatic),

-CON(R')

2 or -SO 2

R';

each R 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN,

-S

2 R, -SR, -N(R 2

-CON(R')

2

-SO

2

N(R

4 2 -N(R)COR,

-N(R')CO

2 (optionally substituted C16 aliphatic),

-N(R

4

)N(R)

2

-C=NN(R

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

-N(R

4

)SO

2

N(R

4

-N(R

4

)SO

2 R, or -OC(=O)N(R )2; V is -SO2-, -N(R 6 So 2

-SO

2 -CO2-, C O-, N(R')CON(R6)-, -N(R6)SON -N -OC(0)N(R 6

-C(R

6 2 2

S-,

-C(R 2 SO-, -c(R 6 2 so 2

-(R

6 2 so 2

N(R

6

-C(R)

2

-C(R)

2 N(R6)C(0)

-C(R

6 2

N(R

6 -C(R6) =NN(R 6 Va N-9- -C C (R) 2 N -C 2 (R6) S2N or C (R 6 2N CON W is 20-, -C 2SO-, 2So- R -C(R2SON( -CO2-, -C OC OC N(R) C 2N CO-, -C(R -C(R6)2N(RC)N(R6)- 2

N(R

6 )S0 2 o-C(R) 2 or -CON(R 6 each R 6 is independently selected from hydrogen or an o 10 optionally substituted

C

1 4 aliphatic group, or two R 6 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 C,.4 aliphatic group, or two R' on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring; each R' is independently selected from-hydrogen or an optionally substituted

C

16 aliphatic group; or two R' on the same nitrogen are takeh together with the nitrogen to form a 5-8 membered heterocyclyl or heteroaryl ring; and R8 is selected from -R,.halo, -OR,

-CO

2 R, -COCOR,

-NO

2 -CN,

-SO

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

-CON(R

4 2

-SO

2

N(R

4 2 -N(R')COR,

-N(R

4 C02 (optionally substituted C1s aliphatic),

-N(R)N(R)

2

-C=NN(R')

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

-N(R

4

')SO

2 R, or

-OC(=O)N(R

4 2 As used'herein, the following definitions shall apply unless otherwise indicated. The phrase "optionally substituted" is used interchangeably with the phrase "substituted or unsubstituted" or with the term "(un)substituted." Unless otherwise indicated, an optionally substituted group may have a substituent at o Seach substitutable position of the group, and each substitution is independent of the other.

SThe term "aliphatic" as used herein means straight-chain, branched or cyclic C 1

-C

12 hydrocarbons which are completely saturated-or which contain one or h more units of unsaturation but which are not aromatic.

For example, suitable aliphatic groups include substituted or unsubstituted linear, branched or cyclic 0 alkyl, alkenyl, alkynyl groups and hybrids thereof such

S

1 0 as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl. The terms "alkyl", "alkoxy", "hydroxyalkyl", "alkoxyalkyi", and "alkoxycarbonyl", used alone or as part of a larger moiety includes both straight and branched chains containing one to twelve carbon atoms. The terms "alkenyl" and "alkynyl" used alone or as part of a larger moiety shall include both straight and branched chains containing two.to twelve carbon atoms. The term "cycloalkyl" used alone or as part of a larger moiety shall include cyclic 'C-C 12 hydrocarbons which are completely saturated or which contain one or more units of unsaturation, but which are not aromatic.

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

The term "heteroatom" means nitrogen, oxygen, or sulfur and includesany oxidized form of nitrogen and sulfur, and the quaternized form of any basic nitrogen.

Also the term "nitrogen" includes.a substitutable nitrogen of a heterocyclic ring. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur orlnitrogen, the 0 11nitrogen.may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as t in pyrrolidinyl) or NR (as.in N-substituted pyrrolidinyl).

C^ The terms "carbocycle", "carbocyclyl", -"carbocyclo", or ."carbocyclic" as used herein means an aliphatic ring system having-three to fourteen members.

The terms "carbocycle", "carbocyclyl", "carbocyclo", or o "carbocyclic" whether saturated or partially unsaturated, NO also refers to rings that are optionally substituted.

.The terms "carbocycle", "carbocyclyl", "carbocyclo", or "carbocyclic" also include aliphatic rings that are fused to one or more aromatic or nonaromatic rings, such as in a decahydronaphthyl or tetrahydronaphthyl, where the radical or point of attachment is on the aliphatic-ring.

The term "aryl". used alone or as part of-a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl",. refers to aromatic-ring groups having five to fourteen members, such as phenyl, benzyl, phenethyl, l-naphthyl, 2-naphthyl, i-anthracyl and 2anthracyl. The term "aryl" also refers to rings that are optionally substituted. .The term "aryl" may be used interchangeably with the term "aryl ring". "Aryl" also includes fused polycyclic aromatic ring systems in which an aromatic ring is fused to one .or more rings. Examples include l-naphthyl, 2-naphthyl, 1-anthracyl and 2anthracyl. Also included within the scope of the term "aryl", as it is.used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as in an indanyl, phenanthridinyl, or tetrahydronaphthyl,. where the radical or point of attachment is on the aromatic ring.

SThe term "heterocycle", "heterocyclyl", or "heterocyclic" as-used herein includes non-aromatic ring D 0-12- C-i systems having five to fourteen members, preferably five t to ten, in which one or more ring carbons, preferably one to four, are each replaced by a heteroatom such as N, O, or S. Examples of heterocyclic rings include 3-1Hbenzimidazol-2-one, (1-substituted)-2-oxo-benzimidazol-3- 0^ yl, 2-tetrahydrofuranyl, 3 -tetrahydrofuranyl, 2q tetrahydropyranyl, 3 -tetrahydropyranyl, 4- Stetrahydropyranyl, 11,3]-dioxalanyl, [1,3]-dithiolanyl, \D [1,3]-dioxanyl, 2 -tetrahydrothiophenyl, 3tetrahydrothiophenyl, 2-morpholinyl, 3-morpholinyl, 4morpholinyl, 2 -thiomorpholinyl, 3-thiomorpholinyl, 4thiomorpholinyl, l-pyrrolidinyl, 2-pyrrolidinyl, 3pyrrolidinyl, 1-piperazinyl, 2-piperazinyl, 1piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, 4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1phthalimidinyl, benzoxanyl, benzopyrrolidinyl, benzopiperidinyl, benzoxolanyl, benzothiolanyl, and benzothianyl. Also included within the scope of the term "heterocyclyl" or "heterocyclic", as it is used herein, is a group in which a non-aromatic heteroatom-containing ring is fused to one or more aromatic or non-aromatic rings, such as in an indolinyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the non-aromatic heteroatom-containing ring. The term "heterocycle", "heterocyclyl", or "heterocyclic" whether saturated or partially unsaturated, also refers to rings that are optionally substituted.

The term "heteroaryl", used alone or as part of a larger moiety as in "heteroaralkyl" or "heteroarylalkoxy", refers to heteroaromatic ring groups having five to fourteen members. Examples of heteroaryl rings include 2-furanyl, 3-furanyl,.3-furazanyl,

N-

IND

0 -13- C imidazolyl, 2-imidazolyl,.4-imidazolyl, 5-imidazolyl, 3t isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-oxadiazolyl, oxadiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1- C' pyrrolyl, 2-pyrrolyl, 3-pyrrolyl; 1-pyrazolyl, 2pyrazolyl, 3-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl, 2- C thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2o triazolyl, 5-triazolyl, 2-thienyl, 3-thienyl, carbazolyl, ND benzimidazolyl, benzothienyl, benzofuranyl, indolyl, 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 to one or more aromatic or nonaromatic rings where the radical or point of attachment is on the heteroaromatic ring. Examples include tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[3,4-d]pyrimidinyl.

The term "heteroaryl" also refers to rings that are optionally substituted. The term."heteroaryl" may be used interchangeably with the term "heteroaryl ring" or the term "heteroaromatic".

An aryl (including aralkyl, aralkoxy, aryloxyalkyl and the like) or heteroaryl (including heteroaralkyl and heteroarylalkoxy and the like) group may'contain one or more substituents. Examples of suitable substituents on the unsaturated carbon atom of an aryl, heteroaryl, aralkyl,:or heteroaralkyl group include a halogen,

-SR

0 1,2-methylene-dioxy, 1,2-ethylenedioxy, protected OH (such as .acyloxy), phenyl substituted Ph, substituted -O(Ph),

-CH

2 substituted

-CH

2

-CH

2 CH2(Ph), substituted

-CH

2

CH

2 -N02, -CN, -N(R 0 2

-NROC(O)R

6 -NMRC(0)N(RO)2, -14- Cl

-NROCO

2 RO, -NRoNROC Ro, -NRNROC N (R) 2 -NRONRC0 2 no Ct -C(o)C(o)Ro, -C(o)CHC(o) Ro, -C0 2 Ro, -C(0)RO 0 C N (R) 2 -OC(0)N(R 0 2 -S(0) 2

R

0

-SO

2 N(RO) 2 -NROS0 2

N(R)

2 Cl -NR 0

SO

2

R

0 -C(=S)N(Ro) 2

-C(=NH)-N(RO)

2 -(CHa)ymNHC()R,

(CH

2 )yNHC(0)CH(V-R) wherein each R is independently C selected from hydrogen, a substituted or unsubstituted aliphatic group, an unsubstituted heteroaryl or Cl heterocyclic ring, phenyl substituted Ph, -0(Ph), o substituted -0 -CH 2 or substituted -CH 2 y 0 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, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

An aliphatic group or a non-aromatic heterocyclic ring may contain one or more substituents.

Examples of suitable substituents on the saturated carbon of- an aliphatid 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: =NNHR, =NN(R') 2 =NNHC(O)R, =NNHCO 2 (alkyl),

=NNHSO

2 (alkyl), or =NR, where each'R* is independently selected from hydrogen, an unsubstituted aliphatic group or a substituted aliphatic group. Examples of substituents on the aliphatic group include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

'Suitable substituents on the nitrogen of a nonaromatic heterocyclic ring include

-N(R

2

-C(O)R

-CO

2

-C(O)C(O)R

-C CH 2 C R, -SO 2 R, -S0 2 N(R 2 N 2 2 and -NR*S0 2 wherein each R is independently selected from hydrogen, an aliphatic a O group, a substituted aliphatic group, phenyl (Ph)- C substituted Ph, substituted CH2(Ph), 0 *substituted CH 2 or an unsubstituted heteroaryl or ND heterocyclic ring. Examples of substituents on the S 10 aliphatic group or the phenyl ring include amino, alkylamino, dialkylamino, aminocarbonyl, halogen, alkyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylaminocarbonyloxy, dialkylaminocarbonyloxy, alkoxy, nitro, cyano, carboxy, alkoxycarbonyl, alkylcarbonyl, hydroxy, haloalkoxy, or haloalkyl.

The term "linker group" or "linker"means an organic moiety that connects two parts of a compound.

Linkers are typically comprised of an atom such as oxygen or sulfur, a unit such as -CH2-,

-C(O)NH-,

or a chain of atoms, such as an alkylidene chain. The.

molecular mass of a linker is typically in the range of.

about 14 to 200, preferably in the range of 14 to 96 with a length of up to about six atoms. Examples of linkers include a saturated or unsaturated Ci-6 alkylidene chain which is optionally substituted, and wherein one or two saturated carbons of the chain are optionally replaced by CONH-,. -CONHNH-, -CO2-,

-NHCO

2 -NHCONH-, -OC(O)NH-, -NHNH-, -NHCO-, -SO2-, -S02NH-, or -NHS02-.

.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 NO *-16- C unsaturation. The optional substituents are as described above for an aliphatic group.

A combination of substituents or variables is permissible only if such a combination results in a stable or chemically feasible compound. A stable compound or chemically feasible compound is one in which Ce the chemical structure is not substantially altered when o kept at a temperature of 40 OC or less, in the absence of \0 moisture or other chemically reactive conditions, for at 0 10 least a week.

Unless otherwise stated, structures depicted herein are also meant to include all stereochemical forms of the structure; the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric and diastereomeric mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, structures depicted herein are also meant to include compounds which differ only in the presence of one or more isotopically.

enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by a or "C-enriched carbon are within the scope of this invention.

Compounds of formula I or salts thereof may.be formulated into compositions. In a preferred embodiment, the composition is a pharmaceutical composition. In one embodiment, the composition comprises an amount of the protein kinase inhibitor effective to inhibit a protein kinase, particularly Aurora-2, in a biological sample or in a patient. Compounds of this invention and pharmaceutical compositions thereof, which comprise an amount of the protein kinase inhibitor effective to treat

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o0 -17- Sor prevent an Aurora-2-mediated condition and a t pharmaceutically acceptable carrier, adjuvant, or vehicle, may be formulated for administration to a patient.

Another aspect of this invention relates to a C method of treating or preventingan Aurora-2-mediated Ci disease with.an Aurora-2 inhibitor, which method o comprises administering to a patient in need of such a IND treatment a therapeutically effective amount of a 0 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 known to play a role. The terms "Aurora-2-mediated disease" or -"Aurora-2-mediated condition" also mean those diseases or conditions.that are alleviated by treatment with an Aurora-2 inhibitor. Such conditions include, without limitation, colon, breast, stomach, and.ovarian cancer.

Another aspect of the invention relates to inhibiting Aurora-2 activity.in a biological sample, which method comprises contacting the biological sample with the Aurora-2 inhibitor of formula I, or a composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises

NO

o0 -18c 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-3mediated condition", as used. herein, mean any disease or other deleterious condition or state in which-GSK-3 is C. known to play a role. Such diseases or conditions include, without limitation, diabetes, Alzheimer's disease, Huntington's Disease, Parkinson's Disease, AIDSassociated dementia, amyotrophic lateral sclerosis (AML), C multiple sclerosis schizophrenia, cardiomycete hypertrophy _reperfusion/ischemia, and baldness.

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

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

Another aspect of this invention relates to-a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.

VO

o. -19- Cr Another aspect of this invention relates to a t method of treating or preventing a CDK-2-mediated disease with a CDK-2 inhibitor, which method comprises pC administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula C* I or a pharmaceutical composition thereof.

C The terms "CDK-2-mediated disease" or "CDK-2o mediated condition", as used herein, mean.any disease or ID other deleterious condition in which CDK-2 is known to o 10 play a role. The terms "CDK-2-mediated disease" or "CDK- 2-mediated condition" also mean.those diseases or conditions that are alleviated by treatment with a CDK-2 inhibitor. Such conditions include, without limitation, cancer, Alzheimer's disease, restenosis, angiogenesis, glomerulonephritis,' cytomegalovirus, HIV, herpes, psoriasis, atherosclerosis, alopecia, and autoimmune diseases such as rheumatoid arthritis. See Fischer, P.M.

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

Another aspect of the invention relates to inhibiting CDK-2 activity in a biological sample or.a patient, which method comprises administering to the.

patient a compound of formula I or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing an ERK-2-mediated diseases with an ERK-2.inhibitor, which method comprises administering to a patient in need of such a treatment a IND 0 therapeutically effective amount of a compound.of formula I or a pharmaceutical composition thereof.

SThe terms "ERK-mediated disease" or "ERKmediated condition", as used herein mean any disease or other deleterious condition in-which ERK is known to play a role. The terms "ERK-2-mediated disease" or "ERK-2- C mediated condition" also mean those diseases or conditions that are alleviated by treatment with a ERK-2 inhibitor. Such conditions include, without limitation, o 10 cancer, stroke, diabetes, hepatomegaly, cardiovascular C disease including cardiomegaly, Alzheimer's disease, cystic fibrosis, viral disease, .autoimmune diseases, atherosclerosis, restenosis, psoriasis, allergic disorders including asthma, inflammation, neurological disorders and hormone-related diseases. The term "cancer" includes, but is not limited to the following cancers: breast', ovary, cervix, prostate, testis, genitourinary tract, esophagus, larynx, glioblastoma, neuroblastoma, stomach,- skin,.keratoacanthoma, lung, epidermoid carcinoma, large cell carcinoma, small cell carcinoma, lung adenocarcinoma, bone, colon, adenoma, pancreas, adenocarcinoma, thyroid, follicular carcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, sarcoma, bladder carcinoma, liver carcinoma.and biliary passages, kidney carcinoma, myeloid disorders, lymphoid disorders, Hodgkin's, hairy cells, buccal cavity and pharynx (oral), lip,.tongue; mouth, pharynx, small intestine, colon-rectum, large intestine, rectum, brain and central nervous system, and leukemia.

ERK-2 protein kinase and its implication in various diseases has been described. [Bokemeyer et al. 1996, Kidney Int. 49, 1187; Anderson et al., 1990, Nature 343, 651; Crews et al., 1992, Science 258, 478; Bjorbaek et

VO

o -21- C- al., 1995, J. Biol. Chem. 270, 18848; Rouse et al., 1994, cCell 78, 1027; Raingeaud et al., 1996, Mol. Cell Biol.

G 16, 1247; Raingeaud et al. 1996; Chen.et al., 1993 Proc.

Natl. Acad. Sci. USA 90, 10952; Oliver et al., 1995, Proc. Soc.-Exp..Biol. Med. 210, 162; Moodie et al., 1993, SScience 260, 1658; Frey and Mulder, 1997, Cancer Res. 57, C- 628; Sivaraman et al., 1997, J Clin. Invest. 99, 1478; o Whelchel et al., 1997, Am. J. Respir. Cell Mol. Biol. 16, 589] o 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.

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

The terms "AKT-mediated disease" or "AKTmediated 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 "AKTmediated condition" also mean those diseases or conditions that are'alleviated by treatment with a AKT -inhibitor. AKT-mediated diseases or conditions include, but are not limited to, proliferative disorders, cancer, and neurodegenerative disorders. The association of AKT, also known as.protein kinase B, with various diseases has been described [Khwaja, .Nature, pp. 33-34, 1990; Zang, Q. et al, Oncogene, 19 2000; Kazuhiko, et al, The Journal of Neuroscience, 20 2000].

INO -22- O Another aspect of the invention relates to inhibiting AKT activity in a biological sample or a Spatient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.

Another aspect of this invention relates to. a Cq method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises C administering to a patient in need of such a treatment a

NO

10 therapeutically effective amount of a compound of formula Ci I or a pharmaceutical composition thereof.

The terms "Src-mediated disease" or "Srcmediated condition", as used herein mean any disease or other deleterious condition in which Src is known to play a role. The terms "Src-mediated disease" or "Srcmediated condition" also mean those diseases or conditions that are alleviated by treatment with a Src inhibitor. -Such conditions include, without limitation, hypercalcemia, osteoporosis, osteoarthritis, cancer, symptomatic treatment of bone metastasis, and Paget's disease. Src protein kinase and its implication in various diseases has been described [Soriano, Cell, 69, 551 (1992); Soriano et al., Cell, 64,'.69.3 (1991); Takayanagi, J. Clin. Invest., 104, 137 (1999); Boschelli, Drugs of the Future 2000, 25(7), .717,. (2000); Talamonti, J. Clin. Invest., 91, 53 (1993); Lutz, Biochem. Biophys.

Res. 243, 503 (1998); Rosen, J. Biol. Chem., 261, 13754 (.1986); Bolen, Proc. Natl. Acad. Sci. USA, 84, 2251 (1987); Masaki, Hepatology, 27, 1257 (1998); Biscardi, Adv. Cancer Res., 76, 61 (1999); Lynch, Leukemia, 7, 1416 (1993); Wiener, Clin. Cancer Res., 5, 2164 (1999); Staley, Cell Growth Diff., 8, 269 (1997)].

VO

o -23- S. Another aspect of the invention relates to t inhibiting Src activity in a biological sample or. a patient, which method comprises administering to the (c patient a compound of formula I or a composition comprising said compound.

Another aspect of this invention relates to a Ci method of treating or preventing an Lck-mediated diseases 0 with an Lck inhibitor, which method comprises D administering to a patient in need of such a treatment a 0 10 therapeutically effective amount of a compound of formula I or a pharmaceutical composition thereof.

The terms "Lck-mediated disease" or "Lckmediated condition", as used herein, mean any disease state or other deleterious condition in which Lck is known to play a role. The terms."Lck-mediated disease" or "Lck-mediated condition" also mean those diseases or conditions that are alleviated by treatment with an Lck inhibitor. Lck-mediated diseases or conditions include, but are not limited to, autoimmune diseases such as transplant rejection, allergies, rheumatoid arthritis, and leukemia. The association of Lck with various diseases has been described [Molina et al., Nature, 357, 161 '(1992)].

Another aspect of the invention relates to inhibiting Lck activity in a biological sample or a patient, which method comprises administering to the patient a compound of formula I or a composition comprising said compound.

The term "pharmaceutically acceptable carrier, adjuvant, or vehicle" refers to a non-toxic carrier, adjuvant, or vehicle that may be administered to a patient, together with a compound of this invention, and 24o which does not destroy the pharmacological activity thereof.

SThe term "patient" includes human and veterinary subjects.

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

C An amount effective to inhibit protein kinase, for example, Aurora-2 and GSK-3, is an amount that causes.

measurable inhibition of the kinase activity when compared to the activity of the enzyme in the absence of an inhibitor. Any method may be used to determine inhibition, such as, for example, the Biological Testing Examples described below.

Pharmaceutically acceptable carriers that may be used in these pharmaceutical compositions are generally known in the art. They include, but are not limited.to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic Sacid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

VO

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

SPreferably, the compositions are adiinistered orally, intraperitoneally or intravenously.

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

These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a-sterile injectable solution or suspension in a non-toxic parenterallyacceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic monoor di-glycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceuticallyacceptable oils, such as olive oil or castor oil, especially.in their polyoxyethylated versions. These oil 'solutions or suspensions may also contain a long-chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable IND 26- 0 dosage forms including emulsions and suspensions. Other Scommonly used surfactants, such as Tweens, Spans and

S

o ther emulsifying agents or bioavailability enhancers which are commonly used in' the manufacture of pharmaceutically acceptable solid, liquid, or.other dosage forms may also be used for the purposes of formulation.

The pharmaceutical compositions of this c invention may be orally administered in any orally acceptable dosage form including, but not limited to; Ci capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral use, carriers commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.

For oral administration in a capsule form,.useful diluents- include lactose and dried cornstarch. When aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying .and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.

Alternatively, the pharmaceutical compositions of this invention may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but.liquid at rectal temperature and therefore will melt in the'rectum to release'the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention-may also be administered topically, especially when the target of.treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal

VO

o -27- CN tract. Suitable topical formulations are readily Sprepared for each of these areas or organs.

Topical application for the lower intestinal C- tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.

O Topically-transdermal patches may also be used.

For topical applications, the pharmaceutical o compositions may be formulated in a suitable ointment IND containing the active component suspended or dissolved in o 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 wax and .water. Alternatively, the pharmaceutical compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.

For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic, pH adjusted sterile.saline, or, preferably, as solutions in isotonic, pH adjusted sterile saline, either with or without a preservative-such as benzylalkonium chloride. Alternatively, for ophthalmic uses, the pharmaceutical compositions may be formulated in an ointment such as petrolatum.

The pharmaceutical compositions of this invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to NO *-28techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, Semploying benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbonsl *and/or other conventional solubilizing or dispersing agents.

c In addition to the compounds of this invention, pharmaceutically acceptable derivatives or prodrugs of S-.the compounds of this invention may also be employed in

NO

compositions to treat or prevent the above-identified Ci diseases or disorders.

A "pharmaceutically acceptable derivative or prodrug" means any pharmaceutically acceptable salt, ester, salt.of an ester or other derivative of a compound of this invention which, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this invention or an inhibitorily active metabolite or residue thereof.

Particularly favored derivatives or prodrugs are those that increase the bioavailability of the compounds of this invention when such compounds are administered to a patient by allowing an orally administered compound to be more readily absorbed into the blood) or which enhance delivery of the parent compound to a biological compartment the brain or lymphatic system) relative to the parent species.

Pharmaceutically acceptable prodrugs of the compounds of this invention include, without limitation, the following derivatives of the present compounds: esters, amino acid esters, phosphate esters, metal salts sulfonate esters, carbamates, and amides.

Pharmaceutically-acceptable salts of the compounds of this invention include those derived from -29- C- pharmaceutically acceptable inorganic and organic acids C and bases. Examples of suitable acid salts include C acetate, adipate,-alginate, aspartate, benzoate, q benzenesulfonate, bisulfate, butyrate,. citrate; camphorate, camphorsulfonate, cyclopentanepropionate, CA digluconate, dodecylsulfate, ethanesulfonate, formate, q fumarate, glucoheptanoate, glycerophosphate, glycolate, o hemisulfate, heptanoate, hexanoate, hydrochloride, NO hydrobromide, hydroiodide, 2 -hydroxyethanesulfonate, o 10 lactate, maleate, malonate, methanesulfonate, 2naphthalenesulfonate, nicotinate, nitrate, oxalate, palmoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, salicylate, succinate, sulfate,.tartrate, thiocyanate, tosylate and undecanoate. Other acids, such as oxalic, while not in themselves pharmaceutically acceptable, may.be employed in the preparation of salts useful as intermediates in obtaining the -compounds of the invention and their pharmaceutically acceptable acid addition salts.

Salts derived from appropriate bases include alkali metal sodium and potassium), alkaline earth metal magnesium), ammonium and N'(CI-4 alkyl) 4 salts. This invention also envisions the quaternization of any basic nitrogen-containing groups of .the compounds disclosed herein. Water or oil-soluble or dispersible products may be obtained by such quaternization.

The amount of the protein kinase inhibitor that may be combined with the carrier materials to produce a single dosage form will vary depending upon the patient treated and the particular mode of administration.

Preferably, the compositions should be formulated so that a dosage of between 0.01 100 mg/kg body weight/day of NO the inhibitor can be administered to a patient receiving these compositions.

SIt should also be understood that a specific dosage and treatment regimen for any particular patient will depend-upon a-variety-of-factors, including the activity of the specific compound employed, the age, body C weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and S- the judgment of the treating physician and the severity of the particular disease being treated. The amount of Ci the inhibitor will'also depend upon the particular compound in the composition.

Depending upon the particular protein kinasemediated condition to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may be administered together with the inhibitors of this invention'. For example, in the treatment of cancer other chemotherapeutic agents or other anti-proliferative agents may be combined with the'present compounds to treat cancer. These agents include, without limitation, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferons, and platinum derivatives.

Other examples of agents the. inhibitors of this invention may also be-combined with include, without limitation, agents for treating diabetes such as insulin or insulin analogues,: in injectable or inhalation form, glitazones, alpha glucosidase inhibitors, biguanides, insulin sensitizers, and'sulfonyl ureas; antiinflammatory agents such as corticosteroids,-TNF blockers, IL-1 RA, azathioprine, cyclophosphamide, and sulfasalazine; immunomodulatory and immunosuppressive

VO

o -31- (c agents such as cyclosporin, tacrolimus, rapamycin, t mycophenolate mofetil, interferons, corticosteroids, Scyclophophamide, azathioprine, and sulfasalazine; C neurotrophic factors such as acetylcholinesterase inhibitors,-MAO inhibitors, interferons, anti- 0 convulsants, ion channel blockers, riluzole, and anti- (c Parkinsonian agents; agents for treating cardiovascular O disease such as beta-blockers, ACE inhibitors, diuretics, VO nitrates, calcium channel blockers, and statins; agents for treating liver disease such as corticosteroids, cholestyramine, interferons-, and anti-viral agents; agents for treating blood disorders such as corticosteroids, anti-leukemic agents, and growth factors; and agents for treating immunodeficiency disorders such as gamma globulin.

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

Alternatively, those agents may be part of a single dosage form, mixed together with the protein kinase inhibitor of this invention in a single composition.

Compounds of this invention may'exist in alternative tautomeric forms, as in tautomers i and ii shown below. Unless.otherwise indicated, the representation of either tautomer is meant to include the other.

N -32- 0 2 'a R 2

R

2 R N

NH

C HN'N N HN' N" RX H2 RX z2 A. A z 2

R

Y

_Q-R

1

R

y Z

Q-R

1 o

R

x and R may be taken together to form a fused ring, providing a bicyclic ring-system containing Ring A.

O Preferred RX/RY rings include a 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 Ring A are shown below by compounds I-A through I-BB, wherein Z 1 is nitrogen or C(R) and Z 2 is nitrogen or

C(H).

R

2 N H HN>

HN

RzXQ-R' I-A I-B

I-C

HN HN HN-> R4j R N 2Z2 :f R4- V I:-f I-E

I-F

o -33- R

H

N %Z2 oNK of 1I-GI-II HN%? NiZ HN z 2 I-S -K

I-L

HN Z HN -3 N t ZZ2 I-M I-N HNO?

HN>Z?

S

I-P

IQI-R

I-

I-T

I-s I-T

-I-U.

NO

-34- HN' HN' o R/ R -4 S I-v I-w I-x ciHNA17H HN>7

HNH

N 2 z2X Z2Z R4

RZ

HHN-37 N I N

SBJ

I-BB

Preferred bicyclic Ring A systems include I-A, I-B, I-D, I-E, I-F, I-1, I-J, I-K, I-Q, 3I-V, and I-U, more preferably I-A, I-B, I-D, I-E, I-J, I-P, and I-V, and most preferably I-A, I-B, I-D,"I-E and I-J.

In the monocyclic Ring A system; preferred R" groups, when present, include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 4 aliphatic group such as methyl, ethyl, -cyclopropyl, or isopropyl. Preferred RY groups, when present,' include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L -C(R6)20-, -CO- or and R 3 is -N(R 4 2 or -OR. Preferred Ry groups include 5-6 membered heteroaryl or heterocyclyl rings, such as 2-pyridyl, 4-pyridyl,, pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl; C 1 aliphatic, such as methyl., ethyl, cyclopropyl, isopropyl, or

NO

t-butyl; alkoxyalkylamino such as methoxyethylamino;, alkoxyalkyl such as methoxymethyl or.methoxyethyl; alkylor dialkylamino such as ethylamino or dimethylamino; alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy; acetamido; and optionally substituted phenyl such as phenyl or halo-substituted Cq phenyl.

In the bicyclic Ring A system, the ring formed when R and RY are taken together may be substituted or unsubstituted. Suitable substituents include halo, c -0 (CH2) 2 -4 -N(R 4) 2 -0(CH2) 2 4 -OR, -N(R 4

(CH

2 2 4-N(R 2

-N(R

4

)-(CH

2 2 -CO 2 R; COCOR, -NO 2

-ON,

-SO

2 R, -SR, -N(R 4 2 -CON(R') 2 -SO2N(R 4 2 -N(R4)COR, -N(R 4

)CO

2 (optionally substituted C1-6 aliphatic), -N(R' 4 )N(Rt)2, -C=NN(R4) 2

-C=N-OR,

-N(R)CON 2

-N(R

4

).SO

2

N(R

4 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, -OR, -COR, -C02R, -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 -NR4COR, -NR 4 'S0 2 R, -SO 2

N(R

4 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, pyrido, pyrimido, and a partially unsaturated 6-membered carbocyclo ring, wherein said fused ring is optionallysubstituted. These are exemplified in the following formula I compounds having a pyrazole-containing bicyclic ring system: IND -36- H N 2 N "x

NHHHN

R N _N a n d Preferred substituents on the R 2

/R

2 fused ring 0include one or more of the following: -halo, -N -C 1 oN 5 alkyl, -C 1 3 haloalkyl,

-NO

2 -0(C2-.

3 alkyl) -C0 2

(C

1 3 0alkyl), -S0 2

(C

13 alkyl) -SO 2

NH

2 -OC(O)Nu 2

-NH

2 S0 2 (CI-3 alkyl), NHC (CI-3 alkyl) -C (0)NH 2 and

-CO(C..

3 alkyl), wherein the (C2- 3 alkyl) is most preferably methyl.

When the pyrazole 'ring system is monocycli'c, preferred R 2 groups include hydrogen, CI..

4 aliphatic, alkoxycarbonyl, Cnn) substituted phenyl, hydroxyalkyl, alkoxyalkyl, aminocarbonyl, mono- or dialkylaminocarbo'nyl, aminoalkyl;' alkylaminoalkyl, dialkyl'aminoalkyl, phenylaminocarbonyl;- and.(Nheterocyclyl)carbonyl. Examples of such preferred R' subst ituent s..include methyl, cyclopropyl, ethyl, isopropyl, propyl, .t-butyi, cyclopentyl, phenyl, CO 2

H,

CO

2

CH

3

CE

2 OI{, CH 2

OCH

3

CH

2

CH

2

CH

2 OH, CH 2

CH

2

CH

2

OCH

3

CH

2

CH

2

CH

2

OGI{

2 Ph, CH 2

CH

2

CH

2

NE

2

CH

2

CH

2

CH

2 NHCOOC (CH3) 3 CONHCH (cH 3 2

CONHCH

2

CH=CH

2

CONIICH

2

CH

2

OCH

3

CONHCH

2 Ph, CON~cyclohexyl),

CON(EL)

2

CON(CE

3 )CrI 2 Ph, 'CONI(n-c 3

H

7 CON (Eb) CH 2

CH

2

CH

3

CONHCH

2 CH (CEi 3 2 CON (n-C 3

H,)

2 CO (3- Tethoxymethylpyrrolidir-l-yl), CONE (3-tolyl),r CON C4tolyl), CONUCH 3 CO Cmopholin-l-yl), C0C4-methylpiperazin- 1-yl), CONIICH 2

CH

2 OH, CONK 2 and CO(pipeidin-i-yl).

A

preferred R 2 group is hydrogen.

NO

-37- An embodiment that is particularly useful for Streating Aurora-2-mediated diseases relates to compounds of formula IIa:

R

2 ci-

HN

CD

R

IND R Y N S-R 1 I I a or a pharmaceutically acceptable derivative or prodrug 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 substitutable ring carbon of said fused ring formed by Rx and R Y is independently substituted by 0xo, T-R 3 or L-Z-R3, and each substitutable ring-nitrogen of said ring formed by Rx and R Y 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, 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 s or V-Z-R s and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 T is a valence bond or a C1- 4 alkylidene chain; ND -38- Z is a C 1 4 alkylidene chain; L is -SO2-, -N(R 6 )S0 2

-SO

2

N(R

6 -CO2-, -N(R5)CO-, -N(R')S0 2

-N(R)N(R

6

-OC(O)N(R

6

-C(R

6 2

-C(R

6 2

S-,

-C (R6) 2SO-, -C(R 6 2S2-, -C(R) 2 SNR -C(R 6 2 N(R)

-C(R

6 2 -C(R 6 2

N(R

6

-C(R

6 2N(RN(R 6 2 N(R) SO 2 N(R) or

-C(R

6 2

N(R

6

)CON(R

6 o 10 R 2 and R 2 are independently selected from -T-W-R 6 or 0 2 C 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 selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by

R

2 and R 2 is independently substituted by halo, oxo, -CN, -NO 2 or -V-R6, and each substitutable ring nitrogen of said ring formed by R 2 and R 2 is independently substituted by 'R; R3 is selected from -halo, -OR, -C02R, -COCOR, -COCH 2 COR, -NO 2 -CN, -S(O) 2 R, -SR, -N(R 2 -CON(R7) 2 -S02N(R 7 2

-N(R')COR,

-N(R )CO2 (C 1 6 aliphatic)',

-N(R

4

)N(R

4 2

-C=NN(R

4 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 -OC(=0)N(R7)2; each R is independently selected from hydrogen or an optionally substituted group selected from C1..

aliphatic,- C.o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocycly ring having 5-10 ring atoms; each R4 is independently selected from -COR',

-CO

2 (optionally substituted 'C1- saliphatic), -CON(R') 2 or -S0 2

R

7

NO

o -39- (Neach

R

5 is independently selected from halo, -OR, ct

'-CO

2 R, -COCOR, -NO 2 -CN, -SCO)R, -SO 2 R, -SR, -N(R 4 2 -CON(Rf4l) 2

-SO

2 N (R 4 2 -N(R 4

)COR,

-NC(RtCO 2 (optionally substituted Cas6alip hatic), -N(R 4 4 2 i -C=NN(R 4 2 -C=N-OR, -N(.R 4 )cON(R 4 2 -N(R 4 )5S0 2 NRW) 2 -N (Rt4)So 2 a, or 42C(=O) NC(R.t 2 C~K1V is -SO2-, -N(R 6 )S0 2

-SO

2 o

-NCR

6

-NCR

6 Va

-N(R

6

)CON(R

6 -N(R)5 0 2

NCR

6

-NCR

6

)N(R

6 o 10 -dCo)NCR 6

-OCCO)NCR

6

-CCR').

2

-C(R,

6 2 s-, -WCR) 2S- -cC(R 6 2 S0 2 -cC(R 6 S0,N CR 6 ),-cC 6 2 N

-C(R)

2 -CCR 6 2 -CC(R'yNC 6

-CCR

6

-CCR

6 2 NCR)NCR 2 NCR6tS 2 NqPR6)-, or -C(R6) 2 N CR 6 CON (R 6 W is -C(R) 2 2 2 so-, -CCR5) 2 So 2

R

6 2

SO

2 NCR)-, -CCR').

2 N(R

-CO

2 -1 -C(RtCO- -C (R 6 )OcCO)NC(R)- -CCR')NR 6 c- -CC. R'6) 2 NCR') -cCR')=NN -cCR 6 -CCRt 2

N(R')'N(R

6 -CCR6) 2 NCR6)SO 2

N(R)-

-c (R.6) 2 N (R 6).CON WR) -'or -CON each R6 is independently selected from hydrogen or an 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 heterocycly. or heteroaryl ring.; and each R 1 is independently selected from hydrogen-or an optionally substituted C: 1 6 aliphatic group, or tiwo R 7 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 or 7-inembered unsaturated or partially unsaturated ring having 0 -2 hetiFroatoms, wherein said

IND

o 0 R/RY ring is optionally substituted. This provides a Ct bicyclic ring system containing a pyrimidine ring.

Examples of preferred pyrimidine ring systems of formula I1a.are shown below.

NHHWt HNX1 ciHN N 0 ha-A hla-B Ila-C liNtH HN 327 Ia-D hla-E ha-P HN Z HNkQ

HN

<-N

Ia-J Ila-K hla-L HWt

HA

S

N<

Ila-P 11a-R hla-V

NO

-41-

N

N

R4 IIa-W More preferred pyrimidine ring systems of c formula IIa include IIa-A, IIa-B, IIa-D, IIa-E, IIa-J, Va SIIa-P, and IIa-V, most preferably IIa-A, IIa-B, Ia-D, 0 5 IIa-E, and IIa-J.

The ring formed when RX and Ry are taken together may be substituted or unsubstituted. Suitable substituents include halo, -O(CH 2 2 2 -O(CH2)2- 4 -OR, (CH2) 2 4 -N(R 2" -N (CH2) -4-R,

-CO

2 R, -COCOR, -NO 2 -CN,

-SO

2 R, -SR, -N (R 2

-CON(R')

2

-SO

2 N(R 4 2 COR,

CO

2 (optionally substituted C.6 aliphatic), -N(R )N(R 2

-C=NN(R')

2 -C=N-OR, -N(R')CON(R 2 -N SO 2 NR4) 2 -N(R 4) SO 2 R, or 2 wherein R and R4 are .as defined above. Preferred. RX/R ring substituents include -halo, -OR, -COR, -CO 2

R,

-CON 2, -CN, -O (CH 2 2 4 -N -o (CH 2 2 4

-NO

2 2 -NR'COR, -NR'SO 2 R, -SO 2 N(R 4 2 wherein R is hydrogen or an optionally substituted C 1 6 aliphatic group.

The R 2 and R' groups of formula IIa may be taken together -t6 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 carbacyclo ring.

These are exemplified in the following formula IIa compounds having a pyrazole-containing bicyclic ring system: -42- 0

NH

N N N N\N cN HN N R 7NH NH 3jNH NH SRI N S-R ,and 0 Preferred substituents on the R 2

/R

2 fused ring ci o of formula IIa include one or more of the fbllowing: 0 -halo, -N(R 4 2

-CI.-

4 alkyl, haloalkyl, -NO 2 -0O(C 1 4 alkyl), -C0 2

(C-

4 alkyl), -CN, -S0 2

(C.

4 alkyl), -SO 2

NH

2 -OC(O)NH2, -NH 2 SO (C.

4 alkyl) -NHC(0) (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 (C 1 4 alkyl) group is methyl or ethyl.

When the pyrazole ring system of formula lIa is monocyclic, preferred R 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, 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.

When Ring D of formula IIa is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl,.indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzolbLthiophenyl, indazolyl, benzothiazolyl, o -43- 0 cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

SOn Ring D of formula IIa, preferred

T-R

5 or V-Z-Rs substituents include -halo, -CN, -NO 2 optionally substituted 6 aliphatic group, -oR, -C(O)R,

-CO

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

-N(R

4

)CO

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

SO

2 R, -N (R 6

COCH

2 N 2 -N (R 6

COCH

2

CH

2 N (R4) 2 and -N (Re) COCH 2

CH

2

CH

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

R

5 substituents include -cl, -Br,

-CN,

-CF

3 -COOH; -CONHMe, -CONHEt,

-NH

2 -NHAc, -NHSO0Me, -NHSOZEt, -NHSO2(n-propyl),

-NHSO

2 (isopropyl), -NHCOEt,

-NHCOCH

2 NHCH3,

-NHCOCH

2

N(CO

2 t-Bu)

CH

3

-NHCOCH

2

(CH

3 2,.

-NHCOCH

2

CH

2 N (CH3) 2

-NHCOCH

2

CH

2

CH

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

-NHCOCH

2 (morpholin-4yl), -NHCOCHCH2( morpholin-4-yl),

-NHCCHEC

2 cH 2 (morpholin- 4

-NHCO

2 (t-butyl),

-NH(C

1 4 aliphatic) such as -NHMe,

-N(C.

4 aliphatic) 2 such as -NMe 2 OH, -O(C 1 -4 aliphatic) such as -OMe, C3 4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2 (C.-4 aliphatic).

Preferred formula IIa compounds have one or more, and more preferably all' of the features selected from the group.consisting of: RX and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated,-5-6 membered ring having 0-2 heteroatoms selected from. oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and Ry is independently substituted by oxo, T-R, or L-Z-R, and each substitutable ring nitrogen of

VO

IND -44said ring formed by Rx and R Y is independently t substituted by R 4

R

I is T-(Ring wherein T is a valence bond or a methylene unit; Ring-D is-a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an Cq aryl or heteroaryl ring; O R 2 is -R or and R' is hydrogen; or R 2 and ci 2' 1R are taken together to form an optionally substituted benzo ring; and c q RK is selected from -halo, -OR, or -N(R 4 2 More preferred compounds of formula IIa have one or more, and more preferably all, of the features selected from-the group consisting of: Rx and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;

R

1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;.

R

2 is -R-and R 2 is hydrogen, wherein R is selected from hydrogen, C- 1 s aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and

R

3 is selected from -halo, -OR, or -N(R 4 2 wherein R is selected-from.hydrogen, Ci.aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or -N(R 4 Even more preferred compounds of formula IIa have one or'more,, and more preferably all, of the features selected from the group consisting of:

R

x and R Y are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;

R

1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; R is hydrogen or CI-4 aliphatic and R 2 is hydrogen;

R

3 is selected from -OR, or -N(R4) 2 wherein R is selected from hydrogen, aliphatic, 5-6.

membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ring D is substituted by up to three' substituents selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted Ci-_ aliphatic group, -OR, -CO 2 R, -CONH(R 4 -N(R COR, S -N (R 4

)CO

2 R, -SO 2

N(R

4 2 -N (R SOaR, -N (R 6

COCH

2 N (R 4 -N (R 6

COCH

2 CH2N (R 4 2, or

-N(R

6

)COCH

2

CH

2

CH

2

N(R

4 2 .wherein R is selected from hydrogen, Ci-_ aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

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

Table 1..

Me Me Me HN-V HN

HNP

CI

IIa-1 IIa-2 IIa-3 -46- 0 ci Va 0 0 ci Me HNt I Ia-4 Me CalI Ila-7 Me

HNZ$

Me Iha-lo Me

N

Et hla-S Me

HN

4 Ci Ila-S Me

HN

OH

hla'-h Me- HNt hIa-9 Me

HN

CIOe Ila-S Me

HA.

IIa-6 Me Me

HN

4 PX HNtP14

CJNZJJCJL

Ila-13 Ia-14 Me HN -tH 'NCm Me HN p e N C

I

Ila-1E hha-17 al Ila-18 -47- Me HNr$4

H

HN

4 tP IIa-22

HN

4 tP

HN

F

IIa-28 Me

HNI

NH

2

HN

4 Ia-23

HN

4 fP

FN

4 I Ia-29 FIN4 Ia-21

HN

4 Ila-24 HNr 4X Ila-27

HN

4

HN

4 C NN S j Cl HN P

'CI

HN

4 IIa-31. **Ila-32 Ila-33 -48ci ci 0 ci Va 0 0 ci

H

Ila-34 Me HNA* H orl 4qcua N.so2Me IIa-37 Me %4 NHAc

N

(0) *Me o g N H c Y~Q4Jc3JN H *HNki H Ila-35 *Me

HNAP

C9N ~.~NHAc eANkS.) Ila-38

HN

N Sj )NHAc IIa-3E

HN

4

'H

IIa-39 Me Me ~0 IIa-42.

Ila-42 Me Me H H fd, tq{JCOOHjdt jSyNHAc IIa-43 IIa-44 49- Me HN<VIt

H

Ila-46 Me

HN

4 Nt ~CfrrJrN aHriPr IIa-49 Me HN' JtNH' IIa-47 Me HNJ~t H H C eQ SaN'3 2 Pr I Ia-48 Me M H Nt X HN -tHe 0%ZJNHYEt ZtCrNH Ila-So ha-si Me Me HN.-

H

0_N ,1ctN NHAc SZ yN r -Ila-52 Ila-53 llaAS54 Me M HN H H HN(IqH C1Nk1E Ho.NQJI

H

Me

HN

IIa-57 *hIa-SS ha-5E Me Me M HNPHN Xt HJj$Hp (0) H~c$JN~~~rNHAc

N

N HNN Ia-58 IIa-S9 Ila-SO

HN

4 J N H Ila-61 Me 02 HN&>1.

HX

Ila-64 Me

HNJ

,NH

Ila-62 Me HN V* 0.

Ila-65- NHAc

NS

Ila-63 Me.

H N' 4 Vl HH ,1'NV~ Me VNS J 00 OMe .Ia-6E Me *.Me.

MeM.

Me HN<N HH

OH

Ila-69 Ia-67.

ha-68 Me Me HNP 0 HN< H H N 4 MNt 0. ONMe' M6 Or Ye IIa-71 hIa-72 Me 9j

NH.A(.

me Ila-73 *Me HN4 flrNHAc HO wN',S (cc ,_ksQr N'Me rF4e IIa-74 ha7 Ila-75

VO

0 -51- SHN H HN H HN S 0 o c t NlrN QN e Nc -NHA CS FF C* IIa-76 IIa-77 IIa-78 cci

NO

IIa-79 In another embodiment, this invention provides a composition comprising a compound of formula IIa and a pharmaceutically acceptable carrier.

Another.aspect of this-invention relates-to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which .method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical .composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in .a patient, which method comprises administering to.the patient a compound of formula IIa or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a IND -52oM therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition thereof.

SOne 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, h which method comprises administering to the patient a therapeutically effective amount of a compound of formula SIIa or a pharmaceutical composition thereof.. This method Siis especially useful for diabetic patients. Another method relates to inhibiting the production of (C hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia.

Another aspect of. this, invention relates to a method of inhibiting GSK-3 activity: in a patient, which method comprises administering to the patient a compound of formula IIa or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a CDK-2-mediated disease with a CDK-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIa or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting CDK-2 activity in a patient, which method comprises administering to the patient a compound of formula IIa or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need. of such a treatment a

NO

0 53- (C therapeutically effective amount of a compound of formula t

I

la or a pharmaceutical composition thereof.

Another aspect of the invention relates to py inhibiting Src activity in a patient, which method comprises administering to .the patient a compound of A formula IIa or a composition comprising -said compound.

C *Another method relates to inhibiting.Aurora-2, o GSK-3, CDK2, or Src activity in-a biological sample, C0 which method comprises contacting the biological sample o 10 with the Aurora-2, GSK-3, CDK2, or Src inhibitor of formula IIa, or a.pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2, GSK-3, CDK2, or Src.

Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, CDK2, or Src,.or the treatment of a disease alleviated thereby, is preferably carried out with a preferred compound of formula IIa, as described above.

Another embodiment of this invention relates to compounds of formula lib: RxN RY N O-R 1 lIb or a pharmaceutically acceptable derivative or prodrug thereof, wherein;

R

x 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- C from oxygen, sulfur, or nitrogen, wherein each Ssubstitutable ring carbon of said fused ring formed by SRx 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 R Y is independently substituted O\ by R 4 C R' is T-(Ring D); o Ring D is a 5-7 membered monocyclic ring or 8-10. membered \O 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 substitutable ring. nitrogen of Ring D is independently substituted by -R 4 T is a valence bond or a Ci-4 alkylidene -chain; Z is a CI-4 alkylidene chain; L is -SO 2 -N(R')S0 2 -SO2N(R')-,

-N(R

6 -CO2-, -N(R6)CO-,

-N(R

6 CON(R)-, -N(R' SO 2N R 6 -N (R)N (R 6 2 0 2

S-,

2 SO, -c (R 6 2 S0 2 2N(R 6 2

N(R

6 2

N(

R

)C(0) 0

-C(R

6

-C(R

6 -C(R6) 2

N(R

6

-C(R)

2 N(R6)SO2N(R)-, or -C 2 N (R CON (R 6

R

2 and R 2 are independently selected from -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 selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by

R

2 and R 2 is independently substituted by halo, oxo,

NO

-NO

2 -R or -V-R 6 and each substitutable ring ct nitrogen of said ring f ormed by R 2 and R'2 is independently substituted by R 4 R 3 is selected from -halo, -OR, -00 2

R,

S. 000R,40ER, N0 2 -S(0) 2 R, -SR,

-NCR

4 2 -OON(R 2

-SO

2

N(R')

2 OCc)R -N (R 00R, -N (R7) C02 (01L-6 aliphatic),, -N (Rt4)N (R4) 2 -C=NN(R 4 2

-N(R')CON(R')

2 -N(R7) SO 2

N(R')

2 -N(Rt4SO 2 R, or each R. is independently selected from'hydrogen or an optionally substituted group selected from C:aliphatic, C61.o aryl., a* heteroary. ring having s-ia ring atoms, or a heterocyclyl ring-having 5-10 ring atoms; each R 4 is independently selected from

-OR';

-C02 (optionally substituted C>L- aliphatic)',

-OON(R')

2 or.S27 each R' is independently selected from halo,.-OR, -C0 2 R, -000CR,

-NO

2 -ON,

-SO

2 R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2 N R) 2 O(OR

COR,

-N(Rt 0)02 (optionally substituted C1_6 -aliphatic), -N (Rt)N(R 4 2 -0=NN(R 4 2 -C=U-OR, -N (R 4 )OON (R 4 2 -N (R4tSO 2 NRW) 2 4

)SO

2 R, or -OC.(=O)NCR 4 2 *V is

-SO

2

N(R

6

-NC(R

6

-N(R

6

-NCR

6

-NCR

6

)OON(R

6 -N(RS)So 2 N(R6)

-N(R

6

)N(R

6 -CO(O) N(R 6

-C(R

6 2

-O(R

6 2

-CO(R

6 2 SO-, -O(R, 6 2 S0 2

-C(R

6 2 S0 2

-C(R

6 2

N(R

6

-O(R

6 2

NCR

6 -CR 6 2 N CR)-=NN

-CR

6 -0(R 6 2 N CR 6

NCR

6 -OCR6) 2 N(CR5)S02N(

R

6 or -CR 6 2N1CR 6 CZON (R 6 wis -CR 6 2

-CR

6 2 -cCft 6 2 so-, -cCRt 2 so 2 r-OCR 6 250 2 N CR 6

-OCR

6 2 1CR 6 -C02-, S..-56-

S-C(R

6 O -C (R 6 OC(0)N (R 6 -C (R 6 2 N(R) CO-, S* C(R 6 2

-C(R

6 )=NN (R6) -C (R 2

N(R

6

)N(R

6 2 N(R) SO 2

N(R

6 C- 2

N(R')CON(R

6 or -CON(R 6 each R 6 is independently selected from hydrogen or an 0 optionally substituted Ci-4 aliphatic group, or two R 6 Cl l groups on the same nitrogen atom are taken together o with the nitrogen atom to form.a 5-6 membered ND heterocyclyl or heteroaryl ring; and o 10' each R 7 is independently selected from hydrogen or an Cl optionally substituted C1.- 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 rings, formed by Rx and R Y include a or 7 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.

Examples of preferred pyrimidine ring systems of formula IIb are shown below.

R2 R NHN HNb' *N 'H t HN N

NO-R

1 IIb-A IIb-B IIb-C A131?

R

4 IIb-D IIb-E IIb-F NO7 HN>2 HN HN Z

N

NA;

NS

flb-J IIb-KIb- *HN~ HN

HN%

o" SS 00 R4 Ilb-p XIb-n l1b -V'

HA

N

Ilb-W.

More Preferred pyrimidine ring systems of formula 11b iticlude Ilb-A, Ilb-B, flb-D, flb-E, Ilb-J, IIb-P,'andxIIb-v, most preferably Ilb-A;' Ilb-3, IIb-n,' Ilb-E, andIlb-J.

The ring formed when RX and RY are taken *together may be substituted or unsubstituted. Suitable *substituients include halo, -O0(CH 2 2 4 -N(R 4 2 P, -CO 2 -COCOR, -NO 2 -aN, -S -SO 2

-SR,

-N(R

4 2 -CON (R 4

SO

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

COR,

-N (R 4

)C

0 2(optionally substituted

C

1 6 aliphatic), -NR)NCRt) 2

-C=NN(R

4 2 -0C=N-OR, -N (R CON 2

NRS

2 NR 2 -N(Rt)SO 2 R, or -OCC=O)N(R) 2 R and a 4 are.

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

-CN,

S-O(CH2)..

4

-N(R

4 2 -0 (CH 2

-NO

2

-N(R

4 2

-NR

4

COR,

-NR

4

SO

2 R, -SO2N(R4) 2 wherein R is hydrogen or an optionally substituted C1-6 aliphatic group.

O The R 2 and R 2 groups of formula lrb may be c- *taken together to form a fused ring, thus providing a o bicyclic ring system containing a pyrazole ring.

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

These are exemplified in the following formula IIb .compounds having a pyrazole-containing bicyclic ring system: R 9

NH

SHN N N N 'NH Q NH NH NH Ry~N O-R, and Preferred substituents on the R2/R 2 fused ring of formula lib .include one or more of the following: -halo, -N(R 4 2 -C-4 alkyl, -C3-4 haloalkyl, -NO 2 -O(Ci-4 alkyl), -CO 2 4 alkyl), -CN, -S0 2

(C

1 -4 alkyl), -S0 2

NH

2 -OC (0)NH 2

-NH

2 SO2 (C 1 -4 alkyl), -NHC alky) -C(O)NH2, and -C0(Ci-4 alkyl), wherein the (C1.4 alkyl) is astraight, branched,. or cyclic alkyl group. Preferably, the (Cl.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, heteroaryl, or a Ci.- aliphatic group. Examples of such

NO

0preferred. Rgroups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclope-±tyl, hydroxypropyi, *methoxypropyi, and benzyloxcypropyl. A preferred R 2 group.

is hydrogen.

S When RingD of formula Iii, is monocyclic, preferred Ring D groups include phenyl, pyridyl, ci pyridazinyl, pyrimidinyl, and pyr&zinyl.

When Ring D of formula Ilb is bi cyclic, preferred bicyclic Ring fl.groups include naphtbyl, o1i tetrahydronaphthyl, indanyl, benzimidazolyl, guinolinyl, ci indolyl, isoindolyl, indolinyl, benzo~bjfuryl, benzo Eb)thiophenyl, indazolyl, benzothiazolyl,.

cinnolinyl, phthalaziny., quinazolinyl; .quinoxazolinyl, 1, 8-naphthyridinyx and isoquin6liriyl.

On' Ring D of formula lIb,' preferred

T-R

5 or V-Z- R substituents include -halo, -CN, -NO 2 -N(R 4 2 optionally substituted

C

1 6 aliphatic group, -OR, -C(o)R, C'0 2 R, -CONH (R 4

-N(R

4 )COR, -N(PR 4 )C0 2

-SO

2 N (R 4 2 -N (R 4 50 2 -N (R 6

COCH

2 N (R 4 2 -N (R 6

COCII

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 heteroaryl ring, or a 5-6 membered heterocyclic ring.

More pref erred R 5 substituents include -Cl, -Br,

-CN,

-CF

3 -COOH, -COWEMe, -CONEEt,

-NH

2 -NUAc,

-NHSO

2 Me, -N HS0 2 Et, -NI{S0 2 (n-propyj),

-NESO

2 (isopropyl), -NHCOEt,

-N'HCOCH

2

NHCH

3

NHCOCH

2

N(CO

2 t-Bu) CH 3

-NHCOCH

2

N(CH

3 2

-NHCOCH

2 CH4 2 N (CH3)2,

-NRCOCE-

2 CH2CE 2 N (CH 3 2 -bNGCO(cyclopropyl), -NlCO (isobutyl), -NHCOcE 2 (morpholin-4yl), NHCOCH 2

CH

2 ,(morpholiz-4-yl),- -NHCjOCH 2

CH

2

CH

2 (morpholin- -THCO(t-butyl),

NH(C

1 4 aliphat ic) such as -NHMe,*

-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, IO Scyclopropyl, isopropyl, or t-butyl, and -C0 2 (CI-4 aliphatic).

SPreferred formula IIb compounds have one or more, and more preferably all, of the features selected from the group consisting of:

R

x and R Y are'taken together with their c- intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring 0 having 0-2 heteroatoms selected from oxygen, S 1 0 sulfur, or nitrogen, wherein each substitutable q ring' carbon of said .fused ring formed by R x and

R

Y is independently substituted by oxo, T-R 3 or

L-Z-R

3 and each substitutable ring nitrogen of said ring formed by R x and R' is independently substituted by R 4

R

1 is T-(Ring wherein T is a valence bond or .a methylene unit; Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring-selected from an aryl or heteroaryl ring;

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; and

R

3 is selected from -halo, -OR, or -N(R4)2.

More preferred compounds of formula IIb have one or more, and more preferably all, of the features selected from the group consisting of: Rx and R Y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring;.

R

1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an

ID

(ND

CA

Ca 0s -61- 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

R

2 is -R and R 2 is. hydrogen, wherein R is selected from hydrogen, C1-G aliphatic, phenyl, a 5-6 membered heteroaryl-ring, or a 5-6 membered heterocyclic ring; and

R

3 is selected from -halo, -OR, or -N(R)2, wherein R is selected from hydrogen, CI.6 aliphatic, or 5-6 membered heterocyclyl, phenyl, 1 0 or 5-6 membered heteroaryl, and L is or -N(R 4 Even more preferred compounds of formula lib have one or more, and more preferably all, of the features selected from the group consisting of: Rx and R are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring;

R

1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring;

R

2 is hydrogen or C 14 aliphatic and R 2 is hydrogen;

R

3 is selected from -OR, or -N(R4) 2 wherein.

R is selected from hydrogen, CI-. aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ring D is substituted by up to three substituents selected from.-halo, -CN, -NO2,

-N.R

4 optionally substituted C1r- aliphatic group, -OR, -CO2R, -CONH(R 4

-N(R')COR,

-N(R

4 COR,. -SO2N (R 4 -N (R S0 2

R,

-N COCHN (R 4

-N(R

6 COCH2CHN

(R

4 2 or

-N(R

6 COCH2CH2CH2N(R4)2, wherein R is selected from hydrogen, Ci- 6 aliphatic, phenyl, a 5-6 -62membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IIb are shown below in Table 2.

Table 2.

HN N IIb-1 Me

HN

IIb-2 Me HN<b IIb-3 HN h HN Ib- NO-a Me IIb-4 IIb-5 Me.

HN

lIb-6 IIb-6 Me H HI t'N'O -a CO 2 Me IIb-9 Me HN H IIb-7 OMe IIb-7 Me.

HN#NH

N Ib- IIb-8 In another embodiment, this invention provides a composition comprising a compound of formula IIb and a pharmaceut'ically acceptable carrier.

Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a -63treatment a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a.

compound of formula IIb or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a.GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition thereof.

One aspect of this invention relates to a -method of enhancing glycogen.synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIb or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing-the progression of Alzheimer's disease. Another method relates to inhibiting the .phosphorylation of I-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula lib or a composition comprising said compound.

Another method relates to inhibiting Aurora-2 or GSK-3 activity in a.biological sample, which method k.

0 -64- 0 0 comprises contacting the biological sample- with the t Aurora-2 or GSK-3 inhibitor of formula lib, or a Spharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.

Each of the*-aforementioned methods directed to 0 the inhibition of Aurora-2 or GSK-3, or the treatment of ci C\ a disease alleviated thereby, is preferably carried out o with a preferred compound of formula lib,'as described N above.

Another embodiment of this invention relates to Ci compounds of formula IIc:

R

2 R 2,

[NH

HN')N

RY N-Ft 1

H

Ic or a pharmaceutically acceptable derivative or prodrug thereof, wherein; RX and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-.7 membered ring having .0-3 ring heteroatoms selected from oxygen; sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by RX and R y is independently substituted by oxo, T-R 3 or L-Z-R3,. and each substitutable ring nitrogen of said ring formed by RX and RY is independently substituted by R 4

R

1 is. T-(Ring D); Va oND c 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 heterocycly1 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-Rs, and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 o 10 T is a valence bond or a C 1 4 alkylidene chain; Z is a 014 alkylidene chain; L is

-SO

2 -N(R)S0 2

-SO

2 -CO2-, -N{R6)CO-,

-N(R')SO

2 2 2

S-,

2 SO-, 2

SO

2

C(R')

2 S0 2 C,(R6) 2N(R6)- 2 N CR') C(0) 2 C -C(R =NW -C(Rt) 2

N(R')SO

2 N(R6) or 2 N(R')CON(R')

R

2 and-R 2 are independently selected from or R 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 R' and R 2 is independently substituted by halo, oxo, -CN, -NO 2

-R

7 or and each substitutable ring nitrogen of said ring formed by R 2 and R 2 is independently substituted by R 4 R is selected from -halo, -OR,

-CO

2

R,

-COCOR,

-COCH

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

-N(R

4 2

-CON(R')

2

-SO

2

N(R')

2 -N(R 7

)COR,

-N(R

7 )CO (C1, aliphatic)

-N(R

4

)N(R

4 2, -C=NN(R4) 2 -66- 0 -C=N-OR, -N(R')CO 7)2 -N(R')S0 2

N(R)

2 -N(R4S0 2 R, or

-OC(=O)N(R

7 2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, d 6 aryl, -a'heteroaryl ring having 5-10 ring atoms, or a heterocyclyi ring having 5-10 ring atoms; each R 4 is independently selected from

-COR

7

-CO

2 (optionally substituted qI- 6 aliphatic),

-CON(R

7 2 o 10 or -S0 2

R

7 Ci each R 5 is independentiy selected from halo, -OR,

-CO

2 R, -COCOR,

-NO

2 -CN,

-SO

2 R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R')

2 N(R)COR,

-N(R

4 )CQ2 (optionally substituted Ca._ aliphatic),

-N(R

4

)N(R

4 2

-CNN(PI)

2 -CnN-OR,

-NCR

4 )CON(R4) 2

-N(R

4 )S0 2

N(R

4 2 -(Rt4)so 2 R, or V is

-SO

2

-N(R

6 )S0 2 -S0 2

N(R

6

-N(R

6 -C0 2 -N(R6 CO_, -N(R6)

-N(R

6

-N(R

6

)SO

2

-N(R

6

)N(R

6 -C(O)u(R 6 -OC(O)w(R 6

-C(R

6 2

-C(R

6 2

S-,

-C(R

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

-C(R

6 )2S0 2

N(R

6

-C}R

6 2

-C(R

6 2

N(R

6

_-C(R

6

)N(R

6

-C(R

6

=NN(R

6

-C(R

6

-C(RS)

2 N(R5)i-T(R6) -C(R6N(Rs(Rp, or -C (RS6 2 M(R6) CON(R6) W is -C(R 6 2

-C(R

6 2

-C(R

6 )2SO-,

-C(R

6 2

SO

2 -C(R6) 2

SO

2 -C(R6)2N(R 6 -CO2-,

-C(R

6 )OC

-C(R

6 )OC o)N (R 6 2

N(R

6

CO-,

-C(R

6 2

N(R

6

-C(R

6 -C(R6)2N(R(NR0)-,

(C(R

6 2 N(RG)So 2 N(R6)~, 3Q t)2-C(R6)ON(R)CN(R6)J-, or -CON (R 6 each R 6 is independently selected from hydrogen or an optionally substituted c 1 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together

VO

-67cr with the nitrogen atom to form a 5-6 membered.

t heterocyclyl or heteroaryl ring; and Seach

R

7 is independently selected from hydrogen or an (C optionally substituted Ci-6 aliphatic group, or two R 7 on the same nitrogen are taken together with the Ch nitrogen to form a 5-8 membered heterocyclyl or Cr heteroaryl ring.

O Preferred rings formed by Rx and R Y include a ID or 7-membered unsaturated or partially 0 10 unsaturated ring having 0-2 heteroatoms, wherein said R/RY.ring is optionally substituted. This provides a.

bicyclic ring system containing a pyrimidine ring.

Examples of preferred pyrimidine ring systems of formula IIc are shown below.

R2 R

NH

HN HN>"

HN-

R- NNO&N c NI R4N-, N IIc-D IIC-E IIc-F -68- HNHN>31 HN>9r I~~c-J lIcIC Ic- (0 N H N HN

HN?

0N

HN

I1e-W More preferred pyrimidine ring systems of formula lie include Il-A, IIC-B, Ilc-D, I~c-E, Ilc-J, 11c-P, and lie-V, most preferably Ie-A, Ie-B, Ile-f, le-H,. and IIe-J.

The ring formed when R 1 and W' of formula Ilc are taken together may be substituted or unsubstituted.

Suitable substituents include 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,

R, -C0 2 R, -COCOR, -NO 2 -CN, S(O) -SO 2 R, -SR,'

N(RW)

2

-CON(

4 2

-SO

2

NI(R

4 2 -OC -1N(RW)COR, -N (R 4 )CO2(optionally 'substituted C3acaliphatic), N(R 4

N(R

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

-N(R

4 S0 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 RX/RY ring substituents

VO

D -69c- include -halo,, -OR, -COR, -CO 2 R, '-CON(R4) 2

-CN,

S-O (CH 2 )2-4-N(R 4 2

-O(CH

2 2

-NO

2

-N(R)

2

-NR

4

COR,

S-NR4SOzR,

-SO

2

N(R

4 2 wherein R is hydrogen or an optionally substituted C1z- aliphatic group.

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

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

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

NH

HN NN

N\N

R

Y N-R' NNH NH NH fNH H and Preferred substituents on the R 2

/R

2 fused ring of formula Ic .include one or more of the following: -halo, -N(R 4 2 -C1.4 alkyl, -CI-4 haloalkyl,

-NO

2 -0(C-.4 alkyl), -C02 (CI-4 alkyl), -CN, -SO 2 (C14 alkyl) -SO 2

NH

2 -OC(0) NH2, -NH2SO2 alkyl), -NHC(O) alkyl)

-C(O)NH

2 and -CO(Ci.4alkyl), 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 Ic is monocyclic, preferred R 2 .groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a Ci- 6 aliphatic group. Examples of such preferred

R

2 groups include H, methyl, ethyl, propyl, ocycf .opropyi,.'i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyi. A preferred R 2 group is hydrogen.

When Ring.Dof formula lio is monocyclic, preferred Ring D .groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

when Ring D) of formula lie is bicyclic, preferred bicyclic Ring D groups include naphthyl, N I tetrahydronaphthyl, indanyl, benziinidazolyl, quinolinyl, -indolyl, isoindolyl, indolinyl, benzolbfuryl, ci benzo[blthiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, guinazolinyl, guinoxazolinyl, 1, B-naphthyridinyl and isoguinolinyl On. Ring D of formula Iho, preferred T-.R 5 or.

V-Z-R

5 substituents include -halo, -CM, -NO 2 -N(Rt4 2 optionally substituted C>- 6 aliphatic group, -OR, -02R, -CON14(R 4

-N(R

4 )COR, -N (R 4

)CO

2 R, -50 2

N(R

2 -N (R 4

SO

2 -N (R 6 COCHN (R 4 2 -N (R 6

COCH

2

CII

2 N (R 4 2 and N14(R 6

COGE

2

CH

2

CH

2 N (R 4 2 Wherein R is selected from hydrogen, C3.

6 aliphatic, phenyl,"a 5-6 memubered.

heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred R 5 substituents include -Br, CN, 7CF 3 -COOR, -CONRMe, -CONHEt, -N H 2 -NHAc, '-NHSO 2 Me,

-NHSO

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

-NHCOCH

2

NHCH

31

-NHCOCH

2

N(CO

2 t-Bu) CH 3

-NHCOCH

2 N (CR 3 2

-NHCOCH

2 CjH 2 N (OH 3 2

-NHCOCH

2

CH

2

CH

2 N (013) 2, -NHCO (cyclopropyl), -NHCO (isobutyl), -NHiCOCH 2 (morpholin-4yl), -NHCOCH 2

CH

2 (torpholin-4

-NHCOCH

2

CH

2

CH

2 (morpholin-: 4-yl) -NHC0 2 (t-butyl) -NH 4 aliphatic) such as -NEMe,

-N(C

1 4 aliphatic) 2 such as. -NMe 2 OR, -O(C1.-4 aliphatic) such as -OMe, C1..4 aliphatic'such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -002 (Cl..

4 aliphatic)

VO

o0 -71- C' Preferred formula IIc compounds have one or .more, and more preferably all, of the features selected Sfrom-the group consisting of: Ce Rx and RY are taken together with their intervening-atoms to form a fused, unsaturated

O

A or partially unsaturated, 5-6 membered ring C' having 0-2 heteroatoms selected from oxygen, O sulfur, or nitrogen, wherein each substitutable \0 ring carbon of said fused ring formed by Rx and

R

Y 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 R Y is independently substituted by R 4

R

1 is T-(Ring wherein T is a valence bond or a methylene unit; Ring D. is a 5-7 membered monocyclic ring or an.

8-10 membered bicyclic ring selected from an aryl or heteroaryl-ring;

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; and

R

3 is selected from -halo, -OR, or -N(R) 2 More preferred compounds of formula IIa have one or more,. and more preferably all, of the features selected from the-group consisting of:

R

x and R' are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring; R1'is T-(Ring D) wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; IND -72- D

R

2 is -R and R 2 is.hydrogen, wherein R is selected from hydrogen, CI-1 aliphatic, phenyl, a t 5-6 membered heteroaryl ring, or a 5-6 membered Sheterocyclic ring; and

R

3 is-selected from -halo,--OR, or -N(R 4 2 wherein R is selected from hydrogen, CI-6 c aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is C or -N(R 4 D 1 0 Even more preferred compounds .of formula IIc C have one or more, and more preferably all, of the features selected from the group consisting of: RX and R Y are taken together to form a.benzo, pyrido, piperidino, or cyclohexo.ring; 1.

R

1 is T-Ring D, wherein T is a valence bond and Ring 'Dis a 5-6 membered aryl or.heteroaryl ring;

R

2 is hydrogen or C1-4 aliphatic and R 2 is hydrogen;

R

3 is selected from -OR, or -N(R 4 2 wherein R is selected from hydrogen,. aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and (e)'Ring D is substituted.by up to three.

substituents selected from -halo, -CN, -NO 2

-N(R

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

-CO

2 R, -CONH(R)

-N(R

4

)COR,

-N(R

4 )C0 2

-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 wherein R is selected from hydrogen, Ci-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic'ring.

VO

D -73- C Preferred compounds of formula IIc include c compounds of formula lic': SR2' HN

N

Rx o R Y N N-R' c H

N

SIIc' or a pharmaceutically acceptable derivative or prodrug thereof, wherein; 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

x and R Y is independently substituted by T-R 3 or L-Z-R 3

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 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 4 T is a valence bond or a CI.4 alkylidene chain; Z is a CI- 4 alkylidene chain; L is -SO,

-N(R')SO

2

-SO

2

N(R

6

-N(R

6 -C0 2

-N(R

6

)CO

-N(R

6 -N (R 6 CON R 6

S

0 2N

R

6 -N(R6) N(R 6 -C(o)N(R 6 -C (R 6

-C(R

6 )2S-, -74- 0 -C 2 SO-, 250 2

-C(R

6 2

S

2

N(R

6

-C(R

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

N(R

6

-C(R

6

-C(R

6 -C(R6) 2

N(R')N(R

6 -C(R 2 (R)S0 2 N (R 6 or

-C(R

6 2

N(R

6

)CON(R

6

R

2 and 2 are independently selected from 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 heteroatomns selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by Ci R 2 and R 2 is independently substituted by halo, oxo, -CN, -NO 2 -R orbi -V-R5, 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 -halo, -OR, -CO 2

R,

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

-N(R

2

-CON(R

7

-SO

2 N (R 7 2 -N(R )COR, -N(R")C0 2

(C

1 6 S aliphatic), -N(Rt)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(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 C,- 6 aliphatic, C-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 -COR',

-CO

2 (optionally substituted C 1 aliphatic), -CON(R') or -SO 2 R7; each R 5 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO2, -CN, -SO 2 R, -SR, 2

-CON(R

4 2 -S0 2

(R

4 2 -N(R 4

)COR,

-N(R

4 )CO2(optionally substituted C 1 6 aliphatic), cl -N(R4tN(R 4 2

-C=NN(R

4 2 -C=N-OR, -NCR 4 )cONR 4 2

-N(R

4

)SON(R

4 4) 2 -N(R)S0 2 R, or .V is -S02-, -N(R6)S0 2

-SO

2

N(RG)-,

-C02-, S -N(R')CON(R

SO

2 (R6) (R6)N(R6)

-C(RG)

2 -c(R6) 2 s-, C 2 SO-, -C(R),So 2 -C(R6) 2

SO

2 -C(R) 2 -c (R6' 2 N -C(R6)=NNR6) IN -0(R 6 -C(R6) 2 N(R)DNRR) -C(R6)2N(R')S3011 or C (R6) 2 N(R')CON(R6) W is -C(R) 2 -O(R6) 2 -C(R6) 2 so-, 2 so 2

-C(RE)

2

S

2 -C(RG)2

N

2

NR')CO-,

2 C(0)0-0 -OAR6)=NNCR') CR') is -C(R 6) NRN)N(R), -C(RS) 2 N(R6)S02N 2 N(R6)CONRR6) or -CON(R6); each R6 is independently selected from hydrogen or an optionally substituted C3.-4 aliphatic group, or two R6 groups on the same'nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and.

each R 7 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.

The ring formed when R 1 and Ry of formula [1c' are taken together may be substituted or unsubstituted.

Suitable substituents include halo, -OCCH 2 2 4

-N(R

4 2 -o(CH2) 2 4 -OR, R 4 (CH) 2-4-N (R 4 2i -N(R 4 (012) 2- 4

-R,

-00 2 R, -COCOR, -NO, -ON,

-SO

3 R, -SR,

-NCR

4 2

-CON(R

4 2

-SO

2

NCR

4 2 -OCC;O)R,

-N(R

4

)COR,

-N(R

4 0 0 2(optionally substituted C.1, aliphatic), IND -76- 0 -N(R

N

(R

4 2

-C=NN(R

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

)CON(R

4 2 t -N(R)SO 2

N(R

4 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, -OR, -COR, -CO 2

R,

CON(R

4 -CN, -O(CH2)2- 4

-N(R

4 -O(CH2) 2 -4-

R

-NO

2 O -N(R4)2, -NR 4 COR, -NR 4

SO

2 R, -SO 2

N(R

4 2 wherein R is Ci hydrogen or an optionally substituted Ci-6 aliphatic group.

SThe R 2 and R 2 groups of formula IIc' may be c0 taken together to form a fused ring, thus providing a o 10 bicyclic ring system containing a pyrazole ring.

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

These are exemplified in the following formula IIc' compounds having a pyrazole-containing bicyclic ring system: S

NH

HN N N N N

<-N

XN 2 NH -7NH NH

NH

Ry N N-R 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: -halo, -N(R 4 2 -Ci-4 alkyl, -C1-4 haloalkyl, -NO2, -0(C-.4 alkyl), -C02(C-4 alkyl), -CN, -S02 (C-4 alkyl), -S02NH2, -C (0)NH 2

-NM

2 SO2 (CI-4 alkyl), -NHC(O) (CI-4 alkyl) -C(0)NH 2 and-CO(CI-4alkyl), wherein the (C 1 4 alkyl) is a straight, branched, or .cyclic.alkyl group. Preferably, the alkyl) group is methyl.

When the pyrazole ring system of formula IIc' is monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group sel ected from aryl, Ct heteroaryl, or a C-6 aliphatic group. Examples of such.

preferred

R

2 groups include -HI methyl, ethyl, propyl, cyclopropyl, 1-propyl, cyclopentyl, hydroxypropyi, methoxypropyl, and-benzylocypropy±. A pref erred R 2 grou'p is hydrogen.

ci -When Ring D of formula lic' is Tnonocyclic, opreferred Ring D groups include phenyl, pyridyl, IND pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula lIc' is bicyclic, preferred bicyclic Ring D'groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, guinolinyl, indolyl,.isoindolyl, indolinyl, benzo(blfuryl, benzo~b]thiophenyl, indazolyl, benzothiazolyl,..

is cinnoliny., phthalazinyl, quinazblinyl, cruinoxazolinyl, 1 ,8-naphthyridinya and isoquinliny...

On Ring D of formula 11o', preferred

T-R

5 or

V-Z-R

5 substituents include -halo,. -CN, :N0 2

-NCR

4 2 optionally substituted.C 1 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

-NCR

4

SO

2 R, -N (R )COCR 2 N (Rh4 2 -N CR 6

COCM

2

CI{

2 NWh 2 and

-NC(R

6

)CCCH

2

CH

2 N wherein R is selected from hydrogen; Cj: 6 aliphatic, phenyl, a 5-6"membered heteroaryl ring, or a 5-6 memnbered heterocyclic ring.

More preferred R9 substituents include -Cl, -Br,

CN,

-CF

3 -COOM,. -CONEMe, CONHEt, -NH 2 -NEAc, -NHSO 2 Me,

-NHSO

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

-NISO

2 (isopropyl), -NI{COEt,.

-NHCOCM

2

NHCH

3

-NHCOCH

2 N (CO 2 t -Eu) CM 3

-NHCOCH

2 N (CH 3 2

NHCOCH

2

CM

2 N(CH 2, -NHCOCH 2

CH

2

C{

2 N (CM 2 2 -NHC(cyclopropyl), -NHCO(isobutyl),

-NHCOCH

2 (morpholin-4yl), -NI{COCJI 2

CH

2 Cmorpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin- 4-yl), NVHC0 2 (t-butyl),

-NR(C

1 4 aliphatic) such as -NHMe, -N (C 1 4 aliphatic) 2 Such as.-NMe 2 OH, -0CC 1 4 aliphatic) -78- 0 such as. -OMe, CI-4 aliphatic such as methyl, ethyl, Scyclopropyl, isopropyl, or t-butyl, and -C02(C 1 -4 aliphatic).

Preferred formula Ilc' compounds have one or more, -and more preferably all, of the features selected from the group consisting of: R' is- T-(Ring wherein T is a valence bond or a methylene unit; S(b) Ring D is a 5-7 membered monocyclic ring or an o 10 8-10 membered bicyclic ring selected from an C. aryl or heteroaryl ring;.

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; and

R

3 is selected from -halo, OR, or More preferred compounds of formula IIc' have one or more, and more preferably all, of the features selected from the group consisting of:

R

1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;.

R

2 is -R and R 2 is hydrogen, wherein R is selected from hydrogen, Ci.- aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered .heterocyclic ring; and

R

3 is selected from -halo, -OR, or -N(R4)2, wherein R-is selected from hydrogen, Ci- 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or VO ID -79-

C

Even more preferred compounds of formula IIc' Chave one or more, and more preferably all, of the Sfeatures selected from the group consisting of: 1q

R

1 is T-Ring D, wherein T is a valence bond and Ring D is.a 5-6 membered aryl or heteroaryl .ring; N

R

2 is hydrogen or C1-4 aliphatic and'R 2 '.is hydrogen; ID

R

3 is selected from -OR, or -N(R4) 2 wherein R is selected from hydrogen, CI-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ring D is substituted by up to .three substituents selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted Ci.e aliphatic group, -OR,

-CO

2 R, -CONH(R 4

COR,

-N(R

4

)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(R

4 2 or

-N(R

6

COCH

2

CH

2 CH2N 2, wherein R is -selected from hydrogen, CI-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Other preferred.compounds of formula tIc include compounds of formula IIc":

R

2 R2' R N H

"HNN

Iyc"

*H

lie" ID or a pharmaceutically acceptable derivative or prodrug thereof, wherein; SR'X and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membe'ked ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by ax and Ry is optionally substituted by oxo, T-R 3 or L- 0 3 Z-R and each substitutable ring nitrogen of said ring formed by Rx and RY is optionally substituted by R 4 c provided that said fused ring formed by Rx and RY is other than benzo; R3 is. T-(Ring

D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, heterocyclyl- or carbocyclyl, said heteroaryl or heterocyclyl -ring having 1-4 ring heteroatoms-selected from nitrogen, oxygen or sulfur,. wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently substituted by -R 4 T is' a vale6nce bond or a C 1 4 alkylidene 'chain; 2-is a C,1 4 alkylidene chain; L is -S02-, -N(Rt)So 2

-SO

2

N(R

6

TCO

2

-N(R

6 -N(R6)C(O)d-, CON.(R) -N(R S0 2 a 6

-N(R

6

)N(R

6

-C(O)N(R

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

S

2 2

-C(R

6 2

N(R'

6 2 -C(R')2

N

(R')N(R

6 2

N(R')SO

2 or 2 CON Vai o -81- R and R are independently selected from -T-W-R6, or R. 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 S 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" and R 2 is independently substituted by R; (R is selected from -halo, -OR,

-CO

2

R,

-COCOR,

-COCH

2 COR, -NO 2 -CN,

-S(O)

2 R, -SR, 2 -CON(R)2,

-SO

2

N(R

7 2 -N(R?)COR, -N (R 7

CO

2

(C-

6 aliphatic), -N(R )N(R4) 2

-C=NN(R')

2 -C=N-OR,

-N(R

7

CON(R)

2 -N(R7)S02N(R') 2

-N(R

4

)SO

2 R, or -OC(=O)N(R7) 2; each R is independently selected from hydrogen or an optionally substituted group seledted from C,- 6 aliphatic,

C

61 o aryl, a heteroary1 ring having 5-10 ring atoms, or a heterocycly1 ring having 5-10id ring atoms; each R 4 is independently selected from -R 7

-COR

7 -C02(optionally substituted Ci-s aliphatic),

-CON(R

7 2 or -S 2

R

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

-C

2 R, -COCOR,

-NO

2 -CN,

-SO

2 R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R

4 2 -OC

-N(R

4

)COR,

-N(R

4

).CO

2 (optionally substituted

C

1 -6 aliphatic),

-C=NN(R

4 2 -C=N-OR,

-N(R

4 )CON(R4) 2

-N(R

4 )S0 2

N(R

4 2

-N(R

4

)SO

2 R, or -OC(=)N(R4)2; V is -S02-,

-NR

6 )S0 2

-SO

2

N(R

6

-N(R

6

-CO

2

-N(R

6

-N(R

6 -N CON(R6)-, SOz 2 N(R) N -82- 0 -C(o)N(R 6

-OC(O)N(R

6 2

-C(R

6 2

S-,

-C(R)

2 SO, -C(R) 2

SO

2

-C(R

6 2

SO

2

-C(R

6 2

N(R

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

-C(R

6 2 -C(R 6

)=NN(R

6

-C(R

6

-C(R

6 2

N(R

6

)N(R

6

-C(R

6 2 N(R)0 2

RON(R

6 or C (R6) 2N (R6) CON w is -C(Rt)20-, -C(R 6 2 -C(R6) 2 SO-, -C(R 6 2 S0 2 S-C(R6) 2

SO

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

-C(R

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

-C(R

6 2

N(R

6

)CO-,

-C (R 6 2 N C -C(R 6

=NN(R

6

-C(R

6

-C(R

6 )2N(R 6

)N(R

6

-C(R

6 2

N(R)SO

2

-C(R

6 2

N(R

6

CON(R

6

-CON(R)-;

eah R' is independently selected from hydrogen or an optionally substituted C 1 4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; .and each R' 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 nitrogen to form a 5-8 membered heterbcyclyl or heteroaryl ring.

Preferred rings formed byRX and RY of formula IIc" include a 6-,'or 7-membered unsaturated or partially unsaturated ring having 1-2 heteroatoms, or a partially unsaturated carbocyclo ring, wherein said R"x/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Examples of preferred -pyrimidine ring systems of formula IIc" are shown below.

NO

o -83- HNN% HNt1

N'_

HNI

IND

(/)tN31 aN3 fomuali"inldeI~"BIc-,~-IIcc-J IIc-P, and IH-V motpeealHl-,IcD c nd Uc- N 3.' a~ Mre taento eerre ayeubsitued r usst tuted.

Suitable substituents include halo, -O(CH 2 2 4 -N(R 4 2 -o (CH 2 2-4R, -OR, -NP (CH 2 2 4 -N (R 4 2e -N (R 4

-(CR

2 2 4

-R,

-84- 0

-CO

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

-N(R

4 2 -CON(R) 2

-SO

2

N(R

4 2 -OC(=O0)R, -N(R 4

COR,

S -N(R 4 C02 (optionally substituted C3-6 aliphatic), -N N (R 2

=NN(R

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

R

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

R,

-CON (R 4 2, -ON, -O(CH 2 2 4 -N R) 2, -0 (CH 2 2 4

-NO

2 -N(R 4 2

-NR

4 COR, -NR 4

SO

2 R, -SON(R) 2 wherein R is hydrogen 10 or an optionally substituted C1- aliphatic group.

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

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

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

NH

HN N N

N

R 1 NH NH NH

NH

RY)NQ N-R'N'-N H ,and Preferred substituents on the R 2

/R

2 fused ring of formula hIe" include one or more of the following: -halo, -N(R 4 2 C-4 alkyl, -C1.4 haloalkyl, -NO 2 -O(C1-4 alkyl), -C02(C1-4 alkyl), -CN, -s0 2

(C

1 4 alkyl), -SO 2

NH

2 -OC NH 2

-NH

2 S02(C2- 4 alkyl),. -NHC (C.

4 alkyl).,

C(O)NH

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

When the pyrazole ring system of formula IIc" is monocyclic, preferred

R

2 groups include hydrogen or a substituted or unsubstituted..group selected from aryl, heteroaryl, or a C 16 r aliphatic group. Examples of such Ci prefe red R' groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyi, and benzyloxypropy. A preferred,

R

2 group is hydrogen.

When Ring D of formula Ic 5 is monocyclic, preferred Ring D groups includephenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIcn is bicyclic, preferred bicyclic Ring 0 groups include naphthyl, tetrahydronaphthy, indanyl, benzimidazoly, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[blfuryl, benzo[blthiopienyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyj, quinoxazolinyl l,8-naphthyridinyj.and isoquinolinyl.

On RingD of formula IIc, preferred

T-R

5 or V-Z-R substituents include -halo, -CN, -NO, optionally substituted C,g aliphatic group, -OR, -C(O)R,

-CO

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

-N-(R

4 )CO,R, -SON(R 4 -N (R 4 SOR, -N(R 6

COCH

2 N R 4 2, -N (R 6 COCHCH2N

(R

4 2 and -N (R 6

COCH

2

CHCH

2 N(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 R5 substituents include -Cl, -Br, -Ci, -Cr 3 -COOH, -CONHMe, -CONHEt, -NH2, -NHAc, -NHS02Me, -NHS0 2 Et, -NHSO(n-propyl),

-NHSO

2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 -NRCOCH2N(COt-Bu) CH3, -NHCOCH 2 N(CH3)2,

-NICOCH

2 CH2N (CH2, -NHCOCH2CH2CH2N

(CH

3 2 S-86o -NHCO(cyclopropyl), -HCO.(isobutyl), -NHCOCH 2 (morpholin-4yl), -NHCOCH2CH 2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholin- S.4-yl), -NHC02(t-butyl), -NH(Ci4. aliphatic) such as -NHMe,

-N(CI-

4 aliphatic) 2 such as -NMe 2 OH, 4 aliphatic) such as -OMe, C 4 -aliphatic such as methyl, ethyl, Scyclopropyl, isopropyl, or t-butyl, 'and -CO 2 (Ci-4 c aliphatic).

Preferred formula IIc" compounds have one or C more, and more preferably all, of the features selected o 10 from the group consisting of: Ci

R

x and Ry are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 1-2 heteroatoms selected from oxygen, sulfur, or nitrogen, or a partially unsaturated 6-membered carbocyclo ring, wherein each substitutable ring carbon of said fused ring formed by R x 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 x and R Y is independently substituted by R4;

R

I is T-(Ring wherein T is a valence bond or a methylene unit, and Ring D is .a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;

R

2 is -R or and R 2 is -hydrogen; or R 2 and

R

2 are taken together to form an optionally substituted benzd ring; and

R

3 is selected from halo, -OR, or -N(R 4 2 More preferred compounds of formula IIc" have one or more, .and more preferably all, of the features selected from the group consisting of:

VO

o -87- C Rx and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein *each substitutable ring carbon of said fused ring formed by-R and R y is independently h substituted by oxo, T-R 3 or L-Z-R 3 and each C .substitutable ring nitrogen of said ring formed 0 by R x and Ry is independently substituted by R 4

R

1 is T-(Ring wherein T is a valence bond and 1 0 Ring D is a 5-6 membered monocyclic ring or an C 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring;

R

2 is -R and R 2 is hydrogen, wherein R is -selected from hydrogen,

C

I

-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a.5-6 membered .heterocyclic ring; and

R

3 is selected from.-R, -halo, -OR, or -N(R)2, wherein R is selected from hydrogen, C-s aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5- 6 membered heteroaryl, and L is -S-i or -N(R 4 Even more preferred compounds of formula lic" have one or more, and more preferably all, of the features selected from the group consisting of:

R

x and R y are taken together to form a pyrido, piperidino, or cyclohexo ring, wherein each substitutable ring carbon of said fused ring formed by R x 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 x and RY is independently substituted by R 4 O -88-

R

1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl Sring;

R

2 is hydrogen or CI-4 aliphatic and R 2 is

CA

hydrogen;

R

3 is selected from -OR, or -N(R 4 2 wherein C R is selected from hydrogen, C 1 -e .aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered CA heteroaryl, and L is or and o 10 Ring D is substituted by up to three C substituents selected from -halo, -CN, -NO 2

-N(R

4 2 optionally substituted Ci-6 aliphatic group, -OR, -CO 2 R, -CONH(R 4

-N(R

4

)COR,

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

)SOAR,

-N COCH 2

N(R

4 2, -N(R 6

COCH

2

CH

2 N (R 4 2, or

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.

Representative compounds of formula lic are shown below in Table 3.

Table 3.

Me Me

HN'

4 HN ,H HN H N N 'N N Me Me k

OH

IIc-1 IIc-2 IIc-3 -89- Me

UN

H

IIc-4 Me HNAPt

H

Ilc-7 Me H N J

'NH

Ilc-5 Me HN<Pe IC-8N Me

H

Ilc-6- Me HN Jt H H- Me

H

4 I*Ic-ao0 Me

HN<

'NN

Xlc-13 Me Me HNAP HN<V-d H.

H

.11C-11 Ilc-J22

H

4

OH

Ilc-14 Me c<NJP

H

12c-iS Me Me HNJ NHN' NH H

H

IIC-isli-i

H

IIc-i8 Va 0 0 ci (Ni

-SQ-

HNJP

H

I~c-19 HN r t;P- N N OMe

H

Ilc-20

HN

H

I Xc-21

HN

H H IIc-22 N 4t

H

HNJ& HN 4 fP H H Ilc-23 IIc-24

HN

Ilc-26 Z $N

WH

I-INN'

HN

4

J

OH

H

IIc-27

HN

4 tP

O&NW

Ilc-28 IIc-29 Ic3 -91- HN ~H N 1 H H Ilc-31 Ilc-32 IIC-33

HN

4

HN

4 "N 4N J-rCOH II c-34 IIc-35 IIc-36

N

4 Ilc-39

H

Ic-37 IIC-38- HN~

HN

4 dq NJ'j O N NQEt H

H

H N H H' HMe IIC-42 IIc-41 -92- Me

HN

4 HN J:tP

HN

4

P

IZ$ N ~QO

M

e Q$NJ

N

H H

H

Ilc-43 IIc-44 Me .HN HH64P N ,,aNHAc Q&lN-N N N Me IIc-46 IIc-47 I~tc-4B HN JH

H

Ilc-49 Me

MN

H

Ilc-SO Me HNfiPMe H CI

IH

Me Me HN. ft N NN (iMe c N(CMe H H- IIc-52 IIC-53 Ilc-54 -93- Me

H

Me Me HNeN HNt* CN N NHAc WNNaOMe CZANLN CN H

H

IIC-56 IIC-57 Me

HN

CX-NJcXNHAc

H

lIC-59 Me HNt N N

H

Ilc-EO Me

HNA$X

H

Ilc-62 Ilc-63 Me Me HNHNfd

.JN

KONJZCOe Me N-CO

HH

IIC-64 Ic-ES Me HNArp NN

NH

H

Et

H

Me 0$N-KIYBr

H

Me,

HN

4 H CH 3

H

Ilc-67 lIC-68 tlc-ES 94- N -%NO

H

IIc -70 9HH

HN

H

Ilc-71

NN

H

IXc -72

H

&NQ

IIc-76 Me HNt

ONJ

H

HN

Me IIc-74 H CI Ilc-7S H HN< H.

H

IIc-77 IIc-78 Me Me HN, erp HH N<ApVH

NN

H H H Ilc-79 IIc-80 I llc-sl- Me Me Bn, d 4 N 'A HN-jN NH HN

NH

N N N H H H ci

IN

0 c-i 0 0 0 IIc-82 Me

HN

HNA N^^O

H

IIc-83 HN N

H

IIc-86 Me HN

N

H

Bn N N.f1

H

IIc-87

HN

S H

CN

IIc-8 H CN >HN HN HN N CN N CN H

H

IIc-88 Tr-no In another embodiment, this invention provides a composition comprising a compound of formula IIc, IIc', or IIc", and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to .a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIc, IIc', or IIc", or. a pharmaceutical composition thereof.

'Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, \O -96- C which method comprises administering to the patient a compound of formula lic, IIc', or IIc", or a composition t comprising said compound.

Another aspect of this invention relates to a method of treating.or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula c IIc, IIc', or IIa",.or a pharmaceutical composition o 10 thereof.

C0 One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIc, IIc', or HIc", or a pharmaceutical composition thereof. This.method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of.

Alzheimer's disease. Another method relates to inhibiting the phosphorylation of catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IIc, II', or IIcH or a composition comprising said compound.

Another aspect of this'invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula D -97- SIXc, IIc', or II", or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in a patient, which method comprises administering to the.patient a compound of Sformula IIc, IIc', or IIc-, or a composition comprising Ci said compound.

Another aspect of .this invention relates to a ci method of treating or preventing an ERK-2-mediated diseases with an ERK-2 inhibitor; which method comprises C administering to a .patient in need of such a treatment a therapeutically effective amount of.a compound of formula ZIc, IIc', or IIc", or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting ERK-2 activity in a patient, which method comprises administering to the patient a compound-of formula IIc, IIc', or IIc", or a composition comprisingsaid compound.

Another aspect of this invention relates'to a method of treating or preventing an AKT-mediated diseases with an AKT inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIc, IIc', or IIc", or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting AKT activity in a patient, which method comprises administering to the patient a compound of formula IIc, IIc', or IIc", or a composition comprising said compound.

Another method relates to inhibiting Aurora-2,.

GSK-3, Src, ERK-2, or AKT activity in a biological O 98o sample, which method comprises contacting the biological.

sample with the Aurora-2, GSK-3, Src, ERK-2, or AKT Sinhibitor of formula IIc, IIc', or. IIcU, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2, GSK-3, Src, ERK-2, or AKT.

Each of the aforementioned methods directed to C the inhibition of Aurora-2, GSK-3, Src, ERK-2, or AKT, or the treatment of a disease alleviated thereby, is C preferably carried out with a preferred compound of o 10 .formula IIc, Ic', or IIc", as described above.

C] Another embodiment that is particularly useful for treating Aurora-2-mediated diseases relates to compounds of.formula lid:

R

2

R

2

NH

HN'

N

R^N Q'-R 1 IId or a pharmaceutically acceptable derivative or prodrug thereof, wherein; Q' is selected from -C(R 6 2 -,1,2-cyclopropanediyl, 1,2cyclobutanediyl, or 1,3-cyclobutanediyl; Rx and RY are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said.fused ring formed by Rx and R Y is independently substituted by oxo, T-R 3 or

L-Z-R

3 and each substitutable ring nitrogen of said -99c ring formed by RX and RI is independently substituted Sby R 4 R1 is T-(Ring

D);

Ring D is a 5-7 membered monocyclic ring or 8-10 membered bicyclic ring selected from aryl, heteroaryl, C heterocyclyl or carbocyclyl, said heteroaryl or .heterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, oxygen or sulfur, wherein each IN 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 substituted by -R 4 T is a valence bond or a C 1 4 alkylidene chain, wherein when Q' is -C(R 6 2 a methylene group of said CI-4 alkylidene chain is -optionally .replaced by

-N(R

4 -CONH-, -NHCO-,

-SO

2

-SO

2 NH-, -NHSO 2 -CO2-, -OC(0)NH-, or -NHCO 2 Z is a C..4 alkylidene chain; L is

-SO

2 -N(R')S0 2

-SO

2 -CO2-, -N(R6)CO-, CON -N (R 6

)SO

2

-C(R

6 2 2

S-,

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

-C(R

6 2

S

2 2 2 N

-C(R)N(R

6 2 C C(R 6 =NN (R 6

-C(R

6 2 -C(R 6 2

SO

2 or

-C(R

6 2 N(R')CON(R')

R

2 and R 2 are independently selected from or

R

2 and RV are taken together with their.interveningatoms 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

R

2 and R 2 is independently substituted by halo, oxo, IND _100o-CN,

-NO

2 -R7, or -V-R 6 and each substitutable ring nitrogen of said ring formed by R 2 and is independently -substituted by R 4

*R

3 .is selected, from -halo, -OR,

-CO

2

R,

S -COCOR, -COCH 2 COR, -NO 2 -ENI, 2 R, -SR., -N (R 4 -CON(R 7) 2

SO

2 N(R 7) 2 -OC R; -N coR,

-N(R

7 )C0 2 (Ci..

6 aliphatic), -N(R 4

)NX(R

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

NCR')

2 C)S0 2 R, or o1i each R is independently selected from hydrogen or an 0op tionally substituted group selected from C 1 6 aliphatic, C610o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocycly ring having 5-la ring atoms; each R 4 is independently selected from -COR 7 -CO2 Coption~lly sub~tituted

C

1 ~r aliphatic), -CON (R7) 2 or -50 2

R'

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

-CO

2 R, -COCQ.R, -NO 2 -CJN,

-SO

2 R, -SR,

-N(R

4 2 -CON(R 4

-SO

2 N(Rf4l 2 -OC -NC(Rt)CoR, -N (R 4 C0 2 (optionally substituted C1,r, aliphatic"), -NCRt)NR 4 2

C=NN(R

4 2 -N(R 4 ')CON(n 4 2 -N (R 4 )S0 2 N

(R

4

)SO

2 R, or -OC =Q.)NCR 4

Y

2 V is -S _SO2, -N(R 6 )S0 2

-SO

2

N(CR

6 -N (R 6 -CO2-,

-NC(R

6 C(0)Q0-,,

-N(R

6

CON(R

6

-N(R

6

')SO

2

N(R

6 6

)N(R

6 -C(o)N(R 6

-OC(O)N(R

6

-C(R

6 2

-C(R'

6 2 s-,

-C(R

6 2 6 2 s0 2 -C(Rs) 2 So 2 6 2

-CC(R

5 2 N (R 6 )CC(0) -C.(R 6 2

N(R

6 -C(R6)=NN(R) -C(R 6

-C(R

6 2 N (R 6 N(R 6 (CR6) 2 N(R) S0 2 N or -C (R 6 2 R)CN(6 w is -C(R6) 2 C(R6) 2

-CCR

6 2 S0-, -C(R 6 2 so 2 2 S0 2 N R 6 -C CR6) 2 N( C 6 COa- CG2-,

VO

o0 -101c

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

6 -C 2N(R 6

CO-,

S-C(R')

2 -C(R 6

)=NN(R

6 -C

S

C(R

2 N C)2N (R 6

S

2 N (R 6

-C(R

6 N (R')CON (R 6 or -CON(R) 6 each R 6 is independently selected from hydrogen or an Soptionally substituted

C.-

4 aliphatic group, or two R 6 cq groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered ND heterocyclyl or heteroaryl ring; each R 6 is independently selected from hydrogen or a CI-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 7 is independently selected from hydrogen or an optionally substituted

C

I

-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 rings formed by R x and R Y include a 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..

Examples. of preferred pyrimidine ring systems of formula IId are shown below.

R2

R

2 'RNH

HN

H N t N t H't r~r^ ii ,r U^IJ ^A IId-A IId-B IId-C -102- IId-D IlId-E Id-F HNX3Z IId-J IId-~C

(NK

Ild-L R Ild-V HNA37 Ild-R Ild-P

H??

N

4

R

Ild-W More preferred pyrimidine ring systems of formula Ild include lid-A, lId-B, lId-D, lId-EHp IId-J, Ild-P 1 and.Ild-v, most preferably ld-A, ld-B, ld-fl, Ild-B, and Ild-JT.

SThe ring formed when RX and RY of formula lid, are taken together may be substituted or unsubstituted..

Suitable substituents include halo, -O(0H 2 2 4

-N(R

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

(CH

2 2 4

-R,

Va o -103- -CO2R, -COCOR, -NO 2 -CN,

-SO

2 R, -SR, 2

-CON(R)

2

-SO

2

N(R')

2 -N(R )COR,

CO

2 (optionally substituted C-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)SO2N(R) 2

-N(R)SO

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

-ON,

o -O (CH 2 2 4 4 2 -0 (CH 2 2 4

-NO

2 -N (R 4 2, -NR 4

COR,

Va

-NR

4

SO

2 R, -SO 2

N(R')

2 wherein R is hydrogen or an optionally substituted C16 aliphatic group.

The R 2 -and R' 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, pyrimidd, and a partially unsaturated 6-membered carbocyclo riig.

These are exemplified in the following formula IId compounds having a pyrazole-containing bicyclic.ring system: 9NH HN NN N N NN SNH j NH $1 NH R N 0-R' ,and Preferred substituents on the R/R 2 fused ring of formula IId include one or more of the following: -halo, -N(R4) 2 -Cl-4 alkyl, -C1.4 haloalkyl,

-NO

2 -01(C-4 alkyl), -CO,2(C4 alkyl), -CN, -S02 (C alkyl), -S0 2 NH2, -OC NH2, -NI2SO2 (C 4 alkyl), -NHC (01.4 alkyl), -C NH 2 and -CO(C 1 4 alkyl), wherein the (C1-4 alkyl) is a IND -1'04o 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 -substituted or unsubstituted group selected from aryl, heteroaryl, or a Cl- 6 aliphatic group. Examples of such ciprefert ed R 2 groups include H, methyl, ethyl', propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, 0methoxypropyl, and benzyloxypropyl. A preferred

R

2 'gru oN 10 is hydrogen.

When Ring D of formula lid is monocycli-c, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and'pyrazinyl.

When Ring D of formula lid is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyx, indanyl, benzimidazolyl, guinolinyl,' indolyl, isoindolyl, indolinyl, benzo (b]furyl, benzo~blthiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl., quinoxazolinyl,- 1,8-naplithyridinyl and isoquinolinyl.

On Ring D of formula lid, prefetred

T-R

5 or V-Z- RS substituents include -halo, -ON, -NO 2

-N(R

4 2 optionally Substituted'C016 aliphatic group,

C(O)R,

-CO

2 3R, -CONH(Rfl,

N(R

4 )COR, -N(R 4

CO

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

SO

2 R, -N( 6

OHN(R

4 2 -N (R 6

COCH

2

CH

2 N (Rt 2 and -N (R 6

)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.R 5 substituents include -Cl, -Br, -CN, -a' 3 -COO?, -CONEMe, -CONHEt,

-NH

2 -NHAc, NHSO 2 Me,

NHSO

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

-NRSO

2 (isopropyl), -NUCOEt,

-NHCQCH

2

NECH

3 -NHCOCIN

(CO

2 t-Bu) CH 3

-NRCOCH

2 N (CH 3

-NHCOCH

2

CH

2 N 2,H3 -NHCOCH 2

CH

2

CH

2 N (CE 3 2

VO

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

-NHCOCH

2 (morpholin-4yl), -NHCOCH 2

CH

2 (morpholin-4-yl)

-NHCOCH

2

CH

2

CH

2 (morpholin- 2 4-yl),

-NHCO

2 (t-butyl), -NH(Cz.4 aliphatic) such as -NHMe, S -N(C-4 aliphatic) 2 such as -NMe 2 OH, -O(C.

4 aliphatic) such as -OMe, Ci-4 aliphatic such as methyl, ethyl, 0 cyclopropyl, isopropyl, or t-butyl, and -CO2(C.

4 aliphatic).

O Preferred Q' groups of formula IId include D

C(R

6 2- or 1,2-cyclopropanediyl, wherein each R 6 is independently selected from hydrogen or methyl. A more preferred Q' group is -CH 2 Preferred formula IIc compounds have one or more, and more preferably all, of the features selected from the group consisting of:

R

x and R y are taken together with their intervening atoms to form a 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 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 x and R Y is independently substituted.by

R

4

R

l is T-(Ring wherein T is a valence bond:or a methylene unit and wherein said methylene unit is optionally replaced by or Ring D is. a 5-7 membered'monocyclic ring or an 8-10 membered bicyclic ring-selected from an ~aryl or heteroaryl ring;

R

2 is -R or and R 2 is hydrogen; or R 2 and R are taken together to form an optionally substituted benzo ring; and: S* -106o

R

3 is selected from -halo, -OR, or -N(R 4 More preferred compounds of formula IIc have Sone or more, and more preferably all, of the features selected from the group consisting of: RX and R y are. taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, C thieno, piperidino, or imidazo ring;

R

I is T-(Ring wherein T is a valence bond or a methylene unit and wherein said methylene unit o 10 is optionally replaced by and Ring D is a Ci -5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl. or heteroaryl ring;

R

2 is -R and is hydrogen, wherein R is selected from hydrogen, C1-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;

R

3 is selected from -halo, -OR, or -N(R4) 2 wherein R is selected from hydrogen, CI-s aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or -N(R 4 and Q' is -C(R 6 2 or 1,2-cyclopropanediyl, wherein each R 6 is independently selected from hydrogen or methyl.

Even more preferred compounds of formula lIc have one or more, and more preferably all, of the features selected from the group consisting of: Rx and R Y are taken together to form a benzo, .pyrido, piperidino, or cyclohexo ring;

R

1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; S-107- CA

R

2 is hydrogen or CI-4 aliphatic and R 2 is t hydrogen;

R

3 is selected from -OR, or -N(R 4 2 wherein C R is selected from hydrogen, CI-6 aliphatic, 5-6 membered -heterocyclyl-, phenyl, or 5-6 membered Ch heteroaryl, and L is or -NH-; Cq Ring D is substituted by up to three.

o substituents selected from -halo, -CN, -N0 2 CAD

-N(R)

2 optionally substituted CI-6 aliphatic o 10 group, -OR, -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 COCH 2 N (R 4 2, -N COCH 2

CH

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

CCH

2 NiR4) 2 wherein R is selected from hydrogen, Ci-6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and Q'-is

-CH-.

Representative compounds of formula lid are shown below in Table 4.

Table 4.

HN HN

HN

1

U--

1 1 IId-I IId-2 Ild-3 -108- Me ftlpH Ild-4 Me lId-S I Id-6 Me

HN<AP

*Qfz~tcLme lId-8, Il NMe IId-9 Ild-7' Me HNAIt

CI

lId-lo Me HN'eN Me fN lId-11 Me

HN

Me HNe gH Ild-12 Me'

HN

IId-13 Ild-14

VO

CD

o Me

II

d-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 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IId or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2'activity in-a patient, which method comprises administering to the patient a compound of formula IId or a composition comprising said compound.

SAnother 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 -110- C therapeutically effective amount of a compound of formula IId or a pharmaceutical composition thereof.

SOne 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 Ci +therapeutically effective amount of a compound of formula IId or a pharmaceutical composition thereof. This method is especially useful for diabetic patients. Another method relates to inhibiting the production of C .hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IId or a composition comprising said compound.

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

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

Another embodiment of this invention relates to compounds of formula IIIa: -111- C R2

NH

RxfN R: NIS-R 01 IIa o) or a pharmaceutically acceptable derivative or prodrug O 5 thereof, wherein: RX and RY are independently selected from T-R 3 .or L--R

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, heterocyclyi.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-Rs, 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 C 1 4 alkylidene chain; L is

-SO

2 -N(R')So 2

-SON(R

6

-N(R

6

-CO

2

CON(R

6

-N(R

6

)SO

2

-OC()N(R

6

-C(R

6 2

-C(R

6 )2S-, -C(RP) 2 S0-, -C(R 6 2SO 2 2

SO

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

-C(R)

2

N(R

6

-C(R

6 2

N(R

6

)SO

2 or -C 2N CON

R

2 and R 2 are independently selected from

-T-W-R

6 or.

R' and R" are taken together with their intervening atoms to form afused, S-8 membered, unsaturated or IN -112- 0 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 R' and R" is independently substituted by halo, oxo, -CN, NO2, or -V-R 6 and each substitutable ring nitrogen of said ring, formed by R2 and RV is Cl independently substituted by R 4 R is selected from -halo, -OR, -COCOR, -COCH 2 COR, -N02, -CN,

-SR,

-N (R 4 -CON 2, -S02N 2 -N(R')COR,.

c: CO2(CI_ aliphatic),. -N(R 4 )N(R2, -C=NNR) 2, -C=N-OR,

CON(R')

2 SO2N(R 2 -N SO2R, or each R is independently selected from hydrogen or an optionally substituted group selected from C1..6 aliphatic, Cs..o10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10.ringatoms;each R 4 is independently selected from COR', -CO2(optionally substituted C 1 6 aliphatic), -CONC(R') 2 or -SOR; each R 5 is independently selected from halo, -OR, -CO2R, -COCOR, -NO 2 -CN, -SO 2 R, -SR,

-N(R

4 2, -CON (R 4 2 -SO2N (R 4 2

-N(R)COR,

-N (R 4

CO

2 (optionally -substituted Cj_-s aliphatic),

-N(R

4

)N(R

4 2

-C=NN(R

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

)CON(R

4 )2,

-N(R

4 SO2N(R 4 )2 -N(R 4 )SO2R, or -bC(=o)N(R 4 2;.

V is

-N(R

6

-N(R

6

-N(R

6

-N(R

6 SO2N(R).-, -N(R 6

)N(R

6 -OC(o)N(R 6

-C(R

6 -C(R)2so2-, -CR 6

)SO

2

N(R

6

-C(R

6 2N(R 6

-C(R

6 )2N(R 6

-C(R

6 =NN (R 6 \o -113- 0

-C(R

6 )2N(R 6

)N(R

6 2

N(R

6

SO

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

-C(R

6 )2S0 2 2

SO

2 N(R6)

-C(R

6 )2NR), -C02-, (R)ocC(0 -C C(R6) OC 2

N(R

6

)CO-

-C(R)

2 N(R C 2 N SON (R 6 2 N(R) CON(R 6 or -CON(R) each R 6 is independently selected from hydrogen or an optionally substituted C:-4 aliphatic group, or two R' c groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; and each R 7 is independently selected from hydrogen or 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 heteroaryl ring.

Preferred RX groups of formula IlIa- include hydrogen, alkyl- or dialkylamino, acetamido, or a Cp,aliphatic group such as methyl, ethyl,- cyclopropyl, or isopropyl.

Preferred RY groups..of formula IIIa include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is or

-C(R

6 2 -CO- and R 3 is -R, -N(R4 2, or -OR. Examples of preferred RY groups include 2-pyridyl, 4 -pyridyl,. pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl,. ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamfino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyi- or. dialkylaminoalkoxy such as -114- 0 dimethylaminopropyloxy, acetamido, optionally substituted cphenyl such as phenyl or halo-substituted phenyl.

S.The

R

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

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

These are exemplified in the following formula IIIa c compounds having a pyrazole-containing bicyclic ring O 10 system: HN NH N N .NkN HN N rl Rx N NH •NH H

NH

R

Y S-R, and.

Preferred substituents on the R 2

/R

2 fused ring of formula IIIa include one or more of the following: -halo, -N(R4) 2 -C-4 alkyl, -C 1 .4 haloalkyi, -NO 2

-O(C

1 -4 alkyl), -C02(C1-4 alkyl), -CN, -SOz (C-4 alkyi) -SO2NH 2

-OC(O)NH

2

-NH

2 SO2(Ci-4 alkyl), -NHC(O) (C-4 alkyl),

-C(O)NH

2 and -CO(Ci_4 alkyl), wherein the (C 1 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 lIIa 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, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, 0 methoxypropyl, and benzyloxypropy1 A preferred R" group is hydrogen.

When Ring D of formula Ilia is monocyclic, preferred R ing D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula Ilia is bicyclic, *preferred bicyclic Ring D groups include naphthylyo tetrahydronaphthyi', indanyl, benzimidazolyl, quinolinyl, Ci indoJlyl, isoindolyl, indolinyl, benzo[blfuryl,

IND

benzo(blthiophenyl, indazolyl, benzothiazolyl, (N cinnolinyl, phthalazinyi, quinazolinyl, quinoxazolinyl, 1, 8-naphthyridinyl and isoquinolinyl.

On Ring D of formula Ilia, prefe'rred

T-R

5 or V-

Z-R

5 substituents include -halo,. -ON, -NO 2 -N(Rt) 2 -optionally substituted C316 'aliphatic .group, -OR, -C(O)R,

-CO

2 R, -CONH(R 4 -N(Rt)coR,

-N(R

4 )Co 2 R, -SO 2

N(R

4 2 -N(R 4

SO

2 R, -NiR 6 C0dH 2 N (R4) 2 '-N(k 6 coc 2 d 2 N (R4 2 anid'

-NM(R

6

COCH

2

,CH

2 CHN1R') 2 wherein R is selected f rom.

hydrogen, C1_ aliphatic, phenyl, a 5-6 memrbered.

heteroary. ring, or a 5-6 membered heterocyclic ring.

More preferred R, substituents include -Cl, -r

-ON,

-OF

3 -COON; -CONHMe, -CONHEt,

-NH

2 -NHAc,

-NHSO

2 Me,

-NHSO

2 Et, -NHSO 2 (n-propyl), -N1150 2 (isopropyl), -NHCOEt;*

-NHCOCH

2

NMCH

3

-NHCOCH

2 N(0 2 t-Bu) CH 3

-NHCOCH

2 N (CH 3 2

-NRCOCH

2

CH

2 N (CH) 2, -NHCOCH 2

CH

2

Q{

2

N,(CR

3 2 -NHCO(cyclopropyl), -NHC (isobutylj,

-NHCOCR

2 (morpholin-4 yl), -UHCOCH 2

CH

2 (morpholin-4-yl),

-NECQOH

2

CH

2

CE

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

4 liphatic) such as -NHMe,

-N(C

1 4 aliphatic) 2 such as -N14e 2 OH, -OCL4 aliphatic) -such'as -OMe, C3-.4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and. -C02 (01.4 aliphatic).

v. -116- O Preferred formula IIIa compounds have one.or more, and more preferably all, of.the features selected.

from the group consisting of: Rx is hydrogen, alkyl- or dialkylamino, acetamido, or -a C-.4 aliphatic group; S(b) R Y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is -N(R4) 2 or -OR; S(c) R 1 is T-(Ring wherein T is a valence bond or C. a methylene unit; Ring D is a 5-7 membered monocyclic or an 8-10 Ci membered bicyclic.aryl or heteroaryl ring; and

R

2 is -Ror -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 IIIa have one or more,, and more preferably all, of the features selected from thegroup consisting of:

R

Y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -OR, or -N(R 4 2 wherein R is selected from hydrogen, Ci-6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;

R

1 is T-(Ring wherein T is a valence bond; Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;.

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 L is or Even more preferred compounds of formula liIa have one or'more, and more preferably all, of the features selected from the group consisting of:

VO

0 -117- C- Rx is hydrogen methyl, ethyl, propyl, Scyclopropyl, isopropyl,.methylamino or Sacetimido; S(b) R y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, pi-peridinyl, morpholinyl, A piperazinyl, methyl, ethyl, cyclopropyl, (q isopropyl, t-butyl, alkoxyalkylamino,.

o alkoxyalkyl,.alkyl- or dialkylamino aikyl- or dialkylaminoalkoxy, acetamido, optionally.

substituted phenyl, or methoxymethyl;

R

1 is T-(Ring 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 Czialiphatic group, -OR, -CO 2 R, -CONH(R)

-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) 2 and

R

2 is hydrogen or a substituted or unsubstituted.

C1-. aliphatic, and L is or -NH-.

Representative compounds of formula IIIa are shown below in Table Table HN HN

HN.

N S NS CO2M

N

Cr1 IIIa-1 IIIa-2 IIIa-3 -118-

HNSZ

M

etN mI Me AN-Jt ]Ita-4

M

e<Nc ila-s IIla-E

HN

4

CNN

HN

4 dH

N'

M&-N

IIIa-7 Ila-8' lIIa -9 Illa-lo IIla-li IIIa-12 Me -NjNH Me HHt Pr itN ellM ,JaNHEt Illa-13IIa1 Illa-14 IIla-16 Me

H

Illa-17 Me IINC_'p H NNw[ Me ,fdKlq Illa-is Me HN 4NdlH m IN lIla-iS Ila-20 IIIa-21 Me

HN

4

H

A'N N K~ AN N 3flS IIIa-23 IIIa-22 Me N. N

N

Krr 111ar24 Me

HNN

HN4 MeOQ ci IIla-- 27 Me

HA

NIP N ,N SaI II~a~0 Me e 2 HN

'P

CA

o.Ql IIIa-26 Me

J~H

MeMQ N Me HNitP IIIa-28 IIIa-29 *Ia3 ct cIN

CA

Me 120- Me HN<IP H Ht aBu' Nl- IIla-32 lIIa-3i IIIa-33 Me HN

<V

IIIa-34 IIIa-35. IIIa-36 me r~j g.Et MeO IIla-38 Me JtC2Me MeQ lIla39 IIIa-37.

Me N.N$s,-NqoMe OMe II~a-40 IIla-41IIa4 IIIa-42 -121- Me gJdH Me 4~

H

0 Et

HI

IIla-43 Ila-44 0 ci Va 0 0 ci Me IIIa -46 Me Me H -pH Q NN1 EtH 0 .0 IIIa-47 IXla-48 Me Me H P H Me, HN>

H

kA N N irNrEt N 0 0-CI.

H

-N

0 IIla-49 Me M HN N-MefNCoNHAc IIla-52 lla-O IlIa-Si Me Me Me HNI 4 P H* HN f 4 t N N Me9) 4 Nf.A Me Me Me-Me IIIa-53 I-IIa -54 Me 'Me Me, HN t HIM NN~ H N t H Ck rN 'N-N NY N 0 Me.N2 e%- IlIa-56 .IIIa-57 -122- HNX HN JH H HNIJ H Me2N 0 N S N E.1 S N O iMe O NMe

CN

IIIa-58 IIIa-59

§O

iH ?H H H HN HN H N '^NMe2 N N Me N HAc H "N N S N Eto MeOA N%*kg f.NW.J N'-s 00 Me Me Me N J 0 Me 2 N NMe 2 IIIa-61 IIIa-62 IIIa-63 In another embodiment, this invention provides a composition comprising a compound of formula Ilia and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIa or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity.in a patient, which method comprises administering to the patient a compound of formula IIIa or a composition comprising said compound.

o -123- C( Another aspect of this invention relates to a t method of treating or preventing a GSK-3-mediated disease Swith a GSK-3 inhibitor, which method comprises (C administering to a patient in need of such a treatment a therapeutically effective-amount of a compound of formula 0 IIIa or a pharmaceutical composition thereof.

C1 One aspect of this invention relates to a O method of enhancing glycogen synthesis and/or lowering \D blood levels of glucose in a patient in need thereof, o 10 which method comprises administering to the patient a therapeutically effective amount of a compound of formula IIIa'or a pharmaceutical composition thereof. This method is especially'useful for diabetic patients.

Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which.is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula. IIIa.or a composition comprising said compound..

Another aspect of this invention relates to a method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering.to a patient in need of such a treatment a therapeutically effective amount, of a compound of formula IIIa or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in a patient, which method IND -124o comprises administering to the patient a compound of formula IIIa or a .composition comprising said compound.

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

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

Another embodiment of this invention relates to compounds of formula IIIb: R2 R2' I NH HN 'N RX^

R

Y

O-R

1 IIIb or a pharmaceutically acceptable derivative or prodrug thereof, wherein: Rx and R Y are independently selected from T-R 3 or L-Z-R 3

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 selectedfrom nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently -125- 0g substituted by oxo, T-R 5 or V-Z-Rs, and each substitutable ring nitrogen of Ring D is independently substituted by T is a valence bond or a Ci.4 alkylidene chain; Z is a C1-4 alkylidene chain; SL is -S02-,

-N(R

6 )so 2

-SO

2 C

-N(R

6 -CO2-, -N(R 6

-N(R

6 -N (R 6 )CON (R 6 SO2N(R.) N (R6), Ci -OC(0)N(R 6 2 o 10 2 s0 2 2

SO

2 2 wN(R.) -CR(R) 2

(R

6 2 =NN(R 6

-C(R

6 2

(R

6

N(

6 -0(R 6 )21R 6

)S

2 N(R) (R or C 2 N (R 6 CON (R 6 R2 and R2' are independently selected from

-T-W-R

6 or

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable 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 nitrogen of said ring formed by R 2 and R 2 is independently substituted by.R 4 R 3is selected from -halo, -OR, -C0 2

R,

25 -COCOR, -COCH2COR,

-NO

2 CN, S (0) 2 R, -SR,

-N(R

4

-CON(R

2 2 0 2

N(R

7 2 -N(R 7

)COR,

-N(R

7 C02 (C-6 aliphatic),

-N(R

4 )N(R 4 2

-C=NN(R

4 2 -C=N-OR,

-NT(R')CON(R')

2

-N(R

7

SO

2 N 2

-N(R

4

)SO

2 R, or 7)2; each R is independently selected from hydrogen or an optionally substituted group selected from'C 1 6 aliphatic, C6_1 aryl, a heteroaryl ring having 5-10 \O -126- 0 o ring atoms, or a heterocycly ring having 5-10 ring atoms; each R is independently selected from

-COR

7 -C02(optionally substituted CI-6 aliphatic),

-CON(R')

2 Or -SO 2 R 7; Seach Rs is independently selected from halo, -OR,

-C

2 R, -COCOR,

-NO

2 -CN,

-SO

2 R, -SR,

-N(R

4

-COW(R)

2

-SO

2

N(R

4 2 -N(R 4

)COR,

-N (R 4

CO

2 (optionally substituted Q- aliphatic), 4 2

-C=NN.(R

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

SO

2

N(R

4 2

-N(R

4

)SO

2 R, or 2; V is -So02-, -N(R 6 )S0 2

-SO

2

N(R

6 CO-, N(R 6 )C2 -N(R 6 -N (R6) CON(R') -N SO 2 N -C(0)N(R 6

-C(R

6 20, -C(R 6

S-,

-C(R

6 )2SO-, -C(R6) 2 sO 2

-C(R)

2 SO2N(R')-, 2

-C(R)

2 2 2 N(R) SO 2 N(R) or C 2 CON W is 2 2

-C(R

6 2 SO-, 2

SO

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

-C(R

6 -C (R 6 2 N N -C(R 6 2 N (R')SO 2 N 2 or each R 6 is independently selected froni 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 formja 5-6 membered heterocyclyl orheteroaryl ring; and each R 7 is independently selected from hydrogen or an optionally substituted aliphatic group, or two R' on the same nitrogen are taken together with the 0 -127q nitrogen to form a 5-8 membered heterocyclyl or cheteroaryl ring.

SPreferred

R

x groups of formula IIIb include hydrogen, alkyl- or dialkylamino, acetamido, or a Cz.

4 aliphatic group-such as methyl, ethyl, cyclopropyl, or isopropyl.

Preferred

R

y groups of formula IIIb include T-R 3 Sor

L-Z-R

3 wherein T is a valence bond or a methylene, L is or -N(R 4

-C(R

6 2 0 -CO- and R 3 i -R,

-N(R

4 2 or -OR. Examples of preferred RY groups include S2-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 dialkylaminb 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 IIIb may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.

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

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

NH

HN

Rx, R RN "NH NH NH anNH ANo-R N N N i and ND -128- Preferred substituents on the R 2

/R

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

-C

1 4 alkyl, -Ci- 4 haloalkyl, -NO 2

-O(C

1 -4 alkyl), -C0 2 (C1- 4 alkyl), -CN, -SO 2

(C

1 -4 alkyl) -SO 2

NH

2 -OC NH 2 -NH2SO (C1.

4 alkyl), -NHC(O) (C2-4 alkyl),

-C(O)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.

When the pyrazole ring system of formula IIIb Ci is monocyclic, preferred R 2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a CI- 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 is hydrogen.

When Ring D of formula IIIb is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IIIb-is bicyclid, .preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzolb]furyl, 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

5 substituents include -halo, -CN, -NO 2 -N(R 2 optionally substituted C±-6 aliphatic group, -OR, -C(O)R,

-CO

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

)CO

2 R, -SO 2

N(R')

2 -N(R 4 S0 2 R, -N(R 6

COCH

2

N(R

4 2

-N(R

6

COCH

2

CH

2 N (R4) 2 and

-N(R

6

)COCH

2

CH

2

CH

2

N(R')

2 wherein R is selected from Va oD -129- C- hydrogen, C 1 aliphatic, phenyl, a 5-6 membered t heteroaryl ring, or a 5-6. membered heterocyclic ring.

More preferred

R

5 substituents include -C1, -Br,

-CN,

c- -CF3, -COOH, -CONIHMe, -CONEt, -NH2, -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO2 (n-propyl) -NHSO2(isopropyl) -NHCOEt,

-NHCOCH

2

NHCH

2

-NHCOCH

2

N(CO

2 t-Bu) CH 3

-NHCOCH

2 N (CH 3 2, c-

-NHCOCH

2

CH

2 N(CH3) 2

-NHCOCH

2

CHCH

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

-NHCOCH

2 (morpholin-4yl), -NHCOCCH 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, -0 (C 1 -4 aliphatic) such as -OMe, C 1 -4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2

(C

1 4 aliphatic).

Preferred formula IIIb compounds.have one or more, and more preferably all, of .the features selected from the group consisting of: RX is hydrogen, alkyl- or dialkylamino, acetamido, or a CI-4 aliphatic group; RY is T-R3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is -N(R 4 2 or -OR; R" is T-.(Ring wherein T is a valence bond or a methylene unit; Ring-D is a 5-7 membered monocyclic or an 8.-10 .membered bicyclic aryl or heteroaryl ring; and R is -R or -T-W-R 6 and R' is hydrogen, or R2 and R2 are.taken together to form an optionally substituted benzo ring.

More preferred compounds'of formula IIIb have one or more, and more preferably all, of the features selected from the group consisting of: Rr is T-R 3 or L-Z-R3 wherein*T is a valence bond or a methylene and R 3 is selected from -OR, -130or -N(R4) 2 wherein R is selected from hydrogen,

C

1 -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; R' is T-(Ring wherein T is a valence bond; Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;

R

2 is.-R and R' is hydrogen, wherein R is selected from hydrogen, CI., aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and L is or -N(R 4 Even more preferred compounds of formula IIIb have one or more, and more preferably all, of the features selected from the group consisting of:

R

x is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetimido;

R

Y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, Spiperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or.

dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl;

R

1 is T-(Ring 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 Ci., aliphatic group, -OR, -CO 2 R, -CONH(R4), -N COR, -N (R 4 S02R, -N (R 6

COCH

2

CH

2

R

4 2 or -N (R 6

COCH

2

CH

2 C2N R 4 2; and

I

-131-

R

2 is hydrogen or a substituted or unsubstituted

C

1 6 aliphatic, and L is or -NH-.

Representative compounds of formula IlIb are shown below in Table 6.

Table 6.

H N{ H N H N N IN TaCO 2 Me -Ot IIIb-i IIIb-2 IIIb-3

[HN

Mee Me N~O IIIb-4

HN&

Me 't HN'd IIbN IIIb-7 IIIb-8 fIIb-9 t-qrrx yNH 9LN z- qi II q H N H H oz-qlii ET-qirt OVHNM.N,Xv ery.

HNr evi vr-qiii H N OyN aGV4 OVHNJ

T

jq-Y-NH HINr. j evy ei-gi sr-gnuI

H*

sT -gin yNH

HN

eIyv uT-giin Ei-qjjj 0 H HN--rN or-gui 0 0 0 ovHN'JYN

NH

r *o -133- Me ,Me Me S iHN r H NMe N HN

H

o NO MeO

O

Cl CI IIIb-26 IIIb-27 ci o Me Me Me a composition comprising a compound of formula IIIb and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIb or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IIIb or a composition comprising said compound.

Another aspect of this invention relates to a method of treating-or preventing a GSK-3-mediated disease with a GSK-3-inhibitor, which method comprises ID -134c administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula SIIIb 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, C which method comprises administering to the patient a therapeutically effective amount of a compound of formula 1 IIIb or a pharmaceutical composition thereof. This S 1 0 method is especially useful for diabetic patients.

Ci Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of P-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula-IIIb or a composition comprising said compound.

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

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

-135- Another embodiment of this invention relates to compounds of formula IIIc:

R

2

TNH

HNN

RX, N RY N-R

H

.IIIc or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

R

x and R Y are independently selected from T-R 3 or L-Z-R;

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 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 s and each substitutable ring nitrogen of Ring D is independently substituted.by

-R

4 T is a valence bond or a .Ci4 alkylidene chain; Z is a C 1 -4 alkylidene chain; .L is S2O-, -N(R 6 )SO0-, -SO 2

N(R

6

-N(R

6

-CO

2

-N(R

6

-N(R

6

-N(R

6

CON(R

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

-C(O)N(R

6 -OC(0)N(R 6 -C(R6) 2

-C(R

6 2

S-,

-C(R

6 )2 S O

C(R

6 2 0 2

-C(R

6 2

SO

2 NR) -C(R 6 2

N(R

6

-C(R)

2

N(R

6

-C(R

6 2 N (R 6

C(R

6

)=NN(R

6 \O -136-

-C(R

6 2

N(R

6 2

N(R')SO

2

N(R

6 or

-C(R

6 2 N (R 6 )CON(R6)-;

R

2 and R' are independently selected from -T-W-R 6 or

R

2 and R 2 are taken together with their intervening atoms to form a fused, 5-8 membered, unsaturated or partially unsaturated, ring having 0-3 ring heteroatoms selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by

R

2 R and R 2 is independently substituted by halo, oxo, o 10. -NO 2 or -V-R 6 and each substitutable ring ci *nitrogen of said ring formed by R 2 and R 2 is independently substituted by R 4

R

3 is selected from -halo, -OR,

-CO

2

R,

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

-N(R

4 2

-CON(R

7 2

-SO

2

N(R

7 2

-N(R

7

COR,

-N(R )CO 2 (C1.6 aliphatic), -N(R )N(R 4 2

-C=NN(R

4 2 -C=N-OR, -N(R 7 CON(R?) 2, -N(R 7 )S0 2

N(R

7 2

SO

2 R, or -OC(=0)N(R )2; each R is independently selected from hydrogen or an optionally substituted group selected from CI-6 aliphatic, Cs-10 aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyl ring having 5-10 ring atoms; each R' is independently selected from -R 7 -CORt -C0 2 (optionally substituted C1-6 aliphatic), -CON(R') 2 or -SO 2 R7; each R 5 is independently selected from -R,-halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN, -S2R, -SR,

-N(R

4 2

-CON(R

4 2

-SO

2

N(R)

2

-N(R

4

)COR,

-N(R)CO2(optionally substituted C1-6 aliphatic),

-N(R

4 )N(R 2

-C=NN(R)

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

)CON(R

4 2

-N(R

4

)SO

2 N (R4 -N(R 4

SO

2 R, or -OC(=)N(R4)2;

NO

o -137- V is-0-, -SO2-, -N(R6)SO2-, -SON(R6) S

-C

2

-N(R

6

-N(R

6 -N(R)CON(R6)-,

-N(R)SO

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

-C(R

6 2 2 SO-, -C(R')2S0 2

-C(R)

2

SO

2 N

-C(R)

2 N(R6)

-C(R

6 2 N C 2

N(R

6 C 0o -C(RS)=NN(R6)-,

-C(RS)

2 N(R6)N(R6)-, -C(R5) 2 N(R6)SO 2 N(R6) or -C (R6) 2N(R6) CON(R6) W is -C(R 20-, -C(R6)2S-, -C(R6) 2S-, -C(R)2SOc-, -C (R SO2(R6)_, 2N -CO2-, C C (R 2N

CO-,.

-C(

6 2 N(R)

-C(R

6

=NN(R

6 -C (R 6 -C(R6) 2 N.(RS)N(R6) C(R6) 2 N(R) SO 2 (R6).r 2

N(R

6 or -CON(R 6 each R" is independently selected from hydrogen or an optionally substituted

C

1 4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocycly1 or heteroaryl ring; and each R7 is independently selected from hydrogen or an optionally substituted

C

1 6 aliphatic group, or two. R 7 on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocyclya or heteroaryl ring.

Preferred

R

2 groups of formula IIc include hydrogen, alkyl- or dialkylamino, acetamido, or a C 1 4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.

Preferred RY groups of formula Ilic include

T-R

or L-Z-R 3 wherein Tis a valence bond or a methylene, L is or 2 -CO- and R? is -R,

-N(R

4 2 .or -OR. Examples. of preferred RY groups include 2-pyridyl, 4 -pyridyl, pyrrolidinyl, piperidinyl; Va o~ -13 8ci morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as mnethoxymethyl or ci methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted ci phenyl such as phenyl or halo-substituted phenyl.

Si The R and groups of formula IlIc may be O taken together to form afused ring, thus providing a.

Ci 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 system:

NH

HN 'NN N .\NN Rx NH NH NH NH RYN W N-RI -NN H ,and Preferred substituents on the R 2

/R

2 fused ring of formula. IIIC include one or more 'of the following: -halo, -N(R 4 2 -C1-4 alkyl, haloalkyl,

-NO

2 -O(C-4 alkyl), -C02 (C 1 -4 alkyl) -CN, -S02 (C1-4 alkyl), -SO2NH 2

-OC(O)NH

2 -NH2SO2 (C.

4 alkyl) -NHC (C-4 alkyl)

-C(Q)NH

2 and -CO(CI-4 (C.4 alkyl), wherein the(C- alkyl) s a straight, branched, :or.cyclic alkyl group. Preferably, .the (1-4 alkyl) group is methyl.

When the pyrazole ring system of formula.IIIc is monocyclic, preferred.R groups include hydrogen or-a Va S -139substituted or unsubstituted group selected from aryl, heteroaryl, or a aliphatic group. Examples of such preferred R groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred

R

2 group is hydrogen.

When Ring D of formula IlIc is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of fortula IIxc is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, behzo[bjfuryl, benzo~b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula ml~c, preferred

T-R

5 or

V-Z-R

5 substituents include -halo, -CN,'-N0 2 -N(Rt 2 optionally substituted

C

1 6 aliphatic group,' -OR, -CCO)R,

-CO

2 R, -CONH(R),

-N(R

4 )COR, -N(R 4

)CO

2 R, -SO 2 NCRt) 2

(R

4

S

2 R, C 6

COCH

2 N (R 4 2 -N (R 6

COCH

2 CHN (R4 2 ,and

-N(R

6

COCH

2

CH

2

CH

2

N(R)

2 wherein R is selected from hydrogen, Ci-s aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a.5-6 membered heterocyclic ring.

More preferred RS substituents include -Cl, -Br, -CN,

-CF

3 -COOR, -CONHMe, -CONIEt,

-NH

2 -NHAc, -NHSO 2 Me,

-NHSO

2 Et, -NHSO 2 (n-propvl), -NHSO(isopropyl), -NXCOEt,

-NHCOCH

2

NHCH

3

-_NHCOCH

2 4N(CO 2 t-Bu) CH 3

-NHCOCH

2 N (CR 3 2

-NHCOCH

2

CH

2

N'(CH

3 2

-NHCOCR

2

CH

2

CH

2 N (CH3) 2 -NHCO(cyclopropyl), -NECO~isobutyl),

-NICOCH

2 Cmorpholin.4-

-NHCOCH

2

CH

2 (morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (norpholin- 4-yl), -NHCOa(t-butyl)

-NHCC

1 4 aliphatic) such as -NHMe,

-N(C

1 4 aliphatic) 2 such as -N~e 2 OI, -O(C 1 4 aliphatic)

NO

o -140such as -OMe, C.-4 aliphatic such as'methyl, ethyl, Scyclopropyl, isopropyl, or t-butyl, and -C0 2

(C

1 -4 aliphatic).

S. Preferred formula IIIc compounds have one or more, and more preferably all, of the features selected C( from the group consisting of:

R

x is hydrogen, alkyl- or dialkylamino, c acetamido, or a C1.4 aliphatic group; S(b)

R

Y is T-R 3 or-L-Z-R 3 wherein T is a valence bond CN 10 or a methylene and R 3 is -N(R4! 2 or -OR;

*R

1 is T- (Ring wherein T is a valence bond or a methylene unit; Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and

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 selected from the group consisting of: 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 -OR, or -N(R4)2, wherein R is selected from Ci-3 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl;..

R

1 is T-(Ring wherein T is a valence bond; Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;

R

2 is.-R and R 2 is hydrogen, wherein R.is.

selected from hydrogen, Ci06 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring; and L is or'-N(R 4

VO

o -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: RX is hydrogen methyl, ethyl, propyl, -cyclopropyl, isopropyl, methylamino or acetimido; RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; R' is T-(Ring 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 C1aliphatic group, -OR, -CO 2 R, -CONH(R 4 COR,

SO

2 R,

COCH

2

CH

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

COCH

2

CH

2

CH

2 N (R4) 2 and

R

2 is hydrogen or a substituted or unsubstituted

C

1 I-6 aliphatic, and L is or -NH-.

Representative compounds of formula IIIc are shown below in Table 7.

-142- Table 7.

*IlIc-1 IIlc-2 IIIc-3 IIIC-4

HN

4 "-CN'0N N N N

NO

IIlc-s Me

HN<H

*-MeO eO

H

IlIC-8 IIIc-E Me Alp

H

IIIc-7 IIIc-9 Me Et4ANN

H

Ph.

HN

H

Me

J~H

Et.,$Nif

H

IIC-3.o IlaC-ilIc1 IIlc-12 -143- I1c-13 Ph HNZIpH Mel -N

N

H

IIC-16 Ph N

NNO

H

NO

2 IIIC-14

*H

IIzc-1 HNt?

H

Me

H

Me Me

H

IIIC-21 Me

HN

4 MeN Me N N at

H

II~c-19 Me HNeJNJH Me Nk

H

Me Me

HN(S

MeO11NtJN 2 MeQ...

4 ,N N'21 Me

HN

4 MeLP

H

IIIc-22 .1c.2 ITIC-23 IIIC-24

VO

S -144-

CH

HN H HN Me N Me N 'S H

H

IIC-25 IIIc-26 ci C< In another embodiment, this invention provides D a composition comprising a compound of formula IIIc and a Ci pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IIIc or a composition comprising said compound.

Another.aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need.of such a treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition thereof.

One aspect of this invention relates to a method.of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula S-145- IIIc or a pharmaceutical composition thereof. This Smethod is especially useful for diabetic patients.

Another method relates to inhibiting the production of c< hyperphosphorylated Tau protein, which is useful in -halting or slowing the progression of Alzheimer's c disease. Another method relates to inhibiting the.

phosphorylation of P-catenin, which is useful for N treating schizophrenia.

Another aspect of this invention relates to a C 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 method of treating or preventing a Src-mediated disease with a Src inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIIc or a pharmaceutical composition thereof.

Another aspect of the invention relates to inhibiting Src activity in a patient, which method comprises administering to the patient a compound of formula IIc or a composition comprising said compound.

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

Each of the aforementioned methods directed to the inhibition of Aurora-2, GSK-3, or Src, or .the treatment of a disease alleviated thereby, is-preferably

VO

o 146- 0 0( carried out with a preferred compound of formula IIIc, as Sdescribed above.

Another embodiment of this invention relates to C( compounds of formula HIId: C R2 D2

NH

IDN

N R NQ'-R

I

IIId or a pharmaceutically acceptable derivative or prodrug thereof, wherein: is selected from -C(R 6 2 1,2-cyclopropanediyl, 1,2cyclobutanediyl, or 1,3-cyclobutanediyl;

R

x and R y are independently selected from T-R 3 or L-Z-R3;

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 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 4 T is a valence bond or a C 1 -4 alkylidene chain, wherein when Q' is -C(R 6 2 a methylene group of said C 1 .4 alkylidene .chain is optionally replaced by

-N(R

4 -CONH-, -NHCO-, -S02NH-, -NHSO 2 -COa-, -OC(0)NH-, or -NHCO2- Z is a Ci- 4 alkylidene chain; Va o -147- L. is

-SO

2

-N(R

6 )S0 2

-SO

2

N(R

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

-N(R

6 )S0 2 N(R) -NRC(R 6 (N -C(0)N(R 6 -OC(o)N(R 6

-C(R

6 2

-C(R

6 2

S-,

-C(R

6 2

SO

2

-C(RE)

2

S

2 -C(R 6 2 N

-C(R

6 2

N(R

6

-C(R)

2 2

N(R

6 -C(R')2N(R6)so 2 or c -C (R 6 2 N CON

SR

2 and R 2 are independently selected from or CN 10 R 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 R? and R 2 is independently substituted by halo, oxo, -CN, -NO 2 or -V-R 6 and each substitutable ring nitrogen of said ring formed by R2 and R" is independently substituted by R 4 R is selected from -halo, -OR, -C02R, -COCOR, -COCH2COR;

-NO

2 -CN,

-S(O)

2 R, -SR, 2

-CON(R

7 2

-SO

2

N(R

7 2 -N(R 7

)COR,

-N (R 7 C02 (C- 6 aliphatic), -N (R 4 )N (R 2 -C=NN

R)

-C=N-OR, -N CON 2 -N SO 2

N(R

7 2 -N S 2 R, or :-OC each R is independently selected from hydrogen or' an optionally substituted group selected from C3,6 aliphatic, C6-.

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 -R 7, -COR 7 -CO2 (optionally substituted C.-j aliphatic), -CON (R 7 2 or. -S0 2

R

7 f

NO

S-148- C each R 5 is independently selected from halo, -OR,

-CO

2 R, -COCOR, -NO 2 -CN,

-SO

2 R, -SR,

-N(R

4 2

-CON(R)

2 -SO2N(R') 2 COR,.

Cl -N (R 4 C0 2 (optionally substituted C- 6 aliphatic),

-N(R

4 2 -C=NNR4) 2 -C=N-OR, -N(R 4

)CON(R

4 2 N -N(R SO 2

N(R

4 2

-N(R

4 )S0 2 R, or 2 V is -SO2-, -N(R)S0 2

-SO

2

N(R

6 S-N(R6)V, -CO2-, -N(R 6

-N(R

6 CON -N (R 6

)SO

2

N(R

6

-N(R

6 N (R 6 C 10 -OC(O)N(R) 2 2

S-,

-C(R

6 2

SO

2

-C(R

6 2

SO

2 2 N(R)

-C(R)

2

N(R

6

-C(R)

2

N(R

6

-C(R

6

)=NN(R

6 -c(R 6

-C(R)

2

N(R')N(R

6

-C(R

6 2 S0 2

N(R

6 or -c(R 6 2 N (R 6 CON w is -C(R 6 2 2 -C(Rf)2SO-, -C(R 6 2 S0 2

-C(R)

2 S0 2

N(R

6 2

-CO

2 2 N -c(R 6 2

-C(R

6 2 N N 2 N S 2

N(R)

-C (R 6 2 N CON(R') -,or -CON(R') each R' is independently selected from hydrogen or an optionally substituted C 1 4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with.the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R6' is independently selected from.hydrogen or a C-4 aliphatic group, or two R6 on the same carbon atom are taken together to form a 3-6 membered carbocyclic ring; and 7 each R is independently selected from hydrogen or an optionally substituted C3- 6 aliphatic group,' or -two R7 on the same nitrogen are taken together.with the

\O

8-149nitrogen to form a 5-8 membered heterocyclyl or t heteroaryl ring.

Preferred Rx groups of formula IIId include hydrogen, alkyl- or dialkylamino, acetamido, or a CI-4 aliphatic group such-as methyl, ethyl, cyclopropyl, or c isopropyl.

SPreferred R Y groups of formula IIId include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is or -N(R 4

-C(R

6 -CO- and R 3 is -R,

-N(R

4 2 or -OR. Examples of preferred R Y groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or.dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.

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

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

These are exemplified in the following formula 1Id compounds having a pyrazole-containing bicyclic ring system: l\ RHN CH N N 2 R Na

N

R N CH2R N N N *Y 'H2R1 and C .0 -150- 0 Preferred substituents on the R 2

/R

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

-C

1 4 alkyl, -C 1 4 haloalkyl,

-NO

2 -0(C.

4 alkyl), -C0 2

(C-

4 alkyl),--CN,- -S02 (CI- 4 alkyl),--so02NH 2

-OC(O)NH

2

-NH

2

SO

2

(C

1 4 alkyl), -NHC(O) alkyl), -C NH2, and -CO(C.

4 alkyl) wherein the (CI.

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

c 10 When the pyrazole ring system of formula IIId is monocyclic, preferred

R

2 groups include hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C 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 is hydrogen.

When Ring.D of formula IIId is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula XIId is .bicyclic, preferred bicyclic Ring D groups include'naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzo[b]furyl, benzolb]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-Rs. substituents include -halo,. -CN, -NO 2

(R)

2 optionally substituted C1- 6 aliphatic group, -OR, -C(0)R,

-CO

2 R, -CONH(R 4

-N(R

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

N(R

4 2 -N (R 4

SO

2 R, -N(R 6

COCHI

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

COCH

2

CH

2 N(R) 2 and -N (R 6

)COCH

2

CH

2

CH

2 N(R) 2 wherein R .is selected from Va -151hydrogen, C3- 6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred

R

5 substituents include -Cl, -Br,

-CN,

-CF

3 -COOH, -CONIHMe, -CONHEt, -NH 2 -NHAc, -NHISO 2 Me, Ch 5 -NHSO 2 Et, -NHSO 2 (n-propyl), -NHS0 2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3

-NHCOCH

2

N(CO

2 t -Bu) CH3, -NHCOCH 2

N(CH

3 2

-NHCOCH

2

CH

2 N (C 3 2, -NHCOCH 2 CH2CH 2

CH

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

-NHCOCH

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

CH

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

CH

2

CH

2 (morpholin- 4y1), -NHCO 2 (t-butyl),

-NH(CI-.

4 aliphatic) such as -NHMe, 4 aliphatic) 2 such as -NIMe 2 OH, -O(C 1 .4 aliphatic) such as -OMe, C1.4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C1-4 aliphatic).

Preferred Q' groups of formula IId include or 1, 2 -cyclopropanediyl, wherein each R 6 is independently selected from hydrogen or methyl. A more preferred Q' group is -CH2-.

Preferred formula IId compounds have one or more, and more preferably all,.of the features selected from the group consisting of: -Rx is hydrogen, alkyl- or dialkylamino, acetamido, or a C1.4 aliphatic group;

R

7 is T-R or L-Z-R, wherein T is a valence bond or a methyleneand

R

3 is -N(R 4 2 or -OR; R' is T-(Ring wherein T is a valence bond or a methylene unit and wherein said methylene unit is optionally replaced by or Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;.and R is -R or -T-W-R 6 and R 2 is hydrogen, orR 2 and R are taken together to form an optionally substituted benzo ring.

VO

SD -152- C- More preferred compounds of formula IIId have 3 one or more, and more preferably all, of the features selected from the group consisting of: C-

R

y is T-R 3 or L-Z-R 3 wherein'T is a valence bond or a methylene and R 3 is selected from -OR, c or -N(R4) 2 wherein R is selected from hydrogen,

C

1 -6 aliphatic, or 5-6 membered heterocyclyl, c phenyl, or 5-6 membered heteroaryl;

R

1 is T-(Ring wherein T is a valence bond; C 10 Ring D is a 5-6 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring;

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; L is or -N(R 4 and Q' is -C(R 6 2 or 1,2-cyclopropanediyl, wherein each R 6 is independently selected from hydrogen or methyl.

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

R

x is hydrogen methyl, ethyl, propyi, cyclopropyl, isopropyl, methylamino.or acetimido;

R

y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or.methoxymethyl; -153-

R

1 is T-(Ring 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,

S.-NO

2

-N-(R

4 2 optionally substituted-CI.

6 aliphatic group,. -OR, -CO 2 R, -CONH(R 4 -N COR, -N SO 2 R, -N(R 6 COCH2CHN

(R

4 2 or -N (R 6 COCH2CH 2

CH

2 N (R 4 2

R

2 is hydrogen or a substituted or unsubstituted

C-.

6 aliphatic; and L is or and Q' is -CH2-.

Representative compounds of formula IIId are shown below in 'Table 8.

Table 8.

Ph

HNN

H'N

CI

IIId-l "Hf

HN'N

W',

O::

HN N Me N' 0 IIId-2

NO

HNVC

Me N &s O I"\sD Ph

HNANH

Me N IIId-3 Ph

HNNH

Me N 1 1 Me S IIId-4 IIId-5.

IIId-6 -154r HN2

AN

Me N IIId-7 Me

HNH

LrNN Et *Ph HN Q4NH 1116-8 .me

JH

'I'd-li 0

HN

2 Me HN <pH Et4#tJQ 1116-12 Me 4N Me Me 1116-13 Ph Me'CN 1116-14 hdi Illd-15 *Me HN<Vp IIId-iE Me

A

MeN

CI

I11d-18 111d-.17

IN

0 -155- Me c Me Me HN'Y NH NH Me N C1 HN H N MeN EtN- Me eMe ci IIId-19 IIId-20 IIId-21 SMe Me Me HN* HN H

HN

Me4 ^O Et% EtZ P IIId-22 IIId-23 IIId-24 In another embodiment, this invention provides a composition comprising a compound of formula hIId and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating or prevehting an Aurora-2-mediated disease with an-Aurora-2 inhibitor, which method Scomprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IIId or a pharmaceutical composition thereof.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to-the patient a compound of formula IIId or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises.

administering to a patient in need of such a treatment a

VO

o 156- C therapeutically effective amount of.a compound of formula SIIId or a pharmaceutical composition thereof.

One aspect of this invention relates to a C method of enhancing glycogen synthesis and/or, lowering blood levels of-glucose-in a patient in need thereof, Ci which method comprises administering to the patient a therapeutically effective amount of a compound of formula C IIId or a pharmaceutical composition thereof. This o method is especially useful for diabetic patients.

C 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 P-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IIId or a composition comprising said compound.

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

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

Another embodiment of this invention .relates to compounds of formula IVa:

VO

cNH -157 RY Z S-R c IVa

VO

or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

x is nitrogen or C-R 8 and Z 2 is nitrogen or CH, wherein one of or Z2 is nitrogen; Rx and R y are independently selected from T-R 3 or L-Z-R3 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 ring formed by Rx and R Y is independently substituted by oxo,,T-R, or L-Z-R 3 and each substitutable ring Snitrogen of said 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, 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 s and each substitutable ring nitrogen of Ring D is independently substituted by -R 4

I

Va 0D -158ci T is a valence bond or a c 14 alkylidene chain; S Z is a C 1 -4 alkylidene chain; L is -SO2-,

-N(R')SO

2

-SO

2

N(R

6 -N(R6)Co-, S -N (R 6

CON-(R

6 -N (Rq) SO 2

N-(R

6 -N (R 6 N (R 6

-OC(O)N(R

6

-C(R)

2

S-,

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

SO

2 C(R6) 2

SO

2 .C(RE) 2 N(R)6y, S-C(R) 2

N(R

6

C(R

6 2 aN(R 6 -C

-C(RS)

2 -C(R 6 2

N(R

6

)SO

2 or S 10 -C 2N(R) CON

R

2 and R 2 are independently selected from or

R

2 and 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

R

2 and R 2 is independently.substituted by-halo, oxo, -CN,

-NO

2 or -V-R ,.and'each substitutable ring nitrogen of said ring formed by R 2 and R 2 is independently substituted by R; R is selected from -halo, -OR,

-CO

2

R,

-COCOR,

-COCH

2 COR, -NO 2 -CN, -S(0) 2 R; -SR, -N(R 4 2

-CON(R

7 2

-SO

2 Nl(R') 2 -N(R')COR, -N (R 7 CO 2.(C1-6 aliphatic),

-N(R

4 )N(R 2

-C=NN(R')

2 -C=N-OR, -N(R)CON(R7) 2 -1(R 7 )SO2N(R7) 2

-N(R

4

)SO

2 R, or )2; each R is independently selected from hydrogen or an optionally substituted group selected from C 1 6 aliphatic, C5-1o aryl, a heteroaryl ring having 5-10 ring atoms, or a heterocyclyi ring having 5-10 ring atoms; Va 0 -159each R s independently selected from -R 7

-COR

7

-CO

2 (optionally 'substituted C1_6 aliphatic),

-CON(R

7 2 or -SO 2

R;

each R5 is independently selected from halo,

-OR,

S C02Rj -COCOR,

-NO

2 -ON,

-SO

2 R, -SR,

-N(R

4 )21 -CON(R) 2

-SO

2

N(R

4 2 -N(R 4

)COR,

-N(R

4 02 (optionally substituted C,-g aliphatic),

-N(R

4

)N(R)

2

-C=NN(R

4 2 -C=N-0R,

-N(R

4

)CON(

4 2 o

-N(R!)SO

2 N(R 2 -N(R)So 2 R, or Vis

-N(R

6 -sd 2 N(R2)-, -CO2-,

-N(R

6

N(R

6 -N(R6) CON

N(R)SO

2 N(R6) -OC(O)N(R)

-C(R

6 2 SO-, -C (R 6 2 S0 2 -c (R 2 S0 2 N R 6 C(R6) 2

N(

2 2 -C(R6)=NP(R)Z,

-C(RG)

2 N(R)N(R6Y.,

-C(RS)

2

N(RG)SO

2 or -C(R6) 2 N CON CR 6 W is -C(R6) 2 2 -C(R6) 2 SO-, -C(R6)sO 2 -C(R6)2S02N(R6)-,, -C(R6)2N(R -C02- -0(Rto0C(O)-, -0(R6)OC()N(R6)y.

-C(R)

2

N(RW)CO-,

2 -C(R 2

N(R

6 C, 0(RS) 2 N(RS) So 2 N (R6.

-C(R6) 2 N(R6)CON(R or -CON(R") each R' is independently selected from hydrogen or an optionally substituted C1-4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together 'with the nitrogen atom to form a 5--6membered heterocyclyl or heteroaryl ring; each R is independently selected from hydrogen or an 3 .0 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 heterocycly or heteroaryl ring; and'.

o -160-.

0 c R8 is selected from halo, -OR,

-CO

2 R, -COCOR,

S-NO

2 -CN, -S0 2 R, -SR,

-CON(R

4 2

-SO

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

-N(R

4

)N(R

4 2

-C=NN(R

4 2 -C=N-OR,

-N(R

4

CON(R')

2 N{R) SO 2 N (R) 2 -N (R 4 S0 2 R, or -OC(=0)N(R) 2 Preferred 'rings formed by RX and RY of formula IVa include a or 7-membered unsaturated or

O

partially unsaturated ring having 0-2 heteroatoms, .wherein said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVa are shown below.

R2

R

2 HN HN ~:W4 HN/" Z7 HN HN

H

R4QYRNaY a S Z -R! -IVa-A IVa-B Iva-C IVa-D IVa-E IVa-F HN> HN? HNrZ QIVa-J IVa- Va- IVa-J **IVa-K *IVa-I.

VO

o -161- 0 HNHN1 HNA1 II I (0 1 R1<N 4 4 PIVa-P X7a-a IVa-V

HNA

ci Cz2 oI N z

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 formula. IVa are those described above, wherein Z 1 is nitrogen and Z 2 is CE.

Preferred RX groups of formula IVa include hydrogen, alkyl- or dialkylamino, acetamido, or a'C.

4 aliphatic group such as methyl, ethyl, cyclopropyl, or 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 or -N(R 4

-C(R

6 2 and R 3 is -R, -N (R4)2, or -OR. Examples of preferred

R

7 groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl,.ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl-. or.dialkylamino such as-ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as -162dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.

The ring formed when the RX and Ry groups of formula IVa are taken together may be substituted or unsubstituted. Suitable- substituents -include.-R, halo, -0 (CH 2 2 4 -N (R 4 2

-O(CH

2 2 4 -OR, -N(R 4

(CH

2 2-4 4 2,

-N(R

4

-(CH

2 )2- 4 -CO 2 R, -COCOR, -NO 2

-CN,

-SO

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

-CON(R

4 2

-SO

2

N(R

4 2 -OC -N(R 4 )COR, -N(R4)'CO 2 (optionally substituted C 1 6 io aliphatic),

-N(R')N(R

4 2

-C=NN(R

4 2

-C=N-OR,

-N(R

4

CON(R

4 2 -N(R S0 2 N 2, -N(R 4

SO

2 R, or

-OC(=O)N(R)

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

-CO

2 R, -CON(R4) 2, -CN, -0 (CH 2 2 -4 4) 2

O(CH

2 )2- 4

-NO

2

-N(R

4 2 -NR'COR, -NR 4

SO

2 R, -S02N(R 4 2 wherein R is hydrogen or an optionally substituted

C

1 aliphatic group.

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

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

These are exemplified in the following formula IVa compounds having a pyrazole-containing-bicyclic ring system: 1.

H H N N

N

R Z2NH 2 NH NH

NH

Z' S- ,an s ,and i Va 0 -163- Preferred substituents on the R 2

/R

2 fused ring of formula.Iva-inclue one or more of the following: -halo,

-C.

4 alkyl, -C2-4haloalkyl,

-NO

2

-O(C

1 -4 alkyl),

-CO

2 (C1-4 alkyl), -CN, -SO 2

(C

1 -4 alkyl),

-SO

2

NH

2 -OC(0)NH 2

-NH

2

SO

2

(C

1 .4 alkyl), -NHC(0) (C2, 4 alkyl),

-C(O)NH

2 and -CO(Cx.-4alkyl), wherein 'the (Ci- 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 IVa is monocyclic, preferred

R

2 groups include hydrogen or a substituted or unsubstituted-group selected from aryl, heteroaryl, or a C 16 aliphatic group. Examples of such preferred R groups include H, methyl, ethyl, propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl., and benzyloxypropy. 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;.

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, benzoCblthiophenyl, indazolyl, benzothiazolyl, 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 Ca_ aliphatic group, -OR, -C(Q)R,

-CO

2 R, -CONH(R 4

-N(R

4 )COR, -N(R 4

CQ

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

COCH

2 N (R4) 2 -N (Rq) COCH2CH2N (R 2, and

-N(R)COCCH

2

CH

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

C

16 5"aliphatic,. phenyl, a. 5-6 membered

IO

o -164- 0 heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred

R

5 substituents include -Cl, -Br,

-CN,

-CF3, -COOH, -CONEMe, -CONHEt,

-NH

2 -NHAc, -NHSO 2 Me,

-NHSO

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

-NHSO

2 (isopropyl), -NHCOEt,

-NHCOCH

2

NHCH

3 r- -NHCOCH 2

N(CO

2 t -Bu) CH3 NHCOCHzN

(CH

3 2 -NHCOCH2CH 2

N(CH

3 2 -NHCOCH2C 2

CH

2

N(CH

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

NHCOCH

2 (morpholin-4yl), -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, C 10 -N(C 1 4 aliphatic) 2 such as NMe 2 OH, -0 (C1-4 aliphatic) such as -OMe, C-4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C0 2

(C

1 -4 aliphatic).

Preferred

R

8 groups of formula IVa, when present, include R, OR, and N(R 4 2 Examples of preferred

R

8 include methyl, ethyl, NH 2

NH

2

CH

2

CH

2 NH, N(CH 3 2

CH

2

CR

2

NH,

N(CH

3 2 CH2CH 2 0, (piperidin-1-yl) HCHO20, and. NH 2 CHaCH 2 0.

Preferred formula IVa compounds have one or more, and more preferably all; of the features Selected from the group consisting. of: RX is hydrogen, alkyl- or dialkylamino, acetamido., or a Ci..

4 aliphatic group and RY is

T-R

3 'br L-Z-R, wherein T is a valence bond or a methylene and R 3 is -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 nitrogen, wherein each substitutable ring carbon of said fused ring .formed by RX and RY is independently substituted by oxo, or L-Z- R and-each substitutable ring hitrogen of said

VO

0 -165- Sring formed by Rx and R Y is independently Ssubstituted by R 4 R1 is T-(Ring wherein T is a valence bond or C a methylene unit; Ring D is a 5-7 membered monocyclic or an 8-10 C membered bicyclic aryl or heteroaryl ring; and C-

R

2 is -R or -T-W-R 6 and R 2 is.hydrogen, or R 2 and 02' C

R

2 are taken together to form an optionally Ssubstituted benzo ring.

Cl 10 More preferred compounds of formula Iva have one or more, and more preferably all, of the features selected from the group-consisting of: RY is T-R3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from

-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" and' R are taken together with their intervening atoms .to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by R x and R Y is independently substituted by oxo, T-R 3 or L-Z-R 3 .and each substitutable ring nitrogen of said ring formed by R x and R y is independently substituted by R 4

R

1 is T-(Ring wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8membered bicyclic aryl or heteroaryl ring;

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 D -166c.

R

3 is selected from -halo, -OR, or wherein R is selected from hydrogen, C3.- Saliphatic, or 5-6 membered heterocyclyi, phenyl, C-I or 5-6 membered heteroaryl, and L is or -N(R 4 C< Even more preferred compounds of formula-IVa Shave one or more, and more preferably all, of the C- features selected from the group consisting of: 0 RX is hydrogen methyl, ethyl, propyl,

C

N 10 cyclopropyl, isopropyl, methylamino or acetamido.

and R Y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl;-or Rx and

R

y are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclohexo ring, wherein said ring is optionally substituted with -halo, -OR, -COR, -CO2R,-

-CON(R

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

-N(R

4 2 -O(CH 2 2 4

-NO

2

-N(R

4

-NR

4 COR,. -NR 4

SO

2 R, or -SO 2 N(R 4 2 wherein R is hydrogen or an optionally substituted Ci,aliphatic group;

R

1 is T-(Ring 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(R4) 2 optionally substituted C.-6 aliphatic, -OR,

-CO

2 R, -CONH(R 4 -N(R COR, -N(R 4 )CO2R,

S-SO

2 N (R 4 -N (R SO 2 R, -N (R 6 COCHN 2

N.(R

6 )COCHCH2N (R4) 2 or. -N (R 6

COCH

2

CH

2

CH

2 N (R 4 2 -167e R is hydrogen or a substituted or unsubstituted Z group selected from aryl, heteroaryl, or a Ci-6 aliphatic group, and R2'.is hydrogen; and R3 is selected from -OR, or -N(R 4 2 wherein 5 R is selected from hydrogen, Ci_. aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ao Ring D is substituted by up to three o substituents selected from -halo,' -CN, -NO 2

-N(R

4 2 optionally substituted Ci-. aliphatic group, -OR, -C02R, -CONH(R 4

-N(R

4

)COR,

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

R,

-N (R 6

COCH

2 N R 4 2, -N (R 6

COCH

2

CH

2 N (R 4 or -N (R' COCHaCH 2 CH2NR 4 wherein R is selected from hydrogen, Ci_- 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 HN IN-H IH- -3 IVa-1 I- Va-2 IVa-3 -168- Me HNi IVa-4 Me HN N H IV-NAc IVa -7.

H

N H HN

H

d AC IVa-5 HN IVa-8

HN

S OMe IVa-6 IVa-9 Me HN IVa-

HN

IS OMe IVa-12 IVa-11 In another embodiment, this invention provides a composition comprising a compound of formula IVa and a pharmaceutically acceptable carrier.

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

VO

8 -169c compound of formula Iva or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula SIVa or a pharmaceutical composition thereof.

o One aspect of this invention relates to-a CI 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 is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of 0-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to a method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IVa or a composition comprising said compound.

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

Each of the aforementioned methods directed to the inhibition of Aurora-2 or GSK-3, or the treatment of CD -170- S a disease alleviated thereby, is preferably carried out t with a preferred compound of formula IVa, as described above.

Another embodiment of this invention relates to compounds of formula. IVb:

HN

RXz 2 2

R

y

-R'

IVb or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

I is nitrogen or C-Ra and Z 2 is nitrogen or CH, wherein one of Z l 'or Z 2 is nitrogen; Rx and RY are independently selected from T-R 3 or L-Z-R 3 or Rx and R Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur,.or nitrogen, wherein each substitutable ring carbon of said fused ring. formed by Rx and R Y 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 R Y 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, heterocyclyl' or carbocyclyl, said heteroaryl or heterocyclyl ring having 1-4 ring heteroatoms selected -171from nitrogen, oxygen or sulfur, wherein each substitutable ring carbon of Ring D is independently substituted by oxo, T-R 5 or V-Z-RP, and each 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 C 1 -4 alkylidene chain; Lis -SO2-,

-N(R

6

)S

2

-SO

2

N(R

6

S-N(R

6 -C0 2

-N(R

6 )CO- -N(R)CON(R)

-N(R

6

SO

2 N(Rs) N

-C(R

6 2

-C(R

6 2 s-,

-C(R

6 2 SO-, 2 SO2-,

-C(RS)

2

SO

2 N(R6)

-C(R

6 2

N(R

6 2

N(R

6 2 -C(R 6 2N 21N (R 6

SO

2 N(R6) or -C(R6) N CON(R6) R2 andR are independently selected from -T-W-R or R 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 R2 and R' 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 ahd R 2 is independently substituted by R 4 R is selected from -halo,.-OR,

-CO

2

R,

-COCOR,-COCH

2 COR, -NO 2 -CN,

-S(O)

2 R, -SR.,

-N(R

4 2

-CON(R')

2

-SO

2

N(R

7 2 -N(R 7

)COR,

-N(R

7 )C0 2

(C-

6 aliphatic)

-N(R

4 )N(R4) 2

-C=NN(R')

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

-N(R')SO

2

N(R)

2 -N(R )SO 2 R, or each R is independently selected from hydrogen or an optionally substituted group selected from C -172aliphatic, C 10 aryl, a heteroary ring having 5-20 E ring atoms, or a heterocyciyl ring having 5-10 ring atoms; each R 4 is independently selected from -R 7 -COR7, -CO2 (optionally -substituted C:26,aliphatic),

-CON(R

7 2 c or-SO 2 R7; each R 5 is independently selected from halo, -OR,

-CO

2 R,.-COCR, -No 2 -CN, -SO 2 R, -SR, -N R 4 2

-CQN(R

4 2 -S0 2

N(R

4 2 N(R4)COR,

-N(R

4 C0 2 (optionaliy substituted CI-c aliphatic), -N (R)N(R 4

-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 )S0 2 R, or -OC(=O)N(R 4)2 V is -S02-, -N(R 6 )S0 2

-SO

2 -N(R 6) -C02-, -N (R6) Co-, -N (R6) C 0

-N(R

6 -N(R6)S0 2 N(R) -N(R 6

)N(R

6

-C(O)N(R

6 -OC(o)N(R 6

-C(R

6 2

-CAR

6 2

S-,

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

SO

2

-OCR

6 2 S0 2 N(Rc) -C(R) 2

N(R

6 2

N"(R

6

-C(R

6 2

N(R

6

=NN(R

6

-C(R

6

-C(R

6 2

N(R

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

-C(R

6 2

N(R

6

CON(R

6 W is -C(R 6 2 2

-CO(R

2 so -C(Rc) 2 So 2

S-O(R

6 2 S0 2

N(R

6

-C(R

6 2 -02-,

LC(R

6 C 6 )OC(0)N(R)-1 -C (R 6 2

N(R

6

CO-,

-C(R

6 2

N(R")N(R

6 -C =N( 6 -C J( 6 2

N(R

6 )CoN( 6 or -CON each R 6 is independently selected from hydrogen or an optionally substituted Ca.4 aliphatic group, or two R 6 groups on-the same nitrogen atom are taken together 'with the nitrogen atom to form a 5-6 membered heterocyclyl'or heteroaryl ring; each R iss independently selected from hydrogen or an optionally substituted 01_6 aliphatic group, or two R'

I

O

-173on the same nitrogen are taken together with the nitrogen to form a 5-8 membered heterocycly1 or heteroaryl ring; and (N

R

8 is.selected from halo,--OR,

-CO

2 R, -COCOR,

-NO

2 -CN,

-SO

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

-CON(R

4 2

SO

2

N(R)

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

C

1 aliphatic),

-N(R)N(R)

2

-C=NN(R

4 2 -C=N-OR, -N(R CON(R)2, -N(R4)SO2N(R)2,

-N(R)SO

2 R, or S- R-OOC N Preferred rings formed by RX and RY of formula IVb include a 6 -,or 7-membered unsaturated orpartially unsaturated ring having 0-2 heteroatoms, wherein .said RX/RY ring is optionally substituted. This provides a bicyclic ring system containing a pyrimidine ring. Preferred pyrimidine ring systems of formula IVb are shown below.

R

2 R2' HN

HN'

O>HN z 2z 2 z Z1 at;) SIVb-A IVb-B IVb-c HN? HN'1?

HN>?

z/rf 2 R 11%N z R RN z IVb-D IVb-E IVb- -174vb-J IVb-K IVb-L HN" HN7 HN t Z, (0 zl IVb-P IMb-R IVb-V

HN

'4

R

IVb-W More preferred pyrimidine ring systems of formula IVb include IVb-A, IVb-B, IVb-D, IVb-E, IVb-J, IVb-P,-and IVb-V, most preferably IVb-A, IVb-B, IVb-D, IVb-E, and IVb-J. Even more preferred.pyridine ring systems of formula IVb are those described above, wherein Z' is nitrogen and Z is CH.

Preferred RX groups of formula IVb include hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.

Preferred RY groups of formula IVb include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is or -C(R 6 -CO- and R 3 is'-R, -N (R or -OR. Examples of preferred RY groups include Va o -175- 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl. or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.

o The ring formed when the Rx and RY groups of C 10 formula IVba are taken together may be substituted or unsubstituted. Suitable substituents include halo, -o(CH 2 2 -4-N(R 4 )2 -O (C 2 2-4-R, -OR, -N (R 4

(CH

2 2 4 -N (R 4 2,

-N(R

4

-(CH

2 )2- 4 -CO 2 R, -COCOR, -NO 2

-CN,

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

-SO

2

N(R

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

)CO

2 (optionally substituted

C

1 aliphatic), -N(R')N(Rf) 2

-C=NN(R

4 2

-C=N-OR,

-N CON 2

SO

2 N(R 4 2

-N(R

4

SO

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

-CO

2 R, -CON(R4) 2 -CN, -O(CH 2 2 4 2 -0t(CH 2 2- 4

-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 substituted

C..

6 aliphatic group.

The R. and R2' groups of formula IVb may be taken together to form a fused ring, thus providing a bicyclic ring system containing a pyrazole ring.

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

These-are exemplified in the following formula IVb compounds having a pyrazole-containing bicyclic ring system: o -176- 0

NHN

H N 2tZ NH H

NH

Z2 Z, and Preferred substituents on the R 2

/R

2 fused ring of formula IVb include one or more of the following: -halo,

-N(R

4 2 -Ci-4 alkyl, -C.4 haloalkyl,

-NO

2

-O(C

1 -4 alkyl), -C02(CI.

4 alkyl), -CN, -S0 2

(C

1 4 alkyl),

-SO

2

NH

2 S -OC(O) NH 2

-NH

2

SO

2

(C

1 -4 alkyl), -NHC (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 (C 1 4 alkyl) group is methyl.

Whenthe pyrazole ring system of formula IVb is monocyclic, preferred R 2 groups include-hydrogen or asubstituted or unsubstituted group selected from aryl,.

heteroaryl, or a CaIsaliphatic group. Examples of such preferred R2 groups include hydrogen, methyl, ethyl, propyl,, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl.

A

preferred

R

2 group is hydrogen; When Ring D of formula IVb is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IVb is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl,.isoindolyl, indolinyl, benzolb]furyl, benzo[b]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

-177- On Ring D of formula IVb, preferred

T-R

5 or V-Z-Rs substituents include -halo, -CN,

-NO

2

-N(R

4 2 optionally substituted C-6 aliphatic group, -OR, -C(O)R,

S-CO

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

-N(R

4 C0 2 R, -SO 2

N(R')

2

-N(R

4 S0 2 R,

COCH

2 N 2 COCH 2

CH

2 N(R4) 2 and COCH2CH2CH2N (R) 2 -wherein R is selected from hydrogen, aliphatic, phenyl, a 5-6 membered i heteroaryl ring, or a 5-6 membered heterocyclic ring.

o More preferred

R

5 substituents include -Cl, -Br,

-CN,

Ci 10 -CF3, -COOH, -CONHMe, -CONHEt,

-NH

2 -NHAc, NHS02Me,

-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 (C013)2,

-NHCOCH

2

CH

2 N (CH3)2,

-NHCOCHH

2 C2CH 2 N (CH) 2, -NHCO (cyclopropyl)., -NHCO(isobutyl),

-NHCOCH

2 (morpholin-4yl), -NHCOCH 2

H

2 (morpholin-4-yl),

NHCOCH

2 CH2CH 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, -Q(Cl-4 aliphatic) such as -OMe, C.-4 aliphatic such.as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C-4 aliphatic).

Preferred R6 groups of formula IVb, when Ipresent, include R, OR, and.'N(R 4 2 Examples of preferred

R

8 include methyl, ethyl, NH2, NH2CH 2

CH

2 NH, N (CH3) 2CH2CH 2

NH,

N(CH3) 2 CHCH20, (piperidin-1-yl)CH 2 ,CH20, and NH 2 CH2Cn 2 0.

Preferred formula IVb compounds have one or more, and more preferably all, of the features selected from the. group consisting of: RX is hydrogen, alkyl- or dialkylamino, acetamido, or a C,4 aliphatic group and RY is T-R or L-Z-R 3 wherein T is a valence.bond or a methylene and R 3 is -N(R 4 2 or -OR; or Rx and .RY are taken together with their intervening atoms to- form a fused, unsaturated or partially o -178ci unsaturated, 5-6 metnbered ring having 0-2

C

t heteroatoms selected from oxygen, sul-fur, or Snitrogen, wherein each substitutable ring carbon CI of said fused ring formed by Rx and R 7 is independently substituted by oxo, T-R, or L-Zcq

R

3 and each substitutable ring nitrogen of said Sring formed by Rx and R Y is independently Ci substituted by R4; o R' is T-(Ring wherein T is a valence bond or Ci 10 a methylene unit; Ring D is a 5-7membered monocyclic or an 8-10 membered bicyclic aryl or. heteroaryl ring; and

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 IVb have one or more, and more preferably all, of the features selected from the group consisting of:

R

Y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and- R is selected from '-OR, or -N(R4) 2 wherein R is selected from'hydrogen,

C

1 -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered'heteroaryl;.orR and R

Y

are taken together with their intervening atoms to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein each substitutable ring carbon of said fused ring formed by Rx and R Y 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 R y is independently substituted by R 4 ci ci -179-

R

1 is T-(Ring wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8membered bicyclic aryl or heteroaryl ring;

R

2 is -R and R 2 is hydrogen, wherein R is selected from hydrogen, Ci-, aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring;and

R

3 is selected from -halo, -OR, or wherein R is selected from hydrogen,

CI-_

aliphatic, or-5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or Even more preferred compounds of formula IVb have one or more, and more preferably all, of the features selected from the group consisting of: Rx is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and R Y is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or RX and Ry are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclohexo ring, wherein said ring is optionally substituted with -halo, R, -OR, -COR, -COzR,

-CON(R

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

-NO

2

-N(R

4 2 -NR4COR, -NR 4 SO2R, or -SO 2

N(R

4 2 wherein R is hydrogen or an optionally substituted CI-g aliphatic group;

NO

-180- R is T-(Ring wherein T is a valence bond and t Ring D is a 5-6 membered aryl or heteroaryl ring optionally substituted with one or two groups.

C- selected from -halo, -CN, -NO 2

-NR^

2 optionally substituted CI-6 aliphatic,.-OR, 9* -CO 2 R, -CONH(R 4 -N (R 4 )COR, -N (R CO2R,

-SO

2

N(R

4 2

-N(R

4

)SO

2 R, -N(R 6

)COCH

2

N(R

4 2 N (R COCH 2

CH

2 N (R or -N(R 6

COCH

2

CH

2

CH

2

N(R

4 2; o R 2 is hydrogen or a substituted or unsubstituted C- 10 group selected from aryl, heteroaryl, or. a CI-6 aliphatic group,.and R 2 is hydrogen; and

R

3 is selected from -OR, or -N(R 4 2 wherein R. is selected from hydrogen, CI-6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ring D is substituted by up to three.

substituents selected from -halo, -CN, -NO 2

S-N(R

4 2 optionally substituted Ci-6 aliphatic group, -OR, -CO 2 -CONH(R4), -N(R 4

)COR,

'-N(R C02R, -SO 2

N(R

2

-N(R

4

)SO

2

R,

-N (R 6

COCH

2 N (R 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, Ci- aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.

Representative compounds of formula IVb are shown below in Table -181- Table Me HN<V-p H NN 0c fl'b-1 Me IVb-4

HN

4 IVb-2 HN XH H 0 N jNAc IVb -5

HN

IVb-3 TVb-6 Me HN~iPN H IVb-7 Ivb -8 ivb-9 Me

HNH

IVb-1O IVb-11Ib-1 lVb 12

\O

-182- Me HN 4 HNJJH. HN NH ON m CN QoNj CN tO CN h IVb-13 IVb-14 Me O H C HN<P 0 |N &Oi CN I Vb-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 method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which-method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition thereof.

Another.aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IVb or a composition comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVb or a pharmaceutical composition thereof.

\O

0 -183- CI One aspect of this invention relates to a Smethod of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, Ci which method comprises administering to the patient a therapeutically effective amount of a compound of formula ^q IVb or a pharmaceutical composition thereof. This method Sis especially useful for diabetic patients. Another C method relates to inhibiting the production of O hyperphosphorylated Tau protein, which is useful in C- 10 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 method of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a compound of formula IVb or a composition comprising said compound.

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

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

SAnother embodiment of this invention relates to compounds of formula IVc: -184- CA R2

NH

SRX z C^ RY Z N-R 1 CN H

\O

_IVca Sor a pharmaceutically.acceptable derivative or prodrug eC thereof, wherein:

Z

1 is nitrogen or C-R 8 and Z 2 is nitrogen or CH, wherein one of Z 1 or Z 2 is nitrogen;

R

x and R y are independently selected from T-R 3 or L-Z-R 3 or R x and R Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable-ring carbon of said.fused ring formed by R x and R Y 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 R Y 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, 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 substitutable ring nitrogen of Ring D is independently substituted by -R 4 T is a valence bond or a Ci-4 alkylidene chain; -185- Z is a C 1 4 alkylidene chain; L is -S02-, -N(R)SO2-, -SO2N 6(RG

-CO

2

SO

2 N -N(R6)N(R6)-, 2 2

S-,

2 SO-, 2

SO

2 2

SO

2 2 2 2 2 or -C 2 CON 10 R 2 and R 2 are independently selected from or R 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 R2 and R 2 is independently substituted by halo, oxo, -CN, -NO 2

-R

7 or -V-R t 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 -halo, -OR,

-CO

2

R,

-COCOR,

-COCH

2 COR -NO 2 -CN -S(0)OR, -S(0) 2 R, -SR, -N (R 4 2

-CON(R')

2

-SO

2

N(R')

2 -N(R 7

)COR,

CO

2 6 aliphatic), -N(RN )N(R 4 2

-C=NN(R

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

-N(R

7

SO

2 N (R 7 2

-N(R

4

SO

2 R, or each R is independently selected from hydrogen or an optionally substituted group selected from Cl-.

aliphatic,

C-O

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

-COR

-CO

2 (optionally substituted

C

1 aliphatic),

-CON(R')

2 or -S0 2

R

7 Va 0 ct cIN -186each R5 is independently' selected from halo, -OR,

-CO

2 R, -COCOR, -N0 2 -CN,

-SO

2 R, -SR, -4T(Rt) 2

-CON(R

4 2

-SO

2

N(R

4 2 -N(R 4

)COR,

-N (t C0 2 (optionally substituted

C

1 _6 aliphatic), S -N (R 4

)N(R

4 2 -C=NN (R 4 -C=N-OR, -N(R 4 )CON4(R 4 2 v -N (R 4

SO

2 N (R 4 2 (R4) S0 2 R, or -OC(=O)N(R 4 2 V is

-SO

2

-N(R

6 )S0 2

-SO

2 N.(R 6

-N(R

6 -C0 2 -N(R 6

-N(R

6

)CON(R

6

-N(R

6 )so 2

N(R

6

-N(R

6

)N(R

6

-OC(O)N(R

6 -C(R6) 2

-C(R

6 2 2 S0-, 2

SO

2

-C(R

6 2 S0 2

N(R

6

-C(R

6 2

N(R

5

-C(R

6 2 2

N(R

6

-C(R

6

-C(R

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

N(R

6

SO

2

N(R

6 or

-C(R

6 2

N(R

6 )CON(R6) is w is -C(R 6 2

-C(R

6 2 2 SO-0, 2 S0 2 -C (R 6 2 s0 2 N(R -C(RW) 2

N(R

6 -C027,

-C(R

6

-C(R

6

-C(R

6 2

N(R

6 )C0-, -c (R 6 2 N (R 6

-C(R

6 =NN (R 6

-C(R

6

-C(R

6 2

N(R

6

)N(R

6

-C(R

6 2 N (R 6

SO

2

NCR

6

-C(R

6 2

N(R

6

),CON(R

6 -or.-CON(R6)-; each R6 is independently selected from-hydrogen or an bptionally substituted C1.4 aliphatic group, or two R6 groups on the same nitrogen atom are taken together with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; each R7 is independently selected from hydrogen or an optionally substituted 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; and'.

R

8 is seiected from halo, -OR,

-CO

2 R, -COCOR,

-NO

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

-CON(R

4 2

-SO

2

N(R

4 2

-N(R

4 )COR, -N(R 4 )C02 (optionally O -187- 0 N substituted

C

1 .S aliphatic),

N(R

4 2

-C=NN(R

4 2 -C=N-OR,

-N(R')CON(R)

2

-N(R

4 S02N 2, -N(R 4

SO

2 R, or

-OC(=O)N(R)

2 c Preferred rings formed by RX and RY of formula IVc-include a or 7-membered unsaturated or c partially unsaturated ring having 0-2 heteroatoms, wherein said RX/RY ring is optionally substituted. This 0 provides a bicyclic ring system.containing a pyridine ring.. Preferred pyridine ring systems of formula IV are C- 10 shown below.

R2

'N

R N H H HN'%

HN-

Zl-tN-R 1 zl~rK

H

IVC-A IVc-B

IV-C

HN>1 HN>Z HN>7 2 RJ

K

z Nr ~2i IVc-D IVc-E IVc-F HN>? HN3 HN Iz 2 N N z2 N

ZI

IVc-J. Vc-K IVc-L -188- CA H HN HN? S. Z2 COU z2.Z N Z2 '44 IVc-P IVc-R IVc-V c13 HN IND 2 N

ZL

/4

IVC-W

More preferred pyridine ring'systems of formula IVe include IVc-A, IVe-B, IVc-D, IVc-E, IVd-J, IVc-P, and IVc-V, most preferably IVc-A, IVC-B, IVc-D, IVo-E, and IVc-J. Even more preferred pyridine ring systems of formula 3Vc are those described above, wherein Z' is nitrogen and Z.is CH Preferred RX groups of formula IVc include hydrogen, alkyl- or dialkylamino, acetamido, or a C.4 aliphatic group such as methyl, ethyl, cyclopropyl, or isopropyl.

Preferred RY groups of formula Ivo include T-R3 or L-Z-R' wherein T is a valence bond or a methylene, L is- -CO- and R 3.iS -R, -N(R4)2, or -OR. -Examples of preferred RI.groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy.such as'.' Va o -189cA dimethylaminpropyoxy, acetamido, optionally substituted phenyl such as phenyl or halo-substituted phenyl.

The ring formed when the Rx and RY groups of C- formula IVc are taken together may be substituted or unsubstituted. -Suitable substituents include halo,

S-O(CH

2 2.

4 -N (R 4 2

-O(CH

2 )2- 4 -OR,

(CH

2 2 4 2

-N(R

4

)-(CH

2 2 4 -CO 2 -COCOR,

-NO

2 -C 0

-SO

2 R, -SR, 2

-CON(R')

2

-SO

2

N(R

4 2

-N(R

4 )CR,

-N(R

4 )C0 2 (optionally substituted

C

1 6 S 10 aliphatic).,

-N(R')N(R

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

SO

2 N 2 SO 2 R, or

-OC(=O)N(R

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

-CO

2 R, -CON(R 4 2 -CN, -O(CH2 2 4

-N(R

4

-O(CH

2 2 4

-NO

2

-N(R

4 2 -NRCOR,

-NR

4

SO

2 R, -SO 2 N(R 2 wherein R is hydrogen or an optionally substituted C-6 aliphatic group.

The R2 and R 2 groups of formula IVc may be taken tojether to form a fused ring, thus providing a bicyclic ring-system containing a pyrazole ring.

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

These are exemplified in the following formula IVc compounds having a pyrazole-containing bicyclic'ring system:

NH

RHN N N \N NN

N

z 2 2 NH NH NH

^$NH

N-R' N H ,and -190c- .Preferred substituents on the R 2

/R

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

-C

1 4 alkyl, -CI- 4 haloalkyl,

-NO

2 -O(C.4 C- alkyl), -CO 2

(C

1 -4 alkyl), -CN, -SO 2

(C

1 4 alkyl),? -50 2

NH

2 -OC NH 2

-NH

2 S0 2

(C

1 4 alkyl), -NHC (C 1 4 alkyl) Cg -C NH 2 and -CO (C 1 -4 alkyl) wherein the (C2- 4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, 0 the (C1..

4 alkyl) group is methyl.

When the pyrazole ring system of formula IVc is monocyclic, preferred R 2 groups include hydrogen or a.

substituted or unsubstituted group selected from aryl, heteroaryl,- or a C 16 aliphatic group. Examples of such preferred R 2 groups include H, methyl, dthyl,. propyl, cyclopropyl, i-propyl, cyclopentyl, hydroxypropyl, methoxypropyl, and benzyloxypropyl. A preferred R 2 'group is hydrogen.

When Ring D of formula IVe is monocyclic, preferred Ring D groups include phenyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl.

When Ring D of formula IVce is bicyclic, preferred bicyclic Ring D groups include naphthyl, tetrahydronaphthyl, indanyl, benzimidazolyl, quinolinyl, indolyl, isoindolyl, indolinyl, benzolblfuryl, benzolb]thiophenyl, indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, uinoxazolinyl, 1,8-naphthyridinyl and isoquinolinyl.

On Ring D of formula IVc, preferred T-R 5 or

V-Z-R

5 substituents include -halo, -CN, -NO 2

-N(R

4 2 optionally substituted C 1 -6 aliphatic group, -OR, -C(O)R,

-CO

2 R, -CONH(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 2

-N(R

6

COCH

2

CH

2 N (R 4 2 and

COCH

2

CH

2

CH

2

N(R

4 2 wherein R is selected -from hydrogen, C 1 aliphatic, phenyl, a5-6 membered Cv 0 -191c- heteroaryl ring, or a 5-6 membered heterocyclic ring.

More preferred Rs substituents include -Cl, -Br,

-CN,

-CF

3 -COOH, -CONHMe, -CONHEt,

-NH

2 -NHAc, -NHS02Me, C-i

-NHSO

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

-NHCOCH

2

CH

2

CH

2 N (CM 3 2 -NCO(cyclopropyl), -NHCO(isobutyl),

-NHCOCH

2 (morpholin-4yl), -NHCOCH 2 CH2.(morpholin-4-yl),

-NHCOCH

2

CH

2

CH

2 (morpholincIN 4-yl), -NHCO 2 (t-butyl),

-NH(C

1 4 aliphatic) such as -rNHMe, S 10 4 aliphatic) 2 such as -NMe 2 OH, -O(C.

1 4 aliphatic) such as -OMe, C 1 -4 aliphatic such as methyl, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02-(C.-4 aliphatic).

Preferred

R

8 groups of formula IVc, when present, include R, OR, and N(R 4 2 Examples of preferred

R

8 include methyl, ethyl, NH 2

NH

2

CH

2

CH

2 NH, N(CH 3 2

CH

2

CH

2

NH,

N (C)CH 2 CH20, (piperidin-l-yl)

CH

2

CH

2 0, and NH 2

CH

2

CH

2

O.

Preferred formula. IVe compounds have one or more, and more preferably all, of the features selected from the group consisting of: RX is hydrogen, alkyl- or dialkylamino, acetamidd, or a C.

4 aliphatic group and R. is T-R or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is 2 or -OR; or RX and RY-are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring-formed by RX and RY is independently substituted by oxo, T-R 3 or L-Z- 3R and each substitutable ring nitrogen of said -192ring.formed by Rx and R Y is independently substituted by R 4

R

1 is T-(Ring wherein T is a valence bond or a methylene unit; Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; and

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 IVc have one or more, and more preferably all, of the features selected from the group consisting of:

R

Y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -OR, or -N(R 4 2 wherein R is selected from hydrogen, CC-6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl; or Rx and R y are taken together with their intervening.atoms to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieho, piperidino, or imidazo ring,.

wherein each substitutable ring carbon of said.

fused ring formed by Rx and R Y is independently substituted by dxo, T-R 3 or L-Z-R 3 and each substitutable ring nitrogen of said ring formed by Rx and R 7 is independently substituted by R 4

R

1 is T-(Ring wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8membered bicyclic aryl or heteroaryl ring;

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

IND

O

C

Va -193- R' is selected from -halo, -OR, or wherein R is selected from hydrogen,

C

1 6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or -N(R4)- Even more preferred compounds of formula IVc..

.have one or more, and more preferably all, of the features selected from the group consisting of: RX is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino or acetamido and RY is selected from 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino, alkoxyalkyl,.alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamidd, optionally substituted phenyl, or methoxymethyl; or RX -and R. are taken together with their intervening atoms to form a benzo, pyrido, piperidino, or cyclohexd ring, wherein said ring is optionally substituted With -halo, -OR, -COR, -CO 2

R,

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

-N(R

4 2

-O(CH

2 2 4

-NO

2

-N(R

4 2

-NR

4 COR, -NR 4

SO

2 2R, or -SO 2 N(R 2 wherein R is hydrogen or an optionally substituted

C

1 6 aliphatic group; R3 is T-(Ring 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 optionally substituted

C

1 6 aliphatic,

-OR,

-CO

2 R, -CONH(R 4

-N(R

4 COR,

CO

2

R,

-SO

2

N(R

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

N(R

4 2, -N COCH 2

CH

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

CH

2

CH

2 N (R 4 2 -194- 02 C-I R 2 is hydrogen or a substituted or unsubstituted group selected from aryl, heteroaryl, or a C1-6 Saliphatic group, and R 2 is hydrogen; and c- R 3 is selected from -OR, or -N(R4) 2 wherein R is selected from hydrogen, C 1 -6 aliphatic, 5-6 7C membered heterocyclyl, phenyl, or 5-6 membered Sheteroaryl, and L is or and (C Ring D is substituted by up .to three

\O

o substituents selected from -halo, -CN, -NO 2 C- 10 -N(R 4 optionally substituted Ci-s aliphatic group, -OR, -CO 2 R, -CONH -N(R 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

H

2

CH

2

N(R

4 2 wherein R is selected from hydrogen, CI- aliphatic, phenyl, .a 5-6 membered heteroaryl ring, or a 5-6 membered Sheterocyclic ring.

Representative compounds of formula IVc are shown below in Table 11.

Table 11.

Me HN- HN 4 .N HNH H >N N S O Me H H H H IVc-1 IVc-2 IVc-3

VO

kO

<D

0 0

D

ci ci ci

O

ci Va ci -195- IVc-4 Me HN N H H

H

VHNc-1

HN

SHN

H

H

IVc 5

HN

HN

IVc-11 IVc-11 IVc-6 IVc-9

HN

H H IVc-12 In another embodiment, this invention provides a composition comprising a compound of formula IVc and a pharmaceutically acceptable carrier.

Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 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.

Another aspect of this invention relates to a method of inhibiting Aurora-2 activity in a patient, -196- C which method comprises administering to the patient a Scompound of formula IVc or a composition comprising said Scompound.

S..Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease C with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a 0 therapeutically effective amount-of a compound of formula cO o IVc or a pharmaceutical composition thereof.

Cq 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 IVc or-a pharmaceutical composition thereof. .This method is especially useful for diabetic patients. Another method relates to inhibiting the production of hyperphosphorylated Tau protein, which is useful in halting or slowing the progression of Alzheimer's disease. Another method relates to inhibiting the phosphorylation of p-catenin, which is useful for treating schizophrenia.

Another aspect of this invention relates to amethod of inhibiting GSK-3 activity in a patient, which method comprises administering to the patient a.compound of formula IVc or a composition comprising said compound.

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

VO

o -197- (c Each of the aforementioned methods directed to t the inhibition of Aurora-2 or GSK-3, 'r the treatment of a disease alleviated thereby, is preferably carried out C( with a preferred compound of formula IVc, as described above.

Ce Another embodiment of this invention relates to Scompounds of formula IVd:

O

(N

D R 2 HN NH Ry Z1 Q'-R' IVd or a pharmaceutically acceptable derivative or prodrug thereof, wherein:

Z

1 is nitrogen or C-R 8 and Z 2 is nitrogen or CH, wherein one. of Z 1 or Z 2 is nitrogen; Q' is selected from -C(R6') 2 ,2-cyclopropanediyl, 1,2cyclobutanediyl,- or 1,3-.cyclobutanediyl;

R

x and R y are independently selected from T-R 3 or L-Z-R 3 or RX and R Y are taken together with their intervening atoms to form.a fused, unsaturated or partially unsaturated, 5-7 membered ring having 0-3 ring heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring carbon of said fused ring formed by R" and R Y 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 substituted by R4;

SR

1 is T-(Ring D); -198- 0 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 cheterocyclyl ring having 1-4 ring heteroatoms selected from nitrogen, -oxygen-or sulfur, wherein each Ssubstitutable ring carbon of Ring' Dis independently substituted by oxo, T-R, or V-Z-R 5 and each 0 substitutable ring nitrogen of Ring D is independently ci o substituted by -R T is a valence bond or a C1.4 alkylidene chain, wherein when Q' is -C(R 6 2 a methylene group of said C..4 alkylidene chain is optionally replaced by -CONH-, -NHCO-, -SO 2

-SO

2 NH-, -NHSO 2 -CO2-, -OC(0)NH-, or -NHC02-; Z is a C1.4 alkylidene chain; L is -SO2-, -N(R 6

)SO

2

-SO

2

N(R

6

-N(R

6

-N(R

6

-N.(R)CON(R

6

-N(R')SO

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

-C(R

6 2SO-, 2S2-, -C(R 6 2 sbN(R 6

-C(R

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

N(R

6 C -C(R 6 =NN

-C(RS)

2 N(R6)N(R) 2 N(R)SO2N(R')-, or -C 2 N(R) CON(R)

R

2 and R 2 are independently selected.from

-T-W-R

6 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 selected from nitrogen, oxygen, or sulfur, wherein each substitutable ring carbon of said fused ring formed by R and.R 2 is independently substituted by halo, oxo, -CN, -NO2, -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 Va -199-

R

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

R,

-COCOR, -COCH 2 COR, -NO 2 -ON,

-S(O)

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

-CON(R')

2 -S0 2 N(R 7 2 OC(=O)FR -N(R7)CQR, Ci

-N(F

7

)CO

2

(CI-

6 aliphatic), -N(R4)N.(R 4 2 -C=NN(R4) 2 -0=N-OR, -N(R 7 )CON(R7) 2

-N(R

7 *)S0 2 N(R 7 2

-N(R

4 )S0 2 R, or c~ -oC(=O)N(R7) 2; each R is independently selected from hydrogen or an Ci optionally substituted group selected from C-6 o aliphatic, C65-lo aryl, a heteroaryl ring having 5-10 Ci .10 ring atoms, or a heterocyclyl ring having 5-1b ring atoms; each R 4 is independently selected from -R7, -COR 7 -C02(optionally substituted 01-6 aliphatic),

-CON(R

7 2 .7 or -S0 2

R;

each F.9 is independently selected from halo, -OR, -C0 2 R, -COCOR, -NO 2 -CN, -S0 2 R, -SR, 2

-CON(R)

2

-SO

2

N(R.)

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

)COR,

C02(optionally substituted CI-6 aliphatic),

-N(R)N(R

4 2

-C=NN(R)

2

-N(R

4

)CON(R

4 2

-NAR

4 )S0 2 N(a 4 2

-N(R

4

)SO

2 R, or -OC(=OR 4)2; V is -S-SO -SO 2

-N(R

6

-SO

2

-N(R

6 -C0 2

-NCR

6 -N (R 6

-N(R

6

)CON(F

6 -N(RtiS0 2

N(R

6

-N(R

6

)N(R

6

-OC(O)N(R

6 2

-C(R

6 2 s-,

'-C(R

6 2SO-, -C(R 6 2SO2-, -C(R 6 2 S0 2 N -C(R6) 2

N(R

6 -C (R 6 2 N C C(Rr) 2 N C0 -C (R 6 =NN (R 6 )-1

-(R

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

SO,

2 or -C 2 N (R6) CON(R) W is 2 -C(Rh) 2 -C(R6) 2 SO1 -C(R 6 )2SO2r,

-C(R

6 2 S0 2 2 -002-, 2

N(R')CO-,

2

N(F.

6 -0(R 6 -0(R 6 ND -200-.

C -C (R 6 2 N(R)N(R6 -C(R 6 2N(R 6 SON -C (R6) 2 N (R CON(R6)-, or -CON(R 6 C each R 6 is independently selected from hydrogen or an Cq optionally substituted Ci.

4 aliphatic group, or two R 6 groups on the same nitrogen atom are taken together C with the nitrogen atom to form a 5-6 membered heterocyclyl or heteroaryl ring; 0( each R 6 is independently selected from hydrogen or a Ci-1 D aliphatic group, or two R 6 on the same carbon atom are 10 taken together to form a 3-6 membered carbocyclic ring; each R 7 is independently selected from hydrogen or an optionally substituted Ci._ 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; and

R

8 is selected from halo, -OR,

-CO

2 R, -COCOR,

-NO

2 -CN, -SO2R, -SR, -N(R 4 2

-CON(R

4 2

-SO

2

N(R

4 2 N COR, -N CR -N(R 4 C02(optionally substituted

.C

1 -6 aliphatic),

-N(R

4

)N(R

4

-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 (=O)N(R 4 2 Preferred rings formed by. R a&nd R' of formula IVd include a or 7-membered unsaturated or partially unsaturated ring having 0-2 heteroatoms, wherein said RX/Ry ring is optionally substituted. This provides a bicyclic ring system containing a pyridine ring. Preferred pyridine ring systems of formula IVa are shown below.

Va 0 0 ci ci -201- HN t ZtCH 2

R

IVd-A HN3 IVd-B IVd- C IVd -D I1Vd- E ZVd -F ivd-j IVd-K HN>7 IVd-R.

IVd-L IIVd- P IVd-V HN3 R IVd-w -202- CA More preferred pyridine ring systems of formula t 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 C IVd-J... Even more preferred pyridine.ring systems of formula IVd include those described above, wherein'Z" is nitrogen and Z 2 is CH.

Preferred RX groups of formula IVd include 0 hydrogen, alkyl- or dialkylamino, acetamido, or a C1-4 ci o aliphatic group such as methyl, ethyl, cyclopropyl, or C 10 isopropyl.

Preferred RY groups of formula IVd include T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene, L is -0 or -N(R 4 2 -CO- and R 3 is--R, -N(R4)2, or -OR. Examples of preferred RY groups include 2-pyridyl, 4-pyridyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, methyl, ethyl, cyclopropyl, isopropyl, t-butyl, alkoxyalkylamino such as methoxyethylamino, alkoxyalkyl such as methoxymethyl or methoxyethyl, -alkyl- or dialkylamino such as ethylamino or dimethylamino, alkyl- or dialkylaminoalkoxy such.as dimethylaminopropyloxy, acetamido, optionally substituted phenyl such as'phenyl or halo-substituted phenyl.

The ring formed when the RX and R groups of formula IVd are taken together may be substituted or unsubstituted. Suitable substituents include halo, -0 (CH 2 2 4 -N(Rt) 2

-O(CH

2 2 4 -OR, -N(R 4

(CH

2 2-4-N(R 4 2

-N(R)-(CH

2 2 -CR, -COCOR, -NO 2

-CN,

-SO

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

-CON(R

4 2

-SO

2

N(R

4 2

-N(R

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

)N(R

4 2, -C=NN(R 4 2

-C=N-OR,

-N(RCON(R 4 2

-NR

4

)SO

2 N(R 4 2

N(R

4 )S0 2 R, or

-OC(=O)N(R

4 2 R andR 4 are as defined above. Preferred RX/RY ring substituents include -halo, -OR, -COR,

VO

0 -203- CO2R, -CON(R 2, -CN, -O(CH 2 2 4 -N (R 4 2 -0 (CH 2 -NO 2

-N(R

2

-NR

4 COR, -NR 4

SO

2 R, -SO 2

N(R

4 2 wherein R is hydrogen or an optionally substituted C- 6 aliphatic group.

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

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

VO

o These. are exemplified in the following formula IVd C 10 compounds having a pyrazole-containing bicyclic ring system: NHN N N N ZH NH NH tNH R Z O-R 2N 'N 'N

'N

Z t 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 -CI-4 alkyl, -CI-4 haloalkyl, -NO2, -O(Ci-4 alkyl), -C alky) -S02 (C-4 alkyl) -SO 2

NH

2 S-OC(0)NH 2

-NH

2 SO (CI-4 alkyl), -NHC (CI 4 alkyl),

-C(O)NH

2 and -CO(C- 4 alkyl), wherein the (CI-4 alkyl) is a straight, branched, or cyclic alkyl group. Preferably, the .(Cz-4 alkyl) group is methyl.

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- aliphatic group. Examples of such preferred R 2 groups include H, methyl, ethyl, propyl, cycloprpyl, i-propyl, cyclopentyl, hydroxypropyl, IND 204c-I methoxypropyl, and benzyloxypropyl. A preferred group Ct is hydrogen.

When Ring D of formula IVd is monocyclic, c-i Preferred Ring D groups include phenyl, pyridyl, Spyridazinyl, -pyrimidinyl, and pytazinyl.

When Ring D of formula 1Wd is bicyclic, preferred bicyclic Ring D groups include naphthyl, 0 tetrahydronapithyl, indanyl, benzimidazolyl, quinolinyl; o indolyl,,isoindolyl, indolinyl, benzotblfuryl, benzofbjIthiophenyl,' indazolyl, benzothiazolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxazolinyl, 1,8-niaphthyridinyl and isoquinolinyl.

On Ring D of f ormula IVd, preferred T-R 5 or

V-Z-R-

5 substituents include,-halo, -ON, -NO 2

-N(R

4 2 optionally substituted 0 1G6 aliphatic group, -OR,

-CO

2 R, -CONR(R 4 -N (R 4 COR, -N (R 4 )C0 2 R, -SO 2 N (R 4) 2 -N (R 4 S0 2 R, -N (R6) COCH 2 N (R 4 2 -N (R 6

CQCH

2

CH

2 N (R 4 2 and -N (RI) CCH 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.

More preferred R 5 substituents include -Cl, -Br, -OCN, -Cr 3 -00011, -CONHMe, -CONREt, -NH 2 -NHAc, -NkSO 2 Me, -NHS0 2 Et, -NHSO 2 (n-propyl),

-NHSO

2 (isopropyl), -NECOEtI

-NRCOCH

2

NHCR

3

-NECOCH

2 N (CO 2 ft -Bu) CH3, 4JRCOCR 2 N (CE 3 2

-NUCOCH

2

CE

2 N (CH) -NHCOCH 2

CH

2

CE

2 N (013) 2, -NHCO (cyclopropyl), -NECO (isobutyl), -NTECOCH 2 (morpholin-4-'

-NHCOCH

2

CR

2 (morholi:'n-4-yl),

-NECOCH

2

CE

2

CH

2 (mtpholin- 4-yl), -NHCO 2 (t-buty:l), -NI{(c 14 aliphatic) such as -NHMe,

-N(C

1 4 aliphatic) 2 such-as -Nile 2 OH,--O(Cl..4 aliphatic) such as -OMe;'C..

4 aliphatic such as meth-ki, ethyl, cyclopropyl, isopropyl, or t-butyl, and -C02(C..4 aliphatic).

I0 -205- C- Preferred R 8 groups of formula IVd, when t present, include R, OR, and N(R4) 2 Examples of preferred S R a include methyl, ethyl,

NH

2 NH2CH 2 CH2NH,

N(CH

3 2

CH

2

CHNH,

C N(CH 3

CH

2

CH

2 0, (piperidin-i-yl)

CH

2

CH

2 O, and NH2CH 2

CH

2 0.

Preferred groupsof-formula IVd include C or 1 2 -cyclopropanediyl, wherein each R 6 is C independently selected from hydrogen or methyl. A more 0 -preferred Q' group is -CHi-.

o Preferred formula IVd compounds have one or Cq 10 more, and more preferably all, of the.features selected from the group consisting of: RX is hydrogen, alkyl- or dialkylamino, acetamido, or a Cl-4 aliphatic group and R y is

T-R

3 or L-Z-R 3 wherein T is a.valence bond or a methylene and R 3 is -N(R 4 2 or -OR; or R x and RY are taken together with their intervening atoms to form a fused, unsaturated-or partially unsaturated, 5-6 membered ring having 0-2 heteroatoms selected from oxygen, sulfur, or nitrogen, wherein each substitutable ring'carbon of said fused ring formed by Rx and R y is independently substituted by oxo,'T-R 3 or L-Z- R and each substitutable ring nitrogen of said ring formed by RX and Ry is independently substituted by R 4

R

I is T-(Ring wherein T is a.valence bond or a methylee .unit and wherein said methylene unit is optionally replaced by or Ring D is a 5-7 membered monocyclic or an 8-10 .membered bicyclic aryl or heteroaryl ring; and

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 Ssubstituted benzo ring.

IND -206- Ce More preferred compounds of formula IVd have Sone or more, and more preferably all, of the features selected from the group consisting of:

R

Y is T-R 3 or L-Z-R 3 wherein T is a valence bond or a methylene and R 3 is selected from -OR, or -N(R 4 2 wherein R is selected from hydrogen, i CI- 6 aliphatic, or 5-6 membered heterocyclyl, Sphenyl, or 5-6 membered heteroaryl; or R x and R y cO oN are taken together with their intervening atoms 0 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 R X and R Y is independently substituted by oxo, T-R 3 or L-Z-R 3 and each substitutable ring nitrogen of said ring formed' by R x and R y is independently substituted by R 4

R

1 is T-(Ring wherein T is a valence bond, and Ring D is a 5-6 membered monocyclic or an 8membered bicyclic aryl or heteroaryl ring;

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;

R

3 is selected from -halo, -OR, or -N(R4) 2 wherein R is selected from hydrogen, Ci-, aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or -N(R 4 and Q' is 2 or 1,2-cyclopropanediyl, wherein each R 6 is independently selected from hydrogen or methyl.

-207c- Even more preferred compounds of formula IVd have one or more, and more preferably all, of the features selected from the group consisting of: c- RX is hydrogen methyl, ethyl, propyl, cyclopropyl, isopropyl, methylamino -or acetamido and RI isselected from 2-pyridyl, 4-pyridy1, pyrrolidinyl, piperidinyl, morpholinyl, C piperazinyl, methyl, ethyl, cyclopropyl, C isopropyl, t-butyl, alkoxyalkylamino, C- 10 alkoxyaikyl, alkyl- or dialkylamino, alkyl- or dialkylaminoalkoxy, acetamido, optionally substituted phenyl, or methoxymethyl; or RX and RY are taken together.with their intervening atoms to form a benzo, pyrido, piperidino, or .cyclohexo ring, wherein said ring is optionally substituted with -halo, -OR, -COR, -c02R, -CON (R 4 2 -CN, -O(CH 2 )2- 4 R 4 2, -O (CH 2 2 4

-NO

2

-N(R

4 2

-NR

4 COR, -NR 4

SO

2 R, or -SO 2

N(R

4 2 wherein R is hydrogen or an optionally substituted

C

1 6 aliphatic group; R' is T-(Ring 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 optionally substituted C 1 -6 aliphatic, -OR,

-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 COCH 2

CH

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

CH

2

C

2 N 2;

R

2 is hydrogen or a substituted or Unsubstituted group selected from aryl, heteroaryl, or a C 16 aliphatic group, and is hydrogen; and R' is selected from -OR, or--N(R 4 2 wherein .R is selected from hydrogen, C 1 aliphatic, 5-6 ND -208- 0 0g membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or -NH-; Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2

-N(R)

2 optionally substitutedC3-s aliphatic group, -OR, -CO 2 R, -CONH(R 4

COR,

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

N(R

4 2

-N(R

4

)SO

2

R,

-N COCH 2 N (R 4 2

COCH

2

CH

2

N(R

4 2, or -N COCH 2

CH

2

CH

2 N (R 2 wherein R is selected 0 from hydrogen, C 1 aliphatic,phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered' heterocyclic ring; and Q' is Representative compounds of -formula-Ivd are shown below in Table 12.

Table 12.' H tVHH

HN

4 HN HNr IVd-1 IVd-2 IVd-3 Me Me Me HN H HNt H HN JPH IVd-4 IVd-5 IVd-6 S-209- C Me Me J H H HNN HN#N SNOMe N OMe IVd-7 t-Vd -8 Inanother embodiment, this invention provides C] a composition comprising a compound of formula IVd and a pharmaceutically acceptable carrier.

C] Another aspect of this invention relates to a method of treating or preventing an Aurora-2-mediated disease with an Aurora-2 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition thereof.

Another aspect.of this invention relates to a method of inhibiting Aurora-2 activity in a patient, which method comprises administering to the patient a compound of formula IVd or a composition.comprising said compound.

Another aspect of this invention relates to a method of treating or preventing a GSK-3-mediated disease with a GSK-3 inhibitor, which method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition thereof.

One aspect of this invention relates to a method of enhancing glycogen synthesis and/or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to the patient a therapeutically effective amount of a compound of formula IVd or a pharmaceutical composition thereof. This method -210- C is especially useful for diabetic patients. Another cmethod relates to inhibiting the production of G hyperphosphorylated Tau protein,- which is useful in C- halting or slowing the .progression'of Alzheimer's disease. Another method relates to inhibiting the Cq phosphorylation of p-catenin, which is useful for -treating schizophrenia.

C- Another aspect of this invention relates to a

VO

o method of inhibiting GSK-3 activity in a patient, which CO 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 .Aurora-2 or GSK-3 inhibitor of formula IVd, or a pharmaceutical composition thereof, in an amount effective to inhibit Aurora-2 or GSK-3.

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

.The compounds of this .invention may be prepared in general by methods known to those skilled in the art for analogous compounds, as illustrated by the general Schemes I-VII, the general-methods that follow, and by the preparative examples below.

.0 -211- C Scheme I .R2 R2 Cl

R

2 H R l R H Rx

RX

N

RYN R CI HaN R NC RY' NIQ-R 1 2 3

II

O Reagents: EtOH, Et 3 N, room temperature; R -QH (Q O S, NH or O) or R -CH2-M/catalyst (M is Al or Mg or Sn, catalyst =Pdo or Ni°) Scheme I above shows a general route for the preparation of the present compounds. The dichlorinated starting material 1 may be prepared using methods similar to the those reported in J. Indian. Chem. Soc.,.61, 690- 693 (1984) or in J. Med. Chem., 37, 3828-3833 (1994).

The reaction of 1 with aminopyrazole (or aminoindazole) 2 in a manner as described in Bioorg. Med. Chem. Lett, 11, 1175-1180, (2000) or in'J. Het: Chem, 21, 1161-1167, (1984) provides the versatile monochloro intermediate 3.

Conditions for displacing the chloro group of 3 by R -Q will .depend on the nature of the Q linker moiety and are generally known in the field. See, for example, J. Med.

Chem, 38, 14, 2763-2773, (1995) (where Q is an N-Link), or Chem. Pharm. Bull., 40, 1, 227-229, (1992) (S-Link), or J. Het. Chem., 21, 1161-1167, (1984) (O-Link) or Bioorg. Med. Chem. Lett, 8,.20, 2891-2896, (1998) (C- Link).

M\ -212- C0 Scheme II

R

2

R

2 OH CI R2 NH IN

.R

x H N a NR H H b R x

R

Y

N'R

1

R

Y

N R1Q-R H 2

R

Y

N'Q-R

1 .4 5 2 II \0 Reagents: POC13, Pr 3 N, 1100C; EtOH, Et 3 N, room o temperature.

Scheme II above shows an alternative route for the preparation of the present compounds. The starting material 4 may be prepared in a manner similar to that described for analogous compounds. See Chem. Heterocycl.

Compd., 35, 7, 818-820;.(1999) (where Q is an N-Link), Indian J. Chem. Sect. B, 22, 1, 37-42 (1983) (N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (O-Link), J. Med.

Chem., 23, 8, 913-918 (1980) (S-Link), or Pharmazie, 43, 7, 475-476 (1988) (C-Link). The chlorination of 4 provides intermediate 5. See J. Med. Chem., 43, 22, 4288-4312 (2000) (Q is an N-Link), Pestic. Sci, 47, 2, 103-114 (1996) (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 intermediate 5 with aminopyrazole (or aminoindazole) 2 to provide compounds of this invention may be performed according to known methods for analogous compounds. See J. Med. Chem., 38, 14, 2763-2773 (1995) (where Q is an N- Link), Bioorg. Med. Chem. Lett., 7, 4, 421-424 (1997) (0- Link), Bioorg. Med. Chem. Lett., 10, 8, 703-706 (2000) (S-Link), or J. Med. Chem., 41, 21, 4021-4035 (1998) (C- Link).

NO

-213- CA Scheme III R2

R

(N R2 SOH Cl R2 2

H

N N H b R x tfN RYN S-Me RN S-Me H 2 b R SR' N S-Me S6 7 2 8 c 8 9 II Oxone; (d) RI-QH (Q S, NH or O) or R -CH2-M/catalyst

(M

is Al or Mg or Sn catalyst =-Pd or NiO Scheme III above shows another alternative route for preparing the present compounds. The starting Displacement of the 4-chloro group in 7 with aminopyrazole (or aminoindazole) 2 gives intermediate 8 which, upon oxidation .of the methylsulfanyl group, provides the methylsulfone 9. The methylsulfonyl group of 9-may be displaced readily with R'-QH to give the desired product I. See J. Am. Chem. Soc., 81, 5997-6006 (1959) (where Q is an N-Link)or in Bioorg. Med. Chem.

Lett., 10, 8, 821-826 (2000) Link).

Io -214- 0 Scheme IV 2 R2

R

SOH C R 2

NH

Rx N Rx R b HN 1 -I N Rx~' -HO NS-Me CI N SMe H rN N AN y CI N S-Me 11 2 12 cO 2' R 2 2 2 C d H e Rx Rx N Rx RY -Me R N SMe N 0-Re 13 14 II Reagents: (a).POC13; EtOH, Et 3 N, room temperature; (c) RY-H (R S, NH or' oxone; R'-QH (Q S, NH or O) or R -CH 2 -M/catalyst (M is Al or Mg or-Sn, catalyst Pdo or Nio) Scheme IV above shows a ,general route for the preparation of the present compounds wherein' R is a group attached to the pyrimidine core via a nitrogen, oxygen or sulfur heteroatom. The starting 4,6-dihydroxy-2methylsulfanylpyrimidine 10 may be prepared' as described in J. Med. Chem., 27, 12, 1621-1629 (1984). The chloro groups of intermediate 11 may be displaced sequentially with aminopyrazole (or aminoindazole) 2 and then with another amine (or alcohol or thiol) following procedures similar to those.reported in Us Patent 258590.6 (ICI, 1949). The methylsulfanyl. group of 13 may then be oxidized to provide the methylsulfone 14. Displacement of the methylsulfonyl -group of 14 gives. the desired product II..

-215- Scheme V R2

R

2 ci ci 0 c-i

O

O

Va 0 0 rcl Cl RY NCI 15

CI

17 R2 R 2

F

H

2 2

R

2 R2

IV

R 2 HNjN

R

Y

Q-R'

IV

R

2

HN"NH

RX 1 18 18 Scheme V above shows general routes for the preparation of compounds of formulae IVa, IVb, IVc, and IVd. Steps and are analogous to the corresponding steps described in Scheme I above. See Indian J. Chem. Sect. B, 34, 9, 1995, 778-790; J. Chem.

Soc., 1947, 899-905; J. Chem. Soc., 34, 9, 1948, 777-782; and Indian J. Chem., 1967, 467-470.

The synthetic transformations shown in Schemes I-IV above are further illustrated by the following methods.

Scheme VI R I N a R 6

R

6 RF1 b

CI

AlI Me"&

NH

2

RA

6

R

6 R11

NH

2

NH

19 IND -216- C Scheme VI above shows a general route for ct preparing the aryl guanidine intermediate used to prepare compounds where Q is -C(R 6 2 The mono- or bis- Cq alkylation of 19 at step to prepare compound 20 can be achieved by using methods substantially similar to C those described by Jeffery, J. et al, J. Chem Soc, SPerkin Trans 1, 1996 (21) 2583-2589; Gnecco, et al, C Org Prep Proced Int, 1996, 28 478-480; Fedorynski, I0N o M. and Jonczyk, Org Prep Proced Int, 1995, 27 CO 10 355-359; Suzuki, S, et al, Can J Chem, 1994, 71 357- 361; and Prasad, et al, J Org Chem, 1991, 7188- 7190. The method of step to prepare compound 21 from compound 20 can be achieved by using methods substantially similar to those described by Moss, et al, Tetrahedron Lett, 1995, 8761-8764 and Garigipati, Tetrahedron Lett, 1990, 1969-1972.

The aryl guanidine intermediates prepared according to Scheme VI may then be used to prepare the compounds of this invention by the methods described in the above Schemes I-V and by methods known to one skilled in the art.

Scheme VII 0 0 SC a b

NH

2 c2 b 22 23 24 0 C C 26 Scheme VII above shows a general method that may be used to prepare compounds of formula II wherein Q 0 -217- C- is 1, 2 -cyclopropanediyl. Compound 26 may then be used to t prepare the desired amino-pyrazole compounds using the methods described above at Scheme I step C- .Method A. To a solution of 2,4dichloroquinazoline (12.69g, 63mmol) and .C (methylpyrazole (6.18g,'63mmol) in ethanol (220mL) is added triethylamine (8.13mL, 63mmol) and the reaction 0C mixture is stirred for 3 hours at room temperature. The D pale yellow precipitate is then collected by filtration, C- 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 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). K 2 C0 3 (83 mg, 0.6 mmol) is added and the suspension is stirred for 2h at room temperature.

The solid that forms is collected and dried under vacuum to give the product [2-(3-chlorophenylamino)-quinazolin- SI 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method B. Sodium hydride (45 mg, 1.12-mmol) in THF (2 mL) is treated with 3-methoxyphenol (0.94g, 7.6 mmol) and the reaction mixture is stirred until effervescence ceases. The THF is removed in vacuo and the above-prepared 2 2H-pyrazol-3-yl)-amine (150 mg, 0.51 mmol)) is added.

The reaction mixture is stirred at 100°C for 20 h, then poured into aqueous K 2 C0 3 and stirred for 2h at room temperature. The solid that forms is.collected and recrystallized from ethanol to give the product -218methoxyphenoxy)-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3yl)-amine.

Method C. To a solution of 4-hydroxy-2phenoxymethylquinazoline (2 g, 7.93 mmol) in phosphorus oxychloride (10mL) is added *tripropylamine (3.02 mL, 15.8 C mmol) and the reaction mixture is heated for 30 minutes S at 1100C. The excess phosphorus oxychloride is C evaporated in vacuo, the residue is poured on ice cold Va q aqueous NaHCO 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 4chloro-2-phenoxymethylquinazoline.

To a solution of the above 4-chloro-2phenoxymethylquinazoline (0.5 g, 1. 85, mmol) in THF 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 dried under vacuum to give (5-cCyclopropyl-2H-pyrazol-3yl)-(2-phenoxymethyl-quinazolin-4-yl)-amine.

Method D. To a solution of the above-prepared (2-chloroquinazolin-4-yl) -(5-cyclopropyl-2H-pyrazol-3yl)-amine (123 mg, 0.43 mmol) in THF (5 mL) is added NiCl2(dppp) (12.mg, 2:1.10- 5 mol), .followed by 1M benzylmagnesium chloride in THF (2.15 mL, 2.15. mmol).

The solution is heated at 500C for.20 hours and the reaction mixture is then quenched with aqueous NH 4 Cl and the product extracted in ethyl acetate. The solvent is evaporated and the residue purified by flash chromatography to yield the desired (2-benzyl-quinazolin- 4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine.

o -219ci Method E. A solution of (2-chloroquinazoljn-4 Ct Yl)-(s-methyl-2H-pyrazo1-3-yl)-amine (200 mg, 0.77 mmol) and"4-acetamidothiophenot (644 mg, 3.85 mmol) is ref luxed ci in tert-butanol (3 niL) over a 20 hour period.

Diethylether- (20 niL) is added t-o the mixture and a solid forms that is collected by filtration. This solid is cisuspended in EtOH/H 2 o lm.L/3mL) then .K 2 00 3 (110 nig, 0. 8 cimiol) is added and the'sseso is sredf 2h a oroom temperature. A'solid forms and is collected and 'dried under vacuum to give the product acetamidophenylsulfanyl) -quinazolin-4-.yl] -(5-methyl-2x-' *pyrazol-3-yl),-amine..

Method F. To a-solution of 2,4-dichioro-- 7 ,B-tetrahydroquinazoljne (500 mg, 2.46 mmol) and 3amino-s-cyclopropylpyrazole (303 mg, 2.46 nimol) in DMF *(l0mL) is added triethylamine (0.357 mL, 2.56 mnnol) followed by sodium iodide. (368 mg,-2.46 nunol) and the *reaction mixture is heated at 90 0 C for 20 hi. Thereaction mixture is partitioned between ethyl acetate and 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/Acost gradient) to give (2-chloro-5, 6,7, a-tetrahydroquinazolin.

4-yl) -(S-cyclopropyl-2H-pyraz'ol.3.-yl)-amine.' The above-prepared (2-chloro--5,G,7,atetrahydrouinazolin.4yl) -(5-cyclopropy1-2-pyrao...> yl) -amine is reacted with 2-naphthajlene mercaptan as described inMethod L to yield the desired cyclopr opyl-2H-pyrazol.3.yl) (naphthalen-2- *ylsulfanyl) 7 ,B-tetrahydro'qinazolin-4yl] -amine.

Method G. A solution of. (S-cyclopropy- 2H pyrazol-3-yl)- 3 -methoxycarbonylpulenylsulfanyl) quinazolin-4 -yl) -amine (110,mg, 0. 26. mmol) in a mixture -220- Ci of THF/water 10 mL) is treated with 1M LiOH (0.75 SmL, 0.75 mmol). The mixture is stirred for 20 houts at Sroom temperature and then neutralized with 1M HC1 (0.75 C-q mL, 0.75 mmol). A solid forms-and is collected by filtration to afford the desired C carboxyphenylsulfanyl) -quinazolin-4-yl] c-i' 2H-pyrazol-3-yl) -amine.

C- Method H. A solution of o acetamidophenylsulfanyl)-7-methoxy-quinazolin-4-yl] Ci 10 methyl-2H-pyrazol-3-yl)-amine (23 mg, 5.54.10 5 mol) in dichloroethane (3 mL) is treated with 1M BBr 3 in dichloromethane (222 [li, 2.21.10.

4 mol),. The mixture os heated at .80 °C for 4 hours before IM BBr 3 in DCM (222 JgL, 2.21.10- 4 mol) is added. The reaction mixture is heated at 80 OC 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. 1M HC1(2 mL) is added to the solid residue and the suspension stirred at room temperature for 15 hours. The solid is collected by filtration and suspended in a mixture water/EtOH 8 mL). The mixture is neutralized with NaHC0 3 and stirred for 2 hours at room temperature. The solid is then collected by filtration, rinsed with water and diethyl ether to give the desired [2-(4-acetamidophenylsulfanyl)- 7-hydroxy-quinazolin-4-yl] (S-methyl-2Hpyrazol-3-yl)amine.

Method I. To a solution'of acetamidophenylsulfanyl)-7-hydroxy-quinazolin-4-yl]-(5- -methyl-2H-pyrazol-3-yl)-amine (32.mg, 7.87.10s mol) in DMF (1 mL) is added potassium carbonate (65 mg, 4.72.10-4 mol) and the reaction mixture is heated to 80 N-(3- -221chloropropyl)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 to afford the desired [2-(4-acetamidophenylsulfanyl)-7- (3-morpholin-4-yl-propoxy)-quinazolin-4-yl]-(5-methyl-2Hpyrazol-3-yl)-amine.

Method J. To a solution of [2-(4-acetamidophenylsulfnyl)-7-nitroquinazolin-4-yl]-(5-methyi-2Hpyrazol-3-yl)-amine (147 mg, 3.38.10-4 mol) in methanol mL) is added Pd/C 10% (40 mg) and the reaction mixture is treated with hydrogen at balloon pressure at 45. OC for hours. The catalyst is filtered through a pad of celite which is then washed .with dilute HC1. the combined yellow filtrate is evaporated and the resulting solid residue is crystallized from methanol to afford the desired 4 -acetamido-phenylsuifanyl)-7hydroxyaminoquinazolin-4-yl] (5S-methyl-2H-pyrazol-3-yl)amine.

Method K. [2-(4-Acetamido-phenylsuilfanyl) -7nitroquinazolin-4-yl-(5-methyl-2H-pyrazol-3-yl)-amine (182 mg, 4.18.10 mol) is dissilved in a mixture EtOH/water/AcOH (25/10/1, 36 mL) and the reaction is heated at 90 OC. .Iron powder (93 mg) is added and the mixture is stirred at 90 oC for 4 hours 1 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 desired [2-(4-acetamido-phenylsuifanyl)-7aminoquinazolin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine..

D* -222- S. Method L. To a solution of 2,4-dichloro-6- C phenyl-pyrimidine (300 mg, 1.33 mmol). and Smethylpyrazole (129 mg, 1.33 mmol) in DMF (7 mL) is added CN triethylamine (195 pL, 1.40 mmol) followed by sodium iodide (200 mg, 1.33 mmol) and the reaction mixture is C- stirred for 15 hours at 90 OC. The resulting solution is partitioned between ethyl acetate and water and the C- organic phase washed with brine, dried over MgS04 then Sconcentrated in vacuo. The residue is triturated in CN 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-phenylpyrimidin-4-yl)-(5-methyl-2H-pyrazol-3-yl)-amine (60 mg, 0.21 mmol) is combined with.4-acetamidothiophenol (176 mg, 1.05 mmol) in tert-butanol (5 mL) and the mixture heated at reflux for 20 hours. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHCO 3 The organic layer is washed with brine, dried over MgS04 and concentrated in vacuo.

The resulting residue is purified by flash chromatography (Si0 2 DCM/MeOH gradient) to afford [2-(4-acetamidophenylsulfanyl)-6-phenyl-pyrimidin-4-yl]-(5-methyl-2Hpyrazol-3-yl)-amine (74 mg, Method M. To a suspension of 4,6dihydroxymercaptopyrimidine (8 g, 55 mmol) in a mixture of EtOH/water 140 mL) is added NaOH (2.33 g, 58.3 mmol) followed by 4-methoxybenzyl chloride (7.90 mL, 58.3 mmol). The solution is stirred for 1.5 hours at 60 °C and then at room temperature for a further 6 hours. The resulting white precipitate is collected by filtration to give 4,6-dihydroxy-2-(4-methoxy-benzylsulfanyl) pyrimidine.

-223- The above-prepared 4,6-dihydroxy-2-(4-mnethoxyt-benzylsulfanyl)-pyrimidine (2.5 g, 9.46 mmol) is suspended in POC1 3 (20 mL), and.tripropylamine (3.60 mL, N 18.9 mmol) is.added dropwise to the mixture. T he reaction is then heated-at 110 OC for 4 hdurs. The brown solution is cooled to room temperature and the solvent is S 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 Ci 10 and the residue is purified by flash chromatography (Sio 2 hexane/AcOEt gradient) to give 4,6-dichloro-2-(4-methoxybenzylsulfanyl)-pyrimidine.

To a solution of-above-prepared 4,6-dichloro-2- (4-methoxy-benzy1sulfanyl)-pyrimidine (915 mg, 3.04 mmol) and 3-amino-5-methylpyrazole (310 mg, 3.19 mmol) in BuOH 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 OC. The -solvent is- removed in vacuo and the residue is purified by flash. chromatography (SiO 2 hexane/AcOEt gardient) to give [6-chloro-2-( 4 -methoxy-benzylsulfanyl)-pyrimidin-4yl)-(5-methyl-2H-pyrazol-3-yl)-amine..

The above-prepared [6-chloro-2-(4-methoxybenzylsulfanyl)-pyrimidin- 4 -yl)-(5-methyl-2HZ-pyrazol-3yl)-amine (500,mg, 1.38 mmol) in 1-methylpiperazine 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-.

benizylsulfanyl)- 6-(4-methylpiperazin-1-yl) -pyrimidin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

Method N. A solution of [2-(4-acetamidophenyl-sulfanyl)-6-(4-methoxyphenyl)-pyrimidin-4-yl]-(5-

VO

S -224- (N methyl-2H-pyrazol-3-yl)-amine (100 mg, 2.24.10- 4 mol) in Sdichloroethane (5 mL) is treated with IM BBr 3 in DCM (896 8.96.10' 4 mol). The mixture is then heated at 80 °C

C

N for 4 -hours before IM BBr 3 in DCM (896 JL, 8.96.10" 4 mol) is added. The reaction mixture is then heated at 80 °C (C for a further 3 hours. The solvent is evaporated and methanol is added to the residue to quench any residual S BBr 3 The solvent is evaporated in vacuo and this S evaporation step is repeated 3 times. IM HC1(8 mL) is

C

N 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 24 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 with diethyl ether to give [2-(4-acetamido-phenyl-sulfanyl)-6- (4-hydroxyphenyl) -pyrimidin-4-yl] (5-methyl-2H-pyrazol-3yl)-amine.

To:a solution of the above-prepared acetamido-phenyl-sulfanyl)-6-(4-hydroxyphenyl)-pyrimidin- 4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (70 mg, 1.62.10" 4 mol) in DMF (3 mL) is added potassium carbonate (134 mg, 9.71.10 4 mol). The reaction mixture is heated to 80 0

C

before l-dimethylamino-3-chloropropane hydrochloride (77 mg, 4.86.10' 4 mol) is added. The mixture is stirred at for 4 hours, cooled to room temperature and the solvent is evaporated. The residue is purified by flash chromatography to afford the desired product acetamido-phenyl-sulfanyl)-6-[4-(3-dimethylaminopropoxy)-phenyl]-pyrimidin-4-yl)-(5-methyl-2H-pyrazol-3yl)-amine.

Method O To a solution of [6-methoxycarbonyl- 2-(4-propionylamino-phenyl-sulfanyl)-pyrimidin-4-yl]-(5- Va o 225methyl-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 500C for 1.5 hours.

N The reaction is then quenched with dilute HC1 and extracted with ethyl acetate. .The organic layer is C successively washed with aqueous saturated NaHC0 3 and brine, dried over MgSO 4 and evaporated. The solid residue is triturated in ethyl acetate and the resulting white o solid-is collected by filtration to give the desired C( 10 product. 6-hydroxymethyl-2- (4-propionylamino-phenylsulfanyl) -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 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 OC. The solvent is then removed in vacuo and the residue is purified by flash chromatography (SiO 2 hexane/AcOEt gradient) to give [6-chloro-2-methylsulfanyl-pyrimidin-4-yl)-(5-methyl-2Hpyrazol-3-yl)--amine.

The above-prepared E6-chloro-2-methlsulfanylpyrimidin-4-yl) -(5-methyl-2H-pyrazol-3-yl)-amine (2.42 g, 9.46 mmol) is heated in morpholine (10 mL)..at 130 OC'for hours. The solvent is then removed in vacuo and the solid residue is triturated in EtOH and collected by filtration to give [2-methy1sulfanyl-6-(morpholin-4-yl)pyrimidin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine.

To a suspension of the above-prepared [2methylsulfanyl-6-(morpholin-4-yI)-pyrimidin-4-ylJ-(5methyl-2H-pyrazol-3-yl)-amine (500 mg, '1.63 mmol) in MeOH mL) is added a solution of oxone (3.0 g) in water -226- C- mL). The reaction mixture is stirred at room temperature t for 15 hours and most of the solvent is evaporated. The i residue is partitioned between DCM and aqueous saturated Cq NaHCO 3 The organic layer is washed with brine, dried, filtered and evaporated. The residue is triturated in MeOH and the resulting white solid is collected by .filtration to give [2-methylsulfonyl-6-(morpholin-4-yl)o pyrimidin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine.

0 The above-prepared [2-methylsulfonyl-6- C 10 (morpholin-4-yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3yl)-amine (178 mg, 0.52 mmol) .and 4-acetamidothiophenol (176 mg, 1.05 mmol) are refluxed in tert-butanol (5 mL) over 20 h. The reaction mixture is cooled to room temperature and partitioned between ethyl acetate and aqueous NaHC03. 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-4yl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine.

In order .that the invention described herein may be more fully understood, the following examples are set forth. It should be understood that these examples are for illustrative purposes only and are not to be construed as limiting this invention in any manner.

SYNTHETIC EXAMPLES The following HPLC methods were used in the analysis of the compounds as specified in the Synthetic Examples set forth below. As used herein, the term "Rt" refers to the retention time observed for the compound using the HPLC method specified.

-227- C HPLC-Method A: Column: C18, 3 um, 2.1 X 50 mm, "Lighting" by Jones SChromatography.

Gradient: 100% water (containing 1% acetonitrile, 0.1% TFA) to 100% acetonitrile (containing 0.1% TFA) over 4.0 min, hold at 100% acetonitrile for 1.4 min C3 and return to initial conditions. Total run time O min. Flow rate: 0.8 mL/min.

O

o 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 and return to initial conditions. Total run time 31.5 min. Flow rate: 1.0 mL/min.

HPLC-Method C: Column: Cyano, 5 um, 4.6 X 150 mm "Microsorb" by Varian.

Gradient: 99% water TFA), 1% acetonitrile (containing 0.1% TFA) to 50% water TFA), acetonitrile (containing 0.1%.TFA) over.20 min, hold for 8.0 min and return to initial conditions. Total run time 30 min. Flow rate: 1.0 mL/min.

HPLC-Method

D:

Column: Waters (YMC) ODS-AQ 2.0x50mm, SS, 120A.

Gradient: 90% water Formic acid), acetonitrile (containing 0.1% Formic acid) to water formic acid), 90% acetonitrile.

(containing 0.1% formic acid) over 5.0 min, hold for -228- 0.8 min and return to initial conditions. Total run Stime 7.0 min.

Flow rate: 1.0 mL/min.

HPLC-Method E: N Column: 50x2.0mm Hypersil C18 BDS;5 gm Gradient: elution 100% water TFA), to 5% water 0 TFA), 95% acetonitrile (containing 0.1% TFA) Sover.2.1 min, returning to initial conditions after 0 Ci 10 2.3 min.

Flow rate: 1 mL/min.

Example 1 (5-Methyl-2H-pyrazol-3-yl)-(2-phenylsulfanylquinazolin-4-yl)-amine (IIa-1): Prepared in a manner similar to the above described Method E to afford-a.pale yellow solid, mp >3000C 1 H NMR (DMSO).8 2.07(3H, 5.54(1H, 7.38(1H, 7.56-7.45(4H, 7.65(2H, 7.73 (1H, 8.55(1,11 10.43(1H, 12.05(1H, br IR (solid) 3259,; 3170, 3109, 1618, 1594, 1565, 1525, .1476; MS 334.0 Example 2 [2-(4-Chlorophenylsulfanyl)-quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (IIa-2): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 259-260C; 1H NMR (DMSO) 8 2.12 (3H, 5.40 (111, 7.60 (1H, 7.64 (2H, 7.76 (3H, 7.92 (1l, 8.70 (1H, 11.50 (1H,br IR (solid) 1627, 1606, 1557, 1484, 1473, 1433, 1400, 1339; 1286, 1219; MS 368.0 (M+H) Example 3 [2-(2,4-Dichlorophenylsulfanyl)-quinazolin-4yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-3): Prepared in Va oN -229c a manner similar to the above described Method E to Ctafford a pale yellow solid, mp 258-259 0 C; 'HNMR (DMSO) 2.12 (3H, 5.40 (1H, 7.54 (1H, 7.63 (1W, m), Cl 7.68 (1H, 7.86 (1H, 7.92 (1H, 7.96 (1H, d), 8.66 (1H, d) 11.20 (1Hi, br IR (solid) 1623, 1610, ON 1551, 1488, 1435, 1410, 1339, 1284, 1217; MS 402.0 i Example 4 [2-(4-Methoxyphenylsulqanyl)'quinazolin-4-ylJ- (5-methyl-2H-pyrazol-3-yl)-amnne (IIa-4): Prepared in a manner similar to the above -described Method E to afford a pale yellow solid, mp 264-2680C; 1H NMR (DMSO) 6 2.04 3.85 (3H, 5..43 (1H, 7.12 (2H, 7.53 7.61 (3H, 7.84 (3H, 8.63 (1H, 11.09 (1H, br 12.30 br IR (solid) 1622, 1598, 1552, 1492, 1404, 1340,.1292, 1249, 1219, 1171, 1161; MS 364.1 Example 5 [2-(2-Ethylphenylsulfanyl)-quinazolin-4-yl-(5methyl-2Hb-pyrazol-3-yl)-amine (IIa-5): Prepared in a.

manner similar to the above described Method E-to afford a pale yellow solid, mp 205-208 0 C; 1H NM (DMSO) 8 2.05 (3H, 5.19 (iH, 7.38 (1i, 7.52-7.64 (3H, m), 7.68 (2H, 7.90 (1H, .8.68 (IH, IR (solid).

3262, 2967, 1632, 1605, 1558, 1492, 1434, 1403, 1344; 1294, 122.4, 1162; MS 362.1 Example 6 (2-[2,4-Bi(trifluoromethyl)phenyisulfanylquinazolin-4-yl}-(5S-methyl-2H-pyrazol-3-yl) -amine (IIa-6): Prepared in a-manner similar to the above described Method E to afford a pale yellow solid,- mp >3000C; 'H NMR (DMSO) 8 1.98 (3H, 7.50 (1H, 7.59 (2H, 7.84 (IH, 8.32 (1i, 8.40 N -230- (2H, 8.66 (1H, 10.73 (1H, br IR '(solid) 1628, 1603, 1577, 1548, 1512, 1493, 1448, 1417, 1354, S1275, 1196, 1124; MS 470.1 (M+H) Example 7 [2-(2-Chlorophenylsulfanyl)-quinazolin-4-yi] ON (5-methyl-2H-pyrazol-3-yl)-amine (IIa-7): Prepared in a C manner similar to the above described Method E to afford eC a pale yellow solid, mp 262-263oC; 'H NMR (DMSO) 8 2.05

VO

S(3H, 5.35 (1H, 7.52 7.65 (2H, 7.74 Ci 10 (1H, 7.83 (1H, 7.88 (1H, 8.62 (1H, 10.97 (1H, br IR (solid) 1621, 1603, 1569, 1544, 1491, 1448, 1400, 1376, 1336, 1288, 1208; MS 368.0 Example 8 2 ,3-Dichlorophenylsulfanyl)-quinazolin-4yl]-(5-methyl-2H-pyrazoi-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) 6 2.05 (3H, 5.34 (1H, 7.50 (2H, 7.60 (iH, d), 7.75 (1H, 7.88 8.62 (1H, 10.72 (1H, br IR (solid) 1632, 1609, 1561, 1532, 1492, 1432, 1400, 1380, 1345, 1298, 1228, 1162, 1125;. MS 402.0 (M+H) Example 9 [2-(3-Chlorophenylsulfanyl)-quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-9): Prepared in a 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, 5.42 (1H, 7.55 (2H, 7.66 7.81 (1H, 7.85 (1H, 8.62 (1i, 11.10 (1H, br IR (solid) 1628, 1611, 1551, 1487, 1432, 1410, 1341, 1292,.

1217, 1165; MS 368.0 (M+H)

NO

-231- Example 10 [2-(1-Methylimidazol-2-ylsulfanyl)-quinazolin- 4-yl]-(5-methyl-21-pyrazol-3-yl)-amine (IIa-10): Prepared in a manner similar to the above described Method E to afford an off white solid, mp 255-256C; 1H NMR (DMSO) B 2.19 (3H, 3.59 (1H, s),.5.51 7.18 (iH, s), 7.45 7.57 (1H, 7.59 (18, 7.77 (in, t), S8.57 (1H, 10.57 (1N, 12.13 (IH, br IR (solid) O 1628, 1565, 1550, 1532, 1492, 1430, 1376, 1333, 1292; o 1278, 1211; MS 338.2 Example 11 [2-(2-Hydroxyphenylsulfanyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl).-amine (IIa-11): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 273-2750C; 1H NMR (DMSO) 6 2.06 (3H, 5.41 6.99 (1H; 7.07 (IH, 7.50 (11, 7.57-7.62 (2H, 7.73 7.94 (iH, t), 8.71 (IH, 10.29 br 11.66 (1i, br IR (solid) 1623, 1597, 1552, 1485, 1442, 1404, 1354, 1341, 1289, 1221, 1165; MS 350.1 (M+H) 4 Example 12 4 -Difluorophenylsulfanyl) -quinazolin-4yll-(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 256-2580C; 'H NMR (DMSO) 2.10 (3H, 5.41 (1H, s),.7.33 (1H, 7.51-7.58' (2H, 7.65 7.82-7.91 (2H, 8.63 (1H, d),.11.06 (1H, br IR (solid) 1626, 1608, 1556, 1482, 1409, 1341, 1288, 1270, 1219, 1162, 1140; MS 370.1 Example 13 (3,4-Dimethoxyphenylsulfanyl) -quinazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-13): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, mp 229-232 0 C; 'H NMR (DMSO) 8 -232- C' 2.05 (3H, 3.70 3.85 (3H, 5.39 (1H, s), 6.95 (1H, 7.30 (2H, 7.60 7.77 (1H, d), 7.94 (1H, 8.72 (1H, 11.66 (1H, br IR (solid) 1625, 1607, 1551, 1503, 1436, 1404, 1342, 1290, 1254, 1237, 1218,- 1161-i 1137- -MS- 394.1 Example 14 1 2 3 -Methylphenylsulfanyl)-quinazolin-4-yl- C (5-methyl-2H-pyrazol-3-yl)-amine (IIa-14): Prepared in a

NO

o manner similar to the above described Method E to afford C 10 a pale yellow solid, mp 249-250 0 C; 'H NMR (DMSO) 8 2.06 (3H, 2.36 (3H, 5.31 (1H, 7.45 (2H, 7.48- 7.58 (3H, 7.61 (1H, 7.88 8.68 11.66 (1H, br IR (solid) 1617, 1587, 1558, 1496, 14414, 1387, 1341, 1283, 1221, 1162, 1140; MS 348.1 (M+H) Example 15 [2-(2-Methoxyphenylsulfanyl)-quinazolin-4-yll (5-methyl-2H-pyrazol-3-yl)-amine (IIa-15): Prepared in a manner similar to the above- described Method E to afford a pale yellow solid,.mp 237-239OC; 1H NMR (DMSO) 8 2.07 (3H, 3.71 (3H, 5.35 (1H, 7.12 (1H, 7.23 7.55 (1H, 7.60-7.67. 7.87 (1H, t), 8.66 11.20 (1i, br IR (solid) 1632, 1606, 1561, 1480, 1430, 1405, 1344, 1292, 1276, 1251, 1224; MS 364.1 (M+H) t Example 16 [2-(2-Naphthalenyisulfanyl) -quinazolin-4-yl] (5-methyl-25-pyrazol-3-yl)-amine (Ia-16): Prepared in a manner similar to the above described Method E to afford a pale yellow solid,. mp 267-2700C; 'H NMR (DMSO) 5 2.05 (3H, 5.09 7.57 (1A, 7.62-7.75 (4H,in), 7.90 8.07 (3H, 8.40 (1H, 8.66 (11, d), -233- 11.28 (1i, br IR (solid) 1624, 1606, 1550, 1487, 1435, 1407, 1341, 1285, 1216, 1158; MS 384.1 Example 17 [2-(2,6-Dichlorophenylsulfanyl)-quinazolin-4yl- (5-methyl-2H-pyrazol-3-yl)-amine (IIa-17): Prepared- N in a manner similar to the above described Method E to afford a pale brown solid, mp >3000C; H NMR (DMSO) 8 2.11 (3H, 5.49 (1H, 7.49 (1H, 7.59-7.67 (2H, m), 0 7.76 (2H, 7.81 (1H, 8.60 (1H, 10.60 (11, s); IR (solid) 1618, 1599, 1565, 1533, 1486, 1424, 1401, 1361, 1344, 1285, 1246, 1216, 1188, 1172; MS 402.0 Example 18 3 4 -Dichlorophenylsulfanyl) -quinazolin-4yl-(S-methyl-2H-pyrazol-3-yl)-amine (Ila-18): Prepared in a manner similar to the above described Method E to afford a pale yellow solid, p 268-272 0 NMR (DMSO) 2.11 (3H, 5.47 (1H, 7.56 (IH, 7.68-7.72 (2H, 7.83 (2H, 7.88 (1H, 8.05 (1H, 8.66 (1H, IR (solid) 1628, 1607, 1556, 1488, 1436, 14412, 1399, 1367, 1341, 1288, 1216, 1166; MS 402.0 Example 19 2 -(Benzimidazol-2-ysulfany).-quinazolin-4yll-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-19): Prepared in a manner similar to the above.described Method E to afford a pale grey solid, mp 192-196 0 C; 1H NMR (DMSO) 1.60 (3H, 5.48 (1H, 7.44 (11, t), 7.69 (2H, 7.76 (2H, 7.85 (1H, 8.64 (1i, d), 10.79 (1H, IR (solid) 1618, 1606, 1569, 1537, 1487, 1411, 1395, 1369, 1343, 1288, 1273, 1170; MS 374.1 Example 20 2 -Aminophenylsulfanyl) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa-20): Prepared in a -234- C( manner similar to the above described Method E to afford S-a bright yellow solid, mp 257-259C; 1 H NMR (DMSO) 6 2.11- 2.30 (3H, 2xbr 6.10 (1H, br 7.10-7.80 (7H, m), C 8.60 (1H, br 9.80 (1H, br 10.80 (1H, br IR (solid) 1623, 1591, 1567, 1538, '1496, 1483, '1410, 1351 Example 21 (5-Cyclopropyl-2H-pyrazol-3-yl) \C phenylsulfanyl-quinazolin-4-yl)-amine (IIa-21): Prepared O in a manner similar to the above described Method E to

C

N 10 afford a yellow solid, mp 233-236C; IHNMR (DMSO) 8 0.89 (2H, 0.98 (2H, 1.67 (1H, 5.48 (1H, 7.54 7.73 (7H, 7.89 (iH, 8.68 (1H, 11.60 (1H, br IR (solid) 1629, 1606, 1577, 1546, 1509, 1484, 1438, 1413, 1370, 1291, 1219; MS 360.3 Example 22 (5-Cyclopropyl-2H-pyrazol-3-yl) methoxycarbonylphenylsulfanyl) -quinazinz-4-yl] -amine .(IIa-22): Prepared in a manner similar to the above described Method E to afford a white solid, mp 224-225 0

C;

'H NMR (DMSO) 6 0.52 (2H, 0.86 (2H, 1.67 (IH, m), 3.86 (3H, 5.60 (1H, 7.45 (1H, 7.56 (1H, d), 7.66 (1H, 7.76 7.93 (1H, 810 (IH, 8.18 (1H, 8.57 (1H, 10.48 (1H, br 12.07 (1H, br IR (solid) 1724, 1617, 1593, 1567, 1526, 1478, 1432, 1400, 1361, 1343, 1283, 1260, 1218, 1169, 1128; MS 418.3 (M+H) Example 23 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3methylphenylsulfanyl)-quinazolin-4-yl] -amine (IIa-23): Prepared in a manner similar to the above described Method E to afford a white solid, mp 241-243 0 C; IH NMR (DMSO) 6 0.55-0.63 (2H, 1.87-1.97 (1H, 1.67-1.79

VO

o '-235- 0 Cl (1H, 2.35 (3H, 5.72 (1H, 7.30-7.60 (6H, m), S7.68-7.78 8.50-8.60 (1H, 10.38 (1H, 12.02 1 H, IR (solid) 1617, 1594, 1568, 1529, 1480, 1401, Cl 1344, 1287, 1176, 758, 665,656; MS (M+H) Example 24 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3- -C methoxyphenylsulfanyl) -quinazolin-4-yl]-amine (IIa-24): C Prepared in a manner similar to the above described

CO

SMethod -E to afford a white solid, mp 232-234°C; 'H NMR Cl 10 (DMSO) 8 0.55-0.62 (2H, 0.88-0.97 (2H, 1.70-1.80 (1H, 3.79 (3H, 5.79 (1H, 7.08 (1H, 7.22- 7.29 (2H, 7.40-7.50 (2H, 7.60 (1H, 7.79 (IH, 8.57 (1H, 10.40 (IH, 12.04 (1H, IR (solid) 3100, 1618, 1592, 1567, 1527, 1477, 1402, 1345, 1284, 1246, 1231, 1171, 1041, 1.001, 969, 826, 761, 692, 667; MS (M+H) Example 25 (5-Cyclopropyl-2H-pyrazol-3-yl) dimethoxyphenylsulfanyl) -quinazolin-4-yl]-amine Prepared in a manner similar to the above described Method E to afford a white solid, mp 250-252oC; 'H NMR (DMSO) a 0.54-0.60 (2H, 0.83-0.91 (2H, 1.68-1.77 3.79 (3H, 3.85 (3H, 5.79 (1H, 7.10 (1H, .7.20-7.26 (2H, 7.45 (1H, 7.57 (1H, d), 7.77 (1H, 8.55 (1H, 10.45 (1H, 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) Example 26 3 -Carboxyphenylsulfanyl) -quinazolin-4-yl] (5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIa-26): Prepared from IIa-22 according to Method G to afford a-yellow IN -236- 0 0 solid, mp >300 0 C; 1 NMR (DMSO) 6 0.53 (2H, 0.86 (2H, 1.65 (11, 5.37 (1H, 7.55 7.68 (1H, 7..81 (1H, 7.88 (1H, 7.95 (1H, 8.15 (1, C 8.15 (11, s),-8.71 (1H, 11.32 (11, br IR (solid) 1702, 1626, 1609, 1559, 1490, 1412, 1355, 1293, 1222, 1170; MS 404.7(M+H).

SExample 27 (5-Cyclopropyl-2-pyrazol-3-yl) (naphtaleno 2-ylsulfanyl)-quinazolin-4-yl] -amine (IIa-27): Prepared C 10 in a manner similar to the above described Method E to afford an off-white solid, mp 285-288 0 C; 1H NMR (DMSO) S 0.25 (2H, br 0.52 (2H, br 0.87 (11, 5.54 (1H, br 7.42 7.77 (4H, 8.00 (3H, 8.30 (1H, br 8.56 (1H, br 10.42 and 11.88 (1H, 2 x br IR (solid) 1615, 1592, 1562, 1527, 1476, 1398, 1366, 1287, 1240, 1216, 1167, 1158, 1142, 1128, 996, .965; MS 410.7(M+H) Example 28 (5-Cyclopropyl-2H-pyrazol-3-yl) (2,4difluorophenylsulfanyl)-quinazolin-4-yll -amine (IIa-28): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 250-253 0 C; 1H NMR (DMSO) 8 0.61 (2H, 0.91 (2H, 1.74 (1H, m), 5.67 (11H, 7.24-7.28 (1H, 7.44-7.48.(3H, 7.53- 7.81 (2H, brm), 8.55 (1H, 10.47 and 12.10 (1H, 2 x br 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)* Example 29 (5-Cyclopropy-2H-pyrazol-3-yl)-[2- (naphthalen-2-ylsulfanyl)-5,6,7,8-tetrahydroquina.olin-4yl]-amine (IIa-29): Prepared in a manner similar. to the Va N.-237above described Method F to afford a white solid, mp 244C; 'H NMR (DMSO) 8 0.13 0.45 0.79 (1i, s) ,1.73 (41, 2.42 (2H, 2.58 (2H, 5.28 (1H, C- 7.58 (2H, 7.61 (2H, 7.97 (3H, 8.23 (1H, 8.56 (11, 11.63 (1H, IR'(solid) 1594, 1561, 1514, 1477, 1423, 1333, 1279, 1251, 990, 808, 744, 657, 651; MS 414.7(M+H)+

O

Example 30 (5-Cyclopropy-2H-pyrazol-3-yl) C 10 dichloropheny1sulfanyl)--quinazolin-4-yl] -amine 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) 6 0.60 (2H, 0.93 (2H, 1.70 (1H, m), 5.54 (1H, 7.47 (2H, 7.57 (1N, 7.76 (1H, t), 7.86 (2H, d),.8.57 10.48 (1K, 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) 4 Example 31 3 -Chlorophenylsul fanyl) -quinazolin-4-yll (5.-cyclopropyl-2H-pyraol-3-yl)-amine (IIa-31): Prepared in a manner similar to theabove described-Method E'to afford an off-white solid, mp 235-2380C; 1H NMR (DMSO) 6 0.58 (2H, 0.92 (2H, 1.75 (1K, 5.71 s), 7.44 (1H, 7.50 7.63 (4H, 7.73 (1H, 7.75 (1K, 8.57 (1H, 10.46 (1K, 12.08 (1K,

IR

(solid) 1616, 1593, 1562.,.1528, 1479; 1456, 1406, 1367, 1343, 1286, 1244, 1216, 1176, 1067, 1051, 997; MS 394.7(M+H)+ Example 32 2 -Chlorophenylsulfanyl)-quinazolin-4-yl]- S(5-cyclopropyl-2-pyrazol-3-yl) -amine (IIa-32) YPrepared O -238- C in a manner similar to the above described Method E to Safford an off-white solid, mp 255-257 0 C; 'H.NMR (DMSO) B 0.59 (2H, 0.91 (2H, 1.71 (iH, 5.62 (1H, s), c 7.45 (2H, 7.57 (1H, 7.69 (1i, 7.75 (1H, t), 7.85 (1H, 8.56 (1H, '10.43 (1H, 12.-03 (1H, s); N IR (solid) 1619, 1596, 1564, 1529, 1480, 1446, 1398, 2 1370, 1343, 1289, 1246, 1218, 1165, 1148- 1089, 1054, 0 1030, 997; MS 394.7(M+H).

ci

IND

ci 10 Example 33 .(5-Cyclopropyl-2H-pyrazol-3-yl) dimethylphenylsulfanyl)-quinazolin-4yrl]-amine (IIa-33): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 255-256 0 C; 1H.

NMR (DMSO) 8 0.56 (2H, 0.90 (2H, 1.67 (iH, m), 2.26 and 2.29 (6H, 2 x 5.75 (1H, br 7.26.(1i5, m), .7.35-7.55 (41, nm), 7.74 (11, 8.54 (1H, br 10.44 and 12.06 (2H, 2 x br IR (solid) 1617, 1596, 1569, 1526, 1479, 1459, 1404, 1366, 1343, 1287, 1243. 1218, 1167, 1145, 1017, 996, 966; MS 388.3(M+H) 4 Example 34 12-(Benzimidazol-2-ylsulfanyl) -quinazolin-4- (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 201-203 0 C; 1H NMR (DMSO) 8 0.44 (2H, 0.71 (2H, 1.17 (1H, m), 5.72 (1H, 7.23 (2H, m),.7.51-7.81. 8.59. (1H, 10.59, .12.06 and 13.17 (3H, 3 x br IR (solid) 1617, 1601, 1572, 1532, 1485, 1402, 1374, 1341, 1290, 1273, 1209, 1168, 1024, 1010, 965; MS 400.2(M+)+ Example 35 (5-Cyclopropyl-2a-pyrazol-3-yl)- methoxycarbonylphenylsulfanyl) -quinazolin-4-yl] -amine

VO

o -239- C- (IIa-35): Prepared in a manner similar to the above Sdescribed Method E to afford an off-white solid, mp 245- 246 0 C; 'H NMR (DMSO) 6 0.47 (2H, .br 0.80 (2H, br s), Cl 1.62 1H 3.85 (3H, 5.69 (1H, br 7.46 (1H, 7.58 (1H, 7.76-7.81 (3H, 8.02-8.05 (2H, m), 8.57 (1H, m),.10.48 and 12.11 (2H, 2 x br IR (solid) 1721, 1712, 1616, 1596, 1572, 1564, 1523, 1481, 1435, S1404, 1360, 1346, 1277, 1181, 1114, 1106, 996, 971; MS C Example 36 2 -(4-Acetamido-phenylsulfanyl)-quinazolin-4yl]-(5-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 239-241oC;

H

NMR (DMSO) S 0.57 (2H, 0.83 (2H, 1.69 (1H, m), 2.02 (3H, 5.73 (1H, br 7.41 (1H, 7.53-7.57 (3H, 7.73-7.75 (3H, 8.54 (1H, 10.18, 10.39 and 11.98 (3H, 3 x br IR (solid) 1665, 1618, 1607, 1586, 1572, 1564, 1529, 1482, 1387, 1343, 1320, 1287, 1243, 1221, 1162, 1005, 968; MS 417.2(M+H) Example 37 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-l-ylsulfanyl)-quinazolin-4-yl]-amine (Ila- 37): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 271-273oC; i

H

NMR (DMSO) 6 0.46-0.47 (2H, 0.87-0.89 (2H, 1.57 (1H, 5.01 (1H, 7.42 (1H, 7.52-7.54 (3H, m), 7.64 (1H, 7.75 (1H, 7.98 (1H, 8.06 (1H, m), 8.17 (1H, 8.28 (1i 8.50 (1H, 10.29 (1H, br 11.84 (1H, br IR (solid) 1615, 1592, 1567, 1528, 1483, 1401, 1362,.1343, 1285, 1242, 1219, 1173, 998, 963; MS 410.2(M+H) IND -240- Example 38 [2-(4-Acetamidophenylsulfanyl)-quinazolin-4yll- (5-methyl-2H-pyrazol-3-yl)-amine (IIa-38): Prepared in a manner similar to the above described Method E to afford an white solid, mp 268-271 0 C; 1H NMR (DMSO) 5 2.02 (3M, 2.09 (3H, 5.56 (1H, 7.40 (1H, 7.55 (3H, 7.75 (3H, 8.55 (lH, d) 10.21 (1H, 10.40 0 (1H, 12.03 (1H, IR (solid) 1662, 1620, 1599, ci o 1572, 1531, 1438, 1397, 1370, 1358, 1341, 1323, 1312, S 10 .1278, 1265, 1245, 1216, 1161, 1006, 966; MS 391.2(M+H)* Example 39 [2-(4-Methanesulfonylamino-phenylsulfanyl)quinazolin-4-ylJ (5-methyl-2H-pyrazol-3-yl)-amine (ha- 39): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 219-222oC; 1H NMR.(DMSO) 3 2.15 (3H, 2.61 (3H, 5.84 (1H, s), 6.91 (2H, 7.22 (2H, 7.36 (1H, 7.52 (11T, d), 7.69 (1H, 8.53 (1H, 10.31 (18, 11.96 (1H, s); IR (solid) 1621, 1602, 1584, 1567, 1528, 1486, 1351, 1287, 1253, 1207, 1179, 1102, 1091, 983; MS 427.0(M+)' Example 40 [2-(4-Acetamidophenylsulfanyl)-7-methoxyquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa- Prepared in a manner similar to the above described Method E to afford a white solid, mp 291-293OC; 1H NMR (DMSO) 8 2.01 (3H, 2.09 (3H, 3.87 (3H, 5.55 (1H, 6.96 (1H, 6.99 7.55 (2H, 7.73 (2H, 8.45 (1H, .10.21 (1H, 10.23 (1H, s), 11.99 (3M, s);-IR (solid) MS 421.2(M+H)' Example 41-[2-(4-Acetamidophenylsulfanyl)-8-(3-morpholin- 4-yl-propoxy) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3- -241yl)-amine (IIa-41): Prepared in a manner similar to the above described Method E to afford a white solid, mp 262- 2 6 4 0 C; H NMR (DMSO) 6 1.94 (2H, quint.), 2.03 (3H, s), 2.09 (3H, 2.38 (4H, 2.45 (2H, 3.58 (4H, s), 4.11 (2H, 5.60 7.24 (1H, 7.30 (1H, t), 7.57 (2H, 7.73 (2H, 8.07 (1H, 10.20 (1H, s), 10.24 (1H, 12.02 (1H, br IR (solid) 3245, 3045, 2954, 2918, 2845, 1663, 1609,.1586, 1527, 1468, 1391, 1332, 1268, 1254, 1159, 1136, 1114, 1054, 995, 823 MS 534.4(M+H) Example 42 4 -Methoxycarbonylphenylsulfanyl) quinazolin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine (IIa- 42): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 257-2609C; 1H NMR (DMSO) 8 1.95 (3H, 3.89 (3H, 5.51 (1H, br s), 7.39 (1H, br 7.51 (1H, br 7.70 (1H, br 7.81 (2H, 8.04 (2H, 8.51 (1H, br 10.48 (1H, br s), 12.03 (1H, br IR (solid) 1718, 1618, 1599, 1568, 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-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (IIa-43): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 3263-265C; 1H NMR (DMSO) 8 1.98 (3H, 5.50 (1H, s),.7.46 (1H, 7.60 (1H, 7.78 (3H, 8.02 (2H, 8.58 (IH; 10.58 (1H, 12.50 (IH, br IR (solid) 1623, 1605, .1574, 1560, 1533, 1490, 1401, 1349, 1318, 1285, 1249, 1216, 1174, 1131, 1088, 1018; MS-378.2(M+H) -242- C Example 44 (4-Acetamidophenylsulfanyl) -8-methoxyq quinazolin-4-yl] (5-methyl-2H-pyrazol-3 -yl) -amine (IIa- 44): Prepared in a manner similar to the above described S Method E to afford an off-white solid, mp 247-249OC; "H NMR (DMSO) 1.99 2.10 (3H, 3.93 (3H, 5.40 (iH, 7.31 (1H, 7.38 (1H, 7.57 (2H, 7.76 S(2H, 8.11 (1H, 10.28 (1H, 10.61 (1H, s), C 12.11 (1H, br IR (solid) 3234, 3052, 2938, 1673, cO S1618, 1591, 1536, 1481, 1459, 1390, 1372, 1345, 1317, C 1~0 1267, 1249, 1158, 1058, 985, 830; MS 421.2(M+H) Example 45 [2-(4-Acetamidophenylsulfanyl) -7-(3-morpholin- 4-yl-propoxy) -quinazolin-4-yl (5-methyl-2H-pyrazol-3yl)-amine (IIa-45): Prepared from IIa-74 according to Method I to afford an off-white solid, mp 153 0 C H.

NMR (DMSO) 5 2.02 (3H, 2.09 2.29 (2H, quint.), 3..16 (2H, 3.36 3.57 4.11 (2H, 5.58 (1H, 7.22-7.29 (2H, 7.55 (2H, d), 7.76 (2H, 8.07 (1H, 10.26 (1H, br 10.35 ((1H, 12.06 (1H, br 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-2H-pyrazol-3-yl)-amine (IIa-46): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp >300 0 oC 1H NMR (DMSO) 6 2.15 (3H, 5.63 (1H, br 7.44 (1H, 7.55-7.62 (3H, m), 7.69-7.77 .8.56 (1H, m) 10.47 and 12.12 (2H, 2 x br IR (solid) 1615, 1597,. 1565, 1525, 1478, 1396, 1362,.1339, 1285, 1218, 1158, 1034, 1009, 967; MS 412.1/414.1 -243- CA Example 47 2 3 -Bromophenylsulfanyl -quinazolin-4-yll (5-methyl-2H-pyrazol-3-y)-amine (IIa-47): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp 280-281 0 C; 1H. NMR (DMSO) 6 2.12 (3H, 5.54 (1H, br 7.46 (1H, 7.55-7.68 (3H, 7.75-7.88 (3H, 8.81 (1H, 10.49 and 12.11 (2H, 2 x br IR (solid) 1617, 1600, 1567, 1530, 1483, 1399, 1362, 1342, 1282, 1200, 1168, 1054, 1034, 1005, o 967; MS 412.2/414.2(M+H)* Example 48 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 0 C; 'H NMR (DMSO) 61.26 (6H, 2.13 (3H, 5.75 (1H, 7.34 (2H, 7.41 (1H, 7.54 (1H, 7.59 (2H, 7.73 (H 8.53 (11, 10.16 10.42 (1H, s), 12.07 (11, br IR (solid) 1613, 1593,.1560, 1530, .1482, 1384, 1364, 1346, 1320, 1290, 1265, 1243, 1216, 1169, 1141, 1084, 1056, 1019,.999, 969, 916; MS 455.2(M+H).

Example 49 12-(4-Isobutyrylamino-phenylsulfanyl)quinazolin-4-yll (5-methyl-2H-pyrazol-3-yl)-amine (Ia- 49):Prepared.in-a manner similar~to the above described Method E.to afford an off-white solid, mp 285-287C; H NMR (DMSO) 6 1.12-1.13 (6H, 1.99 (3H, 2.64 (18, 5.52 (1H, br 7.41 (1H, 7.54-7.57 (3H, m), 7.72-7.77 (3H, 8.54 (1H, 10.12, 10.41 and 12.04 (3H, 3 x br IR (solid) 1704, 1680, 16i7, 1590, 1566, 1516, 1481, 1395, 1358, 1341, 1286, 1247, 1214, 1155, 1052,.1032, 1006, 969; MS 419.3(M+H)+

NO

0 -245- Example 53 2- (4-Acetamido-pheny1sulfanyl)-7nitroquinazolin-4-yll-(5-methyl-2s-pyrazol-3-yl)-amine Cl (IIa-53): Prepared in a manner similar to the above described Method- E to afford a yellow solid; H NMR (DMSO) 6 2.02 (3H, 2.09 (3K, 5.54 (1i, 7.58 (2H, d), 7.75 (2H, 8.08 (1H,yd), 8.22 (18, 8.80 d), 10.24 (1H, 10.85 (1i, 12.15 (1H, IR (solid); 1 MS 436.2(M+H)* Example 54 (5-Methyl-2H-pyrazol-3-yl)-2-[4-(propane-isulfonylamino)-phenylsulfanyll-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 0

C;

H NMR (DMSO)- 6 0.95 (3H, 1.71 (2H, 2.13 (3H,s), 3.18 (2H, 5.70 (1i, 7.31 (2H, 7.41 t), 7.52 (LN, 7.58 (1H, 7.73 (1H, 8.55 (1H, 10.16 (1H, 10.42 (1i, 12.07 (1H, IR (solid) 1615, 1594, 1563, 1530, 1481,; 1389, 1362, 1346, 1325, 1291, 1245, li47, 969; MS 455.2(M+H)+ Example 55 4 -Ethylsulfonylamino-phenylsulfanyl)quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl)-amine Prepared, in a manner similar to the above described Method E to afford an off-white solid, mp 279- 280 0 C; H NMR (DMSO) 6 1.28 (3H, 2.19 3.25 (2H, 5.76 (1H, 7.36 (2H, 7.48 (1H, 7.53 (1H, 7.65 (1H, 7.80 8.61 10.23 (1i, 10.49 (1i, 12.13 (1H, IR (solid) 1615, 1597, 1564,.1532, 1506, 1485, 1455, 1388, 1361, 1347, 1323,.1294, 1218, 1150, 1033, 1016, 998, 968, 918; MS 441.2(M+H) IND -244- Example 50 (5-Methyl-2H-pyrazol-3-yl)-[2-(4propionylamino-phenylsulfanyl)-quinazolin-4-yl]-amine C- (Ila-50): Prepared in a manner similar to the above described Method E to-afford an off-white solid, mp 281- 282WC; 1H NMR (DMSO) 8 1.11-1.13 (3H, 1.98 (3H, 2.33 (2H, 5.51 br 7.41 (1H, 7.55-",57 c- (3H, 7.71-7.78 (3H, 8.54 (11, 10.11, 10.42 O and 12.04 (3H, 3 x br IR'(solid) 1654, 1621, 1599, Ci 10 1571, 1527,.1476, 1398, 1358,- 1341, 1286, 1244, 1216, 1155, 1006, 969; MS 405.3(M+H) 4 Example 51 4 -cyclopropanecarbonylaminophenylsulfanyl)-quinazolin-4-ylj-(5-methyl-2H-pyrazol-3yl)-amine (IIa-51): Prepared in a manner similar to the above described Method E to afford an off-white solid, inmp 300-303WC; 1H NMR (DMSO) S 0.82-0.84 (4H, my, 1.83 (11, 2.01 (3H, 5.55 (1H, br 7.39-7.41 (2H, m), 7.53-7.57 (2H, 7.72-7.77 (2H, 8.53-8.55 (21, m), 10.40, 10.46 and 12.03 (3H, 3 x br 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-phenylsuleanyl)-8hydroxyquinazolin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (IIa-52): tan solid, mp 258-259 0 C; 'H NMR (DMSO) 6 1.99 (3H, 2.09 5.45. (1H, 7.10 (1H, 7.22 (1H, 7.57 (2H, 7.75 (2H, -7.95 (1H, 9.35 .10.22 (11, 10.26 (iH, 12.00 (1H, br s); IR (solid) -3295, 3272,.3181, 3109, 1654, 1591, 1527, 1482, 1459, 1386, 1368, 1314, 1268, 1141, 1077, 991, 814; MS 407.2(M+H).' IND -246- Example 56 4 -Acetamido-pheny1sulfanyl)-7hydroxyaminoquinazolin-4-yl] (5-methyl-2r-pyrazol-3-yl) amine (IIa-56): Prepared from IIa-53 according to Method C- J to afford a yellow solid; 1H NMR (DMSO) 8 1.97. s), 2.11 (3H, 5'19 (1H, 6.88-6.91 (2H, 7.65 (2H, 7.85 (2H, 8.44 (1H, 9.27 (1H, br 10.49 (1H, 11.38 (1H, 14.58 (1H, br IR (solid); MS 0 422.2(M+H)+ ci

IND

Example 57 2 4 -Isobutanecarbonylamino-phenylsulfanyl)quinazolin-4-yll (S5-methyl-2a-pyrazol-3-yl)-amine (IIa- 57): Prepared in a manner similar to the above described Method E to afford a white.solid, mp 281-282 0 C; 'H NMR (DMSO) 8 0.95-0.97 (6H, 2.00 (3H, 2.12 (1H, m), 2.23-2.25 (2H, 5.56 (1H, -7.41 7.54-7.57 (3H, 7.72-7.78 (3H, 8.54 (1H, 10.14, 10.41 and 12.03 (3H, 3 x br 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) 4 Example 58 2-( 4 -tert-Butoxycarbonylaminophenylsulfanyl) -quinazolin-4-yll]- (5-methyl-2H-pyrazo-3yl) -amine. (Ia-58): Prepared in a manner similar to the above described Method E to afford a white.solid,. mp.243- 2460C; H NMR (DMSO) 6 1.50 (9H, 1.97 5.40 (1H, 7.07 (2H,.br 7.36 (1H, br 7.47 (2H, d), 7.58 (2H, 8.12 (1H, br 9.58 (1H, 11.24 (1H, br IR (solid) 1701, 1593, 1559, 1515, 1482,.1396, 1365, .1346, 1308, 1288, 1237, 1154, 1051, 1020, 969; MS 449 Va 0 -247- Example 59 2 4 -Acetamido-phenylsulfanyl).-7- S aminoquinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIa-59): Prepared from IIa-53 according to Method K to afford an off-white solid, mp 264-265 OC; H NMR (DMSO) 8 1.99 (3H, 2.09 5.53 (IH, 5.97 (2H, s), 6.47 (1H, 6.68 (1H, 7.52 (2H, 7.71 (2H, d), 8.15 9.83 (1f, br 10.19 10.87. (1a, br IR (solid); MS 406.2(M+H) 4 Example 60 (5-Methyl-2H-pyrazol-3-yl)-(2- 4-(2-morpholin- 4-yl-acetylamino) -phenylsulfanyl] -quinazolin-4-yl}-amine Prepared in a manner similar to the above described Method E to afford an .off-white solid, mp 266- 267 OC 'H NIMR (DMSO) 8 2.03 (3H, 2.57 (4H, 3.23 3.69 (4H, 5.58 (1H, 7.40 (1H, 7.55- 7.62 (3H, 7.75 (1H, 7.80 (2H, 8.54 (1H, d), 10.02 (11, 10.41 (1H, 12.03 IR (solid) 1686, 1598, 1564, 1533, 1515, 1484, 1387, 1362, 1348, 1291, 1113, 868, 801, 773; MS 476.4(M+H)+ Example 61 (S-Cycloprpyl-2H-pyrazol-3-yl)-[2-(4methylsulfonylamino-pheny1sulfanyl) -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 0

C;

-1H NMR (DMSO) 8 0.61 (2H, 0.92 (2H, 1.82 br 2.98 5.90 (1H, 7.23 (2H, 7.41 (1H, 7.54 (3H, 7.72 8.55 (1N, 10.16 (1H, br 10.38 11.99 (1H, IR (solid) 1621, 1605, 1573, 1532, 1494, 1455, 1375, 1342, 1316, 1290, .1232, 1143, 1113, 985, 972; MS 453.3(M+H)+ IND -248- Example 62 4 -Amino-phenylsulfanyl)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl) -amnine (IIa-62): Prepared in a manner similar to the above described Method E to afford an off-white solid, mp >300OC; 3H NMR (DMSO) 8 2.16 (3H, 5.58 (1H, 6.78 7.36 (2H, 7.64 (2H, 7.94 (1H, 8.74 (1H, 11.82 (1H, br.s); IR _(solid) 1615, 1591, 1561, .1532, 1495, 1480, 1387, 1363, S1344, 1288, 1244, 1148, 966; MS 349.2(M+H) 4 ci S 10 Example 63 2 -(4-Acetamido-pheny1sulfanyl) -quinazolin-4- Y1J-(2H-pyrazol-3-yl)-amine (IIa-63): Prepared in a manner similar to the above described Method E to afford a white solid; 'H NMR (DMSO) 8 2.11 (3H, 5.93 (11, s), 7.31-7.68 (8H, 8.54 (11, 10.17 (11, 10.54 (1H, 12.38 (11, IR (solid); MS 377.4(M+H).t Example 64 (5-Methyl-2H-pyrazol-3-y1) [4-(4-morpholin- 4-yl-butyrylamino) -phenylsulfanyl] -quinazolin-4-y}-amine (IIa-64): Prepared in a manner similar to the above described Method E to afford a white solid, mp 240-243OC; SNMR (DMSO) 8 1.77 (2H, 2.00 (3H, 2.31-2.38 (8H, m),.3.57 (4H, 5.54 (1H, 7.39-7.76 (7H, 8.53 (1H, br 10.15 (11, .10.41 (1H, 12.00 (11, br IR (solid); MS 504.3(M+H)+ Example 65 (5-Methyl-2H-pyrazol-3-yl)-{2-[4-(2-morpholin- 4-yl-ethylcarbamoyl) -phenylsulfanyll -quinazolin-4-yl)amine. (IIa-65): Prepared in a manner similar.to the above described Method E to afford a white solid, mp 246-248C; H NMR (DMSO) 1.97 (3H, s),.2.43 (4H, br 3.30 (2H, 3.42 (2H, 3.58 (4H, br 5.52 (1H, .7.43 7.55 (11H, 7.76 (3H, 7.97 (2H, 8.56

VO

0 -249- (2H, 10.45 (1H, 12.05 (1H, br IR (solid) C 1637, 1618, 1596, 1568, 1530, 1484, 1396, 1362, 1343, S1286, 1247, 1216, 1159, 1116, 1006, 967; MS'490.3(M+H) Example 66- [8-Methoxy-2- (4-methylsulfonylaminoj phenylsulfanyl)-quinazolin-4-yl]-(5-methyl- 2-pyrazol-3yl)-amine (IIa-66): Prepared in a manner similar to the \O above described Method E to afford an off-white solid, mp O1 O 275-277 oC; H NMR (DMSO) 8 2.10 (3H, 3.07 (3H, s), 3.89 (3H, 5.58 (1H, 7.24 (1H, 7.26-7.36 (3H, 7.60 (2H, 8.07 (1H, 10.13 11.26 (1H, 12.03 (1H, IR (solid) 3379, 1622, 1595, 1531, 1481, 1467, 1344, 1326, 1271, 1248, 1143, 1061, 993, 975, 924, 829; MS 457.2(M+H) Example 67 2 -Dimethyiamino-ethylcarbamoyl)phenylsulfanyl]-quinazolin-4-yl}- (5-methyl-2H-pyrazol-3yl)'-amine (IIa-67): Prepared in a manner similar to the above described Method E to afford a white solid, mp 192- 193°C; H-NMR (DMSO) 8 1.99 (3H, 2.20 2.42 S (2H, 3.40 (2H, 5.56 (1H, 7.43 (1H, 7.57 (1H, 7.77 (3H, 7.92 (2H, 8.56 (2H, 10.44 (1H, 12.04 (1H, br IR (solid) 1650, 1618, 1593, 1561, 1525, 1481, 1419, 1395, 1361, 1337, 1287, 1247, 1214, 1165, 1004, 969; MS 448.3(M+H) Example 68 2 -Dimethylamino-acetylamino)phenylsulfanyl -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3yl)-amine (IIa-68): Prepared in a manner similar to the above described Method E to afford a white solid, mp 241- 243°C; IH NMR (DMSO).6 2.00 (3H, 2.33 (6H, 3.14 (2H, 5.60 (1iH, 7.40 (1H, 7.58 (3H, m 7.77 -250- Cl (1H, t 7.76 (2H, 8.58 (IH, 10.04 (11, s), 10.42 (1H, 11.99 (1H, IR (solid) 1707, 1617, 1601, 1571, 1509, 1485, 1420, 1397, 1365, 1304, 1290, Cl 1243, 1215, 1161, 970, 847, 813, 765, 716, 683, 656; MS 434.3(M+H)+ Example 69 [8-Hydroxy- 2-(4-methy1sulfonylamino- 0 phenylsulfanyl) -quinazolin- 4 -yl- (5-methyl-2H-pyrazol-3o yl)-amine (IIa-69): pale green solid, mp 291-293 0 C; H NMR Cl .10 (DMSO) 5 2.10 (31, 3.09 (3H, 5.57 (1H, 7.11 (1H, 7.24 (1H, 7.31 (2H, 7.62 (2H, 7.96 (1H, 9.32 (1H, 10.16 (1H, .11.28 (1H, r), 12.02 (1H, IR (solid) 3256, 1596, 1531, 1460, 1392, 1317, 1334, 1296, 1267, 1146, 993, 968, 931, 824; MS 443.2(M+H) 4 Example 70 (2-[4-(3-Dimethylamino-propylcarbamoyl) phenylsulfanyll -quinazolin-4-yl}-(5-methyl-2H-pyrazol-3yl)-amine (IIa-70): Prepared in.a manner similar to the above described Method E to afford a pink solid, mp 2130C; 1H NMR (DMSO) 5 1.48 (2H, 2.01 (3H, 2.24 2.38 (2H, br 2.93 (2H, 5.57 (1H, 7.48 (1H, 7.62 7.80 (3H, 8.02 (2H, 8.61 (1H, d) 8.74 (1H, 10.50 (11, 12.15.(1H, br IR (solid) 1682, 1618, 1595, 1567, 1528, 1484, 1400, 1361, 1344, 1285, 1247, 1219, 1172, 1084, 1006, 969; MS 462.3(M+H)+ Example 71 (3-Dimethylamino-propionylamino) phenylsulfanyl] -quinazolin-4-yl- (5-methyl-2E-pyrazol-3yl)-amine (IIa-71): Prepared in. a manner similar to the above described Method E to afford an off-white solid, mp 2800C 1H NMR(DfMSO) 82.09 (3H, 2.60 (6H, s), Va -251- 2.93 (2H, 3.10 (2H, 5.64 (11, 7.47 t), 7.59-7.70 (3H, 7.80-7.87 (3H, 8.61 10.47 (11, 10.48 12.15 (1H, IR (solid) 1670, 1619, 1598, 1586, 1571, 1534, 1515, 1481, 1397, 1364, 1348,-1286, 1178,- 1162, 764; MS 448.4(M+H)* SExample 72 2-( 4 -Acetamido-pheny1sulfanyl)-8-methoxyquinazolin-4-yl]- (5-cyclopropyl-2z-pyrazol.-3-yl)-amine S(IIa-72): Prepared in a manner similar to the above C 10 described Method E to afford an off-white solid, mp 265- 268 0 C; 1H NMR (DMSO) 0.49-0.56 0.79-0.83. (2H, 1.55-1.70 2.06 (3H, 3.89 (3H, 5.61 (1H, 7.25 (1H, 7.33 7.56 (2H, 7.74 (2H, 8.07 (1H, 10.17 (11, 10.26 (1H, s), 11.94 (1H, br IR (solid). 3250, 1671, 1617, 1595, 1536, 1480, 1460, 1396, 1373, 1335, 1254, 1160, 1131, 1671, 1011, 984, 869, 815; MS 447.4(M+H)' Example 73 4 -Acetamidophenylaulfanyl)-8-(3dimethylamino-propoxy)-quinazolin-4-yll-(5-methyl-2Hpyrazol-3-yl)-amine (IIa-73): Prepaired in a manner similar to the above described Method E to afford an offwhite solid, mp 170-172 0 C; 1HNMR (DMSO) 5 1.91 (2H, quint.), 2.03 (3H, 2.09 (31, 2.17 (6H, s),.2.40 (2H, 4.10 (2H, 5.59 (1H, 7.23 (1H, 7.30' (1H, 7.57 (2H, 7.73 (2H, 8.06 (1H, 10.20 (11, s),.10.24 (1H, 12.02 (11, br.s); IR (solid) 3234, 3108, 1675, 1614, 1592, 1531, 1484, 1395, 1371, 1338, 1316, 1253,.1161, 1137, 1062, 1038, 994, 958, 823; MS 492.4(M+H)*.

Example 74 [2-(4-Acetamidopheny1sulfany1)-7-hydroxyquinazolin-4-yll-(-methyl-2-pyrazol-3-yl)-amine -252- C (IIa-74): Prepared from IIa-40 according to Method H to Safford an off-white solid, mp 246-248°C; 1H NMR (DMSO) 6 2.00 (3H, 2.08 (3H, 5.52 (1H, 6.78 (1H, s), Cl 6.87 (1H, 7.54 (2H, 7.72 (2H, 8.37 (1H, d), 10.06 (1H, 10.17 (1H, 10.37 11.95 (1H, br CO IR (solid) 1661, 1633, 1594, 1572, 1539, 1492, 1420, 1389, 1359, 1298, 1223, 1176, 1148, 1087, 1026, 1010, Cl 965; MS 407.4(M+H)

VO

Cl 10 Example 75 [2-(4-Acetamidophenylsulfanyl)-7-(3dimethylamino-propoxy) -quinazolin-4-yl] (5-methyl 2pyrazol-3-yl)-amine (IIa-75): Prepared in a manner similar to the above described Method I to afford an offwhite solid, mp .249-250°C; 1H NMR (DMSO) 8 .1.90 (2H, quint.), 2.01 (3H, 2.09 (3H, 2.19 (6H, 2.42 (2H, 4.12 (2H, 5.55 (1H, 6.93 (1H, 6.98 (1H, 7.55 (2H, 7.73 8.43 d) 10.21 (1H, 10.23 (1H, 11.98 (1H, br IR (solid) .3272, 1677, 1615, 1571, 1558, 1530, 1501, 1434, 1420, 1394, 1344, 1320, 1292, 1263, 1222, 1168, 1048, 1034,.

1005, 967, 864, 844; MS- 492.4(M+H) Example 76 (tert-Butoxycarbonyl-methyl-amino) acetylamino] -phenylsulfanyl)-quinazolin-4-yl)- 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°C 1H NMR (DMSO) 8 1.37 (3H, s), 1.40 (3H, 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 (1H, 7.55-7.63 (3H, 7.75-7.80 (3H, 8.60 10.28 10.30 (1H, 2xs), 10.45 (1H, 12.08 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 -Methylamino-acetylamino)phenylsulfanyl] -quinazoli-n-4-yl}-(5-methyl-2H-pyrazol-3yl)-amine (IIa-77): Prepared in a manner similar to the above described Method E to afford a white solid, mp 242- 244°C; 'H NMR (DMSO) 82.01 (3H, 2.34 (3H, 3.32 (2H, 5.58 (1H, s),.7.45 (1H, 7.50-7.60 (3H, m), 7.75 (1H, 7.80 (2H, 8.55 (1H, 10.10 (1H, br 10.42 (1H, 12.02 (1H, 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) Example 78 [2-(4-Acetamidophenylsulfanyl) -8-fluoroquinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIa- 78): Prepared in a manner similar to the above described Method E to afford a white solid, mp 257-2590C; 1H NMR (DMSO) 82.01 (3H, 2.09 (3H, 5.49 (1H, 7.42 (1H, 7.57-7.68 (3H, 7.75 (2H, 8.40 (1H, d), 10.28 (1H, 10.75 (1H, 19F NMR (DMSO) 8-127.3; IR (solid) 1690, 1670, 1637, 1609, 1588, 1543, 1519, 1493, 1456, 1434, 1395, 1366, 1332, 1315, 1289, 1254, 1242, 1032, 838, 829, 808, 744; MS 409.4(M+H) Example 79 (1H-Indazol-3-yl) (2-phenylsulfanylguinazolin-4-yl)-amine (IIa-79): Prepared in a manner similar to the above described Method E to afford a white solid. H NMR (DMSO) 8 7.07 3H), 7.19 1H), 7.37 2H), 7.39 1H), 7.52 (dd, 1H), 7.54 1H), 7.55 IND -254- C( d, 1H), 7.56 11), 7.83 1H), 8.53 1H), 10.71 11), 12.85 1H); MS 370.1 cl Example 80 2 -Hydroxyethyl)phenylamino] -quinazolin-4yl)-(5-methyl-2K-pyrazol-3-yl) -amine (IIc-1):-Prepared in a manner similar to the above described Method A to afford a brown solid, mp 217C; 1H NMR (DMSO) 8 1.99 (3H, C 3.69 (2H, 4.05 (2H, 5.00 (1H, br 5.53 o br 7.09 (1H, 7.25-7.40 (4H, 7.40-7.48 Cl 10 (2H, 7.54 8.34 (1H, 10.07 (1H, 11.67 (11, br IR (solid) 3395, 3155, 3052, 2934, 1623, 1598, 1577, 1475, 1434, 1393; MS .361.2 Example 81 12-(Methylphenylatino)-quinazolin-4-yll-(5methyl-2H-pyrazol-3-yl)-amine (Ilc-2): Prepared in a manner similar to the above described Method A to afford a white solid, mp 154-156C; JH NMR (DMSO) 6 2.03(3H, s), 3.51(3H, 5.70(1H, 7..13(1H, 7.36-7.25(3H, m), 7.48-7.37 (3H, 7.58 (1H, 8.38 (1H, 9.98(1H, 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}-anine (IIc-3): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 1770C; H NMR(DMSO) 8 0.45 (2H, 0.84 (2H, 1.80 (11, s), 3.16 (3H, 4.93 (2H, 6.18 (1H, br 7.10 (1H, 7.34 (2H, 7.55 (1H, 7.64 (11, 8.36 (1H, 8.45 (1H, 8.52 (11, 10.03 (11H, 12.17 (1H, IR (solid) 3104, 2995, 2936, 1618, 1591, 1559, 1541, 1518, 1477, 1409, 1386, 1350, 1300, 1018, 991, 873, 827; MS 372.3 Va o -255- Example 83 (5-Methyl-2-pyrazol-3-yl)-(2-phenylaminoquinazolin-4-yl)-amine (IIc-4): Prepared in a manner similar to the above described Method A to afford a white solid; 1H NMR -(DMSO @60 0 C) .6 2.27(3H, 6. 47(1H,. br s), 6.92(1H, 7.31(3H, 7.53(1l, 7.70 7.91.

(2H, 8.37 (2H, 9.16-(1H, br 10.05 (1H, br s), 12.15 (11, br IR (solid) 1623,.1601, 1573, 1541, 010 Example 84 2 -Benzylamino-quinazolin-4-yl)-(5-methyl-2Hpyrazol-3-yl)-amine (IIc-5): Preparedin a manner similar to the above described Method A to afford a white solid, mp 225-227W0; 1H NMR (DMSO) 6 2.20 (3H, 4.62(2H, d), 7.18 (1H, 7.43-7.60(8H, 8.22 (1H, 9.99 (1H, br 12.05 (1H, br IR (solid) 1630, 1609, 1578, 1538, 1511; MS 331.0 Example 85 2 2 H-pyrazol-3-yl)-amine (IIc-6): Prepared-in a manner similar to the above described Method A to afford an offwhite solid, mp 2800C .H NMR (DMSO) a 1.11- 1.44(5H, 1.56 (1H, 1.71(2H, 1.92 (2H, m), 2.26(3H, 3.75(11, 6.63 (1H, br 7.04 s), 7.28 (11, 7.51(1l, 8.26(1, 9.97(1H, br s), 12.08(1, br 12.75(1H, br IR (solid) 2927, 2853, 1619, 1596, 1569, 1522, 1482; MS 323.0 Example 86 3 -Dihydrobenzo [1,41 dioxin- 6 -ylamino) quinazolin-4-ylJ-(5-methyl-2a-pyrazol-3-yl)-amine (IIc-7): Prepared in a manner similar to the above described Method A to afford an off-green solid, mp -256- 0 c- >250 0 C; 1H NMR (DMSO) 8 2.23 (3H, 4.15 (4H, 6.32 (1H, br 6.76 (1H, 7.16 (1H, 7.22 (1K, dd), 7.39 (IH, 7.57 (1H, 7.66 (1H, 8.34 (1H, d), C- 9.07 br 10.20 (IH, br 12.15 (1i, br IR (solid) 3445, 3045, 2968, 2927, 2868, 1618,. 1595, 1577, 1559, 1509, 1441, 1377, 1073; MS 375.1 c Example 87 2 D methyl-2z-pyrazol-3-yl)-amine (IIc-8): Prepared in a c 10 manner similar to the above described Method A to afford a white solid, mp 2110C; 'H NM (DMSO) 5 0.85-1.30 1.50-1.85 (6H, 2.22 (3H, 3.19 (2H, 6.50- 7.00 (1H, br 7.06 (111, br 7.29 br 7.51 (1H, 8.26 (1H, br 9.97 (1R, br 12.04 (1H, br 12.75 (1H, br IR (solid) 3333, 2927, 2850, 2831, 1627, 1609, 1577, 1540, 1508, 1449; 1422, 1340, 988; MS 337.4 (M+H) Example 88 .[2-(lH-Indazol-6-ylamino)-quinazolin-4-yl]-(5methyl-2H-pyrazol-3-yl)-amine (IIc-9): Prepared in a manner similar to the above described Method A to afford an.off-white solid, mp >2506C; 'H NMR (DMSO) 5 2.24 (3H, 5.93 and 6.89 2xbr 7.05-8.15 (6H,rm), 8.25- 8.90 (2H, 9.25 and 9.97 (1H, -2xbr 10.11 and 10.57 (11, 2xbr 12.15 and 12.80 (2H, 2xbr IR (solid) 3456, 3315, 2923, 1613, 1600, 1577, 1549, 1467; MS 357.1 Example 89 (5-Methyl-2Hzpyrazol-3-yl) -1 2- (pyridin-3ylmethylamino)-quinazolin-4-yl -amine (Ilc-10): Prepared in a manner similar to the above described Method -A to afford an off-white solid, mp 2180C; 'H NMR (DMSO) 5 2.20

IO

0 -257- (3H, 4.59 (2H, 6.30 (1H, br 7.10 (11, s); 7.33 (2H, 7.54 (1H, 7.78 (1H, 8.31 (1H, s), 8.43 8.61 (1N, 10.0 br 12.15 (1H, br IR (solid) 3308, 2945, 2919, 2858, 1623, 1593, 1577, 1552, 1501,-1475,--144 1383; MS 332.1- Example .90 3 methyl-2a-pyrazol-3-yl)-amine (IIc-11): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >250 0 C, 1H NMR (DMSO) 6 2.29 (3H, 5.30-6.98 6.96 (1H, 7.28 (2H, 7.51 (1H, 7.67 7.77 8.23 (1H, 8.46 (1H, 9.35 and 10.00 (1H, 2xbr 10.14 and 10.64 .2xbr 12.20 and 12.82 (1i, 2xbr IR (solid) 3447, 3078, 2945, 2914, 2863, 1618, 1600, 1572, 1549, 1472, 1440, 1403, 1372; MS 351.1 Example 91 4 -Chlorophenylamino)-quinazolin-4-yl methyl-2H-pyrazol-3-yl)-amine. (IIc-12): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >25 0 Oc; 1 NMR (DMSO) 8 2.27 (311H, 5.20-6.80 7.26 (1H, 7.33 (21, 7.51 (11, 7.66 (1H, 7.99 (2H, 8.42 (1H, 9.29 and 9.93 (1H, 2xbr 10.13 and 10.55 (1H, 2xbr s), 12.19 and 12.81 (1H, 2xbr IR (solid) 3439, 3057, 2957, 1618, 1600, 1586, 1572, 1550, 1504, .1486, 1431, 1413, 1367; MS 351.1 (M+H) t Example 92 4 -Fluorobenzylamino) methyl-2H-pyrazol-3-yj)-amine (Ic-13): Prepared in a manner similar to the above described Method A, to afford a white solid,. mp 216 0 C; 'j NMR (DMSO) 2 .20 (3H, s), -258- 4.56 (2H, 6.30 (1W, br 7.05-7.20 (3H, 7.31 (1H, 7.42 (2H, 7.54 (1W, 8.32 (1H, 10.01 and 10.34 (18, 2xbr 12.09 and 12.75 (1H, 2xbr IR (solid) 3333, 2854, 1632, 1609, 1577, 1536, 1508, 1367; MS 349.3 (M+H) 4 Example 93 2 -Hydroxyethyl)phenylamino] -quinazolin- 4-yl)-(-methyl-2H-pyrazol-3-yl)-amine (IIc-14): Prepared in a manner similar to the above described Method A to S 10 afford a white solid, mp 222 0 C; 1 H NMR (DMSO) 5 2.09 (3H, 2.80 (2H, 3.61 (2H, 4.87 (IH, br 5.85 (1H, br 7.30-7.53 (5H, 7.63 (1H, 7.86 (1H, 8.68 (1H, 10.11 (1W, brs), 11.55 (1H, br s), 12.49 (1H, br 1350.s br IR (solid) 3193, 3171, 3111, 3084; 1636, 1577, 1559, 1509, 1486, 1413, 1340, 1058; MS 361.3 Example 94 4 -'Cyanomethylphenylamino).-quinaolin-4yll-(5-methyl-2H-pyrazol-3-yl)-amine (Ilc-15): Prepared 'in a manner similar to the above'described Method A to afford an off-white solid, mp >250 0 C; 1H NMR (DMSO) 2.23 (3H, 4.09 (2H, 6.28 (1H, br 7.41 (2H, 7.48 (1H, 7.57-7.63 (311, 7.87 (1H, 10.70 (11H, 11.56 (11, 12.63 (1H, br 13.25 (1H, br IR.

(solid) 3294, 3271, 3093, 1641, 1586, 1568, 1550, 1513, 1481, 1413, 1336, 1158, 999; MS 356.2 (M+H) t Example 95 3 -Hydroxymethylphenylamino)-quinazolin-4yl]-(5S-methyl-2H-pyrazol-3-yl).-amine (IIc-16): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >250W; 'H NMR (DMSO) 8 2.20 (3H, 4.53 (2H, 5.22 (1H, br 6.31 br s), 7.24 (1H, 7.33-7.53 (4H, 7.61 (1H, 7.86 (1H,

VO

o -259- 8.67 (1H, 10.61 (1H, br 11.52 (1H, br s), S12.59 (1H, br 13.10 (1H, br IR (solid) 3401, 3209, 3108, 3071, 2975, 2916, 1632, 1609, 1595, 1554, 1485, 1421, 1371, 1348, 1046, 1005, 813; MS 347.3 (M+H) C Example 96 2 (3-Hydroxyphenylamino) -quinazolin-4-yl] 5 methyl-2H-pyrazol-3-yl)-amine (IIc-17): Prepared in a manner similar to the above described Method A to afford Sa white solid, mp >250 0 C; 1H NMR (DMSO) 8 2.22 (3H, s), 6.42 (1H, br 6.72 (1H, 6.97 (2H, 7.21 (1H, 7.47 (1H, 7.60 (1H, 7.85 (1H, 8.67 (1H, 9.76 (1H, 10.53 (1H, 11.53 (1H, 12.58 (1H, br 12..99 (1H, br IR (solid) 3354, 3027, 2893, 2817, 1654, 1588, 1541, 1490, 1436, 1418, 1332, 1154, 1004; MS 333.2 (M+H) Example 97 5 -Cyclopropyl-2H-pyrazol-3-yl)-(2phenylamino-quinazolin-4-yl)-amine (IIc-18): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 234°C; IH NMR (DMSO) .0.74 (2H, 0.92 (2H, 1.91 (1H, 5.83 and 6.54 (1H, 2xbr 6.94 (1H, 7.30 (3H, 7.50 (1H, 7.65 (1H, 7.91 (2H, 8.27 (1H, 9.13 and 9.77 (1H, 2xbr 10.07 and 10.52 (1H, 2xbr 12.19 and 12.82 (1H, 2xbr IR (solid) 3443, 1622, 1595, 1577, 1554, S1486, 1449, 1413, 1376, 1340, 1235, 1171, 988, 806;.MS 343.2 (M+H) Example 98 (5-Cyclopropyl-2H-pyrazol-3-yl)- methylphenylamino)-quinazolin-4-yl]-amine (IIc-19): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 117°C; 1H NMR (DMSO) 6 0.72 0.92 (2H, 1.90 (1H, 2.32 -260- 0 0 (3H, 6.20 (1i, br 6.80 (1H, 7.20 (1i, t), 7.27 (1H, br 7.51 (1H, br 7.55-7.85 (3H, 8.43 (iH, br 9.50 (1HI, br 10.44 (1H, 12.55 (1iN, br C IR (solid) 3303, 1618,.1581, 1554, 1536, 1495, 1472, 1436, 1413, 1372, 1336, 1240, 990; MS 357.4 Ol SExample 99 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(6methoxypyridin-3-y1amino)-quinazolin-4-yl] -amine Prepared in a manner similar to the above C 10 described Method A to afford a pink solid, mp 1200W; 'H NMR (DMSO) 5 0.72 (2H, 0.91 (2H, 1.89 (IH,i m), 3.85 (3H, 6.20 (1N, br 6.82 (1H, 7.25 (1H, 7.48 (1Hi, 7.66 (IH, 8.13.(1H, br 8.42.

(1HI, br 8.61 (1H, br 9.50 (1W, br 10.48(1H, br 12.55 (iH, br IR (solid) 3457, 3439, 1622, 1604, 1577, 1554, 1481, 1422, 1386, 1363, 1272, 1235, 1035, 985, 821; MS 374.2 (M+H)t Example 100 (5-cyclopropyl-2-pyrazol-3-yl) ylamino)-quinao1in-4-yl]-amine (IIc-21): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 199-204oC; 'H NMR (DMSO) 8 0.69 (2H, br 0.91 (2H, br 1.90 2.02 (2H, m), 2.68 (1H, 2.83 (3W, 6.46 (1H, br 7.18 (1H, 7.26 (IH, br 7.50 (1H, d),.7.67 (1H, 7.75 (11, br 8.45 (1H, br 9.70 (1H, br 10.60 (1H, br 12.30 and 12.80 (1H, 2xbr IR (solid) 1621, 1601, 1572, 1552, 1495, 1474, 1439, 1425, 1408, 1382, 1363, 1319, 1267; MS 383.3 (M+H) t Example 101 (5-Cyclopropyl-2H-pyrazol-3-yl)-12-(1H-indol- 6-ylamino) -quinaolin-4-yll-amine (IIc-22): Prepared in a manner similar to the above described Method A to afford

VO

D *-261a dark brown solid, mp >300oC; 'H NMR (DMSO) 6 0.69 (2H, S.br 0.89 (2H, br 1.88 (1H, 5.77 and 6.74 (1H, 2xbr 6.35 (1H, 7.22 (3H, br 7.45 (2H, 7.65 (1H, 8.35 (2H, br 8.86, 9.70 and 10.01 (IH, 3xbr 10.4.9, 12.12 and 12.84 (1H, 3xbr 10.94 (s, 1H); IR (solid) 1623, 1603, 1571, 1549,.1495, 1477, 1460, S1419, 1383, 1336, 1264, 1250, 1238; MS 382.4 (M+H)

I<D

o Example 102 4 -Acetamido-3-methylphenylamino)quinazolin-4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIc-23): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp >188 0 C 1H NMR (DMSO) S 0.72 (2H, br 0.94 (2H, .br 1.92 (1H, 2.03 (3H, 2.19 (3H, 5.80 and 6.69 2xbr 7.22 (2H, br 7.49 (1H, br 7;70 (3H, 8.35 (1H, br 9.01, 9.59 and 10.01 (1H, 3xbr 9.19 (1H, 10.53, 12.16 and 12.81 (1H, 3xbr IR (solid) 1637, 1624, 1578, 1542, 1502, 1474, 1428, 1403, 1343, 1320, 1307, 1250; MS 414.4 220 Example 103 4 -Chloro-3-methylphenylamino) -quinazolin- 4-yl]-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIc-24): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 244-246oC; 1H NMR (DMSO) 6 0.69 (2H, br 0.94 (2H, br 1.91 (1H, 2.32 (3H, 5.89 and 6.63 (1H, 2xbr 7.28 (2H, 7.49 (1H, 7.65 (1H, 7.80 (1H, br 7.86 (1H, 8.40 (1H, br 9.17, 9.81 and 10.06 (1H, 3xbr 10.58,. 12.19 and 12.78 (1H, 3xbr IR (solid) 1615, 1578, 1549, 1475, 1419, 1397, 13.65, 1331, 1296, 1261, 1238,'1187, 1139; MS 391.4 (M+H)

IND

IND

CA

Va 0A 0D ci -262- Example 104 (5-Cyclopropyl-2r-pyrazol-3-yl)-[2-(4ethylphenylamino) -quinazolin-4-yl] -amine Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 250-251 0 C; 'H 5 NMR (DMSO) 8 0.72 (2H, br 0.91 (2H, br-s), 1.19 (3H, 1.91 (1H, 2.58 (2H, 5.81. and 6.64 (1H, 2xbr 7.15 (2H, 7.22 (1H, 7.47 (11, 7.64 (1H, 7.78 (2H, 8.36 (1H, br 9.03, 9.66 and 10.05 (1H, 3xbr 10.49, 12.20 and 12.80 (1H, 3xbr IR (solid) 1603, 1574, .1546, 1509, 1497, 1474, 1439, 1417, 1386; MS 371.5 (M+H) 4 Example 105 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(4propylphenylamino)-quinazolin-4-yll -amine (IIc-26): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 255-2560C; H NMR (DMSO) 8 0.72 (2H, br 0.91 (5H, 1.60 (2H, m), 1.90 (11, 2.58 (2H, 5.81 and.6.63 (1H, 2xbr s), 7.12 (2H, 7.21 (18, 7.47 (1H, 7.63 s), 7.77 (2H, 8.36 (11, br 9.01, 9.70 and 10.11 (1H, 3x br 10.51, 12.17 and 12.80 (1H, 3xbr IR (solid) 1595, 1571, 1545, 1499, 1477, 1442, 1413, 1388; MS 385.6 Example 106 (5-Cyclopropy1-2H-pyrazol-3-yl1)-{2-[4-(2hydroxyethyl)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- 256oC; 'H NMR (DMSO) 8 0.73 (2H, br 0.91 (5H, 1.90 (11, 2.69 (2H, 3.60 (2H, 4.62 (1H, 5.81 and 6.65 2xbr 7.15 7.22 (1H, 7.46 (1H, 7.63 (1H, 7.77 (2H, 8.36 br s),

IO

0 -263- 9.05, 9.69 and 10.02 (1H, 3xbr 10.52, 12.17 and 12.79 (in, 3xbr s) IR (solid) 1632, 1569, 1546, 1483, 1452, 1434, 1402, 1371, 1267, 1231; MS 387.4 Example 107 (S-Cyclopropyl-2H-pyrazol-3-yl)-(2phenetylaminb-quinazolin-4-yl)-amine (IIc-28): Prepared in a manner similar to the above described Method A to IN afford a white solid, mp >250 0 C; 1 NMR (DMSO) 6 0.66 (2H, o 0.84 1.83 (1H, 2.90 (2H, 3.56 (2H, 6.29 (1H,br 7.01 (11, 7.12-7.38 (6H, 7.48 (1H, 8.42 (1H, 10.91 (1H, br 13.11 (IH, br IR (solid) 2922, 1650,.1627, 1577, 1550, 1500, 1482, 1395, 1368, 1004, 832; MS 371.3 Example 108 2 -Cyclohexylethylamino) -quinazolin-4-yl]- (5-cyclopropyl-2-pyrazol-3-yl)-amine (IIc-29): Prepared :in a manner similar to the above described Method A to afford a white solid, mp >25 0 aC; 1H NMR (DMSO) 5 0.70 (2H, 0.80-1.00 1.05-1.30 (4H, 1.30-1.50 (3H, 1.55-1.80 (5H, 1.87 (1H, 5.40-6.70 (2H, br 7.04 (11, 7.25 (1H, 7.49 8.25 (1H, 10.06. (11, brs), 11.93 (1H, br IR (solid) 3448, 2920, 2852, 1618, 1600, 1568,' 1550, 1486, 1418, 1395, 1367, 1258, 1008, 985; MS 377.4. (M+H) 4 Example 109 4 -Carboxymethoxyphenylamino)-quinazolin- 4-yl]-(5S-cyclopropyl-2-pyrazol-3-yl)-amine Prepared in a manner similar to the above described Method A to afford a yellow solid, mp >250C; 11 NMR (DMSO) 0.72 (2H, 0.91 1.90 (1H, 4.62 (2H, 6.24 (1H, 6.88 (2H, 7.21 (11, 7.45 (1H, 7.62 (11, 7.78 (2H, 8.35 (1H, 9.31 (1H, 10.25 (1H, 11.70 (11, br IR (solid)

NO

v.0 -264- 0 Cl 1663, 1595, 1563, 1509, 1422, 1331, 1240,.1176, 1053, 999; MS 417.3 C- Example 110 4 -Cyanomethylphenylamino)-quinazolin-4ylJ-(5-cyclopropyl-2H-pyrazol-3-yl).-amine- (IIc-31): C Prepared in a mahner similar to the above described Method A to afford a white solid, mp 222 0 C; 'H NMR (DMSO) 8 0.74 (2H, 0.93 (2H, 1.92 (1l, 3.97 (2H, s), 5.82 and 6.65 (1W, 2xbr 7.29 (3H, 7.50 (1H, m), Cl 10 7.66 (IH, 7.92 (2H, 8.39 (1H, 9.21 and 9.85 (1H, 2xbr 9.90 and 10.56 (1H, 2xs), 12.19 and 12.80 (1W, 2xbr IR (solid) 1641, 1622, 1595, 1581, 1554, 1513, 1486, 1463, 1408, 1372, 985, 821; MS 382.3 (M+H) 4 Example 111 2 -(Benzothiazol-6-ylamino)-quinazolin-4-yl]-'.

(5-cyclopropyl-2H-pyrazol-3-yl)-amine (Iic-32): Prepared in a manner similar to the.above described Method A to afford an off-white solid, mp 255-256 0 C; 'H NMR (DMSO) S 0.73 (2H, 0.92 (2H, 1.92 (1H, 5.83 and 6.63 (1H, 2xbr 7.27 (1H, br 7.59 (1H, br 7.68 (1H, br 7.79 (1H, br 7.98 (1H, br 8.41 (1H, br s), 8.97 (1H, br 9.19 (1W, 9.58 and 10.10 (1W, 2xbr 10.57, 12.21 and 12.85 (1i, 3xbr IR (solid) 1624; 1592, 1575, 1512, 1472, 1411, 1377, 1333, 1244; MS 400.3

(M+H)

t Example 112 (5-Cyclopropyl-2-pyrazol-3-yl)- dimethylphenylamino)-quinazolin-4-yl]-amine (IIc-33): Prepared in a manner similar to the above described Method A to afford a white solid, mp 245-246OC; 'H NMR (DMSO) 8 0.72 (25, brt 0.90 (2H, br 1.90 (1H, m), 2.18 (3HW, 2.23 (3H, 5.77 and 6.63 (1H, 2xbr s) Va 0 -265- 7.09 (1W, 7.23 (1H, br 7.47 (1W, br 7.59 (1H, br 7.64 (1H, br 8.36 (1H, br 9.02, 9.55 and 10.07 (1H, 3xbr 10.49, 12.31 and 12.80 (1k, 3xbr s) IR (solid) 1620, 1600, 1574, 1552, 1497, 1474, 1436, 1416, 1385, 1262; MS 371.5 (M+H) Example 113 (5-Cyclopropyl-2H-pyrazol-3-yl)- 2-(2phenoxyethylamino)-quinazolin-4-yl] -amine (IIc-34): Prepared in a manner similar to the above described Method A to afford a white solid, mp 203 0 C; 1H NMR (DMSO) 6 0.70 (2H, 0.88 1.87 (1N, 3.73 (2H, d), 4.16 (2H, 5.75 and 6.70 (1H, 2xbr 6.93 (1H, t), 6.90-7.20 7.20-7.45 (3H, 7.55 (1H, 7.76 (1W, br 8.32 (1H, 9.95 and 10.35 (1W, 2xs), 12.13.

and 12.75 (1H, 2xbr IR (solid) 3434, 1622, 1600, 1572, 1554, 1499i 1476, 1422, 1399, 1385, 1303, 1267, 1226, 1212, 1052, 829; MS 387.4 (M+H) 4 Example 114 (5-Cyclpropyl-2H-pyrazo-3-yl)-[2-(thiophen- .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 2120C; 1H NMR (DMSO) 6 0.67 (2H, 0.90 1.86 (1W, 4.74 (2H, 5.76 and 6.66 (1H, 2xbr 6.95 (1H, 6.90-7.20 (2H, m), 7.20-8.45 (5H, 9.94 and 10.40 (1H, 2xs), 12.13 and 12.71 (1W, 2xbr IR (solid). 3444, 2948,.2847, 1622, 1600, 1559, 1500, 1481, 1418,.1390, 1358, 1336, 1313, 1263,-1217, 1185, 1149, 990, 821; MS 363.4 Example 115 4 -Carboxymethylphenylamino)-quinazolin-4yl]-(5-cyclopropyl-2H-pyrazol-3-yi)-amine (IIc-36): .Prepared in a.manner similar to the above described Method A to afford a brown solid, mp >2100C 1H NMR O -266- C (DMSO)}- 0.64 (2H, br 0.92 (2H, 1.92 (1H, m), 3.50 (2H, 5.76 and 6.54 (1H, 2xs), 7.19 (1H, 7.24 (1H, 7.49 (1H, .7.64 (1H, 7.84 (2H, 8.37 C- '(1H -10.27 and 12.25 (1H, 2xbr IR (solid) 1648, 1591, 1555; 1512, 1489, 1428, 14,11, 1374; MS 401.4 (M+H) Cl C Example 116 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(1H- C indazol-5-ylamino)-quinazolin-4-yl]-amine (IIc-37): CD Prepared in a manner similar-to the above described Cl 10 Method A to afford a purple solid, mp 268-271 0 C; 1H NMR (DMSO) 6 0.69 (2H, br 0.90 (2H, 1.88 (1H. m), 5.86 and 6.58 (1H, 2xs), 7.22 (1H, 7.61 (1H, 7.71 (2H, 8.01 (1H, 8.37 (2H, 8.58, 9..05 and 9.58 (1H, 3xbr 10.01, 10.68 and 12.38 (1H, 3xbr 12.90 (1H, 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)- (pyridin- 3-ylmethylamino)-quinazolin-4-yl]-amine (IIc-38): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 193 0 C; 'H NMR (DMSO) 6 0.69 (2H, 0.89 (2H, 1.86 (1H, 4.60 (2H, s), 5.76, 6.22 and 6.66 (1H, 3xbr 7.10 (1H, 7.33 (2H, 7.54 (1H, 7.78 (1H, 8.31 (1H, 8.44 (1H, 8.61 (IH, 10.00 and. 10.32 (1H, 2xs), 12.15 and 12.63 (1H, 2xbr IR (solid) 2927, 2850, 1623, 1600, 1577, 1536,. 1477, 1418, 1332, 1254, 814; MS 358.3

(M+H)

Example 118 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2- (3methoxycarbonylphenylamino)-quinazolin-4-yl -amine (IIc-39): Prepared in a manner similar to the above

VO

S -267c described Method A to afford a white solid, mp 228-231oC; SH NMR (DMSO) 8 0.73 (2H, br 0.91 (2H, 1.92 (1H, 3.88 (3H, 5.99 and 6.79 (1H, 2xs), 7.27 (1H, s), 7.46 (3H, 7.68 (1H, 8.36 (1H, 8.48 (2H, s), A 5 9.36, 9.84 and 10.00 (1H, 3xbr 10.63, 12.17 and 12.79 (1H, 3xbr IR (solid) 1716, 1615, 1591, 1579, 1557, o 1473, 1432, 1416, 1379, 1334, 1298, 1276, 1226, 1191, CD 1142, 1110, 1020, 985; MS 401.3 (M+H) Example 119 (3-Carboxyphenylamino) -quinazolin-4-yl] (5-cyclopropyl-2H-pyrazol-3-yl)-amine (IIc-40): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 298-302C; 'H NMR (DMSO) 6 0.73 (2H, br 0.91 (2H, 1.90 (1H, 7.26 (iH, s) .7.35 (1H, 7.50 (2H, 7.66 (1H, 8.31 (2H, 8.41 (1H, IR (solid) 1661, 1597, 1578, 1558, 1517, 1486, 1424, 1385; MS 387.3 (M+H) Example 120 (5-Cyclopropyl-2H-pyrazol-3-yl) (3ethylphenylamino)-quinazolin-4-yl] -amine (IIc-41) Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 186-188OC; 1H NMR (DMSO) 8 0.73 (2H, br .0.91 (2H, br 1.22 (3H, 1.90 (1H, 2.62 (2H, 5.81 and 6.70 (1H, 2 x br 6.78 7.20 (2H, 7.48 (1R, 7.65 (1H, 7.69 (1H, 7.81 (1H, 8.38 (1H, br 9.03, 9.74 and 10.03 (1H, 3 x br 10.55, 12.16 and 12.82 (1H, 3 x br IR (solid) 1614, 1580, 1549, 1534, 1493, 1471, 1433, 1409, 1374, 1340, 1240, 1182, 1165, 1138; MS 371.3 (M+H) Va op -268ci Example 121 (5-Cyclopropyl-2H-pyrazol-3-yl) dimethylphenylamino) -quinazolin-4-yl] -amine (IIc-42): Prepared in a manner similar to the above described C- Method A to afford an off-white solid, mp 241-242 0 C; 1H NMR (DMSO) 6 0.58 (2H,,br s),-0.86 (2H, 1.77 (1K, br O 2.11 (3H, br 2.28 (3H, 5.77 and 6.14 (1I, 2 x br 7.01 (1K, 7.11 (iH, 7.22 (1H, br 7.29 Ci 7.56 (1H, 8.36 (1K, br 8.49, 8.98 and Va o 9.98 (1K, 3 x br 10.48, 12.04 and 12.68 (1K, 3 x br CI 10 IR (solid) 1622, 1603, 1573, 1552, 1495, 1471, 1440, 1428, 1412, 1384, 12684 MS371.4 (M+H) 4 Example 122 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(t,4dimethoxyphenylamino)-quinazolin-4-yll-amine (IIc-43): Prepared in a manner similar to the above described Method A to afford a grey solid, mp 144 0 C; 'H NMR (DMSO) 0.69 0.86 (2H, 1.89 (IH, 3.61 (3H, 3.67 (3H, 5.76 (1H, br 6.12 (1H, 6.31 (1H, 6.66 (1H, 6.94 (1H, d) 7.27 (1H, 7.50-(1, 7.68 (1H, 8.45 and 9.36 (1H, br s, rotamers), 9.42 and 10.54 (1H, s, rotamers), 12.29 and 12.82 (1i, 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) 4 Example 123 (5-Cyclopropyl-2H-pyrazol-3-yl) methoxyphenylamino)-quinazolin-4-ylJ-amine (IIc-44): Prepared in a manner similar to the above described Method A to afford a grey solid, mp 207-211 0 C; 'K NMR (DMSO) 6 0.73 (2H, br 0.91 (21, br 1.91 (1i, m), 3.77 (3H, 5.81 and 6.71 (IH, 2 x br 6.53 (1H, d), 7.19 7.85 (7H, 8.34 (1H, .9.08, 9.79 and 10.06

VO

o ,-269- C (1H, 3 x br 10.56, 12.16 and 12.82 (1H, 3 x br IR (solid) 1611, 1580, 1549, 1533, 1498, 1477, 1430, 1409, 1374, 1337, 1253, 1204, 1180, 1157, 1141,*1041, 1030, C 992-; MS 373.7 (M+H) CA Example 124 (5-Methyl-2H-pyrazol-3-yl) (2-phenylamino- 5,6,7,8-tetrahydroquinazolinin-4-yl)-amine CA Prepared in a manner similar to the above described SMethod C.

C( Example 125 [2-(Biphenyl-3-ylamino)-quinazolin-4-yl] 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 153C; 1H NMR (DMSO) 8 0.73 (2H, 0.90 (2H, 1.89 (1H, 5.83 and 6.70 (1H, br s, rotamers), 7.25 (2H, 7.32 (2H, 7.50 (3H, 7.68 (3H, 8.00 (1H, 8.22 (1H, br 8.40 (1H, br 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, 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) 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 0 1 H NMR (DMSO).

6 0.71 (2H, 0.91 1.89 (3H, 2.69 (2H, s), 3.37 (2H, 5.76 and 6.66 (1H, br s, rotamers), 6.95- 7.60 (8H, 8.10-8.40 (1H, 9.89 and 10.30 (1H, br s, rotamers), 12.10 and 12.75 (1H, br s, rotamers); IR S* (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-2H-pyrazol-3-yl)-amine (IIc-48): Prepared in -a manner similar to the above described Method-A to-afford-a-pale brown solid, mp 251C; H NMR (DMSO) 8 2.04 (3H, 2.19 (3H, 2.56 (3H, 5.92 and 6.80(1H, br s, rotamers), 7.22 (2H, 0 7.48 (1H; 7.64 (12, 7.73 (2H, 8.40 (1H, ci o 9.05 and 9.74 (1H, br s, rotamers), 9.20 (12, s), Ci 10 10.05 and 10.54 (1H, br.s, rotamers), 12.15 and 12.82 (1H, br s, rotamiers); IR (solid) 3309, 2972, 2936, 1641, 1604, 1577, 1536, 1504, 1468, 1423, 1409, 1377, 1341, 1304, 1259, 1223, 1100, 1009, 864; MS 388.2 Example 128 (5-Cyclopropyl-25-pyrazol-3-yl) -[2-(indan-2ylanino)-quinazolin-4-yl]-amine (IIc-49): Prepared in a manner -similar to the above described Method A to afford a brown solid, mp 233-234 0 C; 1H NMR (DMSO) 8 0.65 (2H, s), 0.84 (2H, 1.83 2.91 (2H, 3.33 (2H, s), 4.72 (1H, 6.07 (12, br 7.00-7.60 (82, 8.29 (12, 10.30 (1H, br 12.24 (1H, br IR (solid) 3425, 2941, 2836, 1622, 1595, 1572, 1540, 1495, 1476, 1426, 1394, 1248, 1025, 1007, 870, 833; MS .383.3 Example 129 [2-(3-Methylphenylamino)-quinazolin-4-yl] methyl-2H-pyrazol-3yl)-amine (Ic-50): .Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 240-242 0 C; 1H NMR (DMSO) 8 2.25 (3M, 2.30 (3H, 5.95 (1H, br 6.76 (12, d), 7.10-7.35 (2H, 7.48 (12, 7.55-7.85 (3H, 8.40 (1H, 9.05 and 9.74 (12, br s, rotamers), 10.07 and 10.55 br s, rotamers), 12.14 and 12.81 (1H, br s,

VO

0-271rotamers); IR (solid) 3443, 2914, 2859, 1622, 1586, 1549, t 1536, 1481, 1445, 1408, 1372, 1330, 1267, 1239, 1184, 1166, 1139, 993, 838, 806; MS 331.3 (M+H) ci Example 130 2 CA 4 -yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-51): Prepared Sin a manner similar to the above described Method A to 0 afford a grey solid, mp 246-247oC; 1 H NMR (DMSO) 8 2.19 (3H, 2.31 (3H, 6.37 (1H, br 6.94. (1H, d), 7.23 (1H, 7.37 (1H, 7.43 (1H, 7.64 (1H, t), 7.97 (1H, 8.19 (1H, 8.42 (1H, br 10.17 (1H, br 12.19 (1H, br 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) Example 131 (5-Cyclopropyl-2H-pyrazol-3-yl)-{2-[4- (morpholin-1-yl)phenylamino -quinazolin-4-yl}-amine (Ilc-52): Prepared in a manner similar to the above described Method A to afford a grey solid, mp 275-2760C; H NMR (DMSO) 0.71, (2H, 0.90 (2H, 1.89 (1H, s), 3.05 (4H, 3.75 (4H, 5.78 and 6.'61-(1H, br s, rotamers), 6.93 (2H, 7.20 (1H, 7.43 (1H, s), 7.50-7.90 8.39 (1H, 8.95 and 9.58 (IH, br s, rotamers), 10.07 and 10.47 (1H, br s, rotamers), 12.16 and 12.81 (1H, 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 j(M+H) Example 132 [2-(Benzothiazol-6-ylamino)-quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (IIc-53): Prepared in a manner similar to the above described Method A to afford an off-white solid, mp .236-239 0 C; 1H NMR (DMSO) 8 2.25

O

o -272- (3H, 6.35 (1H, br 7.22 (11, 7.53 (1H, d), 7.62 (1H, 7.76 (1H, 7.98 (1H, 8.39 (IH, d), 9.05 (1H, 9.17 (1H, 9.59 (1H, br 10.30 (1H, Ci br 12.35 (1H, br IR (solid) 1622, 1605, 1567, 1546, 1505, 1473,-1441, 1417, 1385, 1341, 1297, 1273, C -1253, 1192, 1130; MS 374.1 Cl Example 133 2 3 ,4-Dimethylphenylamino) -quinazolin-4-

NO

yl -(5-methyl-2H-pyrazol-3-yl)-amine (IIc-54): Prepared C: 10 in a manner similar to the above described Method A to afford an off-white solid, mp 249-2510C; 1H NMR (DMSO) 8 2.18 (3H, br 2.21 (3H, br 2.24 (3H, br 5.92 and 6.80 (1H, 2 x br 7.05 (1H, br 7.21 (1H, br 7.46 (IH, br -7.64 (3H, br 8.37 (1H, br s), 9.00, 9.51 and 9.73 (1H, 3 x br 10.12, 10.54 and 12.17 (1H, 3-x br IR (solid) 1616, 1582, 1547, 1505, 1473-, 1452, 1413, 1368, 1334, 1294, 1246, 1210, 1188, 1170, 1139; MS 345.3 (M+H) Example 134 3 -Ethylphenylamino) -quinazolin-4-yl] 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; 1H NMR (DMSO) 8 1.21 (3H, 2.25 (3H, br 2.61 (2H, 5.92 and 6.80 (H1, 2 x br 6.78 (1H, 7.21 (2H, br 7.48 (1H, br 7.65 (1H, 7.72 (1H, 7.80 (1H, 8.40 (1H, br 9.09, 9.58 and 10.10 (1H, 3 x br 10.54, 12.26 and 12.81 (1H, 3 x br IR (solid) 1619, 1556, 1535, 1471, 1441, 1407, 1377, 1341, 1274, 1246, 1185, 1167, 1139, 995; MS 345.5 (M+H) Example 135 3 -Methoxyphenylamino) -quinazolin-4-yl] (5-methyl-2H-pyrazol-3-yl)-amine (IIc-56): Prepared in a VO ID S-273manner similar to the above described Method A to afford t an off-white solid, mp 212-215 0 C; H NMR (DMSO) 8 2.25 (3H, br 3.77 (3H, 5.92 and 6.84 (1H, 2.x br s), 6.55 (1H, 7.13 (2H, 7.41-7.50 (2H, 7.65 (1H, C 5 7.77 (1H, 8.41 (1H, br 9.10, 9.79 and 10.10 Ci (1H, 3 x br 10.55, 12.13 and 12.82 (1H, 3 x br IR o (solid) 1610, 1576, 1532, 1494, 1468, 1425, 1337, 1277, ND 1256, 1201, 1159; MS 347.4 0 Example 136 4 -Acetamido-3-cyanophenylamino) quinazolin-4-yl] (5-methyl-2 2-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 0 C; IH NMR (DMSO) 8 2.08 (3H, 2.28 (3H, 6.67 (1H, br 7.27 (1H, 7.43 (1H, 7.53 (1H, s), 7.68 8.04 (1H, 8.45 (2H, 9.41, 10.35 and 12.18 (2H, 3 x br 10.00 (1H, IR (solid) 1620, 1583, 1558, 1237, 1508, 1477, 1446, 1413, 1373, 1341, 1292, 1259, 1241, 1180, 1162, 1142, 1105, 1030, 1000; MS .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 afford a white solid, 222-223oC; H NMR (DMSO) 8 2.22 (3H, 3.75 (3H, 6.82 (1H, br 7.05-7.11 (1H, m), 7.15-7.25 (1H, 7.30-7.36 (1H, 7.40-7.50 (3H, m), 7.49-7.55 (2H, 7.55-7.70 (1H, 7.70-7.82 (1H, m), 7.90-8.02 (1H, 8.30-8.50 (IH, IR (solid) 1625, 1604, 1574, 1556, 1496, 1473, 1444, 1403, 1384, 1258, 1234, 1182, 1018, 824, 806, 755, 698; MS 423.4 (M+H) o -274- Cl Example 138 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

C

N an off-white solid, mp 253-256 0 C; 1H NMR (DMSO) 6 2.02 (3H, 2.25 (3H, br '5.92 and 6.77 (1H, 2 x br s), C 7.21 (1H, 7.49 (3H, 7.63 (1H, 7.83 (2H, d), 8.38 (1H, br 9.03 and 10.05 (1H, 2 x br s),.9.81 (1H, Cql 12.13 and 12.80 (IH, 2 x br IR (solid) 1669, 1635, 1617, 1574, 1535, 1512, 1486, 1422, 1394, 1366, Cl 10 1316, 1268, 1231, 1184, 1119, 1101; MS 374.1 Example 139 4 -tert-Butoxycarbonylamino-phenylamino) quinazolin-4-yll (5-methyl-2H-pyrazol-3-yl) -amine Prepared in a manner similar to the above described Method A to afford an off-white solid, mp 238- 242 0 C; 1H NMR (DMSO) 8 1.48 (9H, 2.24 (3H, 6.23 (fH, br 7.12 (1H, 7.36 (3H, 7.54 (1H, s), 7.67 (2H, 8.30 (1H, 9.14 (2H, br 10.24 and 12.19 (1H, 2 x br.s); IR (solid) 1698, 1620, 1555, 1520, 1475, 1443, 1405, 1371, 1310, 1241, 1167, 1055, 996; MS 432.1 Example 140 (4-Cyanophenylamino) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (IIc-61): Prepared in a manner similar to the.above described Method A to afford an off-white solid, mp 293-298oC; 1 H NMR (DMSO) 8 2.25 6.50 (1H, br 7.27 (1H, 7.51 (1H, s), 7.64 (1H, 7.71 (2H, 8.40 (1H, 9.76 (1H, br 10.34 (1H, br 12.33 (1H, br IR (solid) 1633, 1605, 1571, 1517, 1505, 1469, 1418, 1337, 1255, 1174, 1000; MS 342..1 (M+H) Va -275- Example 141 (5-Methyl-2H-pyrazol-3-yl) (6-oxo-6,1obdihydro-4aH-benzo[c]chromen-2-ylamino)-quinazolin-4-yllamine (IIc-62): Prepared in a manner similar to the above described Method A to afford a pale yellow solid,. mp 293- 2980C; H NMR (DMSO) S 1.72 (3H, br 6.23 (114, br s), 7.50. (1H, 7.66 (2H, 7.75 (1H, 7.87 (1H, t), 7.77 (1H, 8.26 (1H, 8.33 (1H, 8.58-8.72 (2H, 10.55 (11, 11.55 (1H, 12.40

IR

o (solid) 1707, 1629, 1607, 1579, 1540, 1497, 1488, 1471, 1446, 1428, 1417, 1346, 1332, 1298, 1270, 1255, 1207, 1114, 998, 816, 793, 766, 758; 710, 685; MS 435.4 Example 142 [2-(Biphenyl-3-ylamino)-quinazolin-4-yl-(5methyl-2BH-pyrazol-3-yl)-amine (IIc-63): Prepared in a manner similar to the above described Method A to afford a pale brown solid, mp 206-207C; H NMR (DMSO) 5 2.20.

'6.80 (1H, br 7.24-7.27 7.36-7.40 (2H, 7.48-7.52 (3H, m),.7.67-7.69 (3H, 7.94 (11, 8.26 (1w, 8.42 (lj 9.30 (1H, br 10.16 (1W, br 12.13 (1H, br IR (solid) 1593, 1578, 1544, 1498, 1479, 1414, 1384, 1251, 1209,- 1003; MS 393.2 Example 143 4 -Methoxycarbonylmethyl-3 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 0 C; 1H NMR (DMSO) 6 2.23 (3H, 2.26 (3H, 3.63 (3H, 3.64 (2H14, 5.99 (0.5H, br 6.80 (0.5 H, br 7.10 (1w, m) 7.25 (1H, 7.50 7.61-7.80 8.44 (1H, 9.10 (0.5H, br 9.78 (0.5H, br 10.11 (0.5H, br 10.56 (0.5H, br 12.18 Va o -276br 12.90 (0.5H, br 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) t C Example 144 [2-(4-Carboxymethyl-3-methylphenylamino)quinazolin-4-yl (5-methyl-2H-pyrazol-3-yl)-amine C (IIc-65): A solution of [2-(4-methoxycarbonylmethyl-3- O methylphenylamino)-quinazolin-4-yl (5-methyl-2H-pyrazol- C- 10 3-yl)-amine (Iro-64, 200 mg, 0.5 mmol).in a mixture of methanol/water 8 mL) was treated with IM NaOH (2 mL, 2 mmol). The mixture was heated at 700C for 2 hours and then neutralised with IM HC1 (2mL, 2 mmol). The solid that formed was collected by filtration to afford the title compound (185 mg, as a pale yellow solid, mp 2450C 'H NMR (DMSO) S 2.27 (6H, 2xs), 3.55 (2H, 6.49 (1H, 7.13 (1H, 7.26 (1H, 7.50 (1H, 7.62-7.78 8.42 (1H, 9.34 10.26 (1H, 12.36 (11, IR (solid) 1660, 1590, 1562, .1504, 1427, 1385, 810, 776, 751, 693; MS 389.4 Example 145 (4-Aminophenylamino) -quinazolin-4-ylJ- methyl-2H-pyrazol-3-yl)-amine (IIc-66): A solution-of [2- (4 -tert-Butoxycarbonylamino-phenylamino)-quinazolin-4yl]-(5-methyl-2H-pyrazol-3-yl)-amine (IIc-60, 100 mg, 0.232 mmol)- in a-mixture of DCM/TFA 12 mL) was *stirred for 2 hours at room temperature. The solvents were removed in vacuo and the residue triturated in aqueous K003. The resulting solid was collected by filtration and washed with diethyl ether to afford IIc-66 (69 mg, 90%) as an off-white solid, mp 164-1670C; H NMR (DMSO) 8 2.24 (31, 6.33 (1H, br 7.12 (2H, d), 7.48 (3H, 7.58 (1H, 7.86 (1H, 8.64 (1H, d),

O

S-277- S10.86 (1H, br 11.46 (1H, IR (solid) 1681, 1512, S1496, 1433, 1415, 1187, 1129; MS.332.4 (M+H) 4 Example 146 4 -Bromophenylamino) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (IIc-67): Prepared in a manner similar to the above described Method A to afford San off-white solid, mp 290-2930C; H NMR (DMSO) 8 2.27 (D (3H, 6.71 (1H, br 7.22 (11, 7.46-7.50 (3H, Sm), 7.66 (1H, 7.92-7.94 (2H, 8.38 (1H, 9.28, 10.11 and 12.13 (3H, 3 x br IR (solid) 1619, 1572, 1548, 1486, 1436, 1409, 1372, 1238, 1186, 1136, 1071, 997; MS 395.1/397.1

(M+H)

-Example 147 4 -Isobutyrylamino-phenylamino)quinazolin-4-yl]- (5-methyl-2H-pyrazol-3-yl)-amine (IIc- 68): Prepared in a manner similar to the above described Method A to afford a yellow solid, mp 176-179-C; 1 H

NMR

(DMSO) 8 1.11 (6H, 2.15 (3H, 2.62 (11H, 6.25 (1H, br 7.41 (1H, 7.46 (1H, 7.63 (1H, d), 7.71 (2H, 7.84 (1H, 8.64 10.00 (1H, s), 10.34 1H br 11.47 (1H, br 12.47 (1H, br IR (solid) 1676, 1653, 1585, 1561, 1512, 1423, 1407, 1312, 1199, 1177, 1128; MS 402.3

(M+H)

Example 148 (5-Ethyl-2H-pyrazol-3-yl)- [2-(5-ethyl-2Hpyrazol-3-ylamino)-quinazolin-4-yl]-amine (IIc-69): To a solution of 2, 4 -dichloroquinazoline (0.5g, 2 .51mmol) and (558 mg, 5.02 mmol) in ethanol was added triethylamine (0.35mL 2.51mmol) and the 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.

NO

0 278c off-white solid, mp 248-252oC; H NMR (DMSO) 8 1.30 (Im, 6H), 2.72 4H), 6.12 (br.s, 1H), 6.54 and 6.90 Cbr. s, 1H), 7.58 1H), 7.74 (di 1H), 7.90 1H), 8.78 (d, 1H); IR (solid) 1639, 1602, 1591, 1555, 1418; MS 349.2

(M+H)

4 Example 149 (1H-Indazol-3-yl) (2-phenylamino-quinazolin- 4-yl)-amine (IIc-70):.Prepared in a manner similar to the o above.described Method A to afford a white solid; 'H:NR C 10 (DMSO) 8 6.90 3H), 7.11 1H), 7.19 2H), 7.44 I1H), 7.57 1H), 7.62 1H), 7.67 2H), 7.71 7.93 1H), 8.59 1w), 11.55 Cbr. s, 1H), 13.15 1H); MS 353.2 Example 150 (1H-Indazol-3-yl)-[2-c(3trifluoromethylphenylamino)-quinazolin-4-yi]-amine (IIc-71): Prepared in a manner similar to the above described Method.A to afford.a pale yellow solid. 'H NMR (DMSO) 6 7.00 1H), 7.02 1H), 7.22 1H), 7.37 (td, 1iH), 7.56 3H), 7.61 1H), 7.66 2H), 7.92 1H), 8.60 1H), 10.61 Cbr. s, 1H), 11.42'(br. s, 1W), 13.12 1W); MS 421.2 Example 151 (1H-Indazol-3-yl)-[2-(4trifluoromethylphenylamino)-quinazolin-4-yll-amine *(IIc-72): Prepared in a manner similar to the above described Method A to afford a pale yellow solid. 'H NMR (DMSO) 8 7.08 1W), 7.16 2H), 7.44 3H), 7.58 7.6 2H), 7.69 1H), 7.95 8.62 1H), 10.82 Cbr. s, 1H), 11.50 Cbr. s, 12.20 (s, 1H); MS 421.2 (M+H) r Va -279- Example 152 (Adamantan-2-ylamino) -quinazolin-4-yll- (1H-indazol-3-yl)-amine (IIc-73): Prepared in a manner similar to the above described Method A to afford a white solid. 'H NMR (DMSO) 8 0.83 (br. s, 1H), 0.85-(br. s, 1H), 1.44 4H), 1.55 1.63 2H)'i 1.73 1H), 1.82 11), 1.84 3.56 1H), 7.10 1H), 7.41 1H), 7.51 1H), 7.54 1H), 7.57 1H), c 7.69 1H), 7.90 1H), 8.45 1H), 8.58 o 11.60 11), 13.10 11); MS 411.3 (M+H) Example 153 (1H-Indazol 3 -yl) (2 -methyl-phenyl -aminoquinazolin-4-yl)-amine (IIc-74): Prepared in a manner similar to the above described Method A to afford a.white solid; H'NMR (DMSO) 8 3.27 IH), 6.88 1H), 6.93 2K), 7.04 1H), 7.14 2H), 7.22 1W), 7.36 2H), 7.48 7.54 7.62 1H), 8.37 10.11 1H), 12.71 1H);.MS 367.2 (M+H) 4 Example 154 (2-Chloro-phenyl) -amino quinazolin-4-yl] (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 1H), 6.87 (td, 1K), .7.07 1H), 7.34 (dd, 1H), 7.35 1H), 7.40 iH), 7.53 1H), 7.56 1K), 7.63 2H), 7.72 1H), 8.07 1K), 8.46 1H), 10.37 1K), 12.89 1H); MS 387.1 Example 155 .(1H-Indazol-3-yl)-[2-(2trifluoromethylphenylamino)-quinazolin-4-yll -amine (lIc- 76): Prepared in a manner similar to the above described Method A to afford a white solid; 'H NMR (DMSO) 6 7.01 (t, 1H), 7.20 iH), .7.32 1H), 7.36 7.43 (d, -280- 1H) 7.49 iH), 7 .55 iN) 7.61 11), 7.64 (d, 1H) 7. 69 iH) 7.95 2H) 8. 62 iH), 10.15 (in, IH iN, 11.6 2 iN), 13. 03 iN); MS 4 21. 2 Example 156 4 -Cyanomethylphenylamino) -quinazolin-4yl]-(iH-indazol-3-yl)-auite (lIc-77): Prepat~ed in a manner similar to the above described Method A to afford a white solid; 3H NMR '(DM50) 8 13.16 iN), 11.49 (br.

s, iH), 10.38 (br. s, iN), 8.58 iN), 7.92 11'f, 7.67 7.61 1W), 7.56-(m, iN), 7.44 iN), 7 .22 7. 0-8 iN), 6. 86 (mn, 2H) 3. 87 2H); MS 392.2 (M-iiHP Examle 2.57 12- 4 -Chlarophenylamino) -5,6,7,8tetrahydroquinazolinin4-.yl (S-methyl-2H-pyrazol-3-yl) amine (lIc-78): Prepared-~in a manner similar to the above described Method C; MS 355.5 (M+H) t Example as5s (5-Methyl-2a-pyrazol-3-yl) -(2-phenylamino- 6,7,8, S-tetrahydro-5H-cycloheptapyrimiin.4Jyi) -amine (IIc-79): Prepared in-amanner similar to the above described Method C; MS 335.3 Example 159 (Benzimidazol-2-ylanino) -7-benzyl-5,6,7,etetrahydro-pyrido 3 1 4-dlpyrizaidin-4-y1 (5-methyl-25pyrazol-3-yl)--aine (IIc-80): Prepared in a manner similar to the above described Method C; MS 4-52.0 Example 160 7 -Benzrl-2-phenylamino-5,6,7,8-tetrahydro.

pyrido[3,4-dlpyrimitdin-4-yl) (-methyl-2H-pyrazol-3.yi) amine '(IIc-81): Prepared in a manner similar to the above* described Method C; MS 412.1 Va -281- Example 261 [6-Benzy1-2-(4-chlorophenylamino)-5,6,7,8tetrahydro-pyrido 4 i 3 -dpyrimidin4zylJ -(5-methyl-2Hpyrazol-3-yl)-anine (Ilc-82): Prepared in a manner similar to the~above described Method C; MS 446.3 (M+H) t Example 162 [2-(Benzimidazol-2-ylamino)-6-benzyl-5,6,7,8tetrahydro-pyrido 4 3 -d]pyrimidin-4ylJ- (5-methyl-2Hpyrazoi-3-yl)-amine CIIc-83): Prepared in a maner similar to the'above described Method C; MS 452.2 CM+H)+ Example 163 6 -Benzyl-2-phenyamtno-5,6,7, 8-tetrahydro'pyrido [4,3-dpyrimidin-4-yl) (5-methyl-2H-pyrazol-3-yl) amine (Ilc-84): Prepared in a manner similar to the above described Method C; MS 411.9 Example 164 (S-Methyl- 2H-pyrazol.3.yl) (2-phenylamino- 6,7, 8-tetrahydro-pyrido (3,4-dlpyrimidin-4-yl) -amine Prepared in a manner similar to the above described Method C; MS 322.3 ExampJA 165 4 -Cyanomethylphenylamno) -quinazolin-4ylJ-(lH-pyrazolo(3,4-b pyridin-a yl)-amine (hc-86): Prepared in a manner similar to the above described Method A to afford an off-white solid; 1H NMR (DHSO) 13.65 1H), 12.82 (br. s, IH) 11.69 (br. s, 1H) 8.55 (dd, 2H), 8.12. 1H), 7.88 7.66 1H), 7.50 (in, 7.30 7.09 6.94 (in, 2H), 3.89 2H); MS 393.1 (M+H)V.

Example 16 4 -Cyanobenzylamino)-quinazolin-4-yl] .(lHpyrazolo[3, 4-bl'pyridin-3-yl) -amine (IIc-87): Prepared in a manner similar to the above described Method A to afford an off-white solid; 'H NMR CDMSO) 8 13.68 1H),

NO

D 282- 0 Cl 12.82 (br. s, IH), 11.70 (br. s, 1H), 8.55 3H), 8.00 1H), 7.92 1H), 7.59 4H), .6.96 2H), 6.86

C

IH), 4.23 2H); MS..393.1 Example 167 4 -Cyanomethylphenylamino)-quinazolin-4yl]-(4-fluoro-lH-indazol-'3-yl)-amine (IIc-88): Prepared in a manner similar to the above described Method A-to 0 Cl afford a white solid; 'H NMR (DMSO) 8 13.49 1H), 11.61 (br. s, 1H), 10.64 s, 8.56 1H), 7.95. (t, c 10 1H), 7.67 1IH), 7.58 1H), 7.46 1H), 7.43 (dd, 1H), 7.14 2H), 6.85 (dd, 3H), 3.88 2H); MS 410.1 Example 168 4 -Cyanophenylamino)-quinazolin-4-yl]-(IHindazol-3-yl)-amine (IIc-89): Prepared in a manner similar to the above described Method A to afford a white solid; 1 FHNMR (DMSO) 8 13.14 1H), 11.31 (br. s, 11), 10.51 (br. s, 11), 8.59 1H), 7.91 (tt, 1H), 7.65 (d, 3H), 7..56 1H), 7.50 2H), 7.45 (dd, 1H), 7.26 (d, 2H), 7.08 1H); MS 378.2 Example 169 [2-(4-Cyanobenzylamino)-quinazolin-4-yl]-(iHindazol-3-yl)-amine (IIc-90): Prepared in a manner similar to the above described Method A to afford a white solid; 1H NMR (DMSO) 8 13.12 1H), 12.91 (br. s, 1H), 11.60 (br. s, 1H), 8.57 1H), 7.91 1H), 7.63 (d, 1H), 7.55 .7.38 1H), 6.89 1H), 6.84 (br.

d, 2H), 4.19 2H); MS 392.2 Example 170 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-yloxy)-quinazolin-4-yl-amine (IIb-1): Prepared in a manner similar to the above described -283- Method B to afford a white solid, mp 327-3280C; 'H NMR (DMSO) 8 -0.05-0.07 (2H, 0.50-0.68 (2H, 1.28-1.40 (IH, 5.68 7.40-7.50 (2H, 7.50-7.64 (3H, 7.70-7.80 (2H, 7.82-8.08 8.64 (1H,d), 10.58 (1H, 12.07 (1H, IR (solid) 1621' >1595, 1575, 1554, 1508, 1480, 1410, 1385, 1320, 1254, 1240, o 1212, 1166; 830, 819, 758; MS 394.4

C]

o Example 171 (5-ethyl-2H-pyrazo13s-yl)- [2-(naphthalen-2ylocy)-quinazolin-4-yll-amine (IIb-2): Prepared in a manner similar to the above described Method" Eto afford a.pale brown solid, mp >300 0 C; 1H NMR (DMSO) 8 1.62 (3H, s) 5.'65 (1H, 7.96 (2H, br 7.55 (3H, .7.76 (2H, 7.92 (1H, 8.00 8.58 (1H, 10.56 11.99 (11, IR (solid) 1625, 1601, 1571, 1556, 1479, 1377, 1315, 1250, 1236, 1210, 1159; MS S368.7(M+H) 4 Example 172 (5-Methyl-2H-pyrazol-3-yl) (2-phenoxyquinazolin-4-yl)-amine (IIb-3): Prepared in a manner similar to the above described Method B to afford a tan solid, mp 287-290 0 C; 'R NMR (DMSO) 5 2.10 (3H, 5.92 (1H, 7.23 (2H, 7.29 (1H, t),7.38 (1H, 7.46- 7.53 7.85 (11, 8.58 (1H, 10.55 (111, s), 12.11 (1H, IR (solid) 1622, 1602, 1572, 1556, 1542, 1477, 1454, 1402, 1373, 1316, 1249, 1200, 1172, 1158; MS 318.3(M+H)+ Example 173 (S-Cyclopropyl-21-pyrazol-3-yl) -12-(5,6,7,8tetrahydronaphthalen-2-yloxy)-quinazolin-4-yl -amine (IIb-4): Prepared in a manner similar to the above described Method B to afford a solid, mp 277-279 0 C; 1H NMR -284- C' (DMSO) 8 0.40-0.50 (2H, 0.89-0.96 (2H, 1.71-1.87 2.70-2.83 (4H, 5.88 (1H, 6.88-6.96 (2H, 7.12 (1H, 7.39.(IH,t), 7.58 (1H, 7.76 (1H, Cl 8.58 (1H, 10.54 (1H, 12.20 (1H, IR (solid) 1731, 1641, 1614, 1570, 1506, 14-95, 1464, 1424, Cl 1362, 1340, 1240, 880, 831, 812, 776, 758; MS 398.4 (M+H)

O

C< Example 174 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3- O methylphenoxy)-quinazolin-4-yl]-amine (IIb-5): Prepared Cl 10 in a manner similar to the above described Method B to afford an off-white solid, mp 283-284OC; 1 H NMR (DMSO) 6 0.49-0.53 0.89-0.96 (2H, 1.72-1.81 (1H, m), 2.40 (3H, 5.82 (11, 7.03 (1H, 7.08 (1H, s), 7.15 (1H, 7.35-7.46 (2H, 7.58 (1H, 7.78 (1H, 8.62 (1H, 10.58 (1H, 12.25 (IH, IR (solid) 1622, 1604, 1576, 1557, 1483, 1419, 1381, 1319, 1253, 1189, 1158, 997, 842, 789, 763; MS 358.4 (M+H) Example 175 [2-(3-Methoxyphenoxy)-quinazolin-4-yl] methyl-2H-pyrazol-3-yl)-amine (IIb-6): Prepared in a manner similar to the above described Method B to afford a white solid, mp 277-278 0 C; 1H NMR (DMSO) 6 2.15 (3H, s), 3.78 (3H, 6.00 6.77-6.90 (3H, 7.30-7.41 (2H, 7.52 (1H, 7.70 (1H, 8.59 (iH, 10.57 (1H, 12.10 (1H, IR (solid) 1623, 1603, 1575, 1556, 1487, 1456, 1430, 1373, 1316, 1253, 1192, 1142, 1046, 1022, 833, 760; MS 348.4 Example 176 [2-(3,4-Dimethoxyphenoxy)-quinazolin-4-yl] (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 277-278 0 C; 1H NMR (DMSO) 8 2.09

NO

o -285- (3H, 3.70 (31, 3.78 (3H, 5.98 (11; 6.73- 6.77 (1H, 6.90 (1H, 7.00 (1H, 7.35-7.45 (1H, 7.58 (11, 7.70-7.78 (11, 8.63 (11, 10.55 s) 12.19 (1H, IR (solid) 1626, 1603, 1576, 1557, 1509, 1481, -1436-i 1409, 1382, 1372, 1318, 1249, 1227, 1195, 1180, 1158, 1120, 1029, 965, 835, 803, 767,753; MS 378.4 Va Example 177 [2-(Benzo[1,3] diozol-5-yloxy)-quinazolin-4yl- (5-methyl-2R-pyrazol-3-yl)-amine (IIb-8): Prepared in .a manner similar to the above described Method B to afford an off-white solid, mp 296-299 0 C 'H NMR (DMSO) 8 2.13 (3H, 6.05 6.09 (2H, 6.69 (1H, 6.90 (1H, 6.98 (11, 7.39 (1H, 7.53 (1iH, 7.70 8.58 (11, 10.59 (1H, IR (solid) 1602, 1577, 1538, 1508, 1499, 1481, 1455, 1401, 1377, 1323, 1251, 1241, 1169, 1121, 1038, 1022, 951, 935, 863, 813, 75 2 MS 362.4 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 269-270OC; 1H NMR (DMSO) B 2.05 (3H, 3.90 (3H, 5.88 (11, 7.00-7.90 (7H, 8.50-8.65 (1H, 10.65 (1H, 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) Example 179 (5-Cyclopropyl-2n-pyrazol-3-yl)-(2phenoxymethyl-quinazolin-4-yl)-amine (Ild-1): Prepared in a manner similar to the above described Method C to afford a pale yellow solid, mp 265-267 0 'H NMR (DMSO)'.8 -286- CN 0.67 (2H, 0.93 1.87 (1H, 5.19 (2H, s), 6.55 (1H, br 6.90-7.02 (3H, 7.26-7.30 (2H, m), 7.54 (1H, 7.74-7.83 (2H, 8.61 (1H, 10.45 (1H, Ci br 12.18 (1H, br MS 358.4 (M+H) C< Example 180 (2-Benzyloxymethyl-quinazolin-4-yl) c cyclopropyl-2H-pyrazol-3-yl)-amine (IId-2): Prepared in a Cq manner similar to the above described Method C to afford

VO

a white solid, mp 211-213oC; 'H NMR (DMSO) 8 0.65 (2H, m), Ci 10 0.90 (2H, 1.86 (1H, 4.63 (2H, 4.68 (1H, s), 6.71 (1H, 7.28-7.54 (6H, 7.76-7.81 (2H, 8.61 (1H, 10.41 (1H, 12.19 (1H, MS 372.3 (M+H) Example 181 (2-Benzyl-quinazolin-4-yl)-(5-cyclopropyl-2Hpyrazol-3-yl)-amine (IId-3): Prepared in a manner similar to the above described Method D to afford a white solid, mp 219-2216C; H NMR (DMSO) 8 0.66 (2H, 0.95 (2H, m), 1.87 (1H, 4.11 (2H, 6.31 (1H, 7.20-7.50 (6H, 7.71-7.79 (2H, 8.55 (1H, 10.27 (1H, 12.15 (1H, MS 342.7 (M+H) Example 182 (5-Cyclopropyl-2H-pyrazol-3-yl)- (2-methylquinazolin-4-yl)-amine (IId-4): Prepared in a manner similar to the above described Method C to afford a white solid, mp 289-290 0 C; IH NMR (DMSO) 8 2.31 (3H, 2.71 (3H, 6.73 (1H, 7.75 (2H, 8.04 (1H, 8.82 (1H, 11.94 (1H, 12.65 (1H, IR (solid) 3266, 1636, 1607, 1579, 1479, 1407, 769, 668; MS 240.4 (M+H) Example 183 [2-(4-Chlorophenoxymethyl)-6,7,8,9tetrahydro-5H-cycloheptapyrimidin-4-yl (5-methyl-2Hpyrazol-3-yl)-amine (IId-5): Prepared in a manner similar

NO

o -287to the above described Method C to afford a white solid; 11 NMR (DMSO)Y61.58 (2H, 1.68 (2H, 1.85 (2H, m), 2.20 (3H, 2.90 (2H, .3.00 (2H, 5.26 (2H, s), 6.15 (11H, 7.15 (2H1, 7.40 (2H, 10.25 (1H, br); MS 384.3 Example 184 4 -Chlorophenoxymethyl)-5,6,7,8tetrahydro-quinazolin-4-yl]-(5-methyl-2H-pyrazol-3-yl)o amine Prepared in a manner similar to the above -described Method C to afford a white solid; 'H NMR -(DMSO) 81.80 (4H, 2.15 (3H, 2.55 (2H, m obscured), 2-.75 (2H, 5.25 (2H, 6.12 (1H, 7.08 (2H, 7.35 (2H, 9.80 (11, br); MS 370.2 (M+H) 4 Example 185 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2- (naphtalen-2-ylsulfanyl) -6-phenylpyrimidin-4-yll -amine (IlIa-1): Prepared in a manner similar to the above described Method L to afford a white solid, mp 233-234CC; 1H NMR (DMSO) 6 0.21 (2H,.br 0.56 (2H,br 1.17 (1H, br.m), 5.35 (1I, br 7.02 (111, br.s), 7.49 (3H, 7.59 (211, 7.73 (1H, 7.88 (2H, mi), 8.02 (31, 8.30 (11, 10.01 (1H, 11.75 (1H, br IR (solid); MS 436.7(M+H) Example 186 (5-Cyclopropyl-2-pyrazol-3-yl)- 2-(3methoxycarbonyl-phenylylsulfanyl)-6-phenylpyrimidin-4yl]-amine (IIIa-2): Prepared in'a manner similar to the above described Method L to afford a white solid, mp 126- 129 0 C; 1H NMR (DMSO) 8 0.52 (2H, 0.87 (2H, 1.69 (11, 3.87 5.47 (1H, 7.03 (1H, br s), .7.49 (3H, 7.67 (1H, 7.87 (2H, 7.94 m), Va O -288- C 8.09 (1H, 8.23 (1H, 10.07 (1H, 11.94 s); IR (solid); MS 444.7(M+H)* Cl Example 187 (5-Cyclopropyl-2H-pyrazol-3-yl)-[2- (naphthalen-2-y1sulfanyl)-pyrimidin-4-yl] -amine (IIIa-3): C Prepared in a manner similar to the above described Method L to afford a white solid, mp 248-250 0 C; 1H NMR (DMSO) 6 0.21 (2H, br 0.55 (2H, br 0.94 br 1 5.31 (1H, br 6.55 (1H, br 7.57-7.66 (3H, m), -7.99-8.03 (4H, 8.25 9.94 (1H, 11.75 (1H, br IR (solid); MS 360.7(M+H) t Example 188 (5-Cyclopropyl-2H-pyrazol-3-yl)-[5,6dimethyl-2-(naphthalen-2-ylsulfanyl)-pyrimidin-4-yl]amine (IIIa-4): Prepared in a.manner similar to the above described Method L to afford a white solid, mp >270C; iH NMR (DMSO) 8 0.14 (2H, 0.45 (211H, 0.78 (1H, s), 2.05 (3H, 2.27 (3H, 5.26 (1H, 7.60 (3H, 7.99 (3H, d) 8.21 (1H, 8.66 (1H, 11.60 (1H, s); IR (solid) 1560, 1508, 1478, 1288, 1176, 1109, 994, 809, 740, 669;,MS 388.7(M+H)+ Example 189 (5-Cyclopropyl-2-pyrazol-3-yl) 15-methyl-2- (naphthalen-2-ylsulfanyl)-pyrimidin-4-yl -amine 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, 0.51 (2H, 0.78 (1H, 2.08 (3H, s), 5.40 (1H, 7.57 (2H, 7.62 (1H, 7.92 (1H, s), 7.97-(3H, 8.22 (1H, 8.88 (1H, 11.70 (1H, s); IR (solid) 1738, 1583, 1563, 1488,-1460, 1364, 1234,1216, 808, 656; MS 374.2(M+H) Va 0 -289- Example 190 (5-Cyclopropyl-2H-pyrazol -3-yl)-16-methyl-2- (naphthalen-2'-ylsulfanyl)-pyrimidin-4-yll-amine (IIIa-6): Prepared in a manner similar to the above described Method L to afford a white solid, mp 232oC; 'H NMR (DMSO) 0\ 5 6 0.15 (2H, 0.51,(2H, 0.92 (1H, 2.20 (3H, a), g 5.22 (1H, 7.60 (2H, 7.67 (1H, 7.98 (3H, a), o 8.24 (1H, 9.79 (1H, 11.60 (1H, IR (solid) ci 1586, 1508.7, 1485, 1282, 1180, 815, 788, 744, 674, 666; o MS 374.2(M+H)+ Example 191 (5-Cyclopropyl-2H-pyrazol-3-yl)-[6- (morpholin-4-yl)-2- (naphthalen-2-yisulfanyl)-pyrimidin-4yl-amine (IIIa-7): To a solution of 2,4,6trichloropyrimidine (600 mg, 3.27 mmol) and cyclopropylpyrazole (403 mg, 3.27 mmol) in EtOH (10 mLt).

was added triethylamine (456 gL, 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 (Si 2 Hexane/AcOEt gradient) to afford (5-cyclopropyl-2H-pyrazol-3-yl)-(2,6dichloropyrimidin-4-yl)-amne (705 mg, To a solution of (5-cyclopropyl-2H-pyraol-3yl)-(2,6-dichloropyrimidin-4-yl)-amine (211 mg,.0.781 mmol) and 2-naphthalenethiol (125 mg, 0.781 mmol) in tert-butanol (5 mL) was added triethylamine (174 IL, 1.25 mmol) ahd the resulting mixture was heated at reflux for 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, dried over MgSO 4 and concentrated in vacuo. The residue was purified by flash chromatography (Sio2r Hexane/AcOEt gradient) to afford [6-chloro-2-(naphthalen-2-

NO

o. -290ylsulfanyl) -pyrimidin-4-yl] (5-cyclopropyl-2H-pyrazol-3yl)-amine.

The above formed L6-chloro-2-(naphthalen-2ylsulfanyl)-pyrimidin-4-yl]-(5-cyclopropyl-2H-pyrazol-3yl)-amine (70 mg, 1.78-.-10-mol) was dissolved-in morpholine (3 mL) and the mixture heated at 120 0 C for hours. The solvent was evaporated and the residue was o purified by flash chromatography to afford IIIa-7 (50 mg,

O

63%) as a white solid, mp 118-120WC; 1H NM? (DMsO) 6 0.34- C .10 0.91 (4H, 4xm), 1.28 and 1.78 (1H, 2xm), 3.32 (2H, m), 3.60 (6H, 5.38-6.16 (2H, br 7.55-7.66 (3H, m), 7.95-8.02 (3H, 8.19 and 8.23 (iH, 2xs), 9.28 and 9.31 (1H, 2xbr 11.71 and 11.84 (11, 2xbr IR (solid); MS 445.2(M+H)+ Example 192 (5-Cyclopropyl-2H-pyrazol-3-y1) mnethylpiperazin-4-yl)-2-(naphthalen-2-ylsulfanyl)pyrimidin-4-yl-amine (IIIa-8): Prepared in a manner substantially similar to the method describe above for compound IIIb-7 to afford a white solid, mp 113-115"C; 1H NMR (DMSO) 6 0.35-0.91 (4H, 4xm), 1.31 and 1.78 (1H, 2xm),'2.17 and 2.19- 2xs),. 2.29 (4H, 3.35 (2H, 3.61 (2H, 5.38-6.20 (211H, br 7.55-7.66 (3H, 7.95-8.02 (3H, 8.17 and 8.23 (1H, 2xs), 9.26 and 9.32 (1H, 2xbr 11.71 and 11.85 (1H, 2xbr IR (solid); MS 458.3(M+H)* Example 193 2 ,6-Dimethylphenyl) -2-(naphthalen-2ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine (IIIa-9): Prepared in a-manner similar to the above described Method L to afford an off-white solid, mp 148- 152 0 C; 1H NMR (DMSO) 5 2.10 (6H, 2.26 (3H, 5.09 and 6.31 (1H, 2x br 7.03 (3H, 7.22 (1H, 7.59 Va -291- (2H, 7.69 (1H, 7.99 (31, 8.28 9.93 11.67 (1H, br IR (solid)' 2970, 1739, 1436, 1365, 1229, 1217, 1205; MS 438.3(M+H)' Example 194 [6--(2-Methylphenyl)-2-(naphthalen-2ylsulfanyl)-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3-yl)amine (IIIa-10): Prepared in a manner similar to the above described Method L to'afford a white solid, mp 211o 214 0 C; 'H ENMR (DMSO)8 1.41 (3H, 2.30 (3H, 5.26 and 6.55 2x br 7.34 7.62 (2H, 7.70 (1H, 7.99 (3H, 8.30 (1H, 9.97 (IH, 11.73 (1H, br IR.(solid) 2356, 1615, 1582, 1483, 1265, 851, 822, 761; MS 424.0(M+H)+ Example 195 4 -Acetamido-phenylsulfanyl)-6-phenylpyrimidin-4-yll-(5-methyl-2H-pyrazol-3-yl)-amine (IIIa- 11): Prepared in a manner similar to the above described Method IL to afford a white solid, mp 153-155 0 C; 'H NMR (DMSO) 8 2.01 (3H, 2.08 (3H, 5.43 (1H, 6.96.

(IH, br.s), 7.49-7.88 (9H, 10.00 (1H, br 10.23 (1H, 11.86 (1H, br MS 417.2(M+H)+ Example 196 5 -Methyl-2H-pyrazol-3-yl)-[2-(naphthalen-2ylsulfanyl) 6 -phenyl-pyrimidin-4-yll -amine. (IIIa-12): Prepared in a manner similar to-the above described Method L to afford a white solid, mp 237-2390C; 'H NMR (DMSO) 8 1.39 (3H, br 5.12 (1H, br 6.98 (11, br 7.50 7.62-7.63 (2H, 7.72 (1H, 7.90 (2H, 8.03-8.05 (33H, 8.31 (1H, 10.00 (1H, a), 11.73 (1H, br IR (solid) MS 410.2(M+H)" Example 197 4 -Isobutyrylylamino-phenylsulfanyl)-6- .phenylpyrimidin-4-yll-(5-methyl-2H-pyrazol-3-yl) -amine Va O -292- 0 Cl (IIIa-13): Prepared in a manner similar to. the above described-Method L to afford an off-white solid, mp 201- 202C; 1 H NMR (DMSO) 8 1.05-1.13 (6H, 1.97. (3H, s), Cl 2.65 (1H, 5.37 (1w, br 6.93 (1H, br 7.50-7.58 (5H, 7.78-7.90 (4H, 9.99, 10.12 and 11.84 (3H, 3 C x br IR (solid) 1676, 1614, 1586, 1573, 1514, 1483, 1395, 1299, 1262, 1242, 1214, 1168, 1089, 988; MS CA 445.3(M+H)*

NO

Cl 10 Example 198 4 -Methylpiperazin-1-y1)-2-methylsulfanylpyrimidin-4-yll- (5-methyl-2a-pyrazol-3-yl)-amine (IIIa- 14): Prepared in a manner similar to the above described Method M to afford an off-white solid; "H NMR (DMSO) 2.18 (3H, 2.20 2.36 (4H, 2.41 (3H, 3.46 5.91 (1H, 6.41 (1H, br 9.20 (H, 11.87 (1i, IR.(solid); MS.320.3(M+H)' Example 199 (5-Methyl-2H-pyrazol-3-yl)- [6-phenyl-2-(4propionylamino-phenylsulfanyl)-pyrimidin-4-ylJ-amine (IIIa-IS): Prepared in a manner similar to the above described Method L to afford a pale pink solid, mp 204- 2060C; 1 H NMR (DMSO) 8 1.09-1.13 (3H, 2.00 (3H, 2.33-2.37 (2H, 5.40 (1H, br. 6.95 (11, br 7.50 (3H, 7.56-7.58 (2H, 7.76-7.78 (2H, 7.88 (2H, 9.99, 10.15 and 11.85 (3H, 3 x br IR.(solid) 1678, 1623, 1580, 1534,1496, 1453, 1398, 1307, 1245, 1203, 1119, 1049, 1030, 1004; MS 431.2(M+H).

Example 200 4 -Cyclopropanecarbonylaminophenylsulfanyl) -6-phenylpyrimidin-4-yll (5-methyl-2Hpyrazol-3-yl)-amine (IIIa-16): Prepared in a manner similar to the above described Method L to afford an off- Va 0 -293white solid, mp 253-255OC; 'H NMR (DMSO) 6 0.82-0.83 (4H, 1.83 (1H, 2.00 (3H, 5.41 (1H, br 6.88 (11, br 7.42-7.50 (3H, 7.56-7.58 (2K, 7.76- 7.78 (2H, 7.89 (2H,fm), 9.99, 10.47 and 11.85 (3M, 3 x br IR (solid) 1672, 1621, 1591, 1581, 1573, 1537, ci 1495, 1448,,1405, 1390, 1312, 1254, 1246; 1202, 1192, 1179, 1119.2, 1005, 959; MS 443.2(M+P)*

\O

SExample 201 (S-Methyl-2-pyraol3-yl)-6-phenyl-2-1 4- '(propane-1-sulfonylamino) -phenylsulfanyll -pyrimidin.-4yl)-amine (IIa-17): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 232-235 0 C; IH NMR (DMSO) 6 0.94 (3H, 1.71 (2H, m), 2.12 3.13 (2H, 5.59 (lIH, 7,31 (2H, d), 7.49 (3H, 7.59 (2H, d),.7.85 (2H, 10.00 (1W, br 1..16 (1W, 12.05 (1H, br IR (solid) 1628, 1587, 1545, 1525, 1496, 1455, 1311, 1255, 1236, 1212, 1186, 1140, 1032, 1001, 934; MS 481.2(M+H)+ Example 202 [2-(4-Ethanesulfonylamino-phenysulfanyl)-6'phenyl-pyrimidin-4-yl]-(S-methyi-2H-pyrazol-3-yl)-amine (IIIa-18): Prepared in a manner similar to the above described Method L to afford a pale yellow solid, mp 251- 254 0 C; H NMR (DMSO0).6 1.21 (3H, 2.12 3.15 (2H, 5.59 (1H, 7.32 (2H, 7.49 (3H, 7.57 (2H, 7.85 (21H, 9.99 (1H, br 10.15 (1H, br s), 11.90 (1H, br IR (solid) 1621, 1585, 1542, 1523, 1495, 1455, 1315, 1257, 1208, 1142, 1049,'1033, 1002, 932; MS 467.2(M+H)* Example 203 4 -Acetamidophenyl-sulfanyl)-6-(2methylphenyl)-pyrimidin-4-yl-(5-methyl-2H-pyrazol-3-yl)o -294ci amine (IIIa-19): Prepared in a manner similar to the above described Method L to afford a white solid, mp 212- 214oC; H NMR (DMSO) .8 2.01 (3H, 2.08 (31H, 2.24 (3H, 5.43 (1H, 6.56 (1H, br 7.49-7.88 (9H, 10.00 (1H, brts), 10.23 (1IN, 11.86 (1H, br IR (solidl701, 1634, 1588, 1555, 1496, 1390, .1307, 1208, 1169, 823, 803; MS 431.4(M+H)* F) Example 204 [2-(4-Isobutanecarbonylamino -phenyl-, sul-anyl)-6-phenyl-pyrimidin-4-yll -(5-methyl-2H-pyrazol- 3-yl)-amine (IIIa-20); Prepared in a manner similar to the above described Method L to afford an off-white solid; mp 241-243oC; 'H NMR (DMSO)S.0.95-0.96 (6H, m), 2.00 (3H, 2.11 2.23-2.25 (2H, 5.43 (1H, br 6.95 br 7.50-7.58 (5N, 7.77-7.89 (4H, 10.00,.10.13 and 11.84 (3H,.3 x br IR (solid) 1660, 1628,.1589; 1575, 1543, 1525, 1496, 1451, 1398, 1357, 1314, 1301, 1251, 1206, 1108, 995;.MS 459.2 (M+H) Example 205 4 -Acetamido-phenyl-sulfanyl)-5-methyl-6phenyl-pyrimidin-4-yll (5-methyl-2-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- 277C; H NMR (DMSO) 8 1.98 (3H, 2.08 (6H, 5.41 br 7.47-7.55 (7H, 7.72-7.74 (2H, 8.89, 10.20 and 11.87 (3H, 3 x br IR (solid) 1676, 1591, 1555, 1540, 1519, .1493,1393, 1375, 1303, 1260,.1230, 1176, 1148, 1045, 1011, 969; MS 431.2 (M+H) 4 Example 206 4 -Acetamdo-phenyl-sulfanyl)-6-(4methoxyphenyl)-pyrimidin-4-yl] (5-methyl-2H-pyrazol-3yl)-amine (IIIa-22): Prepared in a manner similar to the

INO

o -295- 0 above described Method L to afford an off.white solid, mp E 241-245 0 C; NMR (DMSO) 6 1.99 2.06 (3H, 3.82 (3H, 5.44 (11, 7.03 (2H, 7.53 (2H, 7.71 (2H, 7.83 10.12 (1H, 10.23 s), 11.84 (1H, IR.(solid) 1627, 1606, 1571, 1511, 1313, 1257, 1181, 830; MS 447.2 D Example 207 [6-(3-Acetamidophenyl)- 2-(4-acetamido- 0 Sphenyl-sulfanyl) -pyrimidin-4-yl] (5-xethyl-2K-pyrazol-3yl)-amine (IIIa-23): Prepared in a manner similar to the above described Method L to afford a brown solid, mp 227- 230 0 C; 'H NMR (DMSO) 8 2.01 (3H, 2.11 (6H, 5.34 (1H, 6.99 (1H, br 7.41 (1H, 7.49-7.62 (3H, 3.71-3.76 min), 8.19 (1H 10.09-10.18 (2H, br 10.23 (IH, 12.20 (11, br IR (solid) 1635, 1573, 1533, 1488, 1372, 1318, 1297, 827, 798; MS 474.3 Example 208 4 -Isopropanesulfonylaino-phenylsulfanyl)-6-phenyl-pyrimidin-4-yl (5-methyl-2H-pyrazol- 3-yl)-amine (IIIa-24): Prepared in a manner similar to the above described Method L to afford a.white solid, mp 255-257C; 'H NMR (DMSO). 8 1.28 (611, 2.14 3.32 (1H, 5.60 (11, 7.36 (2H, 7.49 (3H, 7.6 (2H, 7.85 (2H, 10.00 (1H, br 10.11 (iH, s), 11.92 (IH, br IR (solid) 1625, 1587, 1574, 1545, 1525, 1495, 1313,.1295, 1257, 1234, 1136, 1000, 934; MS 481.2 Example 209 (2-[4-(2-Dimethylamino-acetylamino) phenylsulfanyll-6-phenyl-pyrimidin-4-yl)-(5-methyl-2Hpyrazol-3-yl)-amine (IIIa-25): Prepared in a manner 0 -296- CN similar to the above described Method L to afford an off- Swhite solid, mp 213-215 0 C; 1H NMR (DMSO) 62.00 (3H, s), 2.31 (6H, 3.15 (2H, 5.45 (1H, 6.83 (1H, br C 7.46-7.51 (3H, 7.59 (2H, 7.80-7.92 (5H, m), 9.98 (1H, 10.05 (1H, IR (solid) 1701, 1617, 1587, CN 1571, 1509, 1480, 1456, 1304, 1284, 1254, 1238, 1213, 1181, 1156, 987, 833, 782, 754, 695; MS 460.3(M+H)

ND

O

Example 210 [2-(3-Chloro-benzylsulfanyl)-6-morpholin-4- C 10 yl-pyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (IIIa-26): Prepared in a manner similar to the above described Method M to afford a white solid, mp 224-225oC; 1H NMR (DMSO) 6 2.17 3.40-3.50 (4H, 3.60-3.71 (4H, 4.30 (2H, 5.95 (1H,'brs), 6.41 (1H, brs), 7.23-7.55 (4H, 9.31 (1H, 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-methoxyethylamino)-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- 102oC; :H NMR (DMSO) 6 2.15 (3H, 3.21 (3H, 3.28- 3.41 (4H, 4.29 (2H, 5.78 (1H, brs), 6.20 (1H, brs), 7.10 (1H, brs), 7.21-7.50 (4H, 9.01 (1H, brs); IR (solid) 1598, 1555, 1527,.1336, 1293, 1117, 1079, 974, 783; MS 405.4 (M+H) 4 Example 212 [2-Benzylsulfanyl-6-(4-methylpiperazin-l-yl)pyrimidin-4-yl] (5-methyl-2Hf-pyrazol-3-yl) -amine (IIIa-28): Prepared in a manner similar to the above described Method M to afford -a yellow gum; H NMR (CDC1 3 -297- 6 2.23 (3H, 2.28 (3H, 2-.31-2.64 (4H, 3.30- 3.65 (4H, 4.38 (21, 5.83 (11, 6.23 (1H, br 7.17-7.49 (5H, 7.98-8.18 (1H, IR (solid) 1555, 1494, 1371,-1315, 1286, 1233, 999, 977, 801, 774, 709; MS 396.4 Example 213 2 -Benzy1sulfany1-6-morpholin-4-yl-pyrimidin- 4-yl]-(5-methyl-2r-pyrazol-3-yl)-amine (IIIa-29): Prepared in a manner similar to the above described Method M to afford an off-white foam; 'H NMR (CDC1 3

S

2.31 (3H, 3.39-3.80 (81, 4.39 (2H, 5.84 (1H, 6.25 (1H, brs), 7.20-7.50 (5H, 8.10 (1H, IR (solid) 1557, 1486, 1442, 1314, 1229, 1213, 1121, 767, 698; MS 383.4 (M+H)Y Example 214 3 -Chloro-benzylsulfanyl)-6-(4methylpiperazin-1-yl)-pyrimidin-4-yll-(5-methyl-2Hpyrazol-3-yl)-amine. (IIa-30): Prepared in a manner similar to the above described Method M to. afford a white foam; 1H NMR (CDC1 3 8 2.31 (3H, 2.35 (3H, 2.400- 2.51 (4H, 3.56-3.69 (4H, 4.34 (2H, 5.85 (1H, 6.29 (1H, brs), 6.89 (1H, 7.18-7.50 (4H, m).;'IR (solid) 1553, 1514, 1484, 1446, 1277, 1228, 999, 799; MS 430.4 (M+H) t Example 215 4 -methoxy-benzylsalfanyl) -G6-(4methylpiperazin-1-yl)-pyrimidin-4-yl]-(5-methyl-2Hpyrazol-3-yl)-amine (IIIa-31): Prepared in a manner similar to the above described Method M to afford a yellow oil; 1H NMR (CDC1 3 8 2.28 (3H, 2.33 (3H11, s), 2.44-2.45 (4H, 3.62 (4H, 3.80 (3H, 4.34 (2H, 5.32 (1H, 6.28 (1H, br 6.83-6.85 (2 H, m),

IN

0 -298- 7.34-7.36 (2H, IR (solid) 1659, 1554, 1508, 1485, 1449, 1366, 1318, 1302, 1277,.1230,.1166, 1146, 1030, 999, 973, 948; MS 443.4 Example 216 4 -Acetamido-phenyl-sulfanyl)-6-tertbutyl-pyrimidin-4-yl- (5-methyl-2H-pyrazol-3-yl) -amine (IIa-32): Prepared in a manner similar to the above described Method L to afford a white solid, mp 227-228 0

C;

1 H NMR (DMSO) 6 1.10 (3H, br 1.20 (9H, 2.00 2.35 (2H, 5.35 (1H, br 6.55 br 7.55 (2H, 7.75 (2H, 10.1 (iH, br 1.15 s), 12;1 (1H, br IR (solid); MS (M+H) 4 Example 217 (5-Cyclopropyl-2z-pyrazol-3-yl)-(6-phenyl-2- (4-propionylamino-phenyl-sulfanyi) -pyrimidin-4-yl] -amine (IIIa-3-3): Prepared in a manner similar to the above described Method L to afford an off-white solid; mp 208- 209 0 C; H NMR (DMSO) 8 0.52 (2H, 0.80 (2H, 1.08- 1.10 (3H, 1.65 (1H, br 2.33-2.37 (2H, mn), 5.50 (1H, br 7.03 (1H, br 7.47 (3H, 7.50-7.58 (2H, 7.76-7.77 (2H, 7.88-7.98 (2H, 10.00, 10.11 and 11.86 (3H, 3 x br IR (solid) 1676, 1617, 1575, 1539, 1520, 1485, 1459, 1418, 1395,. 1304, 1255, 1243, 1215, 1161, 1071; 990; MS 457.4 Example 218 [2-(3-Chloro-benzylsulfanyl)-6-(piperidin-lyl)-pyrimidin-4-yll-(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 234-235SC; 1H NMR (DMSO) 8 1.40-1.64 (615, 2.13 (3H, 3.42-3.51 (4H, 4.27 (2H, s),.5.85 (1H, br 6.46 brs), 7.23-7.41 (3H, 7.48 (1H, 9.18 (111, 11.83' (1H,

I

IND

Va

CA

0O ci Ci -299- IR (solid) 1598, 1546, 1483, 1398, 1317, 1227, 974, 798, 779; MS 415.4 (M+H)t Example 219 5 -Methyl-2H-pyrazol-3-yl) [4- (morpholinesulfonyl-)-benzylsulfanyl]-6-morpholin-4-ylpyrimidin-4-yl}-amine (IIIa-35): Prepared in a manner similar to the above described Method M to afford a white solid; 1 H NMR (DMSO) 8 2.24 (3H, 2.90-3.01 (4H, m), 3.29-3.36 (4H, 3.48-3.57 (4H, 3.67-3..75 (4H, m), 4.43 (2H, 5.82-6.10 (2H, 7.50-7.70 (5H, IR (solid) 1550, 1483, 1441, 1346, 1308, 1255, 1160, 1112, 941, 726; MS 532.5 Example 220 (6-(2-Methoxy-ethylamino)-2-[4- (morpholinesulfonyl)-benzylsulfanyl] 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 0 C; 1H NMR (DMSO) 6 2.15 (3H, s), 2.79-2.89 (4H, 3.-34 (3H, 3.40-3.51 (4H, 3.59- 3.67 (4H, 4.41 (211, 5.76-5.72 (11, 6.20 (1H, brs), 7.10 (1H, brs)., 7.61-7.74 9.03 brs), 11.81 (1H, brs); IR. (solid) 1593, 1555, 1484, 1350, 1298, 1255, 1160, 1107, 936; MS 520.5 Example 221 {6-(4-methyJpiperazin-1-yl)-2. [4methyl-2H-pyrazol-3-yl)-amine (IIIa-37): Prepared in a manner similar to the above described Method M to afford a white solid, mp 206-207OC; 1H NMR (DMSO) 8 2.09 (3H, s), 2.20 (3H, 2.26-2.40 (4H, 2.78-2.88 (4H, 3.38- 3.49 (4H, 3.56-3.67 (4H, 4.41 (2H, 5.82 (1H, brs),. 6.42 (1H, bra), 7.60-7.74- (4H, 9.26 (1H, s), -300- 0 11.89 (1H, brs).; IR (solid) 1583, 1558, 1479, 1346, 1231, 1160, 1112, 998, 969, 926;*MS 545.5 (M+H) 4 Example 222. [6-Methoxymethyl-2-(4-propionylamino-phenylsulfanyl)-pyrimidin-4-yl -(S5-methyl-2H-pyrazol-3-yl)amine (IIIa-38): Prepared in a manner similar to the above described Method L to afford a white solid; 1H NMR (DMSO) 5 1.03-1.14 (3H, 2.00 (3H, 2.29-2.40 (2H, ci IN OMe under DMSO, 4.22 (2H, 5.26 (1H, brs), 6.45 c .10 (1W, brs), 7.44-7.56 (2H, 7.68-7.80 (2H, 9.86 (1W, brs), 10.11 (1H, 11.t9 (1H, brs); IR (solid) 1670, 1593, 1517, 1479, 1393, 1360, 1269, 1174, 1107; MS 399.4 (M+H) 4 Example 223 4 -Methoxycarbonyl-phenyl-sulfanyl)-6methoxymethyl-pyrimidin-4-yl-(5-methyl-2ir-pyrazol-3-yl)amine (IIIa-39): Prepared in a manner similar to the above described Method L to afford a white solid, mp 204- 205 0 C; 'H NMR (DMSO) 8 1.89 (3H, brs), 3.85 (3H, -OMe under DMSO, 4.23 s),.5.22 (1H, brs), 6.51 (1H, brs), 7.70-7.81 (2H, 7.96-8.06 (2H, 9.99 (1H, brs), 11.857(1H, bra); IR (solid) 1721, 1621, 1583, 1519, 1484, 1289, 1271, 1178, 1119, 1109, 997, 841; MS.386.3 Example 224 -Dimethoxy-benzylsulfanyl)-6morpholin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazol-3yl)-amine (IIIa-40): Prepared in a manner similar to the above described Method M to .afford a white solid; 1H NMR (DMSO) 8 2.15 (3H, 3.40-3.49 (4H, 3.60-3.74 4.25 (2W, 5.88 (1H, brs),. 6.31-6.61 (5H, 9.32 (1H, 11.86 (1H, IR. (solid) 1581, 1556, 1470, 1439, 1315, 1232, 1205, 1159, 1144; MS 443.4 (M+H) t -301- Example 225.[2-( 3 ,5-Dimethoxy-benzysulfanyl)-6pyrrolidin-4-yl-pyrimidin-4-yl]-(5-methyl-2H-pyrazo-3yi)-amine (IIIa-41): Prepared in a manner similar to.the above described.Method M to afford a white.solid; 'H NMR (DMSO) 8 1.80-1.97 (4H, 2.15 (3H, 3.43-3.45 (4H, 3.69 (6H, 4.26 (2H, 5.85 (11; brs), 6.18 (1H, brs), 6.35 (1H, bra), 6.60 (2H, 9.12 (11, 11.88 (1H, IR (solidl598, 1560, 1474, 1470, 1346, 1303, 1207, 1136, 1050; MS 427.4 (M+H) 4 Example 226 (5-Methyl-2-pyrazol-3-yl)- [6-morpholin-4-yl- 2-(naphthalene-2-ylmethy1sulfanyl)-pyrimidin-4-yl-amine (IIIa-42): Prepared-in a manner similar to the above described Method M to afford an off-white solid; 11 NMR (DMSO) 6 2.15 (3H, 3.37-3.50. (4H, 3.59-3.70 (4H, 4.48 (2H, 5.88 (11, brs), 6.40 (1H, brs), 7.40- 7.60 (3H, 7.78-7.95 (4H, 9.30 (1H, 11.89 (11H, brs); IR.(solid) 1607, 1555, 1484, 1441, 1398, 1365, 1308, 1231, 1179, 1112; MS 433.4 Example 227 4 -Acetamido-phenyl-sulfanyl)-6-[4-(3- 2 H-pyrazol-3-yl)-amine (IIIa-43): Prepared in a manner similar to the above described Method N to afford a white solid, mp 219-222oC;- H NMR (CDC1 3 8.1.97-2.07 (2H, m), 2.14 (3H, 2.18 (3H, 2.30 (6H, 2.52 (2H, t), 4.09 (2H, 5.56 (1H, 6.80 (1H, br 6.99 (21H, 7.60 (212H, 7.68-7.78 7.85 (2H, IR (solid) 1606, 1590, 1512, 1482, 1309, 1250, 1238, 1210, 1178, 1151, 1055, 989, 824, 711, 690, 665, 656; MS 518.4 -302- Example 228 [2-(4-Acetamidophenylsulfanyl)-6-(morpholin- 4-yl) -pyrimidin-4-yll- (5-methyl-2H-pyrazol-3 -yl)-amine CA .(IIIa-44): Prepared in a manner similar to the above S described Method P to-afford a white solid; Ms 426.4 Cy (M+H) t i Example 229 16-Hydroxymethyl-2-( 4 -propionylamino-penyl- Ssulfanyl)-pyrimidin-4-yl]-(5-methyl-22H-pyrazol-3-yl)amine (IIIa-45): Prepared from IIIa-48 according to Method O to affotd a white solid; 1H NMR (DMSO) 8 1.08- 1.18 (3H, 1.96 (3H, brs), 2.29-2.40 (2H, 4.20- 4.40 (3H, m),.5.20-5.46 (2H, 6.56 (1H, 7.50 (2H, 7.79 (2H, 9.90 (1H,.brs), 10.13 (11, 11.78 (1H, brs); MS 385.4 Example 230 4 -Acetamido-phenyl-sulfanyl)-pyrimidin-4ylI-(5-methyl-2H-pyrazol-3-yl) -amine (IIIa-46): Prepared in a manner similar to the above described Method L to afford an off-white solid, mp 249-250C; 1H NMR (DMSO) 1.99 (3H, 2.08 (3H, br 6.45 br 7.50 (2H, 7.71 (2H, 7.98 (1H, 9.89 (1H, br 10.19 (IH, br 11.83 (1H, br IR (solid) 1657, 1609, 1584, 1515, 1494, 1468, 1395, 1372, 1355, 1330, 1316, 1201, 1175, 1157, 1027, 993; MS 341.4 (M+H) t Example 231 [6-(l-Butoxycarbonyl)-2-(4-propionylaminophenyl-sulfanyl)-pyrimidin-4-yl (5-methyl-2H-pyrazol-3yl)-anine (IIIa-47):- Prepared in a manner similar to the above described Method L to afford a yellow solid, 1 NMR (DMSO) 8 0.90-0.98 (3H11, 1.03-1.12 (3H, 1.31-1.45 (2H, 1.60-1.71 (2H, 1.94 (3H, brs), 2.29-2.40

IO

0 -303- (2H, 4.20-4.30 (2H, 5.25 (1H, brs), 7.08 (1H, brs), 7.49-7.55 (2H, 7.72-7.81 (2H, 10.15 (1H, S brs), 10.32 (1H, brs), 11.89 (1W, bra); IR (solid) 1736, 1679, 1622, 1584, 1517, 1489, 1284, 1174; MS 455.4 Example 232 [6-Methoxycarbonyl-2- 4 -propionylaminophenyl-sulfanyl)-pyrimidin-4-yll (5-methyl-2ri-pyrazol-3yl)-amine (IIIa-48): Prepared in a manner similar to the o above described Method L to afford a yellow solid; 1H NMR (DMSO) 8 i.10 (3H, 1.94 (3H, brs), 2.35 (2H, 3.84 (3H, 5.22 (iH, brs), 7.05 (1H, 7.52 (2H, 7.79 (2H, 10.18 (1W, brs), 10.38 brs), 11.89 (1H, brs).; IR (solid).1741, 1679, 1617, 1589, 1512, 1484, 1374, 1284, 1250; MS 413.4 Example 233 (5-Methl-2-pyrazol-3-yl)-(6-phenyl-2phenylamino-pyrinidin-4-yl)-amine (IIIc-I): white. solid; MS 343.4 Example 234.. 5(S-Cyclopropyl-2H-pyrazol-3-yl)-(6-phenyl-2phenylamino-pyrimidin-4-yl)-amine (IIc-2): white solid, mp 267-269 0 C; H NMR (DMSO) 8 0.63 (2H, 0.96 (2H, m), 1.87 6.07 (IH, 6.84 (1H,.br 7.20 (1W, m), 7.33-8.05 (S9H, 10.52 (1W, br s),.11..O08(1H, br s), 12.53 (1H, br IR (solid); MS 369.7 Example 235 (5-Cyclopropyl-2-pyrazol-3-yl)- methylphenylamino) 6-phenyl-pyrimidin-4-yl -amine (III white solid, mp 267-270 0 C; 'H NMR (DMSO) 8 0.63 (2H, 0.94 (2H, 1.87 2.36 (3H, 6:12 (1H, 6.81 (1H, br 7.03 (1H, 7.29-7.94 (8H, m), 10.43 (1i, br.s), 11.12 (1iH, br 12.47 (11,.br

IR

(solid); MS 383.7 (M+H)

IND

o -3 04- Exaple 236 E2 -cyanomnethylphenylanino) -6 -phenyl pyrimidin-4-'yl- (5-cycloprbopyl-2H-pyrazol-3-yl) -amine (111c-4): pale yellow solid, mp 29H9 0 1 NMR 0.64 (2H, in), 0.'9'7 2H, mn), 1.89 (111, mn), 4.06 (2H, s), 6.07 (1K, 6.87 (114, br's), 7.40 (2H4, in), 7.63-7.90 (5H4, 7.95 (2H4, in), 10.51 (1H4, br 11.02 (1H4 br 1.2.57 (114, br' IR (solid); MS 408.8 Example 237 (5-Cyclopropyl1-2H-pyrazol-3-yl)-[6-phenyl'2- (pyridin-3-ylmetbylamino) -pyrimidin-4-yl] -amine off-white solid, mp l91-l93 0 C; 1H4 NMR (DMSO) S 0.65 (2H, mn),.0.89 (2K, in), 1.83 (114, in), 4.59 (2H4, 6.04 (1H4, br 6.76 (1H4, br 7.32-7.56 (514, rn), 7.77 (114, mn), -'7.88-7.97 (2H4, mn), 8.43 (lK,in), 8.61 (114, .9.47 (114, br 11-.93 (114, br IR '(solid); MS 384.8 Example 238 (3-Chloropheliyl)amino-6- (3-nitrophenyl) pyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine (IIcoff-white" solid; 1H NNR (CD 3 OD) S 5.95 (1H, s) 6.65 (1H, 6.90 (1K, 7.18 (114, 7.32 (1H, 7.58 (114, 7.82 (1H4, (1H, 8.25 (114, 8.65.

(1H4, s) ;MS 422. 1 (M-iH) Example 239 [2-(3-Chlorophenyl)amino-6-(3,4,5trimethoxyphenyl) -pyriznidir§4-ylJ -(5-methyl-2H;-pyrazol-3- 1 yl-amine white solid;. MS '467.7 Example 240 (5-Me.tYl-2H-pyrazol-3-yl) (4- -3 0 sulfamoylphenylamino) (3,4,5-trimethoxyphenyl) pyrimidin-4-yl]-amine Ch11c-8): white solid; MS 512.6

(M+H)

Examp~le 241 £2 4 -Chloropheyl) amino- 6..methyl..pyrimidin- 4-yl] (furan-2-yl)-2pyrazo..3.y1]-amine (IlIc-9): white solid; MS 367.1 Example 242 2 (Benzimidazo12ylamino-)...ethy.

pyrimidin-4-ylj'- (S-methyl-2-pyrazo.I..3yl) -amine (IlIc- MS 335.5 (M-iH) t oExample 243 [2 (4 -Chioropheny.) amino 6G-methyl -pyrimiain- 4 -ylJ-(S-phenyl-2I-pyrazo..3..y)-ajin (IlIc-li.):'MS 377.5 Exam~ple 244 (4-Chiorophenyl) amino- 6-e thyl-pyrimidn.4 ylJ-(5-methy1-2H-pyrazo1-3-yi)-amine (IIIc-12): MS 329.4 (Mi-H) t Example 245 (S-tert-Butyi-2H-pyrazol3.yx) (2.

chiorophenyl) amino 6 (3 ni trophenyl) pyrimi din -4 -ylJI amine (Ilic-13): off-white solid; 'H NNR (Cfl 3 OD) S1.32.

(9 H, S)1 6. 18 (IH, 7. 04 (111, 7..14' (1H, 7.3 (12, 7. 58 (1wI, 7. 82 (1H, t)I1 7. 91 (iN, 8.3 (iH, 8.40 (1w, 8.90. (12, MS' 464.2 (M+iH) t Example 246 2 3 -Chlorophny)aino-.s..(3..nitropheny).

pyrimidin-4-ylJ- (5-Phenyl-2H-pyrazol-3-yl) -amine (II1c-14): 5off-white solid; 'H NNR (CD 3 QD) 86.66 .(1H, s),-7.12 (iH, 7.30-7.45 (52, 7.50 (iN, 7.62 (2H1, 7.78 (1w, 7.88 (1H1, 8.35 (iN, 8.42 *(IHr 8.85 (iNH, MS .484.1' (M4H) 4 *Example 247 (Furan-2-yl) -2H-pyrazo-3-yl-(6-phenyl2.

*phenylamino-pyrimidin-4-y).amine (Ilic-iS): MS- 395..4 t -306- Example: 248 [2 (Benzimidazol -2 -ylamino) -6 -methyl pyrimidin-4-yl] -(5-phenyl-2-pyrazol-3..yl) -amine (Ilic- (N 16): MS 383.2 NA Example 249 (Benzimidazol-2-ylamino) -6-methyl-.

pyrimidin-4-ylJ (Furan-2-yl) -2H-pyrazol-3-ylJ -amine ci (II1c-17): MS 373.4 (N 10 Example 250 (4-Chiotcophenylamino) -6-methyl-pyriraidin.- 4 -yl3 (5-methyl-2z-pyrazol-3-yl) -amine Cub~-iS): MS 315.4 (M+HP- Examle 251 [2 (4 -Chiorophenyl) amino- 5, 6-dimethylpyrimidin-74-ylJ (5-methyl-2s-pyrazol-3-y.) -amine' (113c- 19): MS 3 29.4 4 Examle 252 6 -fimethyl-2-phenylamino-pyrimidin-4-yl) (5-methyl-2H-pyrazol-3-yl)-amine (IIIc-20): MS 295.5 (M-jH)- Example 253 (4 -Chiorophenyl) amino- 6-methoxymethylpyrimidin-4-yl (5-methyl1-2E-pyrazol-3-yl) -amine (111c- 21): MS 345.1 (M+H) 4 Example 254 (Benzimidazol-2-ylamino) -6-methoxymethylpyrimidin-4-ylJ- (5-methyl-2H--pyrazol1-3-yl)-amine (IlIc-' 22): MS 351.2 (MiI-)+ Example 255 (E-Methoxymethyl-2-phenylamino-pyrimidin-4yl) -(5-methyl-2H-pyrazol-3-yl) -amine (IIjc-23): MS 311.2 -307- Examle 256 (E-Methrl -2-phenylamino.pyrimidn4yl) methyl- 2 H-pyrazo-a-y).-amine (II'Ic-24): MS 281.1 (Mi.R) t Example 257 (Chlorophenoxynmethyl) 6-methyl 59 pyrimidin-4-yl] (S-phenyl-2r-pyrazol..a.y1) -amine (hlId- MS 3.92.1 MH+ Example 258 2 -Chlarophenoxymethyl) -6-methyl-

IN

pyrimidin-4-yl] (fnran-2-yl) -2H-pyrazol-3-y.J -amine MS 382.1 (M+H) 4 Examnple 259 .(E-methYl-2-Phenoxynethyl.pyrjmdn- 4 -y 1 phenyl-2H-pyrazols..y1)..amine (IhId-3): MS 358.2 ExamnplIe 260 (Furan-2-y)-2.pyrazo..3..yl]- (6-methyl-2- Phenoxmethypyrimidin4.yl)..amine MS 348.2 Example 261 ES-(Furan-2-y)-2pyrazol3.ylj (6-methyl-2- *phenylsulfanylmethyl-primidin-4-yi)-amine (Illd-5): MS 364.1 (M+I-H) 4 E .xample 262 16-lMethy1 -2 4 -methyl -phenylsul fany.methyl) pyrimidin-4-ylJ (S-phenyl-2H-pyrazol.3.yl) -amine (hld'- MS 388.1 (Mi-H) t Examle 263 [5-(Furan-2-yl) -2H-pyrazol-3-ylJ 6-Methyl-2- (4-methyl-phenylsulfanylmethyz) -pyrirnidin-4-yl) -amine (hIId-7): MS 378.1 (M-tH)* Examle 264 2 4 -Fluoro-p1henoxymethy1) -6-methylpyrimidin-4-yl (5-pheny1-2H-pyrazo1-3.y1) -amine (lIld-.

MS 376.2 (M-id) t 308- Example 265 4 -Fluoro-phenosymethyl) -6-methyl-* py rimidin-4-yl]'-[5- (furan-2-yl)-2H-pyrazol3.ylJ -amine (111d-9) MS 366.2 Example 266 (S-Ethy1-2-p henylsulftnylmethy..pyrimidin- 4 Ciyl)-(S-methyl-2H-pyrazo..3..y)-amxne (IId-0): MS 326.2 o Eampl 267(S-EthYl-2.-phenoxymethy1.pyrimdn4-yl)methy-2r-pyrazol3.y1) -amine (Id-1i): MS 310.2 Example 268 [6-Ethyl-2- 4 -fluorophenoxymethyl) -pyrimidin- 4-yl (S-me~thyl-2H-pyrazol-3.yl) -amine (IhId-12):

MS

15 328.2 (M+Ifl+ Example 269 [6-Ethyl-2-(:l-methyl-1-pheny.-ethyl) pyrimidin-4-ylJ -(S-mzethyl-2a-pyrazol-3-yl) -amine (hIId- MS 322.2 Example 270 4 -Chlororophenoxymethyl) -6-methylpyrimidin-4-yl (5-phe-nyl-2r-pyrazo.3.y1) -amine (111d- 14): MS 392-.2 (M+H)t Example 271 12- 4 -Chlororophenoxymethyl) -6-mnethyl-: pyrimidin-4-ylJ -(5-methyl-2Rf-pyrazox-3-yl) -amine (hIId- MS 330.2 (M+H) 4 Example 272 4 -Chlororophenoxymetbyl) -6-methoxymethayipyrimidin-4-yl] -(S-methyl-2a-pyrazol-3-yl) -amine (ilId- 16): white solid; 'H NMR (DM50) 8 2.20 (3H, 3.43 (3n, 4.49 5. 20 (2H1, s) .6.05 (1H1, br), 7.05 .(2HI, dl), 7.33 d),.10.55 (1H1, br); MS 360.2 4 -309- Bximple 273 4 -Chlororophenoxymethyi) -6-methylp~yrimidin-4-yl (fuiran-2-yl) -2H-pyrazoi-3-yl] -amine (Ild-17): MS 382;2 Example 274 (5-Methyl-2H-pyrazol-3-y.) o phenylsulfanylmethyl-5,S,7, 8-tetrahydro-quinazolin-4-yl) amine (IId-7): MS 352.5 (Mi-H) t Exaple 2'75 4 -Methylphenylsulfanyl me thyl) 6,7, 8,9 tetrahydro- SH-cycloheptapyrimidin-4-y1] -(5-me thyl-21pyrazol-3-yl)-aminie (lId-B) :MS 380.2 (M-eH) 4 Examle 276 (1-Methyl-1-phenyl-ethyl) -6,7,8,9- -tetrahydro-SH-cycloheptapyrimidn-4.yl (5-methyl-2Hpyrazol-3-yl)-amiLne (lId-9): MS 362.3 (Mi-H) t Example 277 2 2 6 -Dichlorobenzyl).-5,6,7,-tetraiyaroquinazolin-4-yiJ (5-ethyl-2a-pyrazol-3-yl) -amine (Ild- MS 388.1 Exaiple 278 [7-Benzyl-2- (2,6-dichlorobenzyl)-5,6,7,8tetrabydropyrido 4-dJ pyrimidin-4-yl] (5-methyl-2Hpyrazol-3-yl)-amine (Ild-il): MS 479.5 (Mi-H) t Example 279 [S-Benzyl1-2-(4-chlorophaenoxymethyl)-s,s,-7,stetrahydro-pyrido 3-dJ pyrimidin-4-yl] (5-methyl-2Hpyrazol-3-yl)-amine (Ild-12): MS 461.2 (Mi-H) 4 ~Example_280 2 4 -Chlorophenoxymethyl)-5,6,17,etetrahydro-pyrido (4 1 3-dlpyr~imidin-4-yl] -(S-methyl-2Epyrazol-3-yl)-amine (Id-13): Ms 371.3 (Mi-H)+ -310- Example 281 6-Dichlorobenz'yl) -6-methyl-pyrimidin-4yl]-(S-metbyl-2H-pyrazol-3-yl)-amine (li:rd-iS): MS 348.1 Ci (M+H) 4 Example 282 2 1 6-Dichiorobenzyl) -5,6-dimethylpyrimnidin-4-yl] -(5-methyl-2a-pyrazol-3-yx) -amine (11)4- 0 19) white solid; 3-H NNR (DMSO) 0 8. 50 (iH, s) 7.70 (Iii,

NO

o) c, 7. 3- 7. 1 (31H, in), 5. 25 (1W, 4. 10 (1W, s) 2.3 0 ci 10 (31H, 2.10 (3MH, 1. 8 0(3 MS. 3 62. 1 (M HP Example 283 (1H-Indatol-3-yl) (2-phenyl-cyclopropyl) quinazolin-4-y.J-.amine (lid-iS): 3.HNMR (DMSO) 13.2(11, s), 12.0(1W, 8.76.(1W-, in), 8.10(1H, mn), 7.85(2H, in), 7.75(111, mn), .7.61-(1W, mn) 7.41(111, mn), 7.30(214', m), 7. 2 0(2H, in), 7.12(21, in), 2.35(2H1, in), 1.60(11, in), 1.35(111, in); MS: in/z, 378.1 MW-i; HPLC Rt=3.21 min.

Example 284 (?-Fluoro-lH-indazol-3-yl)- (2-phenylcyclopropyl) -quinazolin-4-ylJ -amine (1)4d-17): 'WNNR 13.8(111, 12. 0 5 s) 8. 7 5.(11, mn), 8 .10 (1W, m), 7.85(2W, mn), 7.60(111, 7.35(3W, mn) 7.25-7.10(41, 2.35(21, in), 1.60(111, mn), 1.35(1W, mn); MS: in/z, 396.1 WHPLC Rt=3.2 6-min.

Example 285 (5-Fluoro-1H-.indazoi-3-y1) 2-(2-phienylcyclopropyl) -quinazolin-4-ylJ -amine (lId-iB): 31H14R (DMSO) 13.3(111, 12.0(111, 8.75(1W, 8. 10 (111, in) 7.85(2H1, in), 7.65(2W, mn), 7.235(31, in) 71.2 0(1H1, in), 7.10(2H1, mn) 2.40 (2H1, in),,1.65(111, in), 1.35(111, Th); MS: in/z, 396.1 MW+; WPLC Rt=3.26inmin.

VO

o -311- C Example 286 5 -Methyl-1H-pyrazol- 3yl) (2-phenyl- Scyclopropyl)-quinazolin-4-yl]-amine (IId-19): 'HNMR (DMSO) 12.8 (1H, 11.90(1H, 8.80(1H, 8.10(1H, m), Cl 7.85(2H, mi), 7.30-7.20(5H, .6.55 (1H, s) 2.80 (1H, m), 2.55(1H, 2.35 (3H,s) 2.00(2H, MS: m/z, 342.1 MH+; Ci HPLC Rt=3.13 min.

ci Ci BIOLOGICAL TESTING

NO

S.The activity of the compounds as protein kinase C 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 inhibitor to bind to the protein kinase. Inhibitor.

binding may be measured by radiolabelling the inhibitor prior to binding, isolating the inhibitor/protein kinase complex and determining the amount of radiolabel bound.

Alternatively, inhibitor binding may be determined by running a competition experiment where new inhibitors are incubated with the protein kinase bound to known radioligands.

BIOLOGICAL TESTING EXAMPLE 1 Ki DETERMINATION FOR THE INHIBITION OF GSK-3 Compounds were screened for their ability to inhibit' GSK-3p (AA 1-420) activity using a standard coupled enzyme system (Fox et al. (1998). Protein. Sci. 7, '2249).'Reactions were carried out in a solution containing 100 mM HEPES (pH 10 mM MgC1 2 25.mM NaC1, 300 WM NADH, 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 20 uM ATP (Sigma Chemicals, St Louis, MO) and 300 pM peptide

INO

-312-

(HSSPHQS(PCSH

2 )EDEEE, American Pepti.de, Sunnyvale,

CA).

Reactions were carried out at 30 oC and 20 nM GSK-3p.

Final concentrations of the components of the coupled Ci 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 Ci containing all of the reagents listed above with the

INO

o exception of ATP and the test compound of interest. The C 10 assay stock buffer solution (175.4l) was incubated in a 96 well plate with5 pl of the test compound of interest at final concentrations spanning 0.002 aM to 30 pM at 30 0

C

for 10 min. Typically, a 12 point titration was conducted by preparing serial dilutions (from 10 mM compound stocks) with DMSO of the test compounds in daughter plates. The reaction was initiated .by the addition of 20 pl of ATP (final concentration 20 pM).

Rates of reaction were obtained using a Molecular Devices Spectramax plate reader (Sunnyvale, CA) over 10 min at 300C. 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 M for GSK-3 IIa-2, IIa-3, IIa-8, IIa-9, IIa-ll, IIa-12, Ila-17, Ia-18, IIa-21 to IIa-24, IIa-26, IIa-28,hIIa-30 through IIa-32, IIa-39, IIa-43, lIa-46, Ia-47, IIa-61, IIc-3, IIc-6, IIc-8, IIc-lO through IIc-12, IIc-15, IIc-18, IIc-20 through.IIc-22, IIc-24, IIc-25, IIc-27, IIc-30 through IIc-32, IIc-35 to IIc-39, IIc-42, IIc-53, IIc-61, IIc-67, IIc-77, IIc-78, -IIb-1, IIb-3, IIb-5; IIb-8, IId-1, IIa-2, IIIa-3, IIIa- 6, IIIa-17, .IIa-18, IIIa-24, IIIa-27, IIIc-2 through IIIc-9, IIIc-11, IIIc-12,Ic IIIc-5,I i-8l IIIc-

IND

o -313- 19,.IIIc-21, IIIC-24, IIIb-1 through IIIb-6, IIIb-8 through IXlb-10o; IlIb-13, IIIbA 4, IIId-*2o, IIId-21, iiaand lid-is.

CiThe following compounds were shown to have i values between o.i and 1,0 p14 for GSK-3: ha-i, Ila.-4, hla-7, hIa-14, ha-is, Ia-20, IIa-29, Ila-34 through IIa-36,. I[Ia-38, IIa-41, Ila-42, IIa-48,' Ila-54, Ia-62, Ila-63, Iha-66, ha-69, IIa-78, lIc-1,

IN

hIc-2, IIc-4, I1 c-5, IIc-7, IIc-.9, Ilc-13, IIc-14, Ic- 16, hIc-17, Ilc-is, hlc-23, 11c-26, IIc-28, IIc-29, Ic- .33, Ild-34, IIc-40, IIc-41, IIc-43 through I1c-45, iIc-47 through IIc-52, IIc-54 through IIc-.57, IIc-59, IIc-E3 through lIc-ES, lIc-72, Ilc-75, Ilc-76, Ilc-79, I1c-6, Ilb-7, IIb-9, IId-2, Id-S 1 Id-6, Illa-i, IIIa-4, IIla- 5, IIIa-7, ila-8, lila-iC, lila-li,. lia-IS, IIIa-22, IIIa-23, IIIa-26, Iila-29;' lila-3o, li1a-31, Illa-3a, IIla-34, IIIa-37, IhIa-42, IIIc-1, IIIc-8, IIIc-20, IlIc- 23, IIIb-7, 1 -iIIIb-12, IhIb-iS, IhIb-lE, lid-is, Ild-i?, and IId-18.

The following compounds were show7n to have Kj.

values between 1.0 and 7.0 pM for GSK-3: ha-1, ha-is, IIa-40, IIa-45, Ila-49, hla-SO through IIa-52, IIa-64, hia-ES, Ila-67, ha-6S, Ila-71, IIa-72, Ia-74y, 11a'76, IIa-77, hla-Si, lIc-Sa, hlc-GO, Ilc-62, Ihc-68 through Ilc-'7l, Ic-74, Id-3, IId-4, Il~a-is, IIla-iS; il~a-21, IhIa-25, IhIa-35, IIla-36, Ila-38, hIa-41, hhIa-'43, hIIa-45, IIIa-49, IIc-lo, IlIc-iS 1, hhIc-17, and Ihhc-22.

-BIOLOGICAL TESTING EXAMPLE 2 Ki DETERMINATION FOR THE INHIBITION OF AtJRORA-2 'Compounds were screenaed in the following manner f or their ability to inhibit Aurora-2 -using -a standard.

0 -314- Ci coupled enzyme assay (Fox et al (1998) Protein Sci 7, M 2249).

To an assay stock buffer solution containing C- 0.1M HEPES 7.5, 10 mM MgC12, 1 mM DTT, 25 mM NaC1, 2.5 mM phosphoenolpyruvat-e, 300 mM NADH, 30 mg/ml pyruvate (S kinase, 10 mg/ml lactate dehydrogenase, 40 mM ATP, and S800 iM peptide (LRRASLG, American Peptide, Sunnyvale,. CA) C- was added a DMSO solution of a compound of the present invention to a final concentration of 30 aM. The Cq 10 resulting mixture was incubated at 30 'C for 10 min. The reaction was initiated by the addition of 10 uL of Aurora-2 stock solution to give a final concentration of nM in the assay. The rates of reaction were obtained by monitoring absorbance at 340 nm over a 5 minute read time at 30: C using a BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 0.1 iM-for Aurora-2: IIa-i through IIa- 18, IIa-21 through IIa-64, IIa-66, IIa-68, IIa-69, IIa-71 through IIa-78, IIa-81, IIc-1 through.IIc-13, through IIc-44, IIc-46 through IIc-61, IIc-63-through IIc-67 through IIc-69, IIb-1 through IIb-9, IId-1 through IId-3, IIIa-l through IIa-8, IIIa-10 through IIIa-13, IIIa-15 through IIIa-32, IIIa-36 'through IIIa- 41, IIIa-44 through IIIa-49, IIIc-1 through IIlc-5, IIIc- 12, and The following compounds were shown to have Ki values between 0.1 and 1.0 M for Aurora-2: IIa-20, IIa- 65, IIa-67, IIa-70, IIa-80, IIc-14, IIc-66, IId-5, IId-6, IIIa-14, IIIa-33 through IIIa-35, IIIc-9, IIIc-ll, IIb- 1, IIIb-2, IIIb-7, IIb-10 through IIIb-13, IIIb-16, and

VO

8O -315-

ID

The following compounds were shown to have Ki Z values between 1.0 and 10.0 pM for Aurora-2: IIa-10, IIc- S71, IIc-75, IIc-76, IId-4, IIIa-42, IIIa-43, IIIb-3-6, IIIb-8, IIIb-9, and IIIb-14.

C 5 BIOLOGICAL TESTING EXAMPLE 3 CDK-2 INHIBITION

ASSAY

C] -Compounds were screened in the following manner for their ability to inhibit CDK-2 using a standard C] 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 MgCl 2 1 mM DTT, 25 mM NaCI, 2.5 mM phosphoenolpyruvate, 300 mM NADH, 30 mg/ml pyruvate kinase, 10 mg/ml lactate dehydrogenase, 100 mM ATP; and 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 pM.

The resulting mixture was incubated at 30 oC for 10 min.

The reaction was initiated by.the addition of 10 uL of CDK-2/Cyclin A stock solution to give a final concentration of 25 nM in.the assay. .The rates of.

reaction were obtained by monitoring absorbance at 340 nm over a.5-minute read time. at 30 OC using a BioRad Ultramark plate reader (Hercules, CA). The Ki values were determined from the rate data as a function of inhibitor concentration.

The following compounds were shown to have Ki values less than 1 kM for CDK-2: IIa-14, IIa-36, IIc-27, IIc-32, IIc-53, and IIIc-4.

IN -316- C< The following compounds were shown to have Ki t values between 1.0 and 20.0 pM for CDK-2: IIa-38, l 'IIa-44, IIa-52, and IIa-54.

ci BIOLOGICAL TESTING EXAMPLE 4 Ce ERK INHIBITION ASSAY Compounds were assayed for the inhibition of Ci ERK2 by a spectrophotometric coupled-enzyme assay (Fox et o al (1998) Protein Sci 2249). In this -assay, a fixed Cq 10 concentration of activated ERK2 (10 nM) was incubated with various concentrations of the compound in DMSO for 10 min. at 30 0 C in 0.1 M HEPES buffer, pH containing 10 mM MgC1 2 2.5 mM phosphoenolpyruvate, 200 IM NADH, 150 pg/mL pyruvate kinase, 50 jg/mL lactate dehydrogenase, and 200 pM erktide peptide. The reaction was initiated by the addition of 65 pM ATP. The rate of decrease of absorbance at 340 nM was monitored. The IC 0 was evaluated from the rate'data as a function of.

inhibitor concentration.

The following compounds were shown to have Ki values less than 1 IM .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 VM for ERK-2: IIc-18, and IIa-36.

BIOLOGICAL TESTING EXAMPLE AKT INHIBITION ASSAY Compounds were screened for their ability to inhibit AKT using a standard coupled enzyme assay (Fox et al., Protein Sci., (1998) 7, 2249).- Assays were carried out in a mixture of 100 mM HEPES 7.5, 10 mM.MgCl2, 25 mM

VO

0 317- NaCi 1 mM DTT and 1.5% DMSO. Final substrate concentrations in the assay were 170 pM ATP (Sigma SChemicals) and 200 pM peptide (RPRAATF, American Peptide, Sunnyvale, CA). Assays were carried out at 30 *C and nM.AKT. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, o 300 pM NADH, 30 pg/ML pyruvate kinase and Ci lactate dehydrogenase.

VO

SAn assay stock buffer solution was prepared CI 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 concentration 30 pM). The plate was preincubated for about 10 minutes at 30'C and the reaction initiated by addition of 10 .l of enzyme (final concentration 45 nM) and 1 mM DTT. Rates of reaction were obtained using a BioRad Ultramark plate reader (Hercules, CA) over a minute read time' at 30'C. Compounds showing greater than inhibition versus standard wells containing the assay mixture and DMSO without test compound were titrated to determine ICso values.

The following compounds were shown to have Ki values between 1.0 and 20.0 M for AKT-3: IIc-18,.IIc-22, IIc-27, IIC-31, IIc-32, IIc-37, IIc-39, IIc-42, and IIc-53.

BIOLOGICAL TESTING EXAMPLE 6 SRC INHIBITION ASSAY The compounds were evaluated as inhibitors of human Src.kinase using either a radioactivity-based assay or spectrophotometric assay.

NO

o0 -318- S. Src Inhibition Assay A: Radioactivity-based Assay t The compounds were assayed as inhibitors of full length recombinant human Src kinase (from Upstate C- Biotechnology, cat. no. 14-117) expressed and purified from baculo-viral cells. Src kinase activity-was Cq monitored by following the incorporation of 33 P from ATP ,into the tyrosine of a random poly Glu-Tyr polymer 0g substrate of composition, Glu:Tyr 4:1 (Sigma, cat. no.

N

o P-0275). The following were the final concentrations of C- 10 the assay components: 0.05 M HEPES,.pH 10. mM MgC1 2 2 mM DTT, 0.25 mg/ml BSA, 10 uM ATP (1-2 pCi 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 pre-mixed and aliquoted into assay plate wells.

Inhibitors dissolved in DMSO were added to th6 wells to give a final DMSO concentration of The assay plate was incubated at 30 OC for 10 min before initiating the reaction with "P-ATP. After 20 min.of reaction, the reactions were quenched with 150 l1 of trichloroacetic acid (TCA) containing 20 mMINa 3 P0 4 The quenched-samples were then transferred to a 96-well filter plate (Whatman, UNI-Filter GF/F Glass Fiber Filter, cat no. 7700-3310) installed on a filter plate vacuum manifold. Filter plates were washed four times with 10% .TCA containing.20 mM Na 3 P0 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 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.

\O

0 -319- SSrc Inhibition Assay B: Spectrophotometric Assay The ADP produced from ATP by the human recombinant Src kinase-catalyzed phosphorylation of poly Glu-Tyr substrate-was quanitified using.a coupled enzyme assay (Fox et al (1998) Protein Sci 7, 2249). In this assay one molecule of NADH is oxidised.to NAD for every s molecule of ADP produced in the kinase reaction. The disappearance of NADH can be conveniently followed at 340 nm.

The following were the final concentrations of the assay components: 0.025 M HEPES, pH 7.6, 10 mM MgC12, 2 mM DTT, 0.25 mg/ml poly Glu-Tyr, and 25 nM of recombinant human Src kinase. Final concentrations of the components of the coupled enzyme system were 2.5 mM phosphoenolpyruvate, 200 pM NADH, 30 pg/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 into assay plate wells. Inhibitors dissolved in DMSO were added to the wells to give a final DMSO concentration of The assay plate was incubated at 30'C for 10 min before initiating the reaction with 100 M ATP. The absorbance change at 340 nm with time, the rate of the reaction, was monitored on a molecular devices plate reader. The data of rate as a function of the inhibitor concentration was fitted to compettive inhibition kinetics model to get the Ki for the compound'.

The following compounds were shown to have a Ki value of <100nM on SRC: IIa-8, IIa-21, IIa-23, IIa-24, IIa-27, IIa-28, IIa-30 through IIa-33, IIb-1, IIb-4, IIb- IIc-3, IIc-8, IIc-10, IIc-13, IIc-15, IIc-18, IIc-19, IIc-21 through IIc-24, IIc-31 through IIc-35, IIc-37 o -320- 0 C( through IIc-39, IIc-41 through IIc-44,'IIc-51, IId-1, t IId-2, IIIa-1, IIIa-6 through IIIa-8, IIIa-26 through and IIIc-1 through Ci The following compounds were shown to have a Ki value of between 1OOnM and )M1 for SRC: IIa-l; IIa-2, C- IIa-7, IIa-9,. IIa-12, IIa-14, IIa-22, IIa-25, IIa-26, IIa-29, IIa-34 through IIa-42, IIa-46, IIa-47, IIa-49 CA through IIa-52, IIa-56, IIa-57, IIa-59, IIa-61, IIa-62, SIIa-66, IIa-67, IIa-69, IIa-72, IIa-73, IIa-75, IIb-6, C 10' IIb-8, IIc-4 through IIc-7, IIc-9, IIc-11, IIc-i2, IIc- 14, IIc-16, IIc-17, IIc-20, IIc-25 through IIc-30, IIc- 36, IIc-40, IIc-46 through IIc-50, IIc-52 through IIc-61, IIc-63 through IIc-65, IIc-67, IIc-69, IId-3, IIIa-2 through IIIa-5, IIIa-11, IIIa-14 through IIIa-18, IIIa-22 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-44, IIa-45,. IIa-48, IIa-54, IIa-55, IIa-63, IIa-68, IIa-70, IIa-71, IIa-74, IIa-77, IIa-78, IIa-81, IIb-3, IIb-9, IIc-1, IIc-2, IIc-66, IIc-68, IIIa-13, IIIa-21, IIIa-25, IIIa-34, IIIa-36, IIIa-37, and IIIa-44.

While we have presented a number of embodiments of this invention, it is apparent that our basic 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 been represented by way of example.

321 00 O The term "comprise" and variants of the term such as "comprises" or "comprising" are used herein to denote the O inclusion of a stated integer or stated integers but not to 0 exclude any other integer or any other integers, unless in the context or usage an exclusive interpretation of the term is required.

(1 Any reference to publications cited in this specification is not an admission that the disclosures constitute common IND general knowledge in Australia.

Claims (30)

1. 2. The compound according to claim 1, wherein said compound has one or more features selected from the group consisting of: Rx and R Y 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 any substitutable carbon on said fused ring formed by Rx and RY is substituted by oxo, T-R 3 or L-Z-R 3 and any substitutable nitrogen on said ring formed by Rx and R y is substituted by R 4 R 1 is T-(Ring wherein T is a valence bond or a methylene unit; Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; 325 00 0 R 2 is -R or -T-W-R 6 and R 2 is hydrogen; or R 2 and R 2 C are taken together to form an optionally substituted O benzo ring; and R 3 is selected from -halo, -OR, or -N(R 4 2
2. 3. The compound according to either claim 1 or 2, wherein: C9 Rx and R y are taken together with their intervening atoms to form a fused, unsaturated or partially C unsaturated, 5-6 membered ring having 0-2 heteroatoms Sselected from oxygen, sulfur, or nitrogen, wherein any C substitutable carbon on said fused ring formed by Rx and R y is substituted by oxo, T-R 3 or L-Z-R 3 and any substitutable nitrogen on said ring formed by Rx and R Y is substituted by R 4 R 1 is T-(Ring wherein T is a valence bond or a methylene unit; Ring D is a 5-7 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; 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; and R 3 is selected from -halo, -OR, or -N(R 4 2
3. 4. The compound according to either claim 1 or 2, wherein said compound has one or more features selected from the group consisting of: Rx and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring; R 1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; 326 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 heterocyclic ring; and R 3 is selected from -halo, -OR, or -N(R 4 2 wherein R is selected from hydrogen, C 1 -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or wherein: The compound according to any one of claims 1, 2 and 4, Rx and R Y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring; R 1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; 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 heterocyclic ring; and R 3 is selected from -halo, -OR, or -N(R 4 2 wherein R is selected from hydrogen, C 1 -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or
4. 6. The compound according to any one of claims 1, 2 and 4, wherein said compound has one or more features selected from the group consisting of: Rx and R Y are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring; R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; R 2 is hydrogen or C 1 -4 aliphatic and R 2 is hydrogen; 327 R 3 is selected from -OR, or -N(R 4 2 wherein R is selected from hydrogen, C 1 -6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 -N(R 4 2 optionally substituted C 1 -6 aliphatic group, -OR, -C0 2 R, CONH(R 4 -N(R 4 )COR, -N(R 4 )C02R, -S0 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 or -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.
5. 7. The compound according to any one of claims 1, 2, 4 and 6, wherein: Rx and R y are taken together to form a benzo, pyrido, piperidino, or cyclohexo ring; R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; R 2 is hydrogen or C1- 4 aliphatic and R 2 is hydrogen; R 3 is selected from -OR, or -N(R 4 2 wherein R is selected from hydrogen, C 1 -6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 -N(R 4 2 optionally substituted C1-6 aliphatic group, -OR, -C02R, 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 -N(R 6 )COCH 2 CH 2 N(R 4 or -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. 328
6. 8. The compound according to claim 1, wherein Rx and R Y are taken together with their intervening atoms to form a fused benzo ring, wherein any substitutable carbon on said fused ring formed by R x and R Y is substituted by T-R 3 or L-Z-R 3
7. 9. The compound according to claim 8, wherein: R 1 is T-(Ring wherein T is a valence bond or a methylene unit; Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; 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; and R 3 is selected from -halo, -OR, or -N(R 4 2 wherein: The compound according to either claim 8 or 9, R 1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; 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 heterocyclic ring; and R 3 is selected from -halo, -OR, or -N(R 4 2 wherein R is selected from hydrogen, C 1 -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or
8. 11. wherein: The compound according to any one of claims 8 to R 1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; R 2 is hydrogen or C 1 4 aliphatic and R 2 is hydrogen; r 329 00 O R 3 is selected from -OR, or -N(R 4 2 wherein R is C selected from hydrogen, CI- 6 aliphatic, 5-6 membered O heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or and Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 -N(R 4 2 optionally CI substituted C1- 6 aliphatic group, -OR, -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 S-N(R 6 )COCH 2 CH 2 CH 2 N(R) 2 wherein R is selected from C hydrogen, C 1 -6 aliphatic, phenyl, a 5-6 membered heteroaryl ring, or a 5-6 membered heterocyclic ring.
9. 12. The compound according to claim 1, wherein R x and R y 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 any substitutable carbon on said fused ring formed by R x and R y is substituted by oxo, T-R 3 or L-Z-R 3 and any substitutable nitrogen on said ring formed by Rx and R y is substituted by R 4 provided that said fused ring formed by R x and R Y is other than benzo.
10. 13. The compound according to claim 12, wherein: Rx and R Y are taken together with their intervening atoms to form a fused, unsaturated or partially unsaturated, 5-6 membered ring having 1-2 heteroatoms selected from oxygen, sulfur, or nitrogen, or a partially unsaturated 6-membered carbocyclo ring, wherein any substitutable carbon on said fused ring formed by Rx and RY is substituted by oxo, T-R 3 or L- Z-R 3 and any substitutable nitrogen on said ring formed by Rx and R y is substituted by R 4 330 R 1 is T-(Ring wherein T is a valence bond or a methylene unit, and Ring D is a 5-7 membered monocyclic or an 8-10 membered bicyclic aryl or heteroaryl ring; 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; and R 3 is selected from -halo, -OR, or -N(R4)2.
11. 14. wherein: The compound according to either claim 12 or 13, R x and R y are taken together to form a benzo, pyrido, cyclopento, cyclohexo, cyclohepto, thieno, piperidino, or imidazo ring, wherein any substitutable carbon on said fused ring formed by R x and R Y is substituted by oxo, T-R 3 or L-Z-R 3 and any substitutable nitrogen on said ring formed by Rx and R Y is substituted by R 4 R 1 is T-(Ring wherein T is a valence bond and Ring D is a 5-6 membered monocyclic ring or an 8-10 membered bicyclic ring selected from an aryl or heteroaryl ring; 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 heterocyclic ring; and R 3 is selected from -halo, -OR, or -N(R 4 2 wherein R is selected from hydrogen, C 1 -6 aliphatic, or 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L is or wherein: (a) The compound according to any one of claims 12 to 14, R x and R Y are taken together to form a pyrido, piperidino, or cyclohexo ring, wherein any substitutable carbon on said fused ring formed by RX and RY is substituted by oxo, T-R 3 or L-Z-R 3 and any 331 00 substitutable nitrogen on said ring formed by RX and Ry is substituted by R 4 O R1 is T-Ring D, wherein T is a valence bond and Ring D is a 5-6 membered aryl or heteroaryl ring; Mc, R 2 is hydrogen or C 14 aliphatic and R 2 is hydrogen; R 3 is selected from -OR, or -N(R 4 2 wherein R is CI selected from hydrogen, C 1 -6 aliphatic, 5-6 membered heterocyclyl, phenyl, or 5-6 membered heteroaryl, and L (Ni is or and Ring D is substituted by up to three substituents selected from -halo, -CN, -NO 2 -N(R 4 2 optionally substituted C1-6 aliphatic group, -OR, -CO 2 R, CONH(R 4 -N(R 4 )COR, -N(R 4 )C0 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(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.
12. 16. A compound selected from the group consisting of: {2-[(2-Hydroxyethyl)phenylamino]-quinazolin-4-yl}-(5-methyl- 2H-pyrazol-3-yl)-amine; [2-(Methylphenylamino)-quinazolin-4-yl-(5-methyl-2H-pyrazol- 3-yl)-amine; (5-methyl-2H-pyrazol-3-yl)-{2-[N-methyl-N-(pyridin-3- ylmethyl)amino]-quinazolin-4-yl}-amine; C5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-quinazolin-4-yl)- amine; (2-Benzylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3-yl)- amine; (2-Cyclohexylamino-quinazolin-4-yl)-(5-methyl-2H-pyrazol-3- yl)-amine; [2-(2,3-Dihydrobenzo[1,4]dioxin-6-ylamino)-quinazolin-4-yl)- (5-methyl-2H-pyrazol-3-yl)-amine; 332 00 (2-Cyclohexylmethylamino-quinazolin-4-yl) -(5-methyl-2H- pyrazol-3-yl) -amine; o 2- (1H-Indazol-6-ylamino) -quinazolin-4-yl] pyrazol-3-yl) -amine; M (5-Methyl-2H-pyrazol-3-yl) (pyridin-3-ylmethylamino) quinazolin-4-yl] -amine; (3-Chlorophenylamino) -quinazolin-4-yl (5-methyl-2H- pyrazol-3-yl) -amine; (Ni (4-Chiorophenylamino) -quinazolin-4-yl] -(5-methyl-2H- pyrazol-3-yl) -amine; (4-Fluorobenzylamino) -quinazolin-4-yl (5-methyl-2H- pyrazol-3-yl) -amine; (2-Hydroxyethyl)phenylamino] -quinazolin-4-yl}- methyl-2H-pyrazol-3-yl) -amine; (4-Cyanomethyiphenylamino) -quinazolin-4-yl] -(5-methyl-2H- pyrazol-3-yl) -amine; (3-Hydroxymethyiphenylamino) -quinazolin-4-yl] 2H-pyrazol-3-yl) -amine; (3-Hydroxyphenylamino) -quinazolin-4-yl (5-methyl-2H- pyrazol-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) -(2-phenylamino-quinazolin-4- yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (3-methyiphenylamino) quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (6-methoxypyridin-3- ylamino) -quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (indan-5-ylamino) quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (1H-indol-6-ylamino) quinazolin-4-yl] -amine; (4-Acetamido-3-methylphenylamino) -quinazolin-4-yl] cyclopropyl-2H-pyrazol-3-yl) -amine; (4-Chloro-3-methylphenylamino) -quinazolin-4-yl] cyclopropyl-2H-pyrazol-3-yl) -amine; 333 00 (5-Cyclopropyl-2H-pyrazol-3-yl) (4-ethyiphenylamino) quinazolin-4-yll -amine; o (5-Cyclopropyl-2H-pyrazol-3-yl) (4-propyiphenylamino) quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl)-{2-[4-(2- hydroxyethyl)phenylamino] -quinazolin-4-yl} -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) -(2-phenetylamino-quinazolin- 4 -yl) -amine; (2-Cyclohexylethylamino) -quinazolin-4-yl] 2H-pyrazol-3-yl) -amine; (4-Carboxymethoxyphenylamino) -quinazolin-4-yl] cyclopropyl-2H-pyrazol-3-yl) -amine; (4-Cyanomethyiphenylamino) -quinazolin-4-yl] cyclopropyl-2H-pyrazol-3-yl) -amine; (Benzothiazol-6-ylamino) -quinazolin-4-yl 2H-pyrazol-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (3,4-dimethyiphenylamino) quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (2-phenoxyethylamino) quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (thiophen-2-methylamino) quinazolin-4-yl] -amine; (4-Carboxymethylphenylamino) -quinazolin-4-yl cyclopropyl-2H-pyrazol-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (1H-indazol-5-ylamino) quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (pyridin-3-ylmethylamino) quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3- methoxycarbonyiphenylamino) -quinazolin-4-yl] -amine; (3-Carboxyphenylamino) -quinazolin-4-yl (5-cyclopropyl-2H- pyrazol-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (3-ethyiphenylamino) quinazolin-4-yl] -amine; 334 00 (5-Cyclopropyl-2H-pyrazol-3-yl) (2,3-dimethyiphenylamino) quinazolin-4-yl] -amine; o (5-Cyclopropyl-2H-pyrazol-3-yl)-[2-(3,4- dimethoxyphenylamino) -quinazolin-4-yl] -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (3-rethoxyphenylamino) quinazolin-4-yll -amine; (5-Methyl-2H-pyrazol-3-yl)-(2-phenylamino-5,6,7,8- tetrahydroquinazolinin-4-yl) -amine; (Biphenyl-3-ylamino) -quinazolin-4-yl (5-cyclopropyl-2H- pyrazol-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (3-phenylprop-1-ylamino) quinazolin-4-yl] -amine; (4-acetamido-3-methylphenylamino) -quinazolin-4-yl] rethyl-2H-pyrazol-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (indan-2-ylamino) quinazolin-4-yl] -amine; (3-Methyiphenylamino) -quinazolin-4-yl (5-methyl-2H- pyrazol-3-yl) -amine; (2-Chloro-5-methylphenylamino) -quinazolin-4-yl 2H-pyrazol-3-yl) -amine; (5-Cyclopropyl-2H-pyrazol-3-yl) (morpholin-l- yl) phenylamino] -quinazolin-4 -yl }-amine; (Benzothiazol-6-ylamino) -quinazolin-4-yl (5-methyl-2H- pyrazol-3-yl) -amine; (3,4-Dimethyiphenylamino) -quinazolin-4-yl] -(5-methyl-2H- pyrazol-3-yl) -amine; (3-Ethyiphenylamino) -quinazolin-4-yll -(5-methyl-2H- pyrazol-3-yl) -amine; (3-Methoxyphenylamino) -quinazolin-4-yl] -(5-methyl-2H- pyrazol-3-yl) -amine; (4-Acetamido-3-cyanophenylamino) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl) -amine; (2-Methoxybiphenyl-5-ylamino) -quinazolin-4-yl 2H-pyrazol-3-yl) -amine; 335 00 (4-Acetamidophenylamino) -quinazolin-4-yl (S-methyl-2H- pyrazol-3-yl) -amine; o (4-tert-Butoxycarbonylamino-phenylamino) -quinazolin-4-yli (5-methyl-2H-pyrazol-3-yl) -amine; (4-Cyanophenylamino) -quinazolin-4-yll -(5-methyl-2H- pyrazol-3-yl) -amine; (5-Methyl-2H-pyrazol-3-yl)-[2-(6-oxo-6,10b-dihydro-4aH- benzo [ci chromen-2-ylamino) -quinazolin-4-yli -amine; (Biphenyl-3-ylamino) -quinazolin-4-yl] -(5-methyl-2H- pyrazol-3-yl) -amine; (Ni (4-Methoxycarbonylmethyl-3-methylphenylamino) -quinazolin- 4-yl (5-methyl-2H-pyrazol-3-yl) -amine; (4-Carboxymethyl-3-methylphenylamino) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl) -amine; (4-Aminophenylamino) -quinazolin-4-yl (5-methyl-2H- pyrazol-3-yl) -amine; (4-Bromophenylamino) -quinazolin-4-yl (5-methyl-2H- pyrazol-3-yl) -amine; (4-Isobutyrylamino-phenylamino) -quinazolin-4-yl] methyl-2H-pyrazol-3-yl) -amine; (5-Ethyl-2H-pyrazol-3-yl) (5-ethyl-2H-pyrazoi.-3-ylamino) quinazolin-4-yl] -amine; (lH-Indazol-3-yl) -(2-phenylamino-quinazolin-4-yl) -amine; (1H-Indazol-3-yl) (3-trifluoromethylphenylamino) quinazolin-4-yl] -amine; (1H-Indazol-3-yl) (4-trifluoromethyiphenylamino) quinazolin-4-yl] -amine; (Adamantan-2-ylamino) -quinazolin-4-yl (lH-indazo1-3-yl) amine; (1H4-Indazol-3-yl) -(2-methyl-phenyl-amino-quinazolin-4-yl) amine; (2-Chioro-phenyl) -amino-quinazolin-4-yl (lH-indazol-3- yl) -amine; 336 00 (lH-Indazol-3-yl) (2-trifluoromethylphenylamino) quinazolin-4-yl] -amine; o(2- (4-Cyanomethylphenylamino) -quinazolin-4-yl] -(Hidzl3 yl) -amine; (4-Chlorophenylamino) 8-tetrahydroquinazolinin-4- yl (5-methyl-2H-pyrazol-3-yl) -amine; (5-Methyl-2H-pyrazol-3-yl) -(2-phenylamino-6,7,8, 9-tetrahydro- 5H-cycloheptapyrimidin-4-yl) -amine; (Benzimidazol-2-ylamino) -7-benzyl-5,6,7,8-tetrahydro- pyrido[3,4-dlpyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine; Cl (7-Benzyl-2-phenylamino-5,6,7,8-tetrahydro-pyrido[3,4- dlpyrimidin-4-yl) -(5-methyl-2H-pyrazol-3-yl) -amine; [6-Benzyl-2- (4-chiorophenylamino) -5,6,7,8-tetrahydro- pyrido[4,3-dlpyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine; (Benzimidazol-2-ylamino) -6-benzyl-5,6,7,8-tetrahydro- pyrido[4,3-dlpyrimidin-4-yl (5-methyl-2H-pyrazol-3-yl) -amine; (6-Benzyl-2-phenylamino-5, 6,7,8-tetrahydro-pyrido[4,3- dlpyrimidin-4-yl) -(5-methyl-2H-pyrazol-3-yl) -amine; (5-Methyl-2H-pyrazol-3-yl) -(2-phenylamino-5,6,7,8-tetrahydro- pyrido 4-d] pyrimidin-4-yl) -amine; (4-Cyanomethylphenylamino) -quinazolin-4-yl] -(lH- pyrazolo pyridin-3-yl) -amine; 12- (4-Cyanobenzylamino) -quinazolin-4-yl] -(lH-pyrazolo[3,4- blpyridin-3-yl) -amine; (4-Cyanomethylphenylamino) -quinazolin-4-yl (4-f luoro-1H- indazol-3-yl) -amine; (4-Cyanophenylamino) -quinazolin-4-yl] lH-indazol-3-yl) amine; and (4-Cyanobenzylamino) -quinazolin-4-yl] -(lH-indazol-3-yl) amine.
13. 17. A composition comprising a compound according to any one of claims 1-16, and a pharmaceutically acceptable carrier. 337 00 O 18. The composition according to claim 17, further C comprising an additional therapeutic agent. C) O
14. 19. A method of inhibiting Aurora-2, GSK-3, Src, ERK-2, or AKT activity in a biological sample comprising the step of contacting said biological sample with a compound according to CI any one of claims 1-16.
15. 20. A method of inhibiting Aurora-2 activity in a patient \O Scomprising the step of administering to said patient a compound according to any one of claims 1 to 16 or a composition according to either claim 17 or 18.
16. 21. A method of treating an Aurora-2-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 to 16 or a composition according to claim 17.
17. 22. The method according to claim 21, wherein said disease is selected from colon, breast, stomach, or ovarian cancer.
18. 23. The method according to claim 22, wherein said method further comprises administering an additional therapeutic agent.
19. 24. The method according to claim 23, wherein said additional therapeutic agent is a chemotherapeutic agent. 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 to 16 or a composition according to either claim 17 or 18. 338
20. 26. 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 to 16 or a composition according to either claim 17 or 18.
21. 27. The method according to claim 26, 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 schizophrenia, cardiomycete hypertrophy, reperfusion/ischemia, or baldness.
22. 28. The method according to claim 27, wherein said GSK-3- mediated disease is diabetes.
23. 29. A method of enhancing glycogen synthesis or lowering blood levels of glucose in a patient in need thereof, which method comprises administering to said patient a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a composition according to either claim 17 or 18. A method of inhibiting the production of hyperphosphorylated Tau protein in a patient, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a composition according to either claim 17 or 18.
24. 31. A method of inhibiting the phosphorylation of 1- catenin, which method comprises administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a composition according to either claim 17 or 18. 339 00 O 32. A method of inhibiting Src activity in a patient comprising the step of administering to said patient a compound O according to any one of claims 1 to 16 or a composition according to either claim 17 or 18.
25. 33. A method of treating a Src-mediated disease, which CI method comprises administering to a patient in need of such a treatment a therapeutically effective amount of a compound CI according to any one of claims 1 to 16 or a composition \O Saccording to either claim 17 or 18.
26. 34. A method of inhibiting ERK-2 activity in a patient comprising the step of administering to said patient a compound according to any one of claims 1 to 16 or a composition according to either claim 17 or 18. A method of treating an ERK-2-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 to 16 or a composition according to either claim 17 or 18.
27. 36. A method of inhibiting AKT activity in a patient comprising the step of administering to said patient a compound according to any one of claims 1 to 16 or a composition according to either claim 17 or 18.
28. 37. A method of treating an AKT-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 to 16 or a composition according to either claim 17 or 18. 340 00 S38. A compound of formula IIc according to claim 1 and C substantially as hereinbefore described, with reference to one S or more of the accompanying examples.
29. 39. A composition comprising a compound according to claim 38, and a pharmaceutically acceptable carrier. (N A method of inhibiting Aurora-2, GSK-3, Src, ERK-2, or C' AKT activity in a biological sample comprising the step of Scontacting said biological sample with a compound according to C claim 38 or a composition according to claim 39.
30. 41. A method of inhibiting Aurora-2, GSK-3, Src, ERK-2, or AKT activity in a patient comprising the step of administering to said patient a compound according to claim 38 or a composition according to claim 39. Dated:31 October 2008